BACKGROUND ART <EOH>Recently, along with enhancement of recording density of optical recording mediums such as optical discs, development of the technique of effectively using the area on the recording surface of an optical disc has been pushed forward to enhance the recording density.","The recording surface of any disc substrate has concavo-convex called lands and grooves respectively.","In conventional optical discs, only lands or only grooves were used to record recording marks.","However, with the need of enhancing the recording density of optical discs, a technique for recording record marks on both lands and grooves, i.e.","a land/groove recording technique, has been brought into use as a format of optical discs.","An example of optical discs combined with the land/groove recording as their format is DVD-RAM (Digital Versatile Disc-Random Access Memory).","However, such optical discs employing the land/groove recording suffer a difference of the thermal property exerted to the recording layer because of the difference in physical configuration between lands and grooves when recording laser beams are irradiated to lands and grooves respectively.","In addition, lands and grooves form a periodical structure close to the wavelength of the laser beams.","Therefore, vector diffraction of light causes uneven distribution of irradiated laser beams between lands and grooves, and it has been difficult to record or reproduce record marks from both lands and grooves with a high C/N ratio (carrier-to-noise ratio).","To match lands and grooves in property, it is contemplated, for example, to change widths of lands and grooves and thereby change the duty ratio.","However, only change of the duty ratio cannot bring about ample freedom.","Under the circumstances, an optical disc was proposed, in which the recording layer on grooves is formed thicker than the recording layer on lands by selecting the sputtering condition, for example (Japanese Patent Laid-Open Publication No.","2000-215511, referred to as Literature 1).","However, in case of the optical disk disclosed in Literature 1, the condition for deposition of the recording layer is changed to form the recording layer on grooves thicker than the recording layer on lands.","This condition digresses the optimum condition for deposition of the recording layer and invites deterioration of signal characteristics of the recording layer.","Therefore, it has been demanded to develop a method capable of independently controlling the recording characteristics of lands and grooves.","It is therefore an object of the invention to provide an optical recording medium having a multi-layered film of a recording layer and a record-assist layer stacked adjacently on one surface of a disc substrate having formed a concavo-convex structure, and its manufacturing method, which enable freer designing while ensuring good signal characteristics in the recording layer on the concavo-convex structure and ensuring high reliability."],["<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG.","1 is a cross-sectional view that shows an optical disc according to the first embodiment of the invention FIG.","2 is a graph that shows dependency or a carrier upon the thickness of a record-assist layer in the optical disc according to the first embodiment of the invention; FIG.","3 is a graph that shows dependency of the signal amplitude upon the thickness of the record-assist layer in the optical disc according to the first embodiment of the invention; FIG.","4 is a graph that shows dependency of a cross talk signal upon the thickness of the record-assist layer in the optical disc according to the first embodiment of the invention; FIG.","5 is a cross-sectional view that shows an optical disc according to the second embodiment of the invention; FIG.","6 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention; FIG.","7 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention; and FIG.","8 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention.","detailed-description description=\"Detailed Description\" end=\"lead\"?"],["TECHNICAL FIELD This invention relates to an optical recording medium and its manufacturing method especially suitable for application to an optical recording medium employing a land/groove recording technique.","BACKGROUND ART Recently, along with enhancement of recording density of optical recording mediums such as optical discs, development of the technique of effectively using the area on the recording surface of an optical disc has been pushed forward to enhance the recording density.","The recording surface of any disc substrate has concavo-convex called lands and grooves respectively.","In conventional optical discs, only lands or only grooves were used to record recording marks.","However, with the need of enhancing the recording density of optical discs, a technique for recording record marks on both lands and grooves, i.e.","a land/groove recording technique, has been brought into use as a format of optical discs.","An example of optical discs combined with the land/groove recording as their format is DVD-RAM (Digital Versatile Disc-Random Access Memory).","However, such optical discs employing the land/groove recording suffer a difference of the thermal property exerted to the recording layer because of the difference in physical configuration between lands and grooves when recording laser beams are irradiated to lands and grooves respectively.","In addition, lands and grooves form a periodical structure close to the wavelength of the laser beams.","Therefore, vector diffraction of light causes uneven distribution of irradiated laser beams between lands and grooves, and it has been difficult to record or reproduce record marks from both lands and grooves with a high C/N ratio (carrier-to-noise ratio).","To match lands and grooves in property, it is contemplated, for example, to change widths of lands and grooves and thereby change the duty ratio.","However, only change of the duty ratio cannot bring about ample freedom.","Under the circumstances, an optical disc was proposed, in which the recording layer on grooves is formed thicker than the recording layer on lands by selecting the sputtering condition, for example (Japanese Patent Laid-Open Publication No.","2000-215511, referred to as Literature 1).","However, in case of the optical disk disclosed in Literature 1, the condition for deposition of the recording layer is changed to form the recording layer on grooves thicker than the recording layer on lands.","This condition digresses the optimum condition for deposition of the recording layer and invites deterioration of signal characteristics of the recording layer.","Therefore, it has been demanded to develop a method capable of independently controlling the recording characteristics of lands and grooves.","It is therefore an object of the invention to provide an optical recording medium having a multi-layered film of a recording layer and a record-assist layer stacked adjacently on one surface of a disc substrate having formed a concavo-convex structure, and its manufacturing method, which enable freer designing while ensuring good signal characteristics in the recording layer on the concavo-convex structure and ensuring high reliability.","DISCLOSURE OF INVENTION The Inventor made vigorous researches to overcome the above-discussed problems the conventional techniques involved.","The researches are outlined below.","The recording principle of conventional optical mediums having a multi-layered film of a recording layer for recording information signals and a record-assist layer for supporting the recording layer is presumed to rely upon that, when the temperature is raised higher than the crystallization temperature lower than the melting point of the recording layer by laser beams irradiated to the recording layer, minute crystals produced in the crystallized auxiliary layer, and crystal growth of the recording layer occurs from the minute crystals as the seed crystals.","This principle has been brought about because record marks are different in amplitude between optical discs having the auxiliary layer and optical discs without the auxiliary layer.","The Inventor put forward the researches on the record-assist layer under the above presumption.","That is, the Inventor recorded 2T pulses on samples common in duty ratio but variously different in thickness of the record-assist layer, and measured dependency of a carrier upon the recording power in lands and grooves, respectively.","As a result, the Inventor has found that the dependency of the carrier upon the recording power in lands exhibits similar tendencies regardless of the thickness of the film and that there is almost no change of the carrier in lands even when the thickness of the record-assist layer is changed.","On the other hand, as to the dependency of the carrier upon the recording power in grooves, the Inventor has found that, although the dependency of the carrier upon the recording power in lands exhibits similar tendencies regardless of the thickness of the film, when the record-assist layer is changed thickness, the carrier rises as the thickness decreases.","This tendency was observed in the range close to the optimum value.","Accordingly, the Inventor got inspiration of using the phenomenon confirmed by the above-explained experiment.","That is, in case the duty ratio and the recording power are fixed, dependency of the carrier upon the thickness of the record-assist layer arises particularly in grooves, ad the dependency upon the thickness does not almost appear in lands.","From this fact, the Inventor had the idea that the carriers can be brought into agreement between lands and grooves without the need of changing the duty ratio.","The Inventor made further researches on changes of the carrier in grooves.","That is, the Inventor calculated how the change of amplitude of the recording layer of GeTe alloy depends upon the thickness of the record-assist layer by the effective Fresnel coefficient method.","From the result of the calculation, the Inventor got the knowledge that the amplitude increases as the thickness of the record-assist layer decreases.","With reference to the value when the thickness of the record-assist layer was 30 nm, when the thickness was decreased from 20 nm to 10 nm, the increase of the amplitude was approximately 1 dB according to the calculation by the effective Fresnel coefficient method.","Through the researches by the Inventor, the above-explained phenomenon can be assumed to occur because grooves are closer to the optical pickup than lands and less affected by track grooves, and therefore become more liable to reflect the amplitude changes in response to changes of the reflectance due to the difference of the thickness.","In regard to the carrier changes on the part of the grooves, the amplitude changes of the reflectance by the change of the film structure are considered to be dominant.","The present invention has been made based on the above-explained researches.","To accomplish the object, the first aspect of the invention is an optical recording medium comprising: a disc substrate having formed a concavo-convex structure formed at least on one surface thereof; and a multi-layered film made by stacking at least a recording layer capable of recording information signals by irradiation of a laser beam and a record-assist layer adjacent to the recording layer on the surface of the disc substrate having the concavo-convex structure, wherein d/4<a<3d is satisfied where d is the thickness of the recording layer and a is the thickness of the auxiliary recording layer.","The second aspect of the invention is a method of manufacturing an optical recording medium, which forms a multi-layered film made by stacking at least a recording layer capable of recording information signals by irradiation of a laser beam and a record-assist layer adjacent to the recording layer on the surface of the disc substrate having the concavo-convex structure, comprising: adjusting the thickness of the record-assist layer to satisfy d/4<a<3d where d is the thickness of the recording layer and a is the thickness of the record-assist layer.","In the present invention, d/2≦a≦2d is preferably established when the thickness of the recording layer is d and the thickness of the record-assist layer is a.","In the present invention, the recording layer is typically configured to record the information signals by reversible changes at least between two different states, and it is preferably made of a phase-changeable material capable of recording the information signals by phase changes between a crystal phase and an amorphous phase.","In the present invention, the laser beam used for recording and/or reproducing information signals is typically irradiated to said recording layer from one side of the multi-layered film where the disc substrate exists.","In this case, the recording layer is preferably located nearer to the irradiation side of the laser beam.","More specifically, the multi-layered film is preferably made of a first dielectric layer, recording layer, record-assist layer, second dielectric layer and first reflection layer that are stacked sequentially from near the surface of the disc substrate having formed the concavo-convex structure.","Preferably, a layer of a synthetic resin such as a ultraviolet-setting resin (urethane-family, acrylic family, silicon family, polyester family, and so on) of a hot-melt adhesive agent is additionally formed on the top surface of the multi-layered film on the disc substrate (the surface opposite from the disc substrate) to cover the multi-layered film on the disc substrate for the purpose of protecting and reinforcing the multi-layered film.","Typically, the first dielectric layer and the second dielectric layer are made of zinc sulfide/silicon oxide mixture (ZnS—SiO2) having a diffractive index around 2.1 or a silicon nitride (SiN, Si3N4) having a diffractive index around 2.0.However, other materials are also usable.","In the resent invention, thickness of the first dielectric layer is adjusted not to exceed 200 nm within the range capable of forming the dielectric layer not to disconnect in form of islands.","In the present invention, the second dielectric layer is typically adjusted in thickness in the range not smaller than 1 nm and not smaller than 100 nm.","In the present invention, thickness of the first reflection layer is adjusted not to be smaller than 20 nm and not to be larger than 100 nm.","The first dielectric layer, recording layer, record-assist layer, second dielectric layer and first reflection layer are typically formed by sputtering, but any other film-making methods are also usable, such as electron beam vapor deposition, vacuum vapor deposition, epitaxial growth, chemical vapor deposition (CVD) and physical vapor deposition (PVD).","In the present invention, the laser beam used for recording and/or reproducing information signals is irradiated to the recording layer typically from one side of the disc substrate where the multi-layered film exists.","In the present invention, the multi-layered film is preferably made of a second reflection layer, third dielectric layer, said record-assist layer, said recording layer and a fourth dielectric layer that are stacked sequentially from near one surface of the disc substrate having said concavo-convex structure, and a light-transmitting layer permitting the laser beam to pass through is preferably formed to cover the multi-layered film on the disc substrate.","Although the third dielectric layer and the fourth dielectric layer are typically made of ZnS—SiO2 having a diffractive inde3x around 2.1, or SiN or Si3N4 having a diffractive index around 2.0, other materials can be used as well.","In the present invention, thickness of the third dielectric layer is typically adjusted in the range not thinner than 1 nm and not thicker then 100 nm.","In the present invention, thickness of the fourth dielectric layer is adjusted not to exceed 200 nm within the range capable of forming the dielectric layer not to disconnect in form of islands.","In the present invention, the second reflection layer is adjusted in thickness typically in the range not thinner than 20 nm and not thicker than 100 nm.","Although the second reflection layer, third dielectric layer, record-assist layer, recording layer and fourth dielectric layer are typically formed by sputtering, but any other film-making methods are also usable, such as electron beam vapor deposition, vacuum vapor deposition, epitaxial growth, chemical vapor deposition (CVD) and physical vapor deposition (PVD).","The light-transmitting layer formed to cover the multi-layered film on the disc substrate includes at least a light-transmitting sheet permitting light to pass through and an adhesive layer for bonding the light-transmitting sheet to the disc substrate.","The adhesive layer is an ultraviolet-setting resin or a pressure sensitive tackiness agent.","Instead of using the light-transmitting sheet, an ultraviolet-setting resin is usable to form the light-transmitting layer.","An example of optical discs configured for irradiation of a laser beam to the disc substrate from one side thereof having the multi-layered film is DVR (digital video recording system) having a thin light-transmitting layer.","This invention is applicable to optical discs such as DVR, including so-called DVR-red configured to record or reproduce information signals by using a semiconductor laser having an emission wavelength around 650 nm and so-called DVR-blue configured to record or reproduce information signals by using a semiconductor laser having an emission wavelength around 400 nm.","Such DVR is configured to record signals by using an objective lens that is typically enhanced in NA (Numerical Aperture) to around 0.85 by combining two lenses in series.","More specifically, it has the storage capacity around 22 GB per single plane.","Optical discs including DVR are preferably housed in cartridges, but application of the invention is not limited to cartridge-type optical discs.","In the present invention, if the multi-layered film formed on the disc substrate is covered with a thin light-transmitting layer, the light-transmitting layer is typically made of a non-magnetic material through which the laser beam from a GaN-family semiconductor laser (having an emission wavelength around 400 nm for blue emission), ZnSe-family semiconductor laser (having an emission wavelength around 500 nm for green emission) or AlGaInP-family semiconductor laser (having an emission wavelength around 635 to 680 nm for red emission) used at least for recording and reproducing information signals can pass.","More specifically, it is made of a light-transmitting thermoplastic resin such as polycarbonate.","In the present invention, in the portion of the disc substrate having the concavo-convex structure, width Dg of a level difference of concavo-convex in a portion nearer to the injection side of the laser beam and width Dl of a level difference of concavo-convex in a portion remoter from the injection side of the laser beam satisfy the ratio of 0.5≦Dl/Dg≦2.0, or more preferably the ratio of 0.8≦Dl/Dg≦1.2.In the present invention, numerical aperture of the objective lens used for recording and/or reproducing information signals is typically in the range not smaller than 0.45 and not larger than 0.60.In this range of the numerical aperture, the laser beam is irradiated from one side of the optical recording medium where the disc substrate exists.","To obtain good signals, maintain the optical contrast in a good condition and prevent thermal diffusion while preventing the recording layer from becoming discontinuous islands, thickness of the recording layer is typically adjusted in the range not thinner than 5 nm and not thicker than 50 nm, or more preferably, in the range not thinner than 10 nm and not thicker than 40 nm.","In the present invention, thickness of the record-assist layer is limited not to be thinner than 3 nm and not to be thicker than 100 nm, or more preferably in the range not thinner than 5 nm and not thicker than 60 nm.","In the present invention, the recording layer is typically configured to record information signals in a write only mode.","In this case, the recording layer is preferably made of a GeTe-family alloy or a GeSbTe-family alloy.","However, other materials are also usable for the recording layer, such as Ge—Te, Te—Sb, Te—Ge—Sb, Te—Ge—Sb—Pd, Te—Ge—Sb—Cr, Te—Ge—Sb—Bi, Te—Ge—Sn—O, Te—Ge—Sb—Se, Te—Ge—Sn—Au, In—Sb—Te, In—Sb—Se, Te—Ge—Sb—Sn, In—Sb—Te—Ag, In—Se and Te—Bi.","In the present invention, the optical recording medium is typically configured to record record marks with the laser beam in both the top portions of the ridges and the bottom portions of the furrows of the concavo-convex structure of the disc substrate.","That is, the optical recording medium according to the invention employs the land/groove recording technique.","In the present invention, in case the recording layer is made of a phase-changeable material for the purpose of improving the stability of record marks against reproduced light and simultaneously ensuring a good jitter property in high-density recording by mark-edge recording, the phase-changeable recording layer is typically made of a Te—Ge—Sb family alloy (which may contain other elements in addition to Te, Ge and Sb).","Its composition is in the range encircled by four points in the triangular graph of FIG.","6, which shows the composition of three components Te, Ge and Sb in coordinates (Te, Ge, Sb), namely, A(0.475, 0.05, 0.475), B(0.665, 0.05, 0.285), C(0.60, 0.40, 0) and D(0.40, 0.60, 0) (composition of the point A is Te47.5Ge5Sb47.5, composition of the point B is Te66.5Ge5Sb28.5, composition of the point C is Te60Ge40, and composition of the point D is Te40Ge60).","More preferably, the record-assist layer containing as its major component at least one compound selected from the group consisting of SiN, SiC, GeN, PbSe, PbTe, SnSe, SnTe, Bi2Te3 and Sb2Te3 is preferably formed immediately above and under the phase-changeable recording layer.","If the composition of the phase-changeable recording layer is outside the straight line connecting the point A and the point B on the triangular graph of FIG.","6 (where the content of Ge is less than 5 atomic %), then the crystallization temperature decreases, and portions without record marks (pre-recorded portions) become liable to be crystallized by reproduction reproduced light.","As a result, boundaries between record marks and pre-recorded portions become ambiguous, and the record marks may deteriorate.","Further, if the composition of the phase-changeable recording layer is outside the straight line connecting the point B and the point C and outside the straight line connecting the point D and the point A, then the jitter property deteriorates.","If the phase-changeable recording layer is inside the range surrounded by the points A, B, C and D but close to the straight line connecting the point A and the point B (where the content of Ge is 5 atomic % or more, but relatively small), then the difference in optical constant between the amorphous state and the crystal state becomes small.","This is not desirable from the viewpoint of the signal quality because the amplitude of the reproduction signal decreases.","In the present invention, more preferable composition range of the phase-changeable recording layer is the range where the coordinates (Te, Ge, Sb) are E(0.47, 0.30, 0.23), F(0.58, 0.30, 0.12), G(0.56, 0.44, 0) and H(0.44, 0.56, 0) on the triangular graph of FIG.","7 similar to FIG.","6.Composition of the point E is Te47Ge30Sb23, composition of the point F is Te58Ge30Sb12, composition of the point G is Te56Ge44, and composition of the point H is Te44Ge56.In the present invention, more preferable composition range of the phase-changeable recording layer is the range where the coordinates (Te, Ge, Sb) are J(0.47, 0.40, 0.13), K(0.55, 0.40, 0.05), L(0.52, 0.48, 0) and M(0.44, 0.56, 0) on the triangular graph of FIG.","8 similar to FIG.","6.Composition of the point J is Te47Ge40Sb13, composition of the point K is Te55Ge40Sb5, composition of the point L is Te52Ge48, and composition of the point M is Te44Ge56.In the present invention, the record-assist layer is preferably made of a material containing as its major component at least one compound selected from the group consisting of SnTe, SiN, SiC, SnSe, GeN, PbSe, PbTe, Bi2Te3 and Sb2Te3.The record-assist layer may be in a mixed crystal state mixing any one of those compounds as well.","From the viewpoint of the storage lifetime of the optical recording medium, SnTe is preferably selected from those compounds as the major component of the record-assist layer.","In the present invention, the record-assist layer contains one of above-specified compounds and may additionally contain other appropriate material.","In this case, the content of any of the above-specified compounds is adjusted to be 50 volume % or more.","If the content of the specific compound is less than 50 volume %, the phase-changeable recording layer may fail to crystallize well and may deteriorate the jitter property of the reproduced light.","The content of the specific compound in the record-assist layer is more preferably 70 volume % or more.","More specifically, usable materials of the record-assist layer are thorium phosphide (ThP), lanthanum sulfide (LaS), scandium antimony (ScSb), thorium selenium (ThSe), calcium selenium (CaSe), lead sulfide (PbS), scandium bismuth (ScBi), thorium arsenide (ThAs), BiSe, indium arsenide (InAs), yttrium tellurium (YTe), gallium antimony (GaSb), PbSe, tin antimony (SnSb), aluminum antimony (AlSb), copper iodide (CuI), strontium selenium (SrSe), SnTe, thorium antimony (ThSb), CaTe, barium sulfide (BaS), LaTe, PbTe, BiTe, SrTe, silver ionide (AgI), Sb2Te3, Bi2Se3, Bi2Te3 and so forth.","However, other materials are also usable where appropriate.","In the present invention, in case the multi-layered film on the disc substrate does not include the reflection layer and has the record-assist layer on one surface of the recording layer opposite from the disc substrate, a protective layer is preferably formed on one surface of the record-assist layer opposite from the surface in contact with the recording layer.","The protective layer is made of at least one material selected from metal or semi-metal oxides, carbides, nitrides, fluorides and sulfides.","More specifically, usable materials of the protective layer are oxides such as silicon oxides (SiO2, SiO), tantalum oxide (Ta2O5) and zirconium oxide (ZrO2), carbides such as silicon carbide (SiC) and titanium carbide (TiC) or simplex carbon (C), nitrides such as silicon nitride (Si3N4) aluminum nitride (AlN), sulfides such as zinc sulfide (ZnS), samarium sulfide (SmS) and strontium sulfide (SrS), and fluorides such as magnesium fluoride (MgF2).","Further, a mixture containing at least one or more kinds of those materials is preferably used as the material of the protective layer.","In the present invention, to ensure accurate control of the length of the record mark by mark-edge recording, the first reflection layer of the second reflection layer for reflecting light after passing the recording layer is preferably made of a material having thermal conductivity not lower than 50 W/m·K.","Examples of materials having thermal conductivity not lower than 50 W/m·K are metals selected from the group consisting of Al, Cr, Ni, Au, hafnium (Hf), palladium (Pd), tantalum (Ta), cobalt (Co), Mo, W, Cu and Ti, or alloys of those metals.","Among these materials, desirable materials for forming the reflection layer from various viewpoints are Al—Ti alloys, Al—Cr alloys, Al—Ta alloys, Al—Pd alloys, Al—Cu alloys, Ti—Al alloys, Ti—V alloys, Ti—Pd—Cu alloys, Ag alloys, and so on.","Composition of these alloys is determined in accordance with the required property.","Other materials are also usable if necessary.","According to the invention having the above-summarized configuration, since the thickness a of the record-assist layer is controlled to be larger than ¼ of the thickness d of the recording layer and smaller than three times of the thickness d, signal property can be changed by not only by changing the size of the concavo-convex but also by modifying the thickness of the record-assist layer.","Therefore, design freedom necessary for improvement of the signal property can be increased.","BRIEF DESCRIPTION OF DRAWINGS FIG.","1 is a cross-sectional view that shows an optical disc according to the first embodiment of the invention FIG.","2 is a graph that shows dependency or a carrier upon the thickness of a record-assist layer in the optical disc according to the first embodiment of the invention; FIG.","3 is a graph that shows dependency of the signal amplitude upon the thickness of the record-assist layer in the optical disc according to the first embodiment of the invention; FIG.","4 is a graph that shows dependency of a cross talk signal upon the thickness of the record-assist layer in the optical disc according to the first embodiment of the invention; FIG.","5 is a cross-sectional view that shows an optical disc according to the second embodiment of the invention; FIG.","6 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention; FIG.","7 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention; and FIG.","8 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention.","BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the invention will now be explained below with reference to the drawings.","First explained is an optical disc according to the first embodiment of the invention.","FIG.","1 shows the optical disc according to the first embodiment.","The optical disc according to the first embodiment is a WO (write once) type on which information signals are recorded in a WO mode.","As shown in FIG.","1, the optical disc 1 according to the first embodiment includes a multi-layered film made of a first dielectric layer 3, recording layer 4, record-assist layer 5, second dielectric layer 6 and first reflection layer 7 that are stacked on one major surface 2a of a disc substrate 2, and an ultraviolet-curing resin layer 8 formed to cover the multi-layered film.","The disc substrate 2 is made of a material that can transmit at least a laser beam used for recording and reproducing information signals.","Examples of materials usable for forming the disc substrate 2 are plastic materials such as polycarbonate-family resins, polyolefin resin and acrylic-family resins, and glass.","Among these materials, plastic materials are preferable from the economical viewpoint.","In the first embodiment, the disc substrate 2 is made of, for example, polycarbonate (PC).","The disc substrate 2 is sized 130 mm in diameter and approximately 1.2 mm in thickness, for example.","The major surface 2a of the disc substrate 2 has formed a track-like concavo-convex structure.","Ridges of the track-like concavo-convex structure are portions remoter from the laser beam injection side.","In the first embodiment, the ridges are called lands 2b.","The furrows are portions closer to the laser beam injection side.","In the first embodiment, the furrows are called grooves 2c.","Ratio between the width Dl of each land 2b and the width Dg of each groove 2, i.e.","the duty ratio (Dl/Dg), is selected from the range of 0.5 to 2.0.If the duty ratio is smaller than 0.5, then the width Dl of the land 2b is less than one half of the width Dg of the groove 2c, and it is difficult to control both the lands 2b and the grooves 2c to have a common signal property.","If the duty ratio is larger than 2.0, then the width Dg of the groove 2c is similarly narrowed to less than one half of the width Dl of the land 2b, and it is again difficult to control both the lands 2b and the grooves 2c to have a common signal property.","More preferable range of the duty ratio is 0.8 to 1.2.In an example of configurations and sizes of the disc substrate 2 according to the first embodiment, the track pitch (Tp) of the groove tracks is 0.77 μm, depth of the grooves 2c (depth of the furrows) is 70 nm, width Dl of the lands 2b is 0.82 μm, width Dg of the grooves 2c is 0.72 μm, and the duty ratio is (0.82/0.72=) 1.14.The first dielectric layer 3 is preferably made of a material exhibiting a low absorption power (absorptivity) to recording/reproducing laser beams, and more specifically, an extinction coefficient k not larger than 0.3.Taking the resistance to heat into consideration as well, SiN is one of preferable materials.","Thickness of the first dielectric layer 3 is adjusted not to exceed 200 nm.","In the first embodiment, it may be 10 nm thick, for example.","The recording layer 4 is made of GeTe alloy, for example.","If the thickness d of the recording layer 4 is smaller than 5 nm, the amplitude is optically too small.","If the thickness d is larger than 50 nm, then the recording layer degrades in heat diffusion effect, therefore becomes liable to hold heat therein, and will become incapable of recording record marks clearly.","Therefore, thickness d of the recording layer 4 is adjusted in the range of 5 nm≦d≦50 nm.","According to the knowledge of the Inventor obtained by an experiment of the signal property in the recording layer 4, thickness d of the recording layer is preferably adjusted in the range of 10 nm≦d≦40 nm, taking account of the range capable of obtaining good signals.","In the first embodiment, thickness of the recording layer 4 is around 20 nm, for example.","Material of the record-assist layer 5 contains as its major component at least one compound selected from the group consisting of SnTe, SiN, SiC, GeN, PbTe, SnSe, PbSe, Bi2Te3 and Sb2Te3.More specifically, it is a material containing any of the above-specified compounds by at least 50 volume %, or more preferably, by at least 70 volume %.","The record-assist layer 5 is preferably in uniform contact with the recording layer 4.In the first embodiment, the record-assist layer 5 is made of SnTe, for example.","Thickness a of the record-assist layer 5 is adjusted in the range larger than ¼ of the thickness d of the recording layer 4 and smaller than three times thereof.","That is, record-assist layer 5 is formed to satisfy the following relation between its thickness a and the thickness d of the recording layer 4, d/4<a<3d or more preferably to satisfy d/2≦a≦2d Details of the thickness of the record-assist layer 5 will be explained later.","The second dielectric layer 6 is preferably made of a material exhibiting a low absorption power to recording/reproducing laser beams, and more specifically, an extinction coefficient k not larger than 0.3.Taking the resistance to heat into consideration as well, ZnS—SiO2 (especially one having a mol ratio around 4:1) is one of preferable materials.","In the first embodiment, the first dielectric layer 3 and the second dielectric layer 6 are made of different materials.","However, they may be made of a common material.","The first reflection layer 7 is made of Al alloy, for example.","In the first embodiment, it is made of AlTi alloy.","If the first reflection layer 7 is thinner than 20 nm, heat generated in the recording layer 4 cannot diffuse sufficiently, and heat is not sufficiently cooled down.","If the reflection layer 7 is thicker than 100 nm, then its thermal property and optical property will be adversely affected, and a desired signal property will not be obtained.","Therefore, thickness of the first reflection layer 7 is adjusted in the range from 20 to 100 nm.","In the first embodiment, it is 60 nm thick, for example.","The ultraviolet-setting resin layer 8 is made of an ultraviolet-setting resin that is cured by irradiation of ultraviolet rays.","In the optical disc according to the first embodiment, having the above-explained configuration, a laser beam L1 is injected toward the multi-layered film including the sequentially stacked first dielectric layer 3, recording layer 4, record-assist layer 5, second dielectric layer 6 and first reflection layer 7 from one side thereof where the disc substrate 2 exists as shown in FIG.","1, and when it irradiates the recording layer 4, an information signal is recorded and/or reproduced.","Next explained is a manufacturing method of the optical disc 1 according to the first embodiment having the above-explained configuration.","First prepared is a clean disk substrate 2 having guide grooves (concavo-convex groove tracks) (for example, thickness: 1.2 mm, track pitch: 0.77 μm, width of lands: 0.82 μm, width of grooves: 0.72 μm, depth of grooves: 70 nm).","Subsequently, the disc substrate 2 is transported into a first sputtering chamber in which a Si target is set, and it is placed on a predetermined position.","After that, a film of SiN, for example, is formed on the major surface 2a of the disc substrate 2 by sputtering using nitrogen (N2) gas as the reactive gas.","As a result, the first dielectric layer 3 of SiN is deposited on the major surface 2a of the disc substrate 2.An example of the sputtering conditions is using an inactive gas such as argon (Ar) gas and a reactive gas such as N2 gas as the atmospheric gas, adjusting their flow rates to be Ar:N2=3:1, maintaining the pressure of the atmospheric gas in 0.6 Pa, and supplying the sputtering power of 2.5 kW.","After that, the disc substrate 2 having formed the first dielectric layer 3 is removed from the first sputtering chamber.","The disc substrate 2 is next introduced into a second sputtering chamber and placed on a predetermined position.","Thereafter, a film of GeTe, for example, is formed on the first dielectric layer 3 by sputtering.","As a result, the recording layer 4 of GeTe alloy is obtained.","An example of the puttering conditions used here is using an inactive gas such as Ar gas as the atmospheric gas, and adjusting the sputtering power to 0.3 kW and the pressure of the atmospheric gas to 0.4 Pa (3.0 mTorr).","Under these conditions, the recording layer 4 is formed by using a GeTe alloy target adjusted in composition such that the composition of the layer obtained becomes Ge50Te50, for example.","After that, the disc substrate 2 having formed the recording layer 4 as well is removed from the second sputtering chamber.","The disc substrate 2 having formed layers up to the recording layer 4 is next introduced into a third sputtering chamber and placed on a predetermined position.","After that, a SnTe alloy film is formed on the recording layer 4 by sputtering using a SnTe alloy target.","As a result, the record-assist layer 5 of SnTe alloy is formed evenly on the recording layer 4.An example of the sputtering conditions used here is using an inactive gas such as Ar gas as the atmospheric gas, adjusting the sputtering power to 0.3 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).","Thereafter, the disc substrate 2 having formed layers up to the record-assist layer 5 is removed from the third sputtering chamber.","The disc substrate having formed layers up to the record-assist layer is next introduced into a fourth sputtering chamber and placed on a predetermined position.","Thereafter, a ZnS—SiO2 film is formed on the record-assist layer 5 by sputtering using a ZnS—SiO2 target.","As a result, the second dielectric layer 6 of ZnS—SiO2 is deposited on the record-assist layer 5.An example of the sputtering conditions used here is using an inactive gas like Ar gas as the atmospheric gas and adjusting the sputtering power to 0.6 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).","Thereafter, the disc substrate 2 having formed layers up to the second dielectric layer 6 is removed from the fourth sputtering chamber.","The disc substrate 2 having formed layers up to the second dielectric layer 6 is next introduced into a fifth sputtering chamber and placed on a predetermined position.","Thereafter, an AlTi film is formed on the second dielectric layer 6 by sputtering using a target of AlTi alloy.","As a result, the first reflection layer 7 of AlTi alloy is deposited on the second dielectric layer 6.An example of the sputtering conditions used here is using an inactive gas like Ar gas as the atmospheric gas and adjusting the sputtering power to 2.5 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).","Thereafter, the disc substrate 2 having formed layers up to the first reflection layer 7 is removed from the fifth sputtering chamber.","After that, the ultraviolet-setting resin layer 8 is formed on the top surface of the first reflection layer 7 by spin coating or roll coating.","Through those steps, the WO type optical disc 1 according to the first embodiment, using GeTe, which is a phase-changeable material, as the recording layer 4 is completed.","As the optical disc 1 according to the first embodiment, which can be manufactured as explained above, the Inventor prepared optical discs 1 that are changed in thickness a of the record-assist layer 5 in the range of d/4≦a≦3d, namely as a=d/4, a=d/2, a=d, a=2d and a=3d, and measured their recording and reproducing characteristics by an evaluator.","That is, by evaluating recording/reproducing characteristics of find kinds of optical discs 1, the Inventor evaluated dependency of the carrier upon the thickness of the record-assist layer 5.The evaluator used for evaluation of those optical discs was adjusted to use laser beams having the wavelength of 660 nm and adjusted in numerical aperture of the objective lens to 0.575.A result of this evaluation is shown in FIG.","2.In the graph of FIG.","2, the abscissa indicates the thickness of the record-assist layer 5 and the ordinate indicates the carrier.","Evaluated values of lands are shown by ♦ and evaluated values of grooves by ▪.","The Inventor further carried out optical calculation about dependency of the laser beam amplitude upon the thickness of the record-assist layer 5.A result of the calculation is shown in FIG.","3.It is appreciated from FIG.","2 that, in grooves, the carrier gradually increases as the thickness a of the record-assist layer 5 decreases within the range from d/4 to 3d.","In contrast, in lands, the carrier changes less even when the thickness a of the record-assist layer 5 decreases within the range from d/4 to 3d.","That is, it is understood that the dependency upon the thickness of the record-assist layer 5 in changes of the carrier appears more clearly in grooves.","This means that, by intentionally changing the thickness of the record-assist layer 5, the signal characteristics in grooves can be changed while the signal characteristics in lands are maintained substantially constant.","It is also appreciated from FIG.","3 that the amplitude rapidly decreases as the thickness a of the record-assist layer 5 is once decreased and thereafter decreased to ¼ of the thickness d of the recording layer 4.This demonstrates that the control of the thickness of the record-assist layer 5 carried out for the purpose of assuring predetermined amplitude becomes very difficult.","On the other hand, in case the thickness a of the record-assist layer 5 is larger than ¼ of the thickness of the recording layer 4, changes of the amplitude are very moderate, and it will be easy to control the thickness of the record-assist layer 5.From this point of view, the thickness a of the record-assist layer 5 is preferably larger than ¼ of the thickness d of the recording layer 4.It is further appreciated from FIG.","2 that, when the thickness a of the record-assist layer 5 is decreased to d/4, both the value of the carrier in lands and the value of the carrier in grooves decreases.","Therefore, if the thickness a of the record-assist layer 5 is ¼ or less of the thickness d of the recording layer 4 (a≦d/4), both the signal property of lands and the signal property of grooves deteriorate.","That is, the thickness a of the record-assist layer 5 must be larger than ¼ of the thickness d of the recording layer 4 (d/4<a), and it is preferably adjusted to ½ or more of the thickness d of the recording layer 4 (d/2≦a).","Further, according to the knowledge of the Inventor obtained by the experiment, the record-assist layer 5 can be formed not to disconnect in form of islands on the recording layer 4 by adjusting the thickness a of the record-assist layer 5 to be larger than ¼ of the thickness d of the recording layer 4 (d/4<a).","Accordingly, it is possible to form the record-assist layer 5 evenly.","It is further appreciated from FIG.","3 that, as the thickness a of the record-assist layer 5 is larger, the amplitude gradually decreases.","Therefore, the thickness a of the record-assist layer 5 is preferably adjusted not to exceed three times of the thickness d of the recording layer 4.It is further appreciated from FIG.","2 that, when the thickness a of the record-assist layer 5 is increased to or beyond three times of the thickness d of the recording layer (3d≦a), both the value of the carrier in lands and the value of the carrier in grooves significantly decreases.","Therefore, if the thickness a of the record-assist layer 5 is three times or more of the thickness d of the recording layer (3d≦a), then both the signal property of lands and the signal property of grooves deteriorate and substantially result in the result of calculation shown in FIG.","3.That is, thickness a of the record-assist layer 5 must be limited below three times of the thickness d of the recording layer 4 (a<3d), and it is preferably adjusted not to exceed two times of the thickness d of the recording layer 4 (a≦2d).","For the purpose of investigating dependency of optical cross talk upon the thickness of the record-assist layer, the Inventor measured signal quantities of cross talk from lands to grooves and signal quantities of cross talk from grooves to lands upon recording 2T marks.","FIG.","4 shows the dependency of the cross talk signal quantity upon the dependency of the thickness of the record-assist layer 5.In FIG.","4, the ordinate shows cross talk in relative decibel for enabling comparison with the value of the carrier, and indicates cross talk from grooves to lands by ♦ and cross talk from lands to grooves by ▪.","It is appreciated from FIG.","4 that, as the thickness a of the record-assist layer 5 decreases from 3d to d/2, cross talk leaking from grooves to lands decreases even though the signal quantity in grooves increases (see FIG.","2).","On the other hand, cross talk leaking from lands to grooves increases only a little as the thickness a of the record-assist layer 5 decreases from 3d to d/2, and no remarkable increase is observed.","That is, even when the thickness of the record-assist layer 5 is changed, it is apparent that the carrier can be controlled in lands and grooves while suppressing the increase of the cross talk.","As explained heretofore, the optical disc according to the first embodiment, which has the multi-layered film including the first dielectric layer 3, recording layer 4, record-assist layer 5, second dielectric layer 6 and reflection layer 7 deposited on one major surface of the disc substrate 2 and employs the land/groove recording technique, can increase the signal amplitude especially in grooves 2c by adjustment of the thickness a of the record-assist layer to be larger than ¼ of the thickness d of the recording layer 4 and smaller than three times thereof, and can simultaneously keep both the signal property in lands 2b and the signal property in grooves 2c in a good condition by controlling the thickness of the record-assist layer 5 after optimizing the signal property in lands 2b.","Furthermore, since the signal amplitude in grooves 2c can be changed by while the signal amplitude in lands 2b is maintained constant, by intentional control of the thickness of the record-assist layer 5, both the signal amplitude in lands 2b and the signal amplitude in grooves 2c can be changed independently from each other.","This increases the design freedom and enables optimization of lands 2b and grooves 2c while maintaining the optimum deposition condition of the recording layer 4.Therefore, information signals can be reproduced from optical discs in a good condition of the signal property.","Thus a highly reliable optical disc can be obtained.","Next explained is an optical disc according to the second embodiment of the invention.","FIG.","5 shows the optical disc according to the second embodiment of the invention.","The optical disc according to the second embodiment is a programmable optical disc permitting rewriting of information signals.","As shown in FIG.","5, the optical disc 11 according to the second embodiment includes a multi-layered film made of a second reflection layer 13, third dielectric layer 14, record-assist layer 15, recording layer 16 and fourth dielectric layer 17 sequentially stacked on one major surface 12a of a disc substrate 12, and a light-transmitting layer 18 formed to cover the multi-layered film.","The disc substrate 12 is made of a low water-absorbing material such as polycarbonate (PC) or cycloolefin polymer (such as Zeonex (registered trademark)).","Thickness of the disc substrate 12 is, for example, in the range from 0.6 to 1.2 mm.","In the second embodiment, it is 1.1 mm thick, for example.","Diameter of the disc substrate 12 is 120 mm for example.","The optical disc according to the second embodiment is configured to record/reproduce information signals when a laser beam is irradiated to he disc substrate 12 from one side thereof where the thin light-transmitting layer 18 exists.","Therefore, the disc substrate 12 can be selected without taking it into consideration whether the material is permeable or not, and a substrate of a metal such as Al is also usable.","Alternatively, a glass substrate or a resin substrate of polyolefin, polyimide, polyamide, polyphenylene sulfide or polyethylene terephthalate is also usable as the disc substrate 12.The major surface 12a of the disc substrate 12 has formed a track-like concavo-convex structure.","Furrows of the track-like concavo-convex structure are portions remoter from the laser beam injection side.","In the second embodiment, the furrows are called lands 2b.","The ridges are portions closer to the laser beam injection side.","In the second embodiment, the ridges are called grooves 12c.","From the same reasons as those of the first embodiment, ratio between the width Dl of each land 2b and the width Dg of each groove 2, i.e.","the duty ratio (Dl/Dg), is selected from the range of 0.5 to 2.0, or more preferably from the range of 0.8 to 1.2.In an example of configurations and sizes of the disc substrate 12 according to the second embodiment, the track pitch (Tp) of the groove tracks is 0.77 μm, depth of the grooves (depth of the furrows) is 70 nm, width Dl of the lands 12b is 0.82 μm, width Dg of the grooves 12c is 0.72 μm, and the duty ratio is (0.82/0.72=) 1.14.The second reflection layer 13 is made of Al alloy, for example.","In the second embodiment, it is made of AlTi alloy.","From the same reasons as those of the first embodiment, thickness of the second reflection layer 13 is adjusted in the range from 20 to 100 nm.","For example, it may be 60 nm thick.","The third dielectric layer 14 is preferably made of a material exhibiting a low absorption power to recording/reproducing laser beams, and more specifically, an extinction coefficient k not larger than 0.3.Taking the resistance to heat into consideration as well, ZnS—SiO2 (especially one having a mol ratio around 4:1) is one of preferable materials.","Material of the record-assist layer 15 contains as its major component at least one compound selected from the group consisting of SnTe, SiN, SiC, GeN, PbTe, SnSe, PbSe, Bi2Te3 and Sb2Te3.More specifically, it is a material containing any of the above-specified compounds by at least 50 volume %, or more preferably, by at least 70 volume %.","The record-assist layer 15 is preferably in uniform contact with the recording layer 16.In the second embodiment, the record-assist layer 15 is made of SnTe, for example.","From the same reasons as those of the first embodiment, thickness a of the record-assist layer 15 is adjusted in the range larger than ¼ of the thickness d of the recording layer 16, explained later, and smaller than three times of same.","That is, record-assist layer 15 is formed to satisfy the following relation between its thickness a and the thickness d of the recording layer 16, d/4<a<3d or more preferably to satisfy d/2≦a≦2d from the viewpoint of improving the signal property.","The recording layer 16 is made of GeTe alloy, for example.","From the same reasons as those of the first embodiment, thickness d of the recording layer 4 is adjusted in the range of 5 nm≦d≦50 nm.","According to the knowledge of the Inventor obtained by an experiment of the signal property in the recording layer 16, thickness d of the recording layer is preferably adjusted in the range of 10 nm≦d≦40 nm, taking account of the range capable of obtaining good signals.","In the first embodiment, thickness of the recording layer 16 is around 20 nm, for example.","The fourth dielectric layer 17 is preferably made of a material exhibiting a low absorption power (absorptivity) to recording/reproducing laser beams, and more specifically, an extinction coefficient k not larger than 0.3.Taking the resistance to heat into consideration as well, SiN is one of preferable materials.","Thickness of the fourth dielectric layer 17 is adjusted not to exceed 200 nm.","In the second embodiment, it may be 10 nm thick, for example.","In the second embodiment, the third dielectric layer 14 and the fourth dielectric layer 17 are made of different materials.","However, they may be made of a common material.","In the optical disc according to the second embodiment, having the above-explained configuration, a laser beam L2 is injected toward the disc substrate 12 from one side thereof where the multi-layered film exists as shown in FIG.","5, and when it irradiates the recording layer 16 above the lands 12b and above the grooves 12c, information signals are recorded and/or reproduced.","Next explained is a manufacturing method of the optical disc 11 according to the second embodiment having the above-explained configuration.","First prepared is a clean disk substrate 12 having guide grooves (concavo-convex groove tracks) (for example, thickness: 1.1 mm, track pitch: 0.77 μm, width of lands: 0.82 μm, width of grooves: 0.72 μm, depth of grooves: 70 nm).","Subsequently, the disc substrate 12 having formed the concavo-convex groove tracks is transported into a first sputtering chamber, and placed in a predetermined position.","Thereafter, an AlTi film is formed at least on groove tracks with ridges and grooves by sputtering using a target of AlTi alloy.","As a result, the second reflection layer 13 of AlTi alloy is deposited on the disc substrate 12.An example of the sputtering conditions used here is using an inactive gas like Ar gas as the atmospheric gas and adjusting the sputtering power to 2.5 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).","Thereafter, the disc substrate 12 having formed the second reflection layer 13 is removed from the first sputtering chamber.","The disc substrate having formed the second reflection layer 13 is next introduced into a second sputtering chamber and placed on a predetermined position.","Thereafter, a ZnS—SiO2 film is formed on the second reflection layer 13 by sputtering using a ZnS—SiO2 target.","As a result, the third dielectric layer 14 of ZnS—SiO2 is deposited on the second reflection layer 13.An example of the sputtering conditions used here is using an inactive gas like Ar gas as the atmospheric gas and adjusting the sputtering power to 0.6 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).","Thereafter, the disc substrate 12 having formed layers up to the third dielectric layer 14 is removed from the second sputtering chamber.","The disc substrate 12 having formed layers up to the third dielectric layer 14 is next introduced into a third sputtering chamber and placed on a predetermined position.","After that, a SnTe alloy film is deposited on the third dielectric layer 14 by sputtering using a SnTe alloy target.","As a result, the record-assist layer 15 of SnTe alloy is formed evenly on the third dielectric layer 14.An example of the sputtering conditions used here is using an inactive gas such as Ar gas as the atmospheric gas, adjusting the sputtering power to 0.3 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).","Thereafter, the disc substrate 12 having formed layers up to the record-assist layer 15 is removed from the third sputtering chamber.","The disc substrate 12 having formed layers up to the record-assist layer 15 is next introduced into a fourth sputtering chamber and placed on a predetermined position.","Thereafter, a film of GeSbTe, for example, is formed on the record-assist layer 15 by sputtering.","As a result, the recording layer 16 of GeSbTe alloy is obtained.","An example of the sputtering conditions used here is using an inactive gas such as Ar gas as the atmospheric gas, adjusting the sputtering power to 0.3 kW and the pressure of the atmospheric gas to 0.4 Pa (3.0 mTorr).","Thereafter, the disc substrate 12 having formed layers up to the recording layer 16 is removed from the fourth sputtering chamber.","The disc substrate 12 is next introduced into a fifth sputtering chamber and placed on a predetermined position.","After that, a film of SiN, for example, is formed on the second reflection layer 13 by sputtering using nitrogen (N2) gas as the reactive gas.","As a result, the third dielectric layer 14 of SiN is deposited on the second reflection layer 13.An example of the sputtering conditions is using an inactive gas such as argon (Ar) gas and a reactive gas such as N2 gas as the atmospheric gas, adjusting their flow rates to be Ar:N2=3:1, maintaining its pressure in 0.6 Pa, and supplying the sputtering power of 2.5 kW.","After that, the disc substrate 12 having formed the fourth dielectric layer 17 is removed from the fifth sputtering chamber.","Thereafter, a light-transmitting sheet 18b is bonded via a bonding layer 18a to the multi-layered film made of the second reflection layer 13, third dielectric layer 14, record-assist layer 15, recording layer 16 and fourth dielectric layer 17 by using a predetermined bonding machine (not shown).","As a result, the light-transmitting layer 18 is formed.","Through those steps, the optical disc 11 according to the second embodiment is completed.","With the optical disc 11 according to the second embodiment, the same effects as those of the first embodiment can be obtained by limiting the thickness a of the record-assist layer 15 within the range of d/4<a<3d relative to the thickness d of the recording layer 16, and it has been confirmed that the same effects as those of the optical disc 1 according to the first embodiment can be ensured also with the optical disc 11 having that configuration.","Although the invention has been explained by way of specific embodiments, the invention is not limited to those embodiments but can be modified in various modes based on the technical concept of the invention.","For example, numerical values and materials shown in the explanation of the embodiments are not but mere examples, and other numerical values and materials may be used if necessary.","For example, the first embodiment has been explained as applying the invention to a WO type optical disc having the recording layer 4 made of a phase-changeable material and configured to record in a WO manner.","However, application of the invention is not limited to WO type optical discs, but can be extended to other type optical discs such as programmable optical discs.","The second embodiment has been explained as using AlTi alloy as the material of the second reflection layer 13.However, material of the second reflection layer 13 may be selected from other Al alloys such as AlCu alloy, Al, silver (Ag), Ag alloys such as AgPdCu alloys, copper (Cu), Cu alloys, and so on.","Moreover, although the second embodiment has been explained as using the recording layer made of GeSbTe alloy, any other appropriate material such as GeTe alloy, GeInSbTe alloy, AgInSbTe alloy, or the like, can be used in accordance with the desired property.","Furthermore, although the second embodiment has been explained as employing 0.77 μm as the track pitch Tp of the concavo-convex tracks formed on one major surface 12a of the disc substrate 12, a different value may be employed where necessary.","In case a blue laser having the wavelength around 405 nm is used as the laser beam and NA is enhanced approximately to 0.85 by using two-group lenses, the track pitch Tp may be reduced to 0.74 μm or smaller, such as around 0.3 μm.","As described above, the invention enables freer design of optical recording mediums for obtaining more excellent signal characteristics and ensures optical mediums having excellent signal characteristics and high reliability by adjusting the thickness d of the recording layer and the thickness a of the record-assist layer to satisfy d/4<a<3d in optical recording mediums having the recording layer capable of recording information signals by irradiation of a laser beam and the multi-layered film stacking at least the recording layer and the record-assist layer at least on one surface of the disc substrate having formed concavo-convex."]],"string":"[\n [\n \"Optical recording medium and its manufacturing method\",\n \"A multi-layered film made of sequentially stacked first dielectric layer, recording layer, record-assist layer, second dielectric layer and first reflection layer on a disc substrate having a concavo-convex structure at least on one surface thereof.\",\n \"An ultraviolet-setting resin layer is formed to cover the multi-layered film.\",\n \"The record-assist layer is controlled in thickness to satisfy the relation d/4<a<3d, or more preferably the relation d/2≦a≦2d, between the thickness d of the recording layer and the thickness a of the record-assist layer.\",\n \"The stacking order of the multi-layered film may be opposite.\",\n \"In this case, a light-transmitting sheet is provided to cover the multi-layered film via a bonding layer.\"\n ],\n [\n \"1.An optical recording medium comprising: a disc substrate having formed a concavo-convex structure formed at least on one surface thereof; and a multi-layered film made by stacking at least a recording layer capable of recording information signals by irradiation of a laser beam and a record-assist layer adjacent to the recording layer on the surface of the disc substrate having the concavo-convex structure, wherein d/4<a<3d is satisfied where d is the thickness of the recording layer and a is the thickness of the auxiliary recording layer.\",\n \"2.An optical recording medium according to claim 1 wherein said recording layer can record the information signals by reversible changes at least between two different states.\",\n \"3.An optical recording medium according to claim 1 wherein said recording layer is made of a phase-changeable material capable of recording the information signals by phase changes between a crystal phase and an amorphous phase.\",\n \"4.An optical recording medium according to claim 1 wherein the laser beam used for recording and/or reproducing information signals is irradiated to said recording layer from one side of the multi-layered film where the disc substrate exists.\",\n \"5.An optical recording medium according to claim 4 wherein said multi-layered film includes a first dielectric layer, said recording layer, said record-assist layer, a second dielectric layer and a first reflection layer that are stacked sequentially from near the surface of the disc substrate having formed the concavo-convex structure.\",\n \"6.An optical recording medium according to claim 4 wherein a layer of a synthetic resin is formed to cover the multi-layered film on the disc substrate.\",\n \"7.An optical recording medium according to claim 1 wherein the laser beam used for recording and/or reproducing information signals is irradiated to the recording layer from one side of the disc substrate where the multi-layered film exists.\",\n \"8.An optical recording medium according to claim 7 wherein said multi-layered film is made of a second reflection layer, third dielectric layer, said record-assist layer, said recording layer and a fourth dielectric layer that are stacked sequentially from near one surface of the disc substrate having said concavo-convex structure.\",\n \"9.An optical recording medium according to claim 7 wherein a light-transmitting layer permitting the laser beam to pass through is formed to cover the multi-layered film on the disc substrate.\",\n \"10.An optical recording medium according to claim 1 wherein, in a portion of the disc substrate having the concavo-convex structure, width Dg of a level difference of a portion nearer to the injection side of the laser beam and width Dl of a level difference of a portion remoter from the injection side of the laser beam satisfy the ratio of 0.5≦Dl/Dg≦2.0.11.An optical recording medium according to claim 1 wherein, in a portion of the disc substrate having the concavo-convex structure, width Dg of a level difference of a portion nearer to the injection side of the laser beam and width Dl of a level difference of a portion remoter from the injection side of the laser beam satisfy the ratio of 0.8≦Dl/Dg≦1.2.12.An optical recording medium according to claim 1 wherein an objective lens used for recording and/or reproducing the information signals has a numerical aperture not smaller than 0.45 and not larger than 0.60.13.An optical recording medium according to claim 1 wherein thickness of the recording layer is in the range not smaller than 5 nm and not larger than 50 nm.\",\n \"14.An optical recording medium according to claim 1 wherein thickness of said recording layer is in the range not smaller than 10 nm and not larger than 40 nm.\",\n \"15.An optical recording medium according to claim 1 wherein thickness of said record-assist layer is in the range not smaller than 3 nm and not larger than 100 nm.\",\n \"16.An optical recording medium according to claim 1 wherein thickness of said record-assist layer is in the range not smaller than 5 nm and not larger than 60 nm.\",\n \"17.An optical recording medium according to claim 1 wherein said recording layer is capable of recording the information signals in a write only mode.\",\n \"18.An optical recording medium according to claim 1 wherein said recording layer is made of GeTe alloy or GeSbTe alloy.\",\n \"19.An optical recording medium according to claim 1 wherein said record-assist layer is made of a material containing as its major component at least one compound selected from the group consisting of SnTe, SiN, SiC, SnSe, GeN, PbSe, PbTe, Bi2Te3 and Sb2Te3.20.An optical recording medium according to claim 1 wherein record marks can be recorded on both portions of the recording layer on top surfaces of ridges and portions of the recording layer on bottoms of the furrows of the concavo-convex structure of the disc substrate by said laser beam.\",\n \"21.An optical recording medium according to claim 1 wherein said recording layer is located nearer to the irradiation side of the laser beam.\",\n \"22.A method of manufacturing an optical recording medium, which forms a multi-layered film made by stacking at least a recording layer capable of recording information signals by irradiation of a laser beam and a record-assist layer adjacent to the recording layer on the surface of the disc substrate having the concavo-convex structure, comprising: adjusting the thickness of the record-assist layer to satisfy d/4<a<3d where d is the thickness of the recording layer and a is the thickness of the record-assist layer.\",\n \"23.A method of manufacturing an optical recording medium according to claim 22 wherein said recording layer is made of a material capable of recording the information signals by reversible changes at least between two different states 24.A method of manufacturing an optical recording medium according to claim 22 wherein said recording layer is made of a phase-changeable material capable of recording the information signals by phase changes between a crystal phase and an amorphous phase.\",\n \"25.A method of manufacturing an optical recording medium according to claim 22 wherein the optical recording medium is configured to record the information signals in the recording layer by irradiation of the laser beam to the recording layer from one side of the multi-layered film where the disc substrate exists.\",\n \"26.A method of manufacturing an optical recording medium according to claim 25 wherein said multi-layered film is made by stacking a first dielectric layer, said recording layer, said record-assist layer, a second dielectric layer and a first reflection layer that are stacked sequentially from near the surface of the disc substrate having formed the concavo-convex structure.\",\n \"27.A method of manufacturing an optical recording medium according to claim 25 wherein a layer of a synthetic resin is formed to cover the multi-layered film after the multi-layered film is formed on the disc substrate.\",\n \"28.A method of manufacturing an optical recording medium according to claim 22 wherein the optical recording medium is configured to record the information signals in the recording layer by irradiation of the laser beam to the recording layer from one side of the disc substrate where the multi-layered film exists.\",\n \"29.A method of manufacturing an optical recording medium according to claim 28 wherein said multi-layered film is made by stacking a second reflection layer, third dielectric layer, said record-assist layer, said recording layer and a fourth dielectric layer sequentially from near one surface of the disc substrate having said concavo-convex structure.\",\n \"30.A method of manufacturing an optical recording medium according to claim 28 wherein a light-transmitting layer permitting the laser beam to pass through is formed to cover the multi-layered film after the multi-layered film is formed on the disc substrate.\",\n \"31.A method of manufacturing an optical recording medium according to claim 22 wherein, in a portion of the disc substrate having the concavo-convex structure, width Dg of a level difference of a portion nearer to the injection side of the laser beam and width Dl of a level difference of a portion remoter from the injection side of the laser beam satisfy the ratio of 0.5≦Dl/Dg≦2.0.32.A method of manufacturing an optical recording medium according to claim 22 wherein, in a portion of the disc substrate having the concavo-convex structure, width Dg of a level difference of a portion nearer to the injection side of the laser beam and width Dl of a level difference of a portion remoter from the injection side of the laser beam satisfy the ratio of 0.8≦Dl/Dg≦1.2.33.A method of manufacturing an optical recording medium according to claim 22 wherein an objective lens used for recording and/or reproducing the information signals has a numerical aperture not smaller than 0.45 and not larger than 0.60.34.A method of manufacturing an optical recording medium according to claim 22 wherein the recording layer is formed to have a thickness in the range not smaller than 5 nm and not larger than 50 nm.\",\n \"35.A method of manufacturing an optical recording medium according to claim 22 wherein the recording layer is formed to have a thickness in the range not smaller than 10 nm and not larger than 40 nm.\",\n \"36.A method of manufacturing an optical recording medium according to claim 22 wherein said record-assist layer is formed to have a thickness in the range not smaller than 3 nm and not larger than 100 nm.\",\n \"37.A method of manufacturing an optical recording medium according to claim 22 wherein said record-assist layer is formed to have a thickness in the range not smaller than 5 nm and not larger than 60 nm.\",\n \"38.A method of manufacturing an optical recording medium according to claim 22 wherein said recording layer is formed to be capable of recording the information signals in a write only mode.\",\n \"39.A method of manufacturing an optical recording medium according to claim 22 wherein said recording layer is made of GeTe alloy or GeSbTe alloy.\",\n \"40.A method of manufacturing an optical recording medium according to claim 22 wherein said record-assist layer is made of a material containing as its major component at least one compound selected from the group consisting of SiC, SiN, SnTe, SnSe, GeN, PbSe, PbTe, Bi2Te3 and Sb2Te3.41.A method of manufacturing an optical recording medium according to claim 22 wherein the optical recording medium is formed to be capable of recording record marks in top portions of ridges and bottom portions of furrows of the concavo-convex structure of the disc substrate.\"\n ],\n [\n \"<SOH> BACKGROUND ART <EOH>Recently, along with enhancement of recording density of optical recording mediums such as optical discs, development of the technique of effectively using the area on the recording surface of an optical disc has been pushed forward to enhance the recording density.\",\n \"The recording surface of any disc substrate has concavo-convex called lands and grooves respectively.\",\n \"In conventional optical discs, only lands or only grooves were used to record recording marks.\",\n \"However, with the need of enhancing the recording density of optical discs, a technique for recording record marks on both lands and grooves, i.e.\",\n \"a land/groove recording technique, has been brought into use as a format of optical discs.\",\n \"An example of optical discs combined with the land/groove recording as their format is DVD-RAM (Digital Versatile Disc-Random Access Memory).\",\n \"However, such optical discs employing the land/groove recording suffer a difference of the thermal property exerted to the recording layer because of the difference in physical configuration between lands and grooves when recording laser beams are irradiated to lands and grooves respectively.\",\n \"In addition, lands and grooves form a periodical structure close to the wavelength of the laser beams.\",\n \"Therefore, vector diffraction of light causes uneven distribution of irradiated laser beams between lands and grooves, and it has been difficult to record or reproduce record marks from both lands and grooves with a high C/N ratio (carrier-to-noise ratio).\",\n \"To match lands and grooves in property, it is contemplated, for example, to change widths of lands and grooves and thereby change the duty ratio.\",\n \"However, only change of the duty ratio cannot bring about ample freedom.\",\n \"Under the circumstances, an optical disc was proposed, in which the recording layer on grooves is formed thicker than the recording layer on lands by selecting the sputtering condition, for example (Japanese Patent Laid-Open Publication No.\",\n \"2000-215511, referred to as Literature 1).\",\n \"However, in case of the optical disk disclosed in Literature 1, the condition for deposition of the recording layer is changed to form the recording layer on grooves thicker than the recording layer on lands.\",\n \"This condition digresses the optimum condition for deposition of the recording layer and invites deterioration of signal characteristics of the recording layer.\",\n \"Therefore, it has been demanded to develop a method capable of independently controlling the recording characteristics of lands and grooves.\",\n \"It is therefore an object of the invention to provide an optical recording medium having a multi-layered film of a recording layer and a record-assist layer stacked adjacently on one surface of a disc substrate having formed a concavo-convex structure, and its manufacturing method, which enable freer designing while ensuring good signal characteristics in the recording layer on the concavo-convex structure and ensuring high reliability.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG.\",\n \"1 is a cross-sectional view that shows an optical disc according to the first embodiment of the invention FIG.\",\n \"2 is a graph that shows dependency or a carrier upon the thickness of a record-assist layer in the optical disc according to the first embodiment of the invention; FIG.\",\n \"3 is a graph that shows dependency of the signal amplitude upon the thickness of the record-assist layer in the optical disc according to the first embodiment of the invention; FIG.\",\n \"4 is a graph that shows dependency of a cross talk signal upon the thickness of the record-assist layer in the optical disc according to the first embodiment of the invention; FIG.\",\n \"5 is a cross-sectional view that shows an optical disc according to the second embodiment of the invention; FIG.\",\n \"6 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention; FIG.\",\n \"7 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention; and FIG.\",\n \"8 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\"\n ],\n [\n \"TECHNICAL FIELD This invention relates to an optical recording medium and its manufacturing method especially suitable for application to an optical recording medium employing a land/groove recording technique.\",\n \"BACKGROUND ART Recently, along with enhancement of recording density of optical recording mediums such as optical discs, development of the technique of effectively using the area on the recording surface of an optical disc has been pushed forward to enhance the recording density.\",\n \"The recording surface of any disc substrate has concavo-convex called lands and grooves respectively.\",\n \"In conventional optical discs, only lands or only grooves were used to record recording marks.\",\n \"However, with the need of enhancing the recording density of optical discs, a technique for recording record marks on both lands and grooves, i.e.\",\n \"a land/groove recording technique, has been brought into use as a format of optical discs.\",\n \"An example of optical discs combined with the land/groove recording as their format is DVD-RAM (Digital Versatile Disc-Random Access Memory).\",\n \"However, such optical discs employing the land/groove recording suffer a difference of the thermal property exerted to the recording layer because of the difference in physical configuration between lands and grooves when recording laser beams are irradiated to lands and grooves respectively.\",\n \"In addition, lands and grooves form a periodical structure close to the wavelength of the laser beams.\",\n \"Therefore, vector diffraction of light causes uneven distribution of irradiated laser beams between lands and grooves, and it has been difficult to record or reproduce record marks from both lands and grooves with a high C/N ratio (carrier-to-noise ratio).\",\n \"To match lands and grooves in property, it is contemplated, for example, to change widths of lands and grooves and thereby change the duty ratio.\",\n \"However, only change of the duty ratio cannot bring about ample freedom.\",\n \"Under the circumstances, an optical disc was proposed, in which the recording layer on grooves is formed thicker than the recording layer on lands by selecting the sputtering condition, for example (Japanese Patent Laid-Open Publication No.\",\n \"2000-215511, referred to as Literature 1).\",\n \"However, in case of the optical disk disclosed in Literature 1, the condition for deposition of the recording layer is changed to form the recording layer on grooves thicker than the recording layer on lands.\",\n \"This condition digresses the optimum condition for deposition of the recording layer and invites deterioration of signal characteristics of the recording layer.\",\n \"Therefore, it has been demanded to develop a method capable of independently controlling the recording characteristics of lands and grooves.\",\n \"It is therefore an object of the invention to provide an optical recording medium having a multi-layered film of a recording layer and a record-assist layer stacked adjacently on one surface of a disc substrate having formed a concavo-convex structure, and its manufacturing method, which enable freer designing while ensuring good signal characteristics in the recording layer on the concavo-convex structure and ensuring high reliability.\",\n \"DISCLOSURE OF INVENTION The Inventor made vigorous researches to overcome the above-discussed problems the conventional techniques involved.\",\n \"The researches are outlined below.\",\n \"The recording principle of conventional optical mediums having a multi-layered film of a recording layer for recording information signals and a record-assist layer for supporting the recording layer is presumed to rely upon that, when the temperature is raised higher than the crystallization temperature lower than the melting point of the recording layer by laser beams irradiated to the recording layer, minute crystals produced in the crystallized auxiliary layer, and crystal growth of the recording layer occurs from the minute crystals as the seed crystals.\",\n \"This principle has been brought about because record marks are different in amplitude between optical discs having the auxiliary layer and optical discs without the auxiliary layer.\",\n \"The Inventor put forward the researches on the record-assist layer under the above presumption.\",\n \"That is, the Inventor recorded 2T pulses on samples common in duty ratio but variously different in thickness of the record-assist layer, and measured dependency of a carrier upon the recording power in lands and grooves, respectively.\",\n \"As a result, the Inventor has found that the dependency of the carrier upon the recording power in lands exhibits similar tendencies regardless of the thickness of the film and that there is almost no change of the carrier in lands even when the thickness of the record-assist layer is changed.\",\n \"On the other hand, as to the dependency of the carrier upon the recording power in grooves, the Inventor has found that, although the dependency of the carrier upon the recording power in lands exhibits similar tendencies regardless of the thickness of the film, when the record-assist layer is changed thickness, the carrier rises as the thickness decreases.\",\n \"This tendency was observed in the range close to the optimum value.\",\n \"Accordingly, the Inventor got inspiration of using the phenomenon confirmed by the above-explained experiment.\",\n \"That is, in case the duty ratio and the recording power are fixed, dependency of the carrier upon the thickness of the record-assist layer arises particularly in grooves, ad the dependency upon the thickness does not almost appear in lands.\",\n \"From this fact, the Inventor had the idea that the carriers can be brought into agreement between lands and grooves without the need of changing the duty ratio.\",\n \"The Inventor made further researches on changes of the carrier in grooves.\",\n \"That is, the Inventor calculated how the change of amplitude of the recording layer of GeTe alloy depends upon the thickness of the record-assist layer by the effective Fresnel coefficient method.\",\n \"From the result of the calculation, the Inventor got the knowledge that the amplitude increases as the thickness of the record-assist layer decreases.\",\n \"With reference to the value when the thickness of the record-assist layer was 30 nm, when the thickness was decreased from 20 nm to 10 nm, the increase of the amplitude was approximately 1 dB according to the calculation by the effective Fresnel coefficient method.\",\n \"Through the researches by the Inventor, the above-explained phenomenon can be assumed to occur because grooves are closer to the optical pickup than lands and less affected by track grooves, and therefore become more liable to reflect the amplitude changes in response to changes of the reflectance due to the difference of the thickness.\",\n \"In regard to the carrier changes on the part of the grooves, the amplitude changes of the reflectance by the change of the film structure are considered to be dominant.\",\n \"The present invention has been made based on the above-explained researches.\",\n \"To accomplish the object, the first aspect of the invention is an optical recording medium comprising: a disc substrate having formed a concavo-convex structure formed at least on one surface thereof; and a multi-layered film made by stacking at least a recording layer capable of recording information signals by irradiation of a laser beam and a record-assist layer adjacent to the recording layer on the surface of the disc substrate having the concavo-convex structure, wherein d/4<a<3d is satisfied where d is the thickness of the recording layer and a is the thickness of the auxiliary recording layer.\",\n \"The second aspect of the invention is a method of manufacturing an optical recording medium, which forms a multi-layered film made by stacking at least a recording layer capable of recording information signals by irradiation of a laser beam and a record-assist layer adjacent to the recording layer on the surface of the disc substrate having the concavo-convex structure, comprising: adjusting the thickness of the record-assist layer to satisfy d/4<a<3d where d is the thickness of the recording layer and a is the thickness of the record-assist layer.\",\n \"In the present invention, d/2≦a≦2d is preferably established when the thickness of the recording layer is d and the thickness of the record-assist layer is a.\",\n \"In the present invention, the recording layer is typically configured to record the information signals by reversible changes at least between two different states, and it is preferably made of a phase-changeable material capable of recording the information signals by phase changes between a crystal phase and an amorphous phase.\",\n \"In the present invention, the laser beam used for recording and/or reproducing information signals is typically irradiated to said recording layer from one side of the multi-layered film where the disc substrate exists.\",\n \"In this case, the recording layer is preferably located nearer to the irradiation side of the laser beam.\",\n \"More specifically, the multi-layered film is preferably made of a first dielectric layer, recording layer, record-assist layer, second dielectric layer and first reflection layer that are stacked sequentially from near the surface of the disc substrate having formed the concavo-convex structure.\",\n \"Preferably, a layer of a synthetic resin such as a ultraviolet-setting resin (urethane-family, acrylic family, silicon family, polyester family, and so on) of a hot-melt adhesive agent is additionally formed on the top surface of the multi-layered film on the disc substrate (the surface opposite from the disc substrate) to cover the multi-layered film on the disc substrate for the purpose of protecting and reinforcing the multi-layered film.\",\n \"Typically, the first dielectric layer and the second dielectric layer are made of zinc sulfide/silicon oxide mixture (ZnS—SiO2) having a diffractive index around 2.1 or a silicon nitride (SiN, Si3N4) having a diffractive index around 2.0.However, other materials are also usable.\",\n \"In the resent invention, thickness of the first dielectric layer is adjusted not to exceed 200 nm within the range capable of forming the dielectric layer not to disconnect in form of islands.\",\n \"In the present invention, the second dielectric layer is typically adjusted in thickness in the range not smaller than 1 nm and not smaller than 100 nm.\",\n \"In the present invention, thickness of the first reflection layer is adjusted not to be smaller than 20 nm and not to be larger than 100 nm.\",\n \"The first dielectric layer, recording layer, record-assist layer, second dielectric layer and first reflection layer are typically formed by sputtering, but any other film-making methods are also usable, such as electron beam vapor deposition, vacuum vapor deposition, epitaxial growth, chemical vapor deposition (CVD) and physical vapor deposition (PVD).\",\n \"In the present invention, the laser beam used for recording and/or reproducing information signals is irradiated to the recording layer typically from one side of the disc substrate where the multi-layered film exists.\",\n \"In the present invention, the multi-layered film is preferably made of a second reflection layer, third dielectric layer, said record-assist layer, said recording layer and a fourth dielectric layer that are stacked sequentially from near one surface of the disc substrate having said concavo-convex structure, and a light-transmitting layer permitting the laser beam to pass through is preferably formed to cover the multi-layered film on the disc substrate.\",\n \"Although the third dielectric layer and the fourth dielectric layer are typically made of ZnS—SiO2 having a diffractive inde3x around 2.1, or SiN or Si3N4 having a diffractive index around 2.0, other materials can be used as well.\",\n \"In the present invention, thickness of the third dielectric layer is typically adjusted in the range not thinner than 1 nm and not thicker then 100 nm.\",\n \"In the present invention, thickness of the fourth dielectric layer is adjusted not to exceed 200 nm within the range capable of forming the dielectric layer not to disconnect in form of islands.\",\n \"In the present invention, the second reflection layer is adjusted in thickness typically in the range not thinner than 20 nm and not thicker than 100 nm.\",\n \"Although the second reflection layer, third dielectric layer, record-assist layer, recording layer and fourth dielectric layer are typically formed by sputtering, but any other film-making methods are also usable, such as electron beam vapor deposition, vacuum vapor deposition, epitaxial growth, chemical vapor deposition (CVD) and physical vapor deposition (PVD).\",\n \"The light-transmitting layer formed to cover the multi-layered film on the disc substrate includes at least a light-transmitting sheet permitting light to pass through and an adhesive layer for bonding the light-transmitting sheet to the disc substrate.\",\n \"The adhesive layer is an ultraviolet-setting resin or a pressure sensitive tackiness agent.\",\n \"Instead of using the light-transmitting sheet, an ultraviolet-setting resin is usable to form the light-transmitting layer.\",\n \"An example of optical discs configured for irradiation of a laser beam to the disc substrate from one side thereof having the multi-layered film is DVR (digital video recording system) having a thin light-transmitting layer.\",\n \"This invention is applicable to optical discs such as DVR, including so-called DVR-red configured to record or reproduce information signals by using a semiconductor laser having an emission wavelength around 650 nm and so-called DVR-blue configured to record or reproduce information signals by using a semiconductor laser having an emission wavelength around 400 nm.\",\n \"Such DVR is configured to record signals by using an objective lens that is typically enhanced in NA (Numerical Aperture) to around 0.85 by combining two lenses in series.\",\n \"More specifically, it has the storage capacity around 22 GB per single plane.\",\n \"Optical discs including DVR are preferably housed in cartridges, but application of the invention is not limited to cartridge-type optical discs.\",\n \"In the present invention, if the multi-layered film formed on the disc substrate is covered with a thin light-transmitting layer, the light-transmitting layer is typically made of a non-magnetic material through which the laser beam from a GaN-family semiconductor laser (having an emission wavelength around 400 nm for blue emission), ZnSe-family semiconductor laser (having an emission wavelength around 500 nm for green emission) or AlGaInP-family semiconductor laser (having an emission wavelength around 635 to 680 nm for red emission) used at least for recording and reproducing information signals can pass.\",\n \"More specifically, it is made of a light-transmitting thermoplastic resin such as polycarbonate.\",\n \"In the present invention, in the portion of the disc substrate having the concavo-convex structure, width Dg of a level difference of concavo-convex in a portion nearer to the injection side of the laser beam and width Dl of a level difference of concavo-convex in a portion remoter from the injection side of the laser beam satisfy the ratio of 0.5≦Dl/Dg≦2.0, or more preferably the ratio of 0.8≦Dl/Dg≦1.2.In the present invention, numerical aperture of the objective lens used for recording and/or reproducing information signals is typically in the range not smaller than 0.45 and not larger than 0.60.In this range of the numerical aperture, the laser beam is irradiated from one side of the optical recording medium where the disc substrate exists.\",\n \"To obtain good signals, maintain the optical contrast in a good condition and prevent thermal diffusion while preventing the recording layer from becoming discontinuous islands, thickness of the recording layer is typically adjusted in the range not thinner than 5 nm and not thicker than 50 nm, or more preferably, in the range not thinner than 10 nm and not thicker than 40 nm.\",\n \"In the present invention, thickness of the record-assist layer is limited not to be thinner than 3 nm and not to be thicker than 100 nm, or more preferably in the range not thinner than 5 nm and not thicker than 60 nm.\",\n \"In the present invention, the recording layer is typically configured to record information signals in a write only mode.\",\n \"In this case, the recording layer is preferably made of a GeTe-family alloy or a GeSbTe-family alloy.\",\n \"However, other materials are also usable for the recording layer, such as Ge—Te, Te—Sb, Te—Ge—Sb, Te—Ge—Sb—Pd, Te—Ge—Sb—Cr, Te—Ge—Sb—Bi, Te—Ge—Sn—O, Te—Ge—Sb—Se, Te—Ge—Sn—Au, In—Sb—Te, In—Sb—Se, Te—Ge—Sb—Sn, In—Sb—Te—Ag, In—Se and Te—Bi.\",\n \"In the present invention, the optical recording medium is typically configured to record record marks with the laser beam in both the top portions of the ridges and the bottom portions of the furrows of the concavo-convex structure of the disc substrate.\",\n \"That is, the optical recording medium according to the invention employs the land/groove recording technique.\",\n \"In the present invention, in case the recording layer is made of a phase-changeable material for the purpose of improving the stability of record marks against reproduced light and simultaneously ensuring a good jitter property in high-density recording by mark-edge recording, the phase-changeable recording layer is typically made of a Te—Ge—Sb family alloy (which may contain other elements in addition to Te, Ge and Sb).\",\n \"Its composition is in the range encircled by four points in the triangular graph of FIG.\",\n \"6, which shows the composition of three components Te, Ge and Sb in coordinates (Te, Ge, Sb), namely, A(0.475, 0.05, 0.475), B(0.665, 0.05, 0.285), C(0.60, 0.40, 0) and D(0.40, 0.60, 0) (composition of the point A is Te47.5Ge5Sb47.5, composition of the point B is Te66.5Ge5Sb28.5, composition of the point C is Te60Ge40, and composition of the point D is Te40Ge60).\",\n \"More preferably, the record-assist layer containing as its major component at least one compound selected from the group consisting of SiN, SiC, GeN, PbSe, PbTe, SnSe, SnTe, Bi2Te3 and Sb2Te3 is preferably formed immediately above and under the phase-changeable recording layer.\",\n \"If the composition of the phase-changeable recording layer is outside the straight line connecting the point A and the point B on the triangular graph of FIG.\",\n \"6 (where the content of Ge is less than 5 atomic %), then the crystallization temperature decreases, and portions without record marks (pre-recorded portions) become liable to be crystallized by reproduction reproduced light.\",\n \"As a result, boundaries between record marks and pre-recorded portions become ambiguous, and the record marks may deteriorate.\",\n \"Further, if the composition of the phase-changeable recording layer is outside the straight line connecting the point B and the point C and outside the straight line connecting the point D and the point A, then the jitter property deteriorates.\",\n \"If the phase-changeable recording layer is inside the range surrounded by the points A, B, C and D but close to the straight line connecting the point A and the point B (where the content of Ge is 5 atomic % or more, but relatively small), then the difference in optical constant between the amorphous state and the crystal state becomes small.\",\n \"This is not desirable from the viewpoint of the signal quality because the amplitude of the reproduction signal decreases.\",\n \"In the present invention, more preferable composition range of the phase-changeable recording layer is the range where the coordinates (Te, Ge, Sb) are E(0.47, 0.30, 0.23), F(0.58, 0.30, 0.12), G(0.56, 0.44, 0) and H(0.44, 0.56, 0) on the triangular graph of FIG.\",\n \"7 similar to FIG.\",\n \"6.Composition of the point E is Te47Ge30Sb23, composition of the point F is Te58Ge30Sb12, composition of the point G is Te56Ge44, and composition of the point H is Te44Ge56.In the present invention, more preferable composition range of the phase-changeable recording layer is the range where the coordinates (Te, Ge, Sb) are J(0.47, 0.40, 0.13), K(0.55, 0.40, 0.05), L(0.52, 0.48, 0) and M(0.44, 0.56, 0) on the triangular graph of FIG.\",\n \"8 similar to FIG.\",\n \"6.Composition of the point J is Te47Ge40Sb13, composition of the point K is Te55Ge40Sb5, composition of the point L is Te52Ge48, and composition of the point M is Te44Ge56.In the present invention, the record-assist layer is preferably made of a material containing as its major component at least one compound selected from the group consisting of SnTe, SiN, SiC, SnSe, GeN, PbSe, PbTe, Bi2Te3 and Sb2Te3.The record-assist layer may be in a mixed crystal state mixing any one of those compounds as well.\",\n \"From the viewpoint of the storage lifetime of the optical recording medium, SnTe is preferably selected from those compounds as the major component of the record-assist layer.\",\n \"In the present invention, the record-assist layer contains one of above-specified compounds and may additionally contain other appropriate material.\",\n \"In this case, the content of any of the above-specified compounds is adjusted to be 50 volume % or more.\",\n \"If the content of the specific compound is less than 50 volume %, the phase-changeable recording layer may fail to crystallize well and may deteriorate the jitter property of the reproduced light.\",\n \"The content of the specific compound in the record-assist layer is more preferably 70 volume % or more.\",\n \"More specifically, usable materials of the record-assist layer are thorium phosphide (ThP), lanthanum sulfide (LaS), scandium antimony (ScSb), thorium selenium (ThSe), calcium selenium (CaSe), lead sulfide (PbS), scandium bismuth (ScBi), thorium arsenide (ThAs), BiSe, indium arsenide (InAs), yttrium tellurium (YTe), gallium antimony (GaSb), PbSe, tin antimony (SnSb), aluminum antimony (AlSb), copper iodide (CuI), strontium selenium (SrSe), SnTe, thorium antimony (ThSb), CaTe, barium sulfide (BaS), LaTe, PbTe, BiTe, SrTe, silver ionide (AgI), Sb2Te3, Bi2Se3, Bi2Te3 and so forth.\",\n \"However, other materials are also usable where appropriate.\",\n \"In the present invention, in case the multi-layered film on the disc substrate does not include the reflection layer and has the record-assist layer on one surface of the recording layer opposite from the disc substrate, a protective layer is preferably formed on one surface of the record-assist layer opposite from the surface in contact with the recording layer.\",\n \"The protective layer is made of at least one material selected from metal or semi-metal oxides, carbides, nitrides, fluorides and sulfides.\",\n \"More specifically, usable materials of the protective layer are oxides such as silicon oxides (SiO2, SiO), tantalum oxide (Ta2O5) and zirconium oxide (ZrO2), carbides such as silicon carbide (SiC) and titanium carbide (TiC) or simplex carbon (C), nitrides such as silicon nitride (Si3N4) aluminum nitride (AlN), sulfides such as zinc sulfide (ZnS), samarium sulfide (SmS) and strontium sulfide (SrS), and fluorides such as magnesium fluoride (MgF2).\",\n \"Further, a mixture containing at least one or more kinds of those materials is preferably used as the material of the protective layer.\",\n \"In the present invention, to ensure accurate control of the length of the record mark by mark-edge recording, the first reflection layer of the second reflection layer for reflecting light after passing the recording layer is preferably made of a material having thermal conductivity not lower than 50 W/m·K.\",\n \"Examples of materials having thermal conductivity not lower than 50 W/m·K are metals selected from the group consisting of Al, Cr, Ni, Au, hafnium (Hf), palladium (Pd), tantalum (Ta), cobalt (Co), Mo, W, Cu and Ti, or alloys of those metals.\",\n \"Among these materials, desirable materials for forming the reflection layer from various viewpoints are Al—Ti alloys, Al—Cr alloys, Al—Ta alloys, Al—Pd alloys, Al—Cu alloys, Ti—Al alloys, Ti—V alloys, Ti—Pd—Cu alloys, Ag alloys, and so on.\",\n \"Composition of these alloys is determined in accordance with the required property.\",\n \"Other materials are also usable if necessary.\",\n \"According to the invention having the above-summarized configuration, since the thickness a of the record-assist layer is controlled to be larger than ¼ of the thickness d of the recording layer and smaller than three times of the thickness d, signal property can be changed by not only by changing the size of the concavo-convex but also by modifying the thickness of the record-assist layer.\",\n \"Therefore, design freedom necessary for improvement of the signal property can be increased.\",\n \"BRIEF DESCRIPTION OF DRAWINGS FIG.\",\n \"1 is a cross-sectional view that shows an optical disc according to the first embodiment of the invention FIG.\",\n \"2 is a graph that shows dependency or a carrier upon the thickness of a record-assist layer in the optical disc according to the first embodiment of the invention; FIG.\",\n \"3 is a graph that shows dependency of the signal amplitude upon the thickness of the record-assist layer in the optical disc according to the first embodiment of the invention; FIG.\",\n \"4 is a graph that shows dependency of a cross talk signal upon the thickness of the record-assist layer in the optical disc according to the first embodiment of the invention; FIG.\",\n \"5 is a cross-sectional view that shows an optical disc according to the second embodiment of the invention; FIG.\",\n \"6 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention; FIG.\",\n \"7 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention; and FIG.\",\n \"8 is a triangular graph that shows suitable composition of a phase-changed recording layer in an optical recording medium according to the invention.\",\n \"BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the invention will now be explained below with reference to the drawings.\",\n \"First explained is an optical disc according to the first embodiment of the invention.\",\n \"FIG.\",\n \"1 shows the optical disc according to the first embodiment.\",\n \"The optical disc according to the first embodiment is a WO (write once) type on which information signals are recorded in a WO mode.\",\n \"As shown in FIG.\",\n \"1, the optical disc 1 according to the first embodiment includes a multi-layered film made of a first dielectric layer 3, recording layer 4, record-assist layer 5, second dielectric layer 6 and first reflection layer 7 that are stacked on one major surface 2a of a disc substrate 2, and an ultraviolet-curing resin layer 8 formed to cover the multi-layered film.\",\n \"The disc substrate 2 is made of a material that can transmit at least a laser beam used for recording and reproducing information signals.\",\n \"Examples of materials usable for forming the disc substrate 2 are plastic materials such as polycarbonate-family resins, polyolefin resin and acrylic-family resins, and glass.\",\n \"Among these materials, plastic materials are preferable from the economical viewpoint.\",\n \"In the first embodiment, the disc substrate 2 is made of, for example, polycarbonate (PC).\",\n \"The disc substrate 2 is sized 130 mm in diameter and approximately 1.2 mm in thickness, for example.\",\n \"The major surface 2a of the disc substrate 2 has formed a track-like concavo-convex structure.\",\n \"Ridges of the track-like concavo-convex structure are portions remoter from the laser beam injection side.\",\n \"In the first embodiment, the ridges are called lands 2b.\",\n \"The furrows are portions closer to the laser beam injection side.\",\n \"In the first embodiment, the furrows are called grooves 2c.\",\n \"Ratio between the width Dl of each land 2b and the width Dg of each groove 2, i.e.\",\n \"the duty ratio (Dl/Dg), is selected from the range of 0.5 to 2.0.If the duty ratio is smaller than 0.5, then the width Dl of the land 2b is less than one half of the width Dg of the groove 2c, and it is difficult to control both the lands 2b and the grooves 2c to have a common signal property.\",\n \"If the duty ratio is larger than 2.0, then the width Dg of the groove 2c is similarly narrowed to less than one half of the width Dl of the land 2b, and it is again difficult to control both the lands 2b and the grooves 2c to have a common signal property.\",\n \"More preferable range of the duty ratio is 0.8 to 1.2.In an example of configurations and sizes of the disc substrate 2 according to the first embodiment, the track pitch (Tp) of the groove tracks is 0.77 μm, depth of the grooves 2c (depth of the furrows) is 70 nm, width Dl of the lands 2b is 0.82 μm, width Dg of the grooves 2c is 0.72 μm, and the duty ratio is (0.82/0.72=) 1.14.The first dielectric layer 3 is preferably made of a material exhibiting a low absorption power (absorptivity) to recording/reproducing laser beams, and more specifically, an extinction coefficient k not larger than 0.3.Taking the resistance to heat into consideration as well, SiN is one of preferable materials.\",\n \"Thickness of the first dielectric layer 3 is adjusted not to exceed 200 nm.\",\n \"In the first embodiment, it may be 10 nm thick, for example.\",\n \"The recording layer 4 is made of GeTe alloy, for example.\",\n \"If the thickness d of the recording layer 4 is smaller than 5 nm, the amplitude is optically too small.\",\n \"If the thickness d is larger than 50 nm, then the recording layer degrades in heat diffusion effect, therefore becomes liable to hold heat therein, and will become incapable of recording record marks clearly.\",\n \"Therefore, thickness d of the recording layer 4 is adjusted in the range of 5 nm≦d≦50 nm.\",\n \"According to the knowledge of the Inventor obtained by an experiment of the signal property in the recording layer 4, thickness d of the recording layer is preferably adjusted in the range of 10 nm≦d≦40 nm, taking account of the range capable of obtaining good signals.\",\n \"In the first embodiment, thickness of the recording layer 4 is around 20 nm, for example.\",\n \"Material of the record-assist layer 5 contains as its major component at least one compound selected from the group consisting of SnTe, SiN, SiC, GeN, PbTe, SnSe, PbSe, Bi2Te3 and Sb2Te3.More specifically, it is a material containing any of the above-specified compounds by at least 50 volume %, or more preferably, by at least 70 volume %.\",\n \"The record-assist layer 5 is preferably in uniform contact with the recording layer 4.In the first embodiment, the record-assist layer 5 is made of SnTe, for example.\",\n \"Thickness a of the record-assist layer 5 is adjusted in the range larger than ¼ of the thickness d of the recording layer 4 and smaller than three times thereof.\",\n \"That is, record-assist layer 5 is formed to satisfy the following relation between its thickness a and the thickness d of the recording layer 4, d/4<a<3d or more preferably to satisfy d/2≦a≦2d Details of the thickness of the record-assist layer 5 will be explained later.\",\n \"The second dielectric layer 6 is preferably made of a material exhibiting a low absorption power to recording/reproducing laser beams, and more specifically, an extinction coefficient k not larger than 0.3.Taking the resistance to heat into consideration as well, ZnS—SiO2 (especially one having a mol ratio around 4:1) is one of preferable materials.\",\n \"In the first embodiment, the first dielectric layer 3 and the second dielectric layer 6 are made of different materials.\",\n \"However, they may be made of a common material.\",\n \"The first reflection layer 7 is made of Al alloy, for example.\",\n \"In the first embodiment, it is made of AlTi alloy.\",\n \"If the first reflection layer 7 is thinner than 20 nm, heat generated in the recording layer 4 cannot diffuse sufficiently, and heat is not sufficiently cooled down.\",\n \"If the reflection layer 7 is thicker than 100 nm, then its thermal property and optical property will be adversely affected, and a desired signal property will not be obtained.\",\n \"Therefore, thickness of the first reflection layer 7 is adjusted in the range from 20 to 100 nm.\",\n \"In the first embodiment, it is 60 nm thick, for example.\",\n \"The ultraviolet-setting resin layer 8 is made of an ultraviolet-setting resin that is cured by irradiation of ultraviolet rays.\",\n \"In the optical disc according to the first embodiment, having the above-explained configuration, a laser beam L1 is injected toward the multi-layered film including the sequentially stacked first dielectric layer 3, recording layer 4, record-assist layer 5, second dielectric layer 6 and first reflection layer 7 from one side thereof where the disc substrate 2 exists as shown in FIG.\",\n \"1, and when it irradiates the recording layer 4, an information signal is recorded and/or reproduced.\",\n \"Next explained is a manufacturing method of the optical disc 1 according to the first embodiment having the above-explained configuration.\",\n \"First prepared is a clean disk substrate 2 having guide grooves (concavo-convex groove tracks) (for example, thickness: 1.2 mm, track pitch: 0.77 μm, width of lands: 0.82 μm, width of grooves: 0.72 μm, depth of grooves: 70 nm).\",\n \"Subsequently, the disc substrate 2 is transported into a first sputtering chamber in which a Si target is set, and it is placed on a predetermined position.\",\n \"After that, a film of SiN, for example, is formed on the major surface 2a of the disc substrate 2 by sputtering using nitrogen (N2) gas as the reactive gas.\",\n \"As a result, the first dielectric layer 3 of SiN is deposited on the major surface 2a of the disc substrate 2.An example of the sputtering conditions is using an inactive gas such as argon (Ar) gas and a reactive gas such as N2 gas as the atmospheric gas, adjusting their flow rates to be Ar:N2=3:1, maintaining the pressure of the atmospheric gas in 0.6 Pa, and supplying the sputtering power of 2.5 kW.\",\n \"After that, the disc substrate 2 having formed the first dielectric layer 3 is removed from the first sputtering chamber.\",\n \"The disc substrate 2 is next introduced into a second sputtering chamber and placed on a predetermined position.\",\n \"Thereafter, a film of GeTe, for example, is formed on the first dielectric layer 3 by sputtering.\",\n \"As a result, the recording layer 4 of GeTe alloy is obtained.\",\n \"An example of the puttering conditions used here is using an inactive gas such as Ar gas as the atmospheric gas, and adjusting the sputtering power to 0.3 kW and the pressure of the atmospheric gas to 0.4 Pa (3.0 mTorr).\",\n \"Under these conditions, the recording layer 4 is formed by using a GeTe alloy target adjusted in composition such that the composition of the layer obtained becomes Ge50Te50, for example.\",\n \"After that, the disc substrate 2 having formed the recording layer 4 as well is removed from the second sputtering chamber.\",\n \"The disc substrate 2 having formed layers up to the recording layer 4 is next introduced into a third sputtering chamber and placed on a predetermined position.\",\n \"After that, a SnTe alloy film is formed on the recording layer 4 by sputtering using a SnTe alloy target.\",\n \"As a result, the record-assist layer 5 of SnTe alloy is formed evenly on the recording layer 4.An example of the sputtering conditions used here is using an inactive gas such as Ar gas as the atmospheric gas, adjusting the sputtering power to 0.3 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).\",\n \"Thereafter, the disc substrate 2 having formed layers up to the record-assist layer 5 is removed from the third sputtering chamber.\",\n \"The disc substrate having formed layers up to the record-assist layer is next introduced into a fourth sputtering chamber and placed on a predetermined position.\",\n \"Thereafter, a ZnS—SiO2 film is formed on the record-assist layer 5 by sputtering using a ZnS—SiO2 target.\",\n \"As a result, the second dielectric layer 6 of ZnS—SiO2 is deposited on the record-assist layer 5.An example of the sputtering conditions used here is using an inactive gas like Ar gas as the atmospheric gas and adjusting the sputtering power to 0.6 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).\",\n \"Thereafter, the disc substrate 2 having formed layers up to the second dielectric layer 6 is removed from the fourth sputtering chamber.\",\n \"The disc substrate 2 having formed layers up to the second dielectric layer 6 is next introduced into a fifth sputtering chamber and placed on a predetermined position.\",\n \"Thereafter, an AlTi film is formed on the second dielectric layer 6 by sputtering using a target of AlTi alloy.\",\n \"As a result, the first reflection layer 7 of AlTi alloy is deposited on the second dielectric layer 6.An example of the sputtering conditions used here is using an inactive gas like Ar gas as the atmospheric gas and adjusting the sputtering power to 2.5 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).\",\n \"Thereafter, the disc substrate 2 having formed layers up to the first reflection layer 7 is removed from the fifth sputtering chamber.\",\n \"After that, the ultraviolet-setting resin layer 8 is formed on the top surface of the first reflection layer 7 by spin coating or roll coating.\",\n \"Through those steps, the WO type optical disc 1 according to the first embodiment, using GeTe, which is a phase-changeable material, as the recording layer 4 is completed.\",\n \"As the optical disc 1 according to the first embodiment, which can be manufactured as explained above, the Inventor prepared optical discs 1 that are changed in thickness a of the record-assist layer 5 in the range of d/4≦a≦3d, namely as a=d/4, a=d/2, a=d, a=2d and a=3d, and measured their recording and reproducing characteristics by an evaluator.\",\n \"That is, by evaluating recording/reproducing characteristics of find kinds of optical discs 1, the Inventor evaluated dependency of the carrier upon the thickness of the record-assist layer 5.The evaluator used for evaluation of those optical discs was adjusted to use laser beams having the wavelength of 660 nm and adjusted in numerical aperture of the objective lens to 0.575.A result of this evaluation is shown in FIG.\",\n \"2.In the graph of FIG.\",\n \"2, the abscissa indicates the thickness of the record-assist layer 5 and the ordinate indicates the carrier.\",\n \"Evaluated values of lands are shown by ♦ and evaluated values of grooves by ▪.\",\n \"The Inventor further carried out optical calculation about dependency of the laser beam amplitude upon the thickness of the record-assist layer 5.A result of the calculation is shown in FIG.\",\n \"3.It is appreciated from FIG.\",\n \"2 that, in grooves, the carrier gradually increases as the thickness a of the record-assist layer 5 decreases within the range from d/4 to 3d.\",\n \"In contrast, in lands, the carrier changes less even when the thickness a of the record-assist layer 5 decreases within the range from d/4 to 3d.\",\n \"That is, it is understood that the dependency upon the thickness of the record-assist layer 5 in changes of the carrier appears more clearly in grooves.\",\n \"This means that, by intentionally changing the thickness of the record-assist layer 5, the signal characteristics in grooves can be changed while the signal characteristics in lands are maintained substantially constant.\",\n \"It is also appreciated from FIG.\",\n \"3 that the amplitude rapidly decreases as the thickness a of the record-assist layer 5 is once decreased and thereafter decreased to ¼ of the thickness d of the recording layer 4.This demonstrates that the control of the thickness of the record-assist layer 5 carried out for the purpose of assuring predetermined amplitude becomes very difficult.\",\n \"On the other hand, in case the thickness a of the record-assist layer 5 is larger than ¼ of the thickness of the recording layer 4, changes of the amplitude are very moderate, and it will be easy to control the thickness of the record-assist layer 5.From this point of view, the thickness a of the record-assist layer 5 is preferably larger than ¼ of the thickness d of the recording layer 4.It is further appreciated from FIG.\",\n \"2 that, when the thickness a of the record-assist layer 5 is decreased to d/4, both the value of the carrier in lands and the value of the carrier in grooves decreases.\",\n \"Therefore, if the thickness a of the record-assist layer 5 is ¼ or less of the thickness d of the recording layer 4 (a≦d/4), both the signal property of lands and the signal property of grooves deteriorate.\",\n \"That is, the thickness a of the record-assist layer 5 must be larger than ¼ of the thickness d of the recording layer 4 (d/4<a), and it is preferably adjusted to ½ or more of the thickness d of the recording layer 4 (d/2≦a).\",\n \"Further, according to the knowledge of the Inventor obtained by the experiment, the record-assist layer 5 can be formed not to disconnect in form of islands on the recording layer 4 by adjusting the thickness a of the record-assist layer 5 to be larger than ¼ of the thickness d of the recording layer 4 (d/4<a).\",\n \"Accordingly, it is possible to form the record-assist layer 5 evenly.\",\n \"It is further appreciated from FIG.\",\n \"3 that, as the thickness a of the record-assist layer 5 is larger, the amplitude gradually decreases.\",\n \"Therefore, the thickness a of the record-assist layer 5 is preferably adjusted not to exceed three times of the thickness d of the recording layer 4.It is further appreciated from FIG.\",\n \"2 that, when the thickness a of the record-assist layer 5 is increased to or beyond three times of the thickness d of the recording layer (3d≦a), both the value of the carrier in lands and the value of the carrier in grooves significantly decreases.\",\n \"Therefore, if the thickness a of the record-assist layer 5 is three times or more of the thickness d of the recording layer (3d≦a), then both the signal property of lands and the signal property of grooves deteriorate and substantially result in the result of calculation shown in FIG.\",\n \"3.That is, thickness a of the record-assist layer 5 must be limited below three times of the thickness d of the recording layer 4 (a<3d), and it is preferably adjusted not to exceed two times of the thickness d of the recording layer 4 (a≦2d).\",\n \"For the purpose of investigating dependency of optical cross talk upon the thickness of the record-assist layer, the Inventor measured signal quantities of cross talk from lands to grooves and signal quantities of cross talk from grooves to lands upon recording 2T marks.\",\n \"FIG.\",\n \"4 shows the dependency of the cross talk signal quantity upon the dependency of the thickness of the record-assist layer 5.In FIG.\",\n \"4, the ordinate shows cross talk in relative decibel for enabling comparison with the value of the carrier, and indicates cross talk from grooves to lands by ♦ and cross talk from lands to grooves by ▪.\",\n \"It is appreciated from FIG.\",\n \"4 that, as the thickness a of the record-assist layer 5 decreases from 3d to d/2, cross talk leaking from grooves to lands decreases even though the signal quantity in grooves increases (see FIG.\",\n \"2).\",\n \"On the other hand, cross talk leaking from lands to grooves increases only a little as the thickness a of the record-assist layer 5 decreases from 3d to d/2, and no remarkable increase is observed.\",\n \"That is, even when the thickness of the record-assist layer 5 is changed, it is apparent that the carrier can be controlled in lands and grooves while suppressing the increase of the cross talk.\",\n \"As explained heretofore, the optical disc according to the first embodiment, which has the multi-layered film including the first dielectric layer 3, recording layer 4, record-assist layer 5, second dielectric layer 6 and reflection layer 7 deposited on one major surface of the disc substrate 2 and employs the land/groove recording technique, can increase the signal amplitude especially in grooves 2c by adjustment of the thickness a of the record-assist layer to be larger than ¼ of the thickness d of the recording layer 4 and smaller than three times thereof, and can simultaneously keep both the signal property in lands 2b and the signal property in grooves 2c in a good condition by controlling the thickness of the record-assist layer 5 after optimizing the signal property in lands 2b.\",\n \"Furthermore, since the signal amplitude in grooves 2c can be changed by while the signal amplitude in lands 2b is maintained constant, by intentional control of the thickness of the record-assist layer 5, both the signal amplitude in lands 2b and the signal amplitude in grooves 2c can be changed independently from each other.\",\n \"This increases the design freedom and enables optimization of lands 2b and grooves 2c while maintaining the optimum deposition condition of the recording layer 4.Therefore, information signals can be reproduced from optical discs in a good condition of the signal property.\",\n \"Thus a highly reliable optical disc can be obtained.\",\n \"Next explained is an optical disc according to the second embodiment of the invention.\",\n \"FIG.\",\n \"5 shows the optical disc according to the second embodiment of the invention.\",\n \"The optical disc according to the second embodiment is a programmable optical disc permitting rewriting of information signals.\",\n \"As shown in FIG.\",\n \"5, the optical disc 11 according to the second embodiment includes a multi-layered film made of a second reflection layer 13, third dielectric layer 14, record-assist layer 15, recording layer 16 and fourth dielectric layer 17 sequentially stacked on one major surface 12a of a disc substrate 12, and a light-transmitting layer 18 formed to cover the multi-layered film.\",\n \"The disc substrate 12 is made of a low water-absorbing material such as polycarbonate (PC) or cycloolefin polymer (such as Zeonex (registered trademark)).\",\n \"Thickness of the disc substrate 12 is, for example, in the range from 0.6 to 1.2 mm.\",\n \"In the second embodiment, it is 1.1 mm thick, for example.\",\n \"Diameter of the disc substrate 12 is 120 mm for example.\",\n \"The optical disc according to the second embodiment is configured to record/reproduce information signals when a laser beam is irradiated to he disc substrate 12 from one side thereof where the thin light-transmitting layer 18 exists.\",\n \"Therefore, the disc substrate 12 can be selected without taking it into consideration whether the material is permeable or not, and a substrate of a metal such as Al is also usable.\",\n \"Alternatively, a glass substrate or a resin substrate of polyolefin, polyimide, polyamide, polyphenylene sulfide or polyethylene terephthalate is also usable as the disc substrate 12.The major surface 12a of the disc substrate 12 has formed a track-like concavo-convex structure.\",\n \"Furrows of the track-like concavo-convex structure are portions remoter from the laser beam injection side.\",\n \"In the second embodiment, the furrows are called lands 2b.\",\n \"The ridges are portions closer to the laser beam injection side.\",\n \"In the second embodiment, the ridges are called grooves 12c.\",\n \"From the same reasons as those of the first embodiment, ratio between the width Dl of each land 2b and the width Dg of each groove 2, i.e.\",\n \"the duty ratio (Dl/Dg), is selected from the range of 0.5 to 2.0, or more preferably from the range of 0.8 to 1.2.In an example of configurations and sizes of the disc substrate 12 according to the second embodiment, the track pitch (Tp) of the groove tracks is 0.77 μm, depth of the grooves (depth of the furrows) is 70 nm, width Dl of the lands 12b is 0.82 μm, width Dg of the grooves 12c is 0.72 μm, and the duty ratio is (0.82/0.72=) 1.14.The second reflection layer 13 is made of Al alloy, for example.\",\n \"In the second embodiment, it is made of AlTi alloy.\",\n \"From the same reasons as those of the first embodiment, thickness of the second reflection layer 13 is adjusted in the range from 20 to 100 nm.\",\n \"For example, it may be 60 nm thick.\",\n \"The third dielectric layer 14 is preferably made of a material exhibiting a low absorption power to recording/reproducing laser beams, and more specifically, an extinction coefficient k not larger than 0.3.Taking the resistance to heat into consideration as well, ZnS—SiO2 (especially one having a mol ratio around 4:1) is one of preferable materials.\",\n \"Material of the record-assist layer 15 contains as its major component at least one compound selected from the group consisting of SnTe, SiN, SiC, GeN, PbTe, SnSe, PbSe, Bi2Te3 and Sb2Te3.More specifically, it is a material containing any of the above-specified compounds by at least 50 volume %, or more preferably, by at least 70 volume %.\",\n \"The record-assist layer 15 is preferably in uniform contact with the recording layer 16.In the second embodiment, the record-assist layer 15 is made of SnTe, for example.\",\n \"From the same reasons as those of the first embodiment, thickness a of the record-assist layer 15 is adjusted in the range larger than ¼ of the thickness d of the recording layer 16, explained later, and smaller than three times of same.\",\n \"That is, record-assist layer 15 is formed to satisfy the following relation between its thickness a and the thickness d of the recording layer 16, d/4<a<3d or more preferably to satisfy d/2≦a≦2d from the viewpoint of improving the signal property.\",\n \"The recording layer 16 is made of GeTe alloy, for example.\",\n \"From the same reasons as those of the first embodiment, thickness d of the recording layer 4 is adjusted in the range of 5 nm≦d≦50 nm.\",\n \"According to the knowledge of the Inventor obtained by an experiment of the signal property in the recording layer 16, thickness d of the recording layer is preferably adjusted in the range of 10 nm≦d≦40 nm, taking account of the range capable of obtaining good signals.\",\n \"In the first embodiment, thickness of the recording layer 16 is around 20 nm, for example.\",\n \"The fourth dielectric layer 17 is preferably made of a material exhibiting a low absorption power (absorptivity) to recording/reproducing laser beams, and more specifically, an extinction coefficient k not larger than 0.3.Taking the resistance to heat into consideration as well, SiN is one of preferable materials.\",\n \"Thickness of the fourth dielectric layer 17 is adjusted not to exceed 200 nm.\",\n \"In the second embodiment, it may be 10 nm thick, for example.\",\n \"In the second embodiment, the third dielectric layer 14 and the fourth dielectric layer 17 are made of different materials.\",\n \"However, they may be made of a common material.\",\n \"In the optical disc according to the second embodiment, having the above-explained configuration, a laser beam L2 is injected toward the disc substrate 12 from one side thereof where the multi-layered film exists as shown in FIG.\",\n \"5, and when it irradiates the recording layer 16 above the lands 12b and above the grooves 12c, information signals are recorded and/or reproduced.\",\n \"Next explained is a manufacturing method of the optical disc 11 according to the second embodiment having the above-explained configuration.\",\n \"First prepared is a clean disk substrate 12 having guide grooves (concavo-convex groove tracks) (for example, thickness: 1.1 mm, track pitch: 0.77 μm, width of lands: 0.82 μm, width of grooves: 0.72 μm, depth of grooves: 70 nm).\",\n \"Subsequently, the disc substrate 12 having formed the concavo-convex groove tracks is transported into a first sputtering chamber, and placed in a predetermined position.\",\n \"Thereafter, an AlTi film is formed at least on groove tracks with ridges and grooves by sputtering using a target of AlTi alloy.\",\n \"As a result, the second reflection layer 13 of AlTi alloy is deposited on the disc substrate 12.An example of the sputtering conditions used here is using an inactive gas like Ar gas as the atmospheric gas and adjusting the sputtering power to 2.5 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).\",\n \"Thereafter, the disc substrate 12 having formed the second reflection layer 13 is removed from the first sputtering chamber.\",\n \"The disc substrate having formed the second reflection layer 13 is next introduced into a second sputtering chamber and placed on a predetermined position.\",\n \"Thereafter, a ZnS—SiO2 film is formed on the second reflection layer 13 by sputtering using a ZnS—SiO2 target.\",\n \"As a result, the third dielectric layer 14 of ZnS—SiO2 is deposited on the second reflection layer 13.An example of the sputtering conditions used here is using an inactive gas like Ar gas as the atmospheric gas and adjusting the sputtering power to 0.6 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).\",\n \"Thereafter, the disc substrate 12 having formed layers up to the third dielectric layer 14 is removed from the second sputtering chamber.\",\n \"The disc substrate 12 having formed layers up to the third dielectric layer 14 is next introduced into a third sputtering chamber and placed on a predetermined position.\",\n \"After that, a SnTe alloy film is deposited on the third dielectric layer 14 by sputtering using a SnTe alloy target.\",\n \"As a result, the record-assist layer 15 of SnTe alloy is formed evenly on the third dielectric layer 14.An example of the sputtering conditions used here is using an inactive gas such as Ar gas as the atmospheric gas, adjusting the sputtering power to 0.3 kW and the pressure of the atmospheric gas to 1.3×10−1 Pa (1.0 mTorr).\",\n \"Thereafter, the disc substrate 12 having formed layers up to the record-assist layer 15 is removed from the third sputtering chamber.\",\n \"The disc substrate 12 having formed layers up to the record-assist layer 15 is next introduced into a fourth sputtering chamber and placed on a predetermined position.\",\n \"Thereafter, a film of GeSbTe, for example, is formed on the record-assist layer 15 by sputtering.\",\n \"As a result, the recording layer 16 of GeSbTe alloy is obtained.\",\n \"An example of the sputtering conditions used here is using an inactive gas such as Ar gas as the atmospheric gas, adjusting the sputtering power to 0.3 kW and the pressure of the atmospheric gas to 0.4 Pa (3.0 mTorr).\",\n \"Thereafter, the disc substrate 12 having formed layers up to the recording layer 16 is removed from the fourth sputtering chamber.\",\n \"The disc substrate 12 is next introduced into a fifth sputtering chamber and placed on a predetermined position.\",\n \"After that, a film of SiN, for example, is formed on the second reflection layer 13 by sputtering using nitrogen (N2) gas as the reactive gas.\",\n \"As a result, the third dielectric layer 14 of SiN is deposited on the second reflection layer 13.An example of the sputtering conditions is using an inactive gas such as argon (Ar) gas and a reactive gas such as N2 gas as the atmospheric gas, adjusting their flow rates to be Ar:N2=3:1, maintaining its pressure in 0.6 Pa, and supplying the sputtering power of 2.5 kW.\",\n \"After that, the disc substrate 12 having formed the fourth dielectric layer 17 is removed from the fifth sputtering chamber.\",\n \"Thereafter, a light-transmitting sheet 18b is bonded via a bonding layer 18a to the multi-layered film made of the second reflection layer 13, third dielectric layer 14, record-assist layer 15, recording layer 16 and fourth dielectric layer 17 by using a predetermined bonding machine (not shown).\",\n \"As a result, the light-transmitting layer 18 is formed.\",\n \"Through those steps, the optical disc 11 according to the second embodiment is completed.\",\n \"With the optical disc 11 according to the second embodiment, the same effects as those of the first embodiment can be obtained by limiting the thickness a of the record-assist layer 15 within the range of d/4<a<3d relative to the thickness d of the recording layer 16, and it has been confirmed that the same effects as those of the optical disc 1 according to the first embodiment can be ensured also with the optical disc 11 having that configuration.\",\n \"Although the invention has been explained by way of specific embodiments, the invention is not limited to those embodiments but can be modified in various modes based on the technical concept of the invention.\",\n \"For example, numerical values and materials shown in the explanation of the embodiments are not but mere examples, and other numerical values and materials may be used if necessary.\",\n \"For example, the first embodiment has been explained as applying the invention to a WO type optical disc having the recording layer 4 made of a phase-changeable material and configured to record in a WO manner.\",\n \"However, application of the invention is not limited to WO type optical discs, but can be extended to other type optical discs such as programmable optical discs.\",\n \"The second embodiment has been explained as using AlTi alloy as the material of the second reflection layer 13.However, material of the second reflection layer 13 may be selected from other Al alloys such as AlCu alloy, Al, silver (Ag), Ag alloys such as AgPdCu alloys, copper (Cu), Cu alloys, and so on.\",\n \"Moreover, although the second embodiment has been explained as using the recording layer made of GeSbTe alloy, any other appropriate material such as GeTe alloy, GeInSbTe alloy, AgInSbTe alloy, or the like, can be used in accordance with the desired property.\",\n \"Furthermore, although the second embodiment has been explained as employing 0.77 μm as the track pitch Tp of the concavo-convex tracks formed on one major surface 12a of the disc substrate 12, a different value may be employed where necessary.\",\n \"In case a blue laser having the wavelength around 405 nm is used as the laser beam and NA is enhanced approximately to 0.85 by using two-group lenses, the track pitch Tp may be reduced to 0.74 μm or smaller, such as around 0.3 μm.\",\n \"As described above, the invention enables freer design of optical recording mediums for obtaining more excellent signal characteristics and ensures optical mediums having excellent signal characteristics and high reliability by adjusting the thickness d of the recording layer and the thickness a of the record-assist layer to satisfy d/4<a<3d in optical recording mediums having the recording layer capable of recording information signals by irradiation of a laser beam and the multi-layered film stacking at least the recording layer and the record-assist layer at least on one surface of the disc substrate having formed concavo-convex.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10276126"}}},{"rowIdx":83,"cells":{"text":{"kind":"list like","value":[["Bellows for consant-velocity joints","A convoluted boot for sealing an annular gap between two parts which are connected to one another in a rotationally fast way, which can be articulated relative to one another and which are axially displaceable relative to one another, especially of a constant velocity plunging joint, consisting of a low-strain polymer hard material, having a first larger collar 11 to be secured to a first component, a second smaller collar 12 to be secured to a second component and a plurality of annular fold units which extend between the first collar and the second collar and which, in the form of outer folds consisting of two annular flanks 31, 32, form a fold peak 21 between two fold valleys 22, in a first group A of at least three annular folds with a connection to the first collar 11, the diameters of the fold peaks 21 and fold valleys 22 decrease in the direction from the first collar to the second collar, in a second group B of annular folds with a connection to the second collar 12 of at least one fold, the diameters of the fold valleys and optionally of the fold peaks 21 are constant, the ratio of the diameter D1 of the fold peak 21 of the largest annular fold A1 of the first group A to the diameter D2 of the second collar 12 amounts to ≧2.5."],["1.A convoluted boot for sealing an annular gap between two parts which are connected to one another in a rotationally fast way, which can be articulated relative to one another and which are axially displaceable relative to one another, the boot comprising: a low-strain hard polymer material, having a first larger collar (11) to be secured to a first component, a second smaller collar (12) to be secured to a second component and a plurality of annular fold units which extend between the first collar and the second collar and which, in the form of outer folds comprising two annular flanks (31, 32), form a fold peak (21) between two fold valleys (22); wherein, in a first group (A) of at least three annular folds with a connection to the first collar (11), the diameters of the fold peaks (21) and fold valleys (22) decrease from the first collar to the second collar, and wherein in a second group (B) of at least one annular fold with a connection to the second collar (12), the diameters of the fold valleys are constant; and wherein the ratio of the diameter (D1) of the fold peak (21) of the largest annular fold (A1) of the first group (A) to the diameter (D2) of the second collar (12) is greater than or equal to 2.5 and the two annular flanks (31, 32) of each of the annular folds of the first group (A) form opposed angles with a radial plane (R), wherein a smaller angle (β) is formed by the annular flank (32) pointing towards the second collar (12) and wherein a larger angle (α) is formed by the annular flank pointing towards the first collar (11), the larger angle (α) being at least 25° greater than the smaller angle (β).","2.A convoluted boot according to claim 1, wherein the first group (A) comprises up to five annular folds.","3.A convoluted boot according to claim 1 wherein the second group (B) comprises up to eight annular folds.","4.A convoluted boot according to claim 1 wherein the annular flanks (31, 32) of each of the annular folds of the second group (B) form opposed angles with a radial plane, wherein the annular flank (32) pointing towards the second collar (12) forms first angle (β) and wherein the annular flank (31) pointing towards first collar (11) forms a second angle (α) being in a range from 5° smaller to 5° greater than the first angle (β).","5.A convoluted boot according to claim 1 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there are provided transition folds (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).","6.A convoluted boot according to claim 5, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).","7.A convoluted boot according to claim 1 wherein the convoluted boot comprises a thermoplastic elastomer (TPE).","8.A convoluted boot according to claim 7, wherein the TPE comprises a polyurethane (TPU).","9.A convoluted boot according to claim 7, wherein the TPE comprises a polyester (TPEE).","10.A convoluted boot according to claim 9, wherein the TPEE is a polyether ester or a polyester ester.","11.A convoluted boot according to claim 7, wherein the TPE comprises a polyamide (TPA).","12.A convoluted boot according to claim 7, wherein the TPE comprises a polyolefin (TPO).","13.A convoluted boot according to claim 12, wherein the TPO is a polypropylene or a polyethylene.","14.A convoluted boot according to claim 1 wherein the diameters of the fold peaks (21) of the second group (B) of annular folds are constant.","15.A convoluted boot according to claim 2 wherein the second group (B) comprises up to eight annular folds.","16.A convoluted boot according to claim 2 wherein the annular flanks (31, 32) of each of the annular folds of the second group (B) form opposed angles with a radial plane, wherein the annular flank (32) pointing towards the second collar (12) forms first angle (β) and wherein the annular flank (31) pointing towards first collar (11) forms a second angle (α) which differs from the first angle (β) not more than 5°.","17.A convoluted boot according to claim 3 wherein the annular flanks (31, 32) of each of the annular folds of the second group (B) form opposed angles with a radial plane, wherein the annular flank (32) pointing towards the second collar (12) forms first angle (β) and wherein the annular flank (31) pointing towards first collar (11) forms a second angle (α) which differs from the first angle (β) not more than 5°.","18.A convoluted boot according to claim 2 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).","19.A convoluted boot according to claim 3 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).","20.A convoluted boot according to claim 4 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).","21.A convoluted boot according to claim 16 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).","22.A convoluted boot according to claim 7 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).","23.A convoluted boot according to claim 18, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).","24.A convoluted boot according to claim 19, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).","25.A convoluted boot according to claim 20, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).","26.A convoluted boot according to claim 21, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).","27.A convoluted boot according to claim 22, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).","28.A convoluted boot according to claim 27 wherein the convoluted boot comprises a thermoplastic elastomer (TPE)."],["DESCRIPTION The invention relates to a convoluted boot for sealing an annular gap between two parts which are connected to one another in a rotationally fast way, which can be articulated relative to one another and which are axially displaceable relative to one another, especially of a constant velocity plunging joint, consisting of a low-strain hard polymer material, having a first larger collar to be secured to a first component, a second smaller collar to be secured to a second component and a plurality of annular fold units which extend between the first collar and the second collar and which, in the form of outer folds consisting of two annular flanks, form a fold peak between two fold valleys.","Because requirements become more and more stringent, convoluted boots of said type are produced from hard polymer materials to an increasing extent.","As compared to soft resilient materials used earlier, said hard polymer materials feature an improved resistance in mechanical and chemical respects, and in view of higher speeds and the need for a longer service life, it is inevitable that they are used.","One concern is their reduced flexibility which can be a problem at low temperatures.","In the case of constant velocity fixed joints which effect articulation only between two rotating components, convoluted boots made of said materials, even today, do meet the respective requirements in their entirety.","In the case of constant velocity plunging joints which, in addition to the angular movement, effect an axial displacement between the two rotating components, this means that the sealing convoluted boots are subject to friction contact between the annular flanks on the inside of the angle when the joint is in a telescoped and articulated condition and, when the joint is in the extended and articulated condition, the individual annular folds open up excessively widely on the outside of the angle, causing a collapsing of the annular folds or other irregularities.","At high speeds, in particular, this can result in the elasticity limit of the convoluted boot being exceeded and it can lead to boot damage.","It is therefore the object of the present invention to provide a convoluted boot of said type which is able to meet more stringent requirements in operation without suffering any damage and which is therefore particularly suitable for constant velocity plunging joints.","The objective is achieved by providing a convoluted boot of the initially mentioned type with the following characteristics: in a first group of at least three annular folds joining the first collar, the diameters of the fold peaks and fold valleys decrease from the first collar to the second collar, in a second group of annular folds joining the second collar of at least one fold, the diameters of the fold valleys and—if more than one present—of the fold peaks are constant, the ratio of the diameter D1 of the fold peak of the largest annular fold of the first group to the diameter D2 of the second collar amounts to ≧2.5.By providing two special groups of folds, the deformation of the convoluted boot when articulation and changes in axial length occur is allocated to said two groups in such a way that, in the first group consisting of folds of a decreasing size, deformation largely takes place in the form of articulation, whereas the second group consisting of at least one fold with a small diameter largely accommodates the change in axial length by being extended.","Convoluted boots with two different groups of folds are known from DE 33 09 386 C1, DE 43 23 686 C2, DE 196 01 096 A1 and DE 198 06 173 C1 for example.","However, in these cases, between the two groups of folds, there exists a region which is in constant contact with the inserted shaft.","From DE 38 73 496 T2, there is known a convoluted boot of said type with two different functional regions, having folds whose flanks extend parallel relative to one another and, on the outside, are connected to one another by a rounded annular bead.","The annular folds according to the present invention, however, when the two collars are coaxially aligned relative to one another in the fitted condition, are contact-free relative to the inserted shaft and the annular folds each, approximately, comprise the shape of a double cone.","The first group of folds can comprise up to five annular folds and the second group of folds can comprise up to eight annular folds.","The number of folds depends on the respective requirement profile.","It is obvious that with an increased number of annular folds, the need for a longer boot length also increases, but the angle work to be carried out by the individual folds generally decreases during articulation.","However, this does not affect the possibility of varying the shape of the individual folds within certain ranges, i.e.","that it is possible to provide more pointed and wider folds, but in principle, the folds of the first group are wider (have a larger volume) and the folds of the second group are more pointed (narrower).","According to a preferred embodiment it is proposed that the two annular flanks of each of the annular folds of the first group form opposed angles with a radial plane, wherein a smaller angle β is formed by the annular flank pointing towards the second collar and wherein a larger angle α with ≧(β+25°) is formed by the annular flank pointing towards the first collar.","Furthermore, it is proposed that the annular flanks of each of the annular folds of the second group form opposed angles with a radial plane, wherein the annular flank pointing towards the second collar forms an angle β and wherein the annular flank pointing towards the first collar forms an angle α which is defined by (β+5°) As the approximately conical annular flanks, in particular the annular flanks of the first group which point towards the first collar, can be curved so as to comprise a convex outside, it is specified hereby that the reference for the angle values has to be the conical face between the outer line of a fold valley and the outer line of a fold peak and that, if viewed in a longitudinal section, it has to be the straight line between the smallest outer radius of a fold valley and the greatest outer radius of a fold peak.","According to a further embodiment it is proposed that between the annular folds of the first group and the annular folds of the second group, there is provided a transition fold whose diameters at the fold valleys deviate from one another, wherein the diameter of the annular flank pointing towards the first collar is greater than the diameter of the annular flank pointing towards the second collar.","In particular, it is proposed that the annular flanks of the transition fold form opposed angles with a radial plane, wherein the annular flank pointing towards the second collar forms an angle β and that the annular flank pointing towards the first collar forms an angle α which is defined by (β+25°)≧α≧(β+5°).","Said transition fold is thus similar to the annular folds of the first group in that the diameter of the fold valleys decreases towards the second collar; however, as far as the angle configuration of the annular flanks is concerned, said transition fold is similar to the annular folds of the second group.","The purpose is to ensure that even at larger angular movements of the convoluted boot, there is preferably no friction contact between the fold valleys and the inserted shaft.","A preferred material for the convoluted boot is a thermoplastic elastomer (TPE); in particular, there are proposed materials based on polyurethane (TPU), on polyester (TPEE), in particular a polyether ester or a polyester ester, materials based on polyamide (TPA) or on polyolefin, in particular polypropylene or polyethylene.","A preferred embodiment of the convoluted boot in accordance with the invention will be described below with reference to the drawings wherein FIG.","1 shows an inventive convoluted boot in half a longitudinal section, with different individual characteristics having been drawn in.","FIG.","2 shows an illustration similar to that of FIG.","1 in which the dimensions specified by the invention are given.","FIG.","3 shows two annular folds in half a longitudinal section, giving the values of the angles.","FIG.","1 shows a convoluted boot comprising a first collar 11 with a larger diameter with an attaching region 11′, a second collar 12 with a smaller diameter with an attaching region 12′, as well as a total of seven complete annular folds.","A first group A comprises three annular folds A1, A2, A3, with the diameters of their fold valleys and fold peaks decreasing from fold to fold from the first collar 11 to the second collar 12.A second group B of two complete folds B1 and B2 and with a total of three fold peaks comprises fold valleys and fold peaks which comprise identical diameters.","A third transition fold C is positioned between the first group A and the second group B and comprises fold valleys with decreasing diameters from the first collar 11 to the second collar 12.At fold A1 it is indicated that a complete annular fold is regarded as an outer fold with a fold peak 21 between two fold valleys 22.In FIG.","2, any details identical to those shown in FIG.","1 have been given the same reference numbers.","To that extent, reference is made to the preceding description.","D1 refers to the outer diameter of the first fold A1 of the first group A and D2 refers to the outer diameter of the second collar 12.In accordance with the invention, the ratio of the two diameters is ≧2.5.FIG.","3 shows an individual fold, and in FIG.","3a, one fold, which can be fold A1 for example, comprises a first annular flank 31 and a second annular flank 32.A radial plane R is positioned normally on the longitudinal boot axis L. The opening angle of the first annular flank 31 relative to the radial plane R has been given the reference symbol a and the opening angle of the second annular flank 32 relative to the radial plane R has been given the reference symbol β.","FIG.","3b shows that at an annular flank 31 with a convex outer face or, optionally, with a concave outer face, the arm of the opening angle α deviating from the radial plane is formed by a straight line between the greatest circumferential line 41 of the fold peak and the smallest circumferential line 42 of the adjoining fold valley.","FIG.","3a shows that the arm of, the opening angle α deviating from the radial plane is formed by a strictly conical surface of the annular flank (32) itself."]],"string":"[\n [\n \"Bellows for consant-velocity joints\",\n \"A convoluted boot for sealing an annular gap between two parts which are connected to one another in a rotationally fast way, which can be articulated relative to one another and which are axially displaceable relative to one another, especially of a constant velocity plunging joint, consisting of a low-strain polymer hard material, having a first larger collar 11 to be secured to a first component, a second smaller collar 12 to be secured to a second component and a plurality of annular fold units which extend between the first collar and the second collar and which, in the form of outer folds consisting of two annular flanks 31, 32, form a fold peak 21 between two fold valleys 22, in a first group A of at least three annular folds with a connection to the first collar 11, the diameters of the fold peaks 21 and fold valleys 22 decrease in the direction from the first collar to the second collar, in a second group B of annular folds with a connection to the second collar 12 of at least one fold, the diameters of the fold valleys and optionally of the fold peaks 21 are constant, the ratio of the diameter D1 of the fold peak 21 of the largest annular fold A1 of the first group A to the diameter D2 of the second collar 12 amounts to ≧2.5.\"\n ],\n [\n \"1.A convoluted boot for sealing an annular gap between two parts which are connected to one another in a rotationally fast way, which can be articulated relative to one another and which are axially displaceable relative to one another, the boot comprising: a low-strain hard polymer material, having a first larger collar (11) to be secured to a first component, a second smaller collar (12) to be secured to a second component and a plurality of annular fold units which extend between the first collar and the second collar and which, in the form of outer folds comprising two annular flanks (31, 32), form a fold peak (21) between two fold valleys (22); wherein, in a first group (A) of at least three annular folds with a connection to the first collar (11), the diameters of the fold peaks (21) and fold valleys (22) decrease from the first collar to the second collar, and wherein in a second group (B) of at least one annular fold with a connection to the second collar (12), the diameters of the fold valleys are constant; and wherein the ratio of the diameter (D1) of the fold peak (21) of the largest annular fold (A1) of the first group (A) to the diameter (D2) of the second collar (12) is greater than or equal to 2.5 and the two annular flanks (31, 32) of each of the annular folds of the first group (A) form opposed angles with a radial plane (R), wherein a smaller angle (β) is formed by the annular flank (32) pointing towards the second collar (12) and wherein a larger angle (α) is formed by the annular flank pointing towards the first collar (11), the larger angle (α) being at least 25° greater than the smaller angle (β).\",\n \"2.A convoluted boot according to claim 1, wherein the first group (A) comprises up to five annular folds.\",\n \"3.A convoluted boot according to claim 1 wherein the second group (B) comprises up to eight annular folds.\",\n \"4.A convoluted boot according to claim 1 wherein the annular flanks (31, 32) of each of the annular folds of the second group (B) form opposed angles with a radial plane, wherein the annular flank (32) pointing towards the second collar (12) forms first angle (β) and wherein the annular flank (31) pointing towards first collar (11) forms a second angle (α) being in a range from 5° smaller to 5° greater than the first angle (β).\",\n \"5.A convoluted boot according to claim 1 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there are provided transition folds (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).\",\n \"6.A convoluted boot according to claim 5, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).\",\n \"7.A convoluted boot according to claim 1 wherein the convoluted boot comprises a thermoplastic elastomer (TPE).\",\n \"8.A convoluted boot according to claim 7, wherein the TPE comprises a polyurethane (TPU).\",\n \"9.A convoluted boot according to claim 7, wherein the TPE comprises a polyester (TPEE).\",\n \"10.A convoluted boot according to claim 9, wherein the TPEE is a polyether ester or a polyester ester.\",\n \"11.A convoluted boot according to claim 7, wherein the TPE comprises a polyamide (TPA).\",\n \"12.A convoluted boot according to claim 7, wherein the TPE comprises a polyolefin (TPO).\",\n \"13.A convoluted boot according to claim 12, wherein the TPO is a polypropylene or a polyethylene.\",\n \"14.A convoluted boot according to claim 1 wherein the diameters of the fold peaks (21) of the second group (B) of annular folds are constant.\",\n \"15.A convoluted boot according to claim 2 wherein the second group (B) comprises up to eight annular folds.\",\n \"16.A convoluted boot according to claim 2 wherein the annular flanks (31, 32) of each of the annular folds of the second group (B) form opposed angles with a radial plane, wherein the annular flank (32) pointing towards the second collar (12) forms first angle (β) and wherein the annular flank (31) pointing towards first collar (11) forms a second angle (α) which differs from the first angle (β) not more than 5°.\",\n \"17.A convoluted boot according to claim 3 wherein the annular flanks (31, 32) of each of the annular folds of the second group (B) form opposed angles with a radial plane, wherein the annular flank (32) pointing towards the second collar (12) forms first angle (β) and wherein the annular flank (31) pointing towards first collar (11) forms a second angle (α) which differs from the first angle (β) not more than 5°.\",\n \"18.A convoluted boot according to claim 2 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).\",\n \"19.A convoluted boot according to claim 3 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).\",\n \"20.A convoluted boot according to claim 4 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).\",\n \"21.A convoluted boot according to claim 16 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).\",\n \"22.A convoluted boot according to claim 7 wherein, between the annular folds of the first group (A) and the annular folds of the second group (B), there is provided at least one transition fold (C) whose diameters deviate from one another at the fold valleys (22), wherein the diameter of the fold valley at the annular flank (31) pointing towards the first collar (11) is greater than the diameter of the fold valley at the annular flank (32) pointing towards the second collar (12).\",\n \"23.A convoluted boot according to claim 18, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).\",\n \"24.A convoluted boot according to claim 19, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).\",\n \"25.A convoluted boot according to claim 20, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).\",\n \"26.A convoluted boot according to claim 21, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).\",\n \"27.A convoluted boot according to claim 22, wherein the annular flanks (31, 32) of the transition fold (C) form opposed angles with a radial plane (R), wherein the annular flank (32) pointing towards the second collar (12) forms a first angle (β) and that the annular flank (31) pointing towards the first collar (11) forms a second angle (α) which is defined by (β+25°)≧α≧(β+5°).\",\n \"28.A convoluted boot according to claim 27 wherein the convoluted boot comprises a thermoplastic elastomer (TPE).\"\n ],\n [\n \"DESCRIPTION The invention relates to a convoluted boot for sealing an annular gap between two parts which are connected to one another in a rotationally fast way, which can be articulated relative to one another and which are axially displaceable relative to one another, especially of a constant velocity plunging joint, consisting of a low-strain hard polymer material, having a first larger collar to be secured to a first component, a second smaller collar to be secured to a second component and a plurality of annular fold units which extend between the first collar and the second collar and which, in the form of outer folds consisting of two annular flanks, form a fold peak between two fold valleys.\",\n \"Because requirements become more and more stringent, convoluted boots of said type are produced from hard polymer materials to an increasing extent.\",\n \"As compared to soft resilient materials used earlier, said hard polymer materials feature an improved resistance in mechanical and chemical respects, and in view of higher speeds and the need for a longer service life, it is inevitable that they are used.\",\n \"One concern is their reduced flexibility which can be a problem at low temperatures.\",\n \"In the case of constant velocity fixed joints which effect articulation only between two rotating components, convoluted boots made of said materials, even today, do meet the respective requirements in their entirety.\",\n \"In the case of constant velocity plunging joints which, in addition to the angular movement, effect an axial displacement between the two rotating components, this means that the sealing convoluted boots are subject to friction contact between the annular flanks on the inside of the angle when the joint is in a telescoped and articulated condition and, when the joint is in the extended and articulated condition, the individual annular folds open up excessively widely on the outside of the angle, causing a collapsing of the annular folds or other irregularities.\",\n \"At high speeds, in particular, this can result in the elasticity limit of the convoluted boot being exceeded and it can lead to boot damage.\",\n \"It is therefore the object of the present invention to provide a convoluted boot of said type which is able to meet more stringent requirements in operation without suffering any damage and which is therefore particularly suitable for constant velocity plunging joints.\",\n \"The objective is achieved by providing a convoluted boot of the initially mentioned type with the following characteristics: in a first group of at least three annular folds joining the first collar, the diameters of the fold peaks and fold valleys decrease from the first collar to the second collar, in a second group of annular folds joining the second collar of at least one fold, the diameters of the fold valleys and—if more than one present—of the fold peaks are constant, the ratio of the diameter D1 of the fold peak of the largest annular fold of the first group to the diameter D2 of the second collar amounts to ≧2.5.By providing two special groups of folds, the deformation of the convoluted boot when articulation and changes in axial length occur is allocated to said two groups in such a way that, in the first group consisting of folds of a decreasing size, deformation largely takes place in the form of articulation, whereas the second group consisting of at least one fold with a small diameter largely accommodates the change in axial length by being extended.\",\n \"Convoluted boots with two different groups of folds are known from DE 33 09 386 C1, DE 43 23 686 C2, DE 196 01 096 A1 and DE 198 06 173 C1 for example.\",\n \"However, in these cases, between the two groups of folds, there exists a region which is in constant contact with the inserted shaft.\",\n \"From DE 38 73 496 T2, there is known a convoluted boot of said type with two different functional regions, having folds whose flanks extend parallel relative to one another and, on the outside, are connected to one another by a rounded annular bead.\",\n \"The annular folds according to the present invention, however, when the two collars are coaxially aligned relative to one another in the fitted condition, are contact-free relative to the inserted shaft and the annular folds each, approximately, comprise the shape of a double cone.\",\n \"The first group of folds can comprise up to five annular folds and the second group of folds can comprise up to eight annular folds.\",\n \"The number of folds depends on the respective requirement profile.\",\n \"It is obvious that with an increased number of annular folds, the need for a longer boot length also increases, but the angle work to be carried out by the individual folds generally decreases during articulation.\",\n \"However, this does not affect the possibility of varying the shape of the individual folds within certain ranges, i.e.\",\n \"that it is possible to provide more pointed and wider folds, but in principle, the folds of the first group are wider (have a larger volume) and the folds of the second group are more pointed (narrower).\",\n \"According to a preferred embodiment it is proposed that the two annular flanks of each of the annular folds of the first group form opposed angles with a radial plane, wherein a smaller angle β is formed by the annular flank pointing towards the second collar and wherein a larger angle α with ≧(β+25°) is formed by the annular flank pointing towards the first collar.\",\n \"Furthermore, it is proposed that the annular flanks of each of the annular folds of the second group form opposed angles with a radial plane, wherein the annular flank pointing towards the second collar forms an angle β and wherein the annular flank pointing towards the first collar forms an angle α which is defined by (β+5°) As the approximately conical annular flanks, in particular the annular flanks of the first group which point towards the first collar, can be curved so as to comprise a convex outside, it is specified hereby that the reference for the angle values has to be the conical face between the outer line of a fold valley and the outer line of a fold peak and that, if viewed in a longitudinal section, it has to be the straight line between the smallest outer radius of a fold valley and the greatest outer radius of a fold peak.\",\n \"According to a further embodiment it is proposed that between the annular folds of the first group and the annular folds of the second group, there is provided a transition fold whose diameters at the fold valleys deviate from one another, wherein the diameter of the annular flank pointing towards the first collar is greater than the diameter of the annular flank pointing towards the second collar.\",\n \"In particular, it is proposed that the annular flanks of the transition fold form opposed angles with a radial plane, wherein the annular flank pointing towards the second collar forms an angle β and that the annular flank pointing towards the first collar forms an angle α which is defined by (β+25°)≧α≧(β+5°).\",\n \"Said transition fold is thus similar to the annular folds of the first group in that the diameter of the fold valleys decreases towards the second collar; however, as far as the angle configuration of the annular flanks is concerned, said transition fold is similar to the annular folds of the second group.\",\n \"The purpose is to ensure that even at larger angular movements of the convoluted boot, there is preferably no friction contact between the fold valleys and the inserted shaft.\",\n \"A preferred material for the convoluted boot is a thermoplastic elastomer (TPE); in particular, there are proposed materials based on polyurethane (TPU), on polyester (TPEE), in particular a polyether ester or a polyester ester, materials based on polyamide (TPA) or on polyolefin, in particular polypropylene or polyethylene.\",\n \"A preferred embodiment of the convoluted boot in accordance with the invention will be described below with reference to the drawings wherein FIG.\",\n \"1 shows an inventive convoluted boot in half a longitudinal section, with different individual characteristics having been drawn in.\",\n \"FIG.\",\n \"2 shows an illustration similar to that of FIG.\",\n \"1 in which the dimensions specified by the invention are given.\",\n \"FIG.\",\n \"3 shows two annular folds in half a longitudinal section, giving the values of the angles.\",\n \"FIG.\",\n \"1 shows a convoluted boot comprising a first collar 11 with a larger diameter with an attaching region 11′, a second collar 12 with a smaller diameter with an attaching region 12′, as well as a total of seven complete annular folds.\",\n \"A first group A comprises three annular folds A1, A2, A3, with the diameters of their fold valleys and fold peaks decreasing from fold to fold from the first collar 11 to the second collar 12.A second group B of two complete folds B1 and B2 and with a total of three fold peaks comprises fold valleys and fold peaks which comprise identical diameters.\",\n \"A third transition fold C is positioned between the first group A and the second group B and comprises fold valleys with decreasing diameters from the first collar 11 to the second collar 12.At fold A1 it is indicated that a complete annular fold is regarded as an outer fold with a fold peak 21 between two fold valleys 22.In FIG.\",\n \"2, any details identical to those shown in FIG.\",\n \"1 have been given the same reference numbers.\",\n \"To that extent, reference is made to the preceding description.\",\n \"D1 refers to the outer diameter of the first fold A1 of the first group A and D2 refers to the outer diameter of the second collar 12.In accordance with the invention, the ratio of the two diameters is ≧2.5.FIG.\",\n \"3 shows an individual fold, and in FIG.\",\n \"3a, one fold, which can be fold A1 for example, comprises a first annular flank 31 and a second annular flank 32.A radial plane R is positioned normally on the longitudinal boot axis L. The opening angle of the first annular flank 31 relative to the radial plane R has been given the reference symbol a and the opening angle of the second annular flank 32 relative to the radial plane R has been given the reference symbol β.\",\n \"FIG.\",\n \"3b shows that at an annular flank 31 with a convex outer face or, optionally, with a concave outer face, the arm of the opening angle α deviating from the radial plane is formed by a straight line between the greatest circumferential line 41 of the fold peak and the smallest circumferential line 42 of the adjoining fold valley.\",\n \"FIG.\",\n \"3a shows that the arm of, the opening angle α deviating from the radial plane is formed by a strictly conical surface of the annular flank (32) itself.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10276208"}}},{"rowIdx":84,"cells":{"text":{"kind":"list like","value":[["Method and apparatus of dsp resource allocation and use","Certain embodiments of the invention support the distribution and control of multiple instruction streams going to multiple steps of modules supporting arithmetic and memory, as well as method for numeric data processing optimizing non-additive functions and operations through a novel numeric representation and the use of novel ALU components to support numeric conversions and evaluations of non-additive functions."],["1.A circuit supporting partitioned operation of multiple concurrently presented instructions comprising: a first instruction wire bundle; a second instruction wire bundle; a clock wire bundle possessing a capture state; a partition control wire bundle possessing a partition control state; an arithmetic module circuit coupled to said partition control wire bundle and further comprised of a first memory circuit coupled to said partition control wire bundle; and a first arithmetic logic unit coupled to said partition control wire bundle; wherein said module circuit samples said first instruction wire bundle and said second instruction wire bundle during said capture state on said clock wire bundle respectively generating a first sampled instruction state and a second sampled instruction state; and wherein said arithmetic module circuit responds to at least one member of a sample instruction collection based upon said partition control state; wherein said sample instruction collection is comprised of said first sampled instruction state and to said second sampled instruction state; wherein said arithmetic module circuit response is further comprised of: said first memory circuit responds to at least one member of said sample instruction collection based upon said partition control state; and said first arithmetic logic unit responds to at least one member of said sample instruction collection based upon said partition control state; wherein said first arithmetic logic unit is further comprised of an ALU part collection comprising a first part ALU and a second part ALU; wherein said first memory circuit is further comprised of at least two memory sub-circuits, each memory sub-circuit corresponding to a member of said ALU part collection; wherein each member of said part ALU collection and said corresponding memory sub-circuit are coupled to said partition control wire bundle; and wherein each member of said part ALU collection and said corresponding memory sub-circuit both respond to exactly one and the same member of said sample instruction collection based upon said partition control state.","2.The circuit of claim 1, wherein said first part ALU presents a first carry signal to said second part ALUs; wherein said second part ALU ignores said first carry signal whenever said exactly one sample instruction collection member for said first part ALU is different from said exactly one sample instruction collection member for said second part ALU.","3.The circuit of claim 1, further comprising: an input-output circuit coupled to said arithmetic module circuit, to said partition control wire bundle; wherein said input-output circuit responds to at least one member of said sample instruction collection based upon said partition control state.","4.The circuit of claim 3, wherein said input-output circuit presents a first input to a member of the collection comprising said first ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said first ALU part and said corresponding memory sub-circuit respond; wherein said input-output circuit presents a second input to a member of the collection comprising sad second ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said second ALU part and said corresponding memory sub-circuit respond.","5.The circuit of claim 4, wherein said arithmetic module circuit is further comprised of a second circuit coupled to said partition control wire bundle; wherein said second circuit is comprised of at least two second sub-circuits, each of said second sub-circuits corresponding to exactly one member of said ALU part collection; wherein each of said second sub-circuits corresponding to said member of said ALU responds to exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein for each of said second sub-circuits, said second sub-circuit further responds by approximately performing at least one member of a non-additive function collection comprising multiplication, division, square root, exponential base N, logarithm base N, sine, cosine, arcsine, arccosine, tangent, cotangent, secant, cosecant and polynomial functions based upon exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein said N is a positive number.","6.The circuit of claim 5, wherein an input collection is comprised of said first and said second input; wherein each member of said input collection is comprised of a log-input and a normal-input; 7.The circuit of claim 6, wherein each member of said ALU part collection presents a result to said corresponding said second sub-circuit.","8.The circuit of claim 7, further comprising a second of said arithmetic module circuits coupled to said input-output circuit; wherein said input-output circuit presents said first input to at least one member of the collection comprising said first ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; wherein said input-output circuit presents said second input to at least one member of the collection comprising sad second ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.","9.The circuit of claim 8, wherein a second circuit collection is comprised of said second circuit of said arithmetic module circuit and said second circuit of said second arithmetic module circuit; wherein at least one member of said second circuit collection couples to an internal wire bundle comprised of a first sub-internal wire bundle and a second sub-internal wire bundle; wherein for each member of said second circuit collection coupled to said internal wire bundle asserts a first sub-internal wire state on said first sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; wherein for each member of said second circuit collection coupled to said internal wire bundle asserts a second sub-internal wire state on said second sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.","10.The circuit of claim 1, further comprising a first datapath instruction processor coupled to said first datapath instruction wire bundle presented to said module circuit; wherein said first datapath instruction processor asserts said first datapath instruction wire bundle; and a second datapath instruction processor coupled to said second datapath instruction wire bundle presented to said module circuit; wherein said second datapath instruction processor asserts said second datapath instruction wire bundle.","11.The circuit of claim 10, wherein a datapath instruction processor collection is comprised of said first datapath instruction processor and said second datapath instruction processor; wherein said first datapath instruction wire bundle is an associated datapath instruction wire bundle of said first datapath instruction processor; wherein said second datapath instruction wire bundle is an associated datapath instruction wire bundle of said second datapath instruction processor; wherein at least one member of said datapath instruction processor collection is further comprised of: a datapath instruction pointer coupled to said clock wire bundle, and to a datapath instruction address wire bundle; and a datapath instruction register coupled to said clock wire bundle, to said asserted datapath instruction wire bundle, and to a datapath instruction wire bundle; wherein said clock wire bundle possesses a datapath instruction capture state; wherein said datapath instruction queue pointer responds to said clock wire bundle by asserting an asserted datapath instruction address; wherein said datapath instruction register responds to said clock wire bundle by capturing a datapath instruction capture state whenever said clock wire bundle is in said datapath instruction capture state; and wherein said datapath instruction register further asserts said associated datapath instruction wire bundle based upon said datapath instruction capture state.","12.The circuit of claim 11, wherein for at least one member of said datapath instruction processor collection comprising said datapath instruction pointer is further comprised of: an instruction store coupled to said datapath instruction address wire bundle and to said datapath instruction wire bundle; wherein said instruction store responds to said asserted datapath instruction address via said datapath instruction address wire bundle to asserting said datapath instruction wire bundle based upon said asserted datapath instruction address.","13.The circuit of claim 12, wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction processor is further comprised of a last instruction indicator coupled to a last instruction indicator wire bundle possessing a last instruction state and a non-last instruction state; wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction pointer is further coupled to a new datapath instruction address wire bundle and to said last instruction indicator wire bundle; and wherein for at least one member of said datapath instruction processor collection comprising said instruction store is further comprised of: a branch-cache instruction processor coupled to said last instruction indicator and to said new datapath instruction address wire bundle; wherein said branch-cache instruction processor responds to said last instruction state via said last instruction indicator wire bundle by asserting a new datapath instruction address upon said new datapath instruction address wire bundle; and wherein said datapath instruction pointer responds to said last instruction indicator wire bundle by capturing said new datapath instruction address from said new datapath instruction address wire bundle.","14.A circuit implementation of claim 1, wherein a component list comprises said arithmetic module circuit, said first memory circuit coupled to said partition control wire bundle, and said first arithmetic logic unit; wherein each member of said component list is implemented with at least part of at least one member of the collection comprising a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array (FPGA); and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.","15.The circuit implementation of claim 14, wherein the implementation of all members of said component list further includes only circuitry responding to said exactly one and the same member of said sample instruction collection based upon said partition control state.","16.A method of operating a module circuit containing at least an arithmetic module circuit further containing a first memory circuit and a first arithmetic logic unit using a clock wire bundle possessing a capture state and using a partition control wire bundle possessing a partition control state, said method comprising the steps of: said module circuit sampling a first instruction pair wire bundle and a second instruction pair wire bundle during said capture state on said clock wire bundle respectively generating a first sampled instruction state and a second sampled instruction state; and said arithmetic module circuit responding to at least one member of a sample instruction collection based upon said partition control state; wherein said sample instruction collection is comprised of said first sampled instruction state and to said second sampled instruction state; wherein the step of said arithmetic module circuit responding is further comprised of the steps of: said first memory circuit responding to at least one member of said sample instruction collection based upon said partition control state; and said first arithmetic logic unit responding to at least one member of said sample instruction collection based upon said partition control state; wherein said first arithmetic logic unit is further comprised of an ALU part collection comprising a first part ALU and a second part ALU; wherein the step of said first arithmetic logic unit responding is further comprised of the steps of said first part ALU responding to exactly one member of said sample instruction collection based upon said partition control; and said second part ALU responding to exactly one member of said sample instruction collection based upon said partition control state; wherein said first memory circuit is comprised of at least two memory sub-circuits, each of said memory sub-circuits corresponding to a member of said ALU part collection; wherein the step of said first memory circuit responding is further comprised of, for each of said memory sub-circuits, the step of said memory sub-circuit responding to exactly one and the same member of said sample instruction collection as said corresponding member of said ALU part collection.","17.The method of claim 16, further comprising the step of said first part ALU presenting a first carry signal to said second part ALU; wherein the step of said second ALU responding is comprised of the steps of: said second part ALU ignoring said first carry signal whenever said exactly one sample instruction collection member for said first part ALU is different from said exactly one sample instruction collection member for said second part ALU.","18.The method of claim 16, further comprising the step of: an input-output circuit responding to at least one member of said sample instruction collection based upon said partition control state.","19.The method of claim 18, further comprising the steps of: said input-output circuit presenting a first input to a member of the collection comprising said first ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said first ALU part and said corresponding memory sub-circuit respond; said input-output circuit presenting a second input to a member of the collection comprising sad second ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said second ALU part and said corresponding memory sub-circuit respond.","20.The method of claim 19, wherein said arithmetic module circuit is further comprised of a second circuit coupled to said partition control wire bundle; wherein said second circuit is comprised of at least two second sub-circuits, each of said second sub-circuits corresponding to exactly one member of said ALU part collection; wherein said method is further comprised, for each of said second sub-circuits corresponding to said member of said ALU part collection, of the step of: said second sub-circuit responding to exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein for each of said second sub-circuits, the step of said second sub-circuit responding is further comprised of the step of: said second sub-circuit approximately performing at least one member of a non-additive function collection comprising multiplication, division, square root, exponential base N, logarithm base N, sine, cosine, arcsine, arccosine, tangent, cotangent, secant, cosecant and polynomial functions based upon exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein said N is a positive number.","21.The method of claim 20, wherein an input collection is comprised of said first and said second input; wherein each member of said input collection is comprised of a log-input and a normal-input.","22.The method of claim 21, further comprising the steps of: for each member of said ALU part collection, said member presenting a result to said corresponding said second sub-circuit.","23.The method of claim 22, wherein said module circuit is further comprised of a second of said arithmetic module circuits coupled to said input-output circuit; wherein said method is further comprised of the step of: said input-output circuit presenting said first input to at least one member of the collection comprising said first ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; said input-output circuit presenting said second input to at least one member of the collection comprising sad second ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.","24.The method of claim 23, wherein a second circuit collection is comprised of said second circuit of said arithmetic module circuit and said second circuit of said second arithmetic module circuit; wherein at least one member of said second circuit collection couples to an internal wire bundle comprised of a first sub-internal wire bundle and a second sub-internal wire bundle; wherein said method is further comprised, for each member of said second circuit collection coupled to said internal wire bundle of the step of: said member asserting a first sub-internal wire state on said first sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; said member asserting a second sub-internal wire state on said second sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.","25.The method of claim 16, further comprising the steps of a first datapath instruction processor asserting said first datapath instruction wire bundle presented to said module circuit; and a second datapath instruction processor asserting said second datapath instruction wire bundle presented to said module circuit.","26.The method of claim 25, wherein a datapath instruction processor collection is comprised of said first datapath instruction processor and said second datapath instruction processor; wherein said first datapath instruction wire bundle is an associated datapath instruction wire bundle of said first datapath instruction processor; wherein said second datapath instruction wire bundle is an associated datapath instruction wire bundle of said second datapath instruction processor; wherein at least one member of said datapath instruction processor collection is further comprised of: a datapath instruction pointer coupled to said clock wire bundle, and to a datapath instruction address wire bundle; and a datapath instruction register coupled to said clock wire bundle, to said asserted datapath instruction wire bundle, and to a datapath instruction wire bundle; wherein said clock wire bundle possesses a datapath instruction capture state; wherein said method is further comprised of the steps of said datapath instruction queue pointer responding to said clock wire bundle by asserting an asserted datapath instruction address; said datapath instruction register responding to said clock wire bundle by capturing a datapath instruction capture state whenever said clock wire bundle is in said datapath instruction capture state; and said datapath instruction register asserting said associated datapath instruction wire bundle based upon said datapath instruction capture state.","27.The method of claim 26, wherein for at least one member of said datapath instruction processor collection comprising said datapath instruction pointer is further comprised of an instruction store; wherein said method is further comprised of the steps of said instruction store responding to said asserted datapath instruction address to assert said datapath instruction wire bundle based upon said asserted datapath instruction address.","28.The method of claim 27, wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction processor is further comprised of a last instruction indicator coupled to a last instruction indicator wire bundle possessing a last instruction state and a non-last instruction state; wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction pointer is further coupled to a new datapath instruction address wire bundle and to said last instruction indicator wire bundle; and wherein for at least one member of said datapath instruction processor collection comprising said instruction store is further comprised of: a branch-cache instruction processor coupled to said last instruction indicator and to said new datapath instruction address wire bundle; wherein said branch-cache instruction processor responds to said last instruction state via said last instruction indicator wire bundle by asserting a new datapath instruction address upon said new datapath instruction address wire bundle; and wherein said datapath instruction pointer responds to said last instruction indicator wire bundle by capturing said new datapath instruction address from said new datapath instruction address wire bundle.","29.A circuit implementation of the method of claim 16, wherein the steps of the method are each implemented within at least part of at least one member of the collection comprising a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array (FPGA); and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.","30.A method of operating a module circuit containing at least an arithmetic module circuit further containing a first memory circuit and a first arithmetic logic unit using a clock wire bundle possessing a capture state and using a partition control wire bundle possessing a partition control state, said method comprising the steps of: said module circuit sampling a first instruction pair wire bundle and a second instruction pair wire bundle during said capture state on said clock wire bundle respectively generating a first sampled instruction state and a second sampled instruction state; and said arithmetic module circuit responding to at least one member of a sample instruction collection based upon said partition control state; wherein said sample instruction collection is comprised of said first sampled instruction state and to said second sampled instruction state.","31.The method of claim 30, wherein the step of said arithmetic module circuit responding is further comprised of the steps of: said first memory circuit responding to at least one member of said sample instruction collection based upon said partition control state; and said first arithmetic logic unit responding to at least one member of said sample instruction collection based upon said partition control state.","32.The method of claim 31, wherein said first arithmetic logic unit is further comprised of an ALU part collection comprising a first part ALU and a second part ALU; wherein the step of said first arithmetic logic unit responding is further comprised of the steps of said first part ALU responding to exactly one member of said sample instruction collection based upon said partition control; and said second part ALU responding to exactly one member of said sample instruction collection based upon said partition control state; wherein said first memory circuit is comprised of at least two memory sub-circuits, each of said memory sub-circuits corresponding to a member of said ALU part collection; wherein the step of said first memory circuit responding is further comprised of for each of said memory sub-circuits, the step of said memory sub-circuit responding to exactly one and the same member of said sample instruction collection as said corresponding member of said ALU part collection.","33.The method of claim 32, further comprising the step of said first part ALU presenting a first carry signal to said second part ALU; wherein the step of said second ALU responding is comprised of the steps of: said second part ALU ignoring said first carry signal whenever said exactly one sample instruction collection member for said first part ALU is different from said exactly one sample instruction collection member for said second part ALU.","34.The method of claim 32, further comprising the step of: an input-output circuit responding to at least one member of said sample instruction collection based upon said partition control state.","35.The method of claim 34, further comprising the steps of: said input-output circuit presenting a first input to a member of the collection comprising said first ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said first ALU part and said corresponding memory sub-circuit respond; said input-output circuit presenting a second input to a member of the collection comprising sad second ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said second ALU part and said corresponding memory sub-circuit respond.","36.The method of claim 35, wherein said arithmetic module circuit is further comprised of a second circuit coupled to said partition control wire bundle; wherein said second circuit is comprised of at least two second sub-circuits, each of said second sub-circuits corresponding to exactly one member of said ALU part collection; wherein said method is further comprised, for each of said second sub-circuits corresponding to said member of said ALU part collection, of the step of: said second sub-circuit responding to exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein for each of said second sub-circuits, the step of said second sub-circuit responding is further comprised of the step of: said second sub-circuit approximately performing at least one member of a non-additive function collection comprising multiplication, division, square root, exponential base N, logarithm base N, sine, cosine, arcsine, arccosine, tangent, cotangent, secant, cosecant and polynomial functions based upon exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein said N is a positive number.","37.The method of claim 36, wherein an input collection is comprised of said first and said second input; wherein each member of said input collection is comprised of a log-input and a normal-input.","38.The method of claim 37, further comprising the steps of: for each member of said ALU part collection, said member presenting a result to said corresponding said second sub-circuit.","39.The method of claim 38, wherein said module circuit is further comprised of a second of said arithmetic module circuits coupled to said input-output circuit; wherein said method is further comprised of the step of: said input-output circuit presenting said first input to at least one member of the collection comprising said first ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; said input-output circuit presenting said second input to at least one member of the collection comprising sad second ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.","40.The method of claim 39, wherein a second circuit collection is comprised of said second circuit of said arithmetic module circuit and said second circuit of said second arithmetic module circuit; wherein at least one member of said second circuit collection couples to an internal wire bundle comprised of a first sub-internal wire bundle and a second sub-internal wire bundle; wherein said method is further comprised, for each member of said second circuit collection coupled to said internal wire bundle of the step of: said member asserting a first sub-internal wire state on said first sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; said member asserting a second sub-internal wire state on said second sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.","41.The method of claim 30, further comprising the steps of a first datapath instruction processor asserting said first datapath instruction wire bundle presented to said module circuit; and a second datapath instruction processor asserting said second datapath instruction wire bundle presented to said module circuit.","42.The method of claim 41, wherein a datapath instruction processor collection is comprised of said first datapath instruction processor and said second datapath instruction processor; wherein said first datapath instruction wire bundle is an associated datapath instruction wire bundle of said first datapath instruction processor; wherein said second datapath instruction wire bundle is an associated datapath instruction wire bundle of said second datapath instruction processor; wherein at least one member of said datapath instruction processor collection is further comprised of: a datapath instruction pointer coupled to said clock wire bundle, and to a datapath instruction address wire bundle; and a datapath instruction register coupled to said clock wire bundle, to said asserted datapath instruction wire bundle, and to a datapath instruction wire bundle; wherein said clock wire bundle possesses a datapath instruction capture state; wherein said method is further comprised of the steps of said datapath instruction queue pointer responding to said clock wire bundle by asserting an asserted datapath instruction address; said datapath instruction register responding to said clock wire bundle by capturing a datapath instruction capture state whenever said clock wire bundle is in said datapath instruction capture state; and said datapath instruction register asserting said associated datapath instruction wire bundle based upon said datapath instruction capture state.","43.The method of claim 42, wherein for at least one member of said datapath instruction processor collection comprising said datapath instruction pointer is further comprised of an instruction store; wherein said method is further comprised of the steps of said instruction store responding to said asserted datapath instruction address to assert said datapath instruction wire bundle based upon said asserted datapath instruction address.","44.The method of claim 43, wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction processor is further comprised of a last instruction indicator coupled to a last instruction indicator wire bundle possessing a last instruction state and a non-last instruction state; wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction pointer is further coupled to a new datapath instruction address wire bundle and to said last instruction indicator wire bundle, and wherein for at least one member of said datapath instruction processor collection comprising said instruction store is further comprised of: a branch-cache instruction processor coupled to said last instruction indicator and to said new datapath instruction address wire bundle; wherein said branch-cache instruction processor responds to said last instruction state via said last instruction indicator wire bundle by asserting a new datapath instruction address upon said new datapath instruction address wire bundle; and wherein said datapath instruction pointer responds to said last instruction indicator wire bundle by capturing said new datapath instruction address from said new datapath instruction address wire bundle.","45.A circuit implementation of the method of claim 30, wherein the steps of the method are each implemented within at least part of at least one member of the collection comprising a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array (FPGA); and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.","46.A circuit supporting partitioned operation of multiple concurrently presented instructions comprising: a first instruction wire bundle; a second instruction wire bundle; a clock wire bundle possessing a capture state; a partition control wire bundle possessing a partition control state; an arithmetic module circuit coupled to said partition control wire bundle and further comprised of a first memory circuit coupled to said partition control wire bundle; and a first arithmetic logic unit coupled to said partition control wire bundle; wherein said module circuit samples said first instruction wire bundle and said second instruction wire bundle during said capture state on said clock wire bundle respectively generating a first sampled instruction state and a second sampled instruction state; and wherein said arithmetic module circuit responds to at least one member of a sample instruction collection based upon said partition control state; wherein said sample instruction collection is comprised of said first sampled instruction state and to said second sampled instruction state.","47.The circuit of claim 46, wherein said arithmetic module circuit response is further comprised of: said first memory circuit responds to at least one member of said sample instruction collection based upon said partition control state; and said first arithmetic logic unit responds to at least one member of said sample instruction collection based upon said partition control state.","48.The circuit of claim 47, wherein said first arithmetic logic unit is further comprised of an ALU part collection comprising a first part ALU and a second part ALU; wherein said first memory circuit is further comprised of at least two memory sub-circuits, each memory sub-circuit corresponding to a member of said ALU part collection; wherein each member of said part ALU collection and said corresponding memory sub-circuit are coupled to said partition control wire bundle; and wherein each member of said part ALU collection and said corresponding memory sub-circuit both respond to exactly one and the same member of said sample instruction collection based upon said partition control state.","49.The circuit of claim 48, wherein said partition control state includes to a carry partition control belonging to a partition control state collection comprising first carry control state and a second carry control state; wherein said first part ALU presents a first carry signal to said second part ALUs; wherein said second part ALU ignores said first carry signal whenever said exactly one sample instruction collection member for said first part ALU is different from said exactly one sample instruction collection member for said second part ALU.","50.The circuit of claim 48, further comprising: an input-output circuit coupled to said arithmetic module circuit, to said partition control wire bundle; wherein said input-output circuit responds to at least one member of said sample instruction collection based upon said partition control state.","51.The circuit of claim 50, wherein said input-output circuit presents a first input to a member of the collection comprising said first ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said first ALU part and said corresponding memory sub-circuit respond; wherein said input-output circuit presents a second input to a member of the collection comprising sad second ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said second ALU part and said corresponding memory sub-circuit respond.","52.The circuit of claim 51, wherein said arithmetic module circuit is further comprised of a second circuit coupled to said partition control wire bundle; wherein said second circuit is comprised of at least two second sub-circuits, each of said second sub-circuits corresponding to exactly one member of said ALU part collection; wherein each of said second sub-circuits corresponding to said member of said ALU responds to exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein for each of said second sub-circuits, said second sub-circuit further responds by approximately performing at least one member of a non-additive function collection comprising multiplication, division, square root, exponential base N, logarithm base N, sine, cosine, arcsine, arccosine, tangent, cotangent, secant, cosecant and polynomial functions based upon exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein said N is a positive number.","53.The circuit of claim 52, wherein an input collection is comprised of said first and said second input; wherein each member of said input collection is comprised of a log-input and a normal-input; 54.The circuit of claim 53, wherein each member of said ALU part collection presents a result to said corresponding said second sub-circuit.","55.The circuit of claim 54, further comprising a second of said arithmetic module circuits coupled to said input-output circuit; wherein said input-output circuit presents said first input to at least one member of the collection comprising said first ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; wherein said input-output circuit presents said second input to at least one member of the collection comprising sad second ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.","56.The circuit of claim 55, wherein a second circuit collection is comprised of said second circuit of said arithmetic module circuit and said second circuit of said second arithmetic module circuit; wherein at least one member of said second circuit collection couples to an internal wire bundle comprised of a first sub-internal wire bundle and a second sub-internal wire bundle; wherein for each member of said second circuit collection coupled to said internal wire bundle asserts a first sub-internal wire state on said first sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; wherein for each member of said second circuit collection coupled to said internal wire bundle asserts a second sub-internal wire state on said second sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.","57.The circuit of claim 46, further comprising a first datapath instruction processor coupled to said first datapath instruction wire bundle presented to said module circuit; wherein said first datapath instruction processor asserts said first datapath instruction wire bundle; and a second datapath instruction processor coupled to said second datapath instruction wire bundle presented to said module circuit; wherein said second datapath instruction processor asserts said second datapath instruction wire bundle.","58.The circuit of claim 57, wherein a datapath instruction processor collection is comprised of said first datapath instruction processor and said second datapath instruction processor; wherein said first datapath instruction wire bundle is an associated datapath instruction wire bundle of said first datapath instruction processor; wherein said second datapath instruction wire bundle is an associated datapath instruction wire bundle of said second datapath instruction processor; wherein at least one member of said datapath instruction processor collection is further comprised of: a datapath instruction pointer coupled to said clock wire bundle, and to a datapath instruction address wire bundle; and a datapath instruction register coupled to said clock wire bundle, to said asserted datapath instruction wire bundle, and to a datapath instruction wire bundle; wherein said clock wire bundle possesses a datapath instruction capture state; wherein said datapath instruction queue pointer responds to said clock wire bundle by asserting an asserted datapath instruction address; wherein said datapath instruction register responds to said clock wire bundle by capturing a datapath instruction capture state whenever said clock wire bundle is in said datapath instruction capture state; and wherein said datapath instruction register further asserts said associated datapath instruction wire bundle based upon said datapath instruction capture state.","59.The circuit of claim 58, wherein for at least one member of said datapath instruction processor collection comprising said datapath instruction pointer is further comprised of: an instruction store coupled to said datapath instruction address wire bundle and to said datapath instruction wire bundle; wherein said instruction store responds to said asserted datapath instruction address via said datapath instruction address wire bundle to asserting said datapath instruction wire bundle based upon said asserted datapath instruction address.","60.The circuit of claim 59, wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction processor is further comprised of a last instruction indicator coupled to a last instruction indicator wire bundle possessing a last instruction state and a non-last instruction state; wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction pointer is further coupled to a new datapath instruction address wire bundle and to said last instruction indicator wire bundle; and wherein for at least one member of said datapath instruction processor collection comprising said instruction store is further comprised of: a branch-cache instruction processor coupled to said last instruction indicator and to said new datapath instruction address wire bundle; wherein said branch-cache instruction processor responds to said last instruction state via said last instruction indicator wire bundle by asserting a new datapath instruction address upon said new datapath instruction address wire bundle; and wherein said datapath instruction pointer responds to said last instruction indicator wire bundle by capturing said new datapath instruction address from said new datapath instruction address wire bundle.","61.A circuit implementation of claim 46, wherein a component list comprises said arithmetic module circuit, said first memory circuit coupled to said partition control wire bundle, and said first arithmetic logic unit; wherein each member of said component list is implemented with at least part of at least one member of the collection comprising a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array (FPGA); and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.","62.The circuit implementation of claim 61,: wherein the implementation of all members of said component list further includes only circuitry responding to exactly one and the same member of said sample instruction collection based upon said partition control state.","63.A method of processing numeric data, comprising the step of: representing each member of a number collection by an integer part and a special part; log-converting a member of an input number collection to create a member of said number collection; and exp-converting a member of said number collection to create a member of an output number collection; wherein said special part representing said member of said number collection contains of exactly one member of a first special value collection comprising negative-infinity and not-negative-infinity; wherein said special part of each member of said number collection further contains exactly one member of a second special value collection comprising a special-minus and a special-plus; wherein said integer part of each member of said number collection contains a sign and a magnitude; wherein, for each member of said number collection, said sign is a member of a sign collection consisting essentially of a positive-sign and a negative-sign; wherein said number collection comprises at least a first number and a second number; said method further comprising the steps of: performing all members of the arithmetic operation collection upon at least one of said members of said number collection; wherein said arithmetic operation collection is comprised of the steps of: adding said first number to said second number to create an add-result; subtracting said first number by said second number to create a subtract-result; exponentiating said first number to create an exp-result; and logarithming said first number to create a log-result; wherein said number collection is further comprised of said add-result, said subtract-result, said exp-result and said log-result; wherein the step of adding is further comprised of the steps of: determining whether said special part of said first number contains said negative-infinity; determining whether said special part of said second number contains said negative-infinity; and setting said special part of said add-result to contain said negative-infinity whenever said special part of at least one member of the collection said first number and said second number contains said negative-infinity; wherein the step of subtracting is further comprised of the steps of: determining whether said special part of said first number contains said negative-infinity; setting said special part of said subtract-result to contain said negative-infinity whenever said special part of said first number contains said negative-infinity; wherein the step of exponentiating is further comprised of the step of: determining whether said special part of said first number contains said negative-infinity; setting said special part of said exp-result to contain said not-negative-infinity and setting said integer part to a zero-representation whenever said special part of said first number contains said negative-infinity; and setting said sign of said exp-result to essentially said negative-sign whenever said special part of said first number contains said special-minus; wherein the step of logarithming is further comprised of the steps of: determining whether said integer part of said first number is essentially equal to said zero-representation; setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number essentially equals said zero-representation; determining whether said sign part of said first number is essentially equal to said negative-sign; and setting said special part of said log-result to contain said special-minus whenever said sign part of said first number is essentially said negative-sign; wherein said input number collection is comprised of a first input number and a second input number.","wherein each member of said input number collection is comprised of an integer part; wherein the step log-converting said input number collection member is further comprised of the steps of: determining whether said integer part of said input number collection member is essentially equal to said zero-representation; and setting said special part of said number collection member to contain said negative-infinity whenever said integer part of said input number collection member essentially equals said zero-representation.","wherein said output number collection is comprised of a first output number and a second output number; wherein each of said output number collection members include a magnitude; wherein the step exp-converting is further comprised of the steps of: setting said magnitude of said output number collection member to said zero-representation whenever said special part of said number collection member contains said negative-infinity; and setting said sign of said output number collection member to said positive-sign whenever said special part of said number collection member contains said special-plus.","64.The method of claim 63, wherein said integer part of each of said number collection members is in a non-redundant numeric notation; wherein the step of setting said special part of said log-result is further comprised of the step of: setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number equals said zero-representation.","65.The method of claim 63, wherein said integer part of each of said number collection members is in a redundant numeric notation possessing a zero-representation collection comprising at least two zero-representation instances; wherein the step of setting said special part of said log-result is further comprised of the step of: setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number is a member of said zero-representation collection.","66.The method of claim 63, wherein said integer part of each of said number collection members is in a redundant numeric notation supporting determination of negativity by a negative-test collection comprising at least two negative-test steps; where the step determining whether said sign part of said first number is essentially equal to said negative-sign is further comprised of the step of: determining whether said sign part of said first number is equal to said negative-sign based upon performing at least one of the members of said negative-test collection.","67.The method of claim 63, wherein said integer part of each of said number collection members is in a non-redundant numeric notation possessing exactly one negative-test step; wherein the step of determining whether said sign part of said first number is essentially equal to said negative-sign is further comprised of the step of: performing said exactly one negative-test step based upon said first number.","68.The method of claim 63, wherein said integer part of each of said input number collection members contains a sign belonging to said sign collection and a magnitude; wherein the step of log-converting is further comprised of the steps of: determining whether said sign part of said input number collection member is essentially equal to said negative-sign; and setting said special part of said number collection member to contain said special-minus whenever said sign part of said input number collection member is essentially said negative-sign.","69.The method of claim 63, wherein each of said output number collection members include a sign belong to said sign collection; wherein the step exp-converting is further comprised of the step of: setting said sign of said output number collection member to said negative-sign whenever said special part of said number collection member contains said special-minus.","70.The method of claim 69, wherein each of said input number collection members is encoded as an N1 bit code; wherein said N1 is at least three; wherein said integer part of each of said number collection members is encoded as an N2 bit code; wherein N2 is greater than N1.71.A program system for processing numeric data, implementing the steps of claim 63, comprising program steps residing in a memory accessibly coupled to a computer, said program system comprising the program steps of: representing each member of a number collection by an integer part and a special part; log-converting a member of an input number collection to create a member of said number collection; exp-converting a member of said number collection to create a member of an output number collection; determining whether said special part of said first number contains said negative-infinity; adding said first number to said second number to create an add-result; subtracting said first number by said second number to create a subtract-result; exponentiating said first number to create an exp-result; and logarithming said first number to create a log-result.","72.The program system of claim 71, wherein the program steps implementing the method are embodied in at least one member of the language collection comprising C, C++, JAVA, FORTRAN, PASCAL, VERILOG, VHDL, assembly language and executable code for at least one computational engine implemented upon said computer.","73.A digital circuit generated from the program steps of claim 72.74.A circuit for processing numeric data, implementing the steps of claim 63, comprising: means for representing each member of a number collection by an integer part and a special part; means for determining whether said special part of said first number contains said negative-infinity; means for adding said first number to said second number to create an add-result; means for subtracting said first number by said second number to create a subtract-result; means for exponentiating said first number to create an exp-result; and means for logarithming said first number to create a log-result.","75.The circuit of claim 74, wherein at least one of the means of claim 74 is implemented within at least one circuit component belonging to a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array; and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.","76.The circuit of claim 74, wherein at least one of said input number collection members are implemented as a wire state collection received from a wire bundle coupled to said circuit.","77.The circuit of claim 74, wherein at least one of said output number collection members are implemented as a wire state asserted by said circuit onto a wire bundle.","78.A method of processing numeric data, comprising the step of: representing each member of a number collection by an integer part and a special part; wherein said special part representing said member of said number collection contains of exactly one member of a first special value collection comprising negative-infinity and not-negative-infinity; wherein said number collection comprises at least a first number and a second number; said method further comprising the steps of: performing at least one member of the arithmetic operation collection upon at least one of said members of said number collection; wherein said arithmetic operation collection is comprised of the steps of: adding said first number to said second number to create an add-result; subtracting said first number by said second number to create a subtract-result; exponentiating said first number to create an exp-result; and logarithming said first number to create a log-result; wherein said number collection is further comprised of said add-result, said subtract-result, said exp-result and said log-result; wherein the step of adding is further comprised of the steps of: determining whether said special part of said first number contains said negative-infinity; determining whether said special part of said second number contains said negative-infinity; and setting said special part of said add-result to contain said negative-infinity whenever said special part of at least one member of the collection said first number and said second number contains said negative-infinity; wherein the step of subtracting is further comprised of the steps of: determining whether said special part of said first number contains said negative-infinity; setting said special part of said subtract-result to contain said negative-infinity whenever said special part of said first number contains said negative-infinity; wherein the step of exponentiating is further comprised of the step of: determining whether said special part of said first number contains said negative-infinity; setting said special part of said exp-result to contain said not-negative-infinity and setting said integer part to a zero-representation whenever said special part of said first number contains said negative-infinity; wherein the step of logarithming is further comprised of the steps of: determining whether said integer part of said first number is essentially equal to said zero-representation; and setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number essentially equals said zero-representation.","79.The method of claim 78, wherein said integer part of each of said number collection members is in a non-redundant numeric notation; wherein the step of setting said special part of said log-result is further comprised of the step of: setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number equals said zero-representation.","80.The method of claim 78, wherein said integer part of each of said number collection members is in a redundant numeric notation possessing a zero-representation collection comprising at least two zero-representation instances; wherein the step of setting said special part of said log-result is further comprised of the step of: setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number is a member of said zero-representation collection.","81.The method of claim 78, wherein said integer part of each member of said number collection contains a sign and a magnitude; wherein, for each member of said number collection, said sign is a member of a sign collection consisting essentially of a positive-sign and a negative-sign; wherein said special part of each member of said number collection further contains exactly one member of a second special value collection comprising a special-minus and a special-plus; wherein the step of exponentiating is further comprised of the steps of: setting said sign of said exp-result to essentially said negative-sign whenever said special part of said first number contains said special-minus; wherein the step of logarithming is further comprised of the steps of: determining whether said sign part of said first number is essentially equal to said negative-sign; and setting said special part of said log-result to contain said special-minus whenever said sign part of said first number is essentially said negative-sign.","82.The method of claim 81, wherein said integer part of each of said number collection members is in a redundant numeric notation supporting determination of negativity by a negative-test collection comprising at least two negative-test steps; where the step determining whether said sign part of said first number is essentially equal to said negative-sign is further comprised of the step of: determining whether said sign part of said first number is equal to said negative-sign based upon performing at least one of the members of said negative-test collection.","83.The method of claim 81, wherein said integer part of each of said number collection members is in a non-redundant numeric notation possessing exactly one negative-test step; wherein the step of determining whether said sign part of said first number is essentially equal to said negative-sign is further comprised of the step of: performing said exactly one negative-test step based upon said first number.","84.The method of claim 81, further comprising the step of: log-converting a member of an input number collection to create a member of said number collection; wherein said input number collection is comprised of a first input number and a second input number.","85.The method of claim 84, wherein each member of said input number collection is comprised of an integer part; wherein the step log-converting said input number collection member is further comprised of the steps of: determining whether said integer part of said input number collection member is essentially equal to said zero-representation; and setting said special part of said number collection member to contain said negative-infinity whenever said integer part of said input number collection member essentially equals said zero-representation.","86.The method of claim 85, wherein said integer part of each of said input number collection members contains a sign belonging to said sign collection and a magnitude; wherein the step of log-converting is further comprised of the steps of: determining whether said sign part of said input number collection member is essentially equal to said negative-sign; and setting said special part of said number collection member to contain said special-minus whenever said sign part of said input number collection member is essentially said negative-sign.","87.The method of claim 86, further comprising the step of: exp-converting a member of said number collection to create a member of an output number collection; wherein said output number collection is comprised of a first output number and a second output number.","88.The method of claim 87, wherein each of said output number collection members include a magnitude; wherein the step exp-converting is further comprised of the step of: setting said magnitude of said output number collection member to said zero-representation whenever said special part of said number collection member contains said negative-infinity.","89.The method of claim 88, wherein each of said output number collection members include a sign belong to said sign collection; wherein the step exp-converting is further comprised of the steps of: setting said sign of said output number collection member to said negative-sign whenever said special part of said number collection member contains said special-minus; and setting said sign of said output number collection member to said positive-sign whenever said special part of said number collection member contains said special-plus.","90.The method of claim 89, wherein each of said input number collection members is encoded as an N1 bit code; wherein said N1 is at least three; wherein said integer part of each of said number collection members is encoded as an N2 bit code; wherein N2 is greater than N1.91.A program system for processing numeric data, implementing the steps of claim 78, comprising program steps residing in a memory accessibly coupled to a computer, said program system comprising the program steps of: representing each member of a number collection by an integer part and a special part; adding said first number to said second number to create an add-result; subtracting said first number by said second number to create a subtract-result; exponentiating said first number to create an exp-result; and logarithming said first number to create a log-result.","92.The program system of claim 78, wherein the program steps implementing the method are embodied in at least one member of the language collection comprising C, C++, JAVA, FORTRAN, PASCAL, VERILOG, VHDL, assembly language and executable code for at least one computational engine implemented upon said computer.","93.A circuit generated from the program steps of claim 92.94.A circuit for processing numeric data, implementing the steps of claim 78, comprising: means for representing each member of a number collection by an integer part and a special part; means for adding said first number to said second number to create an add-result; means for subtracting said first number by said second number to create a subtract-result; means for exponentiating said first number to create an exp-result; and means for logarithming said first number to create a log-result.","95.The circuit of claim 94, wherein at least one of the means of claim 94 is implemented within at least one circuit component belonging to a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array; and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.","96.The circuit of claim 94, wherein at least one of said input number collection members are implemented as a wire state collection received from a wire bundle coupled to said circuit.","97.The circuit of claim 94, wherein at least one of said output number collection members are implemented as a wire state asserted by said circuit onto a wire bundle."],["<SOH> BACKGROUND OF INVENTION <EOH>Today, much of the growth in the planetary economy depends on rapid and reliable development of new products, many of which require Digital Signal Processing (DSP) hardware to solve the problems which attract customers to buy such products.","These problems are often solved by a wide variety of digital filtering techniques, often based upon Finite Impulse Response (FIR) filtering including various Discrete Fourier Transform based algorithms as well as Discrete Wavelet Transform algorithms.","Most of these response and transform functions are linear in nature.","Many of these functions operate on a finite grid of data, frequently known as a data window.","While existing hardware vehicles provide vehicles for such algorithms, there are several central problems which are difficult to solve with existing solutions.","Many application systems need non-linear functions.","Some commonly used arithmetic operations in engineering and applied science include but are not limited to the following: square roots, cube roots, division, trigonometric functions, powers of numbers, polynomial functions, rational functions, exponential functions, logarithms, and determinants.","These commonly used arithmetic operations have found significant application in at least the areas of graphics models, statistical and probabilistic tools, dynamical systems, flow simulations, control systems, transistor and circuit modeling and other nonlinear models.","Additionally, there are large applications in the areas of multimedia and image processing including the requirements of filling an HDTV screen with an MPEG stream and various medical imaging applications.","The cellular radio industry possesses a number of base station related applications including 911 call location determination and signal separation in high capacity situations.","What is needed is arithmetic processing circuitry which can address at least these needs in a real-time fashion.","The above mentioned finite grids of data are often sampled in real-time by sensor devices.","Each data sample can vary from as small as 6 bits per data sample to 17 or more bits per data sample.","Usually, the data tends to be of fairly uniform size, the number of sample bits does not vary much, if at all, across a data grid.","Most DSP hardware has a fixed input data size, usually a multiple of 8 or 9 bits.","The consequence of this is that bits go unused.","By way of example, in a device supporting only 8 and 16 bit data input, a 9 bit sample requires all 16 bits be used, even though only slightly more than 50% of the input bits are actively being used.","Further, the data is often sampled at very high rates by multiple sensors, ranging from hundred of thousands of samples per second per sensor to a hundred million samples per second per sensor.","What is further needed is a high speed capability to efficiently accept and process widely varying data sample widths.","Today, arithmetic-based models are in widespread use employing various fixed point and floating point numeric representations.","There is a central problem associated with these representations, the accumulation of arithmetic errors.","This is an architectural result of the limited structural capabilities of contemporary arithmetic processors.","Such processors typically can only perform arithmetic of a fixed number of significant bits in a given instruction execution period.","The consequence of this is that as calculations progress, additional precision is required, but not available.","What is needed is arithmetic circuitry which can be readily configured to provide a wide range of precision for any given instruction sequence in a given instruction execution period.","By way of example, many real-time DSP applications possess the following common constraints.","High speed input sample rates, often on the order of 100K to 100 Million samples per second.","High output result rates, due to the prohibitive expense of storing these samples for longer than a few milliseconds to a few seconds.","Data sample sizes varying from 6 to 16 bits per sample, with a concomitant requirement to preserve or improve the signal to noise ratio from input sensors to internal use of these samples.","Many of these applications are developed against a further constraint of short time-to-market requirement.","Contemporary approaches to the performance problems of DSP include standard instruction processors, VLIW processors and reconfigurable computers.","Standard instruction processors can be further classified as embedded core DSP processors, Single Instruction Single Datapath (SISD) processors and Multiple Instruction Multiple Datapath (MIMD) processors.","Commercial examples of mbedded core DSP processors include the DSP group Oak and Pine processors.","Commercial examples of SISD processors include some of the components of the Analog Devices ADSP product line and products of the Texas Instrument 54XX DSP Family.","Commercial examples of MIMD products include the high-end products of the ADSP product line.","Commercial examples of VLIW processors can be found in the TI 60XX DSP product family.","There are at least two distinct performance bottlenecks which affect all or nearly all of the above mentioned approaches to arithmetic and instruction processing: the instruction fetch bottleneck and data access bottleneck.","The instruction fetch bottleneck is caused by the imbalance of memory access rate compared to instruction processing mechanisms.","Various approaches to solving this problem include adding cache memories, which then put the balance in favor of memories.","This leads to compensating by incorporating instruction decoders operating upon multiple instructions as found in super-scalar microprocessors.","Such circuitry increases the instruction processing capability of a single instruction path device, by greatly increasing the relative size of the instruction decoding mechanism to the arithmetic processors, as well as increasing the complexity of verifying instruction set execution compliance.","What is needed is a flexible instruction processing mechanism which can more efficiently utilize instruction memory bandwidth to drive the arithmetic processing circuitry.","The data access bottleneck often arises when memory is shared with other processes, such as the instruction fetching process mentioned above.","The standard approach to minimizing this problem is the use of either separate memories or providing caches, which in many cases are specifically dedicated to data memory operations.","While these approaches add to the availability of data for arithmetic processing, they do not address what the following major limitations found in all of the prior art.","The prior art does not provide the user with direct control over the input data width, the internal or intermediate precision width, nor the output data width.","What is needed is a way to provide the user of these circuits with direct control over input data with, internal or intermediate precision width and outut data width.","Today, VLIW architectures are available which show some flexibility, but are difficult to program due to complex, multiple-memory cycle instruction fetching mechanism, as well as having little or no flexibility regarding input data widths, internal/intermediate precision and output data widths.","Reconfigurable computers have been extensively researched since the 1990's, but have yet to have large scale commercial success.","These computer have been largely constructed from arrays of FPGA's.","They have tended to be very difficult to program, often requiring gate level or logic cell level programming, as opposed to support procedural computer language compilers.","Such computer also tend to have problems with multiplication.","While some FPGAs now contain cells supporting small multipliers, often 4 by 4 or 4 by 5 bit multipliers, when even a 16 by 16 bit multiplication is to be done, somewhere between 6 and 16 of these cells must be dedicated to that task.","Multipliers built this way do not lend themselves to ease of programming nor show themselves flexible in terms of changing input data width or output data width requirements.","Most people require less development time to create numeric applications using procedural programming languages such as C or Java than using assembly language, much less a gate or function cell level definition language.","The fact that it is possible to build a multiplier with an FPGA is not the problem system developers have to solve.","What is needed is a mechanism providing the user with direct control over the input data width, the internal/intermediate precision width, and the output data width while providing a wide range of arithmetic operations in an efficient fashion.","What is further needed is a method of specifying such control and then generating efficient circuits satisfying those specifications.","What is further needed is an architecture which provides standard procedural language compiler support both for mechanisms supporting user control of input data width, internal/intermediate precision and output data width.","What is further needed is a target circuit compilation architecture providing automated support for procedural compilers specified and generated by such methods.","There are further problems in the organization of instruction processing mechanisms which significantly constrain performance due to the fixed configuration of internal operational resources.","By way of example, the number of arithmetic processing resources available to prepare for a branch decision is fixed.","However, high performance arithmetic-oriented applications often involve very large numbers of arithmetic operations being performed before any branching decisions need be made.","When branching is to be performed, a number of relatively short operation sequences are usually needed to determine the flow of execution and control.","What is needed is an instruction processing mechanism which can be optimally configured for both decision processes and computational sequences.","Today, multiple datapath architectures are either Single Instruction Multiple Datapath (SIMD) or Multiple Instruction Multiple Datapath (MIMD).","However, there are times when a system optimally acts in one fashion, and other times when it optimally would perform in the other fashion.","What is needed is an architecture supporting multiple datapaths in either an SIMD or MIMD mode, which can be rapidly reconfigured from one to the other.","There are additional problems facing the system designer intent upon making a new product: the system designer must often provide a complete systems solution, which often includes a package containing one or more printed circuits, which further contain integrated circuits performing numeric tasks within the package in normal operating modes.","The system designer needs to be able to test the printed circuits containing the integrated circuits in operation as early in the design process as possible.","Additionally, while there have been various attempts to use logarithmic numeric notations to perform arithmetic operations, none of the known approaches are readily extensible to varying precision widths.","Such notations tend to treat numbers as either floating point numbers possessing an exponent and mantissa, or as a fixed point number.","Both mechanisms have decided problems when applied to the varying needs of systems design, where the notation must be useful across a large collection of numeric ranges.","Floating point notations have fixed fields, which further tend to hide the most significant bit of the mantissa, rendering such a notation is inherently difficult to alter.","Both approaches to number notations lack any obvious way to convert 0 into a logarithm of 0.What is needed is a numeric notation readily supporting logarithmic numbers as well as being readily scalable to support differing amounts of precision in a real-time environment.","To summarize, what is needed is arithmetic processing circuitry addressing the need for advanced, often non-linear functions based upon much more than linear arithmetic operations in a real-time fashion.","Such operations include but are not limited to square roots, division, trigonometric functions, powers of numbers, polynomial functions, rational functions, exponential functions, logarithms, and determinants.","What is needed includes the ability to efficiently accept and process widely varying data sample widths at high speeds.","What is needed is arithmetic circuitry readily configured to provide a wide range of precision for any given instruction sequence in a given instruction execution period.","What is needed is a flexible instruction processing mechanism which can more efficiently utilize instruction memory bandwidth to drive the arithmetic processing circuitry.","What is needed is an instruction processing mechanism which can be optimally configured for both decision processes and computational sequences.","What is needed is an architecture supporting multiple datapaths in either an SIMD or MIMD mode, which can be rapidly reconfigured from one to the other.","What is needed is a mechanism providing the user with direct control over the input data width, the internal/intermediate precision width, and the output data width while providing a wide range of arithmetic operations in an efficient fashion.","What is further needed is a method of specifying such control and then generating efficient circuits satisfying those specifications.","What is further needed is an architecture which provides standard procedural language compiler support both for mechanisms supporting user control of input data width, internal/intermediate precision and output data width.","What is further needed is a target circuit compilation architecture providing automated support for procedural compilers specified and generated by such methods."],["<SOH> SUMMARY OF INVENTION <EOH>Certain embodiments of the invention solve all the above mentioned problems found in the prior art.","Certain embodiments utilize partitionable datapath bit width units, which can be configured to provide a requested level of numeric precision.","The partitionable datapath bid width units include at least memory arrays and ALUs, which can collectively be configured to specific bit widths supporting the requested level of numeric precision in both a normal numeric realm and a logarithmic numeric domain.","Certain embodiments of the invention represent a collection of numbers as having at least a minus-infinity as a special part of each represented number.","These minus-infinity numbers act as annihilators in addition, so that minus-infinity plus anything else results in a minus-infinity in the special part of the represented result.","Thus, the fact that zero multiplying anything in the normal numeric realms translates upon taking logarithms of both numbers.","The logarithmic conversion of a zero yields a represented number with a minus-infinity.","The exponential conversion of a represented number with negative-infinity in its special part yields a 0 result.","Represented numbers may further include a special-plus or special-minus in their special parts, further supporting preservation of the input number sign upon into the represented number and conversion back to output numbers.","Note that this also requires that special-minus represented numbers, when added to special-minus represented numbers generate a represented number result with a special-plus.","Special-plus added to special-plus results in a special-plus.","When a special-minus number and a special-plus number are added, the result is a special-minus result.","This effects a logarithm of a first number added to the logarithm of a second number is essentially the same as the logarithm of the product of the first and second numbers.","In the logarithm domain, functions can be calculated which are very computationally expensive in the normal realm of numbers.","A level of efficiency previously unavailable in a programmable device of any kind is achieved by using at least some of the memories as table lookup mechanisms to approximately convert numbers between their logarithms, exponentials and other functions.","Certain embodiments of the invention include a method of using an array of computational resources containing at least one input-output resource, at least one datapath operational resource comprising: selecting the input-output resources to create an input-output access collection comprised of at least an input-output access parameter; and selecting the datapath operational resources based upon the input-output access collection to create a datapath operational resource allocation collection containing at least one datapath operation resource allocation.","This supports selecting input-output resources for optimal data bandwidth throughput.","They also support selecting datapath operational resources for optimal datapath resource allocation operating on data traversing the selected input-output resources.","The computation resource array may contain at least one instruction propagating resource.","The method may selecting the instruction propagating resources based upon the input-output access collection and the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration.","The computation resource array may further contain at least one instruction processing resource.","Instruction processing resources may further be selected based upon the input-output access collection, datapath operational resource allocation and instruction propagating configuration.","The instruction processing resources may contain at least one instruction register.","The computation resource array may further contain at least one instruction fetching resource.","The method may include fetching using the instruction fetching resource to create a fetched instruction and loading the fetched instruction into the instruction register to create an instruction register state based upon the fetched instruction.","Certain embodiments of the invention include circuits generated by methods of this invention.","They may be implemented using collections of one or more programmable logic devices, which may in turn include one or more programmable logic arrays and/or one or more Field Programmable Gate Arrays (FPGAs).","They may be implemented as part or all of an integrated circuit, having been specified using a method of this invention and/or simulated based upon their specification.","Their simulation may include implementations targeting logic hardware accelerators including programmable logic devices as execution elements.","Certain embodiments of the invention include an arithmetic module of multiple basic arithmetic circuits coupled to share several wire bundles including a first shared buss, a second shared buss and a third shared buss that synchronously execute either one or two instructions, depending upon a configuration register.","The shared bus wire bundle state is determined in part by the configuration register.","Each basic arithmetic circuit includes a basic arithmetic memory coupled with a basic arithmetic calculator."],["This application claims priority from the following provisional applications filed with the United States Patent and Trademark Office: Ser.","No.","60/204,113, entitled “Method and apparatus of a digital arithmetic and memory circuit with coupled control system and arrays thereof”, filed May 15, 2000 by inventor, docket number ARITH001PR; Ser.","No.","60/215,894, entitled “Method and apparatus of a digital arithmetic and memory circuit with coupled control system and arrays thereof”, filed Jul.","5, 2000 by inventor, docket number ARITH002PR; Ser.","No.","60/217,353, entitled “Method and apparatus of a digital arithmetic and memory circuit with coupled control system and arrays thereof”, filed Jul.","11, 2000 by inventor, docket number ARITH003PR; Ser.","No.","60/231,873, entitled “Method and apparatus of a digital arithmetic and memory circuit with coupled control system and arrays thereof”, filed Sep. 12, 2000 by inventor, docket number ARITH004PR; Ser.","No.","60/261,066, entitled “Method and apparatus of a DSP resource circuit”, filed Jan. 11, 2001 by inventor, docket number ARITH005PR; and Ser.","No.","60/282,093, entitled “Method and apparatus of a DSP resource circuit”, filed Apr.","6, 2001 by inventor, docket number ARITH006PR.","TECHNICAL FIELD This invention relates to digital signal processing engines, instruction processing mechanisms, arithmetic operational units of same, as well as circuitry generated based upon use of some or all of these elements.","BACKGROUND OF INVENTION Today, much of the growth in the planetary economy depends on rapid and reliable development of new products, many of which require Digital Signal Processing (DSP) hardware to solve the problems which attract customers to buy such products.","These problems are often solved by a wide variety of digital filtering techniques, often based upon Finite Impulse Response (FIR) filtering including various Discrete Fourier Transform based algorithms as well as Discrete Wavelet Transform algorithms.","Most of these response and transform functions are linear in nature.","Many of these functions operate on a finite grid of data, frequently known as a data window.","While existing hardware vehicles provide vehicles for such algorithms, there are several central problems which are difficult to solve with existing solutions.","Many application systems need non-linear functions.","Some commonly used arithmetic operations in engineering and applied science include but are not limited to the following: square roots, cube roots, division, trigonometric functions, powers of numbers, polynomial functions, rational functions, exponential functions, logarithms, and determinants.","These commonly used arithmetic operations have found significant application in at least the areas of graphics models, statistical and probabilistic tools, dynamical systems, flow simulations, control systems, transistor and circuit modeling and other nonlinear models.","Additionally, there are large applications in the areas of multimedia and image processing including the requirements of filling an HDTV screen with an MPEG stream and various medical imaging applications.","The cellular radio industry possesses a number of base station related applications including 911 call location determination and signal separation in high capacity situations.","What is needed is arithmetic processing circuitry which can address at least these needs in a real-time fashion.","The above mentioned finite grids of data are often sampled in real-time by sensor devices.","Each data sample can vary from as small as 6 bits per data sample to 17 or more bits per data sample.","Usually, the data tends to be of fairly uniform size, the number of sample bits does not vary much, if at all, across a data grid.","Most DSP hardware has a fixed input data size, usually a multiple of 8 or 9 bits.","The consequence of this is that bits go unused.","By way of example, in a device supporting only 8 and 16 bit data input, a 9 bit sample requires all 16 bits be used, even though only slightly more than 50% of the input bits are actively being used.","Further, the data is often sampled at very high rates by multiple sensors, ranging from hundred of thousands of samples per second per sensor to a hundred million samples per second per sensor.","What is further needed is a high speed capability to efficiently accept and process widely varying data sample widths.","Today, arithmetic-based models are in widespread use employing various fixed point and floating point numeric representations.","There is a central problem associated with these representations, the accumulation of arithmetic errors.","This is an architectural result of the limited structural capabilities of contemporary arithmetic processors.","Such processors typically can only perform arithmetic of a fixed number of significant bits in a given instruction execution period.","The consequence of this is that as calculations progress, additional precision is required, but not available.","What is needed is arithmetic circuitry which can be readily configured to provide a wide range of precision for any given instruction sequence in a given instruction execution period.","By way of example, many real-time DSP applications possess the following common constraints.","High speed input sample rates, often on the order of 100K to 100 Million samples per second.","High output result rates, due to the prohibitive expense of storing these samples for longer than a few milliseconds to a few seconds.","Data sample sizes varying from 6 to 16 bits per sample, with a concomitant requirement to preserve or improve the signal to noise ratio from input sensors to internal use of these samples.","Many of these applications are developed against a further constraint of short time-to-market requirement.","Contemporary approaches to the performance problems of DSP include standard instruction processors, VLIW processors and reconfigurable computers.","Standard instruction processors can be further classified as embedded core DSP processors, Single Instruction Single Datapath (SISD) processors and Multiple Instruction Multiple Datapath (MIMD) processors.","Commercial examples of mbedded core DSP processors include the DSP group Oak and Pine processors.","Commercial examples of SISD processors include some of the components of the Analog Devices ADSP product line and products of the Texas Instrument 54XX DSP Family.","Commercial examples of MIMD products include the high-end products of the ADSP product line.","Commercial examples of VLIW processors can be found in the TI 60XX DSP product family.","There are at least two distinct performance bottlenecks which affect all or nearly all of the above mentioned approaches to arithmetic and instruction processing: the instruction fetch bottleneck and data access bottleneck.","The instruction fetch bottleneck is caused by the imbalance of memory access rate compared to instruction processing mechanisms.","Various approaches to solving this problem include adding cache memories, which then put the balance in favor of memories.","This leads to compensating by incorporating instruction decoders operating upon multiple instructions as found in super-scalar microprocessors.","Such circuitry increases the instruction processing capability of a single instruction path device, by greatly increasing the relative size of the instruction decoding mechanism to the arithmetic processors, as well as increasing the complexity of verifying instruction set execution compliance.","What is needed is a flexible instruction processing mechanism which can more efficiently utilize instruction memory bandwidth to drive the arithmetic processing circuitry.","The data access bottleneck often arises when memory is shared with other processes, such as the instruction fetching process mentioned above.","The standard approach to minimizing this problem is the use of either separate memories or providing caches, which in many cases are specifically dedicated to data memory operations.","While these approaches add to the availability of data for arithmetic processing, they do not address what the following major limitations found in all of the prior art.","The prior art does not provide the user with direct control over the input data width, the internal or intermediate precision width, nor the output data width.","What is needed is a way to provide the user of these circuits with direct control over input data with, internal or intermediate precision width and outut data width.","Today, VLIW architectures are available which show some flexibility, but are difficult to program due to complex, multiple-memory cycle instruction fetching mechanism, as well as having little or no flexibility regarding input data widths, internal/intermediate precision and output data widths.","Reconfigurable computers have been extensively researched since the 1990's, but have yet to have large scale commercial success.","These computer have been largely constructed from arrays of FPGA's.","They have tended to be very difficult to program, often requiring gate level or logic cell level programming, as opposed to support procedural computer language compilers.","Such computer also tend to have problems with multiplication.","While some FPGAs now contain cells supporting small multipliers, often 4 by 4 or 4 by 5 bit multipliers, when even a 16 by 16 bit multiplication is to be done, somewhere between 6 and 16 of these cells must be dedicated to that task.","Multipliers built this way do not lend themselves to ease of programming nor show themselves flexible in terms of changing input data width or output data width requirements.","Most people require less development time to create numeric applications using procedural programming languages such as C or Java than using assembly language, much less a gate or function cell level definition language.","The fact that it is possible to build a multiplier with an FPGA is not the problem system developers have to solve.","What is needed is a mechanism providing the user with direct control over the input data width, the internal/intermediate precision width, and the output data width while providing a wide range of arithmetic operations in an efficient fashion.","What is further needed is a method of specifying such control and then generating efficient circuits satisfying those specifications.","What is further needed is an architecture which provides standard procedural language compiler support both for mechanisms supporting user control of input data width, internal/intermediate precision and output data width.","What is further needed is a target circuit compilation architecture providing automated support for procedural compilers specified and generated by such methods.","There are further problems in the organization of instruction processing mechanisms which significantly constrain performance due to the fixed configuration of internal operational resources.","By way of example, the number of arithmetic processing resources available to prepare for a branch decision is fixed.","However, high performance arithmetic-oriented applications often involve very large numbers of arithmetic operations being performed before any branching decisions need be made.","When branching is to be performed, a number of relatively short operation sequences are usually needed to determine the flow of execution and control.","What is needed is an instruction processing mechanism which can be optimally configured for both decision processes and computational sequences.","Today, multiple datapath architectures are either Single Instruction Multiple Datapath (SIMD) or Multiple Instruction Multiple Datapath (MIMD).","However, there are times when a system optimally acts in one fashion, and other times when it optimally would perform in the other fashion.","What is needed is an architecture supporting multiple datapaths in either an SIMD or MIMD mode, which can be rapidly reconfigured from one to the other.","There are additional problems facing the system designer intent upon making a new product: the system designer must often provide a complete systems solution, which often includes a package containing one or more printed circuits, which further contain integrated circuits performing numeric tasks within the package in normal operating modes.","The system designer needs to be able to test the printed circuits containing the integrated circuits in operation as early in the design process as possible.","Additionally, while there have been various attempts to use logarithmic numeric notations to perform arithmetic operations, none of the known approaches are readily extensible to varying precision widths.","Such notations tend to treat numbers as either floating point numbers possessing an exponent and mantissa, or as a fixed point number.","Both mechanisms have decided problems when applied to the varying needs of systems design, where the notation must be useful across a large collection of numeric ranges.","Floating point notations have fixed fields, which further tend to hide the most significant bit of the mantissa, rendering such a notation is inherently difficult to alter.","Both approaches to number notations lack any obvious way to convert 0 into a logarithm of 0.What is needed is a numeric notation readily supporting logarithmic numbers as well as being readily scalable to support differing amounts of precision in a real-time environment.","To summarize, what is needed is arithmetic processing circuitry addressing the need for advanced, often non-linear functions based upon much more than linear arithmetic operations in a real-time fashion.","Such operations include but are not limited to square roots, division, trigonometric functions, powers of numbers, polynomial functions, rational functions, exponential functions, logarithms, and determinants.","What is needed includes the ability to efficiently accept and process widely varying data sample widths at high speeds.","What is needed is arithmetic circuitry readily configured to provide a wide range of precision for any given instruction sequence in a given instruction execution period.","What is needed is a flexible instruction processing mechanism which can more efficiently utilize instruction memory bandwidth to drive the arithmetic processing circuitry.","What is needed is an instruction processing mechanism which can be optimally configured for both decision processes and computational sequences.","What is needed is an architecture supporting multiple datapaths in either an SIMD or MIMD mode, which can be rapidly reconfigured from one to the other.","What is needed is a mechanism providing the user with direct control over the input data width, the internal/intermediate precision width, and the output data width while providing a wide range of arithmetic operations in an efficient fashion.","What is further needed is a method of specifying such control and then generating efficient circuits satisfying those specifications.","What is further needed is an architecture which provides standard procedural language compiler support both for mechanisms supporting user control of input data width, internal/intermediate precision and output data width.","What is further needed is a target circuit compilation architecture providing automated support for procedural compilers specified and generated by such methods.","SUMMARY OF INVENTION Certain embodiments of the invention solve all the above mentioned problems found in the prior art.","Certain embodiments utilize partitionable datapath bit width units, which can be configured to provide a requested level of numeric precision.","The partitionable datapath bid width units include at least memory arrays and ALUs, which can collectively be configured to specific bit widths supporting the requested level of numeric precision in both a normal numeric realm and a logarithmic numeric domain.","Certain embodiments of the invention represent a collection of numbers as having at least a minus-infinity as a special part of each represented number.","These minus-infinity numbers act as annihilators in addition, so that minus-infinity plus anything else results in a minus-infinity in the special part of the represented result.","Thus, the fact that zero multiplying anything in the normal numeric realms translates upon taking logarithms of both numbers.","The logarithmic conversion of a zero yields a represented number with a minus-infinity.","The exponential conversion of a represented number with negative-infinity in its special part yields a 0 result.","Represented numbers may further include a special-plus or special-minus in their special parts, further supporting preservation of the input number sign upon into the represented number and conversion back to output numbers.","Note that this also requires that special-minus represented numbers, when added to special-minus represented numbers generate a represented number result with a special-plus.","Special-plus added to special-plus results in a special-plus.","When a special-minus number and a special-plus number are added, the result is a special-minus result.","This effects a logarithm of a first number added to the logarithm of a second number is essentially the same as the logarithm of the product of the first and second numbers.","In the logarithm domain, functions can be calculated which are very computationally expensive in the normal realm of numbers.","A level of efficiency previously unavailable in a programmable device of any kind is achieved by using at least some of the memories as table lookup mechanisms to approximately convert numbers between their logarithms, exponentials and other functions.","Certain embodiments of the invention include a method of using an array of computational resources containing at least one input-output resource, at least one datapath operational resource comprising: selecting the input-output resources to create an input-output access collection comprised of at least an input-output access parameter; and selecting the datapath operational resources based upon the input-output access collection to create a datapath operational resource allocation collection containing at least one datapath operation resource allocation.","This supports selecting input-output resources for optimal data bandwidth throughput.","They also support selecting datapath operational resources for optimal datapath resource allocation operating on data traversing the selected input-output resources.","The computation resource array may contain at least one instruction propagating resource.","The method may selecting the instruction propagating resources based upon the input-output access collection and the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration.","The computation resource array may further contain at least one instruction processing resource.","Instruction processing resources may further be selected based upon the input-output access collection, datapath operational resource allocation and instruction propagating configuration.","The instruction processing resources may contain at least one instruction register.","The computation resource array may further contain at least one instruction fetching resource.","The method may include fetching using the instruction fetching resource to create a fetched instruction and loading the fetched instruction into the instruction register to create an instruction register state based upon the fetched instruction.","Certain embodiments of the invention include circuits generated by methods of this invention.","They may be implemented using collections of one or more programmable logic devices, which may in turn include one or more programmable logic arrays and/or one or more Field Programmable Gate Arrays (FPGAs).","They may be implemented as part or all of an integrated circuit, having been specified using a method of this invention and/or simulated based upon their specification.","Their simulation may include implementations targeting logic hardware accelerators including programmable logic devices as execution elements.","Certain embodiments of the invention include an arithmetic module of multiple basic arithmetic circuits coupled to share several wire bundles including a first shared buss, a second shared buss and a third shared buss that synchronously execute either one or two instructions, depending upon a configuration register.","The shared bus wire bundle state is determined in part by the configuration register.","Each basic arithmetic circuit includes a basic arithmetic memory coupled with a basic arithmetic calculator.","BRIEF DESCRIPTION OF DRAWINGS FIG.","1 depicts a basic arithmetic processing unit 1400 comprised of a first memory circuit 1200 and a first ALU 1300 in accordance with certain embodiments of the invention; FIG.","2 shows a refinement of FIG.","1 further depicting an input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 of basic arithmetic unit 1400; FIG.","3 shows a refinement of FIG.","2 further depicting input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 and further coupled to a second memory circuit 1250 forming a basic arithmetic unit 1402, which is a refinement of basic arithmetic unit 1400; FIG.","4 shows a refinement of FIG.","3 depicting input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 and coupled to a second memory circuit 1400 with additional interconnections forming a basic arithmetic unit 1402, which is a refinement of basic arithmetic unit 1400; FIG.","5 shows a refinement of FIGS.","1, 2, 3 and 4 depicting input-output circuit 1100 coupled to multiple instances of basic arithmetic unit 1400; FIG.","6 shows a refinement of FIG.","5 depicting a first input-output circuit 1100 coupled to multiple instances of basic arithmetic unit 1400 and a second instance of input-output circuit 1100; FIG.","7 shows a detail diagram of an ALU circuit 1300 in terms of four interconnected instances of a second ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002; FIG.","8 shows a detail diagram of first ALU circuit 1300 in terms of eight interconnected instances of a second ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002; FIG.","9 depicts an arithmetic logic unit 1310 with multiple add-inputs presented to shifters and then added to generate an add-result; FIG.","10 shows Arithmetic Process Array 3000 comprising at least one Arithmetic Processor 3002, each coupled with 3104 Instruction Memory 3200 and with 3106 Instruction Memory 3300; FIG.","11A show a single column of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8; FIG.","11B show four columns of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8; FIGS.","12 to 16 show a configuration of instruction memories and MSRI[K] sufficient to perform a large number of realtime filtering and more sophisticated tasks upon an input stream of 8 or 9 bit samples; FIG.","17A show a single column of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8, with two instructions memories 3200 and 3300 providing two instructions transmitted to each.","Note that in other embodiments of the invention, i could range over a different range; FIG.","17B show four columns of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8, with two instructions memories 3200 and 3300 providing two instructions transmitted to each.","FIGS.","18 to 20 show various configurations of PISRI's and their neighboring instruction memories; FIG.","21 shows a high level data flow diagram of a two dimensional array block 1300 of ALU2 circuits 1310 and connecting datapaths between them by which data may be transported; FIG.","22A depicts a flowchart performing a method of using an array of computational resources containing at least one input-output resource and at least one datapath operational resource; FIG.","22B depicts a detail flowchart of user operation 2000 of FIG.","22A further performing selecting the instruction propagating resources based upon the input-output access collection and based upon the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration; FIG.","23A depicts a detail flowchart of user operation 2000 of FIG.","22A performing selecting the instruction processing resources based upon the input-output access collection, the datapath operational resource allocation collection, and the instruction propagating configuration collection to create an instruction processing configuration collection containing at least one instruction processing configuration; FIG.","23B depicts a detail flowchart of user operation 2000 of FIG.","22A further performing the method of using/operating the array of computational resources; FIG.","24A shows a detail block diagram of an instruction memory 3200 comprised of instruction register 3600, branch processor 3700 and instruction memory array 3500; FIG.","24B shows a detail block diagram of an instruction memory 3200 extending the block diagram of FIG.","24A further comprised of instruction fetch mechanism 3800; FIG.","25 shows a detail block diagram of an branch processor 3700 comprised of branch sequence register 3710, program counter 3730 and branch address look-up table 3720; and FIG.","26 shows a detail block diagram of a branch processor 3700 extending the block diagram of FIG.","25 further comprised of cache manager 3740; FIG.","27 depicts a high level system block diagram of a DSP Resource Circuit in accordance with certain embodiments of the invention; FIG.","28 depicts a simplified floor plan of a layout of the DSP Resource Circuit of FIG.","27; FIG.","29 depicts a preferred version of ALU 1400, as used in FIG.","28 and earlier Figures supporting configurations of its internal memories and system input 1002 emulating a multiplier-accumulator with local register bank; FIG.","30 depicts a flowchart of a method of processing numeric data, which may be variously embodied; FIG.","31 depicts a detail flowchart of operation 2222 of FIG.","30 further performing the arithmetic operation collection; FIG.","32A depicts a detail flowchart of operation 2272 of FIG.","31 further adding; FIG.","32B depicts a detail flowchart of operation 2282 of FIG.","31 further subtracting; FIG.","33A depicts a detail flowchart of operation 2292 of FIG.","31 further exponentiating; FIG.","33B depicts a detail flowchart of operation 2302 of FIG.","31 further logarithming; FIG.","34A depicts a detail flowchart of operation 2442 of FIG.","33B further setting the special part of the log-result; FIG.","34B depicts a detail flowchart of operation 2442 of FIG.","33B further setting the special part of the log-result; FIG.","35A depicts a detail flowchart of operation 2292 of FIG.","31 further exponentiating; FIG.","35B depicts a detail flowchart of operation 2302 of FIG.","31 further logarithming; FIG.","36A depicts a detail flowchart of operation 2532 of FIG.","35B further determining whether the sign part of the first number is essentially equal to the negative-sign; FIG.","36B depicts a detail flowchart of operation 2532 of FIG.","35B further determining whether the sign part of the first number is essentially equal to the negative-sign; FIG.","37A depicts a detail flowchart of operation 2232 of FIG.","30 further log-converting the input number collection member; FIG.","37B depicts a detail flowchart of operation 2232 of FIG.","30 further log-converting the input number collection member; FIG.","38A depicts a detail flowchart of operation 2242 of FIG.","30 further exp-converting; and FIG.","38B depicts a detail flowchart of operation 2242 of FIG.","30 further exp-converting.","DETAILED DESCRIPTION OF DRAWINGS As used herein a wire refers to a path connecting nodes of a circuit which carries a state between the connected nodes and/or refers to a resonant cavity propagating information in terms of state between the connected nodes.","A wire may be made out of metal, an optical chamber, or a tunnel path through a molecular substrate.","A wire bundle is a collection of at least one wire.","State as used herein refers to an element of a finite alphabet, which contains at least two symbols.","These two minimal symbols relate to ‘0’ and ‘1’ as used in Boolean logic.","FIG.","1 depicts a basic arithmetic processing unit 1400 comprised of a first memory circuit 1200 and a first ALU 1300 in accordance with certain embodiments of the invention.","The basic arithmetic unit 1400 includes a partitioning wire bundle 1002 presented to first memory circuit 1200 and first ALU 1300.Input wire bundle 1008 is presented to first memory circuit 1200 and first ALU 1300.Input wire bundle 1010 is presented only to first memory circuit 1200.First memory instruction wire bundle 1202 is presented to first memory circuit 1200.First memory circuit 1200 generates signals for first memory output wire bundle 1016 presented to first ALU 1300.First ALU instruction wire bundle 1302 is presented to first ALU circuit 1300.First ALU 1300 receives a carry-in wire bundle 1150, first ALU instruction wire bundle 1302 and generates a carry-out wire bundle 1152 and further generates signals for first ALU output wire bundle 1018.The basic arithmetic processing unit operates by receiving the signal state of partitioning wire bundle 1002, which determines the partitioning of the signaling of input wire bundle 1008, input wire bundle 1010, first memory output wire bundle 1016 and first ALU output wire bundle 1018, as well as first memory instruction wire bundle 1202, first ALU instruction wire bundle 1302 and carry-input wire bundle 1150.The received signal state of the partitioning wire bundle 1.002, further determines the operational partitioning of first memory circuit 1200 and first ALU circuit 1300 with regards to the signaling of input wire bundle 1008, input wire bundle 1010, first memory output wire bundle 1016 and first ALU output wire bundle 1018.First memory circuit 1200 receives the signal state of partitioning wire bundle 1002, which determines the partitioning of the signaling of input wire bundle 1008, input wire bundle 1010 and first memory instruction wire bundle 1202.Partitioning wire bundle 1002 signal state is used by first memory circuit 1200 to determine from the signal state of first memory instruction wire bundle 1202 at least one of first memory local instructions to be executed.","The first memory local instructions are executed by the first memory circuit 1200.First memory circuit 1200 asserts the signal state of first memory output wire bundle 1016.First ALU 1300 receives the signal state of partitioning wire bundle 1002, which determines the partitioning of the signaling of input wire bundle 1008, first memory output wire bundle 1016, first ALU instruction wire bundle 1302 and the effect of the signal state of carry-input wire bundle 1150.Partitioning wire bundle 1002 signal state is used by first ALU circuit 1300 to determine from the signal state of first ALU instruction wire bundle 1302 of at least one of first first ALU local instructions to be executed.","The first ALU local instructions are executed by the first ALU circuit 1300.First ALU circuit 1200 asserts the signal state of first ALU output wire bundle 1018.FIG.","2 shows a refinement of FIG.","1 further depicting an input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 of basic arithmetic unit 1400.Note that FIG.","2 operates in much the same fashion as FIG.","1, excepting Input-output circuit 1100 acts as an interface between at least three external data bus wire bundles, 1004 and 1006 controlled by instruction wire bundle 1102 as well as partitioning wire bundle 1002 and creating the state on wire bundles 1008, 1010 and 1012.FIG.","3 shows a refinement of FIG.","2 further depicting input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 and further coupled to a second memory circuit 1250 forming a basic arithmetic unit 1402, which is a refinement of basic arithmetic unit 1400.Note that FIG.","3 operates in a similar fashion to FIGS.","1 and 2 with regards to elements of similar reference numbers.","Second memory circuit 1250 may receive output 1018 from ALU 1300 as well as wire bundle 1014 from input-output circuit 1100 based upon partitioning wire bundle 1002.Second memory circuit 1250 may drive the state of wire bundle 1014.Second memory circuit 1250 may receive wire bundle 1012 from input-output circuit 1100.FIG.","4 shows a refinement of FIG.","3 depicting input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 and coupled to a second memory circuit 1400 with additional interconnections forming a basic arithmetic unit 1402, which is a refinement of basic arithmetic unit 1400.Note that FIG.","4 operates in a similar fashion to FIG.","1, 2, and 3 with regards to elements of similar reference numbers.","FIG.","5 shows a refinement of FIGS.","1, 2,3 and 4 depicting input-output circuit 1100 coupled to multiple instances of basic arithmetic unit 1400.Basic arithmetic unit 1400 may at least be basic arithmetic unit 1402 as shown in FIGS.","2, 3 and 4.FIG.","6 shows a refinement of FIG.","5 depicting a first input-output circuit 1100 coupled to multiple instances of basic arithmetic unit 1400 and a second instance of input-output circuit 1100.Basic arithmetic unit 1400 may at least be basic arithmetic unit 1402 as shown in FIGS.","2, 3 and 4.FIG.","7 shows a detail diagram of an ALU circuit 1300 in terms of four interconnected instances of a second ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002.FIG.","8 shows a detail diagram of first ALU circuit 1300 in terms of eight interconnected instances of a second ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002.In FIGS.","8 and 9, each ALU circuit 1310 may support a consistent datapath bit width.","Each ALU circuit 1310 may further support a constant datapath bit width.","The constant datapath bit width may be at least one of 3, 4, and 5.In FIGS.","8 and 9, ALU circuit 1300 may contain instances of ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002.The number of instances of ALU circuit 1310 is a power of two not necessarily shown in these Figures.","The number of instances of ALU circuit 1310 may not be a power of two.","The number of instances of ALU circuit 1310 may be 12.The constant bit width of ALU circuit 1310 may be 4 and the number of instances of ALU circuit 1310 belongs to a collection comprising 8, 12, 16, 24, 32, 48 and 64.The constant bit width of ALU circuit 1310 is 3 and the number of instances of ALU circuit 1310 belongs to a collection comprising 12, 16, 24, 32, 48 and 64.FIG.","9 depicts an arithmetic logic unit 1310 with multiple add-inputs presented to shifters and then added to generate an add-result.","Each shifter (S1, S2, S2, and S4)is controlled by add-instruction-components belonging to a collection comprising at least values representing same-sign, reverse-sign, do-not-use, shift-up and shift-down.","The effects of these values acting on the add-input are as follows: The add-input acted upon by the corresponding add-inst-component having same-sign generates the add-input.","The add-input acted upon by the corresponding add-inst-component having reverse-sign generates the negative of the add-input.","The add-input acted upon by the corresponding add-inst-component having do-not-use generates a zero.","The add-input acted upon by the corresponding add-inst-component having shift-up generates a positive power of two times the add-input.","The add-input acted upon by the corresponding add-inst-component having shift-down generates a negative power of two times the add-input.","The shift-instruction collection may further include shift-up-by-m and shift-down-by-m, where m is at least two.","Partitioning wire bundle 1002 is used to control carry propagation and shift bit propagation, but are not shown in this Figure to simplify the discussion.","The omission of partitioning wire bundle 1002 is not meant to limit nor require its presence for all embodiments of the invention.","Note that the logarithm of 0 will be negative-infinity, and that the square and square root of 0 are each 0.To preserve these facts in the logarithmic domain, shifting negative-infinity should produce negative infinity.","The add-inst controls for each shifter S1-S4 may further include shift-up-2 and shift-down-2, supporting shifting by 2 bits, as well as shift-up-3 and shift-down-3 supporting shifting by 3 bits.","Certain preferred embodiments of the invention employ a subset of all these add-inst controls including same-sign, reverse-sign, do-not-use, shift-up, shift-down, shift-up-2, shift-up-3, which may be coded as 2 bits designating same-sign, reverse-sign, do-not-use, shift-down; and 2 additional bits coding pass-through, shift-up, and shift-up-2.Note that as shown hereafter, when do-not-use is asserted, it does not matter what the other two bit field contains.","In general, when do-not-use is asserted, the contents of the other two bit field will be chosen to optimize at least one system characteristic, such as testability and/or logic complexity and/or signal propagation through the circuit, also known as the circuit's critical path delay.","The add-inst control signals may originate from the datapath instruction being presented for execution, or may alternatively be generated based upon part of a numeric data to perform a limited range of multiplications.","Consider the following table Multiplier Add-inst-1 Add-inst-2 000 => 0 do-not-use do-not-use 001 => 1 same-sign, pass-through do-not-use 010 => 2 do-not-use same-sign, shift-up-1 011 => 3 = 2 + 1 same-sign, pass-through same-sign, shift-up-1 100 => 4 same-sign, shift-up-2 do-not-use 101 => 5 = 4 + 1 same-sign, shift-up-2 same-sign, pass-through 110 => 6 = 4 + 2 same-sign, shift-up-2 same-sign, shift-up-1 111 => 7 = 8 − 1 reverse-sign, pass-through same-sign shift-up-3 Table One: a three bit multiplication based upon controlling a pair of shifter inputs.","Note that this further supports the circuitry shown in FIG.","9 as supporting the multiplication of 6 bits of an operand acting upon a second number, which may be further provided by a local memory.","Using this circuitry in such a fashion provides an interpolation capability supporting successive approximations, which may involve linear, multi-linear and through the feedback-cascading of partial results based upon this circuit, some forms of non-linear approximations to various non-linear functions including but not limited to various exponential functions, logarithms, trigonometric functions, among others.","An alternative approach to approximation interprets a three bit number as a signed number, leading to the following table: Multiplier Add-inst-1 Add-inst-2 000 => 0 do-not-use do-not-use 001 => 1 same-sign, pass-through do-not-use 010 => 2 same-sign, pass-through same-sign, pass-through 011 => 3 = 2 + 1 same-sign, pass-through same-sign, shift-up-1 100 => −4 reverse-sign, shift-up-1 reverse-sign, shift-up-1 101 => −3 = −4 + 1 reverse-sign, pass-through reverse-sign, shift-up-1 110 => −2 reverse-sign, pass-through reverse-sign, pass-through 111 => −1 reverse-sign, pass-through do-no-use Table Two: a signed three bit multiplication based upon controlling a pair of shifter inputs.","Note that these two tables may be concurrently employed in certain situations where a signed 6 bit numeric multiplication is desired.","The most significant 3 bits affect multiplication as shown in Table Two.","When the sign of the 6 bit quantity is negative, the least significant 3 bits may affect the multiplication as shown in Table One, with every instance of reverse-sign changed to same-sign, and every instance of same-sign changed to reverse-sign.","When the sign of the 6 bit quantity is positive, Table One may be used as shown.","These tables and discussions have been provided by way of example and are not meant to limit the scope of the claims.","As one of skill in the art will readily recognize, there are many alternative notations for the various operations presented herein which are essentially equivalent to the examples presented herein.","FIG.","10 shows Arithmetic Process Array 3000 comprising at least one Arithmetic Processor 3002, each coupled with 3104 Instruction Memory 3200 and with 3106 Instruction Memory 3300, in accordance with certain embodiments of the invention.","In certain embodiments of the invention, only one instruction memory 3200 is coupled to Arithmetic Processor Array 3000, feeding one instruction to each Arithmetic Processor 3002.FIGS.","11A to 16 refer to such embodiments of the invention.","Note that these embodiments of the invention do not require the partitioning wire bundle 3102, nor the partitioning wire bundle 1002.FIG.","11A show a single column of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8.Note that in other embodiments of the invention, i could range over a different range.","Note also that in other embodiments of the invention, each ALU2 1310 unit could be coupled to the first memories 1210 as second memories.","Note that these circuits would be simpler, thus take up less circuit area and consume less power, but could not reconfigure the datapath bit-width, which would be determined by the number of cells (the range of i) and the datapath width of the horizontal strips.","The two dimensional strips containing memories 1210-i and ALU2 cells 1310-i are further integrated as an MSRI[k] cell array where i ranges from 1 to k. FIG.","11B show four columns of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8.Note that in other embodiments of the invention, i could range over a different range.","Note also that in other embodiments of the invention, each ALU2 1310 unit could be coupled to the first memories 1210 as second memories.","Note that these circuits would be simpler, thus take up less circuit area and consume less power, but could not reconfigure the datapath bit-width, which would be determined by the number of cells (the range of i) and the datapath width of the horizontal strips.","The two dimensional strips containing memories 1210-i and ALU2 cells 1310-i are further integrated as an MSRI[k] cell array where i ranges from 1 to k. FIGS.","12 to 16 show a configuration of instruction memories and MSRI[k] sufficient to perform a large number of realtime filtering and more sophisticated tasks upon an input stream of 8 or 9 bit samples.","Assume the horizontal datapath width of the ALU2 and memories in each MSRI is at least 3, preferably 4, bits.","When the horizontal datapath width of the ALU2 and memories in each MSRI is 4 bits, 10 bit samples could also be accepted.","The data stream enters MSRI[4] in FIG.","12 flowing to MSRI[5], then MSRI[6], MSRI[7], then MSRI[8] of FIG.","13 eventually leaving MSRI[231 having performed as a 12 pass arithmetic stream processor.","If each MSRI component performs a radix 4 FFT, then the system as a whole performs a 1K FFT by the time the data leaves MSRI[21], and a 4K FFT upon leaving MSRI[23].","The increase in depth of the MSRI's is to consistently extend the precision of the calculations to account for the accumulation of rounding errors.","In certain other embodiments of the invention, two instruction memories 3200 and 3300 are coupled to Arithmetic Processor Array 3000, feeding two instructions to each Arithmetic Processor 3002, the selection of which instruction is executed determined by the partitioning wire bundle 3102, which in turn drives the partitioning wire bundle 1002.FIGS.","17A to 20 refer to such embodiments of the invention.","FIG.","17A show a single column of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8, with two instructions memories 3200 and 3300 providing two instructions transmitted to each.","Note that in other embodiments of the invention, i could range over a different range.","Note also that in other embodiments of the invention, each ALU2 1310 unit could be coupled to the firstmemories 1210 as second memories.","Note that these circuits would be simpler, thus take up less circuit area and consume less power, but could not reconfigure the datapath bit-width, which would be determined by the number of cells (the range of i) and the datapath width of the horizontal strips.","The two dimensional strips containing memories 1210-i and ALU2 cells 1310-i are further integrated as an PISRI[k] cell array where i ranges from 1 to k. This circuit and the circuit of FIG.","17B use the partitioning wire bundle 1002 to control carry propagation and determination of which of the two instructions are executed in each horizontal strip of the PISRI.","FIG.","17B show four columns of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8, with two instructions memories 3200 and 3300 providing two instructions transmitted to each.","Note that in other embodiments of the invention, i could range over a different range.","Note also that in other embodiments of the invention, each ALU2 1310 unit could be coupled to the first memories 1210 as second memories.","Note that these circuits would be simpler, thus take up less circuit area and consume less power, but could not reconfigure the datapath bit-width, which would be determined by the number of cells (the range of i) and the datapath width of the horizontal strips.","The two dimensional strips containing memories 1210-i and ALU2 cells 1310-i are further integrated as an PISRI[K] cell array where i ranges from 1 to k. FIGS.","18 to 20 show various configurations of PISRI's and their neighboring instruction memories.","In FIG.","18, PSRI[11] can be configured to act as an MSRI[4] and MSRI[7], or as an MSRI[5] and MSRI[6].","The net effect can then be the processing flow of MSRI[4]==>MSRI[5]==>MSRI[6]==>MSRI[7].","Similarly, the PSRI[19]'s can be configured as ==>MSRI[9]==>MSRI[10]==>MSRI[11].","FIG.","19 shows a configuration of same size PISRI[8]'s which can be support dataflows as discussed above, and which provide a 32 bit data interface to standard computer memories when the datapath bit width of the ALU2 1310 and memories 1210 cells is 4 bits.","Note that the partitioning wire bundle would also have an effect on the operation of the data interface to standard memories to preserve data alignments or to partition the external data memory into two address ranges, one for each partition.","FIG.","20 shows a configuration of same size PISRI[12]'s which can be support dataflows as discussed above, and which provide a 36 bit data interface to standard computer memories when the datapath bit width of the ALU2 1310 and memories 1210 cells is 3 bits.","Note that the partitioning wire bundle would also have an effect on the operation of the data interface to standard memories to preserve data alignments or to partition the external data memory into two address ranges, one for each partition.","FIG.","21 shows a high level data flow diagram of a two dimensional array blocks 1300 of ALU2 circuits 1310 and connecting datapaths between them by which data may be transported.","Data flow as depicted in FIG.","21 supports both nearest neighbor and global communication of array blocks in each of the two dimensions of the array.","Note that the vertical communications lines shown in FIG.","21 may be used to transfer data via an external data memory interface which is not shown.","Such an external data memory interface may receive addressing signal either from datapath element(s), and/or from one or more instruction processors.","FIG.","22A depicts a flowchart performing a method of using an array of computational resources containing at least one input-output resource, at least one datapath operational resource in accordance with certain embodiments of the invention.","User operation 2000 starts the usage of this flowchart.","Arrow 2002 directs the usage flow from user operation 2000 to user operation 2004.User operation 2004 performs selecting the input-output resources to create an input-output access collection comprised of at least one input-output access parameter Arrow 2006 directs usage from user operation 2004 to user operation 2008.User operation 2008 performs selecting the datapath operational resources based upon the input-output access collection to create a datapath operational resource allocation collection containing at least one datapath operation resource allocation.","Arrow 2010 directs usage from user operation 2008 to user operation 2012.User operation 2012 terminates the usage of this flowchart.","Note that in other embodiments of the invention, the flowchart of FIG.","22A may be used to depict a method of operating an array of computational resources containing at least one input-output resource, at least one datapath operational resource.","The array of computational resources may be implemented using one or more programmable logic devices, which may include or more programmable logic arrays and/or one or more Filed Programmable Gate Arrays (FPGAs).","Certain further embodiments of the invention include the array of computation resources further containing at least one instruction propagating resource.","FIG.","22B depicts a detail flowchart of user operation 2000 of FIG.","22A further performing selecting the instruction propagating resources based upon the input-output access collection and based upon the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration, in accordance with certain embodiments of the invention.","Arrow 2030 directs the usage flow from starting user operation 2000 to user operation 2032.User operation 2032 performs selecting the instruction propagating resources based upon the input-output access collection and based upon the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration.","Arrow 2034 directs usage from user operation 2032 to user operation 2036.User operation 2036 terminates the usage of this flowchart.","FIG.","23A depicts a detail flowchart of user operation 2000 of FIG.","22A performing selecting the instruction processing resources based upon the input-output access collection, the datapath operational resource allocation collection, and the instruction propagating configuration collection to create an instruction processing configuration collection containing at least one instruction processing configuration in accordance with certain embodiments of the invention.","Arrow 2050 directs the usage flow from starting user operation 2000 to user operation 2052.User operation 2052 performs selecting the instruction processing resources based upon the input-output access collection and based upon the datapath operational resource allocation collection and based upon the instruction propagating configuration collection to create an instruction processing configuration collection containing at least one instruction processing configuration.","Arrow 2054 directs usage from user operation 2052 to user operation 2056.User operation 2056 terminates the usage of this flowchart.","Certain further embodiments of the invention include the array of computation resources further containing at least one instruction fetching resource and the instruction processing resources containing at least one instruction register.","FIG.","23B depicts a detail flowchart of user operation 2000 of FIG.","22A further performing the method of using/operating the array of computational resources in accordance with certain embodiments of the invention.","Arrow 2070 directs the usage flow from starting user operation 2000 to user operation 2072.User operation 2072 performs fetching using the instruction fetching resource to create a fetched instruction.","Arrow 2074 directs usage from user operation 2072 to user operation 2076.User operation 2076 performs loading the fetched instruction into the instruction register to create an instruction register state based upon the fetched instruction.","Arrow 2078 directs usage from user operation 2076 to user operation 2080.User operation 2080 terminates the usage of this flowchart.","FIG.","24A shows a detail block diagram of an instruction memory 3200 comprised of instruction register 3600, branch processor 3700 and instruction memory array 3500, in accordance with certain embodiments of the invention.","Branch processor 3700 in certain further embodiments of the invention includes a branch return stack.","In certain further embodiments of the invention, the branch return stack can be unloaded and reloaded via arrow 3702.FIG.","24B shows a detail block diagram of an instruction memory 3200 extending the block diagram of FIG.","24A further comprised of instruction fetch mechanism 3800, in accordance with certain embodiments of the invention.","Branch processor 3700 in certain further embodiments of the invention includes a branch return stack.","In certain further embodiments of the invention, the branch return stack can be unloaded and reloaded via arrow 3702.FIG.","25 shows a detail block diagram of an branch processor 3700 comprised of branch sequence register 3710, program counter 3730 and branch address look-up table 3720, in accordance with certain embodiments of the invention.","Branch processor 3700 in certain further embodiments of the invention includes a branch return stack.","In certain further embodiments of the invention, the branch return stack can be unloaded and reloaded via arrow 3702.Branch Address Loop-Up Table 3720 may include an interpreter address look-up table supporting an interpretive language, in certain further embodiments of the invention.","Such interpretive languages may include but are not limited to JAVA, FORTH and Smalltalk.","FIG.","26 shows a detail block diagram of an branch processor 3700 extending the block diagram of FIG.","25 further comprised of cache manager 3740, in accordance with certain embodiments of the invention.","Branch processor 3700 in certain further embodiments of the invention includes a branch return stack.","In certain further embodiments of the invention, the branch return stack can be unloaded and reloaded via arrow 3702.Branch Address Loop-Up Table 3720 may include an interpreter address look-up table supporting an interpretive language, in certain further embodiments of the invention.","Such interpretive languages may include but are not limited to JAVA, FORTH and Smalltalk.","FIG.","27 depicts a high level system block diagram of a DSP Resource Circuit in accordance with certain embodiments of the invention.","The DSP Resource Circuit is comprised a Datapath Resource Array 5000.The Datapath Resource Array 5000 is coupled to at least one of the following: the Digital Device Interface 5300 and the System and Control Interface 5400.When applicable, Datapath Resource Array 5000 is coupled by at least one of 5312,5314 and/or 5316 with Digital Device Interface 5300.In certain applications, coupling 5312 communicates memory access request information including but not limited to address information, and where appropriate, memory access length.","Coupling 5314 preferably communicates data received from the Datapath Resource Array 5000 for storage elsewhere, as well as data being sent to the Datapath Resource Array 5000.Coupling 5316 may be used to convey status information, which may include but is not limited to at least one of the following: memory latency-wait states, which may be current or projected, as well as error status information including but not limited to checksum errors and other error detection related information.","Note that the couplings 5302, 5304, and 5306 preferably respectively relate to the external communications associated with couplings 5312, 5314, and 5316 in such applications.","In other applications, one input-output processor may strictly receive data via coupling 5316 which is generated based upon an external input stream via coupling 5306.Additionally, an input-output processor may strictly output data via coupling 5312 which is used to generate an external data stream presented via coupling 5302.In certain applications, each of these coupling may be preferably split into two such couplings, each under the control of a separate input-output processor.","The Datapath Resource Array 5000 may also be coupled to a Local Memory Interface 5500.When applicable, Datapath Resource Array 5000 is coupled by at least one of 5512,5514 and/or 5516 to Local Memory Interface 5500.Preferably, coupling 5512 communicates memory access request information including but not limited to address information, and where appropriate, memory access length.","Coupling 5514 preferably communicates data received from the Datapath Resource Array 5000 for storage elsewhere, as well as data being sent to the Datapath Resource Array 5000.Coupling 5516 may be used to convey status information, which may include but is not limited to at least one of the following: memory latency-wait states, which may be current or projected, as well as error status information including but not limited to checksum errors and other error detection related information.","Note that preferably, couplings 5502, 5504, and 5506 respectively relate to the external communications associated with couplings 5512, 5514, and 5516.When applicable, Datapath Resource Array 5000 is coupled by at least one of 5402 and/or 5404 to System and Control Interface 5400.Each or either of couplings 5402 and 5404 may be comprised of a collection of couplings such as discussed above in FIG.","27 with unidirectional couplings and possibly strictly bi-directional couplings.","In certain applications, coupling 5402 may preferably convey system control and status information related via 5406 with an external system environment.","In certain applications, coupling 5404 may convey data communicated via 5406 with the external system environment.","Such data may be provided during system initialization time for conveyance not only into internal memory within the Datapath Resource Array 5000.Coupling 5404 may also be used during system initialization for further data conveyance through Datapath Resource Array 5000 to Local Memory Interface 5500 for storage in local memory.","Coupling 5404 may also be used during system initialization for further data conveyance through Datapath Resource Array 5000 to Digital Device Interface 5300 for use elsewhere.","FIG.","28 depicts a simplified floor plan of a layout of the DSP Resource Circuit of FIG.","27.Datapath Resource Array 5000 is comprised of at least one instruction processor 3800 and an array of DSP resources 1400.By way of example, FIG.","28 depicts an array of 8 rows and 8 columns of DSP resource 1400 instances.","Instruction processor 3800 may be closely coupled with an instruction memory array 3500.In certain applications, Datapath Resource Array 5000 is preferably comprised of two instruction processors 3800-1 and 3800-2.At this level of abstraction the partition control wire bundle is not visible.","However, it is assumed to support partitioning the array of DSP resources into two horizontal regions.","By way of example, the top three rows of the array of DSP resources may be partitioned to act based upon an instruction state communicated from instruction processor 1 3800-1.The remaining bottom 5 rows of the array of DSP resources may be partitioned to act based upon an instruction state communicated from instruction processor 2 3800-2.In certain applications a further partitioning of instruction processing resources may be preferred.","An instruction processor 3800 may be partitioned into two instruction processing streams, each with independent branch mechanism.","The first instruction processing stream may be partitioned to control the instruction state asserted for the three left-most columns of the array of DSP resources.","The second instruction processing stream would control the remaining 5 columns of the array of DSP resources.","Note that in certain applications, partitioning may support more than two instruction processing streams being sent from an instruction processor.","For simplicity of discussion, no more than two instruction streams will be discussed hereafter.","This is not meant to limit the scope of the claims.","By way of example, the applications and configurations of FIGS.","12 to 20 may be implemented by circuitry illustrated in FIG.","28.Digital Device Interface 5300 is comprised of at least one at least one input-output instruction processor 1130-1 controlling an input-output processor 1120-1.Digital Device Interface 5300 may be further comprised of a second input-output instruction processor 1130-2 controlling input-output processor 1120-2.In certain applications, at least one input-output instruction processor 1130 may be coupled to an input-output instruction memory 1140.Input-output processors preferably possess couplings to all the rows of their associated array of DSP resources 1400.Input-output processors preferably configure communication to the array of DSP resources based upon the partition state information which configures the rows of the array of DSP resources to communicate together.","By way of example, the first input-output processor 1120-1 may communicate with the top three rows of the array of DSP resources, when they are so partitioned.","The second input-output processor 1120-2 may then preferably communicate with the remaining 5 bottom rows.","Note that the rows of DSP resources may be partitioned into more than two communicating components.","Similarly, the Digital Device Interface 5300 may comprise more than two input-output instruction processors controlling more than two input-output processors.","Each input-output processor may include at least one of the following: a data memory, ALU, and specialized logical functions such as bit packing-unpacking circuits.","Note that the circuitry of FIGS.","27 and 28 may further reside in a package where at least one of the interfaces couples to analog circuitry including but not limited to at least one of the following: A/D converters, D/A converters, frequency synthesizers, threshold detectors, and amplifiers.","Note that implementations of multiple instances of the circuitry of FIG.","28 may include situations where one input-output processor of a first instance may not couple to elements of another array of DSP resources 1400 within another instance.","System and Control Interface 5400 may be comprised of at least one input-output processor 1120-3 controlled by input-output instruction processor 1130-3.The preceding discussion regarding the Digital Device Interface is applicable to System and Control Interface 5400, and will not be repeated for reasons of brevity.","However, this is not meant limit the scope of the claims.","A common branching mechanism is preferably employed through the instruction processors discussed in FIG.","28.This branching mechanism can be embodied to support caching and accessing of memory through a local memory interface 5500, or may be embodied without support of external memory.","The overall instruction processing principles embodied in this invention include the following design/architectural goals: Input-output and datapath configurations dominate the embodied architectures, not the other way around.","The hardware supports software debugging and test.","The embodied architectures can support multiple systems levels of instruction fetching.","They can support both SIMD and MIMD, as well as SISD and MISD processing applications.","Implementations support separate references to data and instructions.","There are several consequences to separate data and instruction references.","The runtime environments of procedural languages such C, C++, PASCAL, FORTRAN and JAVA.","By employing an invariant instruction set across a variety of datapath size ranges, a single program can handle a wide range of input data sizes with the arithmetical precision preserved by construction.","Another consequence is the requirement of parameter passing to functions and subroutines by reference only.","Consider for a moment the runtime stack frame requirements of the C programming language.","C's runtime stack frame contains the following components: Branch related pointers, loop counters, data address references and data values, all of which may have differing data widths.","By partitioning the stack frame into multiple stack frame into separate stack frames to handle differing data widths, the communication and manipulation of data to “fit” onto a single stack frame, or “fit” back into the processing element where it is needed is minimized.","There are further architectural preferences which ease the task of compilation of procedural language programs as well as improve the reliability of these translations.","FIG.","29 depicts a preferred version of ALU 1400, as used in FIG.","28 and earlier Figures supporting configurations of its internal memories and system input 1002 emulating a multiplier-accumulator with local register bank.","Arithmetic processor 1400 preferably contains 3 ALUs, 1300-1, 1300-2 and 1300-3, with two memories 1200-1 and 1200-2 respectively feeding 1016 and 1018 the first two ALUs 1300-1 and 1300-2.The third ALU 1300-3 is feed by at least ALU 1300-2 and wire bundle 1002.System input 1002 preferably contains representations of normal numbers and numbers in a logarithmic domain.","The logarithmic domain will be discussed in detail shortly.","The normal number representation be stored in memory 1200-1.ALU 1300-2 may further be implemented in a fashion as shown in FIG.","9, with shift controls being provided from part of the numeric signaling received from wire bundle 1018, as well as at least part of the addressing being provided by parts of the numeric signals received from wire bundle 1018.The results of the two ALU 1300-1 and 1300-2 operations are sent 1018 and 1036 to ALU 1300-3, where the results are combined to form an efficient and very accurate approximation of a sum of numerical products.","As mentioned earlier, there are some fundamental problems with multipliers.","Most importantly, they tend to grow with the product of the input precision.","While this may be somewhat constrained by output precision requirements, it remains a fundamental problem.","An approach that solve this problem will now be described.","Consider the action of representing each member of a number collection by an integer part and a special part, where the special part contains exactly one member of a first special value collection comprising negative-infinity and not-negative-infinity.","FIG.","30 depicts a flowchart of a method of processing numeric data, which may be variously embodied.","Arrow 2210 directs the flow of execution from starting operation 2200 to operation 2212.Operation 2212 performs representing each member of a number collection by an integerpart and a special part.","Arrow 2214 directs execution from operation 2212 to operation 226.Operation 226 terminates the operations of this flowchart.","Arrow 2220 directs the flow of execution from starting operation 2200 to operation 2222.Operation 2222 performs performing at least one member of the arithmetic operation collection upon at least one of the members of the number collection.","Arrow 2224 directs execution from operation 2222 to operation 226.Operation 226 terminates the operations of this flowchart.","Certain embodiments of the invention may perform all members of the arithmetic operation collection upon the relevant member of the number collection.","Certain embodiments of the invention may further include one or both of the following operational steps.","Arrow 2230 directs the flow of execution from starting operation 2200 to operation 2232.Operation 2232 performs log-converting a member of an input number collection to create a member of the number collection.","Arrow 2234 directs execution from operation 2232 to operation 226.Operation 226 terminates the operations of this flowchart.","Arrow 2240 directs the flow of execution from starting operation 2200 to operation 2242.Operation 2242 performs exp-converting a member of the number collection to create a member of an output number collection.","Arrow 2244 directs execution from operation 2242 to operation 2216.Operation 2216 terminates the operations of this flowchart.","FIG.","31 depicts a detail flowchart of operation 2222 of FIG.","30 further performing the arithmetic operation collection.","Arrow 2270 directs the flow of execution from starting operation 2222 to operation 2272.Operation 2272 performs adding the first number to the second number to create an add-result.","Arrow 2274 directs execution from operation 2272 to operation 2276.Operation 2276 terminates the operations of this flowchart.","Arrow 2280 directs the flow of execution from starting operation 2222 to operation 2282.Operation 2282 performs subtracting the first number by the second number to create a subtract-result.","Arrow 2284 directs execution from operation 2282 to operation 2276.Operation 2276 terminates the operations of this flowchart.","Arrow 2290 directs the flow of execution from starting operation 2222 to operation 2292.Operation 2292 performs exponentiating the first number to create an exp-result.","Arrow 2294 directs execution from operation 2292 to operation 2276.Operation 2276 terminates the operations of this flowchart.","Arrow 2300 directs the flow of execution from starting operation 2222 to operation 2302.Operation 2302 performs logarithming the first number to create a log-result.","Arrow 2304 directs execution from operation 2302 to operation 2276.Operation 2276 terminates the operations of this flowchart.","Note that the number collection is further comprised of the add-result, the subtract-result, the exp-result and the log-result.","FIG.","32A depicts a detail flowchart of operation 2272 of FIG.","31 further adding.","Arrow 2330 directs the flow of execution from starting operation 2272 to operation 2332.Operation 2332 performs determining whether the special part of the first number contains the negative-infinity.","Arrow 2334 directs execution from operation 2332 to operation 2336.Operation 2336 terminates the operations of this flowchart.","Arrow 2340 directs the flow of execution from starting operation 2272 to operation 2342.Operation 2342 performs determining whether the special part of the second number contains the negative-infinity.","Arrow 2344 directs execution from operation 2342 to operation 2336.Operation 2336 terminates the operations of this flowchart.","Arrow 2350 directs the flow of execution from starting operation 2272 to operation 2352.Operation 2352 performs setting the special part of the add-result to contain the negative-infinity whenever the special part of at least one member of the collection the first number and the second number contains the negative-infinity.","Arrow 2354 directs execution from operation 2352 to operation 2336.Operation 2336 terminates the operations of this flowchart.","FIG.","32B depicts a detail flowchart of operation 2282 of FIG.","31 further subtracting.","Arrow 2370 directs the flow of execution from starting operation 2282 to operation 2372.Operation 2372 performs determining whether the special part of the first number contains the negative-infinity.","Arrow 2374 directs execution from operation 2372 to operation 2376.Operation 2376 terminates the operations of this flowchart.","Arrow 2380 directs the flow of execution from starting operation 2282 to operation 2382.Operation 2382 performs setting the special part of the subtract-result to contain the negative-infinity whenever the special part of the first number contains the negative-infinity.","Arrow 2384 directs execution from operation 2382 to operation 2376.Operation 2376 terminates the operations of this flowchart.","FIG.","33A depicts a detail flowchart of operation 2292 of FIG.","31 further exponentiating.","Arrow 2410 directs the flow of execution from starting operation 292 to operation 2412.Operation 2412 performs determining whether the special part of the first number contains the negative-infinity.","Arrow 2414 directs execution from operation 2412 to operation 2416.Operation 2416 terminates the operations of this flowchart.","Arrow 2420 directs the flow of execution from starting operation 292 to operation 2422.Operation 2422 performs setting the special part of the exp-result to contain the not-negative-infinity and setting the integer part to a zero-representation whenever the special part of the first number contains the negative-infinity.","Arrow 2424 directs execution from operation 2422 to operation 2416.Operation 2416 terminates the operations of this flowchart.","FIG.","33B depicts a detail flowchart of operation 2302 of FIG.","31 further logarithming.","Arrow 2430 directs the flow of execution from starting operation 2302 to operation 2432.Operation 2432 performs determining whether the integer part of the first number is essentially equal to the zero-representation.","Arrow 2434 directs execution from operation 2432 to operation 2436.Operation 2436 terminates the operations of this flowchart.","Arrow 2440 directs the flow of execution from starting operation 2302 to operation 2442.Operation 2442 performs setting the special part of the log-result to contain the negative-infinity whenever the integer part of the first number essentially equals the zero-representation.","Arrow 2444 directs execution from operation 2442 to operation 2436.Operation 2436 terminates the operations of this flowchart.","Note that the integer part of each of the number collection members may be in a non-redundant numeric notation.","FIG.","34A depicts a detail flowchart of operation 2442 of FIG.","33B further setting the special part of the log-result.","Arrow 2470 directs the flow of execution from starting operation 2442 to operation 2472.Operation 2472 performs setting the special part of the log-result to contain the negative-infinity whenever the integer part of the first number equals the zero-representation.","Arrow 2474 directs execution from operation 2472 to operation 2476.Operation 2476 terminates the operations of this flowchart.","Alternatively, the integer part of each of the number collection members may be in a redundant numeric notation possessing a zero-representation collection comprising at least two zero-representation instances.","FIG.","34B depicts a detail flowchart of operation 2442 of FIG.","33B further setting the special part of the log-result.","Arrow 2490 directs the flow of execution from starting operation 2442 to operation 2492.Operation 2492 performs setting the special part of the log-result to contain the negative-infinity whenever the integer part of the first number is a member of the zero-representation collection.","Arrow 2494 directs execution from operation 2492 to operation 2496.Operation 2496 terminates the operations of this flowchart.","Note that the integer part of each member of the number collection may contains a sign and a magnitude.","Further, for each member of the number collection, the sign may be a member of a sign collection consisting essentially of a positive-sign and a negative-sign.","The special part of each member of the number collection may further contain exactly one member of a second special value collection comprising a special-minus and a special-plus.","FIG.","35A depicts a detail flowchart of operation 2292 of FIG.","31 further exponentiating.","Arrow 2510 directs the flow of execution from starting operation 2292 to operation 2512.Operation 2512 performs setting the sign of the exp-result to essentially the negative-sign whenever the special part of the first number contains the special-minus.","Arrow 2514 directs execution from operation 2512 to operation 2516.Operation 2516 terminates the operations of this flowchart.","FIG.","35B depicts a detail flowchart of operation 2302 of FIG.","31 further logarithming.","Arrow 2530 directs the flow of execution from starting operation 2302 to operation 2532.Operation 2532 performs determining whether the sign part of the first number is essentially equal to the negative-sign.","Arrow 2534 directs execution from operation 2532 to operation 2536.Operation 2536 terminates the operations of this flowchart.","Arrow 2540 directs the flow of execution from starting operation 2302 to operation 2542.Operation 2542 performs setting the special part of the log-result to contain the special-minus whenever the sign part of the first number is essentially the negative-sign.","Arrow 2544 directs execution from operation 2542 to operation 2536.Operation 2536 terminates the operations of this flowchart.","The integer part of each of the number collection members may be in a redundant numeric notation supporting determination of negativity by a negative-test collection comprising at least two negative-test steps.","FIG.","36A depicts a detail flowchart of operation 2532 of FIG.","35B further determining whether the sign part of the first number is essentially equal to the negative-sign.","Arrow 2570 directs the flow of execution from starting operation 2532 to operation 2572.Operation 2572 performs determining whether the sign part of the first number is equal to the negative-sign based upon performing at least one of the members of the negative-test collection.","Arrow 2574 directs execution from operation 2572 to operation 2576.Operation 2576 terminates the operations of this flowchart.","Alternatively, the integer part of each of the number collection members is in a non-redundant numeric notation possessing exactly one negative-test step.","FIG.","36B depicts a detail flowchart of operation 2532 of FIG.","35B further determining whether the sign part of the first number is essentially equal to the negative-sign.","Arrow 2590 directs the flow of execution from starting operation 2532 to operation 2592.Operation 2592 performs performing the exactly one negative-test step based upon the first number.","Arrow 2594 directs execution from operation 2592 to operation 2596.Operation 2596 terminates the operations of this flowchart.","Note that each member of the input number collection may be comprised of an integer part.","FIG.","37A depicts a detail flowchart of operation 2232 of FIG.","30 further log-converting the input number collection member.","Arrow 2600 directs the flow of execution from starting operation 2232 to operation 2602.Operation 2602 performs determining whether the integer part of the input number collection member is essentially equal to the zero-representation.","Arrow 2604 directs execution from operation 2602 to operation 2606.Operation 2606 terminates the operations of this flowchart.","Arrow 2610 directs the flow of execution from starting operation 2232 to operation 2612.Operation 2612 performs setting the special part of the number collection member to contain the negative-infinity whenever the integer part of the input number collection member essentially equals the zero-representation.","Arrow 2614 directs execution from operation 2612 to operation 2606.Operation 2606 terminates the operations of this flowchart.","Note that the integer part of each of the input number collection members may contain a sign belonging to the sign collection and a magnitude.","FIG.","37B depicts a detail flowchart of operation 2232 of FIG.","30 further log-converting the input number collection member.","Arrow 2630 directs the flow of execution from starting operation 2232 to operation 2632.Operation 2632 performs determining whether the sign part of the input number collection member is essentially equal to the negative-sign.","Arrow 2634 directs execution from operation 2632 to operation 2636.Operation 2636 terminates the operations of this flowchart.","Arrow 2640 directs the flow of execution from starting operation 2232 to operation 2642.Operation 2642 performs setting the special part of the number collection member to contain the special-minus whenever the sign part of the input number collection member is essentially the negative-sign.","Arrow 2644 directs execution from operation 2642 to operation 2636.Operation 2636 terminates the operations of this flowchart.","Note that each of the output number collection members may include a magnitude.","FIG.","38A depicts a detail flowchart of operation 2242 of FIG.","30 further exp-converting.","Arrow 2650 directs the flow of execution from starting operation 2242 to operation 2652.Operation 2652 performs setting the magnitude of the output number collection member to the zero-representation whenever the special part of the number collection member contains the negative-infinity.","Arrow 2654 directs execution from operation 2652 to operation 2656.Operation 2656 terminates the operations of this flowchart.","Also, each of the output number collection members may include a sign belonging to the sign collection.","FIG.","38B depicts a detail flowchart of operation 2242 of FIG.","30 further exp-converting.","Arrow 2670 directs the flow of execution from starting operation 2242 to operation 2672.Operation 2672 performs setting the sign of the output number collection member to the negative-sign whenever the special part of the number collection member contains the special-minus.","Arrow 2674 directs execution from operation 2672 to operation 2676.Operation 2676 terminates the operations of this flowchart.","Arrow 2680 directs the flow of execution from starting operation 2242 to operation 2682.Operation 2682 performs setting the sign of the output number collection member to the positive-sign whenever the special part of the number collection member contains the special-plus.","Arrow 2684 directs execution from operation 2682 to operation 2686.Operation 2686 terminates the operations of this flowchart.","Note that each of the input number collection members may be encoded as an N1 bit code; wherein the N1 is at least three.","The integer part of each of the number collection members may be encoded as an N2 bit code; wherein N2 is greater than N1.This method of numeric processing may be implemented as a program system comprised of program steps implementing the steps of the method.","The program steps may reside in a memory accessibly coupled to a computer, which executes these program steps.","The program system may further be implemented as program steps in at least one member of the language collection comprising C, C++, JAVA, FORTRAN, PASCAL, VERILOG, VHDL, assembly language and executable code for at least one computational engine implemented upon the computer.","The invention includes circuitry generated from those program steps.","The invention also includes circuitry implemented within at least one circuit component belonging to a programmable logic device collection and a fixed architecture device collection.","Where the programmable logic device collection refers to all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array.","The fixed architecture device collection refers to all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.","The preceding embodiments of the invention have been provided by way of example and are not meant to constrain the scope of the following claims."]],"string":"[\n [\n \"Method and apparatus of dsp resource allocation and use\",\n \"Certain embodiments of the invention support the distribution and control of multiple instruction streams going to multiple steps of modules supporting arithmetic and memory, as well as method for numeric data processing optimizing non-additive functions and operations through a novel numeric representation and the use of novel ALU components to support numeric conversions and evaluations of non-additive functions.\"\n ],\n [\n \"1.A circuit supporting partitioned operation of multiple concurrently presented instructions comprising: a first instruction wire bundle; a second instruction wire bundle; a clock wire bundle possessing a capture state; a partition control wire bundle possessing a partition control state; an arithmetic module circuit coupled to said partition control wire bundle and further comprised of a first memory circuit coupled to said partition control wire bundle; and a first arithmetic logic unit coupled to said partition control wire bundle; wherein said module circuit samples said first instruction wire bundle and said second instruction wire bundle during said capture state on said clock wire bundle respectively generating a first sampled instruction state and a second sampled instruction state; and wherein said arithmetic module circuit responds to at least one member of a sample instruction collection based upon said partition control state; wherein said sample instruction collection is comprised of said first sampled instruction state and to said second sampled instruction state; wherein said arithmetic module circuit response is further comprised of: said first memory circuit responds to at least one member of said sample instruction collection based upon said partition control state; and said first arithmetic logic unit responds to at least one member of said sample instruction collection based upon said partition control state; wherein said first arithmetic logic unit is further comprised of an ALU part collection comprising a first part ALU and a second part ALU; wherein said first memory circuit is further comprised of at least two memory sub-circuits, each memory sub-circuit corresponding to a member of said ALU part collection; wherein each member of said part ALU collection and said corresponding memory sub-circuit are coupled to said partition control wire bundle; and wherein each member of said part ALU collection and said corresponding memory sub-circuit both respond to exactly one and the same member of said sample instruction collection based upon said partition control state.\",\n \"2.The circuit of claim 1, wherein said first part ALU presents a first carry signal to said second part ALUs; wherein said second part ALU ignores said first carry signal whenever said exactly one sample instruction collection member for said first part ALU is different from said exactly one sample instruction collection member for said second part ALU.\",\n \"3.The circuit of claim 1, further comprising: an input-output circuit coupled to said arithmetic module circuit, to said partition control wire bundle; wherein said input-output circuit responds to at least one member of said sample instruction collection based upon said partition control state.\",\n \"4.The circuit of claim 3, wherein said input-output circuit presents a first input to a member of the collection comprising said first ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said first ALU part and said corresponding memory sub-circuit respond; wherein said input-output circuit presents a second input to a member of the collection comprising sad second ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said second ALU part and said corresponding memory sub-circuit respond.\",\n \"5.The circuit of claim 4, wherein said arithmetic module circuit is further comprised of a second circuit coupled to said partition control wire bundle; wherein said second circuit is comprised of at least two second sub-circuits, each of said second sub-circuits corresponding to exactly one member of said ALU part collection; wherein each of said second sub-circuits corresponding to said member of said ALU responds to exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein for each of said second sub-circuits, said second sub-circuit further responds by approximately performing at least one member of a non-additive function collection comprising multiplication, division, square root, exponential base N, logarithm base N, sine, cosine, arcsine, arccosine, tangent, cotangent, secant, cosecant and polynomial functions based upon exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein said N is a positive number.\",\n \"6.The circuit of claim 5, wherein an input collection is comprised of said first and said second input; wherein each member of said input collection is comprised of a log-input and a normal-input; 7.The circuit of claim 6, wherein each member of said ALU part collection presents a result to said corresponding said second sub-circuit.\",\n \"8.The circuit of claim 7, further comprising a second of said arithmetic module circuits coupled to said input-output circuit; wherein said input-output circuit presents said first input to at least one member of the collection comprising said first ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; wherein said input-output circuit presents said second input to at least one member of the collection comprising sad second ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.\",\n \"9.The circuit of claim 8, wherein a second circuit collection is comprised of said second circuit of said arithmetic module circuit and said second circuit of said second arithmetic module circuit; wherein at least one member of said second circuit collection couples to an internal wire bundle comprised of a first sub-internal wire bundle and a second sub-internal wire bundle; wherein for each member of said second circuit collection coupled to said internal wire bundle asserts a first sub-internal wire state on said first sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; wherein for each member of said second circuit collection coupled to said internal wire bundle asserts a second sub-internal wire state on said second sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.\",\n \"10.The circuit of claim 1, further comprising a first datapath instruction processor coupled to said first datapath instruction wire bundle presented to said module circuit; wherein said first datapath instruction processor asserts said first datapath instruction wire bundle; and a second datapath instruction processor coupled to said second datapath instruction wire bundle presented to said module circuit; wherein said second datapath instruction processor asserts said second datapath instruction wire bundle.\",\n \"11.The circuit of claim 10, wherein a datapath instruction processor collection is comprised of said first datapath instruction processor and said second datapath instruction processor; wherein said first datapath instruction wire bundle is an associated datapath instruction wire bundle of said first datapath instruction processor; wherein said second datapath instruction wire bundle is an associated datapath instruction wire bundle of said second datapath instruction processor; wherein at least one member of said datapath instruction processor collection is further comprised of: a datapath instruction pointer coupled to said clock wire bundle, and to a datapath instruction address wire bundle; and a datapath instruction register coupled to said clock wire bundle, to said asserted datapath instruction wire bundle, and to a datapath instruction wire bundle; wherein said clock wire bundle possesses a datapath instruction capture state; wherein said datapath instruction queue pointer responds to said clock wire bundle by asserting an asserted datapath instruction address; wherein said datapath instruction register responds to said clock wire bundle by capturing a datapath instruction capture state whenever said clock wire bundle is in said datapath instruction capture state; and wherein said datapath instruction register further asserts said associated datapath instruction wire bundle based upon said datapath instruction capture state.\",\n \"12.The circuit of claim 11, wherein for at least one member of said datapath instruction processor collection comprising said datapath instruction pointer is further comprised of: an instruction store coupled to said datapath instruction address wire bundle and to said datapath instruction wire bundle; wherein said instruction store responds to said asserted datapath instruction address via said datapath instruction address wire bundle to asserting said datapath instruction wire bundle based upon said asserted datapath instruction address.\",\n \"13.The circuit of claim 12, wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction processor is further comprised of a last instruction indicator coupled to a last instruction indicator wire bundle possessing a last instruction state and a non-last instruction state; wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction pointer is further coupled to a new datapath instruction address wire bundle and to said last instruction indicator wire bundle; and wherein for at least one member of said datapath instruction processor collection comprising said instruction store is further comprised of: a branch-cache instruction processor coupled to said last instruction indicator and to said new datapath instruction address wire bundle; wherein said branch-cache instruction processor responds to said last instruction state via said last instruction indicator wire bundle by asserting a new datapath instruction address upon said new datapath instruction address wire bundle; and wherein said datapath instruction pointer responds to said last instruction indicator wire bundle by capturing said new datapath instruction address from said new datapath instruction address wire bundle.\",\n \"14.A circuit implementation of claim 1, wherein a component list comprises said arithmetic module circuit, said first memory circuit coupled to said partition control wire bundle, and said first arithmetic logic unit; wherein each member of said component list is implemented with at least part of at least one member of the collection comprising a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array (FPGA); and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.\",\n \"15.The circuit implementation of claim 14, wherein the implementation of all members of said component list further includes only circuitry responding to said exactly one and the same member of said sample instruction collection based upon said partition control state.\",\n \"16.A method of operating a module circuit containing at least an arithmetic module circuit further containing a first memory circuit and a first arithmetic logic unit using a clock wire bundle possessing a capture state and using a partition control wire bundle possessing a partition control state, said method comprising the steps of: said module circuit sampling a first instruction pair wire bundle and a second instruction pair wire bundle during said capture state on said clock wire bundle respectively generating a first sampled instruction state and a second sampled instruction state; and said arithmetic module circuit responding to at least one member of a sample instruction collection based upon said partition control state; wherein said sample instruction collection is comprised of said first sampled instruction state and to said second sampled instruction state; wherein the step of said arithmetic module circuit responding is further comprised of the steps of: said first memory circuit responding to at least one member of said sample instruction collection based upon said partition control state; and said first arithmetic logic unit responding to at least one member of said sample instruction collection based upon said partition control state; wherein said first arithmetic logic unit is further comprised of an ALU part collection comprising a first part ALU and a second part ALU; wherein the step of said first arithmetic logic unit responding is further comprised of the steps of said first part ALU responding to exactly one member of said sample instruction collection based upon said partition control; and said second part ALU responding to exactly one member of said sample instruction collection based upon said partition control state; wherein said first memory circuit is comprised of at least two memory sub-circuits, each of said memory sub-circuits corresponding to a member of said ALU part collection; wherein the step of said first memory circuit responding is further comprised of, for each of said memory sub-circuits, the step of said memory sub-circuit responding to exactly one and the same member of said sample instruction collection as said corresponding member of said ALU part collection.\",\n \"17.The method of claim 16, further comprising the step of said first part ALU presenting a first carry signal to said second part ALU; wherein the step of said second ALU responding is comprised of the steps of: said second part ALU ignoring said first carry signal whenever said exactly one sample instruction collection member for said first part ALU is different from said exactly one sample instruction collection member for said second part ALU.\",\n \"18.The method of claim 16, further comprising the step of: an input-output circuit responding to at least one member of said sample instruction collection based upon said partition control state.\",\n \"19.The method of claim 18, further comprising the steps of: said input-output circuit presenting a first input to a member of the collection comprising said first ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said first ALU part and said corresponding memory sub-circuit respond; said input-output circuit presenting a second input to a member of the collection comprising sad second ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said second ALU part and said corresponding memory sub-circuit respond.\",\n \"20.The method of claim 19, wherein said arithmetic module circuit is further comprised of a second circuit coupled to said partition control wire bundle; wherein said second circuit is comprised of at least two second sub-circuits, each of said second sub-circuits corresponding to exactly one member of said ALU part collection; wherein said method is further comprised, for each of said second sub-circuits corresponding to said member of said ALU part collection, of the step of: said second sub-circuit responding to exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein for each of said second sub-circuits, the step of said second sub-circuit responding is further comprised of the step of: said second sub-circuit approximately performing at least one member of a non-additive function collection comprising multiplication, division, square root, exponential base N, logarithm base N, sine, cosine, arcsine, arccosine, tangent, cotangent, secant, cosecant and polynomial functions based upon exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein said N is a positive number.\",\n \"21.The method of claim 20, wherein an input collection is comprised of said first and said second input; wherein each member of said input collection is comprised of a log-input and a normal-input.\",\n \"22.The method of claim 21, further comprising the steps of: for each member of said ALU part collection, said member presenting a result to said corresponding said second sub-circuit.\",\n \"23.The method of claim 22, wherein said module circuit is further comprised of a second of said arithmetic module circuits coupled to said input-output circuit; wherein said method is further comprised of the step of: said input-output circuit presenting said first input to at least one member of the collection comprising said first ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; said input-output circuit presenting said second input to at least one member of the collection comprising sad second ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.\",\n \"24.The method of claim 23, wherein a second circuit collection is comprised of said second circuit of said arithmetic module circuit and said second circuit of said second arithmetic module circuit; wherein at least one member of said second circuit collection couples to an internal wire bundle comprised of a first sub-internal wire bundle and a second sub-internal wire bundle; wherein said method is further comprised, for each member of said second circuit collection coupled to said internal wire bundle of the step of: said member asserting a first sub-internal wire state on said first sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; said member asserting a second sub-internal wire state on said second sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.\",\n \"25.The method of claim 16, further comprising the steps of a first datapath instruction processor asserting said first datapath instruction wire bundle presented to said module circuit; and a second datapath instruction processor asserting said second datapath instruction wire bundle presented to said module circuit.\",\n \"26.The method of claim 25, wherein a datapath instruction processor collection is comprised of said first datapath instruction processor and said second datapath instruction processor; wherein said first datapath instruction wire bundle is an associated datapath instruction wire bundle of said first datapath instruction processor; wherein said second datapath instruction wire bundle is an associated datapath instruction wire bundle of said second datapath instruction processor; wherein at least one member of said datapath instruction processor collection is further comprised of: a datapath instruction pointer coupled to said clock wire bundle, and to a datapath instruction address wire bundle; and a datapath instruction register coupled to said clock wire bundle, to said asserted datapath instruction wire bundle, and to a datapath instruction wire bundle; wherein said clock wire bundle possesses a datapath instruction capture state; wherein said method is further comprised of the steps of said datapath instruction queue pointer responding to said clock wire bundle by asserting an asserted datapath instruction address; said datapath instruction register responding to said clock wire bundle by capturing a datapath instruction capture state whenever said clock wire bundle is in said datapath instruction capture state; and said datapath instruction register asserting said associated datapath instruction wire bundle based upon said datapath instruction capture state.\",\n \"27.The method of claim 26, wherein for at least one member of said datapath instruction processor collection comprising said datapath instruction pointer is further comprised of an instruction store; wherein said method is further comprised of the steps of said instruction store responding to said asserted datapath instruction address to assert said datapath instruction wire bundle based upon said asserted datapath instruction address.\",\n \"28.The method of claim 27, wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction processor is further comprised of a last instruction indicator coupled to a last instruction indicator wire bundle possessing a last instruction state and a non-last instruction state; wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction pointer is further coupled to a new datapath instruction address wire bundle and to said last instruction indicator wire bundle; and wherein for at least one member of said datapath instruction processor collection comprising said instruction store is further comprised of: a branch-cache instruction processor coupled to said last instruction indicator and to said new datapath instruction address wire bundle; wherein said branch-cache instruction processor responds to said last instruction state via said last instruction indicator wire bundle by asserting a new datapath instruction address upon said new datapath instruction address wire bundle; and wherein said datapath instruction pointer responds to said last instruction indicator wire bundle by capturing said new datapath instruction address from said new datapath instruction address wire bundle.\",\n \"29.A circuit implementation of the method of claim 16, wherein the steps of the method are each implemented within at least part of at least one member of the collection comprising a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array (FPGA); and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.\",\n \"30.A method of operating a module circuit containing at least an arithmetic module circuit further containing a first memory circuit and a first arithmetic logic unit using a clock wire bundle possessing a capture state and using a partition control wire bundle possessing a partition control state, said method comprising the steps of: said module circuit sampling a first instruction pair wire bundle and a second instruction pair wire bundle during said capture state on said clock wire bundle respectively generating a first sampled instruction state and a second sampled instruction state; and said arithmetic module circuit responding to at least one member of a sample instruction collection based upon said partition control state; wherein said sample instruction collection is comprised of said first sampled instruction state and to said second sampled instruction state.\",\n \"31.The method of claim 30, wherein the step of said arithmetic module circuit responding is further comprised of the steps of: said first memory circuit responding to at least one member of said sample instruction collection based upon said partition control state; and said first arithmetic logic unit responding to at least one member of said sample instruction collection based upon said partition control state.\",\n \"32.The method of claim 31, wherein said first arithmetic logic unit is further comprised of an ALU part collection comprising a first part ALU and a second part ALU; wherein the step of said first arithmetic logic unit responding is further comprised of the steps of said first part ALU responding to exactly one member of said sample instruction collection based upon said partition control; and said second part ALU responding to exactly one member of said sample instruction collection based upon said partition control state; wherein said first memory circuit is comprised of at least two memory sub-circuits, each of said memory sub-circuits corresponding to a member of said ALU part collection; wherein the step of said first memory circuit responding is further comprised of for each of said memory sub-circuits, the step of said memory sub-circuit responding to exactly one and the same member of said sample instruction collection as said corresponding member of said ALU part collection.\",\n \"33.The method of claim 32, further comprising the step of said first part ALU presenting a first carry signal to said second part ALU; wherein the step of said second ALU responding is comprised of the steps of: said second part ALU ignoring said first carry signal whenever said exactly one sample instruction collection member for said first part ALU is different from said exactly one sample instruction collection member for said second part ALU.\",\n \"34.The method of claim 32, further comprising the step of: an input-output circuit responding to at least one member of said sample instruction collection based upon said partition control state.\",\n \"35.The method of claim 34, further comprising the steps of: said input-output circuit presenting a first input to a member of the collection comprising said first ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said first ALU part and said corresponding memory sub-circuit respond; said input-output circuit presenting a second input to a member of the collection comprising sad second ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said second ALU part and said corresponding memory sub-circuit respond.\",\n \"36.The method of claim 35, wherein said arithmetic module circuit is further comprised of a second circuit coupled to said partition control wire bundle; wherein said second circuit is comprised of at least two second sub-circuits, each of said second sub-circuits corresponding to exactly one member of said ALU part collection; wherein said method is further comprised, for each of said second sub-circuits corresponding to said member of said ALU part collection, of the step of: said second sub-circuit responding to exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein for each of said second sub-circuits, the step of said second sub-circuit responding is further comprised of the step of: said second sub-circuit approximately performing at least one member of a non-additive function collection comprising multiplication, division, square root, exponential base N, logarithm base N, sine, cosine, arcsine, arccosine, tangent, cotangent, secant, cosecant and polynomial functions based upon exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein said N is a positive number.\",\n \"37.The method of claim 36, wherein an input collection is comprised of said first and said second input; wherein each member of said input collection is comprised of a log-input and a normal-input.\",\n \"38.The method of claim 37, further comprising the steps of: for each member of said ALU part collection, said member presenting a result to said corresponding said second sub-circuit.\",\n \"39.The method of claim 38, wherein said module circuit is further comprised of a second of said arithmetic module circuits coupled to said input-output circuit; wherein said method is further comprised of the step of: said input-output circuit presenting said first input to at least one member of the collection comprising said first ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; said input-output circuit presenting said second input to at least one member of the collection comprising sad second ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.\",\n \"40.The method of claim 39, wherein a second circuit collection is comprised of said second circuit of said arithmetic module circuit and said second circuit of said second arithmetic module circuit; wherein at least one member of said second circuit collection couples to an internal wire bundle comprised of a first sub-internal wire bundle and a second sub-internal wire bundle; wherein said method is further comprised, for each member of said second circuit collection coupled to said internal wire bundle of the step of: said member asserting a first sub-internal wire state on said first sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; said member asserting a second sub-internal wire state on said second sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.\",\n \"41.The method of claim 30, further comprising the steps of a first datapath instruction processor asserting said first datapath instruction wire bundle presented to said module circuit; and a second datapath instruction processor asserting said second datapath instruction wire bundle presented to said module circuit.\",\n \"42.The method of claim 41, wherein a datapath instruction processor collection is comprised of said first datapath instruction processor and said second datapath instruction processor; wherein said first datapath instruction wire bundle is an associated datapath instruction wire bundle of said first datapath instruction processor; wherein said second datapath instruction wire bundle is an associated datapath instruction wire bundle of said second datapath instruction processor; wherein at least one member of said datapath instruction processor collection is further comprised of: a datapath instruction pointer coupled to said clock wire bundle, and to a datapath instruction address wire bundle; and a datapath instruction register coupled to said clock wire bundle, to said asserted datapath instruction wire bundle, and to a datapath instruction wire bundle; wherein said clock wire bundle possesses a datapath instruction capture state; wherein said method is further comprised of the steps of said datapath instruction queue pointer responding to said clock wire bundle by asserting an asserted datapath instruction address; said datapath instruction register responding to said clock wire bundle by capturing a datapath instruction capture state whenever said clock wire bundle is in said datapath instruction capture state; and said datapath instruction register asserting said associated datapath instruction wire bundle based upon said datapath instruction capture state.\",\n \"43.The method of claim 42, wherein for at least one member of said datapath instruction processor collection comprising said datapath instruction pointer is further comprised of an instruction store; wherein said method is further comprised of the steps of said instruction store responding to said asserted datapath instruction address to assert said datapath instruction wire bundle based upon said asserted datapath instruction address.\",\n \"44.The method of claim 43, wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction processor is further comprised of a last instruction indicator coupled to a last instruction indicator wire bundle possessing a last instruction state and a non-last instruction state; wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction pointer is further coupled to a new datapath instruction address wire bundle and to said last instruction indicator wire bundle, and wherein for at least one member of said datapath instruction processor collection comprising said instruction store is further comprised of: a branch-cache instruction processor coupled to said last instruction indicator and to said new datapath instruction address wire bundle; wherein said branch-cache instruction processor responds to said last instruction state via said last instruction indicator wire bundle by asserting a new datapath instruction address upon said new datapath instruction address wire bundle; and wherein said datapath instruction pointer responds to said last instruction indicator wire bundle by capturing said new datapath instruction address from said new datapath instruction address wire bundle.\",\n \"45.A circuit implementation of the method of claim 30, wherein the steps of the method are each implemented within at least part of at least one member of the collection comprising a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array (FPGA); and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.\",\n \"46.A circuit supporting partitioned operation of multiple concurrently presented instructions comprising: a first instruction wire bundle; a second instruction wire bundle; a clock wire bundle possessing a capture state; a partition control wire bundle possessing a partition control state; an arithmetic module circuit coupled to said partition control wire bundle and further comprised of a first memory circuit coupled to said partition control wire bundle; and a first arithmetic logic unit coupled to said partition control wire bundle; wherein said module circuit samples said first instruction wire bundle and said second instruction wire bundle during said capture state on said clock wire bundle respectively generating a first sampled instruction state and a second sampled instruction state; and wherein said arithmetic module circuit responds to at least one member of a sample instruction collection based upon said partition control state; wherein said sample instruction collection is comprised of said first sampled instruction state and to said second sampled instruction state.\",\n \"47.The circuit of claim 46, wherein said arithmetic module circuit response is further comprised of: said first memory circuit responds to at least one member of said sample instruction collection based upon said partition control state; and said first arithmetic logic unit responds to at least one member of said sample instruction collection based upon said partition control state.\",\n \"48.The circuit of claim 47, wherein said first arithmetic logic unit is further comprised of an ALU part collection comprising a first part ALU and a second part ALU; wherein said first memory circuit is further comprised of at least two memory sub-circuits, each memory sub-circuit corresponding to a member of said ALU part collection; wherein each member of said part ALU collection and said corresponding memory sub-circuit are coupled to said partition control wire bundle; and wherein each member of said part ALU collection and said corresponding memory sub-circuit both respond to exactly one and the same member of said sample instruction collection based upon said partition control state.\",\n \"49.The circuit of claim 48, wherein said partition control state includes to a carry partition control belonging to a partition control state collection comprising first carry control state and a second carry control state; wherein said first part ALU presents a first carry signal to said second part ALUs; wherein said second part ALU ignores said first carry signal whenever said exactly one sample instruction collection member for said first part ALU is different from said exactly one sample instruction collection member for said second part ALU.\",\n \"50.The circuit of claim 48, further comprising: an input-output circuit coupled to said arithmetic module circuit, to said partition control wire bundle; wherein said input-output circuit responds to at least one member of said sample instruction collection based upon said partition control state.\",\n \"51.The circuit of claim 50, wherein said input-output circuit presents a first input to a member of the collection comprising said first ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said first ALU part and said corresponding memory sub-circuit respond; wherein said input-output circuit presents a second input to a member of the collection comprising sad second ALU part and said corresponding memory sub-circuit based upon exactly one and the same member of said sample instruction collection to which said second ALU part and said corresponding memory sub-circuit respond.\",\n \"52.The circuit of claim 51, wherein said arithmetic module circuit is further comprised of a second circuit coupled to said partition control wire bundle; wherein said second circuit is comprised of at least two second sub-circuits, each of said second sub-circuits corresponding to exactly one member of said ALU part collection; wherein each of said second sub-circuits corresponding to said member of said ALU responds to exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein for each of said second sub-circuits, said second sub-circuit further responds by approximately performing at least one member of a non-additive function collection comprising multiplication, division, square root, exponential base N, logarithm base N, sine, cosine, arcsine, arccosine, tangent, cotangent, secant, cosecant and polynomial functions based upon exactly one and the same member of said sample instruction collection to which said ALU part collection member responds; wherein said N is a positive number.\",\n \"53.The circuit of claim 52, wherein an input collection is comprised of said first and said second input; wherein each member of said input collection is comprised of a log-input and a normal-input; 54.The circuit of claim 53, wherein each member of said ALU part collection presents a result to said corresponding said second sub-circuit.\",\n \"55.The circuit of claim 54, further comprising a second of said arithmetic module circuits coupled to said input-output circuit; wherein said input-output circuit presents said first input to at least one member of the collection comprising said first ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; wherein said input-output circuit presents said second input to at least one member of the collection comprising sad second ALU part of said second arithmetic module and said corresponding memory sub-circuit of said second arithmetic module based upon exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.\",\n \"56.The circuit of claim 55, wherein a second circuit collection is comprised of said second circuit of said arithmetic module circuit and said second circuit of said second arithmetic module circuit; wherein at least one member of said second circuit collection couples to an internal wire bundle comprised of a first sub-internal wire bundle and a second sub-internal wire bundle; wherein for each member of said second circuit collection coupled to said internal wire bundle asserts a first sub-internal wire state on said first sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said first ALU part of said arithmetic module circuit responds; wherein for each member of said second circuit collection coupled to said internal wire bundle asserts a second sub-internal wire state on said second sub-internal wire bundle based upon said exactly one and the same member of said sample instruction collection to which said second ALU part of said arithmetic module circuit responds.\",\n \"57.The circuit of claim 46, further comprising a first datapath instruction processor coupled to said first datapath instruction wire bundle presented to said module circuit; wherein said first datapath instruction processor asserts said first datapath instruction wire bundle; and a second datapath instruction processor coupled to said second datapath instruction wire bundle presented to said module circuit; wherein said second datapath instruction processor asserts said second datapath instruction wire bundle.\",\n \"58.The circuit of claim 57, wherein a datapath instruction processor collection is comprised of said first datapath instruction processor and said second datapath instruction processor; wherein said first datapath instruction wire bundle is an associated datapath instruction wire bundle of said first datapath instruction processor; wherein said second datapath instruction wire bundle is an associated datapath instruction wire bundle of said second datapath instruction processor; wherein at least one member of said datapath instruction processor collection is further comprised of: a datapath instruction pointer coupled to said clock wire bundle, and to a datapath instruction address wire bundle; and a datapath instruction register coupled to said clock wire bundle, to said asserted datapath instruction wire bundle, and to a datapath instruction wire bundle; wherein said clock wire bundle possesses a datapath instruction capture state; wherein said datapath instruction queue pointer responds to said clock wire bundle by asserting an asserted datapath instruction address; wherein said datapath instruction register responds to said clock wire bundle by capturing a datapath instruction capture state whenever said clock wire bundle is in said datapath instruction capture state; and wherein said datapath instruction register further asserts said associated datapath instruction wire bundle based upon said datapath instruction capture state.\",\n \"59.The circuit of claim 58, wherein for at least one member of said datapath instruction processor collection comprising said datapath instruction pointer is further comprised of: an instruction store coupled to said datapath instruction address wire bundle and to said datapath instruction wire bundle; wherein said instruction store responds to said asserted datapath instruction address via said datapath instruction address wire bundle to asserting said datapath instruction wire bundle based upon said asserted datapath instruction address.\",\n \"60.The circuit of claim 59, wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction processor is further comprised of a last instruction indicator coupled to a last instruction indicator wire bundle possessing a last instruction state and a non-last instruction state; wherein for at least one member of said datapath instruction processor collection comprising said instruction store, said datapath instruction pointer is further coupled to a new datapath instruction address wire bundle and to said last instruction indicator wire bundle; and wherein for at least one member of said datapath instruction processor collection comprising said instruction store is further comprised of: a branch-cache instruction processor coupled to said last instruction indicator and to said new datapath instruction address wire bundle; wherein said branch-cache instruction processor responds to said last instruction state via said last instruction indicator wire bundle by asserting a new datapath instruction address upon said new datapath instruction address wire bundle; and wherein said datapath instruction pointer responds to said last instruction indicator wire bundle by capturing said new datapath instruction address from said new datapath instruction address wire bundle.\",\n \"61.A circuit implementation of claim 46, wherein a component list comprises said arithmetic module circuit, said first memory circuit coupled to said partition control wire bundle, and said first arithmetic logic unit; wherein each member of said component list is implemented with at least part of at least one member of the collection comprising a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array (FPGA); and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.\",\n \"62.The circuit implementation of claim 61,: wherein the implementation of all members of said component list further includes only circuitry responding to exactly one and the same member of said sample instruction collection based upon said partition control state.\",\n \"63.A method of processing numeric data, comprising the step of: representing each member of a number collection by an integer part and a special part; log-converting a member of an input number collection to create a member of said number collection; and exp-converting a member of said number collection to create a member of an output number collection; wherein said special part representing said member of said number collection contains of exactly one member of a first special value collection comprising negative-infinity and not-negative-infinity; wherein said special part of each member of said number collection further contains exactly one member of a second special value collection comprising a special-minus and a special-plus; wherein said integer part of each member of said number collection contains a sign and a magnitude; wherein, for each member of said number collection, said sign is a member of a sign collection consisting essentially of a positive-sign and a negative-sign; wherein said number collection comprises at least a first number and a second number; said method further comprising the steps of: performing all members of the arithmetic operation collection upon at least one of said members of said number collection; wherein said arithmetic operation collection is comprised of the steps of: adding said first number to said second number to create an add-result; subtracting said first number by said second number to create a subtract-result; exponentiating said first number to create an exp-result; and logarithming said first number to create a log-result; wherein said number collection is further comprised of said add-result, said subtract-result, said exp-result and said log-result; wherein the step of adding is further comprised of the steps of: determining whether said special part of said first number contains said negative-infinity; determining whether said special part of said second number contains said negative-infinity; and setting said special part of said add-result to contain said negative-infinity whenever said special part of at least one member of the collection said first number and said second number contains said negative-infinity; wherein the step of subtracting is further comprised of the steps of: determining whether said special part of said first number contains said negative-infinity; setting said special part of said subtract-result to contain said negative-infinity whenever said special part of said first number contains said negative-infinity; wherein the step of exponentiating is further comprised of the step of: determining whether said special part of said first number contains said negative-infinity; setting said special part of said exp-result to contain said not-negative-infinity and setting said integer part to a zero-representation whenever said special part of said first number contains said negative-infinity; and setting said sign of said exp-result to essentially said negative-sign whenever said special part of said first number contains said special-minus; wherein the step of logarithming is further comprised of the steps of: determining whether said integer part of said first number is essentially equal to said zero-representation; setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number essentially equals said zero-representation; determining whether said sign part of said first number is essentially equal to said negative-sign; and setting said special part of said log-result to contain said special-minus whenever said sign part of said first number is essentially said negative-sign; wherein said input number collection is comprised of a first input number and a second input number.\",\n \"wherein each member of said input number collection is comprised of an integer part; wherein the step log-converting said input number collection member is further comprised of the steps of: determining whether said integer part of said input number collection member is essentially equal to said zero-representation; and setting said special part of said number collection member to contain said negative-infinity whenever said integer part of said input number collection member essentially equals said zero-representation.\",\n \"wherein said output number collection is comprised of a first output number and a second output number; wherein each of said output number collection members include a magnitude; wherein the step exp-converting is further comprised of the steps of: setting said magnitude of said output number collection member to said zero-representation whenever said special part of said number collection member contains said negative-infinity; and setting said sign of said output number collection member to said positive-sign whenever said special part of said number collection member contains said special-plus.\",\n \"64.The method of claim 63, wherein said integer part of each of said number collection members is in a non-redundant numeric notation; wherein the step of setting said special part of said log-result is further comprised of the step of: setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number equals said zero-representation.\",\n \"65.The method of claim 63, wherein said integer part of each of said number collection members is in a redundant numeric notation possessing a zero-representation collection comprising at least two zero-representation instances; wherein the step of setting said special part of said log-result is further comprised of the step of: setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number is a member of said zero-representation collection.\",\n \"66.The method of claim 63, wherein said integer part of each of said number collection members is in a redundant numeric notation supporting determination of negativity by a negative-test collection comprising at least two negative-test steps; where the step determining whether said sign part of said first number is essentially equal to said negative-sign is further comprised of the step of: determining whether said sign part of said first number is equal to said negative-sign based upon performing at least one of the members of said negative-test collection.\",\n \"67.The method of claim 63, wherein said integer part of each of said number collection members is in a non-redundant numeric notation possessing exactly one negative-test step; wherein the step of determining whether said sign part of said first number is essentially equal to said negative-sign is further comprised of the step of: performing said exactly one negative-test step based upon said first number.\",\n \"68.The method of claim 63, wherein said integer part of each of said input number collection members contains a sign belonging to said sign collection and a magnitude; wherein the step of log-converting is further comprised of the steps of: determining whether said sign part of said input number collection member is essentially equal to said negative-sign; and setting said special part of said number collection member to contain said special-minus whenever said sign part of said input number collection member is essentially said negative-sign.\",\n \"69.The method of claim 63, wherein each of said output number collection members include a sign belong to said sign collection; wherein the step exp-converting is further comprised of the step of: setting said sign of said output number collection member to said negative-sign whenever said special part of said number collection member contains said special-minus.\",\n \"70.The method of claim 69, wherein each of said input number collection members is encoded as an N1 bit code; wherein said N1 is at least three; wherein said integer part of each of said number collection members is encoded as an N2 bit code; wherein N2 is greater than N1.71.A program system for processing numeric data, implementing the steps of claim 63, comprising program steps residing in a memory accessibly coupled to a computer, said program system comprising the program steps of: representing each member of a number collection by an integer part and a special part; log-converting a member of an input number collection to create a member of said number collection; exp-converting a member of said number collection to create a member of an output number collection; determining whether said special part of said first number contains said negative-infinity; adding said first number to said second number to create an add-result; subtracting said first number by said second number to create a subtract-result; exponentiating said first number to create an exp-result; and logarithming said first number to create a log-result.\",\n \"72.The program system of claim 71, wherein the program steps implementing the method are embodied in at least one member of the language collection comprising C, C++, JAVA, FORTRAN, PASCAL, VERILOG, VHDL, assembly language and executable code for at least one computational engine implemented upon said computer.\",\n \"73.A digital circuit generated from the program steps of claim 72.74.A circuit for processing numeric data, implementing the steps of claim 63, comprising: means for representing each member of a number collection by an integer part and a special part; means for determining whether said special part of said first number contains said negative-infinity; means for adding said first number to said second number to create an add-result; means for subtracting said first number by said second number to create a subtract-result; means for exponentiating said first number to create an exp-result; and means for logarithming said first number to create a log-result.\",\n \"75.The circuit of claim 74, wherein at least one of the means of claim 74 is implemented within at least one circuit component belonging to a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array; and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.\",\n \"76.The circuit of claim 74, wherein at least one of said input number collection members are implemented as a wire state collection received from a wire bundle coupled to said circuit.\",\n \"77.The circuit of claim 74, wherein at least one of said output number collection members are implemented as a wire state asserted by said circuit onto a wire bundle.\",\n \"78.A method of processing numeric data, comprising the step of: representing each member of a number collection by an integer part and a special part; wherein said special part representing said member of said number collection contains of exactly one member of a first special value collection comprising negative-infinity and not-negative-infinity; wherein said number collection comprises at least a first number and a second number; said method further comprising the steps of: performing at least one member of the arithmetic operation collection upon at least one of said members of said number collection; wherein said arithmetic operation collection is comprised of the steps of: adding said first number to said second number to create an add-result; subtracting said first number by said second number to create a subtract-result; exponentiating said first number to create an exp-result; and logarithming said first number to create a log-result; wherein said number collection is further comprised of said add-result, said subtract-result, said exp-result and said log-result; wherein the step of adding is further comprised of the steps of: determining whether said special part of said first number contains said negative-infinity; determining whether said special part of said second number contains said negative-infinity; and setting said special part of said add-result to contain said negative-infinity whenever said special part of at least one member of the collection said first number and said second number contains said negative-infinity; wherein the step of subtracting is further comprised of the steps of: determining whether said special part of said first number contains said negative-infinity; setting said special part of said subtract-result to contain said negative-infinity whenever said special part of said first number contains said negative-infinity; wherein the step of exponentiating is further comprised of the step of: determining whether said special part of said first number contains said negative-infinity; setting said special part of said exp-result to contain said not-negative-infinity and setting said integer part to a zero-representation whenever said special part of said first number contains said negative-infinity; wherein the step of logarithming is further comprised of the steps of: determining whether said integer part of said first number is essentially equal to said zero-representation; and setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number essentially equals said zero-representation.\",\n \"79.The method of claim 78, wherein said integer part of each of said number collection members is in a non-redundant numeric notation; wherein the step of setting said special part of said log-result is further comprised of the step of: setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number equals said zero-representation.\",\n \"80.The method of claim 78, wherein said integer part of each of said number collection members is in a redundant numeric notation possessing a zero-representation collection comprising at least two zero-representation instances; wherein the step of setting said special part of said log-result is further comprised of the step of: setting said special part of said log-result to contain said negative-infinity whenever said integer part of said first number is a member of said zero-representation collection.\",\n \"81.The method of claim 78, wherein said integer part of each member of said number collection contains a sign and a magnitude; wherein, for each member of said number collection, said sign is a member of a sign collection consisting essentially of a positive-sign and a negative-sign; wherein said special part of each member of said number collection further contains exactly one member of a second special value collection comprising a special-minus and a special-plus; wherein the step of exponentiating is further comprised of the steps of: setting said sign of said exp-result to essentially said negative-sign whenever said special part of said first number contains said special-minus; wherein the step of logarithming is further comprised of the steps of: determining whether said sign part of said first number is essentially equal to said negative-sign; and setting said special part of said log-result to contain said special-minus whenever said sign part of said first number is essentially said negative-sign.\",\n \"82.The method of claim 81, wherein said integer part of each of said number collection members is in a redundant numeric notation supporting determination of negativity by a negative-test collection comprising at least two negative-test steps; where the step determining whether said sign part of said first number is essentially equal to said negative-sign is further comprised of the step of: determining whether said sign part of said first number is equal to said negative-sign based upon performing at least one of the members of said negative-test collection.\",\n \"83.The method of claim 81, wherein said integer part of each of said number collection members is in a non-redundant numeric notation possessing exactly one negative-test step; wherein the step of determining whether said sign part of said first number is essentially equal to said negative-sign is further comprised of the step of: performing said exactly one negative-test step based upon said first number.\",\n \"84.The method of claim 81, further comprising the step of: log-converting a member of an input number collection to create a member of said number collection; wherein said input number collection is comprised of a first input number and a second input number.\",\n \"85.The method of claim 84, wherein each member of said input number collection is comprised of an integer part; wherein the step log-converting said input number collection member is further comprised of the steps of: determining whether said integer part of said input number collection member is essentially equal to said zero-representation; and setting said special part of said number collection member to contain said negative-infinity whenever said integer part of said input number collection member essentially equals said zero-representation.\",\n \"86.The method of claim 85, wherein said integer part of each of said input number collection members contains a sign belonging to said sign collection and a magnitude; wherein the step of log-converting is further comprised of the steps of: determining whether said sign part of said input number collection member is essentially equal to said negative-sign; and setting said special part of said number collection member to contain said special-minus whenever said sign part of said input number collection member is essentially said negative-sign.\",\n \"87.The method of claim 86, further comprising the step of: exp-converting a member of said number collection to create a member of an output number collection; wherein said output number collection is comprised of a first output number and a second output number.\",\n \"88.The method of claim 87, wherein each of said output number collection members include a magnitude; wherein the step exp-converting is further comprised of the step of: setting said magnitude of said output number collection member to said zero-representation whenever said special part of said number collection member contains said negative-infinity.\",\n \"89.The method of claim 88, wherein each of said output number collection members include a sign belong to said sign collection; wherein the step exp-converting is further comprised of the steps of: setting said sign of said output number collection member to said negative-sign whenever said special part of said number collection member contains said special-minus; and setting said sign of said output number collection member to said positive-sign whenever said special part of said number collection member contains said special-plus.\",\n \"90.The method of claim 89, wherein each of said input number collection members is encoded as an N1 bit code; wherein said N1 is at least three; wherein said integer part of each of said number collection members is encoded as an N2 bit code; wherein N2 is greater than N1.91.A program system for processing numeric data, implementing the steps of claim 78, comprising program steps residing in a memory accessibly coupled to a computer, said program system comprising the program steps of: representing each member of a number collection by an integer part and a special part; adding said first number to said second number to create an add-result; subtracting said first number by said second number to create a subtract-result; exponentiating said first number to create an exp-result; and logarithming said first number to create a log-result.\",\n \"92.The program system of claim 78, wherein the program steps implementing the method are embodied in at least one member of the language collection comprising C, C++, JAVA, FORTRAN, PASCAL, VERILOG, VHDL, assembly language and executable code for at least one computational engine implemented upon said computer.\",\n \"93.A circuit generated from the program steps of claim 92.94.A circuit for processing numeric data, implementing the steps of claim 78, comprising: means for representing each member of a number collection by an integer part and a special part; means for adding said first number to said second number to create an add-result; means for subtracting said first number by said second number to create a subtract-result; means for exponentiating said first number to create an exp-result; and means for logarithming said first number to create a log-result.\",\n \"95.The circuit of claim 94, wherein at least one of the means of claim 94 is implemented within at least one circuit component belonging to a programmable logic device collection and a fixed architecture device collection; wherein said programmable logic device collection comprises all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array; and wherein said fixed architecture device collection comprises all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.\",\n \"96.The circuit of claim 94, wherein at least one of said input number collection members are implemented as a wire state collection received from a wire bundle coupled to said circuit.\",\n \"97.The circuit of claim 94, wherein at least one of said output number collection members are implemented as a wire state asserted by said circuit onto a wire bundle.\"\n ],\n [\n \"<SOH> BACKGROUND OF INVENTION <EOH>Today, much of the growth in the planetary economy depends on rapid and reliable development of new products, many of which require Digital Signal Processing (DSP) hardware to solve the problems which attract customers to buy such products.\",\n \"These problems are often solved by a wide variety of digital filtering techniques, often based upon Finite Impulse Response (FIR) filtering including various Discrete Fourier Transform based algorithms as well as Discrete Wavelet Transform algorithms.\",\n \"Most of these response and transform functions are linear in nature.\",\n \"Many of these functions operate on a finite grid of data, frequently known as a data window.\",\n \"While existing hardware vehicles provide vehicles for such algorithms, there are several central problems which are difficult to solve with existing solutions.\",\n \"Many application systems need non-linear functions.\",\n \"Some commonly used arithmetic operations in engineering and applied science include but are not limited to the following: square roots, cube roots, division, trigonometric functions, powers of numbers, polynomial functions, rational functions, exponential functions, logarithms, and determinants.\",\n \"These commonly used arithmetic operations have found significant application in at least the areas of graphics models, statistical and probabilistic tools, dynamical systems, flow simulations, control systems, transistor and circuit modeling and other nonlinear models.\",\n \"Additionally, there are large applications in the areas of multimedia and image processing including the requirements of filling an HDTV screen with an MPEG stream and various medical imaging applications.\",\n \"The cellular radio industry possesses a number of base station related applications including 911 call location determination and signal separation in high capacity situations.\",\n \"What is needed is arithmetic processing circuitry which can address at least these needs in a real-time fashion.\",\n \"The above mentioned finite grids of data are often sampled in real-time by sensor devices.\",\n \"Each data sample can vary from as small as 6 bits per data sample to 17 or more bits per data sample.\",\n \"Usually, the data tends to be of fairly uniform size, the number of sample bits does not vary much, if at all, across a data grid.\",\n \"Most DSP hardware has a fixed input data size, usually a multiple of 8 or 9 bits.\",\n \"The consequence of this is that bits go unused.\",\n \"By way of example, in a device supporting only 8 and 16 bit data input, a 9 bit sample requires all 16 bits be used, even though only slightly more than 50% of the input bits are actively being used.\",\n \"Further, the data is often sampled at very high rates by multiple sensors, ranging from hundred of thousands of samples per second per sensor to a hundred million samples per second per sensor.\",\n \"What is further needed is a high speed capability to efficiently accept and process widely varying data sample widths.\",\n \"Today, arithmetic-based models are in widespread use employing various fixed point and floating point numeric representations.\",\n \"There is a central problem associated with these representations, the accumulation of arithmetic errors.\",\n \"This is an architectural result of the limited structural capabilities of contemporary arithmetic processors.\",\n \"Such processors typically can only perform arithmetic of a fixed number of significant bits in a given instruction execution period.\",\n \"The consequence of this is that as calculations progress, additional precision is required, but not available.\",\n \"What is needed is arithmetic circuitry which can be readily configured to provide a wide range of precision for any given instruction sequence in a given instruction execution period.\",\n \"By way of example, many real-time DSP applications possess the following common constraints.\",\n \"High speed input sample rates, often on the order of 100K to 100 Million samples per second.\",\n \"High output result rates, due to the prohibitive expense of storing these samples for longer than a few milliseconds to a few seconds.\",\n \"Data sample sizes varying from 6 to 16 bits per sample, with a concomitant requirement to preserve or improve the signal to noise ratio from input sensors to internal use of these samples.\",\n \"Many of these applications are developed against a further constraint of short time-to-market requirement.\",\n \"Contemporary approaches to the performance problems of DSP include standard instruction processors, VLIW processors and reconfigurable computers.\",\n \"Standard instruction processors can be further classified as embedded core DSP processors, Single Instruction Single Datapath (SISD) processors and Multiple Instruction Multiple Datapath (MIMD) processors.\",\n \"Commercial examples of mbedded core DSP processors include the DSP group Oak and Pine processors.\",\n \"Commercial examples of SISD processors include some of the components of the Analog Devices ADSP product line and products of the Texas Instrument 54XX DSP Family.\",\n \"Commercial examples of MIMD products include the high-end products of the ADSP product line.\",\n \"Commercial examples of VLIW processors can be found in the TI 60XX DSP product family.\",\n \"There are at least two distinct performance bottlenecks which affect all or nearly all of the above mentioned approaches to arithmetic and instruction processing: the instruction fetch bottleneck and data access bottleneck.\",\n \"The instruction fetch bottleneck is caused by the imbalance of memory access rate compared to instruction processing mechanisms.\",\n \"Various approaches to solving this problem include adding cache memories, which then put the balance in favor of memories.\",\n \"This leads to compensating by incorporating instruction decoders operating upon multiple instructions as found in super-scalar microprocessors.\",\n \"Such circuitry increases the instruction processing capability of a single instruction path device, by greatly increasing the relative size of the instruction decoding mechanism to the arithmetic processors, as well as increasing the complexity of verifying instruction set execution compliance.\",\n \"What is needed is a flexible instruction processing mechanism which can more efficiently utilize instruction memory bandwidth to drive the arithmetic processing circuitry.\",\n \"The data access bottleneck often arises when memory is shared with other processes, such as the instruction fetching process mentioned above.\",\n \"The standard approach to minimizing this problem is the use of either separate memories or providing caches, which in many cases are specifically dedicated to data memory operations.\",\n \"While these approaches add to the availability of data for arithmetic processing, they do not address what the following major limitations found in all of the prior art.\",\n \"The prior art does not provide the user with direct control over the input data width, the internal or intermediate precision width, nor the output data width.\",\n \"What is needed is a way to provide the user of these circuits with direct control over input data with, internal or intermediate precision width and outut data width.\",\n \"Today, VLIW architectures are available which show some flexibility, but are difficult to program due to complex, multiple-memory cycle instruction fetching mechanism, as well as having little or no flexibility regarding input data widths, internal/intermediate precision and output data widths.\",\n \"Reconfigurable computers have been extensively researched since the 1990's, but have yet to have large scale commercial success.\",\n \"These computer have been largely constructed from arrays of FPGA's.\",\n \"They have tended to be very difficult to program, often requiring gate level or logic cell level programming, as opposed to support procedural computer language compilers.\",\n \"Such computer also tend to have problems with multiplication.\",\n \"While some FPGAs now contain cells supporting small multipliers, often 4 by 4 or 4 by 5 bit multipliers, when even a 16 by 16 bit multiplication is to be done, somewhere between 6 and 16 of these cells must be dedicated to that task.\",\n \"Multipliers built this way do not lend themselves to ease of programming nor show themselves flexible in terms of changing input data width or output data width requirements.\",\n \"Most people require less development time to create numeric applications using procedural programming languages such as C or Java than using assembly language, much less a gate or function cell level definition language.\",\n \"The fact that it is possible to build a multiplier with an FPGA is not the problem system developers have to solve.\",\n \"What is needed is a mechanism providing the user with direct control over the input data width, the internal/intermediate precision width, and the output data width while providing a wide range of arithmetic operations in an efficient fashion.\",\n \"What is further needed is a method of specifying such control and then generating efficient circuits satisfying those specifications.\",\n \"What is further needed is an architecture which provides standard procedural language compiler support both for mechanisms supporting user control of input data width, internal/intermediate precision and output data width.\",\n \"What is further needed is a target circuit compilation architecture providing automated support for procedural compilers specified and generated by such methods.\",\n \"There are further problems in the organization of instruction processing mechanisms which significantly constrain performance due to the fixed configuration of internal operational resources.\",\n \"By way of example, the number of arithmetic processing resources available to prepare for a branch decision is fixed.\",\n \"However, high performance arithmetic-oriented applications often involve very large numbers of arithmetic operations being performed before any branching decisions need be made.\",\n \"When branching is to be performed, a number of relatively short operation sequences are usually needed to determine the flow of execution and control.\",\n \"What is needed is an instruction processing mechanism which can be optimally configured for both decision processes and computational sequences.\",\n \"Today, multiple datapath architectures are either Single Instruction Multiple Datapath (SIMD) or Multiple Instruction Multiple Datapath (MIMD).\",\n \"However, there are times when a system optimally acts in one fashion, and other times when it optimally would perform in the other fashion.\",\n \"What is needed is an architecture supporting multiple datapaths in either an SIMD or MIMD mode, which can be rapidly reconfigured from one to the other.\",\n \"There are additional problems facing the system designer intent upon making a new product: the system designer must often provide a complete systems solution, which often includes a package containing one or more printed circuits, which further contain integrated circuits performing numeric tasks within the package in normal operating modes.\",\n \"The system designer needs to be able to test the printed circuits containing the integrated circuits in operation as early in the design process as possible.\",\n \"Additionally, while there have been various attempts to use logarithmic numeric notations to perform arithmetic operations, none of the known approaches are readily extensible to varying precision widths.\",\n \"Such notations tend to treat numbers as either floating point numbers possessing an exponent and mantissa, or as a fixed point number.\",\n \"Both mechanisms have decided problems when applied to the varying needs of systems design, where the notation must be useful across a large collection of numeric ranges.\",\n \"Floating point notations have fixed fields, which further tend to hide the most significant bit of the mantissa, rendering such a notation is inherently difficult to alter.\",\n \"Both approaches to number notations lack any obvious way to convert 0 into a logarithm of 0.What is needed is a numeric notation readily supporting logarithmic numbers as well as being readily scalable to support differing amounts of precision in a real-time environment.\",\n \"To summarize, what is needed is arithmetic processing circuitry addressing the need for advanced, often non-linear functions based upon much more than linear arithmetic operations in a real-time fashion.\",\n \"Such operations include but are not limited to square roots, division, trigonometric functions, powers of numbers, polynomial functions, rational functions, exponential functions, logarithms, and determinants.\",\n \"What is needed includes the ability to efficiently accept and process widely varying data sample widths at high speeds.\",\n \"What is needed is arithmetic circuitry readily configured to provide a wide range of precision for any given instruction sequence in a given instruction execution period.\",\n \"What is needed is a flexible instruction processing mechanism which can more efficiently utilize instruction memory bandwidth to drive the arithmetic processing circuitry.\",\n \"What is needed is an instruction processing mechanism which can be optimally configured for both decision processes and computational sequences.\",\n \"What is needed is an architecture supporting multiple datapaths in either an SIMD or MIMD mode, which can be rapidly reconfigured from one to the other.\",\n \"What is needed is a mechanism providing the user with direct control over the input data width, the internal/intermediate precision width, and the output data width while providing a wide range of arithmetic operations in an efficient fashion.\",\n \"What is further needed is a method of specifying such control and then generating efficient circuits satisfying those specifications.\",\n \"What is further needed is an architecture which provides standard procedural language compiler support both for mechanisms supporting user control of input data width, internal/intermediate precision and output data width.\",\n \"What is further needed is a target circuit compilation architecture providing automated support for procedural compilers specified and generated by such methods.\"\n ],\n [\n \"<SOH> SUMMARY OF INVENTION <EOH>Certain embodiments of the invention solve all the above mentioned problems found in the prior art.\",\n \"Certain embodiments utilize partitionable datapath bit width units, which can be configured to provide a requested level of numeric precision.\",\n \"The partitionable datapath bid width units include at least memory arrays and ALUs, which can collectively be configured to specific bit widths supporting the requested level of numeric precision in both a normal numeric realm and a logarithmic numeric domain.\",\n \"Certain embodiments of the invention represent a collection of numbers as having at least a minus-infinity as a special part of each represented number.\",\n \"These minus-infinity numbers act as annihilators in addition, so that minus-infinity plus anything else results in a minus-infinity in the special part of the represented result.\",\n \"Thus, the fact that zero multiplying anything in the normal numeric realms translates upon taking logarithms of both numbers.\",\n \"The logarithmic conversion of a zero yields a represented number with a minus-infinity.\",\n \"The exponential conversion of a represented number with negative-infinity in its special part yields a 0 result.\",\n \"Represented numbers may further include a special-plus or special-minus in their special parts, further supporting preservation of the input number sign upon into the represented number and conversion back to output numbers.\",\n \"Note that this also requires that special-minus represented numbers, when added to special-minus represented numbers generate a represented number result with a special-plus.\",\n \"Special-plus added to special-plus results in a special-plus.\",\n \"When a special-minus number and a special-plus number are added, the result is a special-minus result.\",\n \"This effects a logarithm of a first number added to the logarithm of a second number is essentially the same as the logarithm of the product of the first and second numbers.\",\n \"In the logarithm domain, functions can be calculated which are very computationally expensive in the normal realm of numbers.\",\n \"A level of efficiency previously unavailable in a programmable device of any kind is achieved by using at least some of the memories as table lookup mechanisms to approximately convert numbers between their logarithms, exponentials and other functions.\",\n \"Certain embodiments of the invention include a method of using an array of computational resources containing at least one input-output resource, at least one datapath operational resource comprising: selecting the input-output resources to create an input-output access collection comprised of at least an input-output access parameter; and selecting the datapath operational resources based upon the input-output access collection to create a datapath operational resource allocation collection containing at least one datapath operation resource allocation.\",\n \"This supports selecting input-output resources for optimal data bandwidth throughput.\",\n \"They also support selecting datapath operational resources for optimal datapath resource allocation operating on data traversing the selected input-output resources.\",\n \"The computation resource array may contain at least one instruction propagating resource.\",\n \"The method may selecting the instruction propagating resources based upon the input-output access collection and the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration.\",\n \"The computation resource array may further contain at least one instruction processing resource.\",\n \"Instruction processing resources may further be selected based upon the input-output access collection, datapath operational resource allocation and instruction propagating configuration.\",\n \"The instruction processing resources may contain at least one instruction register.\",\n \"The computation resource array may further contain at least one instruction fetching resource.\",\n \"The method may include fetching using the instruction fetching resource to create a fetched instruction and loading the fetched instruction into the instruction register to create an instruction register state based upon the fetched instruction.\",\n \"Certain embodiments of the invention include circuits generated by methods of this invention.\",\n \"They may be implemented using collections of one or more programmable logic devices, which may in turn include one or more programmable logic arrays and/or one or more Field Programmable Gate Arrays (FPGAs).\",\n \"They may be implemented as part or all of an integrated circuit, having been specified using a method of this invention and/or simulated based upon their specification.\",\n \"Their simulation may include implementations targeting logic hardware accelerators including programmable logic devices as execution elements.\",\n \"Certain embodiments of the invention include an arithmetic module of multiple basic arithmetic circuits coupled to share several wire bundles including a first shared buss, a second shared buss and a third shared buss that synchronously execute either one or two instructions, depending upon a configuration register.\",\n \"The shared bus wire bundle state is determined in part by the configuration register.\",\n \"Each basic arithmetic circuit includes a basic arithmetic memory coupled with a basic arithmetic calculator.\"\n ],\n [\n \"This application claims priority from the following provisional applications filed with the United States Patent and Trademark Office: Ser.\",\n \"No.\",\n \"60/204,113, entitled “Method and apparatus of a digital arithmetic and memory circuit with coupled control system and arrays thereof”, filed May 15, 2000 by inventor, docket number ARITH001PR; Ser.\",\n \"No.\",\n \"60/215,894, entitled “Method and apparatus of a digital arithmetic and memory circuit with coupled control system and arrays thereof”, filed Jul.\",\n \"5, 2000 by inventor, docket number ARITH002PR; Ser.\",\n \"No.\",\n \"60/217,353, entitled “Method and apparatus of a digital arithmetic and memory circuit with coupled control system and arrays thereof”, filed Jul.\",\n \"11, 2000 by inventor, docket number ARITH003PR; Ser.\",\n \"No.\",\n \"60/231,873, entitled “Method and apparatus of a digital arithmetic and memory circuit with coupled control system and arrays thereof”, filed Sep. 12, 2000 by inventor, docket number ARITH004PR; Ser.\",\n \"No.\",\n \"60/261,066, entitled “Method and apparatus of a DSP resource circuit”, filed Jan. 11, 2001 by inventor, docket number ARITH005PR; and Ser.\",\n \"No.\",\n \"60/282,093, entitled “Method and apparatus of a DSP resource circuit”, filed Apr.\",\n \"6, 2001 by inventor, docket number ARITH006PR.\",\n \"TECHNICAL FIELD This invention relates to digital signal processing engines, instruction processing mechanisms, arithmetic operational units of same, as well as circuitry generated based upon use of some or all of these elements.\",\n \"BACKGROUND OF INVENTION Today, much of the growth in the planetary economy depends on rapid and reliable development of new products, many of which require Digital Signal Processing (DSP) hardware to solve the problems which attract customers to buy such products.\",\n \"These problems are often solved by a wide variety of digital filtering techniques, often based upon Finite Impulse Response (FIR) filtering including various Discrete Fourier Transform based algorithms as well as Discrete Wavelet Transform algorithms.\",\n \"Most of these response and transform functions are linear in nature.\",\n \"Many of these functions operate on a finite grid of data, frequently known as a data window.\",\n \"While existing hardware vehicles provide vehicles for such algorithms, there are several central problems which are difficult to solve with existing solutions.\",\n \"Many application systems need non-linear functions.\",\n \"Some commonly used arithmetic operations in engineering and applied science include but are not limited to the following: square roots, cube roots, division, trigonometric functions, powers of numbers, polynomial functions, rational functions, exponential functions, logarithms, and determinants.\",\n \"These commonly used arithmetic operations have found significant application in at least the areas of graphics models, statistical and probabilistic tools, dynamical systems, flow simulations, control systems, transistor and circuit modeling and other nonlinear models.\",\n \"Additionally, there are large applications in the areas of multimedia and image processing including the requirements of filling an HDTV screen with an MPEG stream and various medical imaging applications.\",\n \"The cellular radio industry possesses a number of base station related applications including 911 call location determination and signal separation in high capacity situations.\",\n \"What is needed is arithmetic processing circuitry which can address at least these needs in a real-time fashion.\",\n \"The above mentioned finite grids of data are often sampled in real-time by sensor devices.\",\n \"Each data sample can vary from as small as 6 bits per data sample to 17 or more bits per data sample.\",\n \"Usually, the data tends to be of fairly uniform size, the number of sample bits does not vary much, if at all, across a data grid.\",\n \"Most DSP hardware has a fixed input data size, usually a multiple of 8 or 9 bits.\",\n \"The consequence of this is that bits go unused.\",\n \"By way of example, in a device supporting only 8 and 16 bit data input, a 9 bit sample requires all 16 bits be used, even though only slightly more than 50% of the input bits are actively being used.\",\n \"Further, the data is often sampled at very high rates by multiple sensors, ranging from hundred of thousands of samples per second per sensor to a hundred million samples per second per sensor.\",\n \"What is further needed is a high speed capability to efficiently accept and process widely varying data sample widths.\",\n \"Today, arithmetic-based models are in widespread use employing various fixed point and floating point numeric representations.\",\n \"There is a central problem associated with these representations, the accumulation of arithmetic errors.\",\n \"This is an architectural result of the limited structural capabilities of contemporary arithmetic processors.\",\n \"Such processors typically can only perform arithmetic of a fixed number of significant bits in a given instruction execution period.\",\n \"The consequence of this is that as calculations progress, additional precision is required, but not available.\",\n \"What is needed is arithmetic circuitry which can be readily configured to provide a wide range of precision for any given instruction sequence in a given instruction execution period.\",\n \"By way of example, many real-time DSP applications possess the following common constraints.\",\n \"High speed input sample rates, often on the order of 100K to 100 Million samples per second.\",\n \"High output result rates, due to the prohibitive expense of storing these samples for longer than a few milliseconds to a few seconds.\",\n \"Data sample sizes varying from 6 to 16 bits per sample, with a concomitant requirement to preserve or improve the signal to noise ratio from input sensors to internal use of these samples.\",\n \"Many of these applications are developed against a further constraint of short time-to-market requirement.\",\n \"Contemporary approaches to the performance problems of DSP include standard instruction processors, VLIW processors and reconfigurable computers.\",\n \"Standard instruction processors can be further classified as embedded core DSP processors, Single Instruction Single Datapath (SISD) processors and Multiple Instruction Multiple Datapath (MIMD) processors.\",\n \"Commercial examples of mbedded core DSP processors include the DSP group Oak and Pine processors.\",\n \"Commercial examples of SISD processors include some of the components of the Analog Devices ADSP product line and products of the Texas Instrument 54XX DSP Family.\",\n \"Commercial examples of MIMD products include the high-end products of the ADSP product line.\",\n \"Commercial examples of VLIW processors can be found in the TI 60XX DSP product family.\",\n \"There are at least two distinct performance bottlenecks which affect all or nearly all of the above mentioned approaches to arithmetic and instruction processing: the instruction fetch bottleneck and data access bottleneck.\",\n \"The instruction fetch bottleneck is caused by the imbalance of memory access rate compared to instruction processing mechanisms.\",\n \"Various approaches to solving this problem include adding cache memories, which then put the balance in favor of memories.\",\n \"This leads to compensating by incorporating instruction decoders operating upon multiple instructions as found in super-scalar microprocessors.\",\n \"Such circuitry increases the instruction processing capability of a single instruction path device, by greatly increasing the relative size of the instruction decoding mechanism to the arithmetic processors, as well as increasing the complexity of verifying instruction set execution compliance.\",\n \"What is needed is a flexible instruction processing mechanism which can more efficiently utilize instruction memory bandwidth to drive the arithmetic processing circuitry.\",\n \"The data access bottleneck often arises when memory is shared with other processes, such as the instruction fetching process mentioned above.\",\n \"The standard approach to minimizing this problem is the use of either separate memories or providing caches, which in many cases are specifically dedicated to data memory operations.\",\n \"While these approaches add to the availability of data for arithmetic processing, they do not address what the following major limitations found in all of the prior art.\",\n \"The prior art does not provide the user with direct control over the input data width, the internal or intermediate precision width, nor the output data width.\",\n \"What is needed is a way to provide the user of these circuits with direct control over input data with, internal or intermediate precision width and outut data width.\",\n \"Today, VLIW architectures are available which show some flexibility, but are difficult to program due to complex, multiple-memory cycle instruction fetching mechanism, as well as having little or no flexibility regarding input data widths, internal/intermediate precision and output data widths.\",\n \"Reconfigurable computers have been extensively researched since the 1990's, but have yet to have large scale commercial success.\",\n \"These computer have been largely constructed from arrays of FPGA's.\",\n \"They have tended to be very difficult to program, often requiring gate level or logic cell level programming, as opposed to support procedural computer language compilers.\",\n \"Such computer also tend to have problems with multiplication.\",\n \"While some FPGAs now contain cells supporting small multipliers, often 4 by 4 or 4 by 5 bit multipliers, when even a 16 by 16 bit multiplication is to be done, somewhere between 6 and 16 of these cells must be dedicated to that task.\",\n \"Multipliers built this way do not lend themselves to ease of programming nor show themselves flexible in terms of changing input data width or output data width requirements.\",\n \"Most people require less development time to create numeric applications using procedural programming languages such as C or Java than using assembly language, much less a gate or function cell level definition language.\",\n \"The fact that it is possible to build a multiplier with an FPGA is not the problem system developers have to solve.\",\n \"What is needed is a mechanism providing the user with direct control over the input data width, the internal/intermediate precision width, and the output data width while providing a wide range of arithmetic operations in an efficient fashion.\",\n \"What is further needed is a method of specifying such control and then generating efficient circuits satisfying those specifications.\",\n \"What is further needed is an architecture which provides standard procedural language compiler support both for mechanisms supporting user control of input data width, internal/intermediate precision and output data width.\",\n \"What is further needed is a target circuit compilation architecture providing automated support for procedural compilers specified and generated by such methods.\",\n \"There are further problems in the organization of instruction processing mechanisms which significantly constrain performance due to the fixed configuration of internal operational resources.\",\n \"By way of example, the number of arithmetic processing resources available to prepare for a branch decision is fixed.\",\n \"However, high performance arithmetic-oriented applications often involve very large numbers of arithmetic operations being performed before any branching decisions need be made.\",\n \"When branching is to be performed, a number of relatively short operation sequences are usually needed to determine the flow of execution and control.\",\n \"What is needed is an instruction processing mechanism which can be optimally configured for both decision processes and computational sequences.\",\n \"Today, multiple datapath architectures are either Single Instruction Multiple Datapath (SIMD) or Multiple Instruction Multiple Datapath (MIMD).\",\n \"However, there are times when a system optimally acts in one fashion, and other times when it optimally would perform in the other fashion.\",\n \"What is needed is an architecture supporting multiple datapaths in either an SIMD or MIMD mode, which can be rapidly reconfigured from one to the other.\",\n \"There are additional problems facing the system designer intent upon making a new product: the system designer must often provide a complete systems solution, which often includes a package containing one or more printed circuits, which further contain integrated circuits performing numeric tasks within the package in normal operating modes.\",\n \"The system designer needs to be able to test the printed circuits containing the integrated circuits in operation as early in the design process as possible.\",\n \"Additionally, while there have been various attempts to use logarithmic numeric notations to perform arithmetic operations, none of the known approaches are readily extensible to varying precision widths.\",\n \"Such notations tend to treat numbers as either floating point numbers possessing an exponent and mantissa, or as a fixed point number.\",\n \"Both mechanisms have decided problems when applied to the varying needs of systems design, where the notation must be useful across a large collection of numeric ranges.\",\n \"Floating point notations have fixed fields, which further tend to hide the most significant bit of the mantissa, rendering such a notation is inherently difficult to alter.\",\n \"Both approaches to number notations lack any obvious way to convert 0 into a logarithm of 0.What is needed is a numeric notation readily supporting logarithmic numbers as well as being readily scalable to support differing amounts of precision in a real-time environment.\",\n \"To summarize, what is needed is arithmetic processing circuitry addressing the need for advanced, often non-linear functions based upon much more than linear arithmetic operations in a real-time fashion.\",\n \"Such operations include but are not limited to square roots, division, trigonometric functions, powers of numbers, polynomial functions, rational functions, exponential functions, logarithms, and determinants.\",\n \"What is needed includes the ability to efficiently accept and process widely varying data sample widths at high speeds.\",\n \"What is needed is arithmetic circuitry readily configured to provide a wide range of precision for any given instruction sequence in a given instruction execution period.\",\n \"What is needed is a flexible instruction processing mechanism which can more efficiently utilize instruction memory bandwidth to drive the arithmetic processing circuitry.\",\n \"What is needed is an instruction processing mechanism which can be optimally configured for both decision processes and computational sequences.\",\n \"What is needed is an architecture supporting multiple datapaths in either an SIMD or MIMD mode, which can be rapidly reconfigured from one to the other.\",\n \"What is needed is a mechanism providing the user with direct control over the input data width, the internal/intermediate precision width, and the output data width while providing a wide range of arithmetic operations in an efficient fashion.\",\n \"What is further needed is a method of specifying such control and then generating efficient circuits satisfying those specifications.\",\n \"What is further needed is an architecture which provides standard procedural language compiler support both for mechanisms supporting user control of input data width, internal/intermediate precision and output data width.\",\n \"What is further needed is a target circuit compilation architecture providing automated support for procedural compilers specified and generated by such methods.\",\n \"SUMMARY OF INVENTION Certain embodiments of the invention solve all the above mentioned problems found in the prior art.\",\n \"Certain embodiments utilize partitionable datapath bit width units, which can be configured to provide a requested level of numeric precision.\",\n \"The partitionable datapath bid width units include at least memory arrays and ALUs, which can collectively be configured to specific bit widths supporting the requested level of numeric precision in both a normal numeric realm and a logarithmic numeric domain.\",\n \"Certain embodiments of the invention represent a collection of numbers as having at least a minus-infinity as a special part of each represented number.\",\n \"These minus-infinity numbers act as annihilators in addition, so that minus-infinity plus anything else results in a minus-infinity in the special part of the represented result.\",\n \"Thus, the fact that zero multiplying anything in the normal numeric realms translates upon taking logarithms of both numbers.\",\n \"The logarithmic conversion of a zero yields a represented number with a minus-infinity.\",\n \"The exponential conversion of a represented number with negative-infinity in its special part yields a 0 result.\",\n \"Represented numbers may further include a special-plus or special-minus in their special parts, further supporting preservation of the input number sign upon into the represented number and conversion back to output numbers.\",\n \"Note that this also requires that special-minus represented numbers, when added to special-minus represented numbers generate a represented number result with a special-plus.\",\n \"Special-plus added to special-plus results in a special-plus.\",\n \"When a special-minus number and a special-plus number are added, the result is a special-minus result.\",\n \"This effects a logarithm of a first number added to the logarithm of a second number is essentially the same as the logarithm of the product of the first and second numbers.\",\n \"In the logarithm domain, functions can be calculated which are very computationally expensive in the normal realm of numbers.\",\n \"A level of efficiency previously unavailable in a programmable device of any kind is achieved by using at least some of the memories as table lookup mechanisms to approximately convert numbers between their logarithms, exponentials and other functions.\",\n \"Certain embodiments of the invention include a method of using an array of computational resources containing at least one input-output resource, at least one datapath operational resource comprising: selecting the input-output resources to create an input-output access collection comprised of at least an input-output access parameter; and selecting the datapath operational resources based upon the input-output access collection to create a datapath operational resource allocation collection containing at least one datapath operation resource allocation.\",\n \"This supports selecting input-output resources for optimal data bandwidth throughput.\",\n \"They also support selecting datapath operational resources for optimal datapath resource allocation operating on data traversing the selected input-output resources.\",\n \"The computation resource array may contain at least one instruction propagating resource.\",\n \"The method may selecting the instruction propagating resources based upon the input-output access collection and the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration.\",\n \"The computation resource array may further contain at least one instruction processing resource.\",\n \"Instruction processing resources may further be selected based upon the input-output access collection, datapath operational resource allocation and instruction propagating configuration.\",\n \"The instruction processing resources may contain at least one instruction register.\",\n \"The computation resource array may further contain at least one instruction fetching resource.\",\n \"The method may include fetching using the instruction fetching resource to create a fetched instruction and loading the fetched instruction into the instruction register to create an instruction register state based upon the fetched instruction.\",\n \"Certain embodiments of the invention include circuits generated by methods of this invention.\",\n \"They may be implemented using collections of one or more programmable logic devices, which may in turn include one or more programmable logic arrays and/or one or more Field Programmable Gate Arrays (FPGAs).\",\n \"They may be implemented as part or all of an integrated circuit, having been specified using a method of this invention and/or simulated based upon their specification.\",\n \"Their simulation may include implementations targeting logic hardware accelerators including programmable logic devices as execution elements.\",\n \"Certain embodiments of the invention include an arithmetic module of multiple basic arithmetic circuits coupled to share several wire bundles including a first shared buss, a second shared buss and a third shared buss that synchronously execute either one or two instructions, depending upon a configuration register.\",\n \"The shared bus wire bundle state is determined in part by the configuration register.\",\n \"Each basic arithmetic circuit includes a basic arithmetic memory coupled with a basic arithmetic calculator.\",\n \"BRIEF DESCRIPTION OF DRAWINGS FIG.\",\n \"1 depicts a basic arithmetic processing unit 1400 comprised of a first memory circuit 1200 and a first ALU 1300 in accordance with certain embodiments of the invention; FIG.\",\n \"2 shows a refinement of FIG.\",\n \"1 further depicting an input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 of basic arithmetic unit 1400; FIG.\",\n \"3 shows a refinement of FIG.\",\n \"2 further depicting input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 and further coupled to a second memory circuit 1250 forming a basic arithmetic unit 1402, which is a refinement of basic arithmetic unit 1400; FIG.\",\n \"4 shows a refinement of FIG.\",\n \"3 depicting input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 and coupled to a second memory circuit 1400 with additional interconnections forming a basic arithmetic unit 1402, which is a refinement of basic arithmetic unit 1400; FIG.\",\n \"5 shows a refinement of FIGS.\",\n \"1, 2, 3 and 4 depicting input-output circuit 1100 coupled to multiple instances of basic arithmetic unit 1400; FIG.\",\n \"6 shows a refinement of FIG.\",\n \"5 depicting a first input-output circuit 1100 coupled to multiple instances of basic arithmetic unit 1400 and a second instance of input-output circuit 1100; FIG.\",\n \"7 shows a detail diagram of an ALU circuit 1300 in terms of four interconnected instances of a second ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002; FIG.\",\n \"8 shows a detail diagram of first ALU circuit 1300 in terms of eight interconnected instances of a second ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002; FIG.\",\n \"9 depicts an arithmetic logic unit 1310 with multiple add-inputs presented to shifters and then added to generate an add-result; FIG.\",\n \"10 shows Arithmetic Process Array 3000 comprising at least one Arithmetic Processor 3002, each coupled with 3104 Instruction Memory 3200 and with 3106 Instruction Memory 3300; FIG.\",\n \"11A show a single column of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8; FIG.\",\n \"11B show four columns of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8; FIGS.\",\n \"12 to 16 show a configuration of instruction memories and MSRI[K] sufficient to perform a large number of realtime filtering and more sophisticated tasks upon an input stream of 8 or 9 bit samples; FIG.\",\n \"17A show a single column of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8, with two instructions memories 3200 and 3300 providing two instructions transmitted to each.\",\n \"Note that in other embodiments of the invention, i could range over a different range; FIG.\",\n \"17B show four columns of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8, with two instructions memories 3200 and 3300 providing two instructions transmitted to each.\",\n \"FIGS.\",\n \"18 to 20 show various configurations of PISRI's and their neighboring instruction memories; FIG.\",\n \"21 shows a high level data flow diagram of a two dimensional array block 1300 of ALU2 circuits 1310 and connecting datapaths between them by which data may be transported; FIG.\",\n \"22A depicts a flowchart performing a method of using an array of computational resources containing at least one input-output resource and at least one datapath operational resource; FIG.\",\n \"22B depicts a detail flowchart of user operation 2000 of FIG.\",\n \"22A further performing selecting the instruction propagating resources based upon the input-output access collection and based upon the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration; FIG.\",\n \"23A depicts a detail flowchart of user operation 2000 of FIG.\",\n \"22A performing selecting the instruction processing resources based upon the input-output access collection, the datapath operational resource allocation collection, and the instruction propagating configuration collection to create an instruction processing configuration collection containing at least one instruction processing configuration; FIG.\",\n \"23B depicts a detail flowchart of user operation 2000 of FIG.\",\n \"22A further performing the method of using/operating the array of computational resources; FIG.\",\n \"24A shows a detail block diagram of an instruction memory 3200 comprised of instruction register 3600, branch processor 3700 and instruction memory array 3500; FIG.\",\n \"24B shows a detail block diagram of an instruction memory 3200 extending the block diagram of FIG.\",\n \"24A further comprised of instruction fetch mechanism 3800; FIG.\",\n \"25 shows a detail block diagram of an branch processor 3700 comprised of branch sequence register 3710, program counter 3730 and branch address look-up table 3720; and FIG.\",\n \"26 shows a detail block diagram of a branch processor 3700 extending the block diagram of FIG.\",\n \"25 further comprised of cache manager 3740; FIG.\",\n \"27 depicts a high level system block diagram of a DSP Resource Circuit in accordance with certain embodiments of the invention; FIG.\",\n \"28 depicts a simplified floor plan of a layout of the DSP Resource Circuit of FIG.\",\n \"27; FIG.\",\n \"29 depicts a preferred version of ALU 1400, as used in FIG.\",\n \"28 and earlier Figures supporting configurations of its internal memories and system input 1002 emulating a multiplier-accumulator with local register bank; FIG.\",\n \"30 depicts a flowchart of a method of processing numeric data, which may be variously embodied; FIG.\",\n \"31 depicts a detail flowchart of operation 2222 of FIG.\",\n \"30 further performing the arithmetic operation collection; FIG.\",\n \"32A depicts a detail flowchart of operation 2272 of FIG.\",\n \"31 further adding; FIG.\",\n \"32B depicts a detail flowchart of operation 2282 of FIG.\",\n \"31 further subtracting; FIG.\",\n \"33A depicts a detail flowchart of operation 2292 of FIG.\",\n \"31 further exponentiating; FIG.\",\n \"33B depicts a detail flowchart of operation 2302 of FIG.\",\n \"31 further logarithming; FIG.\",\n \"34A depicts a detail flowchart of operation 2442 of FIG.\",\n \"33B further setting the special part of the log-result; FIG.\",\n \"34B depicts a detail flowchart of operation 2442 of FIG.\",\n \"33B further setting the special part of the log-result; FIG.\",\n \"35A depicts a detail flowchart of operation 2292 of FIG.\",\n \"31 further exponentiating; FIG.\",\n \"35B depicts a detail flowchart of operation 2302 of FIG.\",\n \"31 further logarithming; FIG.\",\n \"36A depicts a detail flowchart of operation 2532 of FIG.\",\n \"35B further determining whether the sign part of the first number is essentially equal to the negative-sign; FIG.\",\n \"36B depicts a detail flowchart of operation 2532 of FIG.\",\n \"35B further determining whether the sign part of the first number is essentially equal to the negative-sign; FIG.\",\n \"37A depicts a detail flowchart of operation 2232 of FIG.\",\n \"30 further log-converting the input number collection member; FIG.\",\n \"37B depicts a detail flowchart of operation 2232 of FIG.\",\n \"30 further log-converting the input number collection member; FIG.\",\n \"38A depicts a detail flowchart of operation 2242 of FIG.\",\n \"30 further exp-converting; and FIG.\",\n \"38B depicts a detail flowchart of operation 2242 of FIG.\",\n \"30 further exp-converting.\",\n \"DETAILED DESCRIPTION OF DRAWINGS As used herein a wire refers to a path connecting nodes of a circuit which carries a state between the connected nodes and/or refers to a resonant cavity propagating information in terms of state between the connected nodes.\",\n \"A wire may be made out of metal, an optical chamber, or a tunnel path through a molecular substrate.\",\n \"A wire bundle is a collection of at least one wire.\",\n \"State as used herein refers to an element of a finite alphabet, which contains at least two symbols.\",\n \"These two minimal symbols relate to ‘0’ and ‘1’ as used in Boolean logic.\",\n \"FIG.\",\n \"1 depicts a basic arithmetic processing unit 1400 comprised of a first memory circuit 1200 and a first ALU 1300 in accordance with certain embodiments of the invention.\",\n \"The basic arithmetic unit 1400 includes a partitioning wire bundle 1002 presented to first memory circuit 1200 and first ALU 1300.Input wire bundle 1008 is presented to first memory circuit 1200 and first ALU 1300.Input wire bundle 1010 is presented only to first memory circuit 1200.First memory instruction wire bundle 1202 is presented to first memory circuit 1200.First memory circuit 1200 generates signals for first memory output wire bundle 1016 presented to first ALU 1300.First ALU instruction wire bundle 1302 is presented to first ALU circuit 1300.First ALU 1300 receives a carry-in wire bundle 1150, first ALU instruction wire bundle 1302 and generates a carry-out wire bundle 1152 and further generates signals for first ALU output wire bundle 1018.The basic arithmetic processing unit operates by receiving the signal state of partitioning wire bundle 1002, which determines the partitioning of the signaling of input wire bundle 1008, input wire bundle 1010, first memory output wire bundle 1016 and first ALU output wire bundle 1018, as well as first memory instruction wire bundle 1202, first ALU instruction wire bundle 1302 and carry-input wire bundle 1150.The received signal state of the partitioning wire bundle 1.002, further determines the operational partitioning of first memory circuit 1200 and first ALU circuit 1300 with regards to the signaling of input wire bundle 1008, input wire bundle 1010, first memory output wire bundle 1016 and first ALU output wire bundle 1018.First memory circuit 1200 receives the signal state of partitioning wire bundle 1002, which determines the partitioning of the signaling of input wire bundle 1008, input wire bundle 1010 and first memory instruction wire bundle 1202.Partitioning wire bundle 1002 signal state is used by first memory circuit 1200 to determine from the signal state of first memory instruction wire bundle 1202 at least one of first memory local instructions to be executed.\",\n \"The first memory local instructions are executed by the first memory circuit 1200.First memory circuit 1200 asserts the signal state of first memory output wire bundle 1016.First ALU 1300 receives the signal state of partitioning wire bundle 1002, which determines the partitioning of the signaling of input wire bundle 1008, first memory output wire bundle 1016, first ALU instruction wire bundle 1302 and the effect of the signal state of carry-input wire bundle 1150.Partitioning wire bundle 1002 signal state is used by first ALU circuit 1300 to determine from the signal state of first ALU instruction wire bundle 1302 of at least one of first first ALU local instructions to be executed.\",\n \"The first ALU local instructions are executed by the first ALU circuit 1300.First ALU circuit 1200 asserts the signal state of first ALU output wire bundle 1018.FIG.\",\n \"2 shows a refinement of FIG.\",\n \"1 further depicting an input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 of basic arithmetic unit 1400.Note that FIG.\",\n \"2 operates in much the same fashion as FIG.\",\n \"1, excepting Input-output circuit 1100 acts as an interface between at least three external data bus wire bundles, 1004 and 1006 controlled by instruction wire bundle 1102 as well as partitioning wire bundle 1002 and creating the state on wire bundles 1008, 1010 and 1012.FIG.\",\n \"3 shows a refinement of FIG.\",\n \"2 further depicting input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 and further coupled to a second memory circuit 1250 forming a basic arithmetic unit 1402, which is a refinement of basic arithmetic unit 1400.Note that FIG.\",\n \"3 operates in a similar fashion to FIGS.\",\n \"1 and 2 with regards to elements of similar reference numbers.\",\n \"Second memory circuit 1250 may receive output 1018 from ALU 1300 as well as wire bundle 1014 from input-output circuit 1100 based upon partitioning wire bundle 1002.Second memory circuit 1250 may drive the state of wire bundle 1014.Second memory circuit 1250 may receive wire bundle 1012 from input-output circuit 1100.FIG.\",\n \"4 shows a refinement of FIG.\",\n \"3 depicting input-output circuit 1100 coupled to the first memory circuit 1200 and a first ALU 1300 and coupled to a second memory circuit 1400 with additional interconnections forming a basic arithmetic unit 1402, which is a refinement of basic arithmetic unit 1400.Note that FIG.\",\n \"4 operates in a similar fashion to FIG.\",\n \"1, 2, and 3 with regards to elements of similar reference numbers.\",\n \"FIG.\",\n \"5 shows a refinement of FIGS.\",\n \"1, 2,3 and 4 depicting input-output circuit 1100 coupled to multiple instances of basic arithmetic unit 1400.Basic arithmetic unit 1400 may at least be basic arithmetic unit 1402 as shown in FIGS.\",\n \"2, 3 and 4.FIG.\",\n \"6 shows a refinement of FIG.\",\n \"5 depicting a first input-output circuit 1100 coupled to multiple instances of basic arithmetic unit 1400 and a second instance of input-output circuit 1100.Basic arithmetic unit 1400 may at least be basic arithmetic unit 1402 as shown in FIGS.\",\n \"2, 3 and 4.FIG.\",\n \"7 shows a detail diagram of an ALU circuit 1300 in terms of four interconnected instances of a second ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002.FIG.\",\n \"8 shows a detail diagram of first ALU circuit 1300 in terms of eight interconnected instances of a second ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002.In FIGS.\",\n \"8 and 9, each ALU circuit 1310 may support a consistent datapath bit width.\",\n \"Each ALU circuit 1310 may further support a constant datapath bit width.\",\n \"The constant datapath bit width may be at least one of 3, 4, and 5.In FIGS.\",\n \"8 and 9, ALU circuit 1300 may contain instances of ALU circuit 1310 supporting carry propagation controlled by partitioning wire bundle 1002.The number of instances of ALU circuit 1310 is a power of two not necessarily shown in these Figures.\",\n \"The number of instances of ALU circuit 1310 may not be a power of two.\",\n \"The number of instances of ALU circuit 1310 may be 12.The constant bit width of ALU circuit 1310 may be 4 and the number of instances of ALU circuit 1310 belongs to a collection comprising 8, 12, 16, 24, 32, 48 and 64.The constant bit width of ALU circuit 1310 is 3 and the number of instances of ALU circuit 1310 belongs to a collection comprising 12, 16, 24, 32, 48 and 64.FIG.\",\n \"9 depicts an arithmetic logic unit 1310 with multiple add-inputs presented to shifters and then added to generate an add-result.\",\n \"Each shifter (S1, S2, S2, and S4)is controlled by add-instruction-components belonging to a collection comprising at least values representing same-sign, reverse-sign, do-not-use, shift-up and shift-down.\",\n \"The effects of these values acting on the add-input are as follows: The add-input acted upon by the corresponding add-inst-component having same-sign generates the add-input.\",\n \"The add-input acted upon by the corresponding add-inst-component having reverse-sign generates the negative of the add-input.\",\n \"The add-input acted upon by the corresponding add-inst-component having do-not-use generates a zero.\",\n \"The add-input acted upon by the corresponding add-inst-component having shift-up generates a positive power of two times the add-input.\",\n \"The add-input acted upon by the corresponding add-inst-component having shift-down generates a negative power of two times the add-input.\",\n \"The shift-instruction collection may further include shift-up-by-m and shift-down-by-m, where m is at least two.\",\n \"Partitioning wire bundle 1002 is used to control carry propagation and shift bit propagation, but are not shown in this Figure to simplify the discussion.\",\n \"The omission of partitioning wire bundle 1002 is not meant to limit nor require its presence for all embodiments of the invention.\",\n \"Note that the logarithm of 0 will be negative-infinity, and that the square and square root of 0 are each 0.To preserve these facts in the logarithmic domain, shifting negative-infinity should produce negative infinity.\",\n \"The add-inst controls for each shifter S1-S4 may further include shift-up-2 and shift-down-2, supporting shifting by 2 bits, as well as shift-up-3 and shift-down-3 supporting shifting by 3 bits.\",\n \"Certain preferred embodiments of the invention employ a subset of all these add-inst controls including same-sign, reverse-sign, do-not-use, shift-up, shift-down, shift-up-2, shift-up-3, which may be coded as 2 bits designating same-sign, reverse-sign, do-not-use, shift-down; and 2 additional bits coding pass-through, shift-up, and shift-up-2.Note that as shown hereafter, when do-not-use is asserted, it does not matter what the other two bit field contains.\",\n \"In general, when do-not-use is asserted, the contents of the other two bit field will be chosen to optimize at least one system characteristic, such as testability and/or logic complexity and/or signal propagation through the circuit, also known as the circuit's critical path delay.\",\n \"The add-inst control signals may originate from the datapath instruction being presented for execution, or may alternatively be generated based upon part of a numeric data to perform a limited range of multiplications.\",\n \"Consider the following table Multiplier Add-inst-1 Add-inst-2 000 => 0 do-not-use do-not-use 001 => 1 same-sign, pass-through do-not-use 010 => 2 do-not-use same-sign, shift-up-1 011 => 3 = 2 + 1 same-sign, pass-through same-sign, shift-up-1 100 => 4 same-sign, shift-up-2 do-not-use 101 => 5 = 4 + 1 same-sign, shift-up-2 same-sign, pass-through 110 => 6 = 4 + 2 same-sign, shift-up-2 same-sign, shift-up-1 111 => 7 = 8 − 1 reverse-sign, pass-through same-sign shift-up-3 Table One: a three bit multiplication based upon controlling a pair of shifter inputs.\",\n \"Note that this further supports the circuitry shown in FIG.\",\n \"9 as supporting the multiplication of 6 bits of an operand acting upon a second number, which may be further provided by a local memory.\",\n \"Using this circuitry in such a fashion provides an interpolation capability supporting successive approximations, which may involve linear, multi-linear and through the feedback-cascading of partial results based upon this circuit, some forms of non-linear approximations to various non-linear functions including but not limited to various exponential functions, logarithms, trigonometric functions, among others.\",\n \"An alternative approach to approximation interprets a three bit number as a signed number, leading to the following table: Multiplier Add-inst-1 Add-inst-2 000 => 0 do-not-use do-not-use 001 => 1 same-sign, pass-through do-not-use 010 => 2 same-sign, pass-through same-sign, pass-through 011 => 3 = 2 + 1 same-sign, pass-through same-sign, shift-up-1 100 => −4 reverse-sign, shift-up-1 reverse-sign, shift-up-1 101 => −3 = −4 + 1 reverse-sign, pass-through reverse-sign, shift-up-1 110 => −2 reverse-sign, pass-through reverse-sign, pass-through 111 => −1 reverse-sign, pass-through do-no-use Table Two: a signed three bit multiplication based upon controlling a pair of shifter inputs.\",\n \"Note that these two tables may be concurrently employed in certain situations where a signed 6 bit numeric multiplication is desired.\",\n \"The most significant 3 bits affect multiplication as shown in Table Two.\",\n \"When the sign of the 6 bit quantity is negative, the least significant 3 bits may affect the multiplication as shown in Table One, with every instance of reverse-sign changed to same-sign, and every instance of same-sign changed to reverse-sign.\",\n \"When the sign of the 6 bit quantity is positive, Table One may be used as shown.\",\n \"These tables and discussions have been provided by way of example and are not meant to limit the scope of the claims.\",\n \"As one of skill in the art will readily recognize, there are many alternative notations for the various operations presented herein which are essentially equivalent to the examples presented herein.\",\n \"FIG.\",\n \"10 shows Arithmetic Process Array 3000 comprising at least one Arithmetic Processor 3002, each coupled with 3104 Instruction Memory 3200 and with 3106 Instruction Memory 3300, in accordance with certain embodiments of the invention.\",\n \"In certain embodiments of the invention, only one instruction memory 3200 is coupled to Arithmetic Processor Array 3000, feeding one instruction to each Arithmetic Processor 3002.FIGS.\",\n \"11A to 16 refer to such embodiments of the invention.\",\n \"Note that these embodiments of the invention do not require the partitioning wire bundle 3102, nor the partitioning wire bundle 1002.FIG.\",\n \"11A show a single column of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8.Note that in other embodiments of the invention, i could range over a different range.\",\n \"Note also that in other embodiments of the invention, each ALU2 1310 unit could be coupled to the first memories 1210 as second memories.\",\n \"Note that these circuits would be simpler, thus take up less circuit area and consume less power, but could not reconfigure the datapath bit-width, which would be determined by the number of cells (the range of i) and the datapath width of the horizontal strips.\",\n \"The two dimensional strips containing memories 1210-i and ALU2 cells 1310-i are further integrated as an MSRI[k] cell array where i ranges from 1 to k. FIG.\",\n \"11B show four columns of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8.Note that in other embodiments of the invention, i could range over a different range.\",\n \"Note also that in other embodiments of the invention, each ALU2 1310 unit could be coupled to the first memories 1210 as second memories.\",\n \"Note that these circuits would be simpler, thus take up less circuit area and consume less power, but could not reconfigure the datapath bit-width, which would be determined by the number of cells (the range of i) and the datapath width of the horizontal strips.\",\n \"The two dimensional strips containing memories 1210-i and ALU2 cells 1310-i are further integrated as an MSRI[k] cell array where i ranges from 1 to k. FIGS.\",\n \"12 to 16 show a configuration of instruction memories and MSRI[k] sufficient to perform a large number of realtime filtering and more sophisticated tasks upon an input stream of 8 or 9 bit samples.\",\n \"Assume the horizontal datapath width of the ALU2 and memories in each MSRI is at least 3, preferably 4, bits.\",\n \"When the horizontal datapath width of the ALU2 and memories in each MSRI is 4 bits, 10 bit samples could also be accepted.\",\n \"The data stream enters MSRI[4] in FIG.\",\n \"12 flowing to MSRI[5], then MSRI[6], MSRI[7], then MSRI[8] of FIG.\",\n \"13 eventually leaving MSRI[231 having performed as a 12 pass arithmetic stream processor.\",\n \"If each MSRI component performs a radix 4 FFT, then the system as a whole performs a 1K FFT by the time the data leaves MSRI[21], and a 4K FFT upon leaving MSRI[23].\",\n \"The increase in depth of the MSRI's is to consistently extend the precision of the calculations to account for the accumulation of rounding errors.\",\n \"In certain other embodiments of the invention, two instruction memories 3200 and 3300 are coupled to Arithmetic Processor Array 3000, feeding two instructions to each Arithmetic Processor 3002, the selection of which instruction is executed determined by the partitioning wire bundle 3102, which in turn drives the partitioning wire bundle 1002.FIGS.\",\n \"17A to 20 refer to such embodiments of the invention.\",\n \"FIG.\",\n \"17A show a single column of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8, with two instructions memories 3200 and 3300 providing two instructions transmitted to each.\",\n \"Note that in other embodiments of the invention, i could range over a different range.\",\n \"Note also that in other embodiments of the invention, each ALU2 1310 unit could be coupled to the firstmemories 1210 as second memories.\",\n \"Note that these circuits would be simpler, thus take up less circuit area and consume less power, but could not reconfigure the datapath bit-width, which would be determined by the number of cells (the range of i) and the datapath width of the horizontal strips.\",\n \"The two dimensional strips containing memories 1210-i and ALU2 cells 1310-i are further integrated as an PISRI[k] cell array where i ranges from 1 to k. This circuit and the circuit of FIG.\",\n \"17B use the partitioning wire bundle 1002 to control carry propagation and determination of which of the two instructions are executed in each horizontal strip of the PISRI.\",\n \"FIG.\",\n \"17B show four columns of coupled first memories 1210-i and ALU2 1310-i, where i=1 to 8, with two instructions memories 3200 and 3300 providing two instructions transmitted to each.\",\n \"Note that in other embodiments of the invention, i could range over a different range.\",\n \"Note also that in other embodiments of the invention, each ALU2 1310 unit could be coupled to the first memories 1210 as second memories.\",\n \"Note that these circuits would be simpler, thus take up less circuit area and consume less power, but could not reconfigure the datapath bit-width, which would be determined by the number of cells (the range of i) and the datapath width of the horizontal strips.\",\n \"The two dimensional strips containing memories 1210-i and ALU2 cells 1310-i are further integrated as an PISRI[K] cell array where i ranges from 1 to k. FIGS.\",\n \"18 to 20 show various configurations of PISRI's and their neighboring instruction memories.\",\n \"In FIG.\",\n \"18, PSRI[11] can be configured to act as an MSRI[4] and MSRI[7], or as an MSRI[5] and MSRI[6].\",\n \"The net effect can then be the processing flow of MSRI[4]==>MSRI[5]==>MSRI[6]==>MSRI[7].\",\n \"Similarly, the PSRI[19]'s can be configured as ==>MSRI[9]==>MSRI[10]==>MSRI[11].\",\n \"FIG.\",\n \"19 shows a configuration of same size PISRI[8]'s which can be support dataflows as discussed above, and which provide a 32 bit data interface to standard computer memories when the datapath bit width of the ALU2 1310 and memories 1210 cells is 4 bits.\",\n \"Note that the partitioning wire bundle would also have an effect on the operation of the data interface to standard memories to preserve data alignments or to partition the external data memory into two address ranges, one for each partition.\",\n \"FIG.\",\n \"20 shows a configuration of same size PISRI[12]'s which can be support dataflows as discussed above, and which provide a 36 bit data interface to standard computer memories when the datapath bit width of the ALU2 1310 and memories 1210 cells is 3 bits.\",\n \"Note that the partitioning wire bundle would also have an effect on the operation of the data interface to standard memories to preserve data alignments or to partition the external data memory into two address ranges, one for each partition.\",\n \"FIG.\",\n \"21 shows a high level data flow diagram of a two dimensional array blocks 1300 of ALU2 circuits 1310 and connecting datapaths between them by which data may be transported.\",\n \"Data flow as depicted in FIG.\",\n \"21 supports both nearest neighbor and global communication of array blocks in each of the two dimensions of the array.\",\n \"Note that the vertical communications lines shown in FIG.\",\n \"21 may be used to transfer data via an external data memory interface which is not shown.\",\n \"Such an external data memory interface may receive addressing signal either from datapath element(s), and/or from one or more instruction processors.\",\n \"FIG.\",\n \"22A depicts a flowchart performing a method of using an array of computational resources containing at least one input-output resource, at least one datapath operational resource in accordance with certain embodiments of the invention.\",\n \"User operation 2000 starts the usage of this flowchart.\",\n \"Arrow 2002 directs the usage flow from user operation 2000 to user operation 2004.User operation 2004 performs selecting the input-output resources to create an input-output access collection comprised of at least one input-output access parameter Arrow 2006 directs usage from user operation 2004 to user operation 2008.User operation 2008 performs selecting the datapath operational resources based upon the input-output access collection to create a datapath operational resource allocation collection containing at least one datapath operation resource allocation.\",\n \"Arrow 2010 directs usage from user operation 2008 to user operation 2012.User operation 2012 terminates the usage of this flowchart.\",\n \"Note that in other embodiments of the invention, the flowchart of FIG.\",\n \"22A may be used to depict a method of operating an array of computational resources containing at least one input-output resource, at least one datapath operational resource.\",\n \"The array of computational resources may be implemented using one or more programmable logic devices, which may include or more programmable logic arrays and/or one or more Filed Programmable Gate Arrays (FPGAs).\",\n \"Certain further embodiments of the invention include the array of computation resources further containing at least one instruction propagating resource.\",\n \"FIG.\",\n \"22B depicts a detail flowchart of user operation 2000 of FIG.\",\n \"22A further performing selecting the instruction propagating resources based upon the input-output access collection and based upon the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration, in accordance with certain embodiments of the invention.\",\n \"Arrow 2030 directs the usage flow from starting user operation 2000 to user operation 2032.User operation 2032 performs selecting the instruction propagating resources based upon the input-output access collection and based upon the datapath operational resource allocation collection to create an instruction propagating configuration collection containing at least one instruction propagating configuration.\",\n \"Arrow 2034 directs usage from user operation 2032 to user operation 2036.User operation 2036 terminates the usage of this flowchart.\",\n \"FIG.\",\n \"23A depicts a detail flowchart of user operation 2000 of FIG.\",\n \"22A performing selecting the instruction processing resources based upon the input-output access collection, the datapath operational resource allocation collection, and the instruction propagating configuration collection to create an instruction processing configuration collection containing at least one instruction processing configuration in accordance with certain embodiments of the invention.\",\n \"Arrow 2050 directs the usage flow from starting user operation 2000 to user operation 2052.User operation 2052 performs selecting the instruction processing resources based upon the input-output access collection and based upon the datapath operational resource allocation collection and based upon the instruction propagating configuration collection to create an instruction processing configuration collection containing at least one instruction processing configuration.\",\n \"Arrow 2054 directs usage from user operation 2052 to user operation 2056.User operation 2056 terminates the usage of this flowchart.\",\n \"Certain further embodiments of the invention include the array of computation resources further containing at least one instruction fetching resource and the instruction processing resources containing at least one instruction register.\",\n \"FIG.\",\n \"23B depicts a detail flowchart of user operation 2000 of FIG.\",\n \"22A further performing the method of using/operating the array of computational resources in accordance with certain embodiments of the invention.\",\n \"Arrow 2070 directs the usage flow from starting user operation 2000 to user operation 2072.User operation 2072 performs fetching using the instruction fetching resource to create a fetched instruction.\",\n \"Arrow 2074 directs usage from user operation 2072 to user operation 2076.User operation 2076 performs loading the fetched instruction into the instruction register to create an instruction register state based upon the fetched instruction.\",\n \"Arrow 2078 directs usage from user operation 2076 to user operation 2080.User operation 2080 terminates the usage of this flowchart.\",\n \"FIG.\",\n \"24A shows a detail block diagram of an instruction memory 3200 comprised of instruction register 3600, branch processor 3700 and instruction memory array 3500, in accordance with certain embodiments of the invention.\",\n \"Branch processor 3700 in certain further embodiments of the invention includes a branch return stack.\",\n \"In certain further embodiments of the invention, the branch return stack can be unloaded and reloaded via arrow 3702.FIG.\",\n \"24B shows a detail block diagram of an instruction memory 3200 extending the block diagram of FIG.\",\n \"24A further comprised of instruction fetch mechanism 3800, in accordance with certain embodiments of the invention.\",\n \"Branch processor 3700 in certain further embodiments of the invention includes a branch return stack.\",\n \"In certain further embodiments of the invention, the branch return stack can be unloaded and reloaded via arrow 3702.FIG.\",\n \"25 shows a detail block diagram of an branch processor 3700 comprised of branch sequence register 3710, program counter 3730 and branch address look-up table 3720, in accordance with certain embodiments of the invention.\",\n \"Branch processor 3700 in certain further embodiments of the invention includes a branch return stack.\",\n \"In certain further embodiments of the invention, the branch return stack can be unloaded and reloaded via arrow 3702.Branch Address Loop-Up Table 3720 may include an interpreter address look-up table supporting an interpretive language, in certain further embodiments of the invention.\",\n \"Such interpretive languages may include but are not limited to JAVA, FORTH and Smalltalk.\",\n \"FIG.\",\n \"26 shows a detail block diagram of an branch processor 3700 extending the block diagram of FIG.\",\n \"25 further comprised of cache manager 3740, in accordance with certain embodiments of the invention.\",\n \"Branch processor 3700 in certain further embodiments of the invention includes a branch return stack.\",\n \"In certain further embodiments of the invention, the branch return stack can be unloaded and reloaded via arrow 3702.Branch Address Loop-Up Table 3720 may include an interpreter address look-up table supporting an interpretive language, in certain further embodiments of the invention.\",\n \"Such interpretive languages may include but are not limited to JAVA, FORTH and Smalltalk.\",\n \"FIG.\",\n \"27 depicts a high level system block diagram of a DSP Resource Circuit in accordance with certain embodiments of the invention.\",\n \"The DSP Resource Circuit is comprised a Datapath Resource Array 5000.The Datapath Resource Array 5000 is coupled to at least one of the following: the Digital Device Interface 5300 and the System and Control Interface 5400.When applicable, Datapath Resource Array 5000 is coupled by at least one of 5312,5314 and/or 5316 with Digital Device Interface 5300.In certain applications, coupling 5312 communicates memory access request information including but not limited to address information, and where appropriate, memory access length.\",\n \"Coupling 5314 preferably communicates data received from the Datapath Resource Array 5000 for storage elsewhere, as well as data being sent to the Datapath Resource Array 5000.Coupling 5316 may be used to convey status information, which may include but is not limited to at least one of the following: memory latency-wait states, which may be current or projected, as well as error status information including but not limited to checksum errors and other error detection related information.\",\n \"Note that the couplings 5302, 5304, and 5306 preferably respectively relate to the external communications associated with couplings 5312, 5314, and 5316 in such applications.\",\n \"In other applications, one input-output processor may strictly receive data via coupling 5316 which is generated based upon an external input stream via coupling 5306.Additionally, an input-output processor may strictly output data via coupling 5312 which is used to generate an external data stream presented via coupling 5302.In certain applications, each of these coupling may be preferably split into two such couplings, each under the control of a separate input-output processor.\",\n \"The Datapath Resource Array 5000 may also be coupled to a Local Memory Interface 5500.When applicable, Datapath Resource Array 5000 is coupled by at least one of 5512,5514 and/or 5516 to Local Memory Interface 5500.Preferably, coupling 5512 communicates memory access request information including but not limited to address information, and where appropriate, memory access length.\",\n \"Coupling 5514 preferably communicates data received from the Datapath Resource Array 5000 for storage elsewhere, as well as data being sent to the Datapath Resource Array 5000.Coupling 5516 may be used to convey status information, which may include but is not limited to at least one of the following: memory latency-wait states, which may be current or projected, as well as error status information including but not limited to checksum errors and other error detection related information.\",\n \"Note that preferably, couplings 5502, 5504, and 5506 respectively relate to the external communications associated with couplings 5512, 5514, and 5516.When applicable, Datapath Resource Array 5000 is coupled by at least one of 5402 and/or 5404 to System and Control Interface 5400.Each or either of couplings 5402 and 5404 may be comprised of a collection of couplings such as discussed above in FIG.\",\n \"27 with unidirectional couplings and possibly strictly bi-directional couplings.\",\n \"In certain applications, coupling 5402 may preferably convey system control and status information related via 5406 with an external system environment.\",\n \"In certain applications, coupling 5404 may convey data communicated via 5406 with the external system environment.\",\n \"Such data may be provided during system initialization time for conveyance not only into internal memory within the Datapath Resource Array 5000.Coupling 5404 may also be used during system initialization for further data conveyance through Datapath Resource Array 5000 to Local Memory Interface 5500 for storage in local memory.\",\n \"Coupling 5404 may also be used during system initialization for further data conveyance through Datapath Resource Array 5000 to Digital Device Interface 5300 for use elsewhere.\",\n \"FIG.\",\n \"28 depicts a simplified floor plan of a layout of the DSP Resource Circuit of FIG.\",\n \"27.Datapath Resource Array 5000 is comprised of at least one instruction processor 3800 and an array of DSP resources 1400.By way of example, FIG.\",\n \"28 depicts an array of 8 rows and 8 columns of DSP resource 1400 instances.\",\n \"Instruction processor 3800 may be closely coupled with an instruction memory array 3500.In certain applications, Datapath Resource Array 5000 is preferably comprised of two instruction processors 3800-1 and 3800-2.At this level of abstraction the partition control wire bundle is not visible.\",\n \"However, it is assumed to support partitioning the array of DSP resources into two horizontal regions.\",\n \"By way of example, the top three rows of the array of DSP resources may be partitioned to act based upon an instruction state communicated from instruction processor 1 3800-1.The remaining bottom 5 rows of the array of DSP resources may be partitioned to act based upon an instruction state communicated from instruction processor 2 3800-2.In certain applications a further partitioning of instruction processing resources may be preferred.\",\n \"An instruction processor 3800 may be partitioned into two instruction processing streams, each with independent branch mechanism.\",\n \"The first instruction processing stream may be partitioned to control the instruction state asserted for the three left-most columns of the array of DSP resources.\",\n \"The second instruction processing stream would control the remaining 5 columns of the array of DSP resources.\",\n \"Note that in certain applications, partitioning may support more than two instruction processing streams being sent from an instruction processor.\",\n \"For simplicity of discussion, no more than two instruction streams will be discussed hereafter.\",\n \"This is not meant to limit the scope of the claims.\",\n \"By way of example, the applications and configurations of FIGS.\",\n \"12 to 20 may be implemented by circuitry illustrated in FIG.\",\n \"28.Digital Device Interface 5300 is comprised of at least one at least one input-output instruction processor 1130-1 controlling an input-output processor 1120-1.Digital Device Interface 5300 may be further comprised of a second input-output instruction processor 1130-2 controlling input-output processor 1120-2.In certain applications, at least one input-output instruction processor 1130 may be coupled to an input-output instruction memory 1140.Input-output processors preferably possess couplings to all the rows of their associated array of DSP resources 1400.Input-output processors preferably configure communication to the array of DSP resources based upon the partition state information which configures the rows of the array of DSP resources to communicate together.\",\n \"By way of example, the first input-output processor 1120-1 may communicate with the top three rows of the array of DSP resources, when they are so partitioned.\",\n \"The second input-output processor 1120-2 may then preferably communicate with the remaining 5 bottom rows.\",\n \"Note that the rows of DSP resources may be partitioned into more than two communicating components.\",\n \"Similarly, the Digital Device Interface 5300 may comprise more than two input-output instruction processors controlling more than two input-output processors.\",\n \"Each input-output processor may include at least one of the following: a data memory, ALU, and specialized logical functions such as bit packing-unpacking circuits.\",\n \"Note that the circuitry of FIGS.\",\n \"27 and 28 may further reside in a package where at least one of the interfaces couples to analog circuitry including but not limited to at least one of the following: A/D converters, D/A converters, frequency synthesizers, threshold detectors, and amplifiers.\",\n \"Note that implementations of multiple instances of the circuitry of FIG.\",\n \"28 may include situations where one input-output processor of a first instance may not couple to elements of another array of DSP resources 1400 within another instance.\",\n \"System and Control Interface 5400 may be comprised of at least one input-output processor 1120-3 controlled by input-output instruction processor 1130-3.The preceding discussion regarding the Digital Device Interface is applicable to System and Control Interface 5400, and will not be repeated for reasons of brevity.\",\n \"However, this is not meant limit the scope of the claims.\",\n \"A common branching mechanism is preferably employed through the instruction processors discussed in FIG.\",\n \"28.This branching mechanism can be embodied to support caching and accessing of memory through a local memory interface 5500, or may be embodied without support of external memory.\",\n \"The overall instruction processing principles embodied in this invention include the following design/architectural goals: Input-output and datapath configurations dominate the embodied architectures, not the other way around.\",\n \"The hardware supports software debugging and test.\",\n \"The embodied architectures can support multiple systems levels of instruction fetching.\",\n \"They can support both SIMD and MIMD, as well as SISD and MISD processing applications.\",\n \"Implementations support separate references to data and instructions.\",\n \"There are several consequences to separate data and instruction references.\",\n \"The runtime environments of procedural languages such C, C++, PASCAL, FORTRAN and JAVA.\",\n \"By employing an invariant instruction set across a variety of datapath size ranges, a single program can handle a wide range of input data sizes with the arithmetical precision preserved by construction.\",\n \"Another consequence is the requirement of parameter passing to functions and subroutines by reference only.\",\n \"Consider for a moment the runtime stack frame requirements of the C programming language.\",\n \"C's runtime stack frame contains the following components: Branch related pointers, loop counters, data address references and data values, all of which may have differing data widths.\",\n \"By partitioning the stack frame into multiple stack frame into separate stack frames to handle differing data widths, the communication and manipulation of data to “fit” onto a single stack frame, or “fit” back into the processing element where it is needed is minimized.\",\n \"There are further architectural preferences which ease the task of compilation of procedural language programs as well as improve the reliability of these translations.\",\n \"FIG.\",\n \"29 depicts a preferred version of ALU 1400, as used in FIG.\",\n \"28 and earlier Figures supporting configurations of its internal memories and system input 1002 emulating a multiplier-accumulator with local register bank.\",\n \"Arithmetic processor 1400 preferably contains 3 ALUs, 1300-1, 1300-2 and 1300-3, with two memories 1200-1 and 1200-2 respectively feeding 1016 and 1018 the first two ALUs 1300-1 and 1300-2.The third ALU 1300-3 is feed by at least ALU 1300-2 and wire bundle 1002.System input 1002 preferably contains representations of normal numbers and numbers in a logarithmic domain.\",\n \"The logarithmic domain will be discussed in detail shortly.\",\n \"The normal number representation be stored in memory 1200-1.ALU 1300-2 may further be implemented in a fashion as shown in FIG.\",\n \"9, with shift controls being provided from part of the numeric signaling received from wire bundle 1018, as well as at least part of the addressing being provided by parts of the numeric signals received from wire bundle 1018.The results of the two ALU 1300-1 and 1300-2 operations are sent 1018 and 1036 to ALU 1300-3, where the results are combined to form an efficient and very accurate approximation of a sum of numerical products.\",\n \"As mentioned earlier, there are some fundamental problems with multipliers.\",\n \"Most importantly, they tend to grow with the product of the input precision.\",\n \"While this may be somewhat constrained by output precision requirements, it remains a fundamental problem.\",\n \"An approach that solve this problem will now be described.\",\n \"Consider the action of representing each member of a number collection by an integer part and a special part, where the special part contains exactly one member of a first special value collection comprising negative-infinity and not-negative-infinity.\",\n \"FIG.\",\n \"30 depicts a flowchart of a method of processing numeric data, which may be variously embodied.\",\n \"Arrow 2210 directs the flow of execution from starting operation 2200 to operation 2212.Operation 2212 performs representing each member of a number collection by an integerpart and a special part.\",\n \"Arrow 2214 directs execution from operation 2212 to operation 226.Operation 226 terminates the operations of this flowchart.\",\n \"Arrow 2220 directs the flow of execution from starting operation 2200 to operation 2222.Operation 2222 performs performing at least one member of the arithmetic operation collection upon at least one of the members of the number collection.\",\n \"Arrow 2224 directs execution from operation 2222 to operation 226.Operation 226 terminates the operations of this flowchart.\",\n \"Certain embodiments of the invention may perform all members of the arithmetic operation collection upon the relevant member of the number collection.\",\n \"Certain embodiments of the invention may further include one or both of the following operational steps.\",\n \"Arrow 2230 directs the flow of execution from starting operation 2200 to operation 2232.Operation 2232 performs log-converting a member of an input number collection to create a member of the number collection.\",\n \"Arrow 2234 directs execution from operation 2232 to operation 226.Operation 226 terminates the operations of this flowchart.\",\n \"Arrow 2240 directs the flow of execution from starting operation 2200 to operation 2242.Operation 2242 performs exp-converting a member of the number collection to create a member of an output number collection.\",\n \"Arrow 2244 directs execution from operation 2242 to operation 2216.Operation 2216 terminates the operations of this flowchart.\",\n \"FIG.\",\n \"31 depicts a detail flowchart of operation 2222 of FIG.\",\n \"30 further performing the arithmetic operation collection.\",\n \"Arrow 2270 directs the flow of execution from starting operation 2222 to operation 2272.Operation 2272 performs adding the first number to the second number to create an add-result.\",\n \"Arrow 2274 directs execution from operation 2272 to operation 2276.Operation 2276 terminates the operations of this flowchart.\",\n \"Arrow 2280 directs the flow of execution from starting operation 2222 to operation 2282.Operation 2282 performs subtracting the first number by the second number to create a subtract-result.\",\n \"Arrow 2284 directs execution from operation 2282 to operation 2276.Operation 2276 terminates the operations of this flowchart.\",\n \"Arrow 2290 directs the flow of execution from starting operation 2222 to operation 2292.Operation 2292 performs exponentiating the first number to create an exp-result.\",\n \"Arrow 2294 directs execution from operation 2292 to operation 2276.Operation 2276 terminates the operations of this flowchart.\",\n \"Arrow 2300 directs the flow of execution from starting operation 2222 to operation 2302.Operation 2302 performs logarithming the first number to create a log-result.\",\n \"Arrow 2304 directs execution from operation 2302 to operation 2276.Operation 2276 terminates the operations of this flowchart.\",\n \"Note that the number collection is further comprised of the add-result, the subtract-result, the exp-result and the log-result.\",\n \"FIG.\",\n \"32A depicts a detail flowchart of operation 2272 of FIG.\",\n \"31 further adding.\",\n \"Arrow 2330 directs the flow of execution from starting operation 2272 to operation 2332.Operation 2332 performs determining whether the special part of the first number contains the negative-infinity.\",\n \"Arrow 2334 directs execution from operation 2332 to operation 2336.Operation 2336 terminates the operations of this flowchart.\",\n \"Arrow 2340 directs the flow of execution from starting operation 2272 to operation 2342.Operation 2342 performs determining whether the special part of the second number contains the negative-infinity.\",\n \"Arrow 2344 directs execution from operation 2342 to operation 2336.Operation 2336 terminates the operations of this flowchart.\",\n \"Arrow 2350 directs the flow of execution from starting operation 2272 to operation 2352.Operation 2352 performs setting the special part of the add-result to contain the negative-infinity whenever the special part of at least one member of the collection the first number and the second number contains the negative-infinity.\",\n \"Arrow 2354 directs execution from operation 2352 to operation 2336.Operation 2336 terminates the operations of this flowchart.\",\n \"FIG.\",\n \"32B depicts a detail flowchart of operation 2282 of FIG.\",\n \"31 further subtracting.\",\n \"Arrow 2370 directs the flow of execution from starting operation 2282 to operation 2372.Operation 2372 performs determining whether the special part of the first number contains the negative-infinity.\",\n \"Arrow 2374 directs execution from operation 2372 to operation 2376.Operation 2376 terminates the operations of this flowchart.\",\n \"Arrow 2380 directs the flow of execution from starting operation 2282 to operation 2382.Operation 2382 performs setting the special part of the subtract-result to contain the negative-infinity whenever the special part of the first number contains the negative-infinity.\",\n \"Arrow 2384 directs execution from operation 2382 to operation 2376.Operation 2376 terminates the operations of this flowchart.\",\n \"FIG.\",\n \"33A depicts a detail flowchart of operation 2292 of FIG.\",\n \"31 further exponentiating.\",\n \"Arrow 2410 directs the flow of execution from starting operation 292 to operation 2412.Operation 2412 performs determining whether the special part of the first number contains the negative-infinity.\",\n \"Arrow 2414 directs execution from operation 2412 to operation 2416.Operation 2416 terminates the operations of this flowchart.\",\n \"Arrow 2420 directs the flow of execution from starting operation 292 to operation 2422.Operation 2422 performs setting the special part of the exp-result to contain the not-negative-infinity and setting the integer part to a zero-representation whenever the special part of the first number contains the negative-infinity.\",\n \"Arrow 2424 directs execution from operation 2422 to operation 2416.Operation 2416 terminates the operations of this flowchart.\",\n \"FIG.\",\n \"33B depicts a detail flowchart of operation 2302 of FIG.\",\n \"31 further logarithming.\",\n \"Arrow 2430 directs the flow of execution from starting operation 2302 to operation 2432.Operation 2432 performs determining whether the integer part of the first number is essentially equal to the zero-representation.\",\n \"Arrow 2434 directs execution from operation 2432 to operation 2436.Operation 2436 terminates the operations of this flowchart.\",\n \"Arrow 2440 directs the flow of execution from starting operation 2302 to operation 2442.Operation 2442 performs setting the special part of the log-result to contain the negative-infinity whenever the integer part of the first number essentially equals the zero-representation.\",\n \"Arrow 2444 directs execution from operation 2442 to operation 2436.Operation 2436 terminates the operations of this flowchart.\",\n \"Note that the integer part of each of the number collection members may be in a non-redundant numeric notation.\",\n \"FIG.\",\n \"34A depicts a detail flowchart of operation 2442 of FIG.\",\n \"33B further setting the special part of the log-result.\",\n \"Arrow 2470 directs the flow of execution from starting operation 2442 to operation 2472.Operation 2472 performs setting the special part of the log-result to contain the negative-infinity whenever the integer part of the first number equals the zero-representation.\",\n \"Arrow 2474 directs execution from operation 2472 to operation 2476.Operation 2476 terminates the operations of this flowchart.\",\n \"Alternatively, the integer part of each of the number collection members may be in a redundant numeric notation possessing a zero-representation collection comprising at least two zero-representation instances.\",\n \"FIG.\",\n \"34B depicts a detail flowchart of operation 2442 of FIG.\",\n \"33B further setting the special part of the log-result.\",\n \"Arrow 2490 directs the flow of execution from starting operation 2442 to operation 2492.Operation 2492 performs setting the special part of the log-result to contain the negative-infinity whenever the integer part of the first number is a member of the zero-representation collection.\",\n \"Arrow 2494 directs execution from operation 2492 to operation 2496.Operation 2496 terminates the operations of this flowchart.\",\n \"Note that the integer part of each member of the number collection may contains a sign and a magnitude.\",\n \"Further, for each member of the number collection, the sign may be a member of a sign collection consisting essentially of a positive-sign and a negative-sign.\",\n \"The special part of each member of the number collection may further contain exactly one member of a second special value collection comprising a special-minus and a special-plus.\",\n \"FIG.\",\n \"35A depicts a detail flowchart of operation 2292 of FIG.\",\n \"31 further exponentiating.\",\n \"Arrow 2510 directs the flow of execution from starting operation 2292 to operation 2512.Operation 2512 performs setting the sign of the exp-result to essentially the negative-sign whenever the special part of the first number contains the special-minus.\",\n \"Arrow 2514 directs execution from operation 2512 to operation 2516.Operation 2516 terminates the operations of this flowchart.\",\n \"FIG.\",\n \"35B depicts a detail flowchart of operation 2302 of FIG.\",\n \"31 further logarithming.\",\n \"Arrow 2530 directs the flow of execution from starting operation 2302 to operation 2532.Operation 2532 performs determining whether the sign part of the first number is essentially equal to the negative-sign.\",\n \"Arrow 2534 directs execution from operation 2532 to operation 2536.Operation 2536 terminates the operations of this flowchart.\",\n \"Arrow 2540 directs the flow of execution from starting operation 2302 to operation 2542.Operation 2542 performs setting the special part of the log-result to contain the special-minus whenever the sign part of the first number is essentially the negative-sign.\",\n \"Arrow 2544 directs execution from operation 2542 to operation 2536.Operation 2536 terminates the operations of this flowchart.\",\n \"The integer part of each of the number collection members may be in a redundant numeric notation supporting determination of negativity by a negative-test collection comprising at least two negative-test steps.\",\n \"FIG.\",\n \"36A depicts a detail flowchart of operation 2532 of FIG.\",\n \"35B further determining whether the sign part of the first number is essentially equal to the negative-sign.\",\n \"Arrow 2570 directs the flow of execution from starting operation 2532 to operation 2572.Operation 2572 performs determining whether the sign part of the first number is equal to the negative-sign based upon performing at least one of the members of the negative-test collection.\",\n \"Arrow 2574 directs execution from operation 2572 to operation 2576.Operation 2576 terminates the operations of this flowchart.\",\n \"Alternatively, the integer part of each of the number collection members is in a non-redundant numeric notation possessing exactly one negative-test step.\",\n \"FIG.\",\n \"36B depicts a detail flowchart of operation 2532 of FIG.\",\n \"35B further determining whether the sign part of the first number is essentially equal to the negative-sign.\",\n \"Arrow 2590 directs the flow of execution from starting operation 2532 to operation 2592.Operation 2592 performs performing the exactly one negative-test step based upon the first number.\",\n \"Arrow 2594 directs execution from operation 2592 to operation 2596.Operation 2596 terminates the operations of this flowchart.\",\n \"Note that each member of the input number collection may be comprised of an integer part.\",\n \"FIG.\",\n \"37A depicts a detail flowchart of operation 2232 of FIG.\",\n \"30 further log-converting the input number collection member.\",\n \"Arrow 2600 directs the flow of execution from starting operation 2232 to operation 2602.Operation 2602 performs determining whether the integer part of the input number collection member is essentially equal to the zero-representation.\",\n \"Arrow 2604 directs execution from operation 2602 to operation 2606.Operation 2606 terminates the operations of this flowchart.\",\n \"Arrow 2610 directs the flow of execution from starting operation 2232 to operation 2612.Operation 2612 performs setting the special part of the number collection member to contain the negative-infinity whenever the integer part of the input number collection member essentially equals the zero-representation.\",\n \"Arrow 2614 directs execution from operation 2612 to operation 2606.Operation 2606 terminates the operations of this flowchart.\",\n \"Note that the integer part of each of the input number collection members may contain a sign belonging to the sign collection and a magnitude.\",\n \"FIG.\",\n \"37B depicts a detail flowchart of operation 2232 of FIG.\",\n \"30 further log-converting the input number collection member.\",\n \"Arrow 2630 directs the flow of execution from starting operation 2232 to operation 2632.Operation 2632 performs determining whether the sign part of the input number collection member is essentially equal to the negative-sign.\",\n \"Arrow 2634 directs execution from operation 2632 to operation 2636.Operation 2636 terminates the operations of this flowchart.\",\n \"Arrow 2640 directs the flow of execution from starting operation 2232 to operation 2642.Operation 2642 performs setting the special part of the number collection member to contain the special-minus whenever the sign part of the input number collection member is essentially the negative-sign.\",\n \"Arrow 2644 directs execution from operation 2642 to operation 2636.Operation 2636 terminates the operations of this flowchart.\",\n \"Note that each of the output number collection members may include a magnitude.\",\n \"FIG.\",\n \"38A depicts a detail flowchart of operation 2242 of FIG.\",\n \"30 further exp-converting.\",\n \"Arrow 2650 directs the flow of execution from starting operation 2242 to operation 2652.Operation 2652 performs setting the magnitude of the output number collection member to the zero-representation whenever the special part of the number collection member contains the negative-infinity.\",\n \"Arrow 2654 directs execution from operation 2652 to operation 2656.Operation 2656 terminates the operations of this flowchart.\",\n \"Also, each of the output number collection members may include a sign belonging to the sign collection.\",\n \"FIG.\",\n \"38B depicts a detail flowchart of operation 2242 of FIG.\",\n \"30 further exp-converting.\",\n \"Arrow 2670 directs the flow of execution from starting operation 2242 to operation 2672.Operation 2672 performs setting the sign of the output number collection member to the negative-sign whenever the special part of the number collection member contains the special-minus.\",\n \"Arrow 2674 directs execution from operation 2672 to operation 2676.Operation 2676 terminates the operations of this flowchart.\",\n \"Arrow 2680 directs the flow of execution from starting operation 2242 to operation 2682.Operation 2682 performs setting the sign of the output number collection member to the positive-sign whenever the special part of the number collection member contains the special-plus.\",\n \"Arrow 2684 directs execution from operation 2682 to operation 2686.Operation 2686 terminates the operations of this flowchart.\",\n \"Note that each of the input number collection members may be encoded as an N1 bit code; wherein the N1 is at least three.\",\n \"The integer part of each of the number collection members may be encoded as an N2 bit code; wherein N2 is greater than N1.This method of numeric processing may be implemented as a program system comprised of program steps implementing the steps of the method.\",\n \"The program steps may reside in a memory accessibly coupled to a computer, which executes these program steps.\",\n \"The program system may further be implemented as program steps in at least one member of the language collection comprising C, C++, JAVA, FORTRAN, PASCAL, VERILOG, VHDL, assembly language and executable code for at least one computational engine implemented upon the computer.\",\n \"The invention includes circuitry generated from those program steps.\",\n \"The invention also includes circuitry implemented within at least one circuit component belonging to a programmable logic device collection and a fixed architecture device collection.\",\n \"Where the programmable logic device collection refers to all integrated circuits at least partially embodying at least one programmable logic array and all integrated circuits at least partially embodying a Field Programmable Gate Array.\",\n \"The fixed architecture device collection refers to all integrated circuits generated using gate array templates, fuse programmable integrated circuits, standard cell libraries, memory generators, and custom layout technologies.\",\n \"The preceding embodiments of the invention have been provided by way of example and are not meant to constrain the scope of the following claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10276414"}}},{"rowIdx":85,"cells":{"text":{"kind":"list like","value":[["Centrifugal pump, in particular a spirally-housed centrifugal pump for a heat exchange medium","In a centrifugal pump—in particular a spiral-casing centrifugal pump—for a heat carrier medium, comprising a spiral casing (14) having an impeller (40), a casing cover (18) and an associated casing attachment portion (34) for a pump shaft (35, 36, 36a) provided with a shaft bearing (76, 76a) near the spiral casing (14) and a shaft seal (56) disposed at a spacing in relation to the shaft bearing in a sealing chamber (48), parts of the casing cover (18) are a bearing cup (28) accommodating the shaft bearing (76, 76a), a tubular portion (32) surrounding the pump shaft (35, 36, 36a) as a heat barrier and support ribs (56) or the like profile elements arranged at a spacing relative to each other in the peripheral direction.","The bearing cup (28) is held at an axial spacing towards the impeller (40) by the tubular portion (32) surrounding the pump shaft (35, 36, 36a), and the casing attachment portion (34) attached to the casing cover (18) or an edge ring (30) carried by the support ribs (26) thereof delimits the sealing chamber (48) for the shaft seal (56)."],["1.A centrifugal pump, in particular a spiral-casing centrifugal pump, for a heat carrier medium, comprising a spiral casing (14) having an impeller (40), a casing cover (18) and an associated casing attachment portion (34) for a pump shaft (35, 36, 36a) provided with a shaft bearing (76, 76a) near the spiral casing (14) and a shaft seal (56) disposed at a spacing in relation to the shaft bearing in a sealing chamber (48), characterised in that a bearing cup (28) accommodating the shaft bearing (76, 76a), a tubular portion (32) surrounding the pump shaft (35, 36, 36a) as a heat barrier and support ribs (56) or the like profile elements arranged at a spacing relative to each other in the peripheral direction are parts of the casing cover (18).","2.A centrifugal pump as set forth in claim 1 characterised in that the bearing cup (28) is held at an axial spacing towards the impeller (40) by the tubular portion (32) surrounding the pump shaft (35, 36, 36a).","3.A centrifugal pump as set-forth in claim 1 or claim 2 characterised in that the casing attachment portion (34) attached to the casing cover (18) or an edge ring (30) carried by the support ribs (26) thereof delimits the sealing chamber (48) for the shaft seal (56).","4.A centrifugal pump as set forth in claim 3 characterised in that at their ends remote from the base region (20) of the casing cover (18) the support ribs (26) are connected by the edge ring (30) surrounding the longitudinal axis (A) of the pump.","5.A centrifugal pump as set forth in one of claims 1 through 4 characterised in that the support ribs (26) are inclined at an angle (w) to the longitudinal axis (A) of the pump from the base region (20) of the casing cover (18) towards the shaft seal (56).","6.A centrifugal pump as set forth in claim 5 characterised by an angle (w) of between 30° and 60°.","7.A centrifugal pump as set forth in one of claims 1 through 6 characterised in that the cross-sectional height (h) of the support ribs (26) which preferably extend in axial planes (E) passing radially through the longitudinal axis (A) of the pump increases towards the sliding ring seal (56).","8.A centrifugal pump as set forth in one of claims 1 through 7 characterised in that the sealing chamber (48) adjoins the shaft bearing (76, 76a).","9.A centrifugal pump as set forth in one of claims 1 through 8 characterised in that at least one abutment step (28) directed away from the spiral casing (24) for a further pump portion (96) is arranged at the casing cover (18).","10.A centrifugal pump as set forth in claim 9 characterised in that the abutment step is a front ring (22) formed on the casing cover (18).","11.A centrifugal pump as set forth in claim 9 or claim 10 characterised in that the abutment step or the front ring (22) projects from an annular flange (21) which surrounds the support ribs (26) and which is disposed at the transition thereof to a base region (20) of the casing cover (18).","12.A centrifugal pump comprising a sealing ring (59) of the shaft seal which is in the form of a sliding ring seal (56), the sealing ring extending peripherally at a counterpart ring (60) provided at the housing side, as set forth in one of claims 1 through 11, characterised in that the counterpart ring (60) for the sealing ring (59) is arranged in a shaped stub portion (64) of the casing attachment portion (34), the stub portion projecting axially into the sealing chamber (48), and associated with the stub portion is at least one passage (58) inclined with respect to the longitudinal axis (A) of the pump, with a closure screw (52) closing the passage.","13.A centrifugal pump as set forth in claim 12 characterised by an angle (z) between the longitudinal axis (A) of the pump and the longitudinal axis (B) of the passage (53) of about 45°.","14.A centrifugal pump as set forth in claim 12 or claim 13 characterised by an axial length (f) of the stub portion (64) which corresponds approximately to half the axial length (e1) of the sealing chamber (48).","15.A centrifugal pump as set forth in one of claims 1 through 14 characterised in that the shaft bearing is in the form of a plain bearing (76) with a ratio of the length (g) of the bearing bush (77) to the diameter (d) of the pump shaft (35, 36, 36a) of between about 1.5 and 2.0, preferably about 1.8.16.A centrifugal pump as set forth in claim 15 characterised in that the bearing bush (77) of the plain bearing (76, 76a) is adapted to be dismantleable.","17.A centrifugal pump as set forth in claim 15 or claim 16 characterised in that the plain bearing (76, 76a) or its bearing bush (77) is externally embraced approximately at its longitudinal center by a clamping or tolerance ring (80) which engages into the bearing cup (28).","18.A centrifugal pump as set forth in claim 17 characterised in that the width (n) of the clamping or tolerance ring (80) corresponds to a fraction of the length (g) of the bearing bush (77).","19.A centrifugal pump as set forth in claim 18 characterised in that the width (n) of the external clamping or tolerance ring (80) corresponds approximately to between a fifth and a sixth of the length (g) of the bearing bush (77).","20.A centrifugal pump as set forth in one of claims 15 through 19 characterised in that the plain bearing (76a) includes an inner bearing sleeve (82) surrounded by a bearing bush (77) at the bearing cup side (FIGS.","6 and 7).","21.A centrifugal pump as set forth in one of claims 15 through 20 characterised in that within the plain bearing (76a) the pump shaft (35, 36a) is embraced by at least one tolerance ring (80i) which engages into the pump shaft.","22.A centrifugal pump as set forth in one of claims 17 through 21 characterised in that provided on respective sides of the outer tolerance ring (80), viewed in longitudinal section of the centrifugal pump (10a), is a respective inward tolerance ring (80i) which engages into the pump shaft (35, 36a).","23.A centrifugal pump as set forth in one of claims 15 through 19 characterised in that the plain bearing (76) includes a bearing bush (77) at the bearing cup side, with a slidable internal peripheral surface portion (78) embracing the pump shaft (36).","24.A centrifugal pump as set forth in claim 23 characterised by an internal peripheral surface portion (28) of the plain bearing (76) comprising carbon (FIGS.","4 and 5).","25.A centrifugal pump as set forth in claim 23 or claim 24 characterised by a hardened pump shaft (36) or a corresponding shaft portion which is associated with the bearing bush (77).","26.A centrifugal pump as set forth in one of claims 1 through 25 characterised in that the sliding ring seal (56) embraces a shaft sleeve (89) at the shaft side, wherein at least one O-ring (88) is provided between the shaft sleeve (89) and the pump shaft (36, 36a).","27.A centrifugal pump as set forth in one of claims 1 through 26 characterised in that a rearward shaft bearing (68) for the pump shaft (36, 36a) is arranged in the casing attachment portion (34) at an axial spacing relative to the sliding ring seal (56) outside the sealing chamber (48).","28.A centrifugal pump as set forth in claim 27 characterised in that at least one hollow space (66) is arranged between the sealing chamber (48) and the shaft bearing (68) in the casing attachment portion (34).","29.A centrifugal pump as set forth in one of claims 1 through 28 characterised in that the pump shaft (36a) is in the form of a plug-in stub shaft with clamping ring (92).","30.A centrifugal pump as set forth in one of claims 8 through 29 characterised in that the spiral casing (14) and the bearing carrier casing (16) are embraced by a spacer (96) which butts against the abutment step or steps or the front ring (22) respectively and it is attached to a motor (100)."],["The invention concerns a centrifugal pump—in particular a spiral-casing centrifugal pump—for a heat carrier medium, comprising a spiral casing having an impeller, a casing cover and an associated casing attachment portion for a pump shaft provided with a shaft bearing near the spiral casing and a shaft seal disposed at a spacing in relation to the shaft bearing in a sealing chamber.","Such centrifugal pumps are described by way of example in a prospectus from the present applicants in relation to the range NHT for heat carrier purposes up to 350° C. A spiral casing for an impeller is connected to a bearing casing by means of a throttle section having external ribs.","The impeller is fixed at one end of a pump shaft which extends in the throttle section.","Arranged between the throttle section and the impeller is a plain bearing of silicon carbide and arranged downstream of the throttle section is a sliding ring seal which is followed by a rolling bearing.","This arrangement involves a horizontal spiral-casing centrifugal pump of a process type of structure which is single-stage in terms of intake flow.","The pump-side silicon carbide plain bearing is lubricated by the fluid being delivered, while used at the drive side is a grease-lubricated grooved-type ball bearing.","In consideration of that state of the art, the inventor set himself the aim of providing a centrifugal pump of the kind set forth in the opening part of this specification, which is simple to manufacture and which can be inexpensively and particularly well used.","That object is attained by the teaching of the independent claim; the appendant claims set forth advantageous developments.","In addition the scope of the invention embraces all combinations comprising at least two of the features disclosed in the description, the drawing and/or the claims.","In accordance with the invention a bearing cup accommodating the shaft bearing, a tubular portion surrounding the pump shaft as a heat barrier and so-called support ribs or the like profile elements arranged at a spacing relative to each other in the peripheral direction are parts of the casing cover.","Those features permit the pump to be of a simple structure with only two pressure-bearing parts for the bearing carrier casing—comprising the casing cover and the casing attachment portion—as well as a particularly high level of stability for the bearing carrier casing.","In addition the bearing cup is to be held at an axial spacing towards the impeller by the tubular portion which surrounds the pump shaft.","The sealing chamber for the shaft seal is advantageously delimited by the casing attachment portion which is preferably joined to the casing cover or an edge ring which is carried by the support ribs thereof and which surrounds the longitudinal axis of the pump; the edge ring is connected to and preferably integrally formed on the support ribs at their ends remote from the base region of the casing cover.","Disposed between the spiral casing and the above-mentioned sealing chamber is a latticework-like or trussing-like rib arrangement comprising those support ribs which are to be inclined towards the longitudinal axis from the spiral casing at a preferred angle of between 40° and 45° and—at a radial spacing relative to each other—surround the bearing cup and the heat barrier and form jointly therewith the casing cover.","For that purpose it has proven to be desirable for the cross-sectional height of the support ribs which preferably extend in axial planes which pass radially through the longitudinal axis of the pump to be caused to increase towards the sliding ring seal in order to enhance the level of stability and minimise heat losses.","In accordance with a further feature of the invention the sealing chamber is to adjoin the shaft bearing.","Inter alia that ensures an adequate supply of lubricating medium to the bearing.","In addition the bearing contributes to circulation of the medium in the sealing chamber for flushing and cooling the seal.","In order to enlarge the use of the centrifugal pump according to the invention and the combination options thereof, it is possible to arrange on the casing cover at least one abutment stage or step directed away from the spiral casing, for a further part of the pump; that abutment step should preferably be a front ring which is formed on the casing cover.","An associated pump part can moreover be a spacer which extends around the bearing carrier casing and which abuts against the abutment step or steps or the front ring and to which a motor is attached.","It has proven to be desirable for the abutment step or the front ring to be arranged to project from an annular flange which extends around the support ribs and which is mounted to the transition thereof to a base region of the casing cover.","The scope of the invention includes a centrifugal pump with a sealing ring of the shaft seal—in the form of a sliding ring seal—, the sealing ring extending therearound on a counterpart ring provided at the casing side; the counterpart ring is arranged for the sealing ring in a shaped stub portion of the casing attachment portion, the stub portion projecting axially into the sealing chamber.","At last one opening or passage which is inclined with respect to the longitudinal axis of the pump and with a closure screw for closing it is to be associated with the stub portion—which is of an axial length approximately corresponding to half the axial length of the sealing chamber—; the longitudinal axis of the passage advantageously delimits an angle of about 45° with the longitudinal axis of the pump.","Thus the sliding ring seal is advanced within the sealing chamber in order to make available sufficient space for collecting air or outgassings of the delivery medium—in particular when the arrangement is positioned vertically.","The described arrangement of the passage with the closure screw easily permits complete venting of the sealing chamber both when the pump is positioned horizontally and also vertically.","The frictional heat of the sliding ring seal is desirably dissipated to the surroundings by virtue of a large surface area of the surrounding sealing chamber and a large volume of fluid in the sealing chamber.","In accordance with the invention the shaft bearing is in the form of a plain bearing with a ratio of the length of the bearing bush to the diameter of the pump shaft of between about 1.5 and 2.0, preferably about 1.8.In addition the bearing bush of the plain bearing should be designed to be dismantled.","Advantageously the plain bearing, as viewed from the impeller, is disposed behind the heat barrier, which contributes to simplicity of possible fixing and also contributes to the heat barrier being of a desirable design configuration.","In order to achieve a low level of heat conduction from the spiral casing to the sealing chamber, a small cross-section and a long length of the tubular portion, which is in the form of the heat barrier, of the casing cover has proven to be desirable.","That can be implemented particularly well with the specified bearing arrangement.","The positioning of the impeller-side bearing behind the heat barrier means that the delivery medium which serves as a lubricating agent is at a lower temperature at that location than in the pump casing.","As a result it is of higher viscosity, which is advantageous for the lubricating capability.","In addition the vapor pressure of the medium at that location is markedly lower than in the pump casing, thereby minimising the risk of the bearing running dry.","It has proven to be desirable for the plain bearing or the bearing bush thereof, for fixing purposes, to be surrounded approximately at the longitudinal center thereof on the outside by a clamping or tolerance ring which engages into the bearing cup.","The width of the clamping or tolerance ring should correspond to a fraction of the length of the bearing bush, for example between a fifth and a sixth of the length of the bearing bush.","That provides for easy (dis-)mantling as well as compensation for alignment errors by virtue of tilting mobility.","There are a number of design configurations of the plain bearing, in accordance with the invention.","In one case the plain bearing includes an inner bearing sleeve which is surrounded by a bearing bush at the bearing cup side.","In that case the pump shaft is surrounded within the plain bearing by at least one tolerance ring which engages into the pump shaft.","In particular an inward tolerance ring should be provided on each of the two sides of the outer tolerance ring which engages into the bearing cup—as viewed in longitudinal section of the centrifugal pump—, the inward tolerance ring engaging into the pump shaft.","The bearing sleeve and the bearing bush are preferably made from silicon carbide.","Another design configuration in accordance with the invention involves a plain bearing with a bearing bush at the bearing cup side, the bearing bush including a slidable internal peripheral surface portion which extends around the pump shaft.","In that case the dismantleable plain bearing bush is preferably provided with an inner carbon coating.","The bush runs on a hardened shaft or a hardened shaft portion.","Fixing is effected by a centrally disposed outer tolerance ring, as already mentioned.","In accordance with a further feature of the invention the sliding ring seal extends around a shaft sleeve at the shaft side, wherein at least one O-ring is provided between the shaft sleeve and the pump shaft.","That arrangement, in a construction which is relieved of load, permits assembly of the sliding ring seal from the impeller side, which is desirable in particular when the shaft is in the form of a plug-in shaft.","In accordance with another feature of the invention arranged in the casing attachment portion at an axial spacing relative to the sliding ring seal outside the sealing chamber is a rearward shaft bearing for the pump shaft; at least one hollow space can also be provided in the casing attachment portion between the sealing chamber and the shaft bearing.","In a particular configuration the pump shaft is in the form of a plug-in shaft with clamping ring.","By virtue of the described different design configurations of the plain bearing, in combination with the three types of structure: pump with main plate and coupling; pump of a block-type structure; and pump of an in-line type of structure there are at least six structural variants for the centrifugal pump according to the invention.","Further advantages, features and details of the invention will be apparent from the description hereinafter of preferred embodiments and with reference to the drawing in which: FIGS.","1 and 8 each show a perspective view of different embodiments of a centrifugal pump according to the invention for heat carrier media, FIG.","2 shows an end view of the FIG.","1 structure, FIG.","3 shows a partial longitudinal section through FIG.","2 along line III-III therein, FIG.","4 shows a view in longitudinal section on an enlarged scale through the pump in FIG.","2 taken along line IV-IV therein, FIG.","5 shows a view on an enlarged scale of a part of the FIG.","4 structure, FIG.","6 shows a longitudinal section corresponding to FIG.","4 through another embodiment of the pump shown in FIG.","1, FIG.","7 shows a view on an enlarged scale of a portion of the FIG.","6 structure, FIG.","9 shows an end view of the FIG.","8 structure, FIG.","10 shows a perspective view of a casing cover of the pump, FIG.","11 shows a view on an enlarged scale through the pump of FIGS.","8 and 9 taken along line XI-XI in FIG.","9, FIG.","12 shows a partial longitudinal section on an enlarged scale in relation to FIG.","11 taken along line XII-XII in FIG.","9, FIGS.","13 and 14 show different perspective views of a part of a further embodiment of a centrifugal pump according to the invention, FIG.","15 shows an end view of the structure shown in FIGS.","13 and 14, FIG.","16 shows a partial longitudinal section through the pump of FIGS.","13 through 15 taken along line XVI-XVI in FIG.","15, and FIG.","17 shows a partial section on an enlarged scale in relation to FIG.","16 through that pump taken along line XVII-XVII in FIG.","15.A spiral-casing centrifugal pump 10, on a volute or spiral casing 14 provided with connecting flanges 12, 12a,—with the interposition of seals (not shown)—has a bearing carrier casing 16 which includes a casing cover 18 with a casing attachment portion 34 fitted thereto.","The casing cover 18 is provided with an annular flange 21 which projects from a dish-like base region 20 and through which pass connecting screws 24, on a front ring 22 which is formed on the annular flange 21 and which forms an abutment step; the connecting screws 24 are fitted into sleeve ribs 15 which are formed in axis-parallel relationship externally on a peripheral wall 13 of the spiral casing 14, the peripheral wall engaging over the dish wall 19, and the screws 24 centeringly connect the casing cover 18 to the spiral casing 14.Formed on the casing cover 18 or the base region 20 thereof respectively are support ribs 26 of substantially constant thickness b, which are determined by axial planes E—passing radially through the longitudinal axis A of the pump—and which are inclined at an angle w of about 40° towards the longitudinal axis A of the pump.","The cross-sectional height h of the support ribs 26 steadily increases in the longitudinal extent or in the axial direction away from the casing cover 18.The support ribs 26 are cast at the other end to a bearing cup 28 axially associated with the longitudinal axis A of the pump and an edge ring 30 which surrounds the bearing cup.","An axial tubular portion 32 which is integral with the casing cover 18 connects the bearing cup 28 thereto, in centered relationship.","The bearing cup 28, with its edge ring 30, and the support rings 26—of which there are four here—are also part of the casing cover 18 whose length a, approximately corresponds to a third of the pump length a.","Passing through the casing cover 18 and the rearward casing attachment portion 34—that is to say the bearing carrier casing 16—is a pump shaft 36 of a diameter d, while an impeller 40 is held on the front stepped end 37 thereof by a nut 38.The impeller 40 rotates in the spiral casing 14 which includes an intake or suction chamber 42, whose inlet in the region of the axial connecting flange 12 is identified by reference 43 and whose radial outlet in the connecting flange 12a is identified by reference 44.Disposed near the impeller 40 in the casing cover 18 is a stuffing-box packing 46 at the periphery of the cylindrical tubular portion 32.The internal space 29 of the bearing cup 28 is connected to the cylindrical tubular portion 32 which extends around the pump shaft 36 to form a heat barrier.","If for example a flow agent of low viscosity at about 350° C. passes through the inlet 43, flow agent of higher viscosity at 130° C. is disposed in the internal space of the bearing cup.","The internal space 29 of the bearing cup 28, which adjoins the cylindrical tube portion 32, communicates with a sealing chamber 48 which is arranged in the bearing carrier casing 16 or in the casing attachment portion 34 and which is surrounded by an annular wall 50 and which is provided with at least one closure screw 52 together with a screwthreaded opening or passage 53 which accommodates the screw and which is inclined at an angle z of 45° relative to the longitudinal axis A of the pump, and with blade-like surface elements 55 which are inclined relative to each other and which each have a respective edge 54 parallel to the axis, the axial length e1 thereof approximately corresponding to half the length e of the casing attachment portion 34.An outlet screw 52b towards the bottom is arranged in a radial opening or passage in the region of the chamber which is towards the bottom.","In addition FIG.","2 shows a lateral closure screw 52a which is required for venting when the pump 10 is used in a vertical position.","A rear axial sliding ring seal 56—which is not relieved of load—can be seen in the sealing chamber 48.Projecting from the annular wall 50 are four radial lugs 51 which are connected to corresponding counterpart lugs 51a of the edge ring 30 by screws 24a.","In embodiments which are not shown here—in particular of large dimensioning—an annular flange can also be provided, instead of the above-mentioned radial lugs 51.In order to increase the surface area of the outside of the annular wall, axially extending surface portions can be arranged on the outside of the annular wall.","The sliding ring seal 56 includes a coil spring 58—which is supported against a ring step or a ring 38 which is pushed on to the pump shaft 36—and which loads a rotating sliding ring 59 which with a stationary counterpart ring 60 forms a sealing gap.","The counterpart ring 60 is disposed in the tubular space 62 of an axial shaped stub portion 64 of an axial length f which here corresponds approximately to half the sealing chamber length e1.Arranged subsequently to the annular end part 65 of the stub portion 64 in the casing attachment portion 34 is a dish-like hollow space 66.Between the latter and the adjacent stepped shaft end 37e the pump shaft 36 is surrounded by a grooved-type ball bearing 68 with spacer disks 69 and a securing ring 70; that unit is covered by a bearing cover 72 of the casing attachment portion 34.Projecting radially beneath the latter is a plate-like support leg 74 which is fixed by screws 24b, comprising an angle plate member, in opposite relationship to which, in the region of the spiral casing 14, are two supports 74a which project in parallel in eccentric relationship.","The supports 74a and the support leg 74 are connected at the other end to a base plate (not shown).","Arranged in the internal space 29 in the bearing cup 28 in FIGS.","3 through 5 is a front hydrodynamic plain bearing 76 comprising a bearing bush 77 of a length g with an internal peripheral surface portion 78 of carbon material; the plain bearing 78, at its longitudinal center, is surrounded by a clamping or tolerance ring 80 of a width n, the ring 80 being provided in the bearing cup 28—that is to say at the housing side—; the ring 80 is of an elastic nature and force-lockingly connects the plain bearing 76 to the bearing cup.","The plain bearing 76a of the pump 10a as shown in FIGS.","6 and 7 has within the bearing bush 77 a coaxial bearing sleeve 82 and—besides the above-described outer tolerance ring 80 at the longitudinal center—two inner tolerance rings 80i of a width i which are disposed at the shaft side and which—viewed in longitudinal section—flank the outer tolerance ring 80 at the pump shaft 36 at a radial spacing on both sides.","The width n of the outer tolerance ring 80 and the width i of the inner tolerance rings 80i are relatively short in relation to the length g of the bearing bush, for example the latter corresponds approximately to between five and six times the width i and n respectively.","Reference 84 in FIGS.","6 and 7 shows a nut which is disposed between the front plain bearing 76a and the rear sliding ring seal 56—which is here relieved of load—for the purposes of fixing the bearing sleeve 82.The sliding ring components for carrying the radial forces which occur preferably comprise silicon carbide in the illustrated embodiment.","The two above-discussed bearing types 76, 76a can also be used in the centrifugal pump 11 shown in FIGS.","8 through 12 in which the pump shaft 35 is in the form of a plug-in or stub shaft and is provided with an O-ring 88 within a shaft sleeve 86 of the sliding ring seal 56a, the shaft sleeve 86 surrounding the pump shaft.","The O-ring 88 is disposed between the pump shaft 35 and a shaft sleeve 89 embracing it.","At the rearward end of the bearing carrier casing 16 the pump shaft 35 includes a clamping ring 92 which carries a fan wheel 90 and which is surrounded towards the front by a protective grid 93 as protection to prevent articles from being poked in.","The rearward shaft bearing—which is disposed in the motor—cannot be seen in the drawing.","The impeller 90 is surrounded by a wall ring 94—with apertured plate members 95—of a spacer 96 with endward flange rings 97, 97a; they are connected by longitudinal ribs 98 which are parallel to the axis.","The flange ring 97 which is at the right in the drawing is screwed to a parallel flange ring 99 of a motor 100, the flange ring 99 bearing against the spiral casing 14; the motor 100 is fixed by means of the spacer 96 to the pump 11.In the configuration of a centrifugal pump 11a with a vertical shaft 35 as shown in FIG.","13 ff, the inlet 43 and the outlet 44 of the spiral casing 14 are on a straight diametral line Q.","This pump 11a can also be provided with both of the described bearing forms 76, 76a."]],"string":"[\n [\n \"Centrifugal pump, in particular a spirally-housed centrifugal pump for a heat exchange medium\",\n \"In a centrifugal pump—in particular a spiral-casing centrifugal pump—for a heat carrier medium, comprising a spiral casing (14) having an impeller (40), a casing cover (18) and an associated casing attachment portion (34) for a pump shaft (35, 36, 36a) provided with a shaft bearing (76, 76a) near the spiral casing (14) and a shaft seal (56) disposed at a spacing in relation to the shaft bearing in a sealing chamber (48), parts of the casing cover (18) are a bearing cup (28) accommodating the shaft bearing (76, 76a), a tubular portion (32) surrounding the pump shaft (35, 36, 36a) as a heat barrier and support ribs (56) or the like profile elements arranged at a spacing relative to each other in the peripheral direction.\",\n \"The bearing cup (28) is held at an axial spacing towards the impeller (40) by the tubular portion (32) surrounding the pump shaft (35, 36, 36a), and the casing attachment portion (34) attached to the casing cover (18) or an edge ring (30) carried by the support ribs (26) thereof delimits the sealing chamber (48) for the shaft seal (56).\"\n ],\n [\n \"1.A centrifugal pump, in particular a spiral-casing centrifugal pump, for a heat carrier medium, comprising a spiral casing (14) having an impeller (40), a casing cover (18) and an associated casing attachment portion (34) for a pump shaft (35, 36, 36a) provided with a shaft bearing (76, 76a) near the spiral casing (14) and a shaft seal (56) disposed at a spacing in relation to the shaft bearing in a sealing chamber (48), characterised in that a bearing cup (28) accommodating the shaft bearing (76, 76a), a tubular portion (32) surrounding the pump shaft (35, 36, 36a) as a heat barrier and support ribs (56) or the like profile elements arranged at a spacing relative to each other in the peripheral direction are parts of the casing cover (18).\",\n \"2.A centrifugal pump as set forth in claim 1 characterised in that the bearing cup (28) is held at an axial spacing towards the impeller (40) by the tubular portion (32) surrounding the pump shaft (35, 36, 36a).\",\n \"3.A centrifugal pump as set-forth in claim 1 or claim 2 characterised in that the casing attachment portion (34) attached to the casing cover (18) or an edge ring (30) carried by the support ribs (26) thereof delimits the sealing chamber (48) for the shaft seal (56).\",\n \"4.A centrifugal pump as set forth in claim 3 characterised in that at their ends remote from the base region (20) of the casing cover (18) the support ribs (26) are connected by the edge ring (30) surrounding the longitudinal axis (A) of the pump.\",\n \"5.A centrifugal pump as set forth in one of claims 1 through 4 characterised in that the support ribs (26) are inclined at an angle (w) to the longitudinal axis (A) of the pump from the base region (20) of the casing cover (18) towards the shaft seal (56).\",\n \"6.A centrifugal pump as set forth in claim 5 characterised by an angle (w) of between 30° and 60°.\",\n \"7.A centrifugal pump as set forth in one of claims 1 through 6 characterised in that the cross-sectional height (h) of the support ribs (26) which preferably extend in axial planes (E) passing radially through the longitudinal axis (A) of the pump increases towards the sliding ring seal (56).\",\n \"8.A centrifugal pump as set forth in one of claims 1 through 7 characterised in that the sealing chamber (48) adjoins the shaft bearing (76, 76a).\",\n \"9.A centrifugal pump as set forth in one of claims 1 through 8 characterised in that at least one abutment step (28) directed away from the spiral casing (24) for a further pump portion (96) is arranged at the casing cover (18).\",\n \"10.A centrifugal pump as set forth in claim 9 characterised in that the abutment step is a front ring (22) formed on the casing cover (18).\",\n \"11.A centrifugal pump as set forth in claim 9 or claim 10 characterised in that the abutment step or the front ring (22) projects from an annular flange (21) which surrounds the support ribs (26) and which is disposed at the transition thereof to a base region (20) of the casing cover (18).\",\n \"12.A centrifugal pump comprising a sealing ring (59) of the shaft seal which is in the form of a sliding ring seal (56), the sealing ring extending peripherally at a counterpart ring (60) provided at the housing side, as set forth in one of claims 1 through 11, characterised in that the counterpart ring (60) for the sealing ring (59) is arranged in a shaped stub portion (64) of the casing attachment portion (34), the stub portion projecting axially into the sealing chamber (48), and associated with the stub portion is at least one passage (58) inclined with respect to the longitudinal axis (A) of the pump, with a closure screw (52) closing the passage.\",\n \"13.A centrifugal pump as set forth in claim 12 characterised by an angle (z) between the longitudinal axis (A) of the pump and the longitudinal axis (B) of the passage (53) of about 45°.\",\n \"14.A centrifugal pump as set forth in claim 12 or claim 13 characterised by an axial length (f) of the stub portion (64) which corresponds approximately to half the axial length (e1) of the sealing chamber (48).\",\n \"15.A centrifugal pump as set forth in one of claims 1 through 14 characterised in that the shaft bearing is in the form of a plain bearing (76) with a ratio of the length (g) of the bearing bush (77) to the diameter (d) of the pump shaft (35, 36, 36a) of between about 1.5 and 2.0, preferably about 1.8.16.A centrifugal pump as set forth in claim 15 characterised in that the bearing bush (77) of the plain bearing (76, 76a) is adapted to be dismantleable.\",\n \"17.A centrifugal pump as set forth in claim 15 or claim 16 characterised in that the plain bearing (76, 76a) or its bearing bush (77) is externally embraced approximately at its longitudinal center by a clamping or tolerance ring (80) which engages into the bearing cup (28).\",\n \"18.A centrifugal pump as set forth in claim 17 characterised in that the width (n) of the clamping or tolerance ring (80) corresponds to a fraction of the length (g) of the bearing bush (77).\",\n \"19.A centrifugal pump as set forth in claim 18 characterised in that the width (n) of the external clamping or tolerance ring (80) corresponds approximately to between a fifth and a sixth of the length (g) of the bearing bush (77).\",\n \"20.A centrifugal pump as set forth in one of claims 15 through 19 characterised in that the plain bearing (76a) includes an inner bearing sleeve (82) surrounded by a bearing bush (77) at the bearing cup side (FIGS.\",\n \"6 and 7).\",\n \"21.A centrifugal pump as set forth in one of claims 15 through 20 characterised in that within the plain bearing (76a) the pump shaft (35, 36a) is embraced by at least one tolerance ring (80i) which engages into the pump shaft.\",\n \"22.A centrifugal pump as set forth in one of claims 17 through 21 characterised in that provided on respective sides of the outer tolerance ring (80), viewed in longitudinal section of the centrifugal pump (10a), is a respective inward tolerance ring (80i) which engages into the pump shaft (35, 36a).\",\n \"23.A centrifugal pump as set forth in one of claims 15 through 19 characterised in that the plain bearing (76) includes a bearing bush (77) at the bearing cup side, with a slidable internal peripheral surface portion (78) embracing the pump shaft (36).\",\n \"24.A centrifugal pump as set forth in claim 23 characterised by an internal peripheral surface portion (28) of the plain bearing (76) comprising carbon (FIGS.\",\n \"4 and 5).\",\n \"25.A centrifugal pump as set forth in claim 23 or claim 24 characterised by a hardened pump shaft (36) or a corresponding shaft portion which is associated with the bearing bush (77).\",\n \"26.A centrifugal pump as set forth in one of claims 1 through 25 characterised in that the sliding ring seal (56) embraces a shaft sleeve (89) at the shaft side, wherein at least one O-ring (88) is provided between the shaft sleeve (89) and the pump shaft (36, 36a).\",\n \"27.A centrifugal pump as set forth in one of claims 1 through 26 characterised in that a rearward shaft bearing (68) for the pump shaft (36, 36a) is arranged in the casing attachment portion (34) at an axial spacing relative to the sliding ring seal (56) outside the sealing chamber (48).\",\n \"28.A centrifugal pump as set forth in claim 27 characterised in that at least one hollow space (66) is arranged between the sealing chamber (48) and the shaft bearing (68) in the casing attachment portion (34).\",\n \"29.A centrifugal pump as set forth in one of claims 1 through 28 characterised in that the pump shaft (36a) is in the form of a plug-in stub shaft with clamping ring (92).\",\n \"30.A centrifugal pump as set forth in one of claims 8 through 29 characterised in that the spiral casing (14) and the bearing carrier casing (16) are embraced by a spacer (96) which butts against the abutment step or steps or the front ring (22) respectively and it is attached to a motor (100).\"\n ],\n [\n \"The invention concerns a centrifugal pump—in particular a spiral-casing centrifugal pump—for a heat carrier medium, comprising a spiral casing having an impeller, a casing cover and an associated casing attachment portion for a pump shaft provided with a shaft bearing near the spiral casing and a shaft seal disposed at a spacing in relation to the shaft bearing in a sealing chamber.\",\n \"Such centrifugal pumps are described by way of example in a prospectus from the present applicants in relation to the range NHT for heat carrier purposes up to 350° C. A spiral casing for an impeller is connected to a bearing casing by means of a throttle section having external ribs.\",\n \"The impeller is fixed at one end of a pump shaft which extends in the throttle section.\",\n \"Arranged between the throttle section and the impeller is a plain bearing of silicon carbide and arranged downstream of the throttle section is a sliding ring seal which is followed by a rolling bearing.\",\n \"This arrangement involves a horizontal spiral-casing centrifugal pump of a process type of structure which is single-stage in terms of intake flow.\",\n \"The pump-side silicon carbide plain bearing is lubricated by the fluid being delivered, while used at the drive side is a grease-lubricated grooved-type ball bearing.\",\n \"In consideration of that state of the art, the inventor set himself the aim of providing a centrifugal pump of the kind set forth in the opening part of this specification, which is simple to manufacture and which can be inexpensively and particularly well used.\",\n \"That object is attained by the teaching of the independent claim; the appendant claims set forth advantageous developments.\",\n \"In addition the scope of the invention embraces all combinations comprising at least two of the features disclosed in the description, the drawing and/or the claims.\",\n \"In accordance with the invention a bearing cup accommodating the shaft bearing, a tubular portion surrounding the pump shaft as a heat barrier and so-called support ribs or the like profile elements arranged at a spacing relative to each other in the peripheral direction are parts of the casing cover.\",\n \"Those features permit the pump to be of a simple structure with only two pressure-bearing parts for the bearing carrier casing—comprising the casing cover and the casing attachment portion—as well as a particularly high level of stability for the bearing carrier casing.\",\n \"In addition the bearing cup is to be held at an axial spacing towards the impeller by the tubular portion which surrounds the pump shaft.\",\n \"The sealing chamber for the shaft seal is advantageously delimited by the casing attachment portion which is preferably joined to the casing cover or an edge ring which is carried by the support ribs thereof and which surrounds the longitudinal axis of the pump; the edge ring is connected to and preferably integrally formed on the support ribs at their ends remote from the base region of the casing cover.\",\n \"Disposed between the spiral casing and the above-mentioned sealing chamber is a latticework-like or trussing-like rib arrangement comprising those support ribs which are to be inclined towards the longitudinal axis from the spiral casing at a preferred angle of between 40° and 45° and—at a radial spacing relative to each other—surround the bearing cup and the heat barrier and form jointly therewith the casing cover.\",\n \"For that purpose it has proven to be desirable for the cross-sectional height of the support ribs which preferably extend in axial planes which pass radially through the longitudinal axis of the pump to be caused to increase towards the sliding ring seal in order to enhance the level of stability and minimise heat losses.\",\n \"In accordance with a further feature of the invention the sealing chamber is to adjoin the shaft bearing.\",\n \"Inter alia that ensures an adequate supply of lubricating medium to the bearing.\",\n \"In addition the bearing contributes to circulation of the medium in the sealing chamber for flushing and cooling the seal.\",\n \"In order to enlarge the use of the centrifugal pump according to the invention and the combination options thereof, it is possible to arrange on the casing cover at least one abutment stage or step directed away from the spiral casing, for a further part of the pump; that abutment step should preferably be a front ring which is formed on the casing cover.\",\n \"An associated pump part can moreover be a spacer which extends around the bearing carrier casing and which abuts against the abutment step or steps or the front ring and to which a motor is attached.\",\n \"It has proven to be desirable for the abutment step or the front ring to be arranged to project from an annular flange which extends around the support ribs and which is mounted to the transition thereof to a base region of the casing cover.\",\n \"The scope of the invention includes a centrifugal pump with a sealing ring of the shaft seal—in the form of a sliding ring seal—, the sealing ring extending therearound on a counterpart ring provided at the casing side; the counterpart ring is arranged for the sealing ring in a shaped stub portion of the casing attachment portion, the stub portion projecting axially into the sealing chamber.\",\n \"At last one opening or passage which is inclined with respect to the longitudinal axis of the pump and with a closure screw for closing it is to be associated with the stub portion—which is of an axial length approximately corresponding to half the axial length of the sealing chamber—; the longitudinal axis of the passage advantageously delimits an angle of about 45° with the longitudinal axis of the pump.\",\n \"Thus the sliding ring seal is advanced within the sealing chamber in order to make available sufficient space for collecting air or outgassings of the delivery medium—in particular when the arrangement is positioned vertically.\",\n \"The described arrangement of the passage with the closure screw easily permits complete venting of the sealing chamber both when the pump is positioned horizontally and also vertically.\",\n \"The frictional heat of the sliding ring seal is desirably dissipated to the surroundings by virtue of a large surface area of the surrounding sealing chamber and a large volume of fluid in the sealing chamber.\",\n \"In accordance with the invention the shaft bearing is in the form of a plain bearing with a ratio of the length of the bearing bush to the diameter of the pump shaft of between about 1.5 and 2.0, preferably about 1.8.In addition the bearing bush of the plain bearing should be designed to be dismantled.\",\n \"Advantageously the plain bearing, as viewed from the impeller, is disposed behind the heat barrier, which contributes to simplicity of possible fixing and also contributes to the heat barrier being of a desirable design configuration.\",\n \"In order to achieve a low level of heat conduction from the spiral casing to the sealing chamber, a small cross-section and a long length of the tubular portion, which is in the form of the heat barrier, of the casing cover has proven to be desirable.\",\n \"That can be implemented particularly well with the specified bearing arrangement.\",\n \"The positioning of the impeller-side bearing behind the heat barrier means that the delivery medium which serves as a lubricating agent is at a lower temperature at that location than in the pump casing.\",\n \"As a result it is of higher viscosity, which is advantageous for the lubricating capability.\",\n \"In addition the vapor pressure of the medium at that location is markedly lower than in the pump casing, thereby minimising the risk of the bearing running dry.\",\n \"It has proven to be desirable for the plain bearing or the bearing bush thereof, for fixing purposes, to be surrounded approximately at the longitudinal center thereof on the outside by a clamping or tolerance ring which engages into the bearing cup.\",\n \"The width of the clamping or tolerance ring should correspond to a fraction of the length of the bearing bush, for example between a fifth and a sixth of the length of the bearing bush.\",\n \"That provides for easy (dis-)mantling as well as compensation for alignment errors by virtue of tilting mobility.\",\n \"There are a number of design configurations of the plain bearing, in accordance with the invention.\",\n \"In one case the plain bearing includes an inner bearing sleeve which is surrounded by a bearing bush at the bearing cup side.\",\n \"In that case the pump shaft is surrounded within the plain bearing by at least one tolerance ring which engages into the pump shaft.\",\n \"In particular an inward tolerance ring should be provided on each of the two sides of the outer tolerance ring which engages into the bearing cup—as viewed in longitudinal section of the centrifugal pump—, the inward tolerance ring engaging into the pump shaft.\",\n \"The bearing sleeve and the bearing bush are preferably made from silicon carbide.\",\n \"Another design configuration in accordance with the invention involves a plain bearing with a bearing bush at the bearing cup side, the bearing bush including a slidable internal peripheral surface portion which extends around the pump shaft.\",\n \"In that case the dismantleable plain bearing bush is preferably provided with an inner carbon coating.\",\n \"The bush runs on a hardened shaft or a hardened shaft portion.\",\n \"Fixing is effected by a centrally disposed outer tolerance ring, as already mentioned.\",\n \"In accordance with a further feature of the invention the sliding ring seal extends around a shaft sleeve at the shaft side, wherein at least one O-ring is provided between the shaft sleeve and the pump shaft.\",\n \"That arrangement, in a construction which is relieved of load, permits assembly of the sliding ring seal from the impeller side, which is desirable in particular when the shaft is in the form of a plug-in shaft.\",\n \"In accordance with another feature of the invention arranged in the casing attachment portion at an axial spacing relative to the sliding ring seal outside the sealing chamber is a rearward shaft bearing for the pump shaft; at least one hollow space can also be provided in the casing attachment portion between the sealing chamber and the shaft bearing.\",\n \"In a particular configuration the pump shaft is in the form of a plug-in shaft with clamping ring.\",\n \"By virtue of the described different design configurations of the plain bearing, in combination with the three types of structure: pump with main plate and coupling; pump of a block-type structure; and pump of an in-line type of structure there are at least six structural variants for the centrifugal pump according to the invention.\",\n \"Further advantages, features and details of the invention will be apparent from the description hereinafter of preferred embodiments and with reference to the drawing in which: FIGS.\",\n \"1 and 8 each show a perspective view of different embodiments of a centrifugal pump according to the invention for heat carrier media, FIG.\",\n \"2 shows an end view of the FIG.\",\n \"1 structure, FIG.\",\n \"3 shows a partial longitudinal section through FIG.\",\n \"2 along line III-III therein, FIG.\",\n \"4 shows a view in longitudinal section on an enlarged scale through the pump in FIG.\",\n \"2 taken along line IV-IV therein, FIG.\",\n \"5 shows a view on an enlarged scale of a part of the FIG.\",\n \"4 structure, FIG.\",\n \"6 shows a longitudinal section corresponding to FIG.\",\n \"4 through another embodiment of the pump shown in FIG.\",\n \"1, FIG.\",\n \"7 shows a view on an enlarged scale of a portion of the FIG.\",\n \"6 structure, FIG.\",\n \"9 shows an end view of the FIG.\",\n \"8 structure, FIG.\",\n \"10 shows a perspective view of a casing cover of the pump, FIG.\",\n \"11 shows a view on an enlarged scale through the pump of FIGS.\",\n \"8 and 9 taken along line XI-XI in FIG.\",\n \"9, FIG.\",\n \"12 shows a partial longitudinal section on an enlarged scale in relation to FIG.\",\n \"11 taken along line XII-XII in FIG.\",\n \"9, FIGS.\",\n \"13 and 14 show different perspective views of a part of a further embodiment of a centrifugal pump according to the invention, FIG.\",\n \"15 shows an end view of the structure shown in FIGS.\",\n \"13 and 14, FIG.\",\n \"16 shows a partial longitudinal section through the pump of FIGS.\",\n \"13 through 15 taken along line XVI-XVI in FIG.\",\n \"15, and FIG.\",\n \"17 shows a partial section on an enlarged scale in relation to FIG.\",\n \"16 through that pump taken along line XVII-XVII in FIG.\",\n \"15.A spiral-casing centrifugal pump 10, on a volute or spiral casing 14 provided with connecting flanges 12, 12a,—with the interposition of seals (not shown)—has a bearing carrier casing 16 which includes a casing cover 18 with a casing attachment portion 34 fitted thereto.\",\n \"The casing cover 18 is provided with an annular flange 21 which projects from a dish-like base region 20 and through which pass connecting screws 24, on a front ring 22 which is formed on the annular flange 21 and which forms an abutment step; the connecting screws 24 are fitted into sleeve ribs 15 which are formed in axis-parallel relationship externally on a peripheral wall 13 of the spiral casing 14, the peripheral wall engaging over the dish wall 19, and the screws 24 centeringly connect the casing cover 18 to the spiral casing 14.Formed on the casing cover 18 or the base region 20 thereof respectively are support ribs 26 of substantially constant thickness b, which are determined by axial planes E—passing radially through the longitudinal axis A of the pump—and which are inclined at an angle w of about 40° towards the longitudinal axis A of the pump.\",\n \"The cross-sectional height h of the support ribs 26 steadily increases in the longitudinal extent or in the axial direction away from the casing cover 18.The support ribs 26 are cast at the other end to a bearing cup 28 axially associated with the longitudinal axis A of the pump and an edge ring 30 which surrounds the bearing cup.\",\n \"An axial tubular portion 32 which is integral with the casing cover 18 connects the bearing cup 28 thereto, in centered relationship.\",\n \"The bearing cup 28, with its edge ring 30, and the support rings 26—of which there are four here—are also part of the casing cover 18 whose length a, approximately corresponds to a third of the pump length a.\",\n \"Passing through the casing cover 18 and the rearward casing attachment portion 34—that is to say the bearing carrier casing 16—is a pump shaft 36 of a diameter d, while an impeller 40 is held on the front stepped end 37 thereof by a nut 38.The impeller 40 rotates in the spiral casing 14 which includes an intake or suction chamber 42, whose inlet in the region of the axial connecting flange 12 is identified by reference 43 and whose radial outlet in the connecting flange 12a is identified by reference 44.Disposed near the impeller 40 in the casing cover 18 is a stuffing-box packing 46 at the periphery of the cylindrical tubular portion 32.The internal space 29 of the bearing cup 28 is connected to the cylindrical tubular portion 32 which extends around the pump shaft 36 to form a heat barrier.\",\n \"If for example a flow agent of low viscosity at about 350° C. passes through the inlet 43, flow agent of higher viscosity at 130° C. is disposed in the internal space of the bearing cup.\",\n \"The internal space 29 of the bearing cup 28, which adjoins the cylindrical tube portion 32, communicates with a sealing chamber 48 which is arranged in the bearing carrier casing 16 or in the casing attachment portion 34 and which is surrounded by an annular wall 50 and which is provided with at least one closure screw 52 together with a screwthreaded opening or passage 53 which accommodates the screw and which is inclined at an angle z of 45° relative to the longitudinal axis A of the pump, and with blade-like surface elements 55 which are inclined relative to each other and which each have a respective edge 54 parallel to the axis, the axial length e1 thereof approximately corresponding to half the length e of the casing attachment portion 34.An outlet screw 52b towards the bottom is arranged in a radial opening or passage in the region of the chamber which is towards the bottom.\",\n \"In addition FIG.\",\n \"2 shows a lateral closure screw 52a which is required for venting when the pump 10 is used in a vertical position.\",\n \"A rear axial sliding ring seal 56—which is not relieved of load—can be seen in the sealing chamber 48.Projecting from the annular wall 50 are four radial lugs 51 which are connected to corresponding counterpart lugs 51a of the edge ring 30 by screws 24a.\",\n \"In embodiments which are not shown here—in particular of large dimensioning—an annular flange can also be provided, instead of the above-mentioned radial lugs 51.In order to increase the surface area of the outside of the annular wall, axially extending surface portions can be arranged on the outside of the annular wall.\",\n \"The sliding ring seal 56 includes a coil spring 58—which is supported against a ring step or a ring 38 which is pushed on to the pump shaft 36—and which loads a rotating sliding ring 59 which with a stationary counterpart ring 60 forms a sealing gap.\",\n \"The counterpart ring 60 is disposed in the tubular space 62 of an axial shaped stub portion 64 of an axial length f which here corresponds approximately to half the sealing chamber length e1.Arranged subsequently to the annular end part 65 of the stub portion 64 in the casing attachment portion 34 is a dish-like hollow space 66.Between the latter and the adjacent stepped shaft end 37e the pump shaft 36 is surrounded by a grooved-type ball bearing 68 with spacer disks 69 and a securing ring 70; that unit is covered by a bearing cover 72 of the casing attachment portion 34.Projecting radially beneath the latter is a plate-like support leg 74 which is fixed by screws 24b, comprising an angle plate member, in opposite relationship to which, in the region of the spiral casing 14, are two supports 74a which project in parallel in eccentric relationship.\",\n \"The supports 74a and the support leg 74 are connected at the other end to a base plate (not shown).\",\n \"Arranged in the internal space 29 in the bearing cup 28 in FIGS.\",\n \"3 through 5 is a front hydrodynamic plain bearing 76 comprising a bearing bush 77 of a length g with an internal peripheral surface portion 78 of carbon material; the plain bearing 78, at its longitudinal center, is surrounded by a clamping or tolerance ring 80 of a width n, the ring 80 being provided in the bearing cup 28—that is to say at the housing side—; the ring 80 is of an elastic nature and force-lockingly connects the plain bearing 76 to the bearing cup.\",\n \"The plain bearing 76a of the pump 10a as shown in FIGS.\",\n \"6 and 7 has within the bearing bush 77 a coaxial bearing sleeve 82 and—besides the above-described outer tolerance ring 80 at the longitudinal center—two inner tolerance rings 80i of a width i which are disposed at the shaft side and which—viewed in longitudinal section—flank the outer tolerance ring 80 at the pump shaft 36 at a radial spacing on both sides.\",\n \"The width n of the outer tolerance ring 80 and the width i of the inner tolerance rings 80i are relatively short in relation to the length g of the bearing bush, for example the latter corresponds approximately to between five and six times the width i and n respectively.\",\n \"Reference 84 in FIGS.\",\n \"6 and 7 shows a nut which is disposed between the front plain bearing 76a and the rear sliding ring seal 56—which is here relieved of load—for the purposes of fixing the bearing sleeve 82.The sliding ring components for carrying the radial forces which occur preferably comprise silicon carbide in the illustrated embodiment.\",\n \"The two above-discussed bearing types 76, 76a can also be used in the centrifugal pump 11 shown in FIGS.\",\n \"8 through 12 in which the pump shaft 35 is in the form of a plug-in or stub shaft and is provided with an O-ring 88 within a shaft sleeve 86 of the sliding ring seal 56a, the shaft sleeve 86 surrounding the pump shaft.\",\n \"The O-ring 88 is disposed between the pump shaft 35 and a shaft sleeve 89 embracing it.\",\n \"At the rearward end of the bearing carrier casing 16 the pump shaft 35 includes a clamping ring 92 which carries a fan wheel 90 and which is surrounded towards the front by a protective grid 93 as protection to prevent articles from being poked in.\",\n \"The rearward shaft bearing—which is disposed in the motor—cannot be seen in the drawing.\",\n \"The impeller 90 is surrounded by a wall ring 94—with apertured plate members 95—of a spacer 96 with endward flange rings 97, 97a; they are connected by longitudinal ribs 98 which are parallel to the axis.\",\n \"The flange ring 97 which is at the right in the drawing is screwed to a parallel flange ring 99 of a motor 100, the flange ring 99 bearing against the spiral casing 14; the motor 100 is fixed by means of the spacer 96 to the pump 11.In the configuration of a centrifugal pump 11a with a vertical shaft 35 as shown in FIG.\",\n \"13 ff, the inlet 43 and the outlet 44 of the spiral casing 14 are on a straight diametral line Q.\",\n \"This pump 11a can also be provided with both of the described bearing forms 76, 76a.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10276581"}}},{"rowIdx":86,"cells":{"text":{"kind":"list like","value":[["Allocating access across shared communication medium","A method of providing network access across a shared communications medium between competing users (86) includes the step of allocating network access for each user for a future time interval (102).","Features include forecasting network access (1100) of the users in a future time interval, and prioritizing the users for allocating network access to the users.","The network access allocations represent network access allowances available to the users during the future time interval, and further may represent network access usage.","Classes of users can be allocated network access first (1114), and then each user allocated network access from the class allocation."],["1.A method of providing network access across a shared communications medium between at least two competing users, comprising the steps of: (a) prior to a first time interval, determining for each user a respective first network access allowance representing a respective first maximum level of network access available to the user during the first time interval, but not necessarily representing the level of network access that will be utilized by the user during the first time interval; (b) during the first time interval, providing network access to each user such that the respective first network access allowance for each user is not exceeded; (c) prior to a second consecutive time interval, determining for each user a respective second network access allowance representing a respective second maximum level of network access available to the user during the second time interval, but not necessarily representing the level of network access that will be utilized by the user during the second time interval, at least one respective second network access allowance for a user differing from such user's respective first network access allowance; and (d) during the second time interval, providing network access to each user such that the respective second network access allowance for each user is not exceeded.","2.The method of claim 1, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.","3.The method of claim 1, wherein the first and second time intervals are consecutive time intervals.","4.The method of claim 1, wherein each of the first time interval and the second time interval has a period of between one minute and sixty minutes.","5.The method of claim 1, wherein the second network access allowance for each respective user differs from the first network access allowance for such user.","6.The method of claim 1, wherein the first network access allowances for the users are determined by allocating network access to each user on a per user basis for the first time interval in accordance with a first selected allocation policy.","7.The method of claim 6, wherein the second network access allowances for the users are determined by allocating network access to each user on a per user basis for the second time interval in accordance with a second selected allocation policy.","8.The method of claim 7, wherein the first allocation policy differs from the second allocation policy.","9.The method of claim 7, further comprising requesting a minimum level of network access for the first time interval for a user, and wherein said allocating network access to such user for the first time interval comprises setting the level of network access allocated to such user to a level equal to or greater than the requested minimum level.","10.The method of claim 9, wherein said allocating network access to such user for the second time interval comprises setting the level of network access allocated to such user to a level less than the requested minimum level for the first time interval.","11.The method of claim 1, further comprising the step of monitoring network access usage by each user.","12.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of logical data units transmitted from and to each user during a past time interval.","13.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a past time interval.","14.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a past time interval.","15.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a past time interval.","16.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during a time interval.","17.The method of claim 1, wherein the shared communications medium is part of a Cable Network and the shared communications medium comprises a coaxial cable.","18.The method of claim 1, wherein the Shared Access Carrier Network comprises a wireless network.","19.The method of claim 1, further comprising prioritizing the users for determining network access allowances.","20.The method of claim 19, wherein said prioritizing is based on fairness considerations.","21.The method of claim 20, wherein the users are prioritized based on user throughput during a past time interval, with a user with lesser throughput receiving priority over a user with greater throughput.","22.The method of claim 20, wherein the users are prioritized based on data loss for each user during a past time interval, with a user with greater data loss having priority over a user with lesser data loss.","23.The method of claim 20, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.","24.The method of claim 20, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.","25.The method of claim 20, wherein users are prioritized based on an established minimum quality of service (QoS) standard.","26.The method of claim 19, wherein said step of prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.","27.The method of claim 26, further comprising the step of monitoring network access usage by each user.","28.The method of claim 27, wherein SLAs specify respective minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.","29.The method of claim 27, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when said monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.","30.The method of claim 27, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and said step of prioritizing includes comparing said monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.","31.The method of claim 27, wherein SLAs provide respective fees for network access usage, and said step of prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.","32.The method of claim 27, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and said step of prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.","33.The method of claim 27, wherein SLAs specify respective minimum levels of network access for users, and said step of allocating network access comprises setting the respective levels of network access equal to each user's specified respective minimum level of network access.","34.The method of claim 11, further comprising the step of forecasting network access usage by each user during a future time interval based on said step of monitoring network access usage by each user.","35.The method of claim 34, wherein said step of forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.","36.The method of claim 34, wherein said step of forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of the users.","37.The method of claim 34, wherein the first network access allowances for the users are determined by allocating network access to each user on a per user basis for the first time interval in accordance with a first selected allocation policy.","38.The method of claim 37, wherein said step of allocating network access comprises setting the respective levels of network access of the users proportional to each user's forecasted network access usage.","39.The method of claim 37, further comprising the step of prioritizing the users for allocating network access.","40.The method of claim 39, wherein said prioritizing is based on each user's forecasted network access usage.","41.The method of claim 40, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.","42.The method of claim 40, wherein said step of allocating network access comprises setting respective user levels of network access equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.","43.The method of claim 40, wherein said step of allocating network access comprises setting respective user levels of network access equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.","44.A method of providing during two consecutive time intervals network access across a shared communications medium between two competing users, comprising the step of varying between the two time intervals a respective network access allowance for each user, each respective network access allowance representing a maximum level of network access available to the respective user during a particular time interval, but not necessarily representing the level of network access that is utilized by the user during the particular time interval.","45.A method of providing network access across a shared communications medium in a downstream direction towards competing users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; and (b) based on said monitored network access usage, allocating network access to each user on a per user basis for a future time interval.","46.The method of claim 45, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.","47.The method of claim 45, wherein each network access allocation represents a bandwidth allowance of a respective user during the future time interval.","48.The method of claim 47, wherein each network access allocation represents bandwidth utilized by each user during the future time interval.","49.The method of claim 45, wherein said step of monitoring comprises monitoring bandwidth that is consumed by each user in a downstream direction at time intervals of fifteen minutes to sixty minutes.","50.The method of claim 45, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.","51.The method of claim 45, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.","52.The method of claim 45, wherein said step of monitoring network access usage includes collecting data representative of logical data units transmitted to each user during a time interval.","53.The method of claim 45, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted to each user during a time interval.","54.The method of claim 45, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.","55.The method of claim 45, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.","56.The method of claim 45, wherein said step of allocating network access comprises allocating network access equally to the users.","57.The method of claim 45, wherein the shared communications medium is part of a Shared Access Carrier Network.","58.The method of claim 57, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.","59.The method of claim 57, wherein the Shared Access Carrier Network comprises a wireless network.","60.The method of claim 45, further comprising prioritizing the users for allocating network access.","61.The method of claim 60, wherein said prioritizing is based on fairness considerations.","62.The method of claim 61, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput receiving priority over a user with greater throughput.","63.The method of claim 61, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss having priority over a user with lesser data loss.","64.The method of claim 61, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.","65.The method of claim 61, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.","66.The method of claim 61, wherein users are prioritized based on an established minimum quality of service (QoS) standard.","67.The method of claim 60, wherein said step of prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.","68.The method of claim 67, wherein SLAs specify respective minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.","69.The method of claim 67, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when said monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.","70.The method of claim 67, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and said step of prioritizing includes comparing said monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.","71.The method of claim 67, wherein SLAs provide respective fees for network access usage, and said step of prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.","72.The method of claim 67, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and said step of prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.","73.The method of claim 67, wherein SLAs specify respective minimum levels of network access for users, and said step of allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.","74.The method of claim 45, further comprising the step of forecasting network access usage by each user during the future time interval based on said step of monitoring network access usage by each user.","75.The method of claim 74, wherein said step of forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.","76.The method of claim 74, wherein said step of forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of the users.","77.The method of claim 74, wherein said step of allocating network access comprises allocating network access to users proportional to each user's forecasted network access usage.","78.The method of claim 74, further comprising the step of prioritizing the users for allocating network access.","79.The method of claim 78, wherein said prioritizing is based on each user's forecasted network access usage.","80.The method of claim 78, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.","81.The method of claim 78, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.","82.The method of claim 78, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.","83.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; (b) forecasting network access usage by each user during a future time interval based on said monitored network access usage by each user; and (c) based on said forecasted network access usage, allocating network access to each user for the future time interval.","84.The method of claim 83, wherein said step of forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.","85.The method of claim 83, wherein said step of forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of the users.","86.The method of claim 83, wherein said step of allocating network access comprises allocating network access to the users proportionally based on each user's forecasted network access usage.","87.The method of claim 83, further comprising the step of prioritizing the users for allocating network access.","88.The method of claim 87, wherein said prioritizing is based on each user's forecasted network access usage.","89.The method of claim 87, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.","90.The method of claim 87, wherein said prioritizing is based on fairness considerations.","91.The method of claim 87, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput rate receiving priority over a user with greater throughput rate.","92.The method of claim 87, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss rate having priority over a user with lesser data loss rate.","93.The method of claim 87, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.","94.The method of claim 87, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.","95.The method of claim 87, wherein users are prioritized based on an established minimum quality of service (QoS) standard.","96.The method of claim 87, wherein said step of prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.","97.The method of claim 96, wherein SLAs specify respective minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.","98.The method of claim 96, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when said monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.","99.The method of claim 96, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and said step of prioritizing includes comparing said monitored network access usages both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access would have been utilized for such users.","100.The method of claim 96, wherein SLAs provide a respective fee for network access usage by users, and said step of prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.","101.The method of claim 96, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and said step of prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.","102.The method of claim 96, wherein SLAs specify respective minimum levels of network access for users, and said step of allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.","103.The method of claim 87, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.","104.The method of claim 87, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.","105.The method of claim 83, wherein each network access allocation represents a bandwidth allowance of a respective user during the future time interval.","106.The method of claim 83, wherein each network access allocation represents bandwidth utilized by each user during the future time interval.","107.A method of providing network access across a shared communications medium of a Cable Network between competing users, comprising the steps of: (a) monitoring network access usage by each user for a time interval; (b) based on said monitoring, forecasting the number of logical data units (LDUs) of each user that will be transmitted over a future time interval; and (c) based on said forecasting, allocating network access available to each user for the future time interval.","108.A method of providing network access across a shared communications medium of a Cable Network between competing users, comprising the steps of: (a) monitoring network access usage requested by each user for a time interval; (b) based on said monitoring, forecasting the number of logical data units (LDUs) that will be requested by each user over a future time interval; and (c) based on said forecasting, allocating network access available to each user for the future time interval.","109.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on said monitoring, forecasting network access usage by each user over a future time interval; (c) prioritizing users based on each user's forecasted network access usage in increasing order, whereby a user with a lesser forecasted network access usage receives a higher priority than a user with a greater forecasted network access usage; and (d) allocating network access available to each user during the future time interval in decreasing order of user priority, each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.","110.The method of claim 109, wherein said step of allocating further comprises allocating any surplus network access remaining equally to the users.","111.The method of claim 109, wherein said step of allocating further comprises allocating in decreasing user priority any surplus network access to the users proportionally to the user's forecasted network access usage.","112.The method of claim 109, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.","113.The method of claim 109, wherein said step of monitoring comprises monitoring network access usage by the users in an upstream direction at time intervals of one minute to fifteen minutes.","114.The method of claim 109, wherein said step of monitoring comprises monitoring network access usage by the users in a downstream direction at time intervals of fifteen minutes to sixty minutes.","115.The method of claim 109, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.","116.The method of claim 109, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.","117.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.","118.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.","119.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.","120.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.","121.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.","122.The method of claim 109, wherein the shared communications medium is part of a Shared Access Carrier Network.","123.The method of claim 122, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.","124.The method of claim 122, wherein the Shared Access Carrier Network comprises a wireless network.","125.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on said monitoring, forecasting network access usage by each user over a future time interval; and (c) allocating network access available to each user during the future time interval, each user's allocation of network access being equal to each user's forecasted network access usage multiplied by a ratio of the total available network access to the total forecasted network access usage of all the users, and subject to a respective, predetermined maximum value and subject to availability.","126.The method of claim 125, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.","127.The method of claim 125, wherein said step of monitoring comprises monitoring network access usage by the users in an upstream direction at time intervals of one minute to fifteen minutes.","128.The method of claim 125, wherein said step of monitoring comprises monitoring network access usage by the users in a downstream direction at time intervals of fifteen minutes to sixty minutes.","129.The method of claim 125, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.","130.The method of claim 125, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.","131.The method of claim 125, wherein said step of monitoring network access includes collecting data representative of the logical data units transmitted from and to each user during a time interval.","132.The method of claim 125, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.","133.The method of claim 125, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.","134.The method of claim 125, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.","135.The method of claim 125, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.","136.The method of claim 125, wherein the shared communications medium is part of a Shared Access Carrier Network.","137.The method of claim 126, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.","138.The method of claim 126, wherein the Shared Access Carrier Network comprises a wireless network.","139.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) charging each user a respective fee for network access usage; (b) monitoring network access usage by each user during a time interval; (c) based on said monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.","140.The method of claim 139, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.","141.The method of claim 139, wherein said step of monitoring comprises monitoring network access usage by the users in an upstream direction at time intervals of one minute to fifteen minutes.","142.The method of claim 139, wherein said step of monitoring comprises monitoring network access usage by the users in a downstream direction at time intervals of fifteen minutes to sixty minutes.","143.The method of claim 139, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.","144.The method of claim 139, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.","145.The method of claim 139, wherein said step of monitoring network access includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.","146.The method of claim 139, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.","147.The method of claim 139, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.","148.The method of claim 139, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.","149.The method of claim 139, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.","150.The method of claim 139, wherein the shared communications medium is part of a Shared Access Carrier Network.","151.The method of claim 150, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.","152.The method of claim 150, wherein the Shared Access Carrier Network comprises a wireless network.","153.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) applying respective credits to users for network access shortfalls below respective levels of network access specified to the users; (b) monitoring network access usage by each user during a past time interval; (c) based on said monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's respective credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum specified value and subject to availability.","154.The method of claim 153, wherein any additional network access remaining after said allocation is earmarked for the users such that each user's allocation equals the user's forecasted network access usage, subject to a respective, predetermined maximum allowed level of network access and subject to availability.","155.The method of claim 154, wherein any surplus network access remaining after said distribution is further earmarked in equal amounts for the users, subject to a respective, predetermined maximum allowed level of network access.","156.The method of claim 154, further comprising allocating to the users network access only in an amount equal to the forecasted network access usage multiplied by the ratio of total network access available for allocation to the total forecasted network access usage of the users, but only when the total forecasted network access usage of the users exceeds the total network access available for allocation.","157.The method of claim 153, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.","158.The method of claim 153, wherein said step of monitoring comprises monitoring network access usage by the users in an upstream direction at time intervals of one minute to fifteen minutes.","159.The method of claim 153, wherein said step of monitoring comprises monitoring network access by the users in a downstream direction at time intervals of fifteen minutes to sixty minutes.","160.The method of claim 153, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.","161.The method of claim 153, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.","162.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.","163.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.","164.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of each user that are dropped during a time interval.","165.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of each user that are dropped during a time interval.","166.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of each user that are requested to be transmitted in the upstream direction during a time interval.","167.The method of claim 153, wherein the shared communications medium is part of a Shared Access Carrier Network.","168.The method of claim 167, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.","169.The method of claim 167, wherein the Shared Access Carrier Network comprises a wireless network.","170.A method of providing network access across a shared communications medium between competing users pursuant to service level agreements (SLAs) of the users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; (b) comparing said monitored network access usage by each user with a predetermined threshold value; and (c) soliciting a user to modify the user's SLA if the user's monitored network access usage varies from the predetermined value by a predetermined tolerance.","171.The method of claim 170, wherein the threshold value represents a respective maximum level of network access for each user.","172.The method of claim 170, wherein the threshold value represents a respective maximum burstable level of network access with target probability for each user.","173.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via email.","174.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via instant messaging.","175.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via redirection of a web browser of the user to a solicitation web page.","176.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via generation and mailing of literature.","177.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via a telephonic communication.","178.The method of claim 170, wherein the modification of the user's SLA includes guaranteeing a level of network access to the user on a permanent basis.","179.The method of claim 170, wherein the modification of the user's SLA includes guaranteeing a level of network access to the user with a maximum burstable level of network access with target probability.","180.The method of claim 170, further comprising charging the user a fee for the modification of the SLA.","181.The method of claim 170, wherein the modification of the user's SLA includes guaranteeing a level of network access to the user on a temporary basis.","182.The method of claim 170, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.","183.The method of claim 170, wherein said step of monitoring comprises monitoring the bandwidth that is consumed by each user in an upstream direction of communication across the shared communications medium at time intervals of one minute to fifteen minutes.","184.The method of claim 170, wherein said step of monitoring comprises monitoring the bandwidth that is consumed by each user in a downstream direction of communication across the shared communications medium at time intervals of fifteen minutes to sixty minutes.","185.The method of claim 170, wherein said step of monitoring network access includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.","186.The method of claim 170, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.","187.The method of claim 170, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.","188.The method of claim 170, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.","189.The method of claim 170, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.","190.The method of claim 170, wherein the shared communications medium is part of a Shared Access Carrier Network.","191.The method of claim 190, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.","192.The method of claim 190, wherein the Shared Access Carrier Network comprises a wireless network.","193.The method of claim 170, further comprising, based on said monitored network access usage, allocating network access to each user for a future time interval.","194.The method of claim 193, wherein said step of allocating network access comprises allocating network access equally to the users.","195.The method of claim 193, further comprising prioritizing the users for allocating network access.","196.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs specify respective minimum levels of network access for the users, and said step of prioritizing includes comparing said monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.","197.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when said monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.","198.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and said step of prioritizing includes comparing said monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.","199.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs provide a respective fee for network access usage by users, and said step of prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.","200.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and said step of prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.","201.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs specify respective minimum levels of network access for users, and said step of allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.","202.The method of claim 195, wherein said prioritizing is based on fairness considerations.","203.The method of claim 202, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput rate receiving priority over a user with greater throughput rate.","204.The method of claim 202, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss rate having priority over a user with lesser data loss rate.","205.The method of claim 202, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.","206.The method of claim 202, wherein the users are prioritized based on both user throughput and data loss during a time interval.","207.The method of claim 202, wherein users are prioritized based on an established minimum quality of service (QoS) standard.","208.The method of claim 193, further comprising the step of forecasting network access usage by each user during the future time interval based on said step of monitoring network access usage by each user.","209.The method of claim 208, wherein said step of forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.","210.The method of claim 208, wherein said step of forecasting comprises applying an adaptive-response-rate signal exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of the users.","211.The method of claim 208, wherein said step of allocating comprises allocating network access to the users proportionally based on each user's forecasted network access usage.","212.The method of claim 208, further comprising the step of prioritizing the users for allocating network access.","213.The method of claim 212, wherein said prioritizing is based on each user's forecasted network access usage.","214.The method of claim 212, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.","215.The method of claim 212, wherein said step of allocating comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.","216.The method of claim 212, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.","217.A method of providing network access across a shared communications medium between competing users pursuant to service level agreements (SLAs) of the users, comprising the steps of: (a) monitoring network access usage by each user for respective predetermined past time intervals; (b) identifying a recurrent period of high network access usage of a user based on said monitoring; and (c) soliciting a user to modify the user's SLA to guarantee a minimum level of network access during an anticipated future recurrent period of high network access usage.","218.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via email.","219.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via instant messaging.","220.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via redirection of a web browser of the user to a solicitation web page.","221.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via generation and mailing of literature.","222.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via a telephonic communication.","223.The method of claim 217, wherein the modification of the user's SLA includes guaranteeing a minimum level of network access to the user for all future recurrent periods of high network access usage.","224.The method of claim 217, wherein the modification of the user's SLA includes guaranteeing a minimum level of network access to the user for a predetermined number of future recurrent periods of high network access usage.","225.The method of claim 217, wherein the modification of the user's SLA includes guaranteeing a minimum level of network access to the user with a maximum burstable level of network access with target probability for the future period of high network access usage.","226.The method of claim 217, wherein the recurrent time period of high network access usage comprises a particular time of day.","227.The method of claim 217, further comprising charging the user a fee for modification of the user's SLA.","228.A method of providing network access across a DOCSIS 1.0 compliant cable network of a data-over-cable (DOC) network to at least two users competing for bandwidth, comprising the steps of: (a) determining for each user a respective first bandwidth allowance for a first future time interval; (b) generating a first set of cable modem configuration files, each of which limits bandwidth consumption by a cable modem (CM) of a respective user to that user's first bandwidth allowance; (c) sending the configuration files to a Trivial File Transfer Protocol (TFTP) Server of the DOC Network; (d) sending a command either to each user's CM or to a cable modem termination system (CMTS) to which each user's CM is connected to cause each CM to acquire its new respective configuration file of the first set for the first time interval; (e) determining for each user a respective second bandwidth allowance for a second future time interval, a second bandwidth allowance of at least one of the users differing from that user's first bandwidth allowance; and (f) for each user having a second bandwidth allowance different from that user's first bandwidth allowance, (i) generating a second cable modem configuration file which limits bandwidth consumption of that user's CM to a value representative of that user's second bandwidth allowance; (ii) sending the second configuration file for that user to the TFTP Server of the DOC Network; and (iii) sending a command either to that user's CM or to the CMTS to which that user's CM is connected to cause the CM to acquire the second configuration file for that user for the second time interval.","229.The method of claim 228, further comprising the steps of monitoring bandwidth of each user for a time interval and, based on said monitored bandwidth, determining each user's second bandwidth allowance.","230.The method of claim 229, wherein said step of determining each user's second bandwidth allowance includes prioritizing each user and allocating bandwidth to each user according to such priority.","231.The method of claim 230, wherein said step of prioritizing includes comparing said monitored bandwidth with respective values specified by service level agreements (SLAs) of the users.","232.The method of claim 230, wherein said step of prioritizing includes comparing said monitored bandwidth of each user with an established minimum quality of service value.","233.The method of claim 229, wherein said step of determining each user's second bandwidth allowance includes forecasting each user's bandwidth for the second future time interval.","234.The method of claim 233, wherein said step of determining each user's bandwidth allowance includes prioritizing the users for allocation of bandwidth based on said forecasting.","235.The method of claim 229, wherein said step of monitoring comprises monitoring the bandwidth that is consumed by each CM in the upstream direction during time intervals of one minute to fifteen minutes.","236.The method of claim 229, wherein said step of monitoring comprises monitoring the bandwidth that is requested by each CM in the upstream direction during time intervals of one minute to fifteen minutes.","237.The method of claim 229, wherein said step of monitoring comprises monitoring the bandwidth that is consumed by each CM in the downstream direction during time intervals of fifteen minutes to sixty minutes.","238.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.","239.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.","240.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.","241.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.","242.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.","243.The method of claim 228, wherein the first time interval and the second time interval are consecutive time intervals.","244.The method of claim 228, wherein each of the first time interval and the second time interval has a period of one to sixty minutes.","245.The method of claim 228, wherein for each user, the first bandwidth allowance of that user differs from the second bandwidth allowance of that user.","246.The method of claim 228, wherein the first bandwidth allowance for each user differs from the first bandwidth allowance of all other users.","247.The method of claim 228, wherein the second bandwidth allowance for each user differs from the second bandwidth allowance of all other users.","248.The method of claim 228, wherein the first bandwidth allowance of each user is determined by allocating bandwidth to each user on a per user basis for the first time interval in accordance with a first selected allocation policy.","249.The method of claim 248, wherein the second bandwidth allowance of each user is determined by allocating bandwidth to each user on a per user basis for the second time interval in accordance with a second selected allocation policy.","250.The method of claim 249, wherein the first and second allocation policies differ.","251.The method of claim 249, wherein the first and second allocation policies are the same.","252.A method of continuously providing network access across a cable network of a data-over-cable (DOC) network to at least two users competing for bandwidth, comprising the steps of: (a) determining for each user during present time intervals bandwidth allowances of such user for respective future time intervals, each bandwidth allowance of such user for a future time interval representing a maximum level of bandwidth consumption for such user during the future time interval, but not necessarily representing the amount of bandwidth that will be consumed by such user during such future time interval, the bandwidth allowances of each user varying as between time intervals; and (b) for each user, limiting during each respective future time interval bandwidth consumption of that user's cable modem (CM) to that user's respective bandwidth allowance for such time interval by implementing a new cable modem configuration file in the CM.","253.The method of claim 252, wherein the present and future time intervals have a uniform period of one minute to sixty minutes.","254.The method of claim 252, wherein each user's bandwidth allowance for each future time interval is determined by allocating bandwidth to the users on a per user basis for such future time interval in accordance with a selected allocation.","255.A Carrier Network for providing communication between multiple users and a Service Provider, comprising: (a) computer network equipment defining an Intermediate Network and a shared communications medium, said Intermediate Network and said shared communications medium extending between the users and the Service Provider for conveying data therebetween, said shared communications medium joining the users with said Intermediate Network such that data of each user is conveyed over said shared communications medium to and from the Intermediate Network whereby the users compete for network access; and (b) software for managing network access of the users across said shared communications medium, said software including computer-executable instructions that performs the steps of: (i) monitoring the network access usage by each user for a time interval; and (ii) based on the monitored network access usage, setting a network access allowance for each user representing a level of network access made available for utilization by the user during a future time interval, but not necessarily representing the level of network access that will be utilized by such user during the future time interval.","256.The Carrier Network of claim 255, wherein said network equipment futher defines a Cable Network and said shared communications medium comprises a coaxial cable of said Cable Network.","257.The Carrier Network of claim 256, wherein said software comprises software modules distributed within computer readable media of said network equipment.","258.The Carrier Network of claim 256, wherein said software comprises software modules stored in a computer readable medium of a hardware component.","259.The Carrier Network of claim 258, wherein said hardware component is physically located with said network equipment.","260.The Carrier Network of claim 259, wherein said Carrier Network comprises a Data-Over-Cable (DOC) Network and said hardware component is located within a regional data center of said DOC Network.","261.The Carrier Network of claim 259, wherein said Carrier Network comprises a Data-Over-Cable (DOC) Network and said hardware component is located within a headend of said DOC Network.","262.The Carrier Network of claim 258, wherein said hardware component is physically located remotely from said network equipment.","263.The Carrier Network of claim 262, wherein said hardware component is directly connected with said network equipment for communication therebetween.","264.The Carrier Network of claim 262, wherein said hardware component is indirectly connected with said network equipment through the Internet for communication therebetween.","265.The Carrier Network of claim 256, wherein said software modules include: (i) a first software component that manages a database for storage and retrieval of data; (ii) a second software component that collects data representative of network access usage from said network equipment, and that sends data representative of network access usage to said first component for storage thereof; and (iii) a third component that retrieves data representative of network access usage stored in said first component and sets, based at least partially thereon, network access allowances for the users for the future time interval.","266.The Carrier Network of claim 265, further includes a fourth component having a graphical user interface for sending data to said first component for storage and for retrieval of data stored by said first component.","267.The Carrier Network of claim 255, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.","268.The Carrier Network of claim 267, wherein the step of monitoring comprises monitoring bandwidth that is consumed by each user in an upstream direction across said shared communications medium in time intervals of one minute to fifteen minutes.","269.The Carrier Network of claim 267, wherein the step of monitoring comprises monitoring bandwidth that is consumed by each user in the downstream direction across said shared communications medium in time intervals of fifteen minutes to sixty minutes.","270.The Carrier Network of claim 255, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.","271.The Carrier Network of claim 255, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.","272.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.","273.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.","274.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.","275.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.","276.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction across said shared communications medium during a time interval.","277.The Carrier Network of claim 255, wherein said step of setting a network access allowance for each user comprises allocating network access equally to the users and setting the network access allowance for each user equal to that user's allocated network access.","278.The Carrier Network of claim 277, wherein said software further includes computer-executable instructions that perform the additional step of prioritizing the users for allocating network access.","279.The Carrier Network of claim 278, wherein the prioritizing is based on fairness considerations.","280.The Carrier Network of claim 279, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput rate receiving priority over a user with greater throughput rate.","281.The Carrier Network of claim 279, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss rate having priority over a user with lesser data loss rate.","282.The Carrier Network of claim 279, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.","283.The Carrier Network of claim 279, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.","284.The Carrier Network of claim 279, wherein users are prioritized based on an established minimum quality of service (QoS) standard.","285.The Carrier Network of claim 278, wherein prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.","286.The Carrier Network of claim 285, wherein SLAs specify respective minimum levels of network access for users, and prioritizing includes comparing each user's monitored network access usage with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.","287.The Carrier Network of claim 285, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and prioritizing includes comparing the monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when the monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.","288.The Carrier Network of claim 285, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and prioritizing includes comparing the monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.","289.The Carrier Network of claim 285, wherein SLAs provide respective fees for network access usage, and prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.","290.The Carrier Network of claim 285, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.","291.The Carrier Network of claim 285, wherein SLAs specify respective minimum levels of network access for users, and allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.","292.The Carrier Network of claim 285, wherein said software further includes computer-executable instructions that perform the step of forecasting network access usage by each user during the future time interval based on the monitoring of network access usage by each user.","293.The Carrier Network of claim 292, wherein forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.","294.The Carrier Network of claim 292, wherein forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to the monitored network access usages of the users.","295.The Carrier Network of claim 292, wherein said step of setting a network access allowance for each user comprises allocating network access to users proportional to each user's forecasted network access usage.","296.The Carrier Network of claim 292, wherein said step of setting a network access allowance for each user comprises allocating network access, and wherein said software further includes computer-executable instructions that perform the step of prioritizing the users for allocating network access.","297.The Carrier Network of claim 296, wherein prioritizing is based on each user's forecasted network access usage.","298.The Carrier Network of claim 296, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.","299.The Carrier Network of claim 292, wherein said step of setting a network access allowance for each user comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.","300.The Carrier Network of claim 292, wherein said step of setting a network access allowance for each user comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.","301.A computer-readable medium having computer-executable instructions that manage network access across a shared communications medium between competing users of a Carrier Network, said instructions performing the steps of: (a) monitoring the network access usage by each user for a time interval; and (b) setting a network access allowance for each user representing a level of network access made available for utilization by the user during a future time interval, but not necessarily representing the level of network access that will be utilized by such user during the future time interval.","302.The computer-readable medium of claim 301, wherein said step of setting a network access allowance for each user comprises allocating network access, and wherein said software further includes computer-executable instructions performing the step of prioritizing the users for allocating network access.","303.The computer-readable medium of claim 302, wherein the prioritizing is based on fairness considerations.","304.The computer-readable medium of claim 302, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput rate receiving priority over a user with greater throughput rate.","305.The computer-readable medium of claim 302, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss rate having priority over a user with lesser data loss rate.","306.The computer-readable medium of claim 302, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.","307.The computer-readable medium of claim 302, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.","308.The computer-readable medium of claim 302, wherein users are prioritized based on an established minimum quality of service (QoS) standard.","309.The computer-readable medium of claim 302, wherein prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.","310.The computer-readable medium of claim 309, wherein SLAs specify respective minimum levels of network access for users, and prioritizing includes comparing the monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when the respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.","311.The computer-readable medium of claim 309, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and prioritizing includes comparing the monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when the monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.","312.The computer-readable medium of claim 309, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and prioritizing includes comparing the monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.","313.The computer-readable medium of claim 309, wherein SLAs provide a respective fee for network access usage, and prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.","314.The computer-readable medium of claim 309, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.","315.The computer-readable medium of claim 309, wherein SLAs specify respective minimum levels of network access for users, and allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.","316.The computer-readable medium of claim 309, further comprising computer-executable instructions performing the step of forecasting network access usage by each user during the future time interval based the monitoring of network access usage by each user.","317.The computer-readable medium of claim 316, wherein forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.","318.The computer-readable medium of claim 316, wherein forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to the monitored network access usages of the users.","319.The computer-readable medium of claim 316, wherein allocating network access comprises allocating network access to users proportional to each user's forecasted network access usage.","320.The computer-readable medium of claim 316, further comprising computer-executable instructions performing the step of prioritizing the users for allocating network access.","321.The computer-readable medium of claim 320, wherein prioritizing is based on each user's forecasted network access usage.","322.The computer-readable medium of claim 320, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.","323.The computer-readable medium of claim 316, wherein allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.","324.The computer-readable medium of claim 316, wherein allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.","325.A computerized method of allocating among a plurality of users bandwidth for conveying information across a shared communications medium, comprising the steps of: (a) receiving data representative of past bandwidth of each user during a time interval; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users; and (d) allocating bandwidth to each user sequentially in decreasing order of user priority.","326.The computerized method of claim 325, wherein the bandwidth that is monitored is the bandwidth requested for each user.","327.The computerized method of claim 325, wherein the bandwidth that is monitored is the bandwidth consumption of each user.","328.The computerized method of claim 327, wherein the bandwidth that is forecasted is the bandwidth consumption of each user.","329.The computerized method of claim 328, wherein users are prioritized based on each user's forecasted future bandwidth consumption in increasing order, whereby a user with a lesser forecasted bandwidth consumption receives a higher priority than a user with a greater forecasted bandwidth consumption.","330.The computerized method of claim 328, wherein each user's allocation of bandwidth for the future time interval is set to equal each user's forecasted bandwidth consumption subject to a respective, predetermined maximum value and subject to bandwidth availability 331.The computerized method of claim 330, further comprising distributing equally to the users any unallocated bandwidth.","332.The computerized method of claim 330, further comprising distributing to the users any unallocated bandwidth remaining in amounts proportional to the users' forecasted bandwidth consumptions.","333.The computerized method of claim 330, wherein the data representative of past bandwidth consumption comprise the number of logical data units transmitted from and to each user during the past time interval.","334.The computerized method of claim 330, wherein the data representative of past bandwidth consumption comprise data representative of the number of bytes transmitted from and to each user during the past time interval.","335.The computerized method of claim 330, wherein the data representative of past bandwidth consumption comprise data representative of the number of data packets transmitted from and to each user during the past time interval.","336.A computerized method of allocating among a plurality of users bandwidth for conveying information across a shared communications medium, comprising the steps of: (a) receiving data representative of past bandwidth of each user during a time interval; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth multiplied by a ratio of the total bandwidth available to the users' total forecasted bandwidth, and subject to a respective, predetermined maximum value and subject to bandwidth availability.","337.The computerized method of claim 336, wherein the data representative of past bandwidth comprise the number of logical data units transmitted from and to each user during the past time interval.","338.The computerized method of claim 336, wherein the data representative of past bandwidth comprise data representative of the number of bytes and data packets transmitted from and to each user during the past time interval.","339.The computerized method of claim 336, wherein the data representative of past bandwidth comprise data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during the past time interval.","340.A computerized method of allocating among a plurality of users bandwidth for conveying information across a shared communications medium, comprising the steps of: (a) receiving data representative of past bandwidth of each user during a time interval, and data representative of respective fees that are charged to the users for bandwidth; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on the respective fee charged to each user in decreasing order, whereby a user with a higher fee receives a higher priority than a user with a lesser fee; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.","341.The computerized method of claim 340, wherein the data representative of past bandwidth comprise the number of logical data units transmitted from and to each user during the past time interval.","342.The computerized method of claim 340, wherein the data representative of past bandwidth comprise data representative of the number of bytes and data packets transmitted from and to each user during the past time interval.","343.The computerized method of claim 340, wherein the data representative of past bandwidth comprise data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during the past time interval.","344.A computerized method of allocating among a plurality of users bandwidth for conveying information across a shared communications medium, comprising the steps of: (a) receiving data representative of past bandwidth of each user during a time interval, and data representative of respective credits that are applied to accounts of the users for bandwidth shortfalls below respective bandwidth levels specified to the users; (b) forecasting future bandwidth by each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on the respective credit in decreasing order, whereby a user with a higher credit receives a higher priority than a user with a lesser credit; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum specified value and subject to availability.","345.The computerized method of claim 344, wherein any unallocated bandwidth remaining is distributed to the users sequentially in decreasing user priority such that each user's allocation equals the user's forecasted bandwidth, subject to a respective, predetermined maximum allowed value of bandwidth and subject to availability.","346.The computerized method of claim 344, wherein any unallocated bandwidth remaining is distributed equally to the users subject to a respective, predetermined maximum allowed value of bandwidth.","347.The computerized method of claim 344, further comprising setting each user's allocation of bandwidth for the future time interval only in an amount equal to the forecasted bandwidth of the user multiplied by the ratio of total bandwidth available for allocation to the total forecasted bandwidth of the users, but only when the total forecasted bandwidth exceeds the total bandwidth available for allocation.","348.The computerized method of claim 344, wherein the data representative of past bandwidth comprise the number of logical data units transmitted from and to each user during the past time interval.","349.The computerized method of claim 344, wherein the data representative of past bandwidth consumption comprise data representative of the number of bytes and data packets transmitted from and to each user during the past time interval.","350.The computerized method of claim 344, wherein the data representative of past bandwidth consumption comprise data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during the past time interval.","351.A computer-readable medium having computer-executable instructions that allocates among a plurality of users bandwidth for conveying information across a shared communications medium, said instructions performing the steps of: (a) receiving data representative of past bandwidth of each user during a time interval; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on each user's forecasted future bandwidth in increasing order, whereby a user with a lesser forecasted bandwidth receives a higher priority than a user with a greater forecasted bandwidth; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to bandwidth availability.","352.The computer-readable medium of claim 351, wherein said instructions further perform the step of distributing equally to the users any unallocated bandwidth.","353.The computer-readable medium of claim 351, wherein said instructions further perform the step of distributing to the users any unallocated bandwidth remaining in amounts proportional to the users' forecasted bandwidths.","354.A computer-readable medium having computer-executable instructions that allocates among a plurality of users bandwidth for conveying information across a shared communications medium, said instructions performing the steps of: (a) receiving data representative of past bandwidth of each user during a time interval; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth multiplied by a ratio of the total bandwidth available to the users' total forecasted bandwidth, and subject to a respective, predetermined maximum value and subject to bandwidth availability.","355.A computer-readable medium having computer-executable instructions that allocates among a plurality of users bandwidth for conveying information across a shared communications medium, said instructions performing the steps of: (a) receiving data representative of past bandwidth by each user during a time interval, and data representative of respective fees that are charged to the users for bandwidth; (b) forecasting future bandwidth by each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on the respective fee in decreasing order, whereby a user with a higher fee receives a higher priority than a user with a lesser fee; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum specified value and subject to availability.","356.A computer-readable medium having computer-executable instructions that allocates among a plurality of users bandwidth for conveying information across a shared communications medium, said instructions performing the steps of: (a) receiving data representative of past bandwidth of each user during a time interval, and data representative of respective credits that are applied to accounts of the users for bandwidth shortfalls below respective levels of network access specified to the users; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on the respective credit in decreasing order, whereby a user with a higher credit receives a higher priority than a user with a lesser credit; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum specified value and subject to availability.","357.The computer-readable medium of claim 356, wherein said instructions further perform the step of distributing any unallocated bandwidth to the users sequentially in decreasing user priority such that each user's allocation equals the user's forecasted bandwidth, subject to a respective, predetermined maximum allowed value of bandwidth and subject to availability.","358.The computer-readable medium of claim 356, wherein said instructions further perform the step of distributing any unallocated bandwidth equally to the users subject to a respective, predetermined maximum allowed value of bandwidth.","359.The computer-readable medium of claim 356, wherein said instructions further perform the step of setting each user's allocation of bandwidth for the future time interval only in an amount equal to the forecasted bandwidth of the user multiplied by the ratio of total bandwidth available for allocation to the total forecasted bandwidth of the users, but only when the total forecasted bandwidth exceeds the total bandwidth available for allocation.","360.A method of providing network access across a shared communications medium between at least four competing users, with at least a first pair of users being grouped within a first class and at least a second pair of different users being grouped within a second class, comprising the steps of: (a) determining class and user allowances of network access for a first time interval by allocating network access to each user class for a first future time interval and, for each user class, allocating network access to each user within the class for the first time interval, (b) providing network access to each user during the first time interval such that no user receives more network access than that user's allowance and no class receives more collective network access than that class' network allowance; (c) determining class and user allowances of network access for a second time interval by allocating network access to each user class for a second future time interval succeeding the first time interval and, for each user class, allocating network access to each user for the second time interval, the allocated network access for the second time interval for at least one user differing from that user's allocated network access for the first time interval; and (d) providing network access to each user during the second time interval such that no user receives more network access than that user's allowance and no class receives more collective network access than that class' allowance.","361.The method of claim 360, wherein for at least one class the allocated network access for the first time interval for each user differs from the allocated network access for the second time interval for that user.","362.The method of claim 360, wherein for each class the allocated network access for the first time interval for each user differs from the allocated network access for the second time interval for that user.","363.The method of claim 360, wherein the collective network access allocated to each class for the first time interval differs from the collective network access allocated to each class for the second time interval.","364.The method of claim 360, further comprising requesting a minimum level of network access for a user for utilization during the first future time interval, and wherein said allocating network access to such user for the first future time interval comprises setting the level of network access allocated to such user to an amount equal to or greater than the requested minimum level.","365.The method of claim 364, wherein said allocating network access to such user for the second future time interval comprises setting the level of network access allocated to such user to an amount less than the requested minimum level for the first time interval.","366.The method of claim 360, wherein each of the first future time interval and the second future time interval has a period of between one minute and sixty minutes.","367.The method of claim 360, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.","368.The method of claim 360, further comprising the step of monitoring network access usage by each user.","369.The method of claim 368, further comprising the step of tracking network access usage for each user class.","370.The method of claim 368, wherein said step of monitoring network access usage by each user includes collecting data representative of logical data units transmitted from and to each user during a past time interval.","371.The method of claim 368, further comprising tracking logical data units transmitted from and to each user class during a past time interval.","372.The method of claim 368, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a past time interval.","373.The method of claim 368, further comprising tracking the number of logical data units that are dropped for each user class during a past time interval.","374.The method of claim 368, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during a past time interval.","375.The method of claim 368, further comprising tracking the number of logical data units of each user class that are requested to be transmitted in an upstream direction during a past time interval.","376.The method of claim 360, wherein the shared communications medium is part of a Cable Network and the shared communications medium comprises a coaxial cable.","377.The method of claim 360, wherein the shared communications medium is part of a Shared Access Carrier Network comprises a wireless network.","378.The method of claim 360, further comprising prioritizing the user classes for allocating network access.","379.The method of claim 378, further comprising prioritizing the users for allocating, network access.","380.The method of claim 378, wherein said prioritizing of the user classes is based on fairness considerations.","381.The method of claim 380, wherein the user classes are prioritized based on collective user throughput during a past time interval, with a user class with lesser collective user throughput receiving priority over a user class with greater collective user throughput.","382.The method of claim 380, wherein the user classes are prioritized based on collective data loss for each user class during a past time interval, with a user class with greater collective data loss having priority over a user class with lesser collective data loss.","383.The method of claim 380, wherein the user classes are prioritized based on collective network access usage for a particular time of day, with a user class with lesser collective network access usage for the particular time of day receiving priority over a user class with greater collective network access usage for the particular time of day.","384.The method of claim 380, wherein the user classes are prioritized based on both collective user throughput for the class and collective data loss of the users for the class during a time interval.","385.The method of claim 380, wherein user classes are prioritized based on an established minimum quality of service (QoS) standard.","386.The method of claim 378, wherein said step of prioritizing is based on class service level agreements (CSLAs) for at least two user classes regarding the provision of network access to each respective class.","387.The method of claim 386, further comprising the step of tracking network access usage by each user class.","388.The method of claim 387, wherein each CSLA specifies a respective minimum level of collective network access for the respective users therein, and said step of prioritizing includes comparing said monitored network access usages for the user classes with the specified respective minimum levels of collective network access therefor, and awarding priority to a user class when said monitored network access usage for such user class falls below the specified respective minimum level of collective network access for such class.","389.The method of claim 387, wherein each CSLA specifies a respective time-of-day (TOD) minimum level of collective network access for the respective users therein, and said step of prioritizing includes comparing said monitored network access usages for such user classes during the specified respective TOD with the specified respective TOD minimum levels of collective network access, and awarding priority to a user class when said monitored network access usage during the specified respective TOD for such user class falls below the specified respective TOD minimum level of collective network access of such user class.","390.The method of claim 387, wherein each CSLA specifies a respective minimum level of collective network access up to a maximum burstable level with target probability for the respective users therein, and said step of prioritizing includes comparing for each user class said monitored network access usage both with the respective minimum level of collective network access and with the respective maximum burstable level of collective network access, and comparing the instances the respective maximum level of network access were obtained out of all instances the respective maximum level of network access could have been utilized.","391.The method of claim 387, wherein each CSLA provides a respective fee for collective network access usage, and said step of prioritizing comprises sorting such user classes based on each class' respective fee in decreasing order, with a user class with a higher fee receiving priority over a user class with a lesser fee.","392.The method of claim 387, wherein each CSLA provides a respective credit for a level of collective network access falling below a respective guaranteed level for the user class, and said step of prioritizing comprises sorting such user classes based on each class' respective credit in decreasing order, with a user class with a higher credit receiving priority over a user class with a lower credit.","393.The method of claim 387, wherein each CSLA specifies a respective minimum level of collective network access for the user class, and said step of allocating network access comprises setting the respective level of collective network access of the user class equal to the class' specified respective minimum level of collective network access.","394.The method of claim 368, further comprising the step of forecasting collective network access usage by each user class during a future time interval based on said step of monitoring network access usage by each user.","395.The method of claim 394, wherein said step of forecasting comprises summing within each class a forecasted network access usage of each user.","396.The method of claim 394, wherein said step of forecasting network access usage of each user comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of each user.","397.The method of claim 395, wherein said step of allocating network access to each user class comprises setting the respective levels of network access of the user classes proportional to each class' forecasted network access usage.","398.The method of claim 395, further comprising the step of prioritizing the user classes for allocating network access.","399.The method of claim 398, wherein said prioritizing is based on each class' forecasted network access usage.","400.The method of claim 398, wherein said user classes are prioritized in increasing order of each class' forecasted network access usage, with a user class with a lesser forecasted network access usage receiving priority over a user class with a greater forecasted network access usage.","401.The method of claim 398, wherein said step of allocating network access comprises setting the respective levels of network access equal to each class' forecasted network access usage, and then allocating any remaining network access to the user classes proportional to the number of users within each class.","402.The method of claim 398, wherein said step of allocating network access comprises setting the respective levels of network access equal to each class' forecasted network access usage, and then allocating any remaining network access to the user classes proportionally based on each class' forecasted network access usage.","403.The method of claim 378, wherein said step of prioritizing is based on class service level agreements (CSLAs) regarding the provision of collective network access.","404.The method of claim 403, further comprising the step of monitoring collective network access usage of each class.","405.The method of claim 404, wherein CSLAs specify respective minimum levels of collective network access for classes, and said step of prioritizing includes comparing said monitored network access usages for such classes with the specified respective minimum levels of collective network access, and awarding priority to a class when said respective monitored network access usage for such class falls below the class' specified respective minimum level of collective network access.","406.The method of claim 404, wherein CSLAs specify respective time-of-day (TOD) minimum levels of collective network access for classes, and said step of prioritizing includes comparing said monitored network access usages for such classes during the specified respective TOD with the specified respective TOD minimum levels of collective network access, and awarding priority to a class when said monitored network access usage during the specified respective TOD for such class falls below the class' specified respective TOD minimum level of collective network access.","407.The method of claim 404, wherein CSLAs specify respective minimum levels of collective network access up to a maximum burstable levels with target probability for classes, and said step of prioritizing includes comparing said monitored network access usage for each such class both with the respective minimum levels of collective network access and with the respective maximum burstable levels of collective network access, and comparing the instances the respective maximum levels of collective network access were obtained for each such class out of all instances the respective maximum levels of collective network access could have been utilized.","408.The method of claim 404, wherein CSLAs provide respective fees for collective network access usage of classes, and said step of prioritizing comprises sorting such classes based on each class' respective fee in decreasing order, with a class with a higher fee receiving priority over a class with a lower fee.","409.The method of claim 404, wherein CSLAs provide respective credits for levels of collective network access below respective guaranteed levels for classes, and said step of prioritizing comprises sorting such classes based on each class' respective credit in decreasing order, with a class with a higher credit receiving priority over a class with a lower credit.","410.The method of claim 404, wherein CSLAs specify respective minimum levels of collective network access for classes, and said step of allocating network access comprises setting the allocations of collective network access for such classes equal to each class' specified respective minimum level of collective network access"],["<SOH> BACKGROUND OF THE PRESENT INVENTION <EOH>As used herein, a “Carrier Network” generally refers to a computer network through which users (such as homes and businesses) communicate with various service providers.","The Carrier Network extends from the location of each user to an intermediate switched/routed network (hereinafter “Intermediate Network”).","The service providers, in turn, are connected to the Intermediate Network, either directly or indirectly via the Internet, for communications with the users.","The Carrier Network is maintained by a “Carrier,” which also may serve as a service provider for certain services.","For example, a Carrier or a related entity may serve as an Internet service provider (ISP).","Two prevalent types of Carrier Networks include a “Shared Access Carrier Network,” in which data of multiple users are conveyed together over a shared communications medium between the users and the Intermediate Network, and a “Dedicated Connection Carrier Network,” in which data of each user are conveyed alone between the user and the Intermediate Network and are not combined with data of other users.","One of the most prevalent Shared Access Carrier Networks today is found in the Data-Over-Cable (DOC) Network, which includes the traditional network constructed from coaxial cable and the hybrid fiber coaxial (HFC) network constructed with both fiber optical cabling and coaxial cable.","Other Shared Access Carrier Networks include wireless and digital subscriber line (XDSL) networks (the xDSL lines typically being aggregated onto an oversubscribed backhaul trunk into the Intermediate Network, with the trunk defining the shared communications medium).","For example, with regard to DOC Networks, and with reference to FIG.","1 wherein a conventional DOC Network 40 is illustrated, data packets are transmitted in a downstream direction from a cable modem termination system (CMTS) 30 , which is located in a headend 36 (or distribution hub) of a Carrier, over a coaxial cable 32 to respective cable modems (CMs) 34 of users.","All of the CMs 34 are attached by the coaxial cable 32 to the CMTS 30 in an inverted tree configuration, and each CM 34 connected to the coaxial cable 32 listens to all broadcasts from the CMTS 30 transmitted through the coaxial cable 32 for data packets addressed to it, and ignores all other data packets addressed to other CMs 34 .","Theoretically, a CM 34 is capable of receiving data in the downstream direction over a 6 MHz channel with a maximum connection speed of 30-40 Mbps.","Data packets also are transmitted in the upstream direction over a 2 MHz channel by the CMs 34 to the CMTS 30 typically using time division multiplexing (TDM) and at a maximum connection speed of 1.5-10 Mbps.","The headend 36 in the DOC Network 40 includes a plurality of CMTSs, with each CMTS supporting multiple groups of CMs each connected together by a respective coaxial cable.","Each such group of CMs connected to a CMTS defines a Shared Access Carrier Network, with the coaxial cable in each representing the shared communications medium.","This arrangement of a group of CMs connected to a CMTS by a coaxial cable is referred to herein as a “Cable Network.” Accordingly, the DOC Network 40 includes a plurality of Cable Networks 38 originating from CMTSs at the headend 36 of the Carrier, with a particular Cable Network 38 being illustrated in an expanded view in FIG.","1 .","The DOC Network 40 also includes multiple headends 36 , 64 , 66 .","In contrast to the Shared Access Carrier Network, a user in the Dedicated Connection Carrier Network establishes a dedicated connection directly with the Intermediate Network for the transfer of data directly therebetween, and no data of other users travel over the dedicated connection.","Examples of a dedicated connection are shown for comparison in FIG.","1 and include a connection established by a telephony modem 74 and a connection established by an ISDN modem 76 .","Both downstream and upstream connection speeds in a Dedicated Connection Carrier Network range from a maximum of 53 kbps in a telephony modem connection to a maximum of 128 kbps in a basic rate interface ISDN connection.","Connection speeds and, more importantly, throughput rate—the amount of data actually transmitted successfully in a given time interval—are important in minimizing downtime that users spend waiting for HTML documents to download from the Web.","A Shared Access Carrier Network is considered superior to a comparable Dedicated Connection Carrier Network because the maximum instantaneous connection speed offered by the Shared Access Carrier Network is greater.","A Shared Access Carrier Network is considered “comparable” to a Dedicated Connection Carrier Network where the entire bandwidth over a shared communications medium of the Shared Access Carrier Network equals an aggregate bandwidth that is divided between and dedicated to users in a Dedicated Connection Carrier Network.","Accordingly, Shared Access Carrier Networks are able to offer significantly faster downloads of web documents, emails, and file transfers that are not considered available in Dedicated Connection Carrier Networks.","Furthermore, new multimedia applications and Internet services, such as voice and video communications via the Internet, now are offered which require even greater throughput rates for acceptable levels of service than that of the traditional Internet services, i.e., throughput rates greater than that required for acceptable text-based Web browsing, file transferring, and email communication.","It is believed that these new multimedia applications and Internet services cannot adequately be provided for over Dedicated Connection Carrier Networks and that, consequently, Shared Access Carrier Networks ultimately will prevail as the predominant type of Carrier Network for Internet access by users.","Of course, the actual throughput rates experienced by a particular user rarely, if ever, will equate to the maximum connection speeds of which the Shared Access Carrier Network is capable because of the shared nature of the communications medium.","For example, in a Cable Network the total bandwidths available over the shared cable in the downstream and upstream directions, which determine the respective maximum connection speeds, must be shared among all of the users communicating at a given time.","Thus, rarely will a single user have available for use a large portion of the entire bandwidth in a particular direction.","Further, as a Carrier adds users to the Cable Network, the actual downstream and upstream bandwidths available to the user—and thus throughput rates of the user—generally will decrease.","A Carrier therefore must be careful to draw a balance between the number of users connected to a Cable Network and the performance users experience communicating over the network.","Unfortunately, Shared Access Carrier Networks that have been established were designed to provide the traditional Internet services, and not the new multimedia applications and Internet services that require higher throughput rates for acceptable levels of service.","Consequently, each balance previously struck by Carriers in establishing Shared Access Carrier Networks was based on considerations of the throughput rates required for the traditional Internet services, and user throughput rates currently experienced by users in such networks are believed to fall short of acceptable quality of service (QoS) standards believed required in a Carrier Network for the new multimedia applications and Internet services.","Additionally, with regard to new Shared Access Carrier Networks that are being established, considerations of the new multimedia applications and Internet services tend to reduce the number of users that a Carrier now can reasonably expect to connect to the shared communications medium before degrading the performance levels of the new multimedia applications and Internet services.","The balance is being shifted towards less users per shared access medium in exchange for higher throughput rates and, thus, higher QoS standards.","In an attempt to avoid reducing the number of users, it has been proposed, at least in DOC Networks, to discriminate between the traditional Internet services and the new multimedia applications and Internet services with regard to priority of data packet transmissions.","In particular, the generally accepted standard in the United States governing communication protocols over cable is DOCSIS version 1.0, which was ratified by the International Telecommunication Union in March of 1998.DOCSIS stands for “Data Over Cable Service Interface Specifications.” When DOCSIS 1.0 was developed, it was generally believed that, in view of the “fast” connection speeds of Cable Networks, the provision of bandwidth on a best effort basis would be sufficient to meet all user requirements.","Accordingly, each user subscribed to receive network access pursuant to a service level agreement (SLA) which provided for network access (or bandwidth in Cable Networks) only on a best effort basis.","Now, in an effort to address the foreseen ever-increasing demand for higher throughput rates, DOCISIS version 1.1 has been proposed, in accordance with which each data packet transmitted over a DOC Network now must include a classification designation for prioritization purposes by network equipment.","Subsequently, data packets representing voice or video, for example, now can be identified and given priority transmission over data packets representing email, file transfers, and text-based Web documents.","A benefit of such flow classification is that, while overall bandwidth generally available to a user may otherwise remain unchanged, throughput rates of data for voice and video now may be provided at a higher rate than throughput rates of data for the traditional Internet services, thereby increasing the performance of voice and video applications and services while at least maintaining the traditional number of users connected to a Cable Network.","A disadvantage of the revisions to DOCSIS 1.1 is that the revisions do not enhance established Cable Networks constructed with only DOCSIS 1.0 compliant equipment, as such equipment does not support the added functionality of DOCSIS 1.1 so as to distinguish between data packets.","More broadly, another disadvantage of the classification of data packets into Internet Protocol (IP) flows based on the services represented by the data packets is that such classification discriminates against users who do not utilize multimedia applications and services receiving the prioritized transmissions.","At least for some extensive users of the traditional Internet services, some degradation in performance may be noticed by lower classification of their data packets, particularly if the user engages in, for example, web hosting.","While the transmissions of data packets for documents, files, and emails are not as time-sensitive as data packets for voice and video, increased data packet latency for documents, files, and emails, even if incrementally small, nevertheless will result in service degradation for large or numerous documents, files, and emails.","Accordingly, a need exists for a method and apparatus that will accommodate differing demands for network access by users competing for such access across a shared communications medium of a Shared Access Carrier Network, whether new or established, and irrespective of data packet classifications.","Furthermore, as Shared Access Carrier Networks emerge as the favored type of network, it is believed that open access to such networks by different competing service providers will become an important commercial and legislative issue.","Moreover, as more and more service providers seek to provide users with services over Shared Access Carrier Networks, it is believed that users of such service providers will receive inadequate bandwidth over the Shared Access Carrier Networks to meet minimum standards of quality, especially in Cable Networks where bandwidth is provided on a best efforts basis.","Accordingly, it is believed that an additional need exists for a method by which a service provider competing for users of a shared communications medium can seek protection against bandwidth starvation of the users of the shared communications medium that are its customers.","Conversely, it is also believed that a need exists for a method that will accommodate differing demands for network access by users competing for such access across the shared communications medium."],["<SOH> SUMMARY OF THE PRESENT INVENTION <EOH>Briefly summarized, the present invention relates to a method of providing network access across a shared communications medium between competing users, and include eight different aspects.","First Aspect of the Present Invention In the first aspect of the present invention, the method broadly includes the steps of: (a) prior to first and second time intervals, respectively determining for each user first and second network access allowances; (b) during the first time interval, providing network access to each user such that the respective first network access allowance is not exceeded; and (c) during the second time interval, providing network access to each user such that the respective second network access allowance for each user is not exceeded.","In accordance with the present invention, the “network access allowance” represents a respective maximum level of network access that can be made available to the user during a particular time interval, and does not represent necessarily the level of network access that will be utilized by the user during such time interval.","Furthermore, at least one respective second network access allowance for a user differs from such user's respective first network access allowance.","The first network access allowances for the users preferably are determined by allocating network access to each user on a per user basis for the first time interval in accordance with a first allocation policy.","The first network access allowance for each respective user then is equated to the network access allocated to that user under the first allocation policy.","Likewise, the second network access allowances for the users are determined by allocating network access to each user on a per user basis for the second time interval in accordance with a second allocation policy that may or may not differ from the first allocation policy.","Again, the second network access allowance for each respective user then is equated to the network access allocated to that user under the second allocation policy.","In additional features of the present invention, the method includes the steps of monitoring network access usage by the users, and forecasting network access usage of each user in a future time interval.","Another additional feature of the present invention includes the step of prioritizing the users for the allocation of network access.","One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network; based on the monitored bandwidth consumption, the forecasting of bandwidth consumption of each user in a future time interval; the prioritization of users; and the subsequent allocation of bandwidth to each user in decreasing priority for determining bandwidth allowances during the future time interval.","Users are prioritized based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.","Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval.","In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.","With regard to at least two users, the favored user allocations, and thus the user allowances, differ as between future time intervals.","Second Aspect of the Present Invention In the second aspect of the present invention, the method broadly includes the steps of monitoring network access usage of each user for a past time interval and, based on the monitored network access usage, allocating network access to each user for a future time interval.","In a feature of the present invention, the network access that is monitored and allocated is in the downstream direction towards the users.","In a separate and independent feature of the present invention, network access usage of each user is forecast for a future time interval based on the monitoring, and allocations are made based on the forecasting.","Another additional feature of the present invention includes the prioritizing of the users for allocating network access.","One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network; based on the monitored bandwidth consumption, the forecasting of bandwidth consumption of each user in a future time interval; the prioritization of users; and the subsequent allocation of bandwidth to each user in decreasing priority for the future time interval.","Users are prioritized based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.","Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval.","In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.","Third Aspect of the Present Invention In the third aspect of the present invention, the method broadly includes the steps of monitoring network access usage by each user for a past time interval and, based on the monitored network access usage, allocating network access for each user for a future time interval.","In a feature of the present invention, network access usage of each user is forecast for a future time interval based on the monitoring, and allocations are made based on the forecasting.","Another feature of the present invention includes the prioritizing of the users for allocating network access.","A preferred method of providing network access to the users includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on the monitoring, forecasting network access usage by each user over a future time interval; (c) prioritizing users based on each user's forecasted network access usage in increasing order, whereby a user with a lesser forecasted network access usage receives a higher priority than a user with a greater forecasted network access usage; and (d) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.","Another preferred method of providing network access to the users includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on the monitoring, forecasting network access usage by each user over a future time interval; and (c) allocating network access available to each user during the future time interval, with each user's allocation of network access being equal to each user's forecasted network access usage multiplied by a ratio of the total network access available for allocation to the total forecasted network access usage of all users, and subject to a respective, predetermined maximum value and subject to availability.","A third preferred method of providing network access to the users includes the steps of: (a) charging each user a respective fee for network access usage; (b) monitoring network access usage by each user during a time interval; (c) based on the monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.","Yet a fourth preferred method of providing network access to the users includes the steps of: (a) applying respective credits to users for network access shortfalls below respective levels of network access specified to the users; (b) monitoring network access usage by each user during a past time interval; (c) based on the monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's respective credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum guaranteed value and subject to availability.","Fourth Aspect of the Present Invention In the fourth aspect of the present invention, the method includes providing network access across a shared communications medium between competing users pursuant to service level agreements (SLAs) of the users.","The method broadly includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) comparing the monitored network access usage by each user with a predetermined threshold value; and (c) soliciting a user to modify the user's SLA if the user's monitored network access usage varies from the predetermined value by a predetermined tolerance.","Features of the present invention include the additional steps of allocating network access to each user for a future time interval, and forecasting network access usage by users in the future time interval.","Another additional feature of the present invention includes the step of prioritizing the users for allocating network access to the users.","The network access usage includes the user throughput rate, bandwidth consumption, and/or bandwidth requested for a predetermined period of time.","The threshold value preferably represents a respective maximum level of network access (whether maximum allowed or maximum guaranteed) for each user or a respective maximum burstable level of network access with target probability for each user.","The solicitation is conducted via email, instant messaging, redirection of a web browser of the user to a solicitation web page, generation and mailing of literature, telephonic communication, or other communication means.","The solicited modification of the user's SLA includes guaranteeing a level of network access to the user on a permanent or on a temporary basis.","A charge preferably is applied to the user for the modification.","A preferred method of the present invention includes the identification of a recurrent period of high network access usage by a user based on the monitoring, and in response thereto, the solicitation of the user to modify the user's SLA in order to guarantee a minimum level of network access during an anticipated future recurrent period of high network access usage.","Fifth Aspect of the Present Invention In the fifth aspect of the present invention, the method includes incorporating allocations of network access into a DOCSIS 1.0 compliant cable network wherein users compete for bandwidth.","A preferred method includes the steps of: (a) generating cable modem configuration files, each of which limits bandwidth consumption by a cable modem of a user to a value representative of that user's allowance of bandwidth; (b) sending the configuration files to a Trivial File Transfer Protocol (TFTP) Server of the DOC Network; and (c) sending a command either to each user's cable modem, or to a cable modem termination system to which each user's cable modem is connected, to cause the cable modem to acquire its new respective configuration file.","Features of the present invention include the additional steps of prioritizing users for allocation of bandwidth, and forecasting bandwidth of each user in a future time interval.","Sixth Aspect of the Present Invention In the sixth aspect of the present invention, a Carrier Network provides communications between multiple users and Service Providers.","The Carrier Network includes computer network equipment defining a Cable Network and an Intermediate Network which, combined, extends between the users and the Service Providers.","The Cable Network includes a shared communications medium joining the users with the Intermediate Network, and users compete for network access across the shared communications medium in conveying data.","The Carrier Network also includes software that manages the network access of the users.","In accordance with the present invention, the software includes computer-executable instructions performing the steps of monitoring network access usage by each user for a time interval and, based thereon, allocating network access to the users for a future time interval.","In additional features of the present invention, the software includes computer-executable instructions performing the additional steps of forecasting network access usage by each user during the future time interval, and prioritizing the users for allocation of network access In additional features of the present invention, the software is distributed within network equipment of the Carrier Network or, alternatively, is stored in hardware physically located at a remote location from the Carrier Network but linked with the Carrier Network for communications therebetween.","The hardware remotely located is directly linked with the Carrier Network or is linked indirectly through the Internet.","One of many preferred embodiments of the present invention includes prioritization of users based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, network access usage for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.","Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted network access usage for a future time interval.","Seventh Aspect of the Present Invention In the seventh aspect of the present invention, the present invention relates to a method of (and to a computer-readable medium with computer-executable instructions for performing the method of) providing network access across a shared communications medium between competing users.","The method broadly includes the steps of receiving data representative of past bandwidth of each user during a time interval; forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; and setting each user's allocation of bandwidth for the future time interval.","A feature of the present invention includes the step of prioritizing the users for allocating bandwidth to the users.","Preferably, each user's bandwidth allocation represents that user's limit on bandwidth consumption for the future time interval (“bandwidth allowance”), and does not necessarily represent that user's bandwidth consumption during the future time interval.","In a first preferred method, the users are prioritized based on each user's forecasted future bandwidth in increasing order, whereby a user with a lesser forecasted bandwidth receives a higher priority than a user with a greater forecasted bandwidth.","The users are then allocated sequentially in decreasing order of user priority, with each user's allocation being set to equal the user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to bandwidth availability.","Another preferred method includes allocating bandwidth that is to be made available to each user during the future time interval, with each user's allocation of bandwidth being set to equal each user's forecasted bandwidth multiplied by a ratio of the total bandwidth available for allocation to the total forecasted bandwidth of all users, and subject to a respective, predetermined maximum value and subject to availability.","A third preferred method includes receiving data representative of a respective fee that is charged to each user for bandwidth, prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee, and setting in decreasing user priority each user's allocation of bandwidth equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.","Yet a fourth preferred method includes receiving data representative of a respective credit that is applied to each user's account for bandwidth shortfalls below a specified bandwidth value, prioritizing users based on each user's credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit, and setting in decreasing user priority each user's allocation of bandwidth equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.","The bandwidth monitored and forecast includes bandwidth that is consumed or, alternatively, bandwidth that is requested for consumption.","Eighth Aspect of the Present Invention Finally, in the eighth aspect of the present invention, the present invention relates to a method of providing network access across a shared communications medium between competing users.","In particular, the present invention includes the steps of allocating network access to at least two “user classes” for a first future time interval and, for each user class, allocating network access to each user within the class for the first time interval.","The present invention further includes the additional step of allocating network access to each user class for a second future time interval succeeding the first time interval and, for each user class, allocating network access to each user for the second time interval.","Each user receives a first determined allowance of network access for utilization during the first time interval equal to that user's allocation for the first time interval, and a second determined allowance of network access for utilization during the second time interval equal to that user's allocation for the second time interval.","The user allocations—and hence the user allowances—preferably differ as between the first and second time intervals.","As used herein, a “bandwidth allowance” represents a respective maximum level of network access that will be made available to a user class or to a user during a particular time interval, and does not necessarily represent the level of network access that will be utilized by the user class or user during such time interval.","As used herein, a “user class” is intended to refer to a grouping of users who compete for access across a shared communications medium and who have some characteristic in common.","The characteristic may, for example, be that the users are customers who receive Internet service over the shared communications medium from the same service provider.","The characteristic also may, for example, be that the users each subscribe to receive a particular level of network access across the shared communications medium, or that the users receive the same level of a particular service that is provided across the shared communications medium.","Furthermore, a user class is a grouping of users to which, collectively, a determined amount of bandwidth is allocated as opposed to other user classes.","In this regard, users that are not classified are considered to be part of a default user class having in common that fact that no other classification applies to them.","Accordingly, all users of a shared communications network can be classified.","In features of the present invention, the method includes the steps of monitoring network access usage by the users, and forecasting network access usage of each user in a future time interval.","Another feature includes the step of prioritizing the users for the allocation of network access.","One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network and tracking the collective bandwidth consumption of each user class; based on the monitored bandwidth consumptions, the forecasting of bandwidth consumption of each user in a future time interval and the calculation based thereon of the collective bandwidth consumption of each user class; the prioritization of users and the prioritization of user classes; and the subsequent allocation of bandwidth to each user class, and then to each user, in decreasing order of priority for determining bandwidth allowances during the future time interval.","Users and user classes are prioritized based on one or more various prioritization policies, including fairness considerations such as individual or collective user throughput during a particular time interval, individual or collective user data loss for a particular time interval, individual or collective user bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.","Other prioritization policies include the prioritization of users and user classes based upon provisions found in each user's respective service level agreement (SLA) or provisions found in each class' service level agreement (CSLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval and the prioritization of user classes based upon each class' collective forecasted bandwidth consumption.","In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted."],["FIELD OF THE PRESENT INVENTION The present invention generally relates to allocating access across a shared communications medium and, in particular, to allocating bandwidth used to convey data of competing users across a shared communications medium of a Carrier Network.","BACKGROUND OF THE PRESENT INVENTION As used herein, a “Carrier Network” generally refers to a computer network through which users (such as homes and businesses) communicate with various service providers.","The Carrier Network extends from the location of each user to an intermediate switched/routed network (hereinafter “Intermediate Network”).","The service providers, in turn, are connected to the Intermediate Network, either directly or indirectly via the Internet, for communications with the users.","The Carrier Network is maintained by a “Carrier,” which also may serve as a service provider for certain services.","For example, a Carrier or a related entity may serve as an Internet service provider (ISP).","Two prevalent types of Carrier Networks include a “Shared Access Carrier Network,” in which data of multiple users are conveyed together over a shared communications medium between the users and the Intermediate Network, and a “Dedicated Connection Carrier Network,” in which data of each user are conveyed alone between the user and the Intermediate Network and are not combined with data of other users.","One of the most prevalent Shared Access Carrier Networks today is found in the Data-Over-Cable (DOC) Network, which includes the traditional network constructed from coaxial cable and the hybrid fiber coaxial (HFC) network constructed with both fiber optical cabling and coaxial cable.","Other Shared Access Carrier Networks include wireless and digital subscriber line (XDSL) networks (the xDSL lines typically being aggregated onto an oversubscribed backhaul trunk into the Intermediate Network, with the trunk defining the shared communications medium).","For example, with regard to DOC Networks, and with reference to FIG.","1 wherein a conventional DOC Network 40 is illustrated, data packets are transmitted in a downstream direction from a cable modem termination system (CMTS) 30, which is located in a headend 36 (or distribution hub) of a Carrier, over a coaxial cable 32 to respective cable modems (CMs) 34 of users.","All of the CMs 34 are attached by the coaxial cable 32 to the CMTS 30 in an inverted tree configuration, and each CM 34 connected to the coaxial cable 32 listens to all broadcasts from the CMTS 30 transmitted through the coaxial cable 32 for data packets addressed to it, and ignores all other data packets addressed to other CMs 34.Theoretically, a CM 34 is capable of receiving data in the downstream direction over a 6 MHz channel with a maximum connection speed of 30-40 Mbps.","Data packets also are transmitted in the upstream direction over a 2 MHz channel by the CMs 34 to the CMTS 30 typically using time division multiplexing (TDM) and at a maximum connection speed of 1.5-10 Mbps.","The headend 36 in the DOC Network 40 includes a plurality of CMTSs, with each CMTS supporting multiple groups of CMs each connected together by a respective coaxial cable.","Each such group of CMs connected to a CMTS defines a Shared Access Carrier Network, with the coaxial cable in each representing the shared communications medium.","This arrangement of a group of CMs connected to a CMTS by a coaxial cable is referred to herein as a “Cable Network.” Accordingly, the DOC Network 40 includes a plurality of Cable Networks 38 originating from CMTSs at the headend 36 of the Carrier, with a particular Cable Network 38 being illustrated in an expanded view in FIG.","1.The DOC Network 40 also includes multiple headends 36,64,66.In contrast to the Shared Access Carrier Network, a user in the Dedicated Connection Carrier Network establishes a dedicated connection directly with the Intermediate Network for the transfer of data directly therebetween, and no data of other users travel over the dedicated connection.","Examples of a dedicated connection are shown for comparison in FIG.","1 and include a connection established by a telephony modem 74 and a connection established by an ISDN modem 76.Both downstream and upstream connection speeds in a Dedicated Connection Carrier Network range from a maximum of 53 kbps in a telephony modem connection to a maximum of 128 kbps in a basic rate interface ISDN connection.","Connection speeds and, more importantly, throughput rate—the amount of data actually transmitted successfully in a given time interval—are important in minimizing downtime that users spend waiting for HTML documents to download from the Web.","A Shared Access Carrier Network is considered superior to a comparable Dedicated Connection Carrier Network because the maximum instantaneous connection speed offered by the Shared Access Carrier Network is greater.","A Shared Access Carrier Network is considered “comparable” to a Dedicated Connection Carrier Network where the entire bandwidth over a shared communications medium of the Shared Access Carrier Network equals an aggregate bandwidth that is divided between and dedicated to users in a Dedicated Connection Carrier Network.","Accordingly, Shared Access Carrier Networks are able to offer significantly faster downloads of web documents, emails, and file transfers that are not considered available in Dedicated Connection Carrier Networks.","Furthermore, new multimedia applications and Internet services, such as voice and video communications via the Internet, now are offered which require even greater throughput rates for acceptable levels of service than that of the traditional Internet services, i.e., throughput rates greater than that required for acceptable text-based Web browsing, file transferring, and email communication.","It is believed that these new multimedia applications and Internet services cannot adequately be provided for over Dedicated Connection Carrier Networks and that, consequently, Shared Access Carrier Networks ultimately will prevail as the predominant type of Carrier Network for Internet access by users.","Of course, the actual throughput rates experienced by a particular user rarely, if ever, will equate to the maximum connection speeds of which the Shared Access Carrier Network is capable because of the shared nature of the communications medium.","For example, in a Cable Network the total bandwidths available over the shared cable in the downstream and upstream directions, which determine the respective maximum connection speeds, must be shared among all of the users communicating at a given time.","Thus, rarely will a single user have available for use a large portion of the entire bandwidth in a particular direction.","Further, as a Carrier adds users to the Cable Network, the actual downstream and upstream bandwidths available to the user—and thus throughput rates of the user—generally will decrease.","A Carrier therefore must be careful to draw a balance between the number of users connected to a Cable Network and the performance users experience communicating over the network.","Unfortunately, Shared Access Carrier Networks that have been established were designed to provide the traditional Internet services, and not the new multimedia applications and Internet services that require higher throughput rates for acceptable levels of service.","Consequently, each balance previously struck by Carriers in establishing Shared Access Carrier Networks was based on considerations of the throughput rates required for the traditional Internet services, and user throughput rates currently experienced by users in such networks are believed to fall short of acceptable quality of service (QoS) standards believed required in a Carrier Network for the new multimedia applications and Internet services.","Additionally, with regard to new Shared Access Carrier Networks that are being established, considerations of the new multimedia applications and Internet services tend to reduce the number of users that a Carrier now can reasonably expect to connect to the shared communications medium before degrading the performance levels of the new multimedia applications and Internet services.","The balance is being shifted towards less users per shared access medium in exchange for higher throughput rates and, thus, higher QoS standards.","In an attempt to avoid reducing the number of users, it has been proposed, at least in DOC Networks, to discriminate between the traditional Internet services and the new multimedia applications and Internet services with regard to priority of data packet transmissions.","In particular, the generally accepted standard in the United States governing communication protocols over cable is DOCSIS version 1.0, which was ratified by the International Telecommunication Union in March of 1998.DOCSIS stands for “Data Over Cable Service Interface Specifications.” When DOCSIS 1.0 was developed, it was generally believed that, in view of the “fast” connection speeds of Cable Networks, the provision of bandwidth on a best effort basis would be sufficient to meet all user requirements.","Accordingly, each user subscribed to receive network access pursuant to a service level agreement (SLA) which provided for network access (or bandwidth in Cable Networks) only on a best effort basis.","Now, in an effort to address the foreseen ever-increasing demand for higher throughput rates, DOCISIS version 1.1 has been proposed, in accordance with which each data packet transmitted over a DOC Network now must include a classification designation for prioritization purposes by network equipment.","Subsequently, data packets representing voice or video, for example, now can be identified and given priority transmission over data packets representing email, file transfers, and text-based Web documents.","A benefit of such flow classification is that, while overall bandwidth generally available to a user may otherwise remain unchanged, throughput rates of data for voice and video now may be provided at a higher rate than throughput rates of data for the traditional Internet services, thereby increasing the performance of voice and video applications and services while at least maintaining the traditional number of users connected to a Cable Network.","A disadvantage of the revisions to DOCSIS 1.1 is that the revisions do not enhance established Cable Networks constructed with only DOCSIS 1.0 compliant equipment, as such equipment does not support the added functionality of DOCSIS 1.1 so as to distinguish between data packets.","More broadly, another disadvantage of the classification of data packets into Internet Protocol (IP) flows based on the services represented by the data packets is that such classification discriminates against users who do not utilize multimedia applications and services receiving the prioritized transmissions.","At least for some extensive users of the traditional Internet services, some degradation in performance may be noticed by lower classification of their data packets, particularly if the user engages in, for example, web hosting.","While the transmissions of data packets for documents, files, and emails are not as time-sensitive as data packets for voice and video, increased data packet latency for documents, files, and emails, even if incrementally small, nevertheless will result in service degradation for large or numerous documents, files, and emails.","Accordingly, a need exists for a method and apparatus that will accommodate differing demands for network access by users competing for such access across a shared communications medium of a Shared Access Carrier Network, whether new or established, and irrespective of data packet classifications.","Furthermore, as Shared Access Carrier Networks emerge as the favored type of network, it is believed that open access to such networks by different competing service providers will become an important commercial and legislative issue.","Moreover, as more and more service providers seek to provide users with services over Shared Access Carrier Networks, it is believed that users of such service providers will receive inadequate bandwidth over the Shared Access Carrier Networks to meet minimum standards of quality, especially in Cable Networks where bandwidth is provided on a best efforts basis.","Accordingly, it is believed that an additional need exists for a method by which a service provider competing for users of a shared communications medium can seek protection against bandwidth starvation of the users of the shared communications medium that are its customers.","Conversely, it is also believed that a need exists for a method that will accommodate differing demands for network access by users competing for such access across the shared communications medium.","SUMMARY OF THE PRESENT INVENTION Briefly summarized, the present invention relates to a method of providing network access across a shared communications medium between competing users, and include eight different aspects.","First Aspect of the Present Invention In the first aspect of the present invention, the method broadly includes the steps of: (a) prior to first and second time intervals, respectively determining for each user first and second network access allowances; (b) during the first time interval, providing network access to each user such that the respective first network access allowance is not exceeded; and (c) during the second time interval, providing network access to each user such that the respective second network access allowance for each user is not exceeded.","In accordance with the present invention, the “network access allowance” represents a respective maximum level of network access that can be made available to the user during a particular time interval, and does not represent necessarily the level of network access that will be utilized by the user during such time interval.","Furthermore, at least one respective second network access allowance for a user differs from such user's respective first network access allowance.","The first network access allowances for the users preferably are determined by allocating network access to each user on a per user basis for the first time interval in accordance with a first allocation policy.","The first network access allowance for each respective user then is equated to the network access allocated to that user under the first allocation policy.","Likewise, the second network access allowances for the users are determined by allocating network access to each user on a per user basis for the second time interval in accordance with a second allocation policy that may or may not differ from the first allocation policy.","Again, the second network access allowance for each respective user then is equated to the network access allocated to that user under the second allocation policy.","In additional features of the present invention, the method includes the steps of monitoring network access usage by the users, and forecasting network access usage of each user in a future time interval.","Another additional feature of the present invention includes the step of prioritizing the users for the allocation of network access.","One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network; based on the monitored bandwidth consumption, the forecasting of bandwidth consumption of each user in a future time interval; the prioritization of users; and the subsequent allocation of bandwidth to each user in decreasing priority for determining bandwidth allowances during the future time interval.","Users are prioritized based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.","Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval.","In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.","With regard to at least two users, the favored user allocations, and thus the user allowances, differ as between future time intervals.","Second Aspect of the Present Invention In the second aspect of the present invention, the method broadly includes the steps of monitoring network access usage of each user for a past time interval and, based on the monitored network access usage, allocating network access to each user for a future time interval.","In a feature of the present invention, the network access that is monitored and allocated is in the downstream direction towards the users.","In a separate and independent feature of the present invention, network access usage of each user is forecast for a future time interval based on the monitoring, and allocations are made based on the forecasting.","Another additional feature of the present invention includes the prioritizing of the users for allocating network access.","One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network; based on the monitored bandwidth consumption, the forecasting of bandwidth consumption of each user in a future time interval; the prioritization of users; and the subsequent allocation of bandwidth to each user in decreasing priority for the future time interval.","Users are prioritized based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.","Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval.","In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.","Third Aspect of the Present Invention In the third aspect of the present invention, the method broadly includes the steps of monitoring network access usage by each user for a past time interval and, based on the monitored network access usage, allocating network access for each user for a future time interval.","In a feature of the present invention, network access usage of each user is forecast for a future time interval based on the monitoring, and allocations are made based on the forecasting.","Another feature of the present invention includes the prioritizing of the users for allocating network access.","A preferred method of providing network access to the users includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on the monitoring, forecasting network access usage by each user over a future time interval; (c) prioritizing users based on each user's forecasted network access usage in increasing order, whereby a user with a lesser forecasted network access usage receives a higher priority than a user with a greater forecasted network access usage; and (d) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.","Another preferred method of providing network access to the users includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on the monitoring, forecasting network access usage by each user over a future time interval; and (c) allocating network access available to each user during the future time interval, with each user's allocation of network access being equal to each user's forecasted network access usage multiplied by a ratio of the total network access available for allocation to the total forecasted network access usage of all users, and subject to a respective, predetermined maximum value and subject to availability.","A third preferred method of providing network access to the users includes the steps of: (a) charging each user a respective fee for network access usage; (b) monitoring network access usage by each user during a time interval; (c) based on the monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.","Yet a fourth preferred method of providing network access to the users includes the steps of: (a) applying respective credits to users for network access shortfalls below respective levels of network access specified to the users; (b) monitoring network access usage by each user during a past time interval; (c) based on the monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's respective credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum guaranteed value and subject to availability.","Fourth Aspect of the Present Invention In the fourth aspect of the present invention, the method includes providing network access across a shared communications medium between competing users pursuant to service level agreements (SLAs) of the users.","The method broadly includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) comparing the monitored network access usage by each user with a predetermined threshold value; and (c) soliciting a user to modify the user's SLA if the user's monitored network access usage varies from the predetermined value by a predetermined tolerance.","Features of the present invention include the additional steps of allocating network access to each user for a future time interval, and forecasting network access usage by users in the future time interval.","Another additional feature of the present invention includes the step of prioritizing the users for allocating network access to the users.","The network access usage includes the user throughput rate, bandwidth consumption, and/or bandwidth requested for a predetermined period of time.","The threshold value preferably represents a respective maximum level of network access (whether maximum allowed or maximum guaranteed) for each user or a respective maximum burstable level of network access with target probability for each user.","The solicitation is conducted via email, instant messaging, redirection of a web browser of the user to a solicitation web page, generation and mailing of literature, telephonic communication, or other communication means.","The solicited modification of the user's SLA includes guaranteeing a level of network access to the user on a permanent or on a temporary basis.","A charge preferably is applied to the user for the modification.","A preferred method of the present invention includes the identification of a recurrent period of high network access usage by a user based on the monitoring, and in response thereto, the solicitation of the user to modify the user's SLA in order to guarantee a minimum level of network access during an anticipated future recurrent period of high network access usage.","Fifth Aspect of the Present Invention In the fifth aspect of the present invention, the method includes incorporating allocations of network access into a DOCSIS 1.0 compliant cable network wherein users compete for bandwidth.","A preferred method includes the steps of: (a) generating cable modem configuration files, each of which limits bandwidth consumption by a cable modem of a user to a value representative of that user's allowance of bandwidth; (b) sending the configuration files to a Trivial File Transfer Protocol (TFTP) Server of the DOC Network; and (c) sending a command either to each user's cable modem, or to a cable modem termination system to which each user's cable modem is connected, to cause the cable modem to acquire its new respective configuration file.","Features of the present invention include the additional steps of prioritizing users for allocation of bandwidth, and forecasting bandwidth of each user in a future time interval.","Sixth Aspect of the Present Invention In the sixth aspect of the present invention, a Carrier Network provides communications between multiple users and Service Providers.","The Carrier Network includes computer network equipment defining a Cable Network and an Intermediate Network which, combined, extends between the users and the Service Providers.","The Cable Network includes a shared communications medium joining the users with the Intermediate Network, and users compete for network access across the shared communications medium in conveying data.","The Carrier Network also includes software that manages the network access of the users.","In accordance with the present invention, the software includes computer-executable instructions performing the steps of monitoring network access usage by each user for a time interval and, based thereon, allocating network access to the users for a future time interval.","In additional features of the present invention, the software includes computer-executable instructions performing the additional steps of forecasting network access usage by each user during the future time interval, and prioritizing the users for allocation of network access In additional features of the present invention, the software is distributed within network equipment of the Carrier Network or, alternatively, is stored in hardware physically located at a remote location from the Carrier Network but linked with the Carrier Network for communications therebetween.","The hardware remotely located is directly linked with the Carrier Network or is linked indirectly through the Internet.","One of many preferred embodiments of the present invention includes prioritization of users based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, network access usage for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.","Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted network access usage for a future time interval.","Seventh Aspect of the Present Invention In the seventh aspect of the present invention, the present invention relates to a method of (and to a computer-readable medium with computer-executable instructions for performing the method of) providing network access across a shared communications medium between competing users.","The method broadly includes the steps of receiving data representative of past bandwidth of each user during a time interval; forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; and setting each user's allocation of bandwidth for the future time interval.","A feature of the present invention includes the step of prioritizing the users for allocating bandwidth to the users.","Preferably, each user's bandwidth allocation represents that user's limit on bandwidth consumption for the future time interval (“bandwidth allowance”), and does not necessarily represent that user's bandwidth consumption during the future time interval.","In a first preferred method, the users are prioritized based on each user's forecasted future bandwidth in increasing order, whereby a user with a lesser forecasted bandwidth receives a higher priority than a user with a greater forecasted bandwidth.","The users are then allocated sequentially in decreasing order of user priority, with each user's allocation being set to equal the user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to bandwidth availability.","Another preferred method includes allocating bandwidth that is to be made available to each user during the future time interval, with each user's allocation of bandwidth being set to equal each user's forecasted bandwidth multiplied by a ratio of the total bandwidth available for allocation to the total forecasted bandwidth of all users, and subject to a respective, predetermined maximum value and subject to availability.","A third preferred method includes receiving data representative of a respective fee that is charged to each user for bandwidth, prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee, and setting in decreasing user priority each user's allocation of bandwidth equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.","Yet a fourth preferred method includes receiving data representative of a respective credit that is applied to each user's account for bandwidth shortfalls below a specified bandwidth value, prioritizing users based on each user's credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit, and setting in decreasing user priority each user's allocation of bandwidth equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.","The bandwidth monitored and forecast includes bandwidth that is consumed or, alternatively, bandwidth that is requested for consumption.","Eighth Aspect of the Present Invention Finally, in the eighth aspect of the present invention, the present invention relates to a method of providing network access across a shared communications medium between competing users.","In particular, the present invention includes the steps of allocating network access to at least two “user classes” for a first future time interval and, for each user class, allocating network access to each user within the class for the first time interval.","The present invention further includes the additional step of allocating network access to each user class for a second future time interval succeeding the first time interval and, for each user class, allocating network access to each user for the second time interval.","Each user receives a first determined allowance of network access for utilization during the first time interval equal to that user's allocation for the first time interval, and a second determined allowance of network access for utilization during the second time interval equal to that user's allocation for the second time interval.","The user allocations—and hence the user allowances—preferably differ as between the first and second time intervals.","As used herein, a “bandwidth allowance” represents a respective maximum level of network access that will be made available to a user class or to a user during a particular time interval, and does not necessarily represent the level of network access that will be utilized by the user class or user during such time interval.","As used herein, a “user class” is intended to refer to a grouping of users who compete for access across a shared communications medium and who have some characteristic in common.","The characteristic may, for example, be that the users are customers who receive Internet service over the shared communications medium from the same service provider.","The characteristic also may, for example, be that the users each subscribe to receive a particular level of network access across the shared communications medium, or that the users receive the same level of a particular service that is provided across the shared communications medium.","Furthermore, a user class is a grouping of users to which, collectively, a determined amount of bandwidth is allocated as opposed to other user classes.","In this regard, users that are not classified are considered to be part of a default user class having in common that fact that no other classification applies to them.","Accordingly, all users of a shared communications network can be classified.","In features of the present invention, the method includes the steps of monitoring network access usage by the users, and forecasting network access usage of each user in a future time interval.","Another feature includes the step of prioritizing the users for the allocation of network access.","One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network and tracking the collective bandwidth consumption of each user class; based on the monitored bandwidth consumptions, the forecasting of bandwidth consumption of each user in a future time interval and the calculation based thereon of the collective bandwidth consumption of each user class; the prioritization of users and the prioritization of user classes; and the subsequent allocation of bandwidth to each user class, and then to each user, in decreasing order of priority for determining bandwidth allowances during the future time interval.","Users and user classes are prioritized based on one or more various prioritization policies, including fairness considerations such as individual or collective user throughput during a particular time interval, individual or collective user data loss for a particular time interval, individual or collective user bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.","Other prioritization policies include the prioritization of users and user classes based upon provisions found in each user's respective service level agreement (SLA) or provisions found in each class' service level agreement (CSLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval and the prioritization of user classes based upon each class' collective forecasted bandwidth consumption.","In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.","BRIEF DESCRIPTION OF THE DRAWINGS Further features and benefits of the present invention will be apparent from a detailed description of preferred embodiments thereof taken in conjunction with the following drawings, wherein like elements are referred to with like reference numbers, and wherein: FIG.","1 illustrates a conventional DOC Network; FIG.","2 illustrates a first DOC Network of the present invention; FIG.","3 illustrates a second DOC Network of the present invention; FIG.","4 illustrates a third DOC Network of the present invention; FIG.","5 illustrates a fourth DOC Network of the present invention; FIG.","6 illustrates a system architecture of software components that perform preferred methods of the present invention in the DOC Networks of FIGS.","2-5; FIG.","7 illustrates a flowchart of the steps of a preferred routine for forecasting bandwidth of each user for a future time interval; FIG.","8 illustrates a flowchart of the steps of generating a forecasted bandwidth for a user in accordance with the ARRSES Function of the preferred routine of FIG.","7; FIG.","9 illustrates a flowchart of the steps of generating a forecasted bandwidth for a user in accordance with the HW Function of the preferred routine of FIG.","7; FIG.","10 illustrates a graph of user throughput rates versus user data loss rates for two users relative to a target minimum QoS standard; FIG.","11 illustrates a flowchart of a first preferred method of prioritizing classes and allocating collective bandwidth to each class; FIG.","12 illustrates a flowchart of a second preferred method of prioritizing classes and allocating collective bandwidth to each class; FIG.","13 illustrates a flowchart of a third preferred method of prioritizing classes and allocating collective bandwidth to each class; FIG.","14 illustrates a flowchart of a fourth preferred method of prioritizing classes and allocating collective bandwidth to each class; FIGS.","15a and 15b illustrate a flowchart of a fifth preferred method of prioritizing classes and allocating collective bandwidth to each class; FIGS.","16a and 16b illustrate a flowchart of a sixth preferred method of prioritizing classes and allocating collective bandwidth to each class; FIG.","17 illustrates a flowchart of a first preferred method of prioritizing users and allocating bandwidth to each user within a class; FIG.","18 illustrates a flowchart of a second preferred method of prioritizing users and allocating bandwidth within a class; FIG.","19 illustrates a flowchart of a third preferred method of prioritizing users and allocating bandwidth within a class; FIG.","20 illustrates a flowchart of a fourth preferred method of prioritizing users and allocating bandwidth within a class; FIGS.","21a and 21b illustrate a flowchart of a fifth preferred method of prioritizing users and allocating bandwidth within a class; FIGS.","22a and 22b illustrate a flowchart of a sixth preferred method of prioritizing users and allocating bandwidth within a class; FIG.","23 illustrates a flowchart of a preferred method of updating a DOC Network for a DOCSIS 1.0 compliant Cable Network; FIG.","24 illustrates the allocation of bandwidth to users within a class during a first time interval; FIG.","25 illustrates the allocation of bandwidth to the users of FIG.","24 during a second time interval; and FIG.","26 illustrates a flowchart of a preferred method of soliciting a user to modify the user's SLA based on monitored network access usage of the user.","DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS In the following detailed description, numerous specific details are set forth with regard to preferred embodiments of the present invention in order to provide a thorough understanding of the present invention; however, it will be apparent to ordinary artisans that the present invention may be practiced without all of these specific details.","Well-known structures and devices also are shown in block diagram form, the specific details of which are not considered a necessary part of the present invention.","Furthermore, as will become apparent to ordinary artisans, the present invention may be embodied in or performed by hardware, firmware, or software, or various combinations thereof.","As described above, a conventional DOC Network 40 is shown in FIG.","1 and includes a plurality of Cable Networks 38, with a particular Cable Network 38 being illustrated in an expanded view and comprising a group of CMs 34, each connected to a computer 44 representing a user.","Additionally, as used herein, “user” includes not only a person who interacts with a computer 44, but any additional persons who also interact with the same computer 44, as well as any group of persons all of whom interact with computers attached either to the same CM 34 or to the same computer 44 which, itself, is attached to a CM 34.While not shown, such additional arrangements are well known in the art.","The CMs 34 are connected by a coaxial cable 32 with a CMTS 30 and, specifically, to a card 31 mounted within the CMTS 30.Each of the CMTSs of the DOC Network 40 preferably includes a plurality of cards, with each card supporting a group of CMs connected thereto in an inverted tree configuration to define a Cable Network 38.Furthermore, each CMTS conventionally supports up to 1,500 users, although recent CMTSs have been introduced that support up to 15,000 users.","Each Cable Network 38 defines a Shared Access Carrier Network, wherein data of respective users in each are conveyed together through a shared coaxial cable.","For instance, data packets (or frames) addressed to at least one of the computers 44 are transmitted by the CMTS 30 downstream over the coaxial cable 32 to all of the CMs 34 within a 6 MHz data channel.","Conversely, data packets intended for delivery to the CMTS 30 and beyond are transmitted by a CM 34 upstream to the CMTS 30 over the coaxial cable 32 within a 2 MHz channel.","The Cable Network 38 shown in expanded view in FIG.","1 is a traditional all coaxial cable network.","The other Cable Networks 38 collectively include both traditional all coaxial cable networks as well as HFC networks.","The CMTS 30 transmits and receives data packets between the Cable Networks 38 and an Intermediate Network 46, which begins with a router 48 in the headend 36, and includes switched and routed network equipment at a Regional Data Center 50 that provides connectivity to service providers 52,54,56,58, either directly or through the Internet 60.In this regard, during user communications the router 48 conveys data packets from the CMTS 30 to the Regional Data Center 50 of the DOC Network 40 and, conversely, routes data packets received from the Regional Data Center 50 to the appropriate CMTS for delivery to a particular user.","Data packets that are conveyed to the Regional Data Center 50, in turn, are directed on to an appropriate service provider 52,54 directly connected to the Regional Data Center 50, or to an appropriate service provider 56,58 indirectly connected to the Regional Data Center 50 via the Internet 60.Alternatively, data packets from users are conveyed to a server of an application server group 62 of the Regional Data Center 50, which includes, for example, servers supporting Web hosting, news, chat, SMTP, POP3, Proxy, cache and content replication, and streaming media.","The Cable Networks 38 stemming from headend 36 are maintained by a Carrier which also may maintain the Regional Data Center 50 as well as serve as a service provider.","Moreover, the Carrier may maintain the Cable Networks of additional headends 64,66, or of only one or more of the headends 64,66.In any event, the Cable Networks that are maintained by the Carrier are administered on a daily basis through an element management system (EMS) 68.The EMS 68 comprises an operations system designed specifically to configure and manage CMTSs and associated CMs, and includes a CM database 70.Operational tasks performed by the EMS 68 include provisioning, day-to-day administration, and testing of various components of each CMTS.","The EMS 68 typically is located at a central network operations center of the Carrier, but may be collocated at the headend 36 of the Carrier as shown in FIG.","1.The DOC Network 40 is managed through a control plane server group 72 typically located at the Regional Data Center 50.The control plane server group 72 includes the usual servers necessary to run the DOC Network 40, such as user authorization and accounting servers, log control servers (Syslog), IP address assignment and administration servers (DHCP, TFTP), domain name servers (DNS), and DOCSIS control servers.","For purposes of comparison, two dedicated connections also are shown in FIG.","1, wherein a telephony modem 74 and an ISDN modem 76 are connected directly to the Intermediate Network 46 at the Regional Data Center 50.As will be immediately apparent, data conveyed over each dedicated connection is between a single user and the Intermediate Network 46, and is not combined with data of other users over a shared communications medium as in each Cable Network 38.As is common in conventional Cable Networks 38 such as those shown in the DOC Network 40 of FIG.","1, when a CM comes online the CM is assigned a configuration file which, inter alia, sets a constant limit on the bandwidth that can be utilized in the downstream direction by the CM during any particular interval of time, and sets a constant limit on the bandwidth that can be utilized in the upstream direction by the CM during any particular interval of time.","The configuration file also includes other parameters, such as the IP address for the CM.","The configuration file for each CM conventionally is obtained by the CM when first brought online, or when the CM is reset.","The upstream and downstream bandwidth limits are predetermined by the Carrier or other appropriate entity, the determination of which is based on the expected number of users to be serviced by the particular Cable Network 38 to which the CM belongs.","With particular regard to data transmissions in the downstream direction, when the bandwidth limit is reached in receiving data within a particular time interval, the CM transmits a signal to the router 48 to cease further data forwarding for the remainder of the time interval.","Thereafter, whereas any data received by a CMTS is relayed on to the CM as the data is received, any additional data received by the router 48 during the remainder of this time interval is stored for later transmission in a buffer up to a threshold limit and, thereafter, any further data received within the time interval is dropped.","With regard to data transmissions in the upstream direction, when the CM registers with the CMTS following receipt by the CM of its configuration file, the CM informs the CMTS of the constant bandwidth limit to be applied to upstream transmissions from the CM.","Then, actual requests for bandwidth (i.e., requests for timeslots) for transmission of data in the upstream direction are submitted regularly by each CM to the CMTS.","In response to the submissions, the CMTS schedules timeslots in a particular time interval to the CMs for exclusive transmission of data within each timeslot by a respective CM.","However, the CMTS does not grant an amount of bandwidth (by assigning too many timeslots) to a particular CM that would exceed the constant bandwidth limit for the particular CM.","The timeslots are assigned to requesting CMs based on an established assignment policy.","For example, timeslots may be assigned by the CMTS on a first-in-first-out basis, or timeslots may be assigned equally to the CMs that request bandwidth within a particular window of time.","The requesting CMs also may be prioritized by the CMTS for assignment of the timeslots.","Preferred embodiments 78,80,82,84 of a DOC Network in accordance with the present invention are shown, respectively, in FIGS.","2-5, wherein each includes a “network access manager” 86 in accordance with the present invention.","In FIG.","2 the network access manager 86 is located in the headend 36 of the DOC Network 78, in FIG.","3 the network access manager 86 is located at the Regional Data Center 50 of the DOC Network 80, and in FIGS.","4-5 the network access manager 86 is remotely located, but is disposed for communication with the respective DOC Network 82,84, either directly as shown in the DOC Network 82 of FIG.","4, or indirectly via the Internet 60 as shown in the DOC Network 84 of FIG.","5.The network access manager 86 preferably comprises a hardware component having software modules for performing methods in accordance with the present invention.","For commercial purposes, especially in enhancing existing DOC Networks, preferably the network access manager 86 is self-contained and need only be connected in communication with the DOC Network to operate correctly.","In a DOC Network that is being upgraded or established, preferably the software modules are distributed within the DOC Network itself and may or may not include any additional hardware components such as the network access manager 86.For example, the software modules may be incorporated into the EMS, CMTS, and control plane server group of a DOC Network, thereby avoiding the expense of additional computer hardware components.","In order to accommodate deployment and implementation of the present invention, the software modules preferably are designed as peers within a messaging infrastructure and, in particular, within a CORBA infrastructure 87, the system architecture of which is shown in FIG.","6.Due to the interoperability of the peers to the CORBA infrastructure 87, the separate modules readily call upon each other as described in detail below without regard to differences in location between the modules.","Nevertheless, for ease of deployment, the network access manager 86 is best suited for deployment and implementation of the present invention in established DOC Networks, whether situated within the Intermediate Network as in FIGS.","2-3, or remotely situated as in FIGS.","4-5.The software modules include a Data Collector 88, a Database Manager 90, Bandwidth Allocator 92, and GUI & Report Generating Engine 94.The Data Collector 88 and Bandwidth Allocator 92 each includes an external system interface layer 96,98, respectively, that enables it to communicate with network equipment of a DOC Network.","In the system architecture of preferred embodiments, the Data Collector 88 communicates with each CMTS and CMs of each Cable Network for which network access is managed by the network access manager 86, and the Bandwidth Allocator 92 communicates with the control plane server group 72 of the DOC Network as well as with the CMTS and CMs.","If a DOC Network is DOCSIS 1.0 compliant, then each external system interface layer 96,98 is a DOCSIS external system interface layer.","If a DOC Network uses proprietary interface specifications, then each external system interface layer 96,98 is designed based on the proprietary interface specifications.","In either case, however, the Data Collector 88 and Bandwidth Allocator 92 generally need not be modified; only the external systems interface layers 96,98 thereof need be changed based on the particularities of the DOC Network.","Each of the Data Collector 88 and Bandwidth Allocator 92 also includes a scheduling element 100,102, respectively, that schedules the timing of actions and communications thereof with the network equipment of a DOC Network.","The GUI & Report Generating Engine 94 communicates with an Administrator 106 of the network access manager 86, preferably through a web server, whereby the Administrator 106 sets up and configures the network access manager 86 and accesses reports generated by the network access manager 86, such as graphs of bandwidth consumption and bandwidth requested per time interval for a user.","The Administrator 106 may be the Carrier, a service provider, or some other entity, such as the entity managing the Regional Data Center 50 or a third-party responsible for maintenance of the network access manager 86.The Database Manager 90 stores configuration and setup information received from the GUI & Report Generating Engine 94, as well as information processed by the Data Collector 88.The Database Manager 90 also provides information to the Bandwidth Allocator 92 and GUI & Report Generating Engine 94 as requested via the CORBA infrastructure 87.Having now described in detail the structure of preferred DOC Networks 78,80,82,84, preferred methods of the present invention will be described with reference thereto.","In accordance with preferred methods of the present invention, network access usages of each user in the upstream and downstream directions are monitored through the Data Collector 88.Specifically, the Data Collector 88 issues queries to the CMTS and CM to which counter values of logical data units (LDUs) are returned for a user.","Preferably, counter values are returned for the number of bytes and the number of data packets that are transmitted in both the upstream and downstream directions, the number of bytes and the number of data packets that are dropped in both the upstream and downstream directions, the number of bytes and the number of packets that are requested to be transmitted in the upstream direction, and the time for which the counter values are returned.","Accordingly, as used herein the phrase “monitoring network access usage” is intended to refer to the collection of data representative of at least one of: (i) the number of LDUs that are transmitted in a particular direction across a shared communications medium; (ii) the number of LDUs that are dropped in transmitting in a particular direction across a shared communications medium; and (iii) the number of LDUs that are requested to be transmitted in a particular direction across a shared communications medium.","In a DOCSIS compliant DOC Network, the information is collected from the CMTS and CMs of a Cable Network via the simple network management protocol (SNMP).","The counter values for bytes and data packets that are transmitted and that are dropped in the upstream direction from each CM, and the number of bytes and data packets that are requested to be transmitted in the upstream direction from each CM, are recorded by the CMTS in accordance with a management information base (MIB) of a DOCSIS compliant CMTS.","Likewise, the counter values for bytes and data packets that are transmitted and that are dropped in the downstream direction from the CMTS to a CM are recorded by the CM in accordance with a MIB of a DOCSIS compliant CM.","Both bytes and data packets are monitored since each data packet may vary in the number of bytes it contains.","The scheduling element 100 of the Data Collector 88 initiates the data collection from each CMTS and from the CMs connected thereto, preferably at different predetermined time intervals.","For example, the data collection from a CMTS preferably occurs at five minute intervals and data collection from the CMs connected thereto preferably occurs at thirty minute intervals.","The data collection from the CMs preferably is less often than the data collection from the CMTS in order to minimize consumption of bandwidth across the Cable Network that otherwise would be allocated to users.","When the counter values and time thereof are returned to the Data Collector 88, the Data Collector 88 calculates the change over time for each counter value to arrive at the average rates of bytes and data packets that are successfully transmitted, the average rates of bytes and data packets that are requested to be transmitted, and the average rates of bytes and data packets that are dropped.","The respective rates and time intervals for the rates (as well as the counter values and time stamp data) are then communicated to the Database Manager 90, which stores the information in a user statistics table (“stats”) for later use by the Bandwidth Allocator 92 and GUI & Report Generating Engine 94.The Bandwidth Allocator 92 continually determines the network access—or bandwidth in a Cable Network—that may be utilized by each user class, and by each user within each class, over succeeding time intervals.","Each allowance is determined by first allocating bandwidth to the user classes, and then allocating bandwidth to the users in each class, in accordance with one or more selected allocation policies.","Furthermore, as set forth above, each allowance is an amount of bandwidth up to which a user class or user may consume, but is not necessarily the amount of bandwidth that a user class or user will consume; it is an upper limit on such amount.","For example, with reference to FIG.","24, a selected allocation policy has resulted in the allocation of bandwidth to the users of the shared communications medium 2450 for a time interval extending from t0 to (t0+dt), User 2 and User K each is allocated a single bandwidth unit (b/w unit 3 and b/w unit X, respectively), while User 1 and User 3 each is allocated two bandwidth units (b/w unit 1 and b/w unit 2 to User 1, and b/w unit 4 and b/w unit 5 to User 3).","As shown in FIG.","25, in the next time interval extending from (t0+dt) to (t0+2dt), User 1, User 3, and User K each is allocated a single bandwidth unit (b/w unit 1, b/w unit 5, and b/w unit X, respectively), while User 2 is allocated three bandwidth units (b/w unit 2, b/w unit 3, and b/w unit 4).","In this example, all users are grouped within the same class, and the bandwidth units in this example broadly represent network access to the communication member 2400 that is shared between the users across the shared communications medium 2450.In accordance with the present invention, respective user bandwidth allowances for each time interval are equated with these user allocations of bandwidth, whereby no user receives more bandwidth in a time interval than that user's respective bandwidth allowance for that time interval.","Furthermore, it is important to distinguish what a user actually may be “allocated” in the context of the bandwidth that is actually utilized or consumed by such user, as opposed to bandwidth allocations to a user in accordance with the present invention.","The bandwidth allocation in accordance with the present invention represents a limit on the amount of bandwidth that can be allocated to a user for a time interval—and hence is equated with a bandwidth allowance; it does not represent per se the amount of bandwidth that the user actually will utilize in the time interval.","In determining network access allocations (and thus allowances) in the preferred embodiments herein described, the Bandwidth Allocator 92 preferably performs three routines, including: the prediction of bandwidth of each user class, and each user within each class, in a predetermined future interval of time (“First Routine”); the prioritization of user classes, and users within each class, for allocation of bandwidth (“Second Routine”); and the actual allocation of bandwidth for each user class, and each user within each class, for determining the bandwidth allowances for the future time interval (“Third Routine”).","The First Routine preferably is performed utilizing statistical analysis of past bandwidth consumption of each user or, alternatively, past bandwidth requested for each user, and the forecasted bandwidth includes the bandwidth expected to be consumed by each user or, alternatively, the bandwidth expected to be requested by each user.","Any function, method, or algorithm that generates an estimate of a future sample based on previously encountered samples may be used and many are well known in the art of statistical analysis as is evident from SPYROS MAKRIDAKIS ET AL., FORECASTING METHODS AND APPLICATIONS (3d.","Ed.","John Wiley & Sons 1998), which is hereby incorporated by reference.","With regard to user classes, preferably a collective forecasted bandwidth for each class is determined by summing the forecasted bandwidth of all users within the class.","The preferred algorithm for predicting each user's forecasted bandwidth includes the combined use of an adaptive-response-rate single exponential smoothing function (ARRSES Function) and a Holt-Winters' seasonal exponential smoothing function (HW Function).","These two functions are utilized according to the forecast generation flowchart of FIG.","7.The input includes a list of active users and the applicable time intervals for bandwidth allocation.","The First Routine 700 begins by identification (Step 702) of the users of the Cable Network to which bandwidth is to be allocated in the Third Routine.","Then, for each user, bandwidth for a succeeding time interval is predicted according to either the ARRSES Function or HW Function by first determining (Step 704) whether the user previously has been assigned a forecast function.","If not, then in Step 706 the ARRSES Function is assigned to the user and the ARRSES Function is used to generate and record the forecasted bandwidth for the succeeding time interval.","On the other hand, if it is determined in Step 704 that a forecast function is assigned, but it is determined in Step 707 that the forecast function is not the HW Function, then a determination is made (Step 708) whether to check for a seasonal cycle of the user.","This determination in Step 708 is made by checking the elapsed time since the last seasonal check was made, with a seasonal check being made after a predetermined period of time elapses.","If the determination in Step 708 is affirmative, then a seasonal identifier algorithm is executed (Step 710), in which an autocorrelation function and a seasonal identifier function are performed.","The autocorrelation function is well known in the art of statistical analysis, and is used to identify elements in a time series which are influential on a current observation of that same series.","Based on the output of the autocorrelation function, the seasonal identifier function identifies possible seasonal cycles of the time series by identifying local maxima of the results of the autocorrelation function.","Based on the results of the seasonal identifier function, a determination is made (Step 712) whether an actual seasonal pattern exists.","If a seasonal pattern is not found, or if it is not yet time to check for a seasonal cycle, then a forecast is generated and recorded (Step 714) using the ARRSES Function.","If a seasonal pattern is found, then the HW Function is assigned (Step 716) to the user, the HW Function is initialized (Step 718), and the first forecast is generated and recorded (Step 720) using the HW Function.","If it is determined in Step 707 that the current function assigned to the user already is the HW Function, then the determination is made (Step 722) whether the last forecasted bandwidth was acceptable.","This determination is made by comparing whether the forecasted bandwidth was within 10% of the actual bandwidth consumed or requested.","If this determination in Step 722 is negative, then the ARRSES Function is assigned to the user and the new forecast is generated and recorded in accordance with the ARRSES Function (Step 706).","If the last forecast is determined (Step 722) to have been acceptable, then a determination is made (Step 724) whether the seasonal cycle has ended.","If the seasonal cycle has ended, then the HW Function is reinitialized (Step 726), and the first forecast of the next seasonal cycle is generated and recorded (Step 728) via the HW Function.","If the seasonal cycle has not expired, then the next forecast is generated and recorded (Step 730) in accordance with the HW Function.","Following each of Step 706, Step 714, Step 728, and Step 730, the Bandwidth Allocator 92 determines (Step 732) whether the forecasting has been completed for all users and, if not, then repeats (Step 738) a forecast loop for a remaining user.","If it is determined in Step 732 that all users have been evaluated, then the forecasts are communicated (Step 736) to the Database Manager 90 and the forecasting routine ends.","A forecast of bandwidth for a user in a future time interval is generated in accordance with the ARRSES Function via the following formulas: FN+1=FN+αN(BN−FN) αN+1=|SEN/SAEN| SEN+1=SEN+β(BN+1−FN+1−SEN) SAEN=β|(BN−FN)|+(1−β)SAEN−1 wherein, F is the bandwidth that is expected to be consumed by a user for a time interval (or the bandwidth that is expected to be requested by a user); B is the bandwidth that is actually consumed by a user for the time interval (or the bandwidth that is actually requested by a user); N is the present time interval; N−1 is the previous (immediate past) time interval; N+1 is the next (immediate future) time interval; and β is a selected parameter affecting the responsiveness to change of the ARRSES Function when the bandwidth of a user changes between time intervals.","Bandwidth is predicted both for the 6 MHz channel in the downstream direction as well as the 2 MHz channel in the upstream direction.","Preferably each time interval is thirty minutes in length, but preferably may range from fifteen minutes to sixty minutes in length when bandwidth is forecast in the downstream direction.","Preferably each time interval is five minutes in length, but preferably may range from one minute to fifteen minutes in length when bandwidth is forecast in the upstream direction.","The steps in generating a forecast in accordance with the ARRSES Function are set forth in FIG.","8, and include the calculation (Step 802) of a forecast error, the calculation (Step 804) of a smoothed error, the calculation (Step 806) of a smoothed absolute error, the calculation (Step 808) of alpha, and the calculation (Step 810) of the new forecast.","A forecast of bandwidth of a user for a future time interval is generated in accordance the HW Function via the following formulas: Ls=1/s(Y1+Y2+ .",".",".","+Ys) bs=1/S[(Ys+1−Y1)/s+(Ys+2−Y2)/s+ .",".",".","+(Y2s−Ys)/s] S1=Y1/Ls,S2=Y2/Ls, .",".",".","Ss=Ys/Ls Lt=α(Yt/St−s)+(1−α)(Lt−1+bt−1) bt=β(Lt−Lt−1)+(1−β)bt−1 St=γYt/Lt+(1−γ)St−s Ft+m=(Lt+btm)St−s+m wherein, Li=an average level of bandwidth after time interval i, bi=the trend after time interval i, si=the seasonal influence at time interval i, s=length of seasonal cycle (in number of time intervals), Yi=monitored bandwidth consumed or requested in time interval i t=time of initialization, m=the number of time intervals into the future for which a forecast is made, and α, β, and γ are parameters of the forecast method whose values are determined by doing a grid search over the domain of possible values of these parameters in an attempt to minimize the mean-squared-error of the forecast method, each of α, β, and γ falling between 0 and 1.The steps in generating a forecast in accordance with the HW Function are set forth in FIG.","9, and include the initialization of the HW Function by determining Ls, bs, and S1, S2 .",".",".",", Ss in Step 902, if appropriate; the determination of the intermediate values of Lt, bt, and St in Step 904; and the determination of the forecast in Step 906, all in accordance with the above formulas.","The Second Routine performed by the Bandwidth Allocator 92 comprises the prioritizing of user classes, and of users within each class, to determine respective orders of allocations.","Prioritization is performed in accordance with one or more of various possible prioritization policies for users and for user classes.","With regard to users within each class, the prioritization policies may depend upon, for example, (i) each user's SLA, (ii) each user's forecasted bandwidth, (iii) fairness considerations, or (iv) any combination thereof.","User SLAs that at least partially affect prioritization policies include those that specify, for example: (i) a guaranteed minimum level of bandwidth; (ii) a time-of-day (TOD) minimum level of bandwidth; or (iii) a guaranteed minimum level of bandwidth up to a maximum burstable level of bandwidth with target probability.","Equivalently, such provisions also may be found in a CSLA for a class of which the user is a member.","Under a SLA or CSLA providing for a guaranteed minimum level of bandwidth for a user, a user will have a guaranteed minimum level of bandwidth for use at all times.","Accordingly, if the available bandwidth to such a user otherwise would fall below the minimum guaranteed level, then such a user is given priority over all other users whose guaranteed minimum levels of bandwidth (if applicable) have been satisfied.","Similarly, under a SLA or CSLA providing for a TOD minimum level of bandwidth for a user, a user will have a guaranteed minimum level of bandwidth for a particular TOD.","If the available bandwidth to such a user otherwise would fall below the minimum guaranteed level during the particular TOD, then such user is given priority over all other users whose guaranteed minimum levels of bandwidth (if applicable) have been satisfied.","Finally, under a SLA or CSLA providing for a guaranteed minimum level of bandwidth up to a maximum burstable level of bandwidth with target probability for a user, a user will have a guaranteed minimum level of bandwidth at all times and, in addition thereto, probably will have additional bandwidth up to a maximum level at any given time in accordance with the target probability.","Accordingly, if the bandwidth available to such user otherwise would fall below the minimum guaranteed level, then the user is given priority over all other users whose guaranteed minimum levels of bandwidth (if applicable) have been satisfied.","The user also is given priority over such other users in allocating additional bandwidth as needed up to the maximum level in accordance with the target probability.","Other SLA or CSLA provisions not relating to guaranteed levels of bandwidth also may affect a prioritization policy for users.","Thus, for example, a SLA or CSLA may specify a fee (in dollars per unit time per unit bandwidth) that is paid based upon bandwidth consumption by a user for a particular amount of time, and the fee may be different as between users.","Under these circumstances, prioritization may be determined so as to maximize fee revenues that are paid.","Similarly, a SLA or CSLA may specify a credit (in dollars per unit time per unit bandwidth) that is applied by the Carrier to an account based upon a bandwidth shortfall to a user for a particular amount of time when a guaranteed level of bandwidth for the user is not met.","Moreover, the credit may be different as between users.","Under these circumstances, prioritization may be determined so as to minimize the collective credits that a Carrier must apply.","An example of prioritization based upon the forecasted bandwidth of each user includes giving priority to a first user over all other users, each of whom have a forecasted bandwidth that is greater than that of the first user.","Prioritization may also be performed based on unilateral fairness considerations, especially when SLAs or CSLAs do not guarantee minimum levels of bandwidth for individual users, or when users otherwise would share equally in priority.","Thus, users may be prioritized based on, for example: (i) the throughput of each of the users for a given time interval, with priority going to the user with the lesser throughput; (ii) data packets dropped over a given time interval, with priority going to the user with the greater data loss; and (iii) throughput experienced during a particular time of day or day of the week with priority going to the user with the lesser throughput for the particular time of day or day of the week.","An example of fairness considerations that may be utilized in determining priority is illustrated in FIG.","10, wherein user throughput for a time interval is graphed against user data packets dropped in the time interval for Users A and B.","A target QoS standard for minimum throughput and maximum packet loss rates are established by the Carrier, whereby in the illustrated example each user is prioritized based on the user's absolute distance from the target QoS standard.","Thus, under this policy, User A experiencing higher throughput rate and a lower packet loss rate, and thus having a shorter distance from the standard, is prioritized lower than User B having a lower throughput rate and higher data loss rate.","With regard to user classes, prioritization policies are similar to those of the users and include, for example, (i) each CSLA, (ii) each class' collective forecasted bandwidth, (iii) fairness considerations, or (iv) any combination thereof.","CSLAs that at least partially affect prioritization policies for user classes include those that specify, for example: (i) a guaranteed minimum level of collective bandwidth for the user class; (ii) a time-of-day (TOD) minimum level of collective bandwidth for the user class; or (iii) a guaranteed minimum level of collective bandwidth up to a maximum burstable level of collective bandwidth with target probability for the user class.","Other CSLA provisions not relating to guaranteed levels of collective bandwidth also may affect a prioritization policy.","Thus, for example, each CSLA may specify a fee (in dollars per unit time per unit bandwidth) that is paid based upon collective bandwidth consumption by the users of a class for a particular amount of time, and the fee may be different as between different classes of users.","Under these circumstances, prioritization may be determined so as to maximize fee revenues that are paid to a Carrier.","Similarly, each CSLA may specify a credit (in dollars per unit time per unit bandwidth) that is applied by the Carrier based upon a collective bandwidth shortfall to the users of the class for a particular amount of time when a guaranteed level of collective bandwidth is not met.","Moreover, the credit may be different as between user classes.","Under these circumstances, prioritization may be determined so as to minimize the total credits that a Carrier may have to apply.","An example of prioritization based upon the collective forecasted bandwidth of each user class includes giving priority to a first user class over all other user classes, each of which has a respective collective forecasted bandwidth that is greater than that of the first user class.","Prioritization may also be performed based on unilateral fairness considerations, especially when CSLAs do not guarantee minimum levels of collective bandwidth, or when classes otherwise would share equally in priority.","Thus, user classes may be prioritized based on, for example: (i) the collective throughput of the users of a class for a given time interval, with priority going to the class with the lesser collective throughput; (ii) the collective data packets of a user class that are dropped over a given time interval, with priority going to the user class with the greater collective data loss; and (iii) the collective throughput of the users of a class experienced during a particular time of day or day of the week, with priority going to the user class with the lesser collective throughput for the particular time of day or day of the week.","The Third Routine performed by the Bandwidth Allocator 92 is the allocation of bandwidth to the user classes, and then to the users within each class, in accordance with one or more allocation policies as desired.","Examples of allocation policies for users include: (i) the equal distribution of all available bandwidth to all users; (ii) the distribution of all available bandwidth to all users proportional to each user's respective forecasted bandwidth; (iii) the distribution of bandwidth to each user equal to the user's respective forecasted bandwidth, with any surplus bandwidth being distributed to the users either equally or proportionally based upon the user's respective forecasted bandwidth; and (iv) the initial distribution of bandwidth to each user based upon the minimum of the user's guaranteed bandwidth or the forecasted bandwidth and, thereafter, incremental allocations of remaining bandwidth to all of the users.","Likewise, examples of allocation policies for user classes include: (i) the distribution of all available bandwidth by the Bandwidth Allocator 92 to all user classes proportional to the number of active users in each class; (ii) the distribution of all available bandwidth to all user classes proportional to each class' respective collective forecasted bandwidth; (iii) the distribution of bandwidth to each user class equal to the class' respective collective forecasted bandwidth, with any surplus bandwidth being distributed to the user classes either equally or proportionally based upon the class' respective collective forecasted bandwidth; and (iv) the initial distribution of bandwidth to each user class based upon the minimum of the class' guaranteed collective bandwidth or the collective forecasted bandwidth and, thereafter, incremental allocations of remaining bandwidth to all of the users classes.","Examples of alternate preferred methods of prioritizing user classes, and then allocating bandwidth to the classes, will now be described in detail, each of which utilizes one or more of the aforementioned user class prioritization and allocation policies.","Alternative preferred methods of prioritizing users within each class, and then allocating bandwidth to the users in each class, are set forth thereafter.","In either case, the preferred methods of prioritizing and allocating are initiated pursuant to the scheduling module 102 of the Bandwidth Allocator 92, which operates independently of the scheduling module 100 of the Data Collector 88.With regard to prioritization of and allocation to user classes, a first preferred method 1100 is illustrated in FIG.","11 and begins with the retrieval (Step 1102) of the collective forecasted bandwidth from the Database Manager 90 for all active user classes.","Whether a user class is active is determined by past collective bandwidth consumption of the class (or, alternatively, collective requested bandwidth for the users of the class), as revealed by the user stats maintained by the Database Manager 90.All user classes are then prioritized (Step 1104) based on each class' collective forecast in increasing order, whereby a class having a lesser collective forecasted bandwidth will be prioritized over a class having larger collective forecasted bandwidth.","A “surplus” is then set (Step 1106) to the total bandwidth available for allocation to the classes in the particular direction of communication over the shared communications medium at issue, and the total bandwidth available is then allocated (Step 1108) to each user class in an amount equaling the collective forecasted bandwidth subject to a respective maximum collective bandwidth value of the user class.","Preferably the maximum collective bandwidth value is determined either in the appropriate CSLA or by the Carrier, Administrator 106, or other entity.","Allocation of bandwidth to a user class additionally is subject to the actual availability of bandwidth following previous allocations thereof to user classes with equal or higher priority.","Following allocations to all user classes, any bandwidth determined (Step 1110) to be remaining is then allocated (Step 1112) to the classes in amount proportional to the number of active users in each class, subject of course to the respective maximum collective bandwidth value of the class.","The resulting class allocations are then recorded in the Database Manager 90 (Step 1114) as the bandwidth allowances for the classes.","The method 1200 illustrated in FIG.","12 is the same as that of FIG.","11, except that surplus bandwidth, if any, is allocated (Step 1102) proportional to the collective forecasted bandwidths of the user classes, again subject to the respective maximum collective bandwidth value of each user class.","The preferred method 1300 illustrated in FIG.","13 does not prioritize the user classes for purposes of allocation but, instead, treats all classes equally.","The method 1300 begins with the retrieval (Step 1302) of the collective forecasted bandwidth of each user class from the Database Manager 90.The surplus is then set to the total bandwidth available in the particular direction of communication, and the sum of all the collective forecasts is calculated (Step 1304).","The available bandwidth then is allocated (Step 1306) to all classes proportional to the class' collective forecasted bandwidth, again subject to the respective maximum collective bandwidth value for each class.","The resulting class allocations then are recorded in the Database Manage 90 (Step 1308) as the bandwidth allowances for the classes.","The preferred method 1400 illustrated in FIG.","14 seeks to maximize revenues from fees (F) that are paid for class bandwidth consumption.","The method 1400 begins with the retrieval (Step 1402) of the collective forecast for each user class as well as a fee that is paid for the collective bandwidth of the class.","The classes are then sorted (Step 1404) based on these fees in decreasing order, with the class with the highest fee receiving the highest priority.","Next the surplus is set (Step 1406) to the total bandwidth available for allocation to the classes in the particular direction of communication.","Bandwidth then is allocated (Step 1408) to the classes as available from highest to lowest priority in an amount equal to the class' collective forecasted bandwidth, subject to the respective maximum collective bandwidth value for the class.","Both preferred method 1500 of FIGS.","15a and 15b, and preferred method 1600 of FIGS.","16a and 16b differ from the other methods 1100,1200,1300,1400 in that these two methods allocate bandwidth to the user classes in multiple allocation rounds.","Method 1500 begins in FIG.","15a with the retrieval (Step 1502) of the collective forecasted bandwidths of the classes as well as a credit (C) that applies if a respective class does not receive up to a guaranteed maximum level of collective bandwidth.","The classes are then prioritized (Step 1504) based on each class' respective credit in decreasing order, with those classes having higher credits being given priority over classes with lesser credits.","Next, the surplus is set (Step 1506) to the total bandwidth available to the classes in the particular direction of communication.","Bandwidth then is allocated (Step 1508) as available in a first round to the classes from highest to lowest priority.","The allocation for each class in the first round is equal to the minimum of the collective forecasted bandwidth or the maximum collective bandwidth that is guaranteed, subject to the respective maximum collective bandwidth value for the class.","If any additional bandwidth is determined (Step 1510) to remain after the first allocation round, then the surplus is set to the additional bandwidth (Step 1514).","Bandwidth then is allocated (Step 1516) as available to each class in the same class order.","Assuming sufficient bandwidth remains available, the allocation in the second round brings each class' allocation up to the class' collective forecasted bandwidth subject to the class' respective maximum collective bandwidth value.","Following the second allocation round, a determination is made (Step 1518) whether any remaining bandwidth exists and, if so, then the remaining bandwidth is allocated (Step 1522) to the classes proportional to each class' collective forecasted bandwidth, and subject to each class' respective maximum collective bandwidth value.","The resulting class allocations are then recorded (Step 1524) in the Database Manager 90 as the bandwidth allowances of the classes.","If it is determined that no bandwidth remains available in either of Step 1510 or Step 1518, then the class allocations are completed and are recorded in the Database Manager 90 in Steps 1512,1524, respectively.","Method 1600 of FIGS.","16a and 16b differs from that of FIGS.","15a and 15b only in that the sum of the collective forecasted bandwidths for all classes is calculated (Step 1602) and a determination is made (Step 1604) whether the sum exceeds the total bandwidth available for allocation to the classes.","If the sum exceeds the total available bandwidth, then bandwidth is allocated (Step 1606) to each class in an amount equal to the collective forecasted bandwidth of the class, subject to the class' maximum guaranteed collective bandwidth, and less an amount thereof proportional to the total bandwidth shortfall.","Thus, for example, if the sum of all collective forecasted bandwidths exceeds the total available bandwidth for allocation in an amount equal to 20% of all collective forecasted bandwidths, then each class is allocated bandwidth in an amount equal to the class' collective forecasted bandwidth (subject to the class' maximum guaranteed collective bandwidth), then less 20% thereof.","The information including fees, credits, guaranteed collective bandwidths, and respective maximum collective bandwidth values in the aforementioned preferred methods, is obtained from each CSLA and/or is predetermined by the Administrator 106, Carrier, or other entity.","Moreover, this information is retrieved by the Bandwidth Allocator 92 from the Database Manager 90, which includes and maintains a CSLA table for each class as well as information regarding users associated therewith, as updated from time-to-time by the Administrator 106.Specifically, the information is configured and maintained through GUIs provided as part of the GUI & Report Generating Engine 94, and is preferably accessed by the Administrator 106 either directly or indirectly through the Internet 60.Alternatively, information is retrieved by the Bandwidth Allocator 92 from an external database maintained by the Administrator, Carrier, or other entity through an application program interface (API) incorporated into the external system interface layer 98 of the Bandwidth Allocator 92.The use of an external database is preferred, as it eliminates any duplicative maintenance of information otherwise maintained by the Database Manager 90 which must be synchronized with the external database, including periodic updating of class and user records in a timely fashion.","Regardless of the particular method or policies utilized by the Bandwidth Allocator 92, once class allocations have been determined, the Database Manager 90 is updated with the new class allocations.","Then, for each class, allocations of bandwidth are made to the users in the class.","Furthermore, allocations within each class may be made by different methods.","A first preferred method 1700 of prioritizing users and allocating bandwidth (whether upstream or downstream) by the Bandwidth Allocator 92 is illustrated in FIG.","17 and begins with the retrieval (Step 1702) of the forecasted bandwidth from the Database Manager 90 for all active users.","Whether a user is active is determined by past bandwidth consumption of the user (or, alternatively, requested bandwidth for the user), as revealed by the user stats maintained by the Database Manager 90.All users are then prioritized (Step 1704) based on each user's forecast in increasing order, whereby users having lesser forecasted bandwidths will be prioritized over users having larger forecasted bandwidths.","The “surplus” is then set (Step 1706) to the total allocated bandwidth of the class (i.e., the class' collective bandwidth allowance) in the particular direction of communication, and the entire bandwidth allowance of the class is then allocated (Step 1708) to each user in an amount equaling the forecasted bandwidth of the user subject to a respective maximum bandwidth value of the user.","Preferably the respective maximum bandwidth value is determined either in the user's SLA, the respective CSLA of the class, or by the Carrier, Administrator 106, or other entity.","Allocation of bandwidth to a user additionally is subject to the actual availability of bandwidth following previous allocations thereof to users with equal or higher priority.","Following allocations to all users, any bandwidth determined (Step 1710) to be remaining out of the total class allowance is then allocated equally (Step 1712) to the users subject to the respective maximum bandwidth value for each user.","The new user allocations are then incorporated (Step 1714) into the DOC Network as the bandwidth allowances of the users.","The method 1800 illustrated in FIG.","18 is the same as that of FIG.","17, except that surplus bandwidth in the class, if any, is allocated (Step 1802) proportional to the forecasted bandwidths of the users in the class, again subject to each user's respective maximum bandwidth value.","The preferred method 1900 illustrated in FIG.","19 does not prioritize the users for purposes of allocation but, instead, treats all users equally.","The method 1900 begins with the retrieval (Step 1902) of the forecasted bandwidth for each user in the class from the Database Manager 90.The surplus is then set to the total allocated bandwidth of the class in the particular direction of communication, and the sum of all forecasts of the users in the class is calculated (Step 1904).","The total allocated bandwidth of the class then is allocated (Step 1906) to all users in the class proportional to the user's forecasted bandwidth, again subject to each user's respective maximum bandwidth value.","The user allocations then are incorporated into the DOC Network (Step 1908) as the bandwidth allowances of the users.","The preferred method 2000 illustrated in FIG.","20 seeks to maximize revenues from fees (F) that are paid for bandwidth consumption by the users.","The method 2000 begins with the retrieval (Step 2002) of the forecast for each user as well as a fee that is paid for bandwidth by each user.","The users are then sorted (Step 2004) based on user fees in decreasing order, with the user paying the most for bandwidth receiving the highest priority.","Next, the surplus is set (Step 2006) to the total allocated bandwidth of the class in the particular direction of communication.","Bandwidth then is allocated (Step 2008) to the users in the class as available from highest to lowest priority in an amount equal to each user's forecasted bandwidth, and subject to the user's respective maximum bandwidth value.","Both preferred method 2100 of FIGS.","21a and 21b, and preferred method 2200 of FIGS.","22a and 22b differ from the other methods 1700,1800,1900,2000 in that these two methods allocate bandwidth to the users in multiple allocation rounds.","Method 2100 begins in FIG.","21a with the retrieval (Step 2102) of the forecasted bandwidths of the users as well as a credit (C) that applies if a respective user does not receive up to a guaranteed maximum level of bandwidth.","The users are then prioritized (Step 2104) based on each user's respective credit in decreasing order, with those users having higher credits being given priority over users with lesser credits.","Next, the surplus is set (Step 2106) to the total allocated bandwidth of the class in the particular direction of communication.","Bandwidth then is allocated (Step 2108) as available in a first round to the users from highest to lowest priority.","The allocation in the first round for each user is equal to the minimum of the forecasted bandwidth or the maximum bandwidth that is guaranteed, subject to the user's respective maximum bandwidth value.","If any additional bandwidth is determined (Step 2110) to remain after the first allocation round, then the surplus is set to the additional bandwidth (Step 2114).","Bandwidth then is allocated (Step 2116) as available to each user in the same user order.","Assuming sufficient bandwidth remains available, the allocation in the second round brings the user's allocation up to the user's forecasted bandwidth subject to the user's respective maximum bandwidth value.","Following the second allocation round, a determination is made (Step 2118) whether any remaining bandwidth exists and, if so, then the remaining bandwidth is allocated (Step 2122) equally to the users, subject to each user's respective maximum bandwidth value.","The user allocations are then incorporated (Step 2124) into the DOC Network as the users' bandwidth allowances.","If it is determined that no bandwidth remains available in either of Step 2110 or Step 2118, then the user allocations are completed and are incorporated into DOC Network in Steps 2112,2124, respectively, as the users' bandwidth allowances.","Method 2200 of FIGS.","22a and 22b differs from that of FIGS.","21a and 21b only in that the sum of the forecasted bandwidths for all users is calculated (Step 2202) and a determination is made (Step 2204) whether the sum exceeds the total allocated bandwidth of the class.","If the sum exceeds the total allocated bandwidth of the class, then the bandwidth is allocated (Step 2206) to each user in an amount equal to the forecasted bandwidth, subject to the user's maximum guaranteed bandwidth, and less an amount thereof proportional to the total bandwidth shortfall.","Thus, for example, if the sum of all forecasted bandwidths exceeds the total allocated bandwidth of the class in an amount equal to 20% of the sum of all the forecasted bandwidths, then each user is allocated bandwidth in an amount equal to the user's forecasted bandwidth (subject to the user's maximum guaranteed bandwidth), then less 20% thereof.","The applicable class bandwidth allowances used in the aforementioned methods are obtained from the Database Manager 90.The information, including fees, credits, guaranteed user bandwidths, and maximum bandwidth values in the aforementioned methods, is obtained from each user's SLA or from any applicable CSLA, and/or is predetermined by the Administrator 106, Carrier, or other entity.","Moreover, this information is retrieved by the Bandwidth Allocator 92 from the Database Manager 90, which includes and maintains a user SLA table as well as a user billing table, as updated from time-to-time by the Administrator 106.Specifically, the information is configured and maintained through GUIs provided as part of the GUI & Report Generating Engine 94, and is preferably accessed by the Administrator 106 either directly or indirectly through the Internet 60.Alternatively, information is retrieved by the Bandwidth Allocator 92 from an external database maintained by the Administrator, Carrier, or other entity through an application program interface (API) incorporated into the external system interface layer 98 of the Bandwidth Allocator 92.The use of an external database is preferred not only for the CSLAs, but also for the SLAs and user billing tables, as it eliminates any duplicative maintenance of information otherwise maintained by the Database Manager 90 which must be synchronized with the external database, including periodic updating of user records in a timely fashion.","Regardless of the particular method or policies utilized by the Bandwidth Allocator 92, once user allocations have been determined under the aforementioned allocation policies, the respective DOC Network is updated with the resulting user allocations as the bandwidth allowances for the users for a particular time interval.","Each user is then allocated bandwidth during the particular time interval in an amount that is less than, or equal to, that user's bandwidth allowance.","Similarly, the collective bandwidth consumptions of a class by users therein is limited by that class' bandwidth allowance.","Preferably, the DOC Network is updated at periodic intervals of between one to fifteen minutes and, preferably every five minutes.","Furthermore, the periodic interval preferably corresponds to the scheduling of the Bandwidth Allocator 92 with regard to upstream transmissions.","With particular reference to FIG.","23, a preferred method 2300 of updating a DOC Network for a DOCSIS 1.0 compliant Cable Network with the user allowances is illustrated.","The DOC Network is updated by incorporating (Step 2302) the user allocations as bandwidth allowances (i.e., bandwidth limits) into CM configuration files (MD-5 files) for the CMs of the respective users.","As set forth above, each CM configuration file contains instructions for a respective CM that limits the actual bandwidth consumed by the CM in the upstream direction and in the downstream direction.","The CM configuration files are then sent (Step 2304) by the Bandwidth Allocator 92 to a Trivial File Transfer Protocol (TFTP) Server of the DOC Network, which maintains CM configuration files for the CMs of the Cable Network.","A command is also sent (Step 2306) to either of the CMs or the CMTS of the respective Cable Network causing the CMs to acquire and implement the CM configuration files maintained on the TFTP Server.","In addition to maintaining information regarding CSLAs, class allocations, SLAs, and user billing data in the Database Manager 90, the GUI & Report Generating Engine 94 further enables the Administrator 106 to analyze the user stats updated by the Data Collector 88, including the generation of reports and graphs regarding, for example, network access usage of the users over time as well as user throughput rates vs. data loss rates similar to that shown in FIG.","10.It additionally should be noted that a user may or may not be permitted to be grouped in one or more classes in accordance with the present invention.","If it is desired that classes be mutually exclusive, then some policy should be established for determining which class with which a user is associated as between competing classes.","If it is desired that classes not be mutually exclusive, then users falling within two or more classes will be allocated bandwidth within each class to the extent that no conflict arises as between the classes, and subject to any maximum allowed aggregated user bandwidth for all classes that may be established.","As now will readily be seen, the preferred methods and preferred networks of the present invention described in detail herein enable a Carrier to accommodate bandwidth concerns of service providers competing for the business of users of a shared communications medium in a Shared Access Carrier Network.","In particular, CSLAs now can be constructed in accordance with the present invention whereby a service provider is guaranteed some collective level of network access for the users of the shared communications medium that are customers of the service provider.","Furthermore, the provision of bandwidth to users who are customers of competing service providers can now be based on fairness considerations, even if one of the service providers is related to the Carrier.","In addition thereto, the differing demands for instantaneous throughput by users competing for access across the shared communications medium now can be accommodated in accordance with the present invention.","Indeed, a Carrier now is able to continuously vary bandwidth consumption limits for each user on an individual basis and for small time intervals, either in accordance with fairness considerations, forecasted network access usage of the users, or under contractual provisions governing network access.","It also will now be evident that the present invention gives rise to new business models that may be implemented by service providers for providing network access to users thereof and, in particular, to new ways of selling network access, which is also considered part of the present invention.","For example, in accordance with the present invention, network access now can be “wholesaled” to service providers by considering the users of the service provider a class and allocating bulk network access to such class pursuant to a CSLA between the Carrier and the service provider.","Through a CSLA, a Carrier can offer to the service provider a guaranteed minimum level of network access for the class that is constant throughout the day or week, or a guaranteed minimum level of network access that varies depending upon considerations such as the time of day or the day of week.","A Carrier also now can offer a guaranteed minimum level of network access to the class with a guaranteed maximum level of network access provided as needed in accordance with a target probability.","The service providers, in turn, then can offer different SLAs to the users that are its customers, essentially selling network access at the retail level.","Accordingly, service providers can be assured of levels of network access for the users that are their customers, and users can be assured of appropriate levels of network access to meet their individual demands.","Moreover, Carriers and/or service providers now can differentiate between users in charging for network access, thereby allowing Carriers and/or service providers to differentiate revenue streams for maximization of revenues.","The present invention also enables Carriers and/or service providers to offer “dynamic SLAs” to users.","The term “dynamic SLA” refers to a SLA that can be modified by a user as the user's demand for network access significantly changes, whether such modification is permanent or temporary.","In this regard, and in accordance with a preferred method 2600 of the present invention as illustrated in FIG.","26, the “network access retailer” (the entity selling the network access to the user) monitors (Step 2602) network access usage by users of a Shared Access Carrier Network and determines (Step 2604), for each user based on network access usage, whether a SLA provision other than those found in the user's current SLA would better meet the user's needs.","This determination is made by comparing the user's throughput, bandwidth consumption, and/or bandwidth requested for a predetermined period of time against a set of threshold values, including any guaranteed level of network access provided for in the user's SLA as well as any minimum QoS standard that are deemed necessary for user satisfaction by the network access retailer or other appropriate entity.","Thus, if the user's level of throughput, bandwidth consumption, and/or bandwidth requested for the predetermined time interval differs by a predetermined tolerance from a minimum threshold value, then the user is identified (Step 2606) as a “candidate” for modifying the SLA.","A similar process alternatively is used, wherein the user's forecasted bandwidth is compared to the threshold values and, if the difference exceeds a predetermined tolerance, then the user is deemed a candidate for modifying the user's SLA.","Once users have been identified as candidates, the candidates are filtered by screening (Step 2608) the candidates against a list of users for which solicitations are not to be made.","Those candidates passing the screening are then invited (Step 2610) to modify their respective SLAs.","The solicitation of the user preferably is performed via email, instant messaging, redirection of the user's web browser to a solicitation web page, generation and mailing of solicitation literature via U.S. mail, telemarketing, or other means of communication.","The solicitation includes an invitation for the user to modify the user's SLA by increasing for a fee the minimum level of network access guaranteed to the user.","The solicitation preferably also includes an invitation to make the modification permanent, or to make the modification only temporary and for a specific period of time.","Thus, for example, if a user is identified as having a high usage pattern at recurrent periods of time (such as every Saturday night when a particular webcast is viewed, or when an Internet game is played), then the user automatically is solicited with an invitation via instant messaging on the following Saturday night to increase the user's guaranteed network access for that night, for a predetermined number of following Saturday nights, and/or for every Saturday night.","Acceptance of the invitation by each user results in the modification (Step 2612) of the user's SLA for the appropriate period of time by increasing the level of network access the user is guaranteed (and/or the user's respective maximum bandwidth value, depending upon the policies used).","The solicited modification to the user's SLA is updated in the SLA database, which is then used during user prioritization and allocation of bandwidth by the Bandwidth Allocator 92.The resulting higher bandwidth allowance should enhance the user's experience and overall satisfaction with the Carrier Network.","In particular, the higher bandwidth (greater network access) should enhance the viewing of the webcast or the playing of the Internet game.","On the other hand, SLAs for which users decline solicitations are not modified.","Furthermore, if deemed appropriate, users declining a solicitation are recorded in the list against which candidates are screened.","Preferably, the Bandwidth Allocator 92 analyzes the user stats maintained by the Database Manager 90, identifies those users that are candidates for SLA modification, and initiates the solicitation of such candidates.","Information for each user's SLA for comparison with the user's stats automatically is obtained either from the Database Manager 90, or from an external database maintained by the network access retailer or other appropriate entity.","Furthermore, the Bandwidth Allocator 92 preferably performs this analysis for solicitation on a regularly scheduled basis.","In addition to such solicitations, a user of course may request a change in the level of network access guaranteed without having to receive first a solicitation.","Furthermore, the user may request that the change be for a temporary period of time such that, for example, the change is reversed after only a few hours, which would cover a viewing of a particular webcast or the playing of a particular Internet game beginning at the time of the request.","In view of the foregoing detailed description of the preferred embodiments and methods of the present invention, it readily will be understood by those persons skilled in the art that the present invention is susceptible of broad utility and application.","Many embodiments and adaptations of the present invention other than those herein described, as well as many variations, modifications, and equivalent arrangements, will be apparent from or reasonably suggested by the present invention and the foregoing description thereof, without departing from the substance or scope of the present invention.","Accordingly, while the present invention has been described herein in detail in relation to preferred embodiments, it is to be understood that this disclosure only is illustrative and exemplary of the present invention and is made merely for purposes of providing a full and enabling disclosure of the invention.","The foregoing disclosure is not intended nor is to be construed to limit the present invention or otherwise to exclude any such other embodiments, adaptations, variations, modifications and equivalent arrangements, the present invention being limited only by the claims appended hereto and the equivalents thereof.","Thus, for example, it will be apparent that, while preferred embodiments of the present invention have been described in the context of DOC Networks (including either a network of all coaxial cable, or a HFC network), the present invention nevertheless relates to any other network (whether wireline or wireless) wherein competing users share access across a shared communications medium including, for example, home networks and small networks in mass transit vehicles."]],"string":"[\n [\n \"Allocating access across shared communication medium\",\n \"A method of providing network access across a shared communications medium between competing users (86) includes the step of allocating network access for each user for a future time interval (102).\",\n \"Features include forecasting network access (1100) of the users in a future time interval, and prioritizing the users for allocating network access to the users.\",\n \"The network access allocations represent network access allowances available to the users during the future time interval, and further may represent network access usage.\",\n \"Classes of users can be allocated network access first (1114), and then each user allocated network access from the class allocation.\"\n ],\n [\n \"1.A method of providing network access across a shared communications medium between at least two competing users, comprising the steps of: (a) prior to a first time interval, determining for each user a respective first network access allowance representing a respective first maximum level of network access available to the user during the first time interval, but not necessarily representing the level of network access that will be utilized by the user during the first time interval; (b) during the first time interval, providing network access to each user such that the respective first network access allowance for each user is not exceeded; (c) prior to a second consecutive time interval, determining for each user a respective second network access allowance representing a respective second maximum level of network access available to the user during the second time interval, but not necessarily representing the level of network access that will be utilized by the user during the second time interval, at least one respective second network access allowance for a user differing from such user's respective first network access allowance; and (d) during the second time interval, providing network access to each user such that the respective second network access allowance for each user is not exceeded.\",\n \"2.The method of claim 1, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.\",\n \"3.The method of claim 1, wherein the first and second time intervals are consecutive time intervals.\",\n \"4.The method of claim 1, wherein each of the first time interval and the second time interval has a period of between one minute and sixty minutes.\",\n \"5.The method of claim 1, wherein the second network access allowance for each respective user differs from the first network access allowance for such user.\",\n \"6.The method of claim 1, wherein the first network access allowances for the users are determined by allocating network access to each user on a per user basis for the first time interval in accordance with a first selected allocation policy.\",\n \"7.The method of claim 6, wherein the second network access allowances for the users are determined by allocating network access to each user on a per user basis for the second time interval in accordance with a second selected allocation policy.\",\n \"8.The method of claim 7, wherein the first allocation policy differs from the second allocation policy.\",\n \"9.The method of claim 7, further comprising requesting a minimum level of network access for the first time interval for a user, and wherein said allocating network access to such user for the first time interval comprises setting the level of network access allocated to such user to a level equal to or greater than the requested minimum level.\",\n \"10.The method of claim 9, wherein said allocating network access to such user for the second time interval comprises setting the level of network access allocated to such user to a level less than the requested minimum level for the first time interval.\",\n \"11.The method of claim 1, further comprising the step of monitoring network access usage by each user.\",\n \"12.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of logical data units transmitted from and to each user during a past time interval.\",\n \"13.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a past time interval.\",\n \"14.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a past time interval.\",\n \"15.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a past time interval.\",\n \"16.The method of claim 11, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during a time interval.\",\n \"17.The method of claim 1, wherein the shared communications medium is part of a Cable Network and the shared communications medium comprises a coaxial cable.\",\n \"18.The method of claim 1, wherein the Shared Access Carrier Network comprises a wireless network.\",\n \"19.The method of claim 1, further comprising prioritizing the users for determining network access allowances.\",\n \"20.The method of claim 19, wherein said prioritizing is based on fairness considerations.\",\n \"21.The method of claim 20, wherein the users are prioritized based on user throughput during a past time interval, with a user with lesser throughput receiving priority over a user with greater throughput.\",\n \"22.The method of claim 20, wherein the users are prioritized based on data loss for each user during a past time interval, with a user with greater data loss having priority over a user with lesser data loss.\",\n \"23.The method of claim 20, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.\",\n \"24.The method of claim 20, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.\",\n \"25.The method of claim 20, wherein users are prioritized based on an established minimum quality of service (QoS) standard.\",\n \"26.The method of claim 19, wherein said step of prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.\",\n \"27.The method of claim 26, further comprising the step of monitoring network access usage by each user.\",\n \"28.The method of claim 27, wherein SLAs specify respective minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.\",\n \"29.The method of claim 27, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when said monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.\",\n \"30.The method of claim 27, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and said step of prioritizing includes comparing said monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.\",\n \"31.The method of claim 27, wherein SLAs provide respective fees for network access usage, and said step of prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.\",\n \"32.The method of claim 27, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and said step of prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.\",\n \"33.The method of claim 27, wherein SLAs specify respective minimum levels of network access for users, and said step of allocating network access comprises setting the respective levels of network access equal to each user's specified respective minimum level of network access.\",\n \"34.The method of claim 11, further comprising the step of forecasting network access usage by each user during a future time interval based on said step of monitoring network access usage by each user.\",\n \"35.The method of claim 34, wherein said step of forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.\",\n \"36.The method of claim 34, wherein said step of forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of the users.\",\n \"37.The method of claim 34, wherein the first network access allowances for the users are determined by allocating network access to each user on a per user basis for the first time interval in accordance with a first selected allocation policy.\",\n \"38.The method of claim 37, wherein said step of allocating network access comprises setting the respective levels of network access of the users proportional to each user's forecasted network access usage.\",\n \"39.The method of claim 37, further comprising the step of prioritizing the users for allocating network access.\",\n \"40.The method of claim 39, wherein said prioritizing is based on each user's forecasted network access usage.\",\n \"41.The method of claim 40, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.\",\n \"42.The method of claim 40, wherein said step of allocating network access comprises setting respective user levels of network access equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.\",\n \"43.The method of claim 40, wherein said step of allocating network access comprises setting respective user levels of network access equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.\",\n \"44.A method of providing during two consecutive time intervals network access across a shared communications medium between two competing users, comprising the step of varying between the two time intervals a respective network access allowance for each user, each respective network access allowance representing a maximum level of network access available to the respective user during a particular time interval, but not necessarily representing the level of network access that is utilized by the user during the particular time interval.\",\n \"45.A method of providing network access across a shared communications medium in a downstream direction towards competing users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; and (b) based on said monitored network access usage, allocating network access to each user on a per user basis for a future time interval.\",\n \"46.The method of claim 45, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.\",\n \"47.The method of claim 45, wherein each network access allocation represents a bandwidth allowance of a respective user during the future time interval.\",\n \"48.The method of claim 47, wherein each network access allocation represents bandwidth utilized by each user during the future time interval.\",\n \"49.The method of claim 45, wherein said step of monitoring comprises monitoring bandwidth that is consumed by each user in a downstream direction at time intervals of fifteen minutes to sixty minutes.\",\n \"50.The method of claim 45, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.\",\n \"51.The method of claim 45, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.\",\n \"52.The method of claim 45, wherein said step of monitoring network access usage includes collecting data representative of logical data units transmitted to each user during a time interval.\",\n \"53.The method of claim 45, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted to each user during a time interval.\",\n \"54.The method of claim 45, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.\",\n \"55.The method of claim 45, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.\",\n \"56.The method of claim 45, wherein said step of allocating network access comprises allocating network access equally to the users.\",\n \"57.The method of claim 45, wherein the shared communications medium is part of a Shared Access Carrier Network.\",\n \"58.The method of claim 57, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.\",\n \"59.The method of claim 57, wherein the Shared Access Carrier Network comprises a wireless network.\",\n \"60.The method of claim 45, further comprising prioritizing the users for allocating network access.\",\n \"61.The method of claim 60, wherein said prioritizing is based on fairness considerations.\",\n \"62.The method of claim 61, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput receiving priority over a user with greater throughput.\",\n \"63.The method of claim 61, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss having priority over a user with lesser data loss.\",\n \"64.The method of claim 61, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.\",\n \"65.The method of claim 61, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.\",\n \"66.The method of claim 61, wherein users are prioritized based on an established minimum quality of service (QoS) standard.\",\n \"67.The method of claim 60, wherein said step of prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.\",\n \"68.The method of claim 67, wherein SLAs specify respective minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.\",\n \"69.The method of claim 67, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when said monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.\",\n \"70.The method of claim 67, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and said step of prioritizing includes comparing said monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.\",\n \"71.The method of claim 67, wherein SLAs provide respective fees for network access usage, and said step of prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.\",\n \"72.The method of claim 67, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and said step of prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.\",\n \"73.The method of claim 67, wherein SLAs specify respective minimum levels of network access for users, and said step of allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.\",\n \"74.The method of claim 45, further comprising the step of forecasting network access usage by each user during the future time interval based on said step of monitoring network access usage by each user.\",\n \"75.The method of claim 74, wherein said step of forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.\",\n \"76.The method of claim 74, wherein said step of forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of the users.\",\n \"77.The method of claim 74, wherein said step of allocating network access comprises allocating network access to users proportional to each user's forecasted network access usage.\",\n \"78.The method of claim 74, further comprising the step of prioritizing the users for allocating network access.\",\n \"79.The method of claim 78, wherein said prioritizing is based on each user's forecasted network access usage.\",\n \"80.The method of claim 78, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.\",\n \"81.The method of claim 78, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.\",\n \"82.The method of claim 78, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.\",\n \"83.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; (b) forecasting network access usage by each user during a future time interval based on said monitored network access usage by each user; and (c) based on said forecasted network access usage, allocating network access to each user for the future time interval.\",\n \"84.The method of claim 83, wherein said step of forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.\",\n \"85.The method of claim 83, wherein said step of forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of the users.\",\n \"86.The method of claim 83, wherein said step of allocating network access comprises allocating network access to the users proportionally based on each user's forecasted network access usage.\",\n \"87.The method of claim 83, further comprising the step of prioritizing the users for allocating network access.\",\n \"88.The method of claim 87, wherein said prioritizing is based on each user's forecasted network access usage.\",\n \"89.The method of claim 87, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.\",\n \"90.The method of claim 87, wherein said prioritizing is based on fairness considerations.\",\n \"91.The method of claim 87, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput rate receiving priority over a user with greater throughput rate.\",\n \"92.The method of claim 87, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss rate having priority over a user with lesser data loss rate.\",\n \"93.The method of claim 87, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.\",\n \"94.The method of claim 87, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.\",\n \"95.The method of claim 87, wherein users are prioritized based on an established minimum quality of service (QoS) standard.\",\n \"96.The method of claim 87, wherein said step of prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.\",\n \"97.The method of claim 96, wherein SLAs specify respective minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.\",\n \"98.The method of claim 96, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when said monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.\",\n \"99.The method of claim 96, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and said step of prioritizing includes comparing said monitored network access usages both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access would have been utilized for such users.\",\n \"100.The method of claim 96, wherein SLAs provide a respective fee for network access usage by users, and said step of prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.\",\n \"101.The method of claim 96, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and said step of prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.\",\n \"102.The method of claim 96, wherein SLAs specify respective minimum levels of network access for users, and said step of allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.\",\n \"103.The method of claim 87, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.\",\n \"104.The method of claim 87, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.\",\n \"105.The method of claim 83, wherein each network access allocation represents a bandwidth allowance of a respective user during the future time interval.\",\n \"106.The method of claim 83, wherein each network access allocation represents bandwidth utilized by each user during the future time interval.\",\n \"107.A method of providing network access across a shared communications medium of a Cable Network between competing users, comprising the steps of: (a) monitoring network access usage by each user for a time interval; (b) based on said monitoring, forecasting the number of logical data units (LDUs) of each user that will be transmitted over a future time interval; and (c) based on said forecasting, allocating network access available to each user for the future time interval.\",\n \"108.A method of providing network access across a shared communications medium of a Cable Network between competing users, comprising the steps of: (a) monitoring network access usage requested by each user for a time interval; (b) based on said monitoring, forecasting the number of logical data units (LDUs) that will be requested by each user over a future time interval; and (c) based on said forecasting, allocating network access available to each user for the future time interval.\",\n \"109.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on said monitoring, forecasting network access usage by each user over a future time interval; (c) prioritizing users based on each user's forecasted network access usage in increasing order, whereby a user with a lesser forecasted network access usage receives a higher priority than a user with a greater forecasted network access usage; and (d) allocating network access available to each user during the future time interval in decreasing order of user priority, each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.\",\n \"110.The method of claim 109, wherein said step of allocating further comprises allocating any surplus network access remaining equally to the users.\",\n \"111.The method of claim 109, wherein said step of allocating further comprises allocating in decreasing user priority any surplus network access to the users proportionally to the user's forecasted network access usage.\",\n \"112.The method of claim 109, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.\",\n \"113.The method of claim 109, wherein said step of monitoring comprises monitoring network access usage by the users in an upstream direction at time intervals of one minute to fifteen minutes.\",\n \"114.The method of claim 109, wherein said step of monitoring comprises monitoring network access usage by the users in a downstream direction at time intervals of fifteen minutes to sixty minutes.\",\n \"115.The method of claim 109, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.\",\n \"116.The method of claim 109, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.\",\n \"117.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.\",\n \"118.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.\",\n \"119.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.\",\n \"120.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.\",\n \"121.The method of claim 109, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.\",\n \"122.The method of claim 109, wherein the shared communications medium is part of a Shared Access Carrier Network.\",\n \"123.The method of claim 122, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.\",\n \"124.The method of claim 122, wherein the Shared Access Carrier Network comprises a wireless network.\",\n \"125.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on said monitoring, forecasting network access usage by each user over a future time interval; and (c) allocating network access available to each user during the future time interval, each user's allocation of network access being equal to each user's forecasted network access usage multiplied by a ratio of the total available network access to the total forecasted network access usage of all the users, and subject to a respective, predetermined maximum value and subject to availability.\",\n \"126.The method of claim 125, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.\",\n \"127.The method of claim 125, wherein said step of monitoring comprises monitoring network access usage by the users in an upstream direction at time intervals of one minute to fifteen minutes.\",\n \"128.The method of claim 125, wherein said step of monitoring comprises monitoring network access usage by the users in a downstream direction at time intervals of fifteen minutes to sixty minutes.\",\n \"129.The method of claim 125, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.\",\n \"130.The method of claim 125, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.\",\n \"131.The method of claim 125, wherein said step of monitoring network access includes collecting data representative of the logical data units transmitted from and to each user during a time interval.\",\n \"132.The method of claim 125, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.\",\n \"133.The method of claim 125, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.\",\n \"134.The method of claim 125, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.\",\n \"135.The method of claim 125, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.\",\n \"136.The method of claim 125, wherein the shared communications medium is part of a Shared Access Carrier Network.\",\n \"137.The method of claim 126, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.\",\n \"138.The method of claim 126, wherein the Shared Access Carrier Network comprises a wireless network.\",\n \"139.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) charging each user a respective fee for network access usage; (b) monitoring network access usage by each user during a time interval; (c) based on said monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.\",\n \"140.The method of claim 139, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.\",\n \"141.The method of claim 139, wherein said step of monitoring comprises monitoring network access usage by the users in an upstream direction at time intervals of one minute to fifteen minutes.\",\n \"142.The method of claim 139, wherein said step of monitoring comprises monitoring network access usage by the users in a downstream direction at time intervals of fifteen minutes to sixty minutes.\",\n \"143.The method of claim 139, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.\",\n \"144.The method of claim 139, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.\",\n \"145.The method of claim 139, wherein said step of monitoring network access includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.\",\n \"146.The method of claim 139, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.\",\n \"147.The method of claim 139, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.\",\n \"148.The method of claim 139, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.\",\n \"149.The method of claim 139, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.\",\n \"150.The method of claim 139, wherein the shared communications medium is part of a Shared Access Carrier Network.\",\n \"151.The method of claim 150, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.\",\n \"152.The method of claim 150, wherein the Shared Access Carrier Network comprises a wireless network.\",\n \"153.A method of providing network access across a shared communications medium between competing users, comprising the steps of: (a) applying respective credits to users for network access shortfalls below respective levels of network access specified to the users; (b) monitoring network access usage by each user during a past time interval; (c) based on said monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's respective credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum specified value and subject to availability.\",\n \"154.The method of claim 153, wherein any additional network access remaining after said allocation is earmarked for the users such that each user's allocation equals the user's forecasted network access usage, subject to a respective, predetermined maximum allowed level of network access and subject to availability.\",\n \"155.The method of claim 154, wherein any surplus network access remaining after said distribution is further earmarked in equal amounts for the users, subject to a respective, predetermined maximum allowed level of network access.\",\n \"156.The method of claim 154, further comprising allocating to the users network access only in an amount equal to the forecasted network access usage multiplied by the ratio of total network access available for allocation to the total forecasted network access usage of the users, but only when the total forecasted network access usage of the users exceeds the total network access available for allocation.\",\n \"157.The method of claim 153, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.\",\n \"158.The method of claim 153, wherein said step of monitoring comprises monitoring network access usage by the users in an upstream direction at time intervals of one minute to fifteen minutes.\",\n \"159.The method of claim 153, wherein said step of monitoring comprises monitoring network access by the users in a downstream direction at time intervals of fifteen minutes to sixty minutes.\",\n \"160.The method of claim 153, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.\",\n \"161.The method of claim 153, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.\",\n \"162.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.\",\n \"163.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.\",\n \"164.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of each user that are dropped during a time interval.\",\n \"165.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of each user that are dropped during a time interval.\",\n \"166.The method of claim 153, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of each user that are requested to be transmitted in the upstream direction during a time interval.\",\n \"167.The method of claim 153, wherein the shared communications medium is part of a Shared Access Carrier Network.\",\n \"168.The method of claim 167, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.\",\n \"169.The method of claim 167, wherein the Shared Access Carrier Network comprises a wireless network.\",\n \"170.A method of providing network access across a shared communications medium between competing users pursuant to service level agreements (SLAs) of the users, comprising the steps of: (a) monitoring network access usage by each user during a time interval; (b) comparing said monitored network access usage by each user with a predetermined threshold value; and (c) soliciting a user to modify the user's SLA if the user's monitored network access usage varies from the predetermined value by a predetermined tolerance.\",\n \"171.The method of claim 170, wherein the threshold value represents a respective maximum level of network access for each user.\",\n \"172.The method of claim 170, wherein the threshold value represents a respective maximum burstable level of network access with target probability for each user.\",\n \"173.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via email.\",\n \"174.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via instant messaging.\",\n \"175.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via redirection of a web browser of the user to a solicitation web page.\",\n \"176.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via generation and mailing of literature.\",\n \"177.The method of claim 170, wherein said step of soliciting a user comprises contacting the user via a telephonic communication.\",\n \"178.The method of claim 170, wherein the modification of the user's SLA includes guaranteeing a level of network access to the user on a permanent basis.\",\n \"179.The method of claim 170, wherein the modification of the user's SLA includes guaranteeing a level of network access to the user with a maximum burstable level of network access with target probability.\",\n \"180.The method of claim 170, further comprising charging the user a fee for the modification of the SLA.\",\n \"181.The method of claim 170, wherein the modification of the user's SLA includes guaranteeing a level of network access to the user on a temporary basis.\",\n \"182.The method of claim 170, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.\",\n \"183.The method of claim 170, wherein said step of monitoring comprises monitoring the bandwidth that is consumed by each user in an upstream direction of communication across the shared communications medium at time intervals of one minute to fifteen minutes.\",\n \"184.The method of claim 170, wherein said step of monitoring comprises monitoring the bandwidth that is consumed by each user in a downstream direction of communication across the shared communications medium at time intervals of fifteen minutes to sixty minutes.\",\n \"185.The method of claim 170, wherein said step of monitoring network access includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.\",\n \"186.The method of claim 170, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.\",\n \"187.The method of claim 170, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.\",\n \"188.The method of claim 170, wherein said step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.\",\n \"189.The method of claim 170, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.\",\n \"190.The method of claim 170, wherein the shared communications medium is part of a Shared Access Carrier Network.\",\n \"191.The method of claim 190, wherein the Shared Access Carrier Network comprises a Cable Network and the shared communications medium comprises a coaxial cable.\",\n \"192.The method of claim 190, wherein the Shared Access Carrier Network comprises a wireless network.\",\n \"193.The method of claim 170, further comprising, based on said monitored network access usage, allocating network access to each user for a future time interval.\",\n \"194.The method of claim 193, wherein said step of allocating network access comprises allocating network access equally to the users.\",\n \"195.The method of claim 193, further comprising prioritizing the users for allocating network access.\",\n \"196.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs specify respective minimum levels of network access for the users, and said step of prioritizing includes comparing said monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.\",\n \"197.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and said step of prioritizing includes comparing said monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when said monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.\",\n \"198.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and said step of prioritizing includes comparing said monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.\",\n \"199.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs provide a respective fee for network access usage by users, and said step of prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.\",\n \"200.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and said step of prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.\",\n \"201.The method of claim 195, wherein said step of prioritizing is based on the SLAs of the users, wherein the SLAs specify respective minimum levels of network access for users, and said step of allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.\",\n \"202.The method of claim 195, wherein said prioritizing is based on fairness considerations.\",\n \"203.The method of claim 202, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput rate receiving priority over a user with greater throughput rate.\",\n \"204.The method of claim 202, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss rate having priority over a user with lesser data loss rate.\",\n \"205.The method of claim 202, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.\",\n \"206.The method of claim 202, wherein the users are prioritized based on both user throughput and data loss during a time interval.\",\n \"207.The method of claim 202, wherein users are prioritized based on an established minimum quality of service (QoS) standard.\",\n \"208.The method of claim 193, further comprising the step of forecasting network access usage by each user during the future time interval based on said step of monitoring network access usage by each user.\",\n \"209.The method of claim 208, wherein said step of forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.\",\n \"210.The method of claim 208, wherein said step of forecasting comprises applying an adaptive-response-rate signal exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of the users.\",\n \"211.The method of claim 208, wherein said step of allocating comprises allocating network access to the users proportionally based on each user's forecasted network access usage.\",\n \"212.The method of claim 208, further comprising the step of prioritizing the users for allocating network access.\",\n \"213.The method of claim 212, wherein said prioritizing is based on each user's forecasted network access usage.\",\n \"214.The method of claim 212, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.\",\n \"215.The method of claim 212, wherein said step of allocating comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.\",\n \"216.The method of claim 212, wherein said step of allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.\",\n \"217.A method of providing network access across a shared communications medium between competing users pursuant to service level agreements (SLAs) of the users, comprising the steps of: (a) monitoring network access usage by each user for respective predetermined past time intervals; (b) identifying a recurrent period of high network access usage of a user based on said monitoring; and (c) soliciting a user to modify the user's SLA to guarantee a minimum level of network access during an anticipated future recurrent period of high network access usage.\",\n \"218.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via email.\",\n \"219.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via instant messaging.\",\n \"220.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via redirection of a web browser of the user to a solicitation web page.\",\n \"221.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via generation and mailing of literature.\",\n \"222.The method of claim 217, wherein said step of soliciting a user comprises contacting the user via a telephonic communication.\",\n \"223.The method of claim 217, wherein the modification of the user's SLA includes guaranteeing a minimum level of network access to the user for all future recurrent periods of high network access usage.\",\n \"224.The method of claim 217, wherein the modification of the user's SLA includes guaranteeing a minimum level of network access to the user for a predetermined number of future recurrent periods of high network access usage.\",\n \"225.The method of claim 217, wherein the modification of the user's SLA includes guaranteeing a minimum level of network access to the user with a maximum burstable level of network access with target probability for the future period of high network access usage.\",\n \"226.The method of claim 217, wherein the recurrent time period of high network access usage comprises a particular time of day.\",\n \"227.The method of claim 217, further comprising charging the user a fee for modification of the user's SLA.\",\n \"228.A method of providing network access across a DOCSIS 1.0 compliant cable network of a data-over-cable (DOC) network to at least two users competing for bandwidth, comprising the steps of: (a) determining for each user a respective first bandwidth allowance for a first future time interval; (b) generating a first set of cable modem configuration files, each of which limits bandwidth consumption by a cable modem (CM) of a respective user to that user's first bandwidth allowance; (c) sending the configuration files to a Trivial File Transfer Protocol (TFTP) Server of the DOC Network; (d) sending a command either to each user's CM or to a cable modem termination system (CMTS) to which each user's CM is connected to cause each CM to acquire its new respective configuration file of the first set for the first time interval; (e) determining for each user a respective second bandwidth allowance for a second future time interval, a second bandwidth allowance of at least one of the users differing from that user's first bandwidth allowance; and (f) for each user having a second bandwidth allowance different from that user's first bandwidth allowance, (i) generating a second cable modem configuration file which limits bandwidth consumption of that user's CM to a value representative of that user's second bandwidth allowance; (ii) sending the second configuration file for that user to the TFTP Server of the DOC Network; and (iii) sending a command either to that user's CM or to the CMTS to which that user's CM is connected to cause the CM to acquire the second configuration file for that user for the second time interval.\",\n \"229.The method of claim 228, further comprising the steps of monitoring bandwidth of each user for a time interval and, based on said monitored bandwidth, determining each user's second bandwidth allowance.\",\n \"230.The method of claim 229, wherein said step of determining each user's second bandwidth allowance includes prioritizing each user and allocating bandwidth to each user according to such priority.\",\n \"231.The method of claim 230, wherein said step of prioritizing includes comparing said monitored bandwidth with respective values specified by service level agreements (SLAs) of the users.\",\n \"232.The method of claim 230, wherein said step of prioritizing includes comparing said monitored bandwidth of each user with an established minimum quality of service value.\",\n \"233.The method of claim 229, wherein said step of determining each user's second bandwidth allowance includes forecasting each user's bandwidth for the second future time interval.\",\n \"234.The method of claim 233, wherein said step of determining each user's bandwidth allowance includes prioritizing the users for allocation of bandwidth based on said forecasting.\",\n \"235.The method of claim 229, wherein said step of monitoring comprises monitoring the bandwidth that is consumed by each CM in the upstream direction during time intervals of one minute to fifteen minutes.\",\n \"236.The method of claim 229, wherein said step of monitoring comprises monitoring the bandwidth that is requested by each CM in the upstream direction during time intervals of one minute to fifteen minutes.\",\n \"237.The method of claim 229, wherein said step of monitoring comprises monitoring the bandwidth that is consumed by each CM in the downstream direction during time intervals of fifteen minutes to sixty minutes.\",\n \"238.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.\",\n \"239.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.\",\n \"240.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.\",\n \"241.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.\",\n \"242.The method of claim 229, wherein said step of monitoring includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in the upstream direction during a time interval.\",\n \"243.The method of claim 228, wherein the first time interval and the second time interval are consecutive time intervals.\",\n \"244.The method of claim 228, wherein each of the first time interval and the second time interval has a period of one to sixty minutes.\",\n \"245.The method of claim 228, wherein for each user, the first bandwidth allowance of that user differs from the second bandwidth allowance of that user.\",\n \"246.The method of claim 228, wherein the first bandwidth allowance for each user differs from the first bandwidth allowance of all other users.\",\n \"247.The method of claim 228, wherein the second bandwidth allowance for each user differs from the second bandwidth allowance of all other users.\",\n \"248.The method of claim 228, wherein the first bandwidth allowance of each user is determined by allocating bandwidth to each user on a per user basis for the first time interval in accordance with a first selected allocation policy.\",\n \"249.The method of claim 248, wherein the second bandwidth allowance of each user is determined by allocating bandwidth to each user on a per user basis for the second time interval in accordance with a second selected allocation policy.\",\n \"250.The method of claim 249, wherein the first and second allocation policies differ.\",\n \"251.The method of claim 249, wherein the first and second allocation policies are the same.\",\n \"252.A method of continuously providing network access across a cable network of a data-over-cable (DOC) network to at least two users competing for bandwidth, comprising the steps of: (a) determining for each user during present time intervals bandwidth allowances of such user for respective future time intervals, each bandwidth allowance of such user for a future time interval representing a maximum level of bandwidth consumption for such user during the future time interval, but not necessarily representing the amount of bandwidth that will be consumed by such user during such future time interval, the bandwidth allowances of each user varying as between time intervals; and (b) for each user, limiting during each respective future time interval bandwidth consumption of that user's cable modem (CM) to that user's respective bandwidth allowance for such time interval by implementing a new cable modem configuration file in the CM.\",\n \"253.The method of claim 252, wherein the present and future time intervals have a uniform period of one minute to sixty minutes.\",\n \"254.The method of claim 252, wherein each user's bandwidth allowance for each future time interval is determined by allocating bandwidth to the users on a per user basis for such future time interval in accordance with a selected allocation.\",\n \"255.A Carrier Network for providing communication between multiple users and a Service Provider, comprising: (a) computer network equipment defining an Intermediate Network and a shared communications medium, said Intermediate Network and said shared communications medium extending between the users and the Service Provider for conveying data therebetween, said shared communications medium joining the users with said Intermediate Network such that data of each user is conveyed over said shared communications medium to and from the Intermediate Network whereby the users compete for network access; and (b) software for managing network access of the users across said shared communications medium, said software including computer-executable instructions that performs the steps of: (i) monitoring the network access usage by each user for a time interval; and (ii) based on the monitored network access usage, setting a network access allowance for each user representing a level of network access made available for utilization by the user during a future time interval, but not necessarily representing the level of network access that will be utilized by such user during the future time interval.\",\n \"256.The Carrier Network of claim 255, wherein said network equipment futher defines a Cable Network and said shared communications medium comprises a coaxial cable of said Cable Network.\",\n \"257.The Carrier Network of claim 256, wherein said software comprises software modules distributed within computer readable media of said network equipment.\",\n \"258.The Carrier Network of claim 256, wherein said software comprises software modules stored in a computer readable medium of a hardware component.\",\n \"259.The Carrier Network of claim 258, wherein said hardware component is physically located with said network equipment.\",\n \"260.The Carrier Network of claim 259, wherein said Carrier Network comprises a Data-Over-Cable (DOC) Network and said hardware component is located within a regional data center of said DOC Network.\",\n \"261.The Carrier Network of claim 259, wherein said Carrier Network comprises a Data-Over-Cable (DOC) Network and said hardware component is located within a headend of said DOC Network.\",\n \"262.The Carrier Network of claim 258, wherein said hardware component is physically located remotely from said network equipment.\",\n \"263.The Carrier Network of claim 262, wherein said hardware component is directly connected with said network equipment for communication therebetween.\",\n \"264.The Carrier Network of claim 262, wherein said hardware component is indirectly connected with said network equipment through the Internet for communication therebetween.\",\n \"265.The Carrier Network of claim 256, wherein said software modules include: (i) a first software component that manages a database for storage and retrieval of data; (ii) a second software component that collects data representative of network access usage from said network equipment, and that sends data representative of network access usage to said first component for storage thereof; and (iii) a third component that retrieves data representative of network access usage stored in said first component and sets, based at least partially thereon, network access allowances for the users for the future time interval.\",\n \"266.The Carrier Network of claim 265, further includes a fourth component having a graphical user interface for sending data to said first component for storage and for retrieval of data stored by said first component.\",\n \"267.The Carrier Network of claim 255, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.\",\n \"268.The Carrier Network of claim 267, wherein the step of monitoring comprises monitoring bandwidth that is consumed by each user in an upstream direction across said shared communications medium in time intervals of one minute to fifteen minutes.\",\n \"269.The Carrier Network of claim 267, wherein the step of monitoring comprises monitoring bandwidth that is consumed by each user in the downstream direction across said shared communications medium in time intervals of fifteen minutes to sixty minutes.\",\n \"270.The Carrier Network of claim 255, wherein the time interval for which network access usage is monitored and the future time interval are equal in length.\",\n \"271.The Carrier Network of claim 255, wherein the time interval for which network access usage is monitored and the future time interval each is approximately one minute to sixty minutes in length.\",\n \"272.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of logical data units transmitted from and to each user during a time interval.\",\n \"273.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of bytes and data packets transmitted from and to each user during a time interval.\",\n \"274.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a time interval.\",\n \"275.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of bytes and data packets of the user that are dropped during a time interval.\",\n \"276.The Carrier Network of claim 255, wherein the step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction across said shared communications medium during a time interval.\",\n \"277.The Carrier Network of claim 255, wherein said step of setting a network access allowance for each user comprises allocating network access equally to the users and setting the network access allowance for each user equal to that user's allocated network access.\",\n \"278.The Carrier Network of claim 277, wherein said software further includes computer-executable instructions that perform the additional step of prioritizing the users for allocating network access.\",\n \"279.The Carrier Network of claim 278, wherein the prioritizing is based on fairness considerations.\",\n \"280.The Carrier Network of claim 279, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput rate receiving priority over a user with greater throughput rate.\",\n \"281.The Carrier Network of claim 279, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss rate having priority over a user with lesser data loss rate.\",\n \"282.The Carrier Network of claim 279, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.\",\n \"283.The Carrier Network of claim 279, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.\",\n \"284.The Carrier Network of claim 279, wherein users are prioritized based on an established minimum quality of service (QoS) standard.\",\n \"285.The Carrier Network of claim 278, wherein prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.\",\n \"286.The Carrier Network of claim 285, wherein SLAs specify respective minimum levels of network access for users, and prioritizing includes comparing each user's monitored network access usage with the specified respective minimum levels of network access, and awarding priority to a user when said respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.\",\n \"287.The Carrier Network of claim 285, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and prioritizing includes comparing the monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when the monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.\",\n \"288.The Carrier Network of claim 285, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and prioritizing includes comparing the monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.\",\n \"289.The Carrier Network of claim 285, wherein SLAs provide respective fees for network access usage, and prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.\",\n \"290.The Carrier Network of claim 285, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.\",\n \"291.The Carrier Network of claim 285, wherein SLAs specify respective minimum levels of network access for users, and allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.\",\n \"292.The Carrier Network of claim 285, wherein said software further includes computer-executable instructions that perform the step of forecasting network access usage by each user during the future time interval based on the monitoring of network access usage by each user.\",\n \"293.The Carrier Network of claim 292, wherein forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.\",\n \"294.The Carrier Network of claim 292, wherein forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to the monitored network access usages of the users.\",\n \"295.The Carrier Network of claim 292, wherein said step of setting a network access allowance for each user comprises allocating network access to users proportional to each user's forecasted network access usage.\",\n \"296.The Carrier Network of claim 292, wherein said step of setting a network access allowance for each user comprises allocating network access, and wherein said software further includes computer-executable instructions that perform the step of prioritizing the users for allocating network access.\",\n \"297.The Carrier Network of claim 296, wherein prioritizing is based on each user's forecasted network access usage.\",\n \"298.The Carrier Network of claim 296, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.\",\n \"299.The Carrier Network of claim 292, wherein said step of setting a network access allowance for each user comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.\",\n \"300.The Carrier Network of claim 292, wherein said step of setting a network access allowance for each user comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.\",\n \"301.A computer-readable medium having computer-executable instructions that manage network access across a shared communications medium between competing users of a Carrier Network, said instructions performing the steps of: (a) monitoring the network access usage by each user for a time interval; and (b) setting a network access allowance for each user representing a level of network access made available for utilization by the user during a future time interval, but not necessarily representing the level of network access that will be utilized by such user during the future time interval.\",\n \"302.The computer-readable medium of claim 301, wherein said step of setting a network access allowance for each user comprises allocating network access, and wherein said software further includes computer-executable instructions performing the step of prioritizing the users for allocating network access.\",\n \"303.The computer-readable medium of claim 302, wherein the prioritizing is based on fairness considerations.\",\n \"304.The computer-readable medium of claim 302, wherein the users are prioritized based on user throughput during a time interval, with a user with lesser throughput rate receiving priority over a user with greater throughput rate.\",\n \"305.The computer-readable medium of claim 302, wherein the users are prioritized based on data loss for each user during a time interval, with a user with greater data loss rate having priority over a user with lesser data loss rate.\",\n \"306.The computer-readable medium of claim 302, wherein the users are prioritized based on network access usage for a particular time of day, with a user with lesser network access usage for the particular time of day receiving priority over a user with greater network access usage for the particular time of day.\",\n \"307.The computer-readable medium of claim 302, wherein the users are prioritized based on both user throughput and data loss of the user during a time interval.\",\n \"308.The computer-readable medium of claim 302, wherein users are prioritized based on an established minimum quality of service (QoS) standard.\",\n \"309.The computer-readable medium of claim 302, wherein prioritizing is based on service level agreements (SLAs) of the users regarding the provision of network access.\",\n \"310.The computer-readable medium of claim 309, wherein SLAs specify respective minimum levels of network access for users, and prioritizing includes comparing the monitored network access usages for the users with the specified respective minimum levels of network access, and awarding priority to a user when the respective monitored network access usage for such user falls below the user's specified respective minimum level of network access.\",\n \"311.The computer-readable medium of claim 309, wherein SLAs specify respective time-of-day (TOD) minimum levels of network access for users, and prioritizing includes comparing the monitored network access usages for such users during the specified respective TOD with the specified respective TOD minimum levels of network access, and awarding priority to a user when the monitored network access usage during the specified respective TOD for such user falls below the user's specified respective TOD minimum level of network access.\",\n \"312.The computer-readable medium of claim 309, wherein SLAs specify respective minimum levels of network access up to a maximum burstable levels with target probability for users, and prioritizing includes comparing the monitored network access usage both with the respective minimum levels of network access for such users and with the respective maximum burstable levels of network access for such users, and comparing the instances the respective maximum levels of network access were obtained for such users out of all instances the respective maximum levels of network access were requested for such users.\",\n \"313.The computer-readable medium of claim 309, wherein SLAs provide a respective fee for network access usage, and prioritizing comprises sorting such users based on each user's respective fee in decreasing order, with a user with a higher fee receiving priority over a user with a lesser fee.\",\n \"314.The computer-readable medium of claim 309, wherein SLAs provide respective credits for levels of network access below respective guaranteed levels for users, and prioritizing comprises sorting such users based on each user's respective credit in decreasing order, with a user with a higher credit receiving priority over a user with a lower credit.\",\n \"315.The computer-readable medium of claim 309, wherein SLAs specify respective minimum levels of network access for users, and allocating network access comprises allocating network access to such users equal to each user's specified respective minimum level of network access.\",\n \"316.The computer-readable medium of claim 309, further comprising computer-executable instructions performing the step of forecasting network access usage by each user during the future time interval based the monitoring of network access usage by each user.\",\n \"317.The computer-readable medium of claim 316, wherein forecasting comprises predicting future network access usage of each user based upon monitored past network access usage patterns of each user.\",\n \"318.The computer-readable medium of claim 316, wherein forecasting comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to the monitored network access usages of the users.\",\n \"319.The computer-readable medium of claim 316, wherein allocating network access comprises allocating network access to users proportional to each user's forecasted network access usage.\",\n \"320.The computer-readable medium of claim 316, further comprising computer-executable instructions performing the step of prioritizing the users for allocating network access.\",\n \"321.The computer-readable medium of claim 320, wherein prioritizing is based on each user's forecasted network access usage.\",\n \"322.The computer-readable medium of claim 320, wherein said users are prioritized in increasing order of each user's forecasted network access usage, with a user with a lesser forecasted network access usage receiving priority over a user with a greater forecasted network access usage.\",\n \"323.The computer-readable medium of claim 316, wherein allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access equally to the users.\",\n \"324.The computer-readable medium of claim 316, wherein allocating network access comprises allocating network access to the users equal to each user's forecasted network access usage, and then allocating any remaining network access to the users proportionally based on each user's forecasted network access usage.\",\n \"325.A computerized method of allocating among a plurality of users bandwidth for conveying information across a shared communications medium, comprising the steps of: (a) receiving data representative of past bandwidth of each user during a time interval; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users; and (d) allocating bandwidth to each user sequentially in decreasing order of user priority.\",\n \"326.The computerized method of claim 325, wherein the bandwidth that is monitored is the bandwidth requested for each user.\",\n \"327.The computerized method of claim 325, wherein the bandwidth that is monitored is the bandwidth consumption of each user.\",\n \"328.The computerized method of claim 327, wherein the bandwidth that is forecasted is the bandwidth consumption of each user.\",\n \"329.The computerized method of claim 328, wherein users are prioritized based on each user's forecasted future bandwidth consumption in increasing order, whereby a user with a lesser forecasted bandwidth consumption receives a higher priority than a user with a greater forecasted bandwidth consumption.\",\n \"330.The computerized method of claim 328, wherein each user's allocation of bandwidth for the future time interval is set to equal each user's forecasted bandwidth consumption subject to a respective, predetermined maximum value and subject to bandwidth availability 331.The computerized method of claim 330, further comprising distributing equally to the users any unallocated bandwidth.\",\n \"332.The computerized method of claim 330, further comprising distributing to the users any unallocated bandwidth remaining in amounts proportional to the users' forecasted bandwidth consumptions.\",\n \"333.The computerized method of claim 330, wherein the data representative of past bandwidth consumption comprise the number of logical data units transmitted from and to each user during the past time interval.\",\n \"334.The computerized method of claim 330, wherein the data representative of past bandwidth consumption comprise data representative of the number of bytes transmitted from and to each user during the past time interval.\",\n \"335.The computerized method of claim 330, wherein the data representative of past bandwidth consumption comprise data representative of the number of data packets transmitted from and to each user during the past time interval.\",\n \"336.A computerized method of allocating among a plurality of users bandwidth for conveying information across a shared communications medium, comprising the steps of: (a) receiving data representative of past bandwidth of each user during a time interval; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth multiplied by a ratio of the total bandwidth available to the users' total forecasted bandwidth, and subject to a respective, predetermined maximum value and subject to bandwidth availability.\",\n \"337.The computerized method of claim 336, wherein the data representative of past bandwidth comprise the number of logical data units transmitted from and to each user during the past time interval.\",\n \"338.The computerized method of claim 336, wherein the data representative of past bandwidth comprise data representative of the number of bytes and data packets transmitted from and to each user during the past time interval.\",\n \"339.The computerized method of claim 336, wherein the data representative of past bandwidth comprise data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during the past time interval.\",\n \"340.A computerized method of allocating among a plurality of users bandwidth for conveying information across a shared communications medium, comprising the steps of: (a) receiving data representative of past bandwidth of each user during a time interval, and data representative of respective fees that are charged to the users for bandwidth; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on the respective fee charged to each user in decreasing order, whereby a user with a higher fee receives a higher priority than a user with a lesser fee; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.\",\n \"341.The computerized method of claim 340, wherein the data representative of past bandwidth comprise the number of logical data units transmitted from and to each user during the past time interval.\",\n \"342.The computerized method of claim 340, wherein the data representative of past bandwidth comprise data representative of the number of bytes and data packets transmitted from and to each user during the past time interval.\",\n \"343.The computerized method of claim 340, wherein the data representative of past bandwidth comprise data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during the past time interval.\",\n \"344.A computerized method of allocating among a plurality of users bandwidth for conveying information across a shared communications medium, comprising the steps of: (a) receiving data representative of past bandwidth of each user during a time interval, and data representative of respective credits that are applied to accounts of the users for bandwidth shortfalls below respective bandwidth levels specified to the users; (b) forecasting future bandwidth by each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on the respective credit in decreasing order, whereby a user with a higher credit receives a higher priority than a user with a lesser credit; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum specified value and subject to availability.\",\n \"345.The computerized method of claim 344, wherein any unallocated bandwidth remaining is distributed to the users sequentially in decreasing user priority such that each user's allocation equals the user's forecasted bandwidth, subject to a respective, predetermined maximum allowed value of bandwidth and subject to availability.\",\n \"346.The computerized method of claim 344, wherein any unallocated bandwidth remaining is distributed equally to the users subject to a respective, predetermined maximum allowed value of bandwidth.\",\n \"347.The computerized method of claim 344, further comprising setting each user's allocation of bandwidth for the future time interval only in an amount equal to the forecasted bandwidth of the user multiplied by the ratio of total bandwidth available for allocation to the total forecasted bandwidth of the users, but only when the total forecasted bandwidth exceeds the total bandwidth available for allocation.\",\n \"348.The computerized method of claim 344, wherein the data representative of past bandwidth comprise the number of logical data units transmitted from and to each user during the past time interval.\",\n \"349.The computerized method of claim 344, wherein the data representative of past bandwidth consumption comprise data representative of the number of bytes and data packets transmitted from and to each user during the past time interval.\",\n \"350.The computerized method of claim 344, wherein the data representative of past bandwidth consumption comprise data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during the past time interval.\",\n \"351.A computer-readable medium having computer-executable instructions that allocates among a plurality of users bandwidth for conveying information across a shared communications medium, said instructions performing the steps of: (a) receiving data representative of past bandwidth of each user during a time interval; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on each user's forecasted future bandwidth in increasing order, whereby a user with a lesser forecasted bandwidth receives a higher priority than a user with a greater forecasted bandwidth; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to bandwidth availability.\",\n \"352.The computer-readable medium of claim 351, wherein said instructions further perform the step of distributing equally to the users any unallocated bandwidth.\",\n \"353.The computer-readable medium of claim 351, wherein said instructions further perform the step of distributing to the users any unallocated bandwidth remaining in amounts proportional to the users' forecasted bandwidths.\",\n \"354.A computer-readable medium having computer-executable instructions that allocates among a plurality of users bandwidth for conveying information across a shared communications medium, said instructions performing the steps of: (a) receiving data representative of past bandwidth of each user during a time interval; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth multiplied by a ratio of the total bandwidth available to the users' total forecasted bandwidth, and subject to a respective, predetermined maximum value and subject to bandwidth availability.\",\n \"355.A computer-readable medium having computer-executable instructions that allocates among a plurality of users bandwidth for conveying information across a shared communications medium, said instructions performing the steps of: (a) receiving data representative of past bandwidth by each user during a time interval, and data representative of respective fees that are charged to the users for bandwidth; (b) forecasting future bandwidth by each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on the respective fee in decreasing order, whereby a user with a higher fee receives a higher priority than a user with a lesser fee; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum specified value and subject to availability.\",\n \"356.A computer-readable medium having computer-executable instructions that allocates among a plurality of users bandwidth for conveying information across a shared communications medium, said instructions performing the steps of: (a) receiving data representative of past bandwidth of each user during a time interval, and data representative of respective credits that are applied to accounts of the users for bandwidth shortfalls below respective levels of network access specified to the users; (b) forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; (c) prioritizing users based on the respective credit in decreasing order, whereby a user with a higher credit receives a higher priority than a user with a lesser credit; and (d) sequentially for each user in decreasing order of user priority, setting each user's allocation of bandwidth for the future time interval equal to each user's forecasted bandwidth subject to a respective, predetermined maximum specified value and subject to availability.\",\n \"357.The computer-readable medium of claim 356, wherein said instructions further perform the step of distributing any unallocated bandwidth to the users sequentially in decreasing user priority such that each user's allocation equals the user's forecasted bandwidth, subject to a respective, predetermined maximum allowed value of bandwidth and subject to availability.\",\n \"358.The computer-readable medium of claim 356, wherein said instructions further perform the step of distributing any unallocated bandwidth equally to the users subject to a respective, predetermined maximum allowed value of bandwidth.\",\n \"359.The computer-readable medium of claim 356, wherein said instructions further perform the step of setting each user's allocation of bandwidth for the future time interval only in an amount equal to the forecasted bandwidth of the user multiplied by the ratio of total bandwidth available for allocation to the total forecasted bandwidth of the users, but only when the total forecasted bandwidth exceeds the total bandwidth available for allocation.\",\n \"360.A method of providing network access across a shared communications medium between at least four competing users, with at least a first pair of users being grouped within a first class and at least a second pair of different users being grouped within a second class, comprising the steps of: (a) determining class and user allowances of network access for a first time interval by allocating network access to each user class for a first future time interval and, for each user class, allocating network access to each user within the class for the first time interval, (b) providing network access to each user during the first time interval such that no user receives more network access than that user's allowance and no class receives more collective network access than that class' network allowance; (c) determining class and user allowances of network access for a second time interval by allocating network access to each user class for a second future time interval succeeding the first time interval and, for each user class, allocating network access to each user for the second time interval, the allocated network access for the second time interval for at least one user differing from that user's allocated network access for the first time interval; and (d) providing network access to each user during the second time interval such that no user receives more network access than that user's allowance and no class receives more collective network access than that class' allowance.\",\n \"361.The method of claim 360, wherein for at least one class the allocated network access for the first time interval for each user differs from the allocated network access for the second time interval for that user.\",\n \"362.The method of claim 360, wherein for each class the allocated network access for the first time interval for each user differs from the allocated network access for the second time interval for that user.\",\n \"363.The method of claim 360, wherein the collective network access allocated to each class for the first time interval differs from the collective network access allocated to each class for the second time interval.\",\n \"364.The method of claim 360, further comprising requesting a minimum level of network access for a user for utilization during the first future time interval, and wherein said allocating network access to such user for the first future time interval comprises setting the level of network access allocated to such user to an amount equal to or greater than the requested minimum level.\",\n \"365.The method of claim 364, wherein said allocating network access to such user for the second future time interval comprises setting the level of network access allocated to such user to an amount less than the requested minimum level for the first time interval.\",\n \"366.The method of claim 360, wherein each of the first future time interval and the second future time interval has a period of between one minute and sixty minutes.\",\n \"367.The method of claim 360, wherein network access comprises bandwidth across the shared communications medium for consumption by each user in conveying data of the user.\",\n \"368.The method of claim 360, further comprising the step of monitoring network access usage by each user.\",\n \"369.The method of claim 368, further comprising the step of tracking network access usage for each user class.\",\n \"370.The method of claim 368, wherein said step of monitoring network access usage by each user includes collecting data representative of logical data units transmitted from and to each user during a past time interval.\",\n \"371.The method of claim 368, further comprising tracking logical data units transmitted from and to each user class during a past time interval.\",\n \"372.The method of claim 368, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are dropped during a past time interval.\",\n \"373.The method of claim 368, further comprising tracking the number of logical data units that are dropped for each user class during a past time interval.\",\n \"374.The method of claim 368, wherein said step of monitoring network access usage includes collecting data representative of the number of logical data units of the user that are requested to be transmitted in an upstream direction during a past time interval.\",\n \"375.The method of claim 368, further comprising tracking the number of logical data units of each user class that are requested to be transmitted in an upstream direction during a past time interval.\",\n \"376.The method of claim 360, wherein the shared communications medium is part of a Cable Network and the shared communications medium comprises a coaxial cable.\",\n \"377.The method of claim 360, wherein the shared communications medium is part of a Shared Access Carrier Network comprises a wireless network.\",\n \"378.The method of claim 360, further comprising prioritizing the user classes for allocating network access.\",\n \"379.The method of claim 378, further comprising prioritizing the users for allocating, network access.\",\n \"380.The method of claim 378, wherein said prioritizing of the user classes is based on fairness considerations.\",\n \"381.The method of claim 380, wherein the user classes are prioritized based on collective user throughput during a past time interval, with a user class with lesser collective user throughput receiving priority over a user class with greater collective user throughput.\",\n \"382.The method of claim 380, wherein the user classes are prioritized based on collective data loss for each user class during a past time interval, with a user class with greater collective data loss having priority over a user class with lesser collective data loss.\",\n \"383.The method of claim 380, wherein the user classes are prioritized based on collective network access usage for a particular time of day, with a user class with lesser collective network access usage for the particular time of day receiving priority over a user class with greater collective network access usage for the particular time of day.\",\n \"384.The method of claim 380, wherein the user classes are prioritized based on both collective user throughput for the class and collective data loss of the users for the class during a time interval.\",\n \"385.The method of claim 380, wherein user classes are prioritized based on an established minimum quality of service (QoS) standard.\",\n \"386.The method of claim 378, wherein said step of prioritizing is based on class service level agreements (CSLAs) for at least two user classes regarding the provision of network access to each respective class.\",\n \"387.The method of claim 386, further comprising the step of tracking network access usage by each user class.\",\n \"388.The method of claim 387, wherein each CSLA specifies a respective minimum level of collective network access for the respective users therein, and said step of prioritizing includes comparing said monitored network access usages for the user classes with the specified respective minimum levels of collective network access therefor, and awarding priority to a user class when said monitored network access usage for such user class falls below the specified respective minimum level of collective network access for such class.\",\n \"389.The method of claim 387, wherein each CSLA specifies a respective time-of-day (TOD) minimum level of collective network access for the respective users therein, and said step of prioritizing includes comparing said monitored network access usages for such user classes during the specified respective TOD with the specified respective TOD minimum levels of collective network access, and awarding priority to a user class when said monitored network access usage during the specified respective TOD for such user class falls below the specified respective TOD minimum level of collective network access of such user class.\",\n \"390.The method of claim 387, wherein each CSLA specifies a respective minimum level of collective network access up to a maximum burstable level with target probability for the respective users therein, and said step of prioritizing includes comparing for each user class said monitored network access usage both with the respective minimum level of collective network access and with the respective maximum burstable level of collective network access, and comparing the instances the respective maximum level of network access were obtained out of all instances the respective maximum level of network access could have been utilized.\",\n \"391.The method of claim 387, wherein each CSLA provides a respective fee for collective network access usage, and said step of prioritizing comprises sorting such user classes based on each class' respective fee in decreasing order, with a user class with a higher fee receiving priority over a user class with a lesser fee.\",\n \"392.The method of claim 387, wherein each CSLA provides a respective credit for a level of collective network access falling below a respective guaranteed level for the user class, and said step of prioritizing comprises sorting such user classes based on each class' respective credit in decreasing order, with a user class with a higher credit receiving priority over a user class with a lower credit.\",\n \"393.The method of claim 387, wherein each CSLA specifies a respective minimum level of collective network access for the user class, and said step of allocating network access comprises setting the respective level of collective network access of the user class equal to the class' specified respective minimum level of collective network access.\",\n \"394.The method of claim 368, further comprising the step of forecasting collective network access usage by each user class during a future time interval based on said step of monitoring network access usage by each user.\",\n \"395.The method of claim 394, wherein said step of forecasting comprises summing within each class a forecasted network access usage of each user.\",\n \"396.The method of claim 394, wherein said step of forecasting network access usage of each user comprises applying an adaptive-response-rate single exponential smoothing function and a Holt-Winters' seasonal exponential smoothing function to said monitored network access usages of each user.\",\n \"397.The method of claim 395, wherein said step of allocating network access to each user class comprises setting the respective levels of network access of the user classes proportional to each class' forecasted network access usage.\",\n \"398.The method of claim 395, further comprising the step of prioritizing the user classes for allocating network access.\",\n \"399.The method of claim 398, wherein said prioritizing is based on each class' forecasted network access usage.\",\n \"400.The method of claim 398, wherein said user classes are prioritized in increasing order of each class' forecasted network access usage, with a user class with a lesser forecasted network access usage receiving priority over a user class with a greater forecasted network access usage.\",\n \"401.The method of claim 398, wherein said step of allocating network access comprises setting the respective levels of network access equal to each class' forecasted network access usage, and then allocating any remaining network access to the user classes proportional to the number of users within each class.\",\n \"402.The method of claim 398, wherein said step of allocating network access comprises setting the respective levels of network access equal to each class' forecasted network access usage, and then allocating any remaining network access to the user classes proportionally based on each class' forecasted network access usage.\",\n \"403.The method of claim 378, wherein said step of prioritizing is based on class service level agreements (CSLAs) regarding the provision of collective network access.\",\n \"404.The method of claim 403, further comprising the step of monitoring collective network access usage of each class.\",\n \"405.The method of claim 404, wherein CSLAs specify respective minimum levels of collective network access for classes, and said step of prioritizing includes comparing said monitored network access usages for such classes with the specified respective minimum levels of collective network access, and awarding priority to a class when said respective monitored network access usage for such class falls below the class' specified respective minimum level of collective network access.\",\n \"406.The method of claim 404, wherein CSLAs specify respective time-of-day (TOD) minimum levels of collective network access for classes, and said step of prioritizing includes comparing said monitored network access usages for such classes during the specified respective TOD with the specified respective TOD minimum levels of collective network access, and awarding priority to a class when said monitored network access usage during the specified respective TOD for such class falls below the class' specified respective TOD minimum level of collective network access.\",\n \"407.The method of claim 404, wherein CSLAs specify respective minimum levels of collective network access up to a maximum burstable levels with target probability for classes, and said step of prioritizing includes comparing said monitored network access usage for each such class both with the respective minimum levels of collective network access and with the respective maximum burstable levels of collective network access, and comparing the instances the respective maximum levels of collective network access were obtained for each such class out of all instances the respective maximum levels of collective network access could have been utilized.\",\n \"408.The method of claim 404, wherein CSLAs provide respective fees for collective network access usage of classes, and said step of prioritizing comprises sorting such classes based on each class' respective fee in decreasing order, with a class with a higher fee receiving priority over a class with a lower fee.\",\n \"409.The method of claim 404, wherein CSLAs provide respective credits for levels of collective network access below respective guaranteed levels for classes, and said step of prioritizing comprises sorting such classes based on each class' respective credit in decreasing order, with a class with a higher credit receiving priority over a class with a lower credit.\",\n \"410.The method of claim 404, wherein CSLAs specify respective minimum levels of collective network access for classes, and said step of allocating network access comprises setting the allocations of collective network access for such classes equal to each class' specified respective minimum level of collective network access\"\n ],\n [\n \"<SOH> BACKGROUND OF THE PRESENT INVENTION <EOH>As used herein, a “Carrier Network” generally refers to a computer network through which users (such as homes and businesses) communicate with various service providers.\",\n \"The Carrier Network extends from the location of each user to an intermediate switched/routed network (hereinafter “Intermediate Network”).\",\n \"The service providers, in turn, are connected to the Intermediate Network, either directly or indirectly via the Internet, for communications with the users.\",\n \"The Carrier Network is maintained by a “Carrier,” which also may serve as a service provider for certain services.\",\n \"For example, a Carrier or a related entity may serve as an Internet service provider (ISP).\",\n \"Two prevalent types of Carrier Networks include a “Shared Access Carrier Network,” in which data of multiple users are conveyed together over a shared communications medium between the users and the Intermediate Network, and a “Dedicated Connection Carrier Network,” in which data of each user are conveyed alone between the user and the Intermediate Network and are not combined with data of other users.\",\n \"One of the most prevalent Shared Access Carrier Networks today is found in the Data-Over-Cable (DOC) Network, which includes the traditional network constructed from coaxial cable and the hybrid fiber coaxial (HFC) network constructed with both fiber optical cabling and coaxial cable.\",\n \"Other Shared Access Carrier Networks include wireless and digital subscriber line (XDSL) networks (the xDSL lines typically being aggregated onto an oversubscribed backhaul trunk into the Intermediate Network, with the trunk defining the shared communications medium).\",\n \"For example, with regard to DOC Networks, and with reference to FIG.\",\n \"1 wherein a conventional DOC Network 40 is illustrated, data packets are transmitted in a downstream direction from a cable modem termination system (CMTS) 30 , which is located in a headend 36 (or distribution hub) of a Carrier, over a coaxial cable 32 to respective cable modems (CMs) 34 of users.\",\n \"All of the CMs 34 are attached by the coaxial cable 32 to the CMTS 30 in an inverted tree configuration, and each CM 34 connected to the coaxial cable 32 listens to all broadcasts from the CMTS 30 transmitted through the coaxial cable 32 for data packets addressed to it, and ignores all other data packets addressed to other CMs 34 .\",\n \"Theoretically, a CM 34 is capable of receiving data in the downstream direction over a 6 MHz channel with a maximum connection speed of 30-40 Mbps.\",\n \"Data packets also are transmitted in the upstream direction over a 2 MHz channel by the CMs 34 to the CMTS 30 typically using time division multiplexing (TDM) and at a maximum connection speed of 1.5-10 Mbps.\",\n \"The headend 36 in the DOC Network 40 includes a plurality of CMTSs, with each CMTS supporting multiple groups of CMs each connected together by a respective coaxial cable.\",\n \"Each such group of CMs connected to a CMTS defines a Shared Access Carrier Network, with the coaxial cable in each representing the shared communications medium.\",\n \"This arrangement of a group of CMs connected to a CMTS by a coaxial cable is referred to herein as a “Cable Network.” Accordingly, the DOC Network 40 includes a plurality of Cable Networks 38 originating from CMTSs at the headend 36 of the Carrier, with a particular Cable Network 38 being illustrated in an expanded view in FIG.\",\n \"1 .\",\n \"The DOC Network 40 also includes multiple headends 36 , 64 , 66 .\",\n \"In contrast to the Shared Access Carrier Network, a user in the Dedicated Connection Carrier Network establishes a dedicated connection directly with the Intermediate Network for the transfer of data directly therebetween, and no data of other users travel over the dedicated connection.\",\n \"Examples of a dedicated connection are shown for comparison in FIG.\",\n \"1 and include a connection established by a telephony modem 74 and a connection established by an ISDN modem 76 .\",\n \"Both downstream and upstream connection speeds in a Dedicated Connection Carrier Network range from a maximum of 53 kbps in a telephony modem connection to a maximum of 128 kbps in a basic rate interface ISDN connection.\",\n \"Connection speeds and, more importantly, throughput rate—the amount of data actually transmitted successfully in a given time interval—are important in minimizing downtime that users spend waiting for HTML documents to download from the Web.\",\n \"A Shared Access Carrier Network is considered superior to a comparable Dedicated Connection Carrier Network because the maximum instantaneous connection speed offered by the Shared Access Carrier Network is greater.\",\n \"A Shared Access Carrier Network is considered “comparable” to a Dedicated Connection Carrier Network where the entire bandwidth over a shared communications medium of the Shared Access Carrier Network equals an aggregate bandwidth that is divided between and dedicated to users in a Dedicated Connection Carrier Network.\",\n \"Accordingly, Shared Access Carrier Networks are able to offer significantly faster downloads of web documents, emails, and file transfers that are not considered available in Dedicated Connection Carrier Networks.\",\n \"Furthermore, new multimedia applications and Internet services, such as voice and video communications via the Internet, now are offered which require even greater throughput rates for acceptable levels of service than that of the traditional Internet services, i.e., throughput rates greater than that required for acceptable text-based Web browsing, file transferring, and email communication.\",\n \"It is believed that these new multimedia applications and Internet services cannot adequately be provided for over Dedicated Connection Carrier Networks and that, consequently, Shared Access Carrier Networks ultimately will prevail as the predominant type of Carrier Network for Internet access by users.\",\n \"Of course, the actual throughput rates experienced by a particular user rarely, if ever, will equate to the maximum connection speeds of which the Shared Access Carrier Network is capable because of the shared nature of the communications medium.\",\n \"For example, in a Cable Network the total bandwidths available over the shared cable in the downstream and upstream directions, which determine the respective maximum connection speeds, must be shared among all of the users communicating at a given time.\",\n \"Thus, rarely will a single user have available for use a large portion of the entire bandwidth in a particular direction.\",\n \"Further, as a Carrier adds users to the Cable Network, the actual downstream and upstream bandwidths available to the user—and thus throughput rates of the user—generally will decrease.\",\n \"A Carrier therefore must be careful to draw a balance between the number of users connected to a Cable Network and the performance users experience communicating over the network.\",\n \"Unfortunately, Shared Access Carrier Networks that have been established were designed to provide the traditional Internet services, and not the new multimedia applications and Internet services that require higher throughput rates for acceptable levels of service.\",\n \"Consequently, each balance previously struck by Carriers in establishing Shared Access Carrier Networks was based on considerations of the throughput rates required for the traditional Internet services, and user throughput rates currently experienced by users in such networks are believed to fall short of acceptable quality of service (QoS) standards believed required in a Carrier Network for the new multimedia applications and Internet services.\",\n \"Additionally, with regard to new Shared Access Carrier Networks that are being established, considerations of the new multimedia applications and Internet services tend to reduce the number of users that a Carrier now can reasonably expect to connect to the shared communications medium before degrading the performance levels of the new multimedia applications and Internet services.\",\n \"The balance is being shifted towards less users per shared access medium in exchange for higher throughput rates and, thus, higher QoS standards.\",\n \"In an attempt to avoid reducing the number of users, it has been proposed, at least in DOC Networks, to discriminate between the traditional Internet services and the new multimedia applications and Internet services with regard to priority of data packet transmissions.\",\n \"In particular, the generally accepted standard in the United States governing communication protocols over cable is DOCSIS version 1.0, which was ratified by the International Telecommunication Union in March of 1998.DOCSIS stands for “Data Over Cable Service Interface Specifications.” When DOCSIS 1.0 was developed, it was generally believed that, in view of the “fast” connection speeds of Cable Networks, the provision of bandwidth on a best effort basis would be sufficient to meet all user requirements.\",\n \"Accordingly, each user subscribed to receive network access pursuant to a service level agreement (SLA) which provided for network access (or bandwidth in Cable Networks) only on a best effort basis.\",\n \"Now, in an effort to address the foreseen ever-increasing demand for higher throughput rates, DOCISIS version 1.1 has been proposed, in accordance with which each data packet transmitted over a DOC Network now must include a classification designation for prioritization purposes by network equipment.\",\n \"Subsequently, data packets representing voice or video, for example, now can be identified and given priority transmission over data packets representing email, file transfers, and text-based Web documents.\",\n \"A benefit of such flow classification is that, while overall bandwidth generally available to a user may otherwise remain unchanged, throughput rates of data for voice and video now may be provided at a higher rate than throughput rates of data for the traditional Internet services, thereby increasing the performance of voice and video applications and services while at least maintaining the traditional number of users connected to a Cable Network.\",\n \"A disadvantage of the revisions to DOCSIS 1.1 is that the revisions do not enhance established Cable Networks constructed with only DOCSIS 1.0 compliant equipment, as such equipment does not support the added functionality of DOCSIS 1.1 so as to distinguish between data packets.\",\n \"More broadly, another disadvantage of the classification of data packets into Internet Protocol (IP) flows based on the services represented by the data packets is that such classification discriminates against users who do not utilize multimedia applications and services receiving the prioritized transmissions.\",\n \"At least for some extensive users of the traditional Internet services, some degradation in performance may be noticed by lower classification of their data packets, particularly if the user engages in, for example, web hosting.\",\n \"While the transmissions of data packets for documents, files, and emails are not as time-sensitive as data packets for voice and video, increased data packet latency for documents, files, and emails, even if incrementally small, nevertheless will result in service degradation for large or numerous documents, files, and emails.\",\n \"Accordingly, a need exists for a method and apparatus that will accommodate differing demands for network access by users competing for such access across a shared communications medium of a Shared Access Carrier Network, whether new or established, and irrespective of data packet classifications.\",\n \"Furthermore, as Shared Access Carrier Networks emerge as the favored type of network, it is believed that open access to such networks by different competing service providers will become an important commercial and legislative issue.\",\n \"Moreover, as more and more service providers seek to provide users with services over Shared Access Carrier Networks, it is believed that users of such service providers will receive inadequate bandwidth over the Shared Access Carrier Networks to meet minimum standards of quality, especially in Cable Networks where bandwidth is provided on a best efforts basis.\",\n \"Accordingly, it is believed that an additional need exists for a method by which a service provider competing for users of a shared communications medium can seek protection against bandwidth starvation of the users of the shared communications medium that are its customers.\",\n \"Conversely, it is also believed that a need exists for a method that will accommodate differing demands for network access by users competing for such access across the shared communications medium.\"\n ],\n [\n \"<SOH> SUMMARY OF THE PRESENT INVENTION <EOH>Briefly summarized, the present invention relates to a method of providing network access across a shared communications medium between competing users, and include eight different aspects.\",\n \"First Aspect of the Present Invention In the first aspect of the present invention, the method broadly includes the steps of: (a) prior to first and second time intervals, respectively determining for each user first and second network access allowances; (b) during the first time interval, providing network access to each user such that the respective first network access allowance is not exceeded; and (c) during the second time interval, providing network access to each user such that the respective second network access allowance for each user is not exceeded.\",\n \"In accordance with the present invention, the “network access allowance” represents a respective maximum level of network access that can be made available to the user during a particular time interval, and does not represent necessarily the level of network access that will be utilized by the user during such time interval.\",\n \"Furthermore, at least one respective second network access allowance for a user differs from such user's respective first network access allowance.\",\n \"The first network access allowances for the users preferably are determined by allocating network access to each user on a per user basis for the first time interval in accordance with a first allocation policy.\",\n \"The first network access allowance for each respective user then is equated to the network access allocated to that user under the first allocation policy.\",\n \"Likewise, the second network access allowances for the users are determined by allocating network access to each user on a per user basis for the second time interval in accordance with a second allocation policy that may or may not differ from the first allocation policy.\",\n \"Again, the second network access allowance for each respective user then is equated to the network access allocated to that user under the second allocation policy.\",\n \"In additional features of the present invention, the method includes the steps of monitoring network access usage by the users, and forecasting network access usage of each user in a future time interval.\",\n \"Another additional feature of the present invention includes the step of prioritizing the users for the allocation of network access.\",\n \"One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network; based on the monitored bandwidth consumption, the forecasting of bandwidth consumption of each user in a future time interval; the prioritization of users; and the subsequent allocation of bandwidth to each user in decreasing priority for determining bandwidth allowances during the future time interval.\",\n \"Users are prioritized based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.\",\n \"Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval.\",\n \"In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.\",\n \"With regard to at least two users, the favored user allocations, and thus the user allowances, differ as between future time intervals.\",\n \"Second Aspect of the Present Invention In the second aspect of the present invention, the method broadly includes the steps of monitoring network access usage of each user for a past time interval and, based on the monitored network access usage, allocating network access to each user for a future time interval.\",\n \"In a feature of the present invention, the network access that is monitored and allocated is in the downstream direction towards the users.\",\n \"In a separate and independent feature of the present invention, network access usage of each user is forecast for a future time interval based on the monitoring, and allocations are made based on the forecasting.\",\n \"Another additional feature of the present invention includes the prioritizing of the users for allocating network access.\",\n \"One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network; based on the monitored bandwidth consumption, the forecasting of bandwidth consumption of each user in a future time interval; the prioritization of users; and the subsequent allocation of bandwidth to each user in decreasing priority for the future time interval.\",\n \"Users are prioritized based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.\",\n \"Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval.\",\n \"In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.\",\n \"Third Aspect of the Present Invention In the third aspect of the present invention, the method broadly includes the steps of monitoring network access usage by each user for a past time interval and, based on the monitored network access usage, allocating network access for each user for a future time interval.\",\n \"In a feature of the present invention, network access usage of each user is forecast for a future time interval based on the monitoring, and allocations are made based on the forecasting.\",\n \"Another feature of the present invention includes the prioritizing of the users for allocating network access.\",\n \"A preferred method of providing network access to the users includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on the monitoring, forecasting network access usage by each user over a future time interval; (c) prioritizing users based on each user's forecasted network access usage in increasing order, whereby a user with a lesser forecasted network access usage receives a higher priority than a user with a greater forecasted network access usage; and (d) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.\",\n \"Another preferred method of providing network access to the users includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on the monitoring, forecasting network access usage by each user over a future time interval; and (c) allocating network access available to each user during the future time interval, with each user's allocation of network access being equal to each user's forecasted network access usage multiplied by a ratio of the total network access available for allocation to the total forecasted network access usage of all users, and subject to a respective, predetermined maximum value and subject to availability.\",\n \"A third preferred method of providing network access to the users includes the steps of: (a) charging each user a respective fee for network access usage; (b) monitoring network access usage by each user during a time interval; (c) based on the monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.\",\n \"Yet a fourth preferred method of providing network access to the users includes the steps of: (a) applying respective credits to users for network access shortfalls below respective levels of network access specified to the users; (b) monitoring network access usage by each user during a past time interval; (c) based on the monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's respective credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum guaranteed value and subject to availability.\",\n \"Fourth Aspect of the Present Invention In the fourth aspect of the present invention, the method includes providing network access across a shared communications medium between competing users pursuant to service level agreements (SLAs) of the users.\",\n \"The method broadly includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) comparing the monitored network access usage by each user with a predetermined threshold value; and (c) soliciting a user to modify the user's SLA if the user's monitored network access usage varies from the predetermined value by a predetermined tolerance.\",\n \"Features of the present invention include the additional steps of allocating network access to each user for a future time interval, and forecasting network access usage by users in the future time interval.\",\n \"Another additional feature of the present invention includes the step of prioritizing the users for allocating network access to the users.\",\n \"The network access usage includes the user throughput rate, bandwidth consumption, and/or bandwidth requested for a predetermined period of time.\",\n \"The threshold value preferably represents a respective maximum level of network access (whether maximum allowed or maximum guaranteed) for each user or a respective maximum burstable level of network access with target probability for each user.\",\n \"The solicitation is conducted via email, instant messaging, redirection of a web browser of the user to a solicitation web page, generation and mailing of literature, telephonic communication, or other communication means.\",\n \"The solicited modification of the user's SLA includes guaranteeing a level of network access to the user on a permanent or on a temporary basis.\",\n \"A charge preferably is applied to the user for the modification.\",\n \"A preferred method of the present invention includes the identification of a recurrent period of high network access usage by a user based on the monitoring, and in response thereto, the solicitation of the user to modify the user's SLA in order to guarantee a minimum level of network access during an anticipated future recurrent period of high network access usage.\",\n \"Fifth Aspect of the Present Invention In the fifth aspect of the present invention, the method includes incorporating allocations of network access into a DOCSIS 1.0 compliant cable network wherein users compete for bandwidth.\",\n \"A preferred method includes the steps of: (a) generating cable modem configuration files, each of which limits bandwidth consumption by a cable modem of a user to a value representative of that user's allowance of bandwidth; (b) sending the configuration files to a Trivial File Transfer Protocol (TFTP) Server of the DOC Network; and (c) sending a command either to each user's cable modem, or to a cable modem termination system to which each user's cable modem is connected, to cause the cable modem to acquire its new respective configuration file.\",\n \"Features of the present invention include the additional steps of prioritizing users for allocation of bandwidth, and forecasting bandwidth of each user in a future time interval.\",\n \"Sixth Aspect of the Present Invention In the sixth aspect of the present invention, a Carrier Network provides communications between multiple users and Service Providers.\",\n \"The Carrier Network includes computer network equipment defining a Cable Network and an Intermediate Network which, combined, extends between the users and the Service Providers.\",\n \"The Cable Network includes a shared communications medium joining the users with the Intermediate Network, and users compete for network access across the shared communications medium in conveying data.\",\n \"The Carrier Network also includes software that manages the network access of the users.\",\n \"In accordance with the present invention, the software includes computer-executable instructions performing the steps of monitoring network access usage by each user for a time interval and, based thereon, allocating network access to the users for a future time interval.\",\n \"In additional features of the present invention, the software includes computer-executable instructions performing the additional steps of forecasting network access usage by each user during the future time interval, and prioritizing the users for allocation of network access In additional features of the present invention, the software is distributed within network equipment of the Carrier Network or, alternatively, is stored in hardware physically located at a remote location from the Carrier Network but linked with the Carrier Network for communications therebetween.\",\n \"The hardware remotely located is directly linked with the Carrier Network or is linked indirectly through the Internet.\",\n \"One of many preferred embodiments of the present invention includes prioritization of users based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, network access usage for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.\",\n \"Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted network access usage for a future time interval.\",\n \"Seventh Aspect of the Present Invention In the seventh aspect of the present invention, the present invention relates to a method of (and to a computer-readable medium with computer-executable instructions for performing the method of) providing network access across a shared communications medium between competing users.\",\n \"The method broadly includes the steps of receiving data representative of past bandwidth of each user during a time interval; forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; and setting each user's allocation of bandwidth for the future time interval.\",\n \"A feature of the present invention includes the step of prioritizing the users for allocating bandwidth to the users.\",\n \"Preferably, each user's bandwidth allocation represents that user's limit on bandwidth consumption for the future time interval (“bandwidth allowance”), and does not necessarily represent that user's bandwidth consumption during the future time interval.\",\n \"In a first preferred method, the users are prioritized based on each user's forecasted future bandwidth in increasing order, whereby a user with a lesser forecasted bandwidth receives a higher priority than a user with a greater forecasted bandwidth.\",\n \"The users are then allocated sequentially in decreasing order of user priority, with each user's allocation being set to equal the user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to bandwidth availability.\",\n \"Another preferred method includes allocating bandwidth that is to be made available to each user during the future time interval, with each user's allocation of bandwidth being set to equal each user's forecasted bandwidth multiplied by a ratio of the total bandwidth available for allocation to the total forecasted bandwidth of all users, and subject to a respective, predetermined maximum value and subject to availability.\",\n \"A third preferred method includes receiving data representative of a respective fee that is charged to each user for bandwidth, prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee, and setting in decreasing user priority each user's allocation of bandwidth equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.\",\n \"Yet a fourth preferred method includes receiving data representative of a respective credit that is applied to each user's account for bandwidth shortfalls below a specified bandwidth value, prioritizing users based on each user's credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit, and setting in decreasing user priority each user's allocation of bandwidth equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.\",\n \"The bandwidth monitored and forecast includes bandwidth that is consumed or, alternatively, bandwidth that is requested for consumption.\",\n \"Eighth Aspect of the Present Invention Finally, in the eighth aspect of the present invention, the present invention relates to a method of providing network access across a shared communications medium between competing users.\",\n \"In particular, the present invention includes the steps of allocating network access to at least two “user classes” for a first future time interval and, for each user class, allocating network access to each user within the class for the first time interval.\",\n \"The present invention further includes the additional step of allocating network access to each user class for a second future time interval succeeding the first time interval and, for each user class, allocating network access to each user for the second time interval.\",\n \"Each user receives a first determined allowance of network access for utilization during the first time interval equal to that user's allocation for the first time interval, and a second determined allowance of network access for utilization during the second time interval equal to that user's allocation for the second time interval.\",\n \"The user allocations—and hence the user allowances—preferably differ as between the first and second time intervals.\",\n \"As used herein, a “bandwidth allowance” represents a respective maximum level of network access that will be made available to a user class or to a user during a particular time interval, and does not necessarily represent the level of network access that will be utilized by the user class or user during such time interval.\",\n \"As used herein, a “user class” is intended to refer to a grouping of users who compete for access across a shared communications medium and who have some characteristic in common.\",\n \"The characteristic may, for example, be that the users are customers who receive Internet service over the shared communications medium from the same service provider.\",\n \"The characteristic also may, for example, be that the users each subscribe to receive a particular level of network access across the shared communications medium, or that the users receive the same level of a particular service that is provided across the shared communications medium.\",\n \"Furthermore, a user class is a grouping of users to which, collectively, a determined amount of bandwidth is allocated as opposed to other user classes.\",\n \"In this regard, users that are not classified are considered to be part of a default user class having in common that fact that no other classification applies to them.\",\n \"Accordingly, all users of a shared communications network can be classified.\",\n \"In features of the present invention, the method includes the steps of monitoring network access usage by the users, and forecasting network access usage of each user in a future time interval.\",\n \"Another feature includes the step of prioritizing the users for the allocation of network access.\",\n \"One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network and tracking the collective bandwidth consumption of each user class; based on the monitored bandwidth consumptions, the forecasting of bandwidth consumption of each user in a future time interval and the calculation based thereon of the collective bandwidth consumption of each user class; the prioritization of users and the prioritization of user classes; and the subsequent allocation of bandwidth to each user class, and then to each user, in decreasing order of priority for determining bandwidth allowances during the future time interval.\",\n \"Users and user classes are prioritized based on one or more various prioritization policies, including fairness considerations such as individual or collective user throughput during a particular time interval, individual or collective user data loss for a particular time interval, individual or collective user bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.\",\n \"Other prioritization policies include the prioritization of users and user classes based upon provisions found in each user's respective service level agreement (SLA) or provisions found in each class' service level agreement (CSLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval and the prioritization of user classes based upon each class' collective forecasted bandwidth consumption.\",\n \"In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.\"\n ],\n [\n \"FIELD OF THE PRESENT INVENTION The present invention generally relates to allocating access across a shared communications medium and, in particular, to allocating bandwidth used to convey data of competing users across a shared communications medium of a Carrier Network.\",\n \"BACKGROUND OF THE PRESENT INVENTION As used herein, a “Carrier Network” generally refers to a computer network through which users (such as homes and businesses) communicate with various service providers.\",\n \"The Carrier Network extends from the location of each user to an intermediate switched/routed network (hereinafter “Intermediate Network”).\",\n \"The service providers, in turn, are connected to the Intermediate Network, either directly or indirectly via the Internet, for communications with the users.\",\n \"The Carrier Network is maintained by a “Carrier,” which also may serve as a service provider for certain services.\",\n \"For example, a Carrier or a related entity may serve as an Internet service provider (ISP).\",\n \"Two prevalent types of Carrier Networks include a “Shared Access Carrier Network,” in which data of multiple users are conveyed together over a shared communications medium between the users and the Intermediate Network, and a “Dedicated Connection Carrier Network,” in which data of each user are conveyed alone between the user and the Intermediate Network and are not combined with data of other users.\",\n \"One of the most prevalent Shared Access Carrier Networks today is found in the Data-Over-Cable (DOC) Network, which includes the traditional network constructed from coaxial cable and the hybrid fiber coaxial (HFC) network constructed with both fiber optical cabling and coaxial cable.\",\n \"Other Shared Access Carrier Networks include wireless and digital subscriber line (XDSL) networks (the xDSL lines typically being aggregated onto an oversubscribed backhaul trunk into the Intermediate Network, with the trunk defining the shared communications medium).\",\n \"For example, with regard to DOC Networks, and with reference to FIG.\",\n \"1 wherein a conventional DOC Network 40 is illustrated, data packets are transmitted in a downstream direction from a cable modem termination system (CMTS) 30, which is located in a headend 36 (or distribution hub) of a Carrier, over a coaxial cable 32 to respective cable modems (CMs) 34 of users.\",\n \"All of the CMs 34 are attached by the coaxial cable 32 to the CMTS 30 in an inverted tree configuration, and each CM 34 connected to the coaxial cable 32 listens to all broadcasts from the CMTS 30 transmitted through the coaxial cable 32 for data packets addressed to it, and ignores all other data packets addressed to other CMs 34.Theoretically, a CM 34 is capable of receiving data in the downstream direction over a 6 MHz channel with a maximum connection speed of 30-40 Mbps.\",\n \"Data packets also are transmitted in the upstream direction over a 2 MHz channel by the CMs 34 to the CMTS 30 typically using time division multiplexing (TDM) and at a maximum connection speed of 1.5-10 Mbps.\",\n \"The headend 36 in the DOC Network 40 includes a plurality of CMTSs, with each CMTS supporting multiple groups of CMs each connected together by a respective coaxial cable.\",\n \"Each such group of CMs connected to a CMTS defines a Shared Access Carrier Network, with the coaxial cable in each representing the shared communications medium.\",\n \"This arrangement of a group of CMs connected to a CMTS by a coaxial cable is referred to herein as a “Cable Network.” Accordingly, the DOC Network 40 includes a plurality of Cable Networks 38 originating from CMTSs at the headend 36 of the Carrier, with a particular Cable Network 38 being illustrated in an expanded view in FIG.\",\n \"1.The DOC Network 40 also includes multiple headends 36,64,66.In contrast to the Shared Access Carrier Network, a user in the Dedicated Connection Carrier Network establishes a dedicated connection directly with the Intermediate Network for the transfer of data directly therebetween, and no data of other users travel over the dedicated connection.\",\n \"Examples of a dedicated connection are shown for comparison in FIG.\",\n \"1 and include a connection established by a telephony modem 74 and a connection established by an ISDN modem 76.Both downstream and upstream connection speeds in a Dedicated Connection Carrier Network range from a maximum of 53 kbps in a telephony modem connection to a maximum of 128 kbps in a basic rate interface ISDN connection.\",\n \"Connection speeds and, more importantly, throughput rate—the amount of data actually transmitted successfully in a given time interval—are important in minimizing downtime that users spend waiting for HTML documents to download from the Web.\",\n \"A Shared Access Carrier Network is considered superior to a comparable Dedicated Connection Carrier Network because the maximum instantaneous connection speed offered by the Shared Access Carrier Network is greater.\",\n \"A Shared Access Carrier Network is considered “comparable” to a Dedicated Connection Carrier Network where the entire bandwidth over a shared communications medium of the Shared Access Carrier Network equals an aggregate bandwidth that is divided between and dedicated to users in a Dedicated Connection Carrier Network.\",\n \"Accordingly, Shared Access Carrier Networks are able to offer significantly faster downloads of web documents, emails, and file transfers that are not considered available in Dedicated Connection Carrier Networks.\",\n \"Furthermore, new multimedia applications and Internet services, such as voice and video communications via the Internet, now are offered which require even greater throughput rates for acceptable levels of service than that of the traditional Internet services, i.e., throughput rates greater than that required for acceptable text-based Web browsing, file transferring, and email communication.\",\n \"It is believed that these new multimedia applications and Internet services cannot adequately be provided for over Dedicated Connection Carrier Networks and that, consequently, Shared Access Carrier Networks ultimately will prevail as the predominant type of Carrier Network for Internet access by users.\",\n \"Of course, the actual throughput rates experienced by a particular user rarely, if ever, will equate to the maximum connection speeds of which the Shared Access Carrier Network is capable because of the shared nature of the communications medium.\",\n \"For example, in a Cable Network the total bandwidths available over the shared cable in the downstream and upstream directions, which determine the respective maximum connection speeds, must be shared among all of the users communicating at a given time.\",\n \"Thus, rarely will a single user have available for use a large portion of the entire bandwidth in a particular direction.\",\n \"Further, as a Carrier adds users to the Cable Network, the actual downstream and upstream bandwidths available to the user—and thus throughput rates of the user—generally will decrease.\",\n \"A Carrier therefore must be careful to draw a balance between the number of users connected to a Cable Network and the performance users experience communicating over the network.\",\n \"Unfortunately, Shared Access Carrier Networks that have been established were designed to provide the traditional Internet services, and not the new multimedia applications and Internet services that require higher throughput rates for acceptable levels of service.\",\n \"Consequently, each balance previously struck by Carriers in establishing Shared Access Carrier Networks was based on considerations of the throughput rates required for the traditional Internet services, and user throughput rates currently experienced by users in such networks are believed to fall short of acceptable quality of service (QoS) standards believed required in a Carrier Network for the new multimedia applications and Internet services.\",\n \"Additionally, with regard to new Shared Access Carrier Networks that are being established, considerations of the new multimedia applications and Internet services tend to reduce the number of users that a Carrier now can reasonably expect to connect to the shared communications medium before degrading the performance levels of the new multimedia applications and Internet services.\",\n \"The balance is being shifted towards less users per shared access medium in exchange for higher throughput rates and, thus, higher QoS standards.\",\n \"In an attempt to avoid reducing the number of users, it has been proposed, at least in DOC Networks, to discriminate between the traditional Internet services and the new multimedia applications and Internet services with regard to priority of data packet transmissions.\",\n \"In particular, the generally accepted standard in the United States governing communication protocols over cable is DOCSIS version 1.0, which was ratified by the International Telecommunication Union in March of 1998.DOCSIS stands for “Data Over Cable Service Interface Specifications.” When DOCSIS 1.0 was developed, it was generally believed that, in view of the “fast” connection speeds of Cable Networks, the provision of bandwidth on a best effort basis would be sufficient to meet all user requirements.\",\n \"Accordingly, each user subscribed to receive network access pursuant to a service level agreement (SLA) which provided for network access (or bandwidth in Cable Networks) only on a best effort basis.\",\n \"Now, in an effort to address the foreseen ever-increasing demand for higher throughput rates, DOCISIS version 1.1 has been proposed, in accordance with which each data packet transmitted over a DOC Network now must include a classification designation for prioritization purposes by network equipment.\",\n \"Subsequently, data packets representing voice or video, for example, now can be identified and given priority transmission over data packets representing email, file transfers, and text-based Web documents.\",\n \"A benefit of such flow classification is that, while overall bandwidth generally available to a user may otherwise remain unchanged, throughput rates of data for voice and video now may be provided at a higher rate than throughput rates of data for the traditional Internet services, thereby increasing the performance of voice and video applications and services while at least maintaining the traditional number of users connected to a Cable Network.\",\n \"A disadvantage of the revisions to DOCSIS 1.1 is that the revisions do not enhance established Cable Networks constructed with only DOCSIS 1.0 compliant equipment, as such equipment does not support the added functionality of DOCSIS 1.1 so as to distinguish between data packets.\",\n \"More broadly, another disadvantage of the classification of data packets into Internet Protocol (IP) flows based on the services represented by the data packets is that such classification discriminates against users who do not utilize multimedia applications and services receiving the prioritized transmissions.\",\n \"At least for some extensive users of the traditional Internet services, some degradation in performance may be noticed by lower classification of their data packets, particularly if the user engages in, for example, web hosting.\",\n \"While the transmissions of data packets for documents, files, and emails are not as time-sensitive as data packets for voice and video, increased data packet latency for documents, files, and emails, even if incrementally small, nevertheless will result in service degradation for large or numerous documents, files, and emails.\",\n \"Accordingly, a need exists for a method and apparatus that will accommodate differing demands for network access by users competing for such access across a shared communications medium of a Shared Access Carrier Network, whether new or established, and irrespective of data packet classifications.\",\n \"Furthermore, as Shared Access Carrier Networks emerge as the favored type of network, it is believed that open access to such networks by different competing service providers will become an important commercial and legislative issue.\",\n \"Moreover, as more and more service providers seek to provide users with services over Shared Access Carrier Networks, it is believed that users of such service providers will receive inadequate bandwidth over the Shared Access Carrier Networks to meet minimum standards of quality, especially in Cable Networks where bandwidth is provided on a best efforts basis.\",\n \"Accordingly, it is believed that an additional need exists for a method by which a service provider competing for users of a shared communications medium can seek protection against bandwidth starvation of the users of the shared communications medium that are its customers.\",\n \"Conversely, it is also believed that a need exists for a method that will accommodate differing demands for network access by users competing for such access across the shared communications medium.\",\n \"SUMMARY OF THE PRESENT INVENTION Briefly summarized, the present invention relates to a method of providing network access across a shared communications medium between competing users, and include eight different aspects.\",\n \"First Aspect of the Present Invention In the first aspect of the present invention, the method broadly includes the steps of: (a) prior to first and second time intervals, respectively determining for each user first and second network access allowances; (b) during the first time interval, providing network access to each user such that the respective first network access allowance is not exceeded; and (c) during the second time interval, providing network access to each user such that the respective second network access allowance for each user is not exceeded.\",\n \"In accordance with the present invention, the “network access allowance” represents a respective maximum level of network access that can be made available to the user during a particular time interval, and does not represent necessarily the level of network access that will be utilized by the user during such time interval.\",\n \"Furthermore, at least one respective second network access allowance for a user differs from such user's respective first network access allowance.\",\n \"The first network access allowances for the users preferably are determined by allocating network access to each user on a per user basis for the first time interval in accordance with a first allocation policy.\",\n \"The first network access allowance for each respective user then is equated to the network access allocated to that user under the first allocation policy.\",\n \"Likewise, the second network access allowances for the users are determined by allocating network access to each user on a per user basis for the second time interval in accordance with a second allocation policy that may or may not differ from the first allocation policy.\",\n \"Again, the second network access allowance for each respective user then is equated to the network access allocated to that user under the second allocation policy.\",\n \"In additional features of the present invention, the method includes the steps of monitoring network access usage by the users, and forecasting network access usage of each user in a future time interval.\",\n \"Another additional feature of the present invention includes the step of prioritizing the users for the allocation of network access.\",\n \"One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network; based on the monitored bandwidth consumption, the forecasting of bandwidth consumption of each user in a future time interval; the prioritization of users; and the subsequent allocation of bandwidth to each user in decreasing priority for determining bandwidth allowances during the future time interval.\",\n \"Users are prioritized based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.\",\n \"Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval.\",\n \"In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.\",\n \"With regard to at least two users, the favored user allocations, and thus the user allowances, differ as between future time intervals.\",\n \"Second Aspect of the Present Invention In the second aspect of the present invention, the method broadly includes the steps of monitoring network access usage of each user for a past time interval and, based on the monitored network access usage, allocating network access to each user for a future time interval.\",\n \"In a feature of the present invention, the network access that is monitored and allocated is in the downstream direction towards the users.\",\n \"In a separate and independent feature of the present invention, network access usage of each user is forecast for a future time interval based on the monitoring, and allocations are made based on the forecasting.\",\n \"Another additional feature of the present invention includes the prioritizing of the users for allocating network access.\",\n \"One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network; based on the monitored bandwidth consumption, the forecasting of bandwidth consumption of each user in a future time interval; the prioritization of users; and the subsequent allocation of bandwidth to each user in decreasing priority for the future time interval.\",\n \"Users are prioritized based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.\",\n \"Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval.\",\n \"In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.\",\n \"Third Aspect of the Present Invention In the third aspect of the present invention, the method broadly includes the steps of monitoring network access usage by each user for a past time interval and, based on the monitored network access usage, allocating network access for each user for a future time interval.\",\n \"In a feature of the present invention, network access usage of each user is forecast for a future time interval based on the monitoring, and allocations are made based on the forecasting.\",\n \"Another feature of the present invention includes the prioritizing of the users for allocating network access.\",\n \"A preferred method of providing network access to the users includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on the monitoring, forecasting network access usage by each user over a future time interval; (c) prioritizing users based on each user's forecasted network access usage in increasing order, whereby a user with a lesser forecasted network access usage receives a higher priority than a user with a greater forecasted network access usage; and (d) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.\",\n \"Another preferred method of providing network access to the users includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) based on the monitoring, forecasting network access usage by each user over a future time interval; and (c) allocating network access available to each user during the future time interval, with each user's allocation of network access being equal to each user's forecasted network access usage multiplied by a ratio of the total network access available for allocation to the total forecasted network access usage of all users, and subject to a respective, predetermined maximum value and subject to availability.\",\n \"A third preferred method of providing network access to the users includes the steps of: (a) charging each user a respective fee for network access usage; (b) monitoring network access usage by each user during a time interval; (c) based on the monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum value and subject to availability.\",\n \"Yet a fourth preferred method of providing network access to the users includes the steps of: (a) applying respective credits to users for network access shortfalls below respective levels of network access specified to the users; (b) monitoring network access usage by each user during a past time interval; (c) based on the monitoring, forecasting network access usage by each user over a future time interval; (d) prioritizing users based on each user's respective credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit; and (e) allocating network access available to each user during the future time interval in decreasing order of user priority, with each user's allocation of network access being equal to each user's forecasted network access usage subject to a respective, predetermined maximum guaranteed value and subject to availability.\",\n \"Fourth Aspect of the Present Invention In the fourth aspect of the present invention, the method includes providing network access across a shared communications medium between competing users pursuant to service level agreements (SLAs) of the users.\",\n \"The method broadly includes the steps of: (a) monitoring network access usage by each user during a time interval; (b) comparing the monitored network access usage by each user with a predetermined threshold value; and (c) soliciting a user to modify the user's SLA if the user's monitored network access usage varies from the predetermined value by a predetermined tolerance.\",\n \"Features of the present invention include the additional steps of allocating network access to each user for a future time interval, and forecasting network access usage by users in the future time interval.\",\n \"Another additional feature of the present invention includes the step of prioritizing the users for allocating network access to the users.\",\n \"The network access usage includes the user throughput rate, bandwidth consumption, and/or bandwidth requested for a predetermined period of time.\",\n \"The threshold value preferably represents a respective maximum level of network access (whether maximum allowed or maximum guaranteed) for each user or a respective maximum burstable level of network access with target probability for each user.\",\n \"The solicitation is conducted via email, instant messaging, redirection of a web browser of the user to a solicitation web page, generation and mailing of literature, telephonic communication, or other communication means.\",\n \"The solicited modification of the user's SLA includes guaranteeing a level of network access to the user on a permanent or on a temporary basis.\",\n \"A charge preferably is applied to the user for the modification.\",\n \"A preferred method of the present invention includes the identification of a recurrent period of high network access usage by a user based on the monitoring, and in response thereto, the solicitation of the user to modify the user's SLA in order to guarantee a minimum level of network access during an anticipated future recurrent period of high network access usage.\",\n \"Fifth Aspect of the Present Invention In the fifth aspect of the present invention, the method includes incorporating allocations of network access into a DOCSIS 1.0 compliant cable network wherein users compete for bandwidth.\",\n \"A preferred method includes the steps of: (a) generating cable modem configuration files, each of which limits bandwidth consumption by a cable modem of a user to a value representative of that user's allowance of bandwidth; (b) sending the configuration files to a Trivial File Transfer Protocol (TFTP) Server of the DOC Network; and (c) sending a command either to each user's cable modem, or to a cable modem termination system to which each user's cable modem is connected, to cause the cable modem to acquire its new respective configuration file.\",\n \"Features of the present invention include the additional steps of prioritizing users for allocation of bandwidth, and forecasting bandwidth of each user in a future time interval.\",\n \"Sixth Aspect of the Present Invention In the sixth aspect of the present invention, a Carrier Network provides communications between multiple users and Service Providers.\",\n \"The Carrier Network includes computer network equipment defining a Cable Network and an Intermediate Network which, combined, extends between the users and the Service Providers.\",\n \"The Cable Network includes a shared communications medium joining the users with the Intermediate Network, and users compete for network access across the shared communications medium in conveying data.\",\n \"The Carrier Network also includes software that manages the network access of the users.\",\n \"In accordance with the present invention, the software includes computer-executable instructions performing the steps of monitoring network access usage by each user for a time interval and, based thereon, allocating network access to the users for a future time interval.\",\n \"In additional features of the present invention, the software includes computer-executable instructions performing the additional steps of forecasting network access usage by each user during the future time interval, and prioritizing the users for allocation of network access In additional features of the present invention, the software is distributed within network equipment of the Carrier Network or, alternatively, is stored in hardware physically located at a remote location from the Carrier Network but linked with the Carrier Network for communications therebetween.\",\n \"The hardware remotely located is directly linked with the Carrier Network or is linked indirectly through the Internet.\",\n \"One of many preferred embodiments of the present invention includes prioritization of users based on one or more various prioritization policies, including the prioritization of users based upon fairness considerations, such as user throughput during a particular time interval, user data loss for a particular time interval, network access usage for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.\",\n \"Other prioritization policies include the prioritization of users based upon provisions found in each user's respective service level agreement (SLA), and the prioritization of users based upon each user's forecasted network access usage for a future time interval.\",\n \"Seventh Aspect of the Present Invention In the seventh aspect of the present invention, the present invention relates to a method of (and to a computer-readable medium with computer-executable instructions for performing the method of) providing network access across a shared communications medium between competing users.\",\n \"The method broadly includes the steps of receiving data representative of past bandwidth of each user during a time interval; forecasting future bandwidth of each user over a future time interval based on the data representative of the past bandwidth; and setting each user's allocation of bandwidth for the future time interval.\",\n \"A feature of the present invention includes the step of prioritizing the users for allocating bandwidth to the users.\",\n \"Preferably, each user's bandwidth allocation represents that user's limit on bandwidth consumption for the future time interval (“bandwidth allowance”), and does not necessarily represent that user's bandwidth consumption during the future time interval.\",\n \"In a first preferred method, the users are prioritized based on each user's forecasted future bandwidth in increasing order, whereby a user with a lesser forecasted bandwidth receives a higher priority than a user with a greater forecasted bandwidth.\",\n \"The users are then allocated sequentially in decreasing order of user priority, with each user's allocation being set to equal the user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to bandwidth availability.\",\n \"Another preferred method includes allocating bandwidth that is to be made available to each user during the future time interval, with each user's allocation of bandwidth being set to equal each user's forecasted bandwidth multiplied by a ratio of the total bandwidth available for allocation to the total forecasted bandwidth of all users, and subject to a respective, predetermined maximum value and subject to availability.\",\n \"A third preferred method includes receiving data representative of a respective fee that is charged to each user for bandwidth, prioritizing users based on each user's fee in decreasing order, whereby a user having a greater fee receives a higher priority than a user having a lesser fee, and setting in decreasing user priority each user's allocation of bandwidth equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.\",\n \"Yet a fourth preferred method includes receiving data representative of a respective credit that is applied to each user's account for bandwidth shortfalls below a specified bandwidth value, prioritizing users based on each user's credit in decreasing order, whereby a user having a greater credit receives a higher priority than a user having a lesser credit, and setting in decreasing user priority each user's allocation of bandwidth equal to each user's forecasted bandwidth subject to a respective, predetermined maximum value and subject to availability.\",\n \"The bandwidth monitored and forecast includes bandwidth that is consumed or, alternatively, bandwidth that is requested for consumption.\",\n \"Eighth Aspect of the Present Invention Finally, in the eighth aspect of the present invention, the present invention relates to a method of providing network access across a shared communications medium between competing users.\",\n \"In particular, the present invention includes the steps of allocating network access to at least two “user classes” for a first future time interval and, for each user class, allocating network access to each user within the class for the first time interval.\",\n \"The present invention further includes the additional step of allocating network access to each user class for a second future time interval succeeding the first time interval and, for each user class, allocating network access to each user for the second time interval.\",\n \"Each user receives a first determined allowance of network access for utilization during the first time interval equal to that user's allocation for the first time interval, and a second determined allowance of network access for utilization during the second time interval equal to that user's allocation for the second time interval.\",\n \"The user allocations—and hence the user allowances—preferably differ as between the first and second time intervals.\",\n \"As used herein, a “bandwidth allowance” represents a respective maximum level of network access that will be made available to a user class or to a user during a particular time interval, and does not necessarily represent the level of network access that will be utilized by the user class or user during such time interval.\",\n \"As used herein, a “user class” is intended to refer to a grouping of users who compete for access across a shared communications medium and who have some characteristic in common.\",\n \"The characteristic may, for example, be that the users are customers who receive Internet service over the shared communications medium from the same service provider.\",\n \"The characteristic also may, for example, be that the users each subscribe to receive a particular level of network access across the shared communications medium, or that the users receive the same level of a particular service that is provided across the shared communications medium.\",\n \"Furthermore, a user class is a grouping of users to which, collectively, a determined amount of bandwidth is allocated as opposed to other user classes.\",\n \"In this regard, users that are not classified are considered to be part of a default user class having in common that fact that no other classification applies to them.\",\n \"Accordingly, all users of a shared communications network can be classified.\",\n \"In features of the present invention, the method includes the steps of monitoring network access usage by the users, and forecasting network access usage of each user in a future time interval.\",\n \"Another feature includes the step of prioritizing the users for the allocation of network access.\",\n \"One of many preferred embodiments of the present invention includes the monitoring of bandwidth consumption of each user across the shared communications medium of a Cable Network and tracking the collective bandwidth consumption of each user class; based on the monitored bandwidth consumptions, the forecasting of bandwidth consumption of each user in a future time interval and the calculation based thereon of the collective bandwidth consumption of each user class; the prioritization of users and the prioritization of user classes; and the subsequent allocation of bandwidth to each user class, and then to each user, in decreasing order of priority for determining bandwidth allowances during the future time interval.\",\n \"Users and user classes are prioritized based on one or more various prioritization policies, including fairness considerations such as individual or collective user throughput during a particular time interval, individual or collective user data loss for a particular time interval, individual or collective user bandwidth consumption for a particular time-of-day, an established minimum quality of service (QoS) standard, or combination thereof.\",\n \"Other prioritization policies include the prioritization of users and user classes based upon provisions found in each user's respective service level agreement (SLA) or provisions found in each class' service level agreement (CSLA), and the prioritization of users based upon each user's forecasted bandwidth consumption for the future time interval and the prioritization of user classes based upon each class' collective forecasted bandwidth consumption.\",\n \"In alternative embodiments, the bandwidth that is requested, rather than the bandwidth that is consumed, is monitored and forecasted.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS Further features and benefits of the present invention will be apparent from a detailed description of preferred embodiments thereof taken in conjunction with the following drawings, wherein like elements are referred to with like reference numbers, and wherein: FIG.\",\n \"1 illustrates a conventional DOC Network; FIG.\",\n \"2 illustrates a first DOC Network of the present invention; FIG.\",\n \"3 illustrates a second DOC Network of the present invention; FIG.\",\n \"4 illustrates a third DOC Network of the present invention; FIG.\",\n \"5 illustrates a fourth DOC Network of the present invention; FIG.\",\n \"6 illustrates a system architecture of software components that perform preferred methods of the present invention in the DOC Networks of FIGS.\",\n \"2-5; FIG.\",\n \"7 illustrates a flowchart of the steps of a preferred routine for forecasting bandwidth of each user for a future time interval; FIG.\",\n \"8 illustrates a flowchart of the steps of generating a forecasted bandwidth for a user in accordance with the ARRSES Function of the preferred routine of FIG.\",\n \"7; FIG.\",\n \"9 illustrates a flowchart of the steps of generating a forecasted bandwidth for a user in accordance with the HW Function of the preferred routine of FIG.\",\n \"7; FIG.\",\n \"10 illustrates a graph of user throughput rates versus user data loss rates for two users relative to a target minimum QoS standard; FIG.\",\n \"11 illustrates a flowchart of a first preferred method of prioritizing classes and allocating collective bandwidth to each class; FIG.\",\n \"12 illustrates a flowchart of a second preferred method of prioritizing classes and allocating collective bandwidth to each class; FIG.\",\n \"13 illustrates a flowchart of a third preferred method of prioritizing classes and allocating collective bandwidth to each class; FIG.\",\n \"14 illustrates a flowchart of a fourth preferred method of prioritizing classes and allocating collective bandwidth to each class; FIGS.\",\n \"15a and 15b illustrate a flowchart of a fifth preferred method of prioritizing classes and allocating collective bandwidth to each class; FIGS.\",\n \"16a and 16b illustrate a flowchart of a sixth preferred method of prioritizing classes and allocating collective bandwidth to each class; FIG.\",\n \"17 illustrates a flowchart of a first preferred method of prioritizing users and allocating bandwidth to each user within a class; FIG.\",\n \"18 illustrates a flowchart of a second preferred method of prioritizing users and allocating bandwidth within a class; FIG.\",\n \"19 illustrates a flowchart of a third preferred method of prioritizing users and allocating bandwidth within a class; FIG.\",\n \"20 illustrates a flowchart of a fourth preferred method of prioritizing users and allocating bandwidth within a class; FIGS.\",\n \"21a and 21b illustrate a flowchart of a fifth preferred method of prioritizing users and allocating bandwidth within a class; FIGS.\",\n \"22a and 22b illustrate a flowchart of a sixth preferred method of prioritizing users and allocating bandwidth within a class; FIG.\",\n \"23 illustrates a flowchart of a preferred method of updating a DOC Network for a DOCSIS 1.0 compliant Cable Network; FIG.\",\n \"24 illustrates the allocation of bandwidth to users within a class during a first time interval; FIG.\",\n \"25 illustrates the allocation of bandwidth to the users of FIG.\",\n \"24 during a second time interval; and FIG.\",\n \"26 illustrates a flowchart of a preferred method of soliciting a user to modify the user's SLA based on monitored network access usage of the user.\",\n \"DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS In the following detailed description, numerous specific details are set forth with regard to preferred embodiments of the present invention in order to provide a thorough understanding of the present invention; however, it will be apparent to ordinary artisans that the present invention may be practiced without all of these specific details.\",\n \"Well-known structures and devices also are shown in block diagram form, the specific details of which are not considered a necessary part of the present invention.\",\n \"Furthermore, as will become apparent to ordinary artisans, the present invention may be embodied in or performed by hardware, firmware, or software, or various combinations thereof.\",\n \"As described above, a conventional DOC Network 40 is shown in FIG.\",\n \"1 and includes a plurality of Cable Networks 38, with a particular Cable Network 38 being illustrated in an expanded view and comprising a group of CMs 34, each connected to a computer 44 representing a user.\",\n \"Additionally, as used herein, “user” includes not only a person who interacts with a computer 44, but any additional persons who also interact with the same computer 44, as well as any group of persons all of whom interact with computers attached either to the same CM 34 or to the same computer 44 which, itself, is attached to a CM 34.While not shown, such additional arrangements are well known in the art.\",\n \"The CMs 34 are connected by a coaxial cable 32 with a CMTS 30 and, specifically, to a card 31 mounted within the CMTS 30.Each of the CMTSs of the DOC Network 40 preferably includes a plurality of cards, with each card supporting a group of CMs connected thereto in an inverted tree configuration to define a Cable Network 38.Furthermore, each CMTS conventionally supports up to 1,500 users, although recent CMTSs have been introduced that support up to 15,000 users.\",\n \"Each Cable Network 38 defines a Shared Access Carrier Network, wherein data of respective users in each are conveyed together through a shared coaxial cable.\",\n \"For instance, data packets (or frames) addressed to at least one of the computers 44 are transmitted by the CMTS 30 downstream over the coaxial cable 32 to all of the CMs 34 within a 6 MHz data channel.\",\n \"Conversely, data packets intended for delivery to the CMTS 30 and beyond are transmitted by a CM 34 upstream to the CMTS 30 over the coaxial cable 32 within a 2 MHz channel.\",\n \"The Cable Network 38 shown in expanded view in FIG.\",\n \"1 is a traditional all coaxial cable network.\",\n \"The other Cable Networks 38 collectively include both traditional all coaxial cable networks as well as HFC networks.\",\n \"The CMTS 30 transmits and receives data packets between the Cable Networks 38 and an Intermediate Network 46, which begins with a router 48 in the headend 36, and includes switched and routed network equipment at a Regional Data Center 50 that provides connectivity to service providers 52,54,56,58, either directly or through the Internet 60.In this regard, during user communications the router 48 conveys data packets from the CMTS 30 to the Regional Data Center 50 of the DOC Network 40 and, conversely, routes data packets received from the Regional Data Center 50 to the appropriate CMTS for delivery to a particular user.\",\n \"Data packets that are conveyed to the Regional Data Center 50, in turn, are directed on to an appropriate service provider 52,54 directly connected to the Regional Data Center 50, or to an appropriate service provider 56,58 indirectly connected to the Regional Data Center 50 via the Internet 60.Alternatively, data packets from users are conveyed to a server of an application server group 62 of the Regional Data Center 50, which includes, for example, servers supporting Web hosting, news, chat, SMTP, POP3, Proxy, cache and content replication, and streaming media.\",\n \"The Cable Networks 38 stemming from headend 36 are maintained by a Carrier which also may maintain the Regional Data Center 50 as well as serve as a service provider.\",\n \"Moreover, the Carrier may maintain the Cable Networks of additional headends 64,66, or of only one or more of the headends 64,66.In any event, the Cable Networks that are maintained by the Carrier are administered on a daily basis through an element management system (EMS) 68.The EMS 68 comprises an operations system designed specifically to configure and manage CMTSs and associated CMs, and includes a CM database 70.Operational tasks performed by the EMS 68 include provisioning, day-to-day administration, and testing of various components of each CMTS.\",\n \"The EMS 68 typically is located at a central network operations center of the Carrier, but may be collocated at the headend 36 of the Carrier as shown in FIG.\",\n \"1.The DOC Network 40 is managed through a control plane server group 72 typically located at the Regional Data Center 50.The control plane server group 72 includes the usual servers necessary to run the DOC Network 40, such as user authorization and accounting servers, log control servers (Syslog), IP address assignment and administration servers (DHCP, TFTP), domain name servers (DNS), and DOCSIS control servers.\",\n \"For purposes of comparison, two dedicated connections also are shown in FIG.\",\n \"1, wherein a telephony modem 74 and an ISDN modem 76 are connected directly to the Intermediate Network 46 at the Regional Data Center 50.As will be immediately apparent, data conveyed over each dedicated connection is between a single user and the Intermediate Network 46, and is not combined with data of other users over a shared communications medium as in each Cable Network 38.As is common in conventional Cable Networks 38 such as those shown in the DOC Network 40 of FIG.\",\n \"1, when a CM comes online the CM is assigned a configuration file which, inter alia, sets a constant limit on the bandwidth that can be utilized in the downstream direction by the CM during any particular interval of time, and sets a constant limit on the bandwidth that can be utilized in the upstream direction by the CM during any particular interval of time.\",\n \"The configuration file also includes other parameters, such as the IP address for the CM.\",\n \"The configuration file for each CM conventionally is obtained by the CM when first brought online, or when the CM is reset.\",\n \"The upstream and downstream bandwidth limits are predetermined by the Carrier or other appropriate entity, the determination of which is based on the expected number of users to be serviced by the particular Cable Network 38 to which the CM belongs.\",\n \"With particular regard to data transmissions in the downstream direction, when the bandwidth limit is reached in receiving data within a particular time interval, the CM transmits a signal to the router 48 to cease further data forwarding for the remainder of the time interval.\",\n \"Thereafter, whereas any data received by a CMTS is relayed on to the CM as the data is received, any additional data received by the router 48 during the remainder of this time interval is stored for later transmission in a buffer up to a threshold limit and, thereafter, any further data received within the time interval is dropped.\",\n \"With regard to data transmissions in the upstream direction, when the CM registers with the CMTS following receipt by the CM of its configuration file, the CM informs the CMTS of the constant bandwidth limit to be applied to upstream transmissions from the CM.\",\n \"Then, actual requests for bandwidth (i.e., requests for timeslots) for transmission of data in the upstream direction are submitted regularly by each CM to the CMTS.\",\n \"In response to the submissions, the CMTS schedules timeslots in a particular time interval to the CMs for exclusive transmission of data within each timeslot by a respective CM.\",\n \"However, the CMTS does not grant an amount of bandwidth (by assigning too many timeslots) to a particular CM that would exceed the constant bandwidth limit for the particular CM.\",\n \"The timeslots are assigned to requesting CMs based on an established assignment policy.\",\n \"For example, timeslots may be assigned by the CMTS on a first-in-first-out basis, or timeslots may be assigned equally to the CMs that request bandwidth within a particular window of time.\",\n \"The requesting CMs also may be prioritized by the CMTS for assignment of the timeslots.\",\n \"Preferred embodiments 78,80,82,84 of a DOC Network in accordance with the present invention are shown, respectively, in FIGS.\",\n \"2-5, wherein each includes a “network access manager” 86 in accordance with the present invention.\",\n \"In FIG.\",\n \"2 the network access manager 86 is located in the headend 36 of the DOC Network 78, in FIG.\",\n \"3 the network access manager 86 is located at the Regional Data Center 50 of the DOC Network 80, and in FIGS.\",\n \"4-5 the network access manager 86 is remotely located, but is disposed for communication with the respective DOC Network 82,84, either directly as shown in the DOC Network 82 of FIG.\",\n \"4, or indirectly via the Internet 60 as shown in the DOC Network 84 of FIG.\",\n \"5.The network access manager 86 preferably comprises a hardware component having software modules for performing methods in accordance with the present invention.\",\n \"For commercial purposes, especially in enhancing existing DOC Networks, preferably the network access manager 86 is self-contained and need only be connected in communication with the DOC Network to operate correctly.\",\n \"In a DOC Network that is being upgraded or established, preferably the software modules are distributed within the DOC Network itself and may or may not include any additional hardware components such as the network access manager 86.For example, the software modules may be incorporated into the EMS, CMTS, and control plane server group of a DOC Network, thereby avoiding the expense of additional computer hardware components.\",\n \"In order to accommodate deployment and implementation of the present invention, the software modules preferably are designed as peers within a messaging infrastructure and, in particular, within a CORBA infrastructure 87, the system architecture of which is shown in FIG.\",\n \"6.Due to the interoperability of the peers to the CORBA infrastructure 87, the separate modules readily call upon each other as described in detail below without regard to differences in location between the modules.\",\n \"Nevertheless, for ease of deployment, the network access manager 86 is best suited for deployment and implementation of the present invention in established DOC Networks, whether situated within the Intermediate Network as in FIGS.\",\n \"2-3, or remotely situated as in FIGS.\",\n \"4-5.The software modules include a Data Collector 88, a Database Manager 90, Bandwidth Allocator 92, and GUI & Report Generating Engine 94.The Data Collector 88 and Bandwidth Allocator 92 each includes an external system interface layer 96,98, respectively, that enables it to communicate with network equipment of a DOC Network.\",\n \"In the system architecture of preferred embodiments, the Data Collector 88 communicates with each CMTS and CMs of each Cable Network for which network access is managed by the network access manager 86, and the Bandwidth Allocator 92 communicates with the control plane server group 72 of the DOC Network as well as with the CMTS and CMs.\",\n \"If a DOC Network is DOCSIS 1.0 compliant, then each external system interface layer 96,98 is a DOCSIS external system interface layer.\",\n \"If a DOC Network uses proprietary interface specifications, then each external system interface layer 96,98 is designed based on the proprietary interface specifications.\",\n \"In either case, however, the Data Collector 88 and Bandwidth Allocator 92 generally need not be modified; only the external systems interface layers 96,98 thereof need be changed based on the particularities of the DOC Network.\",\n \"Each of the Data Collector 88 and Bandwidth Allocator 92 also includes a scheduling element 100,102, respectively, that schedules the timing of actions and communications thereof with the network equipment of a DOC Network.\",\n \"The GUI & Report Generating Engine 94 communicates with an Administrator 106 of the network access manager 86, preferably through a web server, whereby the Administrator 106 sets up and configures the network access manager 86 and accesses reports generated by the network access manager 86, such as graphs of bandwidth consumption and bandwidth requested per time interval for a user.\",\n \"The Administrator 106 may be the Carrier, a service provider, or some other entity, such as the entity managing the Regional Data Center 50 or a third-party responsible for maintenance of the network access manager 86.The Database Manager 90 stores configuration and setup information received from the GUI & Report Generating Engine 94, as well as information processed by the Data Collector 88.The Database Manager 90 also provides information to the Bandwidth Allocator 92 and GUI & Report Generating Engine 94 as requested via the CORBA infrastructure 87.Having now described in detail the structure of preferred DOC Networks 78,80,82,84, preferred methods of the present invention will be described with reference thereto.\",\n \"In accordance with preferred methods of the present invention, network access usages of each user in the upstream and downstream directions are monitored through the Data Collector 88.Specifically, the Data Collector 88 issues queries to the CMTS and CM to which counter values of logical data units (LDUs) are returned for a user.\",\n \"Preferably, counter values are returned for the number of bytes and the number of data packets that are transmitted in both the upstream and downstream directions, the number of bytes and the number of data packets that are dropped in both the upstream and downstream directions, the number of bytes and the number of packets that are requested to be transmitted in the upstream direction, and the time for which the counter values are returned.\",\n \"Accordingly, as used herein the phrase “monitoring network access usage” is intended to refer to the collection of data representative of at least one of: (i) the number of LDUs that are transmitted in a particular direction across a shared communications medium; (ii) the number of LDUs that are dropped in transmitting in a particular direction across a shared communications medium; and (iii) the number of LDUs that are requested to be transmitted in a particular direction across a shared communications medium.\",\n \"In a DOCSIS compliant DOC Network, the information is collected from the CMTS and CMs of a Cable Network via the simple network management protocol (SNMP).\",\n \"The counter values for bytes and data packets that are transmitted and that are dropped in the upstream direction from each CM, and the number of bytes and data packets that are requested to be transmitted in the upstream direction from each CM, are recorded by the CMTS in accordance with a management information base (MIB) of a DOCSIS compliant CMTS.\",\n \"Likewise, the counter values for bytes and data packets that are transmitted and that are dropped in the downstream direction from the CMTS to a CM are recorded by the CM in accordance with a MIB of a DOCSIS compliant CM.\",\n \"Both bytes and data packets are monitored since each data packet may vary in the number of bytes it contains.\",\n \"The scheduling element 100 of the Data Collector 88 initiates the data collection from each CMTS and from the CMs connected thereto, preferably at different predetermined time intervals.\",\n \"For example, the data collection from a CMTS preferably occurs at five minute intervals and data collection from the CMs connected thereto preferably occurs at thirty minute intervals.\",\n \"The data collection from the CMs preferably is less often than the data collection from the CMTS in order to minimize consumption of bandwidth across the Cable Network that otherwise would be allocated to users.\",\n \"When the counter values and time thereof are returned to the Data Collector 88, the Data Collector 88 calculates the change over time for each counter value to arrive at the average rates of bytes and data packets that are successfully transmitted, the average rates of bytes and data packets that are requested to be transmitted, and the average rates of bytes and data packets that are dropped.\",\n \"The respective rates and time intervals for the rates (as well as the counter values and time stamp data) are then communicated to the Database Manager 90, which stores the information in a user statistics table (“stats”) for later use by the Bandwidth Allocator 92 and GUI & Report Generating Engine 94.The Bandwidth Allocator 92 continually determines the network access—or bandwidth in a Cable Network—that may be utilized by each user class, and by each user within each class, over succeeding time intervals.\",\n \"Each allowance is determined by first allocating bandwidth to the user classes, and then allocating bandwidth to the users in each class, in accordance with one or more selected allocation policies.\",\n \"Furthermore, as set forth above, each allowance is an amount of bandwidth up to which a user class or user may consume, but is not necessarily the amount of bandwidth that a user class or user will consume; it is an upper limit on such amount.\",\n \"For example, with reference to FIG.\",\n \"24, a selected allocation policy has resulted in the allocation of bandwidth to the users of the shared communications medium 2450 for a time interval extending from t0 to (t0+dt), User 2 and User K each is allocated a single bandwidth unit (b/w unit 3 and b/w unit X, respectively), while User 1 and User 3 each is allocated two bandwidth units (b/w unit 1 and b/w unit 2 to User 1, and b/w unit 4 and b/w unit 5 to User 3).\",\n \"As shown in FIG.\",\n \"25, in the next time interval extending from (t0+dt) to (t0+2dt), User 1, User 3, and User K each is allocated a single bandwidth unit (b/w unit 1, b/w unit 5, and b/w unit X, respectively), while User 2 is allocated three bandwidth units (b/w unit 2, b/w unit 3, and b/w unit 4).\",\n \"In this example, all users are grouped within the same class, and the bandwidth units in this example broadly represent network access to the communication member 2400 that is shared between the users across the shared communications medium 2450.In accordance with the present invention, respective user bandwidth allowances for each time interval are equated with these user allocations of bandwidth, whereby no user receives more bandwidth in a time interval than that user's respective bandwidth allowance for that time interval.\",\n \"Furthermore, it is important to distinguish what a user actually may be “allocated” in the context of the bandwidth that is actually utilized or consumed by such user, as opposed to bandwidth allocations to a user in accordance with the present invention.\",\n \"The bandwidth allocation in accordance with the present invention represents a limit on the amount of bandwidth that can be allocated to a user for a time interval—and hence is equated with a bandwidth allowance; it does not represent per se the amount of bandwidth that the user actually will utilize in the time interval.\",\n \"In determining network access allocations (and thus allowances) in the preferred embodiments herein described, the Bandwidth Allocator 92 preferably performs three routines, including: the prediction of bandwidth of each user class, and each user within each class, in a predetermined future interval of time (“First Routine”); the prioritization of user classes, and users within each class, for allocation of bandwidth (“Second Routine”); and the actual allocation of bandwidth for each user class, and each user within each class, for determining the bandwidth allowances for the future time interval (“Third Routine”).\",\n \"The First Routine preferably is performed utilizing statistical analysis of past bandwidth consumption of each user or, alternatively, past bandwidth requested for each user, and the forecasted bandwidth includes the bandwidth expected to be consumed by each user or, alternatively, the bandwidth expected to be requested by each user.\",\n \"Any function, method, or algorithm that generates an estimate of a future sample based on previously encountered samples may be used and many are well known in the art of statistical analysis as is evident from SPYROS MAKRIDAKIS ET AL., FORECASTING METHODS AND APPLICATIONS (3d.\",\n \"Ed.\",\n \"John Wiley & Sons 1998), which is hereby incorporated by reference.\",\n \"With regard to user classes, preferably a collective forecasted bandwidth for each class is determined by summing the forecasted bandwidth of all users within the class.\",\n \"The preferred algorithm for predicting each user's forecasted bandwidth includes the combined use of an adaptive-response-rate single exponential smoothing function (ARRSES Function) and a Holt-Winters' seasonal exponential smoothing function (HW Function).\",\n \"These two functions are utilized according to the forecast generation flowchart of FIG.\",\n \"7.The input includes a list of active users and the applicable time intervals for bandwidth allocation.\",\n \"The First Routine 700 begins by identification (Step 702) of the users of the Cable Network to which bandwidth is to be allocated in the Third Routine.\",\n \"Then, for each user, bandwidth for a succeeding time interval is predicted according to either the ARRSES Function or HW Function by first determining (Step 704) whether the user previously has been assigned a forecast function.\",\n \"If not, then in Step 706 the ARRSES Function is assigned to the user and the ARRSES Function is used to generate and record the forecasted bandwidth for the succeeding time interval.\",\n \"On the other hand, if it is determined in Step 704 that a forecast function is assigned, but it is determined in Step 707 that the forecast function is not the HW Function, then a determination is made (Step 708) whether to check for a seasonal cycle of the user.\",\n \"This determination in Step 708 is made by checking the elapsed time since the last seasonal check was made, with a seasonal check being made after a predetermined period of time elapses.\",\n \"If the determination in Step 708 is affirmative, then a seasonal identifier algorithm is executed (Step 710), in which an autocorrelation function and a seasonal identifier function are performed.\",\n \"The autocorrelation function is well known in the art of statistical analysis, and is used to identify elements in a time series which are influential on a current observation of that same series.\",\n \"Based on the output of the autocorrelation function, the seasonal identifier function identifies possible seasonal cycles of the time series by identifying local maxima of the results of the autocorrelation function.\",\n \"Based on the results of the seasonal identifier function, a determination is made (Step 712) whether an actual seasonal pattern exists.\",\n \"If a seasonal pattern is not found, or if it is not yet time to check for a seasonal cycle, then a forecast is generated and recorded (Step 714) using the ARRSES Function.\",\n \"If a seasonal pattern is found, then the HW Function is assigned (Step 716) to the user, the HW Function is initialized (Step 718), and the first forecast is generated and recorded (Step 720) using the HW Function.\",\n \"If it is determined in Step 707 that the current function assigned to the user already is the HW Function, then the determination is made (Step 722) whether the last forecasted bandwidth was acceptable.\",\n \"This determination is made by comparing whether the forecasted bandwidth was within 10% of the actual bandwidth consumed or requested.\",\n \"If this determination in Step 722 is negative, then the ARRSES Function is assigned to the user and the new forecast is generated and recorded in accordance with the ARRSES Function (Step 706).\",\n \"If the last forecast is determined (Step 722) to have been acceptable, then a determination is made (Step 724) whether the seasonal cycle has ended.\",\n \"If the seasonal cycle has ended, then the HW Function is reinitialized (Step 726), and the first forecast of the next seasonal cycle is generated and recorded (Step 728) via the HW Function.\",\n \"If the seasonal cycle has not expired, then the next forecast is generated and recorded (Step 730) in accordance with the HW Function.\",\n \"Following each of Step 706, Step 714, Step 728, and Step 730, the Bandwidth Allocator 92 determines (Step 732) whether the forecasting has been completed for all users and, if not, then repeats (Step 738) a forecast loop for a remaining user.\",\n \"If it is determined in Step 732 that all users have been evaluated, then the forecasts are communicated (Step 736) to the Database Manager 90 and the forecasting routine ends.\",\n \"A forecast of bandwidth for a user in a future time interval is generated in accordance with the ARRSES Function via the following formulas: FN+1=FN+αN(BN−FN) αN+1=|SEN/SAEN| SEN+1=SEN+β(BN+1−FN+1−SEN) SAEN=β|(BN−FN)|+(1−β)SAEN−1 wherein, F is the bandwidth that is expected to be consumed by a user for a time interval (or the bandwidth that is expected to be requested by a user); B is the bandwidth that is actually consumed by a user for the time interval (or the bandwidth that is actually requested by a user); N is the present time interval; N−1 is the previous (immediate past) time interval; N+1 is the next (immediate future) time interval; and β is a selected parameter affecting the responsiveness to change of the ARRSES Function when the bandwidth of a user changes between time intervals.\",\n \"Bandwidth is predicted both for the 6 MHz channel in the downstream direction as well as the 2 MHz channel in the upstream direction.\",\n \"Preferably each time interval is thirty minutes in length, but preferably may range from fifteen minutes to sixty minutes in length when bandwidth is forecast in the downstream direction.\",\n \"Preferably each time interval is five minutes in length, but preferably may range from one minute to fifteen minutes in length when bandwidth is forecast in the upstream direction.\",\n \"The steps in generating a forecast in accordance with the ARRSES Function are set forth in FIG.\",\n \"8, and include the calculation (Step 802) of a forecast error, the calculation (Step 804) of a smoothed error, the calculation (Step 806) of a smoothed absolute error, the calculation (Step 808) of alpha, and the calculation (Step 810) of the new forecast.\",\n \"A forecast of bandwidth of a user for a future time interval is generated in accordance the HW Function via the following formulas: Ls=1/s(Y1+Y2+ .\",\n \".\",\n \".\",\n \"+Ys) bs=1/S[(Ys+1−Y1)/s+(Ys+2−Y2)/s+ .\",\n \".\",\n \".\",\n \"+(Y2s−Ys)/s] S1=Y1/Ls,S2=Y2/Ls, .\",\n \".\",\n \".\",\n \"Ss=Ys/Ls Lt=α(Yt/St−s)+(1−α)(Lt−1+bt−1) bt=β(Lt−Lt−1)+(1−β)bt−1 St=γYt/Lt+(1−γ)St−s Ft+m=(Lt+btm)St−s+m wherein, Li=an average level of bandwidth after time interval i, bi=the trend after time interval i, si=the seasonal influence at time interval i, s=length of seasonal cycle (in number of time intervals), Yi=monitored bandwidth consumed or requested in time interval i t=time of initialization, m=the number of time intervals into the future for which a forecast is made, and α, β, and γ are parameters of the forecast method whose values are determined by doing a grid search over the domain of possible values of these parameters in an attempt to minimize the mean-squared-error of the forecast method, each of α, β, and γ falling between 0 and 1.The steps in generating a forecast in accordance with the HW Function are set forth in FIG.\",\n \"9, and include the initialization of the HW Function by determining Ls, bs, and S1, S2 .\",\n \".\",\n \".\",\n \", Ss in Step 902, if appropriate; the determination of the intermediate values of Lt, bt, and St in Step 904; and the determination of the forecast in Step 906, all in accordance with the above formulas.\",\n \"The Second Routine performed by the Bandwidth Allocator 92 comprises the prioritizing of user classes, and of users within each class, to determine respective orders of allocations.\",\n \"Prioritization is performed in accordance with one or more of various possible prioritization policies for users and for user classes.\",\n \"With regard to users within each class, the prioritization policies may depend upon, for example, (i) each user's SLA, (ii) each user's forecasted bandwidth, (iii) fairness considerations, or (iv) any combination thereof.\",\n \"User SLAs that at least partially affect prioritization policies include those that specify, for example: (i) a guaranteed minimum level of bandwidth; (ii) a time-of-day (TOD) minimum level of bandwidth; or (iii) a guaranteed minimum level of bandwidth up to a maximum burstable level of bandwidth with target probability.\",\n \"Equivalently, such provisions also may be found in a CSLA for a class of which the user is a member.\",\n \"Under a SLA or CSLA providing for a guaranteed minimum level of bandwidth for a user, a user will have a guaranteed minimum level of bandwidth for use at all times.\",\n \"Accordingly, if the available bandwidth to such a user otherwise would fall below the minimum guaranteed level, then such a user is given priority over all other users whose guaranteed minimum levels of bandwidth (if applicable) have been satisfied.\",\n \"Similarly, under a SLA or CSLA providing for a TOD minimum level of bandwidth for a user, a user will have a guaranteed minimum level of bandwidth for a particular TOD.\",\n \"If the available bandwidth to such a user otherwise would fall below the minimum guaranteed level during the particular TOD, then such user is given priority over all other users whose guaranteed minimum levels of bandwidth (if applicable) have been satisfied.\",\n \"Finally, under a SLA or CSLA providing for a guaranteed minimum level of bandwidth up to a maximum burstable level of bandwidth with target probability for a user, a user will have a guaranteed minimum level of bandwidth at all times and, in addition thereto, probably will have additional bandwidth up to a maximum level at any given time in accordance with the target probability.\",\n \"Accordingly, if the bandwidth available to such user otherwise would fall below the minimum guaranteed level, then the user is given priority over all other users whose guaranteed minimum levels of bandwidth (if applicable) have been satisfied.\",\n \"The user also is given priority over such other users in allocating additional bandwidth as needed up to the maximum level in accordance with the target probability.\",\n \"Other SLA or CSLA provisions not relating to guaranteed levels of bandwidth also may affect a prioritization policy for users.\",\n \"Thus, for example, a SLA or CSLA may specify a fee (in dollars per unit time per unit bandwidth) that is paid based upon bandwidth consumption by a user for a particular amount of time, and the fee may be different as between users.\",\n \"Under these circumstances, prioritization may be determined so as to maximize fee revenues that are paid.\",\n \"Similarly, a SLA or CSLA may specify a credit (in dollars per unit time per unit bandwidth) that is applied by the Carrier to an account based upon a bandwidth shortfall to a user for a particular amount of time when a guaranteed level of bandwidth for the user is not met.\",\n \"Moreover, the credit may be different as between users.\",\n \"Under these circumstances, prioritization may be determined so as to minimize the collective credits that a Carrier must apply.\",\n \"An example of prioritization based upon the forecasted bandwidth of each user includes giving priority to a first user over all other users, each of whom have a forecasted bandwidth that is greater than that of the first user.\",\n \"Prioritization may also be performed based on unilateral fairness considerations, especially when SLAs or CSLAs do not guarantee minimum levels of bandwidth for individual users, or when users otherwise would share equally in priority.\",\n \"Thus, users may be prioritized based on, for example: (i) the throughput of each of the users for a given time interval, with priority going to the user with the lesser throughput; (ii) data packets dropped over a given time interval, with priority going to the user with the greater data loss; and (iii) throughput experienced during a particular time of day or day of the week with priority going to the user with the lesser throughput for the particular time of day or day of the week.\",\n \"An example of fairness considerations that may be utilized in determining priority is illustrated in FIG.\",\n \"10, wherein user throughput for a time interval is graphed against user data packets dropped in the time interval for Users A and B.\",\n \"A target QoS standard for minimum throughput and maximum packet loss rates are established by the Carrier, whereby in the illustrated example each user is prioritized based on the user's absolute distance from the target QoS standard.\",\n \"Thus, under this policy, User A experiencing higher throughput rate and a lower packet loss rate, and thus having a shorter distance from the standard, is prioritized lower than User B having a lower throughput rate and higher data loss rate.\",\n \"With regard to user classes, prioritization policies are similar to those of the users and include, for example, (i) each CSLA, (ii) each class' collective forecasted bandwidth, (iii) fairness considerations, or (iv) any combination thereof.\",\n \"CSLAs that at least partially affect prioritization policies for user classes include those that specify, for example: (i) a guaranteed minimum level of collective bandwidth for the user class; (ii) a time-of-day (TOD) minimum level of collective bandwidth for the user class; or (iii) a guaranteed minimum level of collective bandwidth up to a maximum burstable level of collective bandwidth with target probability for the user class.\",\n \"Other CSLA provisions not relating to guaranteed levels of collective bandwidth also may affect a prioritization policy.\",\n \"Thus, for example, each CSLA may specify a fee (in dollars per unit time per unit bandwidth) that is paid based upon collective bandwidth consumption by the users of a class for a particular amount of time, and the fee may be different as between different classes of users.\",\n \"Under these circumstances, prioritization may be determined so as to maximize fee revenues that are paid to a Carrier.\",\n \"Similarly, each CSLA may specify a credit (in dollars per unit time per unit bandwidth) that is applied by the Carrier based upon a collective bandwidth shortfall to the users of the class for a particular amount of time when a guaranteed level of collective bandwidth is not met.\",\n \"Moreover, the credit may be different as between user classes.\",\n \"Under these circumstances, prioritization may be determined so as to minimize the total credits that a Carrier may have to apply.\",\n \"An example of prioritization based upon the collective forecasted bandwidth of each user class includes giving priority to a first user class over all other user classes, each of which has a respective collective forecasted bandwidth that is greater than that of the first user class.\",\n \"Prioritization may also be performed based on unilateral fairness considerations, especially when CSLAs do not guarantee minimum levels of collective bandwidth, or when classes otherwise would share equally in priority.\",\n \"Thus, user classes may be prioritized based on, for example: (i) the collective throughput of the users of a class for a given time interval, with priority going to the class with the lesser collective throughput; (ii) the collective data packets of a user class that are dropped over a given time interval, with priority going to the user class with the greater collective data loss; and (iii) the collective throughput of the users of a class experienced during a particular time of day or day of the week, with priority going to the user class with the lesser collective throughput for the particular time of day or day of the week.\",\n \"The Third Routine performed by the Bandwidth Allocator 92 is the allocation of bandwidth to the user classes, and then to the users within each class, in accordance with one or more allocation policies as desired.\",\n \"Examples of allocation policies for users include: (i) the equal distribution of all available bandwidth to all users; (ii) the distribution of all available bandwidth to all users proportional to each user's respective forecasted bandwidth; (iii) the distribution of bandwidth to each user equal to the user's respective forecasted bandwidth, with any surplus bandwidth being distributed to the users either equally or proportionally based upon the user's respective forecasted bandwidth; and (iv) the initial distribution of bandwidth to each user based upon the minimum of the user's guaranteed bandwidth or the forecasted bandwidth and, thereafter, incremental allocations of remaining bandwidth to all of the users.\",\n \"Likewise, examples of allocation policies for user classes include: (i) the distribution of all available bandwidth by the Bandwidth Allocator 92 to all user classes proportional to the number of active users in each class; (ii) the distribution of all available bandwidth to all user classes proportional to each class' respective collective forecasted bandwidth; (iii) the distribution of bandwidth to each user class equal to the class' respective collective forecasted bandwidth, with any surplus bandwidth being distributed to the user classes either equally or proportionally based upon the class' respective collective forecasted bandwidth; and (iv) the initial distribution of bandwidth to each user class based upon the minimum of the class' guaranteed collective bandwidth or the collective forecasted bandwidth and, thereafter, incremental allocations of remaining bandwidth to all of the users classes.\",\n \"Examples of alternate preferred methods of prioritizing user classes, and then allocating bandwidth to the classes, will now be described in detail, each of which utilizes one or more of the aforementioned user class prioritization and allocation policies.\",\n \"Alternative preferred methods of prioritizing users within each class, and then allocating bandwidth to the users in each class, are set forth thereafter.\",\n \"In either case, the preferred methods of prioritizing and allocating are initiated pursuant to the scheduling module 102 of the Bandwidth Allocator 92, which operates independently of the scheduling module 100 of the Data Collector 88.With regard to prioritization of and allocation to user classes, a first preferred method 1100 is illustrated in FIG.\",\n \"11 and begins with the retrieval (Step 1102) of the collective forecasted bandwidth from the Database Manager 90 for all active user classes.\",\n \"Whether a user class is active is determined by past collective bandwidth consumption of the class (or, alternatively, collective requested bandwidth for the users of the class), as revealed by the user stats maintained by the Database Manager 90.All user classes are then prioritized (Step 1104) based on each class' collective forecast in increasing order, whereby a class having a lesser collective forecasted bandwidth will be prioritized over a class having larger collective forecasted bandwidth.\",\n \"A “surplus” is then set (Step 1106) to the total bandwidth available for allocation to the classes in the particular direction of communication over the shared communications medium at issue, and the total bandwidth available is then allocated (Step 1108) to each user class in an amount equaling the collective forecasted bandwidth subject to a respective maximum collective bandwidth value of the user class.\",\n \"Preferably the maximum collective bandwidth value is determined either in the appropriate CSLA or by the Carrier, Administrator 106, or other entity.\",\n \"Allocation of bandwidth to a user class additionally is subject to the actual availability of bandwidth following previous allocations thereof to user classes with equal or higher priority.\",\n \"Following allocations to all user classes, any bandwidth determined (Step 1110) to be remaining is then allocated (Step 1112) to the classes in amount proportional to the number of active users in each class, subject of course to the respective maximum collective bandwidth value of the class.\",\n \"The resulting class allocations are then recorded in the Database Manager 90 (Step 1114) as the bandwidth allowances for the classes.\",\n \"The method 1200 illustrated in FIG.\",\n \"12 is the same as that of FIG.\",\n \"11, except that surplus bandwidth, if any, is allocated (Step 1102) proportional to the collective forecasted bandwidths of the user classes, again subject to the respective maximum collective bandwidth value of each user class.\",\n \"The preferred method 1300 illustrated in FIG.\",\n \"13 does not prioritize the user classes for purposes of allocation but, instead, treats all classes equally.\",\n \"The method 1300 begins with the retrieval (Step 1302) of the collective forecasted bandwidth of each user class from the Database Manager 90.The surplus is then set to the total bandwidth available in the particular direction of communication, and the sum of all the collective forecasts is calculated (Step 1304).\",\n \"The available bandwidth then is allocated (Step 1306) to all classes proportional to the class' collective forecasted bandwidth, again subject to the respective maximum collective bandwidth value for each class.\",\n \"The resulting class allocations then are recorded in the Database Manage 90 (Step 1308) as the bandwidth allowances for the classes.\",\n \"The preferred method 1400 illustrated in FIG.\",\n \"14 seeks to maximize revenues from fees (F) that are paid for class bandwidth consumption.\",\n \"The method 1400 begins with the retrieval (Step 1402) of the collective forecast for each user class as well as a fee that is paid for the collective bandwidth of the class.\",\n \"The classes are then sorted (Step 1404) based on these fees in decreasing order, with the class with the highest fee receiving the highest priority.\",\n \"Next the surplus is set (Step 1406) to the total bandwidth available for allocation to the classes in the particular direction of communication.\",\n \"Bandwidth then is allocated (Step 1408) to the classes as available from highest to lowest priority in an amount equal to the class' collective forecasted bandwidth, subject to the respective maximum collective bandwidth value for the class.\",\n \"Both preferred method 1500 of FIGS.\",\n \"15a and 15b, and preferred method 1600 of FIGS.\",\n \"16a and 16b differ from the other methods 1100,1200,1300,1400 in that these two methods allocate bandwidth to the user classes in multiple allocation rounds.\",\n \"Method 1500 begins in FIG.\",\n \"15a with the retrieval (Step 1502) of the collective forecasted bandwidths of the classes as well as a credit (C) that applies if a respective class does not receive up to a guaranteed maximum level of collective bandwidth.\",\n \"The classes are then prioritized (Step 1504) based on each class' respective credit in decreasing order, with those classes having higher credits being given priority over classes with lesser credits.\",\n \"Next, the surplus is set (Step 1506) to the total bandwidth available to the classes in the particular direction of communication.\",\n \"Bandwidth then is allocated (Step 1508) as available in a first round to the classes from highest to lowest priority.\",\n \"The allocation for each class in the first round is equal to the minimum of the collective forecasted bandwidth or the maximum collective bandwidth that is guaranteed, subject to the respective maximum collective bandwidth value for the class.\",\n \"If any additional bandwidth is determined (Step 1510) to remain after the first allocation round, then the surplus is set to the additional bandwidth (Step 1514).\",\n \"Bandwidth then is allocated (Step 1516) as available to each class in the same class order.\",\n \"Assuming sufficient bandwidth remains available, the allocation in the second round brings each class' allocation up to the class' collective forecasted bandwidth subject to the class' respective maximum collective bandwidth value.\",\n \"Following the second allocation round, a determination is made (Step 1518) whether any remaining bandwidth exists and, if so, then the remaining bandwidth is allocated (Step 1522) to the classes proportional to each class' collective forecasted bandwidth, and subject to each class' respective maximum collective bandwidth value.\",\n \"The resulting class allocations are then recorded (Step 1524) in the Database Manager 90 as the bandwidth allowances of the classes.\",\n \"If it is determined that no bandwidth remains available in either of Step 1510 or Step 1518, then the class allocations are completed and are recorded in the Database Manager 90 in Steps 1512,1524, respectively.\",\n \"Method 1600 of FIGS.\",\n \"16a and 16b differs from that of FIGS.\",\n \"15a and 15b only in that the sum of the collective forecasted bandwidths for all classes is calculated (Step 1602) and a determination is made (Step 1604) whether the sum exceeds the total bandwidth available for allocation to the classes.\",\n \"If the sum exceeds the total available bandwidth, then bandwidth is allocated (Step 1606) to each class in an amount equal to the collective forecasted bandwidth of the class, subject to the class' maximum guaranteed collective bandwidth, and less an amount thereof proportional to the total bandwidth shortfall.\",\n \"Thus, for example, if the sum of all collective forecasted bandwidths exceeds the total available bandwidth for allocation in an amount equal to 20% of all collective forecasted bandwidths, then each class is allocated bandwidth in an amount equal to the class' collective forecasted bandwidth (subject to the class' maximum guaranteed collective bandwidth), then less 20% thereof.\",\n \"The information including fees, credits, guaranteed collective bandwidths, and respective maximum collective bandwidth values in the aforementioned preferred methods, is obtained from each CSLA and/or is predetermined by the Administrator 106, Carrier, or other entity.\",\n \"Moreover, this information is retrieved by the Bandwidth Allocator 92 from the Database Manager 90, which includes and maintains a CSLA table for each class as well as information regarding users associated therewith, as updated from time-to-time by the Administrator 106.Specifically, the information is configured and maintained through GUIs provided as part of the GUI & Report Generating Engine 94, and is preferably accessed by the Administrator 106 either directly or indirectly through the Internet 60.Alternatively, information is retrieved by the Bandwidth Allocator 92 from an external database maintained by the Administrator, Carrier, or other entity through an application program interface (API) incorporated into the external system interface layer 98 of the Bandwidth Allocator 92.The use of an external database is preferred, as it eliminates any duplicative maintenance of information otherwise maintained by the Database Manager 90 which must be synchronized with the external database, including periodic updating of class and user records in a timely fashion.\",\n \"Regardless of the particular method or policies utilized by the Bandwidth Allocator 92, once class allocations have been determined, the Database Manager 90 is updated with the new class allocations.\",\n \"Then, for each class, allocations of bandwidth are made to the users in the class.\",\n \"Furthermore, allocations within each class may be made by different methods.\",\n \"A first preferred method 1700 of prioritizing users and allocating bandwidth (whether upstream or downstream) by the Bandwidth Allocator 92 is illustrated in FIG.\",\n \"17 and begins with the retrieval (Step 1702) of the forecasted bandwidth from the Database Manager 90 for all active users.\",\n \"Whether a user is active is determined by past bandwidth consumption of the user (or, alternatively, requested bandwidth for the user), as revealed by the user stats maintained by the Database Manager 90.All users are then prioritized (Step 1704) based on each user's forecast in increasing order, whereby users having lesser forecasted bandwidths will be prioritized over users having larger forecasted bandwidths.\",\n \"The “surplus” is then set (Step 1706) to the total allocated bandwidth of the class (i.e., the class' collective bandwidth allowance) in the particular direction of communication, and the entire bandwidth allowance of the class is then allocated (Step 1708) to each user in an amount equaling the forecasted bandwidth of the user subject to a respective maximum bandwidth value of the user.\",\n \"Preferably the respective maximum bandwidth value is determined either in the user's SLA, the respective CSLA of the class, or by the Carrier, Administrator 106, or other entity.\",\n \"Allocation of bandwidth to a user additionally is subject to the actual availability of bandwidth following previous allocations thereof to users with equal or higher priority.\",\n \"Following allocations to all users, any bandwidth determined (Step 1710) to be remaining out of the total class allowance is then allocated equally (Step 1712) to the users subject to the respective maximum bandwidth value for each user.\",\n \"The new user allocations are then incorporated (Step 1714) into the DOC Network as the bandwidth allowances of the users.\",\n \"The method 1800 illustrated in FIG.\",\n \"18 is the same as that of FIG.\",\n \"17, except that surplus bandwidth in the class, if any, is allocated (Step 1802) proportional to the forecasted bandwidths of the users in the class, again subject to each user's respective maximum bandwidth value.\",\n \"The preferred method 1900 illustrated in FIG.\",\n \"19 does not prioritize the users for purposes of allocation but, instead, treats all users equally.\",\n \"The method 1900 begins with the retrieval (Step 1902) of the forecasted bandwidth for each user in the class from the Database Manager 90.The surplus is then set to the total allocated bandwidth of the class in the particular direction of communication, and the sum of all forecasts of the users in the class is calculated (Step 1904).\",\n \"The total allocated bandwidth of the class then is allocated (Step 1906) to all users in the class proportional to the user's forecasted bandwidth, again subject to each user's respective maximum bandwidth value.\",\n \"The user allocations then are incorporated into the DOC Network (Step 1908) as the bandwidth allowances of the users.\",\n \"The preferred method 2000 illustrated in FIG.\",\n \"20 seeks to maximize revenues from fees (F) that are paid for bandwidth consumption by the users.\",\n \"The method 2000 begins with the retrieval (Step 2002) of the forecast for each user as well as a fee that is paid for bandwidth by each user.\",\n \"The users are then sorted (Step 2004) based on user fees in decreasing order, with the user paying the most for bandwidth receiving the highest priority.\",\n \"Next, the surplus is set (Step 2006) to the total allocated bandwidth of the class in the particular direction of communication.\",\n \"Bandwidth then is allocated (Step 2008) to the users in the class as available from highest to lowest priority in an amount equal to each user's forecasted bandwidth, and subject to the user's respective maximum bandwidth value.\",\n \"Both preferred method 2100 of FIGS.\",\n \"21a and 21b, and preferred method 2200 of FIGS.\",\n \"22a and 22b differ from the other methods 1700,1800,1900,2000 in that these two methods allocate bandwidth to the users in multiple allocation rounds.\",\n \"Method 2100 begins in FIG.\",\n \"21a with the retrieval (Step 2102) of the forecasted bandwidths of the users as well as a credit (C) that applies if a respective user does not receive up to a guaranteed maximum level of bandwidth.\",\n \"The users are then prioritized (Step 2104) based on each user's respective credit in decreasing order, with those users having higher credits being given priority over users with lesser credits.\",\n \"Next, the surplus is set (Step 2106) to the total allocated bandwidth of the class in the particular direction of communication.\",\n \"Bandwidth then is allocated (Step 2108) as available in a first round to the users from highest to lowest priority.\",\n \"The allocation in the first round for each user is equal to the minimum of the forecasted bandwidth or the maximum bandwidth that is guaranteed, subject to the user's respective maximum bandwidth value.\",\n \"If any additional bandwidth is determined (Step 2110) to remain after the first allocation round, then the surplus is set to the additional bandwidth (Step 2114).\",\n \"Bandwidth then is allocated (Step 2116) as available to each user in the same user order.\",\n \"Assuming sufficient bandwidth remains available, the allocation in the second round brings the user's allocation up to the user's forecasted bandwidth subject to the user's respective maximum bandwidth value.\",\n \"Following the second allocation round, a determination is made (Step 2118) whether any remaining bandwidth exists and, if so, then the remaining bandwidth is allocated (Step 2122) equally to the users, subject to each user's respective maximum bandwidth value.\",\n \"The user allocations are then incorporated (Step 2124) into the DOC Network as the users' bandwidth allowances.\",\n \"If it is determined that no bandwidth remains available in either of Step 2110 or Step 2118, then the user allocations are completed and are incorporated into DOC Network in Steps 2112,2124, respectively, as the users' bandwidth allowances.\",\n \"Method 2200 of FIGS.\",\n \"22a and 22b differs from that of FIGS.\",\n \"21a and 21b only in that the sum of the forecasted bandwidths for all users is calculated (Step 2202) and a determination is made (Step 2204) whether the sum exceeds the total allocated bandwidth of the class.\",\n \"If the sum exceeds the total allocated bandwidth of the class, then the bandwidth is allocated (Step 2206) to each user in an amount equal to the forecasted bandwidth, subject to the user's maximum guaranteed bandwidth, and less an amount thereof proportional to the total bandwidth shortfall.\",\n \"Thus, for example, if the sum of all forecasted bandwidths exceeds the total allocated bandwidth of the class in an amount equal to 20% of the sum of all the forecasted bandwidths, then each user is allocated bandwidth in an amount equal to the user's forecasted bandwidth (subject to the user's maximum guaranteed bandwidth), then less 20% thereof.\",\n \"The applicable class bandwidth allowances used in the aforementioned methods are obtained from the Database Manager 90.The information, including fees, credits, guaranteed user bandwidths, and maximum bandwidth values in the aforementioned methods, is obtained from each user's SLA or from any applicable CSLA, and/or is predetermined by the Administrator 106, Carrier, or other entity.\",\n \"Moreover, this information is retrieved by the Bandwidth Allocator 92 from the Database Manager 90, which includes and maintains a user SLA table as well as a user billing table, as updated from time-to-time by the Administrator 106.Specifically, the information is configured and maintained through GUIs provided as part of the GUI & Report Generating Engine 94, and is preferably accessed by the Administrator 106 either directly or indirectly through the Internet 60.Alternatively, information is retrieved by the Bandwidth Allocator 92 from an external database maintained by the Administrator, Carrier, or other entity through an application program interface (API) incorporated into the external system interface layer 98 of the Bandwidth Allocator 92.The use of an external database is preferred not only for the CSLAs, but also for the SLAs and user billing tables, as it eliminates any duplicative maintenance of information otherwise maintained by the Database Manager 90 which must be synchronized with the external database, including periodic updating of user records in a timely fashion.\",\n \"Regardless of the particular method or policies utilized by the Bandwidth Allocator 92, once user allocations have been determined under the aforementioned allocation policies, the respective DOC Network is updated with the resulting user allocations as the bandwidth allowances for the users for a particular time interval.\",\n \"Each user is then allocated bandwidth during the particular time interval in an amount that is less than, or equal to, that user's bandwidth allowance.\",\n \"Similarly, the collective bandwidth consumptions of a class by users therein is limited by that class' bandwidth allowance.\",\n \"Preferably, the DOC Network is updated at periodic intervals of between one to fifteen minutes and, preferably every five minutes.\",\n \"Furthermore, the periodic interval preferably corresponds to the scheduling of the Bandwidth Allocator 92 with regard to upstream transmissions.\",\n \"With particular reference to FIG.\",\n \"23, a preferred method 2300 of updating a DOC Network for a DOCSIS 1.0 compliant Cable Network with the user allowances is illustrated.\",\n \"The DOC Network is updated by incorporating (Step 2302) the user allocations as bandwidth allowances (i.e., bandwidth limits) into CM configuration files (MD-5 files) for the CMs of the respective users.\",\n \"As set forth above, each CM configuration file contains instructions for a respective CM that limits the actual bandwidth consumed by the CM in the upstream direction and in the downstream direction.\",\n \"The CM configuration files are then sent (Step 2304) by the Bandwidth Allocator 92 to a Trivial File Transfer Protocol (TFTP) Server of the DOC Network, which maintains CM configuration files for the CMs of the Cable Network.\",\n \"A command is also sent (Step 2306) to either of the CMs or the CMTS of the respective Cable Network causing the CMs to acquire and implement the CM configuration files maintained on the TFTP Server.\",\n \"In addition to maintaining information regarding CSLAs, class allocations, SLAs, and user billing data in the Database Manager 90, the GUI & Report Generating Engine 94 further enables the Administrator 106 to analyze the user stats updated by the Data Collector 88, including the generation of reports and graphs regarding, for example, network access usage of the users over time as well as user throughput rates vs. data loss rates similar to that shown in FIG.\",\n \"10.It additionally should be noted that a user may or may not be permitted to be grouped in one or more classes in accordance with the present invention.\",\n \"If it is desired that classes be mutually exclusive, then some policy should be established for determining which class with which a user is associated as between competing classes.\",\n \"If it is desired that classes not be mutually exclusive, then users falling within two or more classes will be allocated bandwidth within each class to the extent that no conflict arises as between the classes, and subject to any maximum allowed aggregated user bandwidth for all classes that may be established.\",\n \"As now will readily be seen, the preferred methods and preferred networks of the present invention described in detail herein enable a Carrier to accommodate bandwidth concerns of service providers competing for the business of users of a shared communications medium in a Shared Access Carrier Network.\",\n \"In particular, CSLAs now can be constructed in accordance with the present invention whereby a service provider is guaranteed some collective level of network access for the users of the shared communications medium that are customers of the service provider.\",\n \"Furthermore, the provision of bandwidth to users who are customers of competing service providers can now be based on fairness considerations, even if one of the service providers is related to the Carrier.\",\n \"In addition thereto, the differing demands for instantaneous throughput by users competing for access across the shared communications medium now can be accommodated in accordance with the present invention.\",\n \"Indeed, a Carrier now is able to continuously vary bandwidth consumption limits for each user on an individual basis and for small time intervals, either in accordance with fairness considerations, forecasted network access usage of the users, or under contractual provisions governing network access.\",\n \"It also will now be evident that the present invention gives rise to new business models that may be implemented by service providers for providing network access to users thereof and, in particular, to new ways of selling network access, which is also considered part of the present invention.\",\n \"For example, in accordance with the present invention, network access now can be “wholesaled” to service providers by considering the users of the service provider a class and allocating bulk network access to such class pursuant to a CSLA between the Carrier and the service provider.\",\n \"Through a CSLA, a Carrier can offer to the service provider a guaranteed minimum level of network access for the class that is constant throughout the day or week, or a guaranteed minimum level of network access that varies depending upon considerations such as the time of day or the day of week.\",\n \"A Carrier also now can offer a guaranteed minimum level of network access to the class with a guaranteed maximum level of network access provided as needed in accordance with a target probability.\",\n \"The service providers, in turn, then can offer different SLAs to the users that are its customers, essentially selling network access at the retail level.\",\n \"Accordingly, service providers can be assured of levels of network access for the users that are their customers, and users can be assured of appropriate levels of network access to meet their individual demands.\",\n \"Moreover, Carriers and/or service providers now can differentiate between users in charging for network access, thereby allowing Carriers and/or service providers to differentiate revenue streams for maximization of revenues.\",\n \"The present invention also enables Carriers and/or service providers to offer “dynamic SLAs” to users.\",\n \"The term “dynamic SLA” refers to a SLA that can be modified by a user as the user's demand for network access significantly changes, whether such modification is permanent or temporary.\",\n \"In this regard, and in accordance with a preferred method 2600 of the present invention as illustrated in FIG.\",\n \"26, the “network access retailer” (the entity selling the network access to the user) monitors (Step 2602) network access usage by users of a Shared Access Carrier Network and determines (Step 2604), for each user based on network access usage, whether a SLA provision other than those found in the user's current SLA would better meet the user's needs.\",\n \"This determination is made by comparing the user's throughput, bandwidth consumption, and/or bandwidth requested for a predetermined period of time against a set of threshold values, including any guaranteed level of network access provided for in the user's SLA as well as any minimum QoS standard that are deemed necessary for user satisfaction by the network access retailer or other appropriate entity.\",\n \"Thus, if the user's level of throughput, bandwidth consumption, and/or bandwidth requested for the predetermined time interval differs by a predetermined tolerance from a minimum threshold value, then the user is identified (Step 2606) as a “candidate” for modifying the SLA.\",\n \"A similar process alternatively is used, wherein the user's forecasted bandwidth is compared to the threshold values and, if the difference exceeds a predetermined tolerance, then the user is deemed a candidate for modifying the user's SLA.\",\n \"Once users have been identified as candidates, the candidates are filtered by screening (Step 2608) the candidates against a list of users for which solicitations are not to be made.\",\n \"Those candidates passing the screening are then invited (Step 2610) to modify their respective SLAs.\",\n \"The solicitation of the user preferably is performed via email, instant messaging, redirection of the user's web browser to a solicitation web page, generation and mailing of solicitation literature via U.S. mail, telemarketing, or other means of communication.\",\n \"The solicitation includes an invitation for the user to modify the user's SLA by increasing for a fee the minimum level of network access guaranteed to the user.\",\n \"The solicitation preferably also includes an invitation to make the modification permanent, or to make the modification only temporary and for a specific period of time.\",\n \"Thus, for example, if a user is identified as having a high usage pattern at recurrent periods of time (such as every Saturday night when a particular webcast is viewed, or when an Internet game is played), then the user automatically is solicited with an invitation via instant messaging on the following Saturday night to increase the user's guaranteed network access for that night, for a predetermined number of following Saturday nights, and/or for every Saturday night.\",\n \"Acceptance of the invitation by each user results in the modification (Step 2612) of the user's SLA for the appropriate period of time by increasing the level of network access the user is guaranteed (and/or the user's respective maximum bandwidth value, depending upon the policies used).\",\n \"The solicited modification to the user's SLA is updated in the SLA database, which is then used during user prioritization and allocation of bandwidth by the Bandwidth Allocator 92.The resulting higher bandwidth allowance should enhance the user's experience and overall satisfaction with the Carrier Network.\",\n \"In particular, the higher bandwidth (greater network access) should enhance the viewing of the webcast or the playing of the Internet game.\",\n \"On the other hand, SLAs for which users decline solicitations are not modified.\",\n \"Furthermore, if deemed appropriate, users declining a solicitation are recorded in the list against which candidates are screened.\",\n \"Preferably, the Bandwidth Allocator 92 analyzes the user stats maintained by the Database Manager 90, identifies those users that are candidates for SLA modification, and initiates the solicitation of such candidates.\",\n \"Information for each user's SLA for comparison with the user's stats automatically is obtained either from the Database Manager 90, or from an external database maintained by the network access retailer or other appropriate entity.\",\n \"Furthermore, the Bandwidth Allocator 92 preferably performs this analysis for solicitation on a regularly scheduled basis.\",\n \"In addition to such solicitations, a user of course may request a change in the level of network access guaranteed without having to receive first a solicitation.\",\n \"Furthermore, the user may request that the change be for a temporary period of time such that, for example, the change is reversed after only a few hours, which would cover a viewing of a particular webcast or the playing of a particular Internet game beginning at the time of the request.\",\n \"In view of the foregoing detailed description of the preferred embodiments and methods of the present invention, it readily will be understood by those persons skilled in the art that the present invention is susceptible of broad utility and application.\",\n \"Many embodiments and adaptations of the present invention other than those herein described, as well as many variations, modifications, and equivalent arrangements, will be apparent from or reasonably suggested by the present invention and the foregoing description thereof, without departing from the substance or scope of the present invention.\",\n \"Accordingly, while the present invention has been described herein in detail in relation to preferred embodiments, it is to be understood that this disclosure only is illustrative and exemplary of the present invention and is made merely for purposes of providing a full and enabling disclosure of the invention.\",\n \"The foregoing disclosure is not intended nor is to be construed to limit the present invention or otherwise to exclude any such other embodiments, adaptations, variations, modifications and equivalent arrangements, the present invention being limited only by the claims appended hereto and the equivalents thereof.\",\n \"Thus, for example, it will be apparent that, while preferred embodiments of the present invention have been described in the context of DOC Networks (including either a network of all coaxial cable, or a HFC network), the present invention nevertheless relates to any other network (whether wireline or wireless) wherein competing users share access across a shared communications medium including, for example, home networks and small networks in mass transit vehicles.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10276654"}}},{"rowIdx":87,"cells":{"text":{"kind":"list like","value":[["Novel nucleic acids and polypeptides","The present invention provides novel nucleic acids, novel polypeptide sequences encoded by these nucleic acids and uses thereof."],["1.An isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-8051, a mature protein coding portion of SEQ ID NO: 1-8051, an active domain of SEQ ID NO: 1-8051, and complementary sequences thereof.","2.An isolated polynucleotide encoding a polypeptide with biological activity, wherein said polynucleotide hybridizes to the polynucleotide of claim 1 under stringent hybridization conditions.","3.An isolated polynucleotide encoding a polypeptide with biological activity, wherein said polynucleotide has greater than about 90% sequence identity with the polynucleotide of claim 1.4.The polynucleotide of claim 1 wherein said polynucleotide is DNA.","5.An isolated polynucleotide of claim 1 wherein said polynucleotide comprises the complementary sequences.","6.A vector comprising the polynucleotide of claim 1.7.An expression vector comprising the polynucleotide of claim 1.8.A host cell genetically engineered to comprise the polynucleotide of claim 1.9.A host cell genetically engineered to comprise the polynucleotide of claim 1 operatively associated with a regulatory sequence that modulates expression of the polynucleotide in the host cell.","10.An isolated polypeptide, wherein the polypeptide is selected from the group consisting of: (a) a polypeptide encoded by any one of the polynucleotides of claim 1; and (b) a polypeptide encoded by a polynucleotide hybridizing under stringent conditions with any one of SEQ ID NO: 1-8051.11.A composition comprising the polypeptide of claim 10 and a carrier.","12.An antibody directed against the polypeptide of claim 10.13.A method for detecting the polynucleotide of claim 1 in a sample, comprising: a) contacting the sample with a compound that binds to and forms a complex with the polynucleotide of claim 1 for a period sufficient to form the complex; and b) detecting the complex, so that if a complex is detected, the polynucleotide of claim 1 is detected.","14.A method for detecting the polynucleotide of claim 1 in a sample, comprising: a) contacting the sample under stringent hybridization conditions with nucleic acid primers that anneal to the polynucleotide of claim 1 under such conditions; b) amplifying a product comprising at least a portion of the polynucleotide of claim 1; and c) detecting said product and thereby the polynucleotide of claim 1 in the sample.","15.The method of claim 14, wherein the polynucleotide is an RNA molecule and the method further comprises reverse transcribing an annealed RNA molecule into a cDNA polynucleotide.","16.A method for detecting the polypeptide of claim 10 in a sample, comprising: a) contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex; and b) detecting formation of the complex, so that if a complex formation is detected, the polypeptide of claim 10 is detected.","17.A method for identifying a compound that binds to the polypeptide of claim 10, comprising: a) contacting the compound with the polypeptide of claim 10 under conditions sufficient to form a polypeptide/compound complex; and b) detecting the complex, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 10 is identified.","18.A method for identifying a compound that binds to the polypeptide of claim 10, comprising: a) contacting the compound with the polypeptide of claim 10, in a cell, under conditions sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and b) detecting the complex by detecting reporter gene sequence expression, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 10 is identified.","19.A method of producing the polypeptide of claim 10, comprising, a) culturing a host cell comprising a polynucleotide sequence selected from the group consisting of a polynucleotide sequence of SEQ ID NO: 1-8051, a mature protein coding portion of SEQ ID NO: 1-8051, an active domain of SEQ ID NO: 1-8051, complementary sequences thereof and a polynucleotide sequence hybridizing under stringent conditions to SEQ ID NO: 1-8051, under conditions sufficient to express the polypeptide in said cell; and b) isolating the polypeptide from the cell culture or cells of step (a).","20.An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 8052-16102, the mature protein portion thereof, or the active domain thereof.","21.The polypeptide of claim 20 wherein the polypeptide is provided on a polypeptide array.","22.A collection of polynucleotides, wherein the collection comprises the sequence information of at least one of SEQ ID NO: 1-8051.23.The collection of claim 22, wherein the collection is provided on a nucleic acid array.","24.The collection of claim 23, wherein the array detects full-matches to any one of the polynucleotides in the collection.","25.The collection of claim 23, wherein the array detects mismatches to any one of the polynucleotides in the collection.","26.The collection of claim 22, wherein the collection is provided in a computer-readable format.","27.A method of treatment comprising administering to a mammalian subject in need thereof a therapeutic amount of a composition comprising a polypeptide of claim 10 or 20 and a pharmaceutically acceptable carrier.","28.A method of treatment comprising administering to a mammalian subject in need thereof a therapeutic amount of a composition comprising an antibody that specifically binds to a polypeptide of claim 10 or 20 and a pharmaceutically acceptable carrier."],["<SOH> 2.BACKGROUND <EOH>Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lymphokines, interferons, circulating soluble factors, chemokines, and interleukins) has matured rapidly over the past decade.","The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides “directly” in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein in the case of hybridization cloning; activity of the protein in the case of expression cloning).","More recent “indirect” cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization-based cloning techniques, have advanced the state of the art by making available large numbers of DNA/amino acid sequences for proteins that are known to have biological activity, for example, by virtue of their secreted nature in the case of leader sequence cloning, by virtue of their cell or tissue source in the case of PCR-based techniques, or by virtue of structural similarity to other genes of known biological activity.","Identified polynucleotide and polypeptide sequences have numerous applications in, for example, diagnostics, forensics, gene mapping; identification of mutations responsible for genetic disorders or other traits, to assess biodiversity, and to produce many other types of data and products dependent on DNA and amino acid sequences."],["<SOH> 3.SUMMARY OF THE INVENTION <EOH>The compositions of the present invention include novel isolated polypeptides, novel isolated polynucleotides encoding such polypeptides, including recombinant DNA molecules, cloned genes or degenerate variants thereof, especially naturally occurring variants such as allelic variants, antisense polynucleotide molecules, and antibodies that specifically recognize one or more epitopes present on such polypeptides, as well as hybridomas producing such antibodies.","The compositions of the present invention additionally include vectors, including expression vectors, containing the polynucleotides of the invention, cells genetically engineered to contain such polynucleotides and cells genetically engineered to express such polynucleotides.","The present invention relates to a collection or library of at least one novel nucleic acid sequence assembled from expressed sequence tags (ESTs) isolated mainly by sequencing by hybridization (SBH), and in some cases, sequences obtained from one or more public databases.","The invention relates also to the proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins.","These nucleic acid sequences are designated as SEQ ID NO: 1-8051.The polypeptides sequences are designated SEQ ID NO: 8052-16102.The nucleic acids and polypeptides are provided in the Sequence Listing.","In the nucleic acids provided in the Sequence Listing, A is adenosine; C is cytosine; G is guanine; T is thymine; and N is any of the four bases.","In the amino acids provided in the Sequence Listing, * corresponds to the stop codon.","The nucleic acid sequences of the present invention also include, nucleic acid sequences that hybridize to the complement of SEQ ID NO: 1-8051 under stringent hybridization conditions; nucleic acid sequences which are allelic variants or species homologues of any of the nucleic acid sequences recited above, or nucleic acid sequences that encode a peptide comprising a specific domain or truncation of the peptides encoded by SEQ ID NO: 1-8051.A polynucleotide comprising a nucleotide sequence having at least 90% identity to an identifying sequence of SEQ ID NO: 1-8051 or a degenerate variant or fragment thereof.","The identifying sequence can be 100 base pairs in length.","The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-8051.The sequence information can be a segment of any one of SEQ ID NO: 1-8051 that uniquely identifies or represents the sequence information of SEQ ID NO: 1-8051.A collection as used in this application can be a collection of only one polynucleotide.","The collection of sequence information or identifying information of each sequence can be provided on a nucleic acid array.","In one embodiment, segments of sequence information is provided on a nucleic acid array to detect the polynucleotide that contains the segment.","The array can be designed to detect full-match or mismatch to the polynucleotide that contains the segment.","The collection can also be provided in a computer-readable format.","This invention also includes the reverse or direct complement of any of the nucleic acid sequences recited above; cloning or expression vectors containing the nucleic acid sequences; and host cells or organisms transformed with these expression vectors.","Nucleic acid sequences (or their reverse or direct complements) according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology, such as use as hybridization probes, use as primers for PCR, use in an array, use in computer-readable media, use in sequencing full-length genes, use for chromosome and gene mapping, use in the recombinant production of protein, and use in the generation of anti-sense DNA or RNA, their chemical analogs and the like.","In a preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-8051 or novel segments or parts of the nucleic acids of the invention are used as primers in expression assays that are well known in the art.","In a particularly preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-8051 or novel segments or parts of the nucleic acids provided herein are used in diagnostics for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.","The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide comprising any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051; a polynucleotide comprising any of the full length protein coding sequences of SEQ ID NO: 1-8051; and a polynucleotide comprising any of the nucleotide sequences of the mature protein coding sequences of SEQ ID NO: 1-8051.The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent hybridization conditions to (a) the complement of any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051; (b) a nucleotide sequence encoding any one of the amino acid sequences set forth in the Sequence Listing (e.g., SEQ ID NO: 8052-16102); (c) a polynucleotide which is an allelic variant of any polynucleotides recited above; (d) a polynucleotide which encodes a species homolog (e.g.","orthologs) of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of any of the polypeptides comprising an amino acid sequence set forth in the Sequence Listing.","The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising any of the amino acid sequences set forth in the Sequence Listing; or the corresponding full length or mature protein.","Polypeptides of the invention also include polypeptides with biological activity that are encoded by (a) any of the polynucleotides having a nucleotide sequence set forth in SEQ ID NO: 1-8051; or (b) polynucleotides that hybridize to the complement of the polynucleotides of (a) under stringent hybridization conditions.","Biologically or immunologically active variants of any of the polypeptide sequences in the Sequence Listing, and “substantial equivalents” thereof (e.g., with at least about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid sequence identity) that preferably retain biological activity are also contemplated.","The polypeptides of the invention may be wholly or partially chemically synthesized but are preferably produced by recombinant means using the genetically engineered cells (e.g.","host cells) of the invention.","The invention also provides compositions comprising a polypeptide of the invention.","Polypeptide compositions of the invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.","The invention also provides host cells transformed or transfected with a polynucleotide of the invention.","The invention also relates to methods for producing a polypeptide of the invention comprising growing a culture of the host cells of the invention in a suitable culture medium under conditions permitting expression of the desired polypeptide, and purifying the polypeptide from the culture or from the host cells.","Preferred embodiments include those in which the protein produced by such process is a mature form of the protein.","Polynucleotides according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology.","These techniques include use as hybridization probes, use as oligomers, or primers, for PCR, use for chromosome and gene mapping, use in the recombinant production of protein, and use in generation of anti-sense DNA or RNA, their chemical analogs and the like.","For example, when the expression of an mRNA is largely restricted to a particular cell or tissue type, polynucleotides of the invention can be used as hybridization probes to detect the presence of the particular cell or tissue mRNA in a sample using, e.g., in situ hybridization.","In other exemplary embodiments, the polynucleotides are used in diagnostics as expressed sequence tags for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.","The polypeptides according to the invention can be used in a variety of conventional procedures and methods that are currently applied to other proteins.","For example, a polypeptide of the invention can be used to generate an antibody that specifically binds the polypeptide.","Such antibodies, particularly monoclonal antibodies, are useful for detecting or quantitating the polypeptide in tissue.","The polypeptides of the invention can also be used as molecular weight markers, and as a food supplement.","Methods are also provided for preventing, treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a polypeptide of the present invention and a pharmaceutically acceptable carrier.","In particular, the polypeptides and polynucleotides of the invention can be utilized, for example, in methods for the prevention and/or treatment of disorders involving aberrant protein expression or biological activity.","The present invention further relates to methods for detecting the presence of the polynucleotides or polypeptides of the invention in a sample.","Such methods can, for example, be utilized as part of prognostic and diagnostic evaluation of disorders as recited herein and for the identification of subjects exhibiting a predisposition to such conditions.","The invention provides a method for detecting the polynucleotides of the invention in a sample, comprising contacting the sample with a compound that binds to and forms a complex with the polynucleotide of interest for a period sufficient to form the complex and under conditions sufficient to form a complex and detecting the complex such that if a complex is detected, the polynucleotide of interest is detected.","The invention also provides a method for detecting the polypeptides of the invention in a sample comprising contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex and detecting the formation of the complex such that if a complex is formed, the polypeptide is detected.","The invention also provides kits comprising polynucleotide probes and/or monoclonal antibodies, and optionally quantitative standards, for carrying out methods of the invention.","Furthermore, the invention provides methods for evaluating the efficacy of drugs, and monitoring the progress of patients, involved in clinical trials for the treatment of disorders as recited above.","The invention also provides methods for the identification of compounds that modulate (i.e., increase or decrease) the expression or activity of the polynucleotides and/or polypeptides of the invention.","Such methods can be utilized, for example, for the identification of compounds that can ameliorate symptoms of disorders as recited herein.","Such methods can include, but are not limited to, assays for identifying compounds and other substances that interact with (e.g., bind to) the polypeptides of the invention.","The invention provides a method for identifying a compound that binds to the polypeptides of the invention comprising contacting the compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and detecting the complex by detecting the reporter gene sequence expression such that if expression of the reporter gene is detected the compound that binds to a polypeptide of the invention is identified.","The methods of the invention also provides methods for treatment which involve the administration of the polynucleotides or polypeptides of the invention to individuals exhibiting symptoms or tendencies.","In addition, the invention encompasses methods for treating diseases or disorders as recited herein comprising administering compounds and other substances that modulate the overall activity of the target gene products.","Compounds and other substances can effect such modulation either on the level of target gene/protein expression or target protein activity.","The polypeptides of the present invention and the polynucleotides encoding them are also useful for the same functions known to one of skill in the art as the polypeptides and polynucleotides to which they have homology (set forth in the sequence listing).","If no homology is set forth for a sequence, then the polypeptides and polynucleotides of the present invention are useful for a variety of applications, as described herein, including use in arrays for detection.","detailed-description description=\"Detailed Description\" end=\"lead\"?"],["1.TECHNICAL FIELD The present invention provides novel polynucleotides and proteins encoded by such polynucleotides, along with uses for these polynucleotides and proteins, for example in therapeutic, diagnostic and research methods.","2.BACKGROUND Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lymphokines, interferons, circulating soluble factors, chemokines, and interleukins) has matured rapidly over the past decade.","The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides “directly” in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein in the case of hybridization cloning; activity of the protein in the case of expression cloning).","More recent “indirect” cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization-based cloning techniques, have advanced the state of the art by making available large numbers of DNA/amino acid sequences for proteins that are known to have biological activity, for example, by virtue of their secreted nature in the case of leader sequence cloning, by virtue of their cell or tissue source in the case of PCR-based techniques, or by virtue of structural similarity to other genes of known biological activity.","Identified polynucleotide and polypeptide sequences have numerous applications in, for example, diagnostics, forensics, gene mapping; identification of mutations responsible for genetic disorders or other traits, to assess biodiversity, and to produce many other types of data and products dependent on DNA and amino acid sequences.","3.SUMMARY OF THE INVENTION The compositions of the present invention include novel isolated polypeptides, novel isolated polynucleotides encoding such polypeptides, including recombinant DNA molecules, cloned genes or degenerate variants thereof, especially naturally occurring variants such as allelic variants, antisense polynucleotide molecules, and antibodies that specifically recognize one or more epitopes present on such polypeptides, as well as hybridomas producing such antibodies.","The compositions of the present invention additionally include vectors, including expression vectors, containing the polynucleotides of the invention, cells genetically engineered to contain such polynucleotides and cells genetically engineered to express such polynucleotides.","The present invention relates to a collection or library of at least one novel nucleic acid sequence assembled from expressed sequence tags (ESTs) isolated mainly by sequencing by hybridization (SBH), and in some cases, sequences obtained from one or more public databases.","The invention relates also to the proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins.","These nucleic acid sequences are designated as SEQ ID NO: 1-8051.The polypeptides sequences are designated SEQ ID NO: 8052-16102.The nucleic acids and polypeptides are provided in the Sequence Listing.","In the nucleic acids provided in the Sequence Listing, A is adenosine; C is cytosine; G is guanine; T is thymine; and N is any of the four bases.","In the amino acids provided in the Sequence Listing, * corresponds to the stop codon.","The nucleic acid sequences of the present invention also include, nucleic acid sequences that hybridize to the complement of SEQ ID NO: 1-8051 under stringent hybridization conditions; nucleic acid sequences which are allelic variants or species homologues of any of the nucleic acid sequences recited above, or nucleic acid sequences that encode a peptide comprising a specific domain or truncation of the peptides encoded by SEQ ID NO: 1-8051.A polynucleotide comprising a nucleotide sequence having at least 90% identity to an identifying sequence of SEQ ID NO: 1-8051 or a degenerate variant or fragment thereof.","The identifying sequence can be 100 base pairs in length.","The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-8051.The sequence information can be a segment of any one of SEQ ID NO: 1-8051 that uniquely identifies or represents the sequence information of SEQ ID NO: 1-8051.A collection as used in this application can be a collection of only one polynucleotide.","The collection of sequence information or identifying information of each sequence can be provided on a nucleic acid array.","In one embodiment, segments of sequence information is provided on a nucleic acid array to detect the polynucleotide that contains the segment.","The array can be designed to detect full-match or mismatch to the polynucleotide that contains the segment.","The collection can also be provided in a computer-readable format.","This invention also includes the reverse or direct complement of any of the nucleic acid sequences recited above; cloning or expression vectors containing the nucleic acid sequences; and host cells or organisms transformed with these expression vectors.","Nucleic acid sequences (or their reverse or direct complements) according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology, such as use as hybridization probes, use as primers for PCR, use in an array, use in computer-readable media, use in sequencing full-length genes, use for chromosome and gene mapping, use in the recombinant production of protein, and use in the generation of anti-sense DNA or RNA, their chemical analogs and the like.","In a preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-8051 or novel segments or parts of the nucleic acids of the invention are used as primers in expression assays that are well known in the art.","In a particularly preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-8051 or novel segments or parts of the nucleic acids provided herein are used in diagnostics for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.","The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide comprising any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051; a polynucleotide comprising any of the full length protein coding sequences of SEQ ID NO: 1-8051; and a polynucleotide comprising any of the nucleotide sequences of the mature protein coding sequences of SEQ ID NO: 1-8051.The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent hybridization conditions to (a) the complement of any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051; (b) a nucleotide sequence encoding any one of the amino acid sequences set forth in the Sequence Listing (e.g., SEQ ID NO: 8052-16102); (c) a polynucleotide which is an allelic variant of any polynucleotides recited above; (d) a polynucleotide which encodes a species homolog (e.g.","orthologs) of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of any of the polypeptides comprising an amino acid sequence set forth in the Sequence Listing.","The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising any of the amino acid sequences set forth in the Sequence Listing; or the corresponding full length or mature protein.","Polypeptides of the invention also include polypeptides with biological activity that are encoded by (a) any of the polynucleotides having a nucleotide sequence set forth in SEQ ID NO: 1-8051; or (b) polynucleotides that hybridize to the complement of the polynucleotides of (a) under stringent hybridization conditions.","Biologically or immunologically active variants of any of the polypeptide sequences in the Sequence Listing, and “substantial equivalents” thereof (e.g., with at least about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid sequence identity) that preferably retain biological activity are also contemplated.","The polypeptides of the invention may be wholly or partially chemically synthesized but are preferably produced by recombinant means using the genetically engineered cells (e.g.","host cells) of the invention.","The invention also provides compositions comprising a polypeptide of the invention.","Polypeptide compositions of the invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.","The invention also provides host cells transformed or transfected with a polynucleotide of the invention.","The invention also relates to methods for producing a polypeptide of the invention comprising growing a culture of the host cells of the invention in a suitable culture medium under conditions permitting expression of the desired polypeptide, and purifying the polypeptide from the culture or from the host cells.","Preferred embodiments include those in which the protein produced by such process is a mature form of the protein.","Polynucleotides according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology.","These techniques include use as hybridization probes, use as oligomers, or primers, for PCR, use for chromosome and gene mapping, use in the recombinant production of protein, and use in generation of anti-sense DNA or RNA, their chemical analogs and the like.","For example, when the expression of an mRNA is largely restricted to a particular cell or tissue type, polynucleotides of the invention can be used as hybridization probes to detect the presence of the particular cell or tissue mRNA in a sample using, e.g., in situ hybridization.","In other exemplary embodiments, the polynucleotides are used in diagnostics as expressed sequence tags for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.","The polypeptides according to the invention can be used in a variety of conventional procedures and methods that are currently applied to other proteins.","For example, a polypeptide of the invention can be used to generate an antibody that specifically binds the polypeptide.","Such antibodies, particularly monoclonal antibodies, are useful for detecting or quantitating the polypeptide in tissue.","The polypeptides of the invention can also be used as molecular weight markers, and as a food supplement.","Methods are also provided for preventing, treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a polypeptide of the present invention and a pharmaceutically acceptable carrier.","In particular, the polypeptides and polynucleotides of the invention can be utilized, for example, in methods for the prevention and/or treatment of disorders involving aberrant protein expression or biological activity.","The present invention further relates to methods for detecting the presence of the polynucleotides or polypeptides of the invention in a sample.","Such methods can, for example, be utilized as part of prognostic and diagnostic evaluation of disorders as recited herein and for the identification of subjects exhibiting a predisposition to such conditions.","The invention provides a method for detecting the polynucleotides of the invention in a sample, comprising contacting the sample with a compound that binds to and forms a complex with the polynucleotide of interest for a period sufficient to form the complex and under conditions sufficient to form a complex and detecting the complex such that if a complex is detected, the polynucleotide of interest is detected.","The invention also provides a method for detecting the polypeptides of the invention in a sample comprising contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex and detecting the formation of the complex such that if a complex is formed, the polypeptide is detected.","The invention also provides kits comprising polynucleotide probes and/or monoclonal antibodies, and optionally quantitative standards, for carrying out methods of the invention.","Furthermore, the invention provides methods for evaluating the efficacy of drugs, and monitoring the progress of patients, involved in clinical trials for the treatment of disorders as recited above.","The invention also provides methods for the identification of compounds that modulate (i.e., increase or decrease) the expression or activity of the polynucleotides and/or polypeptides of the invention.","Such methods can be utilized, for example, for the identification of compounds that can ameliorate symptoms of disorders as recited herein.","Such methods can include, but are not limited to, assays for identifying compounds and other substances that interact with (e.g., bind to) the polypeptides of the invention.","The invention provides a method for identifying a compound that binds to the polypeptides of the invention comprising contacting the compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and detecting the complex by detecting the reporter gene sequence expression such that if expression of the reporter gene is detected the compound that binds to a polypeptide of the invention is identified.","The methods of the invention also provides methods for treatment which involve the administration of the polynucleotides or polypeptides of the invention to individuals exhibiting symptoms or tendencies.","In addition, the invention encompasses methods for treating diseases or disorders as recited herein comprising administering compounds and other substances that modulate the overall activity of the target gene products.","Compounds and other substances can effect such modulation either on the level of target gene/protein expression or target protein activity.","The polypeptides of the present invention and the polynucleotides encoding them are also useful for the same functions known to one of skill in the art as the polypeptides and polynucleotides to which they have homology (set forth in the sequence listing).","If no homology is set forth for a sequence, then the polypeptides and polynucleotides of the present invention are useful for a variety of applications, as described herein, including use in arrays for detection.","4.DETAILED DESCRIPTION OF THE INVENTION 4.1 Definitions It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.","The term “active” refers to those forms of the polypeptide which retain the biologic and/or immunologic activities of any naturally occurring polypeptide.","According to the invention, the terms “biologically active” or “biological activity” refer to a protein or peptide having structural, regulatory or biochemical functions of a naturally occurring molecule.","Likewise “immunologically active” or “immunological activity” refers to the capability of the natural, recombinant or synthetic polypeptide to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.","The term “activated cells” as used in this application are those cells which are engaged in extracellular or intracellular membrane trafficking, including the export of secretory or enzymatic molecules as part of a normal or disease process.","The terms “complementary” or “complementarity” refer to the natural binding of polynucleotides by base pairing.","For example, the sequence 5′-AGT-3′ binds to the complementary sequence 3′-TCA-5′.","Complementarity between two single-stranded molecules may be “partial” such that only some of the nucleic acids bind or it may be “complete” such that total complementarity exists between the single stranded molecules.","The degree of complementarity between the nucleic acid strands has significant effects on the efficiency and strength of the hybridization between the nucleic acid strands.","The term “embryonic stem cells (ES)” refers to a cell that can give rise to many differentiated cell types in an embryo or an adult, including the germ cells.","The term “germ line stem cells (GSCs)” refers to stem cells derived from primordial stem cells that provide a steady and continuous source of germ cells for the production of gametes.","The term “primordial germ cells (PGCs)” refers to a small population of cells set aside from other cell lineages particularly from the yolk sac, mesenteries, or gonadal ridges during embryogenesis that have the potential to differentiate into germ cells and other cells.","PGCs are the source from which GSCs and ES cells are derived The PGCs, the GSCs and the ES cells are capable of self-renewal.","Thus these cells not only populate the germ line and give rise to a plurality of terminally differentiated cells that comprise the adult specialized organs, but are able to regenerate themselves.","The term “expression modulating fragment,” EMF, means a series of nucleotides which modulates the expression of an operably linked ORF or another EMF.","As used herein, a sequence is said to “modulate the expression of an operably linked sequence” when the expression of the sequence is altered by the presence of the EMF.","EMFs include, but are not limited to, promoters, and promoter modulating sequences (inducible elements).","One class of EMFs are nucleic acid fragments which induce the expression of an operably linked ORF in response to a specific regulatory factor or physiological event.","The terms “nucleotide sequence” or “nucleic acid” or “polynucleotide” or “oligonucleotide” are used interchangeably and refer to a heteropolymer of nucleotides or the sequence of these nucleotides.","These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA) or to any DNA-like or RNA-like material.","In the sequences herein A is adenine, C is cytosine, T is thymine, G is guanine and N is A, C, G or T (U).","It is contemplated that where the polynucleotide is RNA, the T (thymine) in the sequences provided herein is substituted with U (uracil).","Generally, nucleic acid segments provided by this invention may be assembled from fragments of the genome and short oligonucleotide linkers, or from a series of oligonucleotides, or from individual nucleotides, to provide a synthetic nucleic acid which is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon, or a eukaryotic gene.","The terms “oligonucleotide fragment” or a “polynucleotide fragment”, “portion,” or “segment” or “probe” or “primer” are used interchangeably and refer to a sequence of nucleotide residues which are at least about 5 nucleotides, more preferably at least about 7 nucleotides, more preferably at least about 9 nucleotides, more preferably at least about 11 nucleotides and most preferably at least about 17 nucleotides.","The fragment is preferably less than about 500 nucleotides, preferably less than about 200 nucleotides, more preferably less than about 100 nucleotides, more preferably less than about 50 nucleotides and most preferably less than 30 nucleotides.","Preferably the probe is from about 6 nucleotides to about 200 nucleotides, preferably from about 15 to about 50 nucleotides, more preferably from about 17 to 30 nucleotides and most preferably from about 20 to 25 nucleotides.","Preferably the fragments can be used in polymerase chain reaction (PCR), various hybridization procedures or microarray procedures to identify or amplify identical or related parts of mRNA or DNA molecules.","A fragment or segment may uniquely identify each polynucleotide sequence of the present invention.","Preferably the fragment comprises a sequence substantially similar to any one of SEQ ID NO: 1-8051.Probes may, for example, be used to determine whether specific mRNA molecules are present in a cell or tissue or to isolate similar nucleic acid sequences from chromosomal DNA as described by Walsh et al.","(Walsh, P. S. et al., 1992, PCR Methods Appl 1:241-250).","They may be labeled by nick translation, Klenow fill-in reaction, PCR, or other methods well known in the art.","Probes of the present invention, their preparation and/or labeling are elaborated in Sambrook, J. et al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY; or Ausubel, F. M. et al., 1989, Current Protocols in Molecular Biology, John Wiley & Sons, New York N.Y., both of which are incorporated herein by reference in their entirety.","The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-8051.The sequence information can be a segment of any one of SEQ ID NO: 1-8051 that uniquely identifies or represents the sequence information of that sequence of SEQ ID NO: 1-8051.One such segment can be a twenty-mer nucleic acid sequence because the probability that a twenty-mer is fully matched in the human genome is 1 in 300.In the human genome, there are three billion base pairs in one set of chromosomes.","Because 420 possible twenty-mers exist, there are 300 times more twenty-mers than there are base pairs in a set of human chromosomes.","Using the same analysis, the probability for a seventeen-mer to be fully matched in the human genome is approximately 1 in 5.When these segments are used in arrays for expression studies, fifteen-mer segments can be used.","The probability that the fifteen-mer is fully matched in the expressed sequences is also approximately one in five because expressed sequences comprise less than approximately 5% of the entire genome sequence.","Similarly, when using sequence information for detecting a single mismatch, a segment can be a twenty-five mer.","The probability that the twenty-five mer would appear in a human genome with a single mismatch is calculated by multiplying the probability for a full match (1÷425) times the increased probability for mismatch at each nucleotide position (3×25).","The probability that an eighteen mer with a single mismatch can be detected in an array for expression studies is approximately one in five.","The probability that a twenty-mer with a single mismatch can be detected in a human genome is approximately one in five.","The term “open reading frame,” ORF, means a series of nucleotide triplets coding for amino acids without any termination codons and is a sequence translatable into protein.","The terms “operably linked” or “operably associated” refer to functionally related nucleic acid sequences.","For example, a promoter is operably associated or operably linked with a coding sequence if the promoter controls the transcription of the coding sequence.","While operably linked nucleic acid sequences can be contiguous and in the same reading frame, certain genetic elements e.g.","repressor genes are not contiguously linked to the coding sequence but still control transcription/translation of the coding sequence.","The term “pluripotent” refers to the capability of a cell to differentiate into a number of differentiated cell types that are present in an adult organism.","A pluripotent cell is restricted in its differentiation capability in comparison to a totipotent cell.","The terms “polypeptide” or “peptide” or “amino acid sequence” refer to an oligopeptide, peptide, polypeptide or protein sequence or fragment thereof and to naturally occurring or synthetic molecules.","A polypeptide “fragment,” “portion,” or “segment” is a stretch of amino acid residues of at least about 5 amino acids, preferably at least about 7 amino acids, more preferably at least about 9 amino acids and most preferably at least about 17 or more amino acids.","The peptide preferably is not greater than about 200 amino acids, more preferably less than 150 amino acids and most preferably less than 100 amino acids.","Preferably the peptide is from about 5 to about 200 amino acids.","To be active, any polypeptide must have sufficient length to display biological and/or immunological activity.","The term “naturally occurring polypeptide” refers to polypeptides produced by cells that have not been genetically engineered and specifically contemplates various polypeptides arising from post-translational modifications of the polypeptide including, but not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation and acylation.","The term “translated protein coding portion” means a sequence which encodes for the full length protein which may include any leader sequence or any processing sequence.","The term “mature protein coding sequence” means a sequence which encodes a peptide or protein without a signal or leader sequence.","The “mature protein portion” means that portion of the protein which does not include a signal or leader sequence.","The peptide may have been produced by processing in the cell which removes any leader/signal sequence.","The mature protein portion may or may not include an initial methionine residue.","The methionine residue may be removed from the protein during processing in the cell.","The peptide may be produced synthetically or the protein may have been produced using a polynucleotide only encoding for the mature protein coding sequence.","The term “derivative” refers to polypeptides chemically modified by such techniques as ubiquitination, labeling (e.g., with radionuclides or various enzymes), covalent polymer attachment such as pegylation (derivatization with polyethylene glycol) and insertion or substitution by chemical synthesis of amino acids such as ornithine, which do not normally occur in human proteins.","The term “variant”(or “analog”) refers to any polypeptide differing from naturally occurring polypeptides by amino acid insertions, deletions, and substitutions, created using, e.g., recombinant DNA techniques.","Guidance in determining which amino acid residues may be replaced, added or deleted without abolishing activities of interest, may be found by comparing the sequence of the particular polypeptide with that of homologous peptides and minimizing the number of amino acid sequence changes made in regions of high homology (conserved regions) or by replacing amino acids with consensus sequence.","Alternatively, recombinant variants encoding these same or similar polypeptides may be synthesized or selected by making use of the “redundancy” in the genetic code.","Various codon substitutions, such as the silent changes which produce various restriction sites, may be introduced to optimize cloning into a plasmid or viral vector or expression in a particular prokaryotic or eukaryotic system.","Mutations in the polynucleotide sequence may be reflected in the polypeptide or domains of other peptides added to the polypeptide to modify the properties of any part of the polypeptide, to change characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate.","Preferably, amino acid “substitutions” are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements.","“Conservative” amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.","For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.","“Insertions” or “deletions” are preferably in the range of about 1 to 20 amino acids, more preferably 1 to 10 amino acids.","The variation allowed may be experimentally determined by systematically making insertions, deletions, or substitutions of amino acids in a polypeptide molecule using recombinant DNA techniques and assaying the resulting recombinant variants for activity.","Alternatively, where alteration of function is desired, insertions, deletions or non-conservative alterations can be engineered to produce altered polypeptides.","Such alterations can, for example, alter one or more of the biological functions or biochemical characteristics of the polypeptides of the invention.","For example, such alterations may change polypeptide characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate.","Further, such alterations can be selected so as to generate polypeptides that are better suited for expression, scale up and the like in the host cells chosen for expression.","For example, cysteine residues can be deleted or substituted with another amino acid residue in order to eliminate disulfide bridges.","The terms “purified” or “substantially purified” as used herein denotes that the indicated nucleic acid or polypeptide is present in the substantial absence of other biological macromolecules, e.g., polynucleotides, proteins, and the like.","In one embodiment, the polynucleotide or polypeptide is purified such that it constitutes at least 95% by weight, more preferably at least 99% by weight, of the indicated biological macromolecules present (but water, buffers, and other small molecules, especially molecules having a molecular weight of less than 1000 daltons, can be present).","The term “isolated” as used herein refers to a nucleic acid or polypeptide separated from at least one other component (e.g., nucleic acid or polypeptide) present with the nucleic acid or polypeptide in its natural source.","In one embodiment, the nucleic acid or polypeptide is found in the presence of (if anything) only a solvent, buffer, ion, or other component normally present in a solution of the same.","The terms “isolated” and “purified” do not encompass nucleic acids or polypeptides present in their natural source.","The term “recombinant,” when used herein to refer to a polypeptide or protein, means that a polypeptide or protein is derived from recombinant (e.g., microbial, insect, or mammalian) expression systems.","“Microbial” refers to recombinant polypeptides or proteins made in bacterial or fungal (e.g., yeast) expression systems.","As a product, “recombinant microbial” defines a polypeptide or protein essentially free of native endogenous substances and unaccompanied by associated native glycosylation.","Polypeptides or proteins expressed in most bacterial cultures, e.g., E. coli, will be free of glycosylation modifications; polypeptides or proteins expressed in yeast will have a glycosylation pattern in general different from those expressed in mammalian cells.","The term “recombinant expression vehicle or vector” refers to a plasmid or phage or virus or vector, for expressing a polypeptide from a DNA (RNA) sequence.","An expression vehicle can comprise a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA and translated into protein, and (3) appropriate transcription initiation and termination sequences.","Structural units intended for use in yeast or eukaryotic expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell.","Alternatively, where recombinant protein is expressed without a leader or transport sequence, it may include an amino terminal methionine residue.","This residue may or may not be subsequently cleaved from the expressed recombinant protein to provide a final product.","The term “recombinant expression system” means host cells which have stably integrated a recombinant transcriptional unit into chromosomal DNA or carry the recombinant transcriptional unit extrachromosomally.","Recombinant expression systems as defined herein will express heterologous polypeptides or proteins upon induction of the regulatory elements linked to the DNA segment or synthetic gene to be expressed.","This term also means host cells which have stably integrated a recombinant genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers.","Recombinant expression systems as defined herein will express polypeptides or proteins endogenous to the cell upon induction of the regulatory elements linked to the endogenous DNA segment or gene to be expressed.","The cells can be prokaryotic or eukaryotic.","The term “secreted” includes a protein that is transported across or through a membrane, including transport as a result of signal sequences in its amino acid sequence when it is expressed in a suitable host cell.","“Secreted” proteins include without limitation proteins secreted wholly (e.g., soluble proteins) or partially (e.g., receptors) from the cell in which they are expressed.","“Secreted” proteins also include without limitation proteins that are transported across the membrane of the endoplasmic reticulum.","“Secreted” proteins are also intended to include proteins containing non-typical signal sequences (e.g.","Interleukin-1 Beta, see Krasney, P. A. and Young, P. R. (1992) Cytokine 4(2):134-143) and factors released from damaged cells (e.g.","Interleukin-1 Receptor Antagonist, see Arend, W. P. et. al.","(1998) Annu.","Rev.","Immunol.","16:27-55) Where desired, an expression vector may be designed to contain a “signal or leader sequence” which will direct the polypeptide through the membrane of a cell.","Such a sequence may be naturally present on the polypeptides of the present invention or provided from heterologous protein sources by recombinant DNA techniques.","The term “stringent” is used to refer to conditions that are commonly understood in the art as stringent.","Stringent conditions can include highly stringent conditions (i.e., hybridization to filter-bound DNA in 0.5 M NaHPO4, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., and washing in 0.1×SSC/0.1% SDS at 68° C.), and moderately stringent conditions (i.e., washing in 0.2×SSC/0.1% SDS at 42° C.).","Other exemplary hybridization conditions are described herein in the examples.","In instances of hybridization of deoxyoligonucleotides, additional exemplary stringent hybridization conditions include washing in 6×SSC/0.05% sodium pyrophosphate at 37° C. (for 14-base oligonucleotides), 48° C. (for 17-base oligos), 55° C. (for 20-base oligonucleotides), and 60° C. (for 23-base oligonucleotides).","As used herein, “substantially equivalent” can refer both to nucleotide and amino acid sequences, for example a mutant sequence, that varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which does not result in an adverse functional dissimilarity between the reference and subject sequences.","Typically, such a substantially equivalent sequence varies from one of those listed herein by no more than about 35% (i.e., the number of individual residue substitutions, additions, and/or deletions in a substantially equivalent sequence, as compared to the corresponding reference sequence, divided by the total number of residues in the substantially equivalent sequence is about 0.35 or less).","Such a sequence is said to have 65% sequence identity to the listed sequence.","In one embodiment, a substantially equivalent, e.g., mutant, sequence of the invention varies from a listed sequence by no more than 30% (70% sequence identity); in a variation of this embodiment, by no more than 25% (75% sequence identity); and in a further variation of this embodiment, by no more than 20% (80% sequence identity) and in a further variation of this embodiment, by no more than 10% (90% sequence identity) and in a further variation of this embodiment, by no more that 5% (95% sequence identity).","Substantially equivalent, e.g., mutant, amino acid sequences according to the invention preferably have at least 80% sequence identity with a listed amino acid sequence, more preferably at least 85% sequence identity, more preferably at least 90% sequence identity, more preferably at least 95% identity, more preferably at least 98% identity, and most preferably at least 99% identity.","Substantially equivalent nucleotide sequences of the invention can have lower percent sequence identities, taking into account, for example, the redundancy or degeneracy of the genetic code.","Preferably, nucleotide sequence has at least about 65% identity, more preferably at least about 75% identity, more preferably at least about 80% sequence identity, more preferably at least about 85% sequence identity, more preferably at least about 90% sequence identity, and most preferably at least about 95% identity, more preferably at least about 98% sequence identity, and most preferably at least about 99% sequence identity.","For the purposes of the present invention, sequences having substantially equivalent biological activity and substantially equivalent expression characteristics are considered substantially equivalent.","For the purposes of determining equivalence, truncation of the mature sequence (e.g., via a mutation which creates a spurious stop codon) should be disregarded.","Sequence identity may be determined, e.g., using the Jotun Hein method (Hein, J.","(1990) Methods Enzymol.","183:626-645).","Identity between sequences can also be determined by other methods known in the art, e.g.","by varying hybridization conditions.","The term “totipotent” refers to the capability of a cell to differentiate into all of the cell types of an adult organism.","The term “transformation” means introducing DNA into a suitable host cell so that the DNA is replicable, either as an extrachromosomal element, or by chromosomal integration.","The term “transfection” refers to the taking up of an expression vector by a suitable host cell, whether or not any coding sequences are in fact expressed.","The term “infection” refers to the introduction of nucleic acids into a suitable host cell by use of a virus or viral vector.","As used herein, an “uptake modulating fragment,” UMF, means a series of nucleotides which mediate the uptake of a linked DNA fragment into a cell.","UMFs can be readily identified using known UMFs as a target sequence or target motif with the computer-based systems described below.","The presence and activity of a UMF can be confirmed by attaching the suspected UMF to a marker sequence.","The resulting nucleic acid molecule is then incubated with an appropriate host under appropriate conditions and the uptake of the marker sequence is determined.","As described above, a UMF will increase the frequency of uptake of a linked marker sequence.","Each of the above terms is meant to encompass all that is described for each, unless the context dictates otherwise.","4.2 Nucleic Acids of the Invention Nucleotide sequences of the invention are set forth in the Sequence Listing.","The isolated polynucleotides of the invention include a polynucleotide comprising the nucleotide sequences of SEQ ID NO: 1-8051; a polynucleotide encoding any one of the peptide sequences of SEQ ID NO: 8052-16102; and a polynucleotide comprising the nucleotide sequence encoding the mature protein coding sequence of the polypeptides of any one of SEQ ID NO: 8052-16102.The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent conditions to (a) the complement of any of the nucleotides sequences of SEQ ID NO: 1-8051; (b) nucleotide sequences encoding any one of the amino acid sequences set forth in the Sequence Listing; (c) a polynucleotide which is an allelic variant of any polynucleotide recited above; (d) a polynucleotide which encodes a species homolog of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of the polypeptides of SEQ ID NO: 8052-16102.Domains of interest may depend on the nature of the encoded polypeptide; e.g., domains in receptor-like polypeptides include ligand-binding, extracellular, transmembrane, or cytoplasmic domains, or combinations thereof; domains in immunoglobulin-like proteins include the variable immunoglobulin-like domains; domains in enzyme-like polypeptides include catalytic and substrate binding domains; and domains in ligand polypeptides include receptor-binding domains.","The polynucleotides of the invention include naturally occurring or wholly or partially synthetic DNA, e.g., cDNA and genomic DNA, and RNA, e.g., mRNA.","The polynucleotides may include all of the coding region of the cDNA or may represent a portion of the coding region of the cDNA.","The present invention also provides genes corresponding to the cDNA sequences disclosed herein.","The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein.","Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials.","Further 5′ and 3′ sequence can be obtained using methods known in the art.","For example, full length cDNA or genomic DNA that corresponds to any of the polynucleotides of SEQ ID NO: 1-8051 can be obtained by screening appropriate cDNA or genomic DNA libraries under suitable hybridization conditions using any of the polynucleotides of SEQ ID NO: 1-8051 or a portion thereof as a probe.","Alternatively, the polynucleotides of SEQ ID NO: 1-8051 may be used as the basis for suitable primer(s) that allow identification and/or amplification of genes in appropriate genomic DNA or cDNA libraries.","The nucleic acid sequences of the invention can be assembled from ESTs and sequences (including cDNA and genomic sequences) obtained from one or more public databases, such as dbEST, gbpri, and UniGene.","The EST sequences can provide identifying sequence information, representative fragment or segment information, or novel segment information for the full-length gene.","The polynucleotides of the invention also provide polynucleotides including nucleotide sequences that are substantially equivalent to the polynucleotides recited above.","Polynucleotides according to the invention can have, e.g., at least about 65%, at least about 70%, at least about 75%, at least about 80%, 81%, 82%, 83%, 84%, more typically at least about 85%, 86%, 87%, 88%, 89%, more typically at least about 90%, 91%, 92%, 93%, 94%, and even more typically at least about 95%, 96%, 97%, 98%, 99%, sequence identity to a polynucleotide recited above.","Included within the scope of the nucleic acid sequences of the invention are nucleic acid sequence fragments that hybridize under stringent conditions to any of the nucleotide sequences of SEQ ID NO: 1-8051, or complements thereof, which fragment is greater than about 5 nucleotides, preferably 7 nucleotides, more preferably greater than 9 nucleotides and most preferably greater than 17 nucleotides.","Fragments of, e.g.","15, 17, or 20 nucleotides or more that are selective for (i.e.","specifically hybridize to any one of the polynucleotides of the invention) are contemplated.","Probes capable of specifically hybridizing to a polynucleotide can differentiate polynucleotide sequences of the invention from other polynucleotide sequences in the same family of genes or can differentiate human genes from genes of other species, and are preferably based on unique nucleotide sequences.","The sequences falling within the scope of the present invention are not limited to these specific sequences, but also include allelic and species variations thereof.","Allelic and species variations can be routinely determined by comparing the sequence provided in SEQ ID NO: 1-8051, a representative fragment thereof, or a nucleotide sequence at least 90% identical, preferably 95% identical, to SEQ ID NO: 1-8051 with a sequence from another isolate of the same species.","Furthermore, to accommodate codon variability, the invention includes nucleic acid molecules coding for the same amino acid sequences as do the specific ORFs disclosed herein.","In other words, in the coding region of an ORF, substitution of one codon for another codon that encodes the same amino acid is expressly contemplated.","The nearest neighbor or homology result for the nucleic acids of the present invention, including SEQ ID NO: 1-8051 can be obtained by searching a database using an algorithm or a program.","Preferably, a BLAST which stands for Basic Local Alignment Search Tool is used to search for local sequence alignments (Altshul, S. F. J. Mol.","Evol.","36 290-300 (1993) and Altschul S. F. et al.","J. Mol.","Biol.","21:403-410 (1990)).","Alternatively a FASTA version 3 search against Genpept, using Fastxy algorithm.","Species homologs (or orthologs) of the disclosed polynucleotides and proteins are also provided by the present invention.","Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species.","The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous or related to that encoded by the polynucleotides.","The nucleic acid sequences of the invention are further directed to sequences which encode variants of the described nucleic acids.","These amino acid sequence variants may be prepared by methods known in the art by introducing appropriate nucleotide changes into a native or variant polynucleotide.","There are two variables in the construction of amino acid sequence variants: the location of the mutation and the nature of the mutation.","Nucleic acids encoding the amino acid sequence variants are preferably constructed by mutating the polynucleotide to encode an amino acid sequence that does not occur in nature.","These nucleic acid alterations can be made at sites that differ in the nucleic acids from different species (variable positions) or in highly conserved regions (constant regions).","Sites at such locations will typically be modified in series, e.g., by substituting first with conservative choices (e.g., hydrophobic amino acid to a different hydrophobic amino acid) and then with more distant choices (e.g., hydrophobic amino acid to a charged amino acid), and then deletions or insertions may be made at the target site.","Amino acid sequence deletions generally range from about 1 to 30 residues, preferably about 1 to 10 residues, and are typically contiguous.","Amino acid insertions include amino- and/or carboxyl-terminal fusions ranging in length from one to one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.","Intrasequence insertions may range generally from about 1 to 10 amino residues, preferably from 1 to 5 residues.","Examples of terminal insertions include the heterologous signal sequences necessary for secretion or for intracellular targeting in different host cells and sequences such as FLAG or poly-histidine sequences useful for purifying the expressed protein.","In a preferred method, polynucleotides encoding the novel amino acid sequences are changed via site-directed mutagenesis.","This method uses oligonucleotide sequences to alter a polynucleotide to encode the desired amino acid variant, as well as sufficient adjacent nucleotides on both sides of the changed amino acid to form a stable duplex on either side of the site of being changed.","In general, the techniques of site-directed mutagenesis are well known to those of skill in the art and this technique is exemplified by publications such as, Edelman et al., DNA 2:183 (1983).","A versatile and efficient method for producing site-specific changes in a polynucleotide sequence was published by Zoller and Smith, Nucleic Acids Res.","10:6487-6500 (1982).","PCR may also be used to create amino acid sequence variants of the novel nucleic acids.","When small amounts of template DNA are used as starting material, primer(s) that differs slightly in sequence from the corresponding region in the template DNA can generate the desired amino acid variant.","PCR amplification results in a population of product DNA fragments that differ from the polynucleotide template encoding the polypeptide at the position specified by the primer.","The product DNA fragments replace the corresponding region in the plasmid and this gives a polynucleotide encoding the desired amino acid variant.","A further technique for generating amino acid variants is the cassette mutagenesis technique described in Wells et al., Gene 34:315 (1985); and other mutagenesis techniques well known in the art, such as, for example, the techniques in Sambrook et al., supra, and Current Protocols in Molecular Biology, Ausubel et al.","Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be used in the practice of the invention for the cloning and expression of these novel nucleic acids.","Such DNA sequences include those which are capable of hybridizing to the appropriate novel nucleic acid sequence under stringent conditions.","Polynucleotides encoding preferred polypeptide truncations of the invention can be used to generate polynucleotides encoding chimeric or fusion proteins comprising one or more domains of the invention and heterologous protein sequences.","The polynucleotides of the invention additionally include the complement of any of the polynucleotides recited above.","The polynucleotide can be DNA (genomic, cDNA, amplified, or synthetic) or RNA.","Methods and algorithms for obtaining such polynucleotides are well known to those of skill in the art and can include, for example, methods for determining hybridization conditions that can routinely isolate polynucleotides of the desired sequence identities.","In accordance with the invention, polynucleotide sequences comprising the mature protein coding sequences corresponding to any one of SEQ ID NO: 1-8051, or functional equivalents thereof, may be used to generate recombinant DNA molecules that direct the expression of that nucleic acid, or a functional equivalent thereof, in appropriate host cells.","Also included are the cDNA inserts of any of the clones identified herein.","A polynucleotide according to the invention can be joined to any of a variety of other nucleotide sequences by well-established recombinant DNA techniques (see Sambrook J et al.","(1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY).","Useful nucleotide sequences for joining to polynucleotides include an assortment of vectors, e.g., plasmids, cosmids, lambda phage derivatives, phagemids, and the like, that are well known in the art.","Accordingly, the invention also provides a vector including a polynucleotide of the invention and a host cell containing the polynucleotide.","In general, the vector contains an origin of replication functional in at least one organism, convenient restriction endonuclease sites, and a selectable marker for the host cell.","Vectors according to the invention include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.","A host cell according to the invention can be a prokaryotic or eukaryotic cell and can be a unicellular organism or part of a multicellular organism.","The present invention further provides recombinant constructs comprising a nucleic acid having any of the nucleotide sequences of SEQ ID NO: 1-8051 or a fragment thereof or any other polynucleotides of the invention.","In one embodiment, the recombinant constructs of the present invention comprise a vector, such as a plasmid or viral vector, into which a nucleic acid having any of the nucleotide sequences of SEQ ID NO: 1-8051 or a fragment thereof is inserted, in a forward or reverse orientation.","In the case of a vector comprising one of the ORFs of the present invention, the vector may further comprise regulatory sequences, including for example, a promoter, operably linked to the ORF.","Large numbers of suitable vectors and promoters are known to those of skill in the art and are commercially available for generating the recombinant constructs of the present invention.","The following vectors are provided by way of example.","Bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene); pTrc99A, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia).","Eukaryotic: pWLneo, pSV2cat, pOG44, PXTI, pSG (Stratagene) pSVK3, pBPV, pMSG, pSVL (Pharmacia).","The isolated polynucleotide of the invention may be operably linked to an expression control sequence such as the pMT2 or pED expression vectors disclosed in Kaufman et al., Nucleic Acids Res.","19, 4485-4490 (1991), in order to produce the protein recombinantly.","Many suitable expression control sequences are known in the art.","General methods of expressing recombinant proteins are also known and are exemplified in R. Kaufman, Methods in Enzymology 185, 537-566 (1990).","As defined herein “operably linked” means that the isolated polynucleotide of the invention and an expression control sequence are situated within a vector or cell in such a way that the protein is expressed by a host cell which has been transformed (transfected) with the ligated polynucleotide/expression control sequence.","Promoter regions can be selected from any desired gene using CAT (chloramphenicol transferase) vectors or other vectors with selectable markers.","Two appropriate vectors are pKK232-8 and pCM7.Particular named bacterial promoters include lacI, lacZ, T3, T7, gpt, lambda PR, and trc.","Eukaryotic promoters include CMV immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-I.","Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art.","Generally, recombinant expression vectors will include origins of replication and selectable markers permitting transformation of the host cell, e.g., the ampicillin resistance gene of E. coli and S. cerevisiae TRP1 gene, and a promoter derived from a highly-expressed gene to direct transcription of a downstream structural sequence.","Such promoters can be derived from operons encoding glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), a-factor, acid phosphatase, or heat shock proteins, among others.","The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein into the periplasmic space or extracellular medium.","Optionally, the heterologous sequence can encode a fusion protein including an amino terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product.","Useful expression vectors for bacterial use are constructed by inserting a structural DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter.","The vector will comprise one or more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and to, if desirable, provide amplification within the host.","Suitable prokaryotic hosts for transformation include E. coli, Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus, although others may also be employed as a matter of choice.","As a representative but non-limiting example, useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR322 (ATCC 37017).","Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and GEM 1 (Promega Biotech, Madison, Wis., USA).","These pBR322 “backbone” sections are combined with an appropriate promoter and the structural sequence to be expressed.","Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter is induced or derepressed by appropriate means (e.g., temperature shift or chemical induction) and cells are cultured for an additional period.","Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification.","Polynucleotides of the invention can also be used to induce immune responses.","For example, as described in Fan et al., Nat.","Biotech.","17:870-872 (1999), incorporated herein by reference, nucleic acid sequences encoding a polypeptide may be used to generate antibodies against the encoded polypeptide following topical administration of naked plasmid DNA or following injection, and preferably intramuscular injection of the DNA.","The nucleic acid sequences are preferably inserted in a recombinant expression vector and may be in the form of naked DNA.","4.3 Antisense Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 1-8051, or fragments, analogs or derivatives thereof.","An “antisense” nucleic acid comprises a nucleotide sequence that is complementary to a “sense” nucleic acid encoding a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence.","In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire coding strand, or to only a portion thereof.","Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a protein of any of SEQ ID NO: 8052-16102 or antisense nucleic acids complementary to a nucleic acid sequence of SEQ ID NO: 1-8051 are additionally provided.","In one embodiment, an antisense nucleic acid molecule is antisense to a “coding region” of the coding strand of a nucleotide sequence of the invention.","The term “coding region” refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues.","In another embodiment, the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence of the invention.","The term “noncoding region” refers to 5′ and 3′ sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5′ and 3′ untranslated regions).","Given the coding strand sequences encoding a nucleic acid disclosed herein (e.g., SEQ ID NO: 1-8051), antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing.","The antisense nucleic acid molecule can be complementary to the entire coding region of a mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of a mRNA.","For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of a mRNA.","An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length.","An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art.","For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.","Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.","Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).","The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a protein according to the invention to thereby inhibit expression of the protein, e.g., by inhibiting transcription and/or translation.","The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix.","An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site.","Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically.","For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens.","The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein.","To achieve sufficient intracellular concentrations of antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.","In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule.","An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual α-units, the strands run parallel to each other (Gaultier et al.","(1987) Nucleic Acids Res 15: 6625-6641).","The antisense nucleic acid molecule can also comprise a 2′-o-methylribonucleotide (Inoue et al.","(1987) Nucleic Acids Res 15: 6131-6148) or a chimeric RNA-DNA analogue (Inoue et al.","(1987) FEBS Lett 215: 327-330).","4.4 Ribozymes and PNA Moieties In still another embodiment, an antisense nucleic acid of the invention is a ribozyme.","Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as a mRNA, to which they have a complementary region.","Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach (1988) Nature 334:585-591)) can be used to catalytically cleave a mRNA transcripts to thereby inhibit translation of a mRNA.","A ribozyme having specificity for a nucleic acid of the invention can be designed based upon the nucleotide sequence of a DNA disclosed herein (i.e., SEQ ID NO: 1-8051).","For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an mRNA of SEQ ID NO: 1-8051 (see, e.g., Cech et al.","U.S. Pat.","No.","4,987,071; and Cech et al.","U.S. Pat.","No.","5,116,742).","Alternatively, polynucleotides of the invention can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules.","See, e.g., Bartel et al., (1993) Science 261:1411-1418.Alternatively, gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of the gene in target cells.","See generally, Helene.","(1991) Anticancer Drug Des.","6: 569-84; Helene.","et al.","(1992) Ann.","N.Y. Acad.","Sci.","660:27-36; and Maher (1992) Bioassays 14: 807-15.In various embodiments, the nucleic acids of the invention can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule.","For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al.","(1996) Bioorg Med Chem 4: 5-23).","As used herein, the terms “peptide nucleic acids” or “PNAs” refer to nucleic acid mimics, e.g.","DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained.","The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength.","The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al.","(1996) above; Perry-O'Keefe et al.","(1996) PNAS 93: 14670-675.PNAs of the invention can be used in therapeutic and diagnostic applications.","For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.","PNAs of the invention can also be used, e.g., in the analysis of single base pair mutations in a gene by, e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S1 nucleases (Hyrup B.","(1996) above); or as probes or primers for DNA sequence and hybridization (Hyrup et al.","(1996), above; Perry-O'Keefe (1996), above).","In another embodiment, PNAs of the invention can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art.","For example, PNA-DNA chimeras can be generated that may combine the advantageous properties of PNA and DNA.","Such chimeras allow DNA recognition enzymes, e.g., RNase H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity.","PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (Hyrup (1996) above).","The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996) above and Finn et al.","(1996) Nucl Acids Res 24: 3357-63.For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5′-(4-methoxytrityl)amino-5′-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5′ end of DNA (Mag et al.","(1989) Nucl Acid Res 17: 5973-88).","PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5′ PNA segment and a 3′ DNA segment (Finn et al.","(1996) above).","Alternatively, chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNA segment.","See, Petersen et al.","(1975) Bioorg Med Chem Lett 5: 1119-11124.In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc.","Natl.","Acad.","Sci.","U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc.","Natl.","Acad.","Sci.","84:648-652; PCT Publication No.","W088/09810) or the blood-brain barrier (see, e.g., PCT Publication No.","W089/10134).","In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (See, e.g., Krol et al., 1988, BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988, Pharm.","Res.","5:539-549).","To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, etc.","4.5 Hosts The present invention further provides host cells genetically engineered to contain the polynucleotides of the invention.","For example, such host cells may contain nucleic acids of the invention introduced into the host cell using known transformation, transfection or infection methods.","The present invention still further provides host cells genetically engineered to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell.","Knowledge of nucleic acid sequences allows for modification of cells to permit, or increase, expression of endogenous polypeptide.","Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the polypeptide at higher levels.","The heterologous promoter is inserted in such a manner that it is operatively linked to the encoding sequences.","See, for example, PCT International Publication No.","WO94/12650, PCT International Publication No.","WO92/20808, and PCT International Publication No.","WO91/09955.It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA.","If linked to the coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.","The host cell can be a higher eukaryotic host cell, such as a mammalian cell, a lower eukaryotic host cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell.","Introduction of the recombinant construct into the host cell can be effected by calcium phosphate transfection, DEAE, dextran mediated transfection, or electroporation (Davis, L. et al., Basic Methods in Molecular Biology (1986)).","The host cells containing one of the polynucleotides of the invention, can be used in conventional manners to produce the gene product encoded by the isolated fragment (in the case of an ORF) or can be used to produce a heterologous protein under the control of the EMF.","Any host/vector system can be used to express one or more of the ORFs of the present invention.","These include, but are not limited to, eukaryotic hosts such as HeLa cells, Cv-1 cell, COS cells, 293 cells, and Sf9 cells, as well as prokaryotic host such as E. coli and B. subtilis.","The most preferred cells are those which do not normally express the particular polypeptide or protein or which expresses the polypeptide or protein at low natural level.","Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters.","Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention.","Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook, et al., in Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y. (1989), the disclosure of which is hereby incorporated by reference.","Various mammalian cell culture systems can also be employed to express recombinant protein.","Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts, described by Gluzman, Cell 23:175 (1981).","Other cell lines capable of expressing a compatible vector are, for example, the C127, monkey COS cells, Chinese Hamster Ovary (CHO) cells, human kidney 293 cells, human epidermal A431 cells, human Colo205 cells, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jurkat cells.","Mammalian expression vectors will comprise an origin of replication, a suitable promoter and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5′ flanking nontranscribed sequences.","DNA sequences derived from the SV40 viral genome, for example, SV40 origin, early promoter, enhancer, splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements.","Recombinant polypeptides and proteins produced in bacterial culture are usually isolated by initial extraction from cell pellets, followed by one or more salting-out, aqueous ion exchange or size exclusion chromatography steps.","Protein refolding steps can be used, as necessary, in completing configuration of the mature protein.","Finally, high performance liquid chromatography (HPLC) can be employed for final purification steps.","Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.","Alternatively, it may be possible to produce the protein in lower eukaryotes such as yeast or insects or in prokaryotes such as bacteria.","Potentially suitable yeast strains include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces strains, Candida, or any yeast strain capable of expressing heterologous proteins.","Potentially suitable bacterial strains include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or any bacterial strain capable of expressing heterologous proteins.","If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced therein, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein.","Such covalent attachments may be accomplished using known chemical or enzymatic methods.","In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination.","As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods.","Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences.","Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting.","These sequence include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.","The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene.","Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element.","Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements.","Here, the naturally occurring sequences are deleted and new sequences are added.","In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the host cell genome.","The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker.","Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.","The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Pat.","No.","5,272,071 to Chappel; U.S. Pat.","No.","5,578,461 to Sherwin et al.","; International Application No.","PCT/US92/09627 (WO93/09222) by Selden et al.","; and International Application No.","PCT/US90/06436 (WO91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.","4.6 Polypeptides of the Invention The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising: the amino acid sequences set forth as any one of SEQ ID NO: 8052-16102 or an amino acid sequence encoded by any one of the nucleotide sequences SEQ ID NO: 1-8051 or the corresponding full length or mature protein.","Polypeptides of the invention also include polypeptides preferably with biological or immunological activity that are encoded by: (a) a polynucleotide having any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051 or (b) polynucleotides encoding any one of the amino acid sequences set forth as SEQ ID NO: 8052-16102 or (c) polynucleotides that hybridize to the complement of the polynucleotides of either (a) or (b) under stringent hybridization conditions.","The invention also provides biologically active or immunologically active variants of any of the amino acid sequences set forth as SEQ ID NO: 8052-16102 or the corresponding full length or mature protein; and “substantial equivalents” thereof (e.g., with at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, 86%, 87%, 88%, 89%, at least about 90%, 91%, 92%, 93%, 94%, typically at least about 95%, 96%, 97%, more typically at least about 98%, or most typically at least about 99% amino acid identity) that retain biological activity.","Polypeptides encoded by allelic variants may have a similar, increased, or decreased activity compared to polypeptides comprising SEQ ID NO: 8052-16102.Fragments of the proteins of the present invention which are capable of exhibiting biological activity are also encompassed by the present invention.","Fragments of the protein may be in linear form or they may be cyclized using known methods, for example, as described in H. U. Saragovi, et al., Bio/Technology 10, 773-778 (1992) and in R. S. McDowell, et al., J. Amer.","Chem.","Soc.","114, 9245-9253 (1992), both of which are incorporated herein by reference.","Such fragments may be fused to carrier molecules such as immunoglobulins for many purposes, including increasing the valency of protein binding sites.","The present invention also provides both full-length and mature forms (for example, without a signal sequence or precursor sequence) of the disclosed proteins.","The protein coding sequence is identified in the sequence listing by translation of the disclosed nucleotide sequences.","The mature form of such protein may be obtained by expression of a full-length polynucleotide in a suitable mammalian cell or other host cell.","The sequence of the mature form of the protein is also determinable from the amino acid sequence of the full-length form.","Where proteins of the present invention are membrane bound, soluble forms of the proteins are also provided.","In such forms, part or all of the regions causing the proteins to be membrane bound are deleted so that the proteins are fully secreted from the cell in which they are expressed.","Protein compositions of the present invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.","The present invention further provides isolated polypeptides encoded by the nucleic acid fragments of the present invention or by degenerate variants of the nucleic acid fragments of the present invention.","By “degenerate variant” is intended nucleotide fragments which differ from a nucleic acid fragment of the present invention (e.g., an ORF) by nucleotide sequence but, due to the degeneracy of the genetic code, encode an identical polypeptide sequence.","Preferred nucleic acid fragments of the present invention are the ORFs that encode proteins.","A variety of methodologies known in the art can be utilized to obtain any one of the isolated polypeptides or proteins of the present invention.","At the simplest level, the amino acid sequence can be synthesized using commercially available peptide synthesizers.","The synthetically-constructed protein sequences, by virtue of sharing primary, secondary or tertiary structural and/or conformational characteristics with proteins may possess biological properties in common therewith, including protein activity.","This technique is particularly useful in producing small peptides and fragments of larger polypeptides.","Fragments are useful, for example, in generating antibodies against the native polypeptide.","Thus, they may be employed as biologically active or immunological substitutes for natural, purified proteins in screening of therapeutic compounds and in immunological processes for the development of antibodies.","The polypeptides and proteins of the present invention can alternatively be purified from cells which have been altered to express the desired polypeptide or protein.","As used herein, a cell is said to be altered to express a desired polypeptide or protein when the cell, through genetic manipulation, is made to produce a polypeptide or protein which it normally does not produce or which the cell normally produces at a lower level.","One skilled in the art can readily adapt procedures for introducing and expressing either recombinant or synthetic sequences into eukaryotic or prokaryotic cells in order to generate a cell which produces one of the polypeptides or proteins of the present invention.","The invention also relates to methods for producing a polypeptide comprising growing a culture of host cells of the invention in a suitable culture medium, and purifying the protein from the cells or the culture in which the cells are grown.","For example, the methods of the invention include a process for producing a polypeptide in which a host cell containing a suitable expression vector that includes a polynucleotide of the invention is cultured under conditions that allow expression of the encoded polypeptide.","The polypeptide can be recovered from the culture, conveniently from the culture medium, or from a lysate prepared from the host cells and further purified.","Preferred embodiments include those in which the protein produced by such process is a full length or mature form of the protein.","In an alternative method, the polypeptide or protein is purified from bacterial cells which naturally produce the polypeptide or protein.","One skilled in the art can readily follow known methods for isolating polypeptides and proteins in order to obtain one of the isolated polypeptides or proteins of the present invention.","These include, but are not limited to, immunochromatography, HPLC, size-exclusion chromatography, ion-exchange chromatography, and immuno-affinity chromatography.","See, e.g., Scopes, Protein Purification: Principles and Practice, Springer-Verlag (1994); Sambrook, et al., in Molecular Cloning: A Laboratory Manual; Ausubel et al., Current Protocols in Molecular Biology.","Polypeptide fragments that retain biological/immunological activity include fragments comprising greater than about 100 amino acids, or greater than about 200 amino acids, and fragments that encode specific protein domains.","The purified polypeptides can be used in in vitro binding assays which are well known in the art to identify molecules which bind to the polypeptides.","These molecules include but are not limited to, for e.g., small molecules, molecules from combinatorial libraries, antibodies or other proteins.","The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art.","In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.","In addition, the peptides of the invention or molecules capable of binding to the peptides may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells.","The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for SEQ ID NO: 8052-16102.The protein of the invention may also be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.","The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but into which modification are naturally provided or deliberately engineered.","For example, modifications in the peptide or DNA sequence can be made by those skilled in the art using known techniques.","Modifications of interest in the protein sequences may include the alteration, substitution, replacement, insertion or deletion of a selected amino acid residue in the coding sequence.","For example, one or more of the cysteine residues may be deleted or replaced with another amino acid to alter the conformation of the molecule.","Techniques for such alteration, substitution, replacement, insertion or deletion are well known to those skilled in the art (see, e.g., U.S. Pat.","No.","4,518,584).","Preferably, such alteration, substitution, replacement, insertion or deletion retains the desired activity of the protein.","Regions of the protein that are important for the protein function can be determined by various methods known in the art including the alanine-scanning method which involved systematic substitution of single or strings of amino acids with alanine, followed by testing the resulting alanine-containing variant for biological activity.","This type of analysis determines the importance of the substituted amino acid(s) in biological activity.","Regions of the protein that are important for protein function may be determined by the eMATRIX program.","Other fragments and derivatives of the sequences of proteins which would be expected to retain protein activity in whole or in part and are useful for screening or other immunological methodologies may also be easily made by those skilled in the art given the disclosures herein.","Such modifications are encompassed by the present invention.","The protein may also be produced by operably linking the isolated polynucleotide of the invention to suitable control sequences in one or more insect expression vectors, and employing an insect expression system.","Materials and methods for baculovirus/insect cell expression systems are commercially available in kit form from, e.g., Invitrogen, San Diego, Calif., U.S.A. (the MaxBat™ kit), and such methods are well known in the art, as described in Summers and Smith, Texas Agricultural Experiment Station Bulletin No.","1555 (1987), incorporated herein by reference.","As used herein, an insect cell capable of expressing a polynucleotide of the present invention is “transformed.” The protein of the invention may be prepared by culturing transformed host cells under culture conditions suitable to express the recombinant protein.","The resulting expressed protein may then be purified from such culture (i.e., from culture medium or cell extracts) using known purification processes, such as gel filtration and ion exchange chromatography.","The purification of the protein may also include an affinity column containing agents which will bind to the protein; one or more column steps over such affinity resins as concanavalin A-agarose, heparin-toyopearl™ or Cibacrom blue 3GA Sepharose™; one or more steps involving hydrophobic interaction chromatography using such resins as phenyl ether, butyl ether, or propyl ether; or immunoaffinity chromatography.","Alternatively, the protein of the invention may also be expressed in a form that will facilitate purification.","For example, it may be expressed as a fusion protein, such as those of maltose binding protein (MBP), glutathione-S-transferase (GST) or thioredoxin (TRX), or as a His-tag.","Kits for expression and purification of such fusion proteins are commercially available from New England BioLab (Beverly, Mass.","), Pharmacia (Piscataway, N.J.) and Invitrogen, respectively.","The protein can also be tagged with an epitope and subsequently purified by using a specific antibody directed to such epitope.","One such epitope (“FLAG®”) is commercially available from Kodak (New Haven, Conn.).","Finally, one or more reverse-phase high performance liquid chromatography (RP-HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, can be employed to further purify the protein.","Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a substantially homogeneous isolated recombinant protein.","The protein thus purified is substantially free of other mammalian proteins and is defined in accordance with the present invention as an “isolated protein.” The polypeptides of the invention include analogs (variants).","This embraces fragments, as well as peptides in which one or more amino acids has been deleted, inserted, or substituted.","Also, analogs of the polypeptides of the invention embrace fusions of the polypeptides or modifications of the polypeptides of the invention, wherein the polypeptide or analog is fused to another moiety or moieties, e.g., targeting moiety or another therapeutic agent.","Such analogs may exhibit improved properties such as activity and/or stability.","Examples of moieties which may be fused to the polypeptide or an analog include, for example, targeting moieties which provide for the delivery of polypeptide to pancreatic cells, e.g., antibodies to pancreatic cells, antibodies to immune cells such as T-cells, monocytes, dendritic cells, granulocytes, etc., as well as receptor and ligands expressed on pancreatic or immune cells.","Other moieties which may be fused to the polypeptide include therapeutic agents which are used for treatment, for example, immunosuppressive drugs such as cyclosporin, SK506, azathioprine, CD3 antibodies and steroids.","Also, polypeptides may be fused to immune modulators, and other cytokines such as alpha or beta interferon.","4.6.1 Determining Polypeptide and Polynucleotide Identity and Similarity Preferred identity and/or similarity are designed to give the largest match between the sequences tested.","Methods to determine identity and similarity are codified in computer programs including, but are not limited to, the GCG program package, including GAP (Devereux, J., et al., Nucleic Acids Research 12(1):387 (1984); Genetics Computer Group, University of Wisconsin, Madison, Wis.), BLASTP, BLASTN, BLASTX, FASTA (Altschul, S. F. et al., J. Molec.","Biol.","215:403-410 (1990), PSI-BLAST (Altschul S. F. et al., Nucleic Acids Res.","vol.","25, pp.","3389-3402, herein incorporated by reference), eMatrix software (Wu et al., J. Comp.","Biol., Vol.","6, pp.","219-235 (1999), herein incorporated by reference), eMotif software (Nevill-Manning et al, ISMB-97, Vol.","4, pp.","202-209, herein incorporated by reference), pFam software (Sonnhammer et al., Nucleic Acids Res., Vol.","26 (1), pp.","320-322 (1998), herein incorporated by reference) and the Kyte-Doolittle hydrophobocity prediction algorithm (J. Mol.","Biol, 157, pp.","105-31 (1982), incorporated herein by reference).","The BLAST programs are publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul, S., et al.","NCB NLM NIH Bethesda, Md.","20894; Altschul, S., et al., J. Mol.","Biol.","215:403-410 (1990).","4.7 Chimeric and Fusion Proteins The invention also provides chimeric or fusion proteins.","As used herein, a “chimeric protein” or “fusion protein” comprises a polypeptide of the invention operatively linked to another polypeptide.","Within a fusion protein the polypeptide according to the invention can correspond to all or a portion of a protein according to the invention.","In one embodiment, a fusion protein comprises at least one biologically active portion of a protein according to the invention.","In another embodiment, a fusion protein comprises at least two biologically active portions of a protein according to the invention.","Within the fusion protein, the term “operatively linked” is intended to indicate that the polypeptide according to the invention and the other polypeptide are fused in-frame to each other.","The polypeptide can be fused to the N-terminus or C-terminus.","For example, in one embodiment a fusion protein comprises a polypeptide according to the invention operably linked to the extracellular domain of a second protein.","In another embodiment, the fusion protein is a GST-fusion protein in which the polypeptide sequences of the invention are fused to the C-terminus of the GST (i.e., glutathione S-transferase) sequences.","In another embodiment, the fusion protein is an immunoglobulin fusion protein in which the polypeptide sequences according to the invention comprises one or more domains are fused to sequences derived from a member of the immunoglobulin protein family.","The immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a ligand and a protein of the invention on the surface of a cell, to thereby suppress signal transduction in vivo.","The immunoglobulin fusion proteins can be used to affect the bioavailability of a cognate ligand.","Inhibition of the ligand/protein interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, e,g., cancer as well as modulating (e.g., promoting or inhibiting) cell survival.","Moreover, the immunoglobulin fusion proteins of the invention can be used as immunogens to produce antibodies in a subject, to purify ligands, and in screening assays to identify molecules that inhibit the interaction of a polypeptide of the invention with a ligand.","A chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques.","For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation.","In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers.","Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, for example, Ausubel et al.","(eds.)","CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992).","Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide).","A nucleic acid encoding a polypeptide of the invention can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the protein of the invention.","4.8 Gene Therapy Mutations in the polynucleotides of the invention gene may result in loss of normal function of the encoded protein.","The invention thus provides gene therapy to restore normal activity of the polypeptides of the invention; or to treat disease states involving polypeptides of the invention.","Delivery of a functional gene encoding polypeptides of the invention to appropriate cells is effected ex vivo, in situ, or in vivo by use of vectors, and more particularly viral vectors (e.g., adenovirus, adeno-associated virus, or a retrovirus), or ex vivo by use of physical DNA transfer methods (e.g., liposomes or chemical treatments).","See, for example, Anderson, Nature, supplement to vol.","392, no.","6679, pp.","25-20 (1998).","For additional reviews of gene therapy technology see Friedmann, Science, 244: 1275-1281 (1989); Verma, Scientific American: 68-84 (1990); and Miller, Nature, 357: 455-460 (1992).","Introduction of any one of the nucleotides of the present invention or a gene encoding the polypeptides of the present invention can also be accomplished with extrachromosomal substrates (transient expression) or artificial chromosomes (stable expression).","Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells.","Treated cells can then be introduced in vivo for therapeutic purposes.","Alternatively, it is contemplated that in other human disease states, preventing the expression of or inhibiting the activity of polypeptides of the invention will be useful in treating the disease states.","It is contemplated that antisense therapy or gene therapy could be applied to negatively regulate the expression of polypeptides of the invention.","Other methods inhibiting expression of a protein include the introduction of antisense molecules to the nucleic acids of the present invention, their complements, or their translated RNA sequences, by methods known in the art.","Further, the polypeptides of the present invention can be inhibited by using targeted deletion methods, or the insertion of a negative regulatory element such as a silencer, which is tissue specific.","The present invention still further provides cells genetically engineered in vivo to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell.","These methods can be used to increase or decrease the expression of the polynucleotides of the present invention.","Knowledge of DNA sequences provided by the invention allows for modification of cells to permit, increase, or decrease, expression of endogenous polypeptide.","Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the protein at higher levels.","The heterologous promoter is inserted in such a manner that it is operatively linked to the desired protein encoding sequences.","See, for example, PCT International Publication No.","WO 94/12650, PCT International Publication No.","WO 92/20808, and PCT International Publication No.","WO 91/09955.It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA.","If linked to the desired protein coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.","In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination.","As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods.","Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences.","Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting.","These sequences include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.","The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene.","Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element.","Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements.","Here, the naturally occurring sequences are deleted and new sequences are added.","In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the cell genome.","The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker.","Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.","The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Pat.","No.","5,272,071 to Chappel; U.S. Pat.","No.","5,578,461 to Sherwin et al.","; International Application No.","PCT/US92/09627 (WO93/09222) by Selden et al.","; and International Application No.","PCT/US90/06436 (WO91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.","4.9 Transgenic Animals In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)].","Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals.","Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as “knockout” animals.","Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Pat.","No.","5,557,032, incorporated herein by reference.","Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states.","Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism.","Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Pat.","No.","5,489,743 and PCT Publication No.","WO94/28122, incorporated herein by reference.","Transgenic animals can be prepared wherein all or part of a promoter of the polynucleotides of the invention is either activated or inactivated to alter the level of expression of the polypeptides of the invention.","Inactivation can be carried out using homologous recombination methods described above.","Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression.","The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.","The polynucleotides of the present invention also make possible the development, through, e.g., homologous recombination or knock out strategies, of animals that fail to express polypeptides of the invention or that express a variant polypeptide.","Such animals are useful as models for studying the in vivo activities of polypeptide as well as for studying modulators of the polypeptides of the invention.","In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)].","Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals.","Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as “knockout” animals.","Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Pat.","No.","5,557,032, incorporated herein by reference.","Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states.","Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism.","Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Pat.","No.","5,489,743 and PCT Publication No.","WO94/28122, incorporated herein by reference.","Transgenic animals can be prepared wherein all or part of the polynucleotides of the invention promoter is either activated or inactivated to alter the level of expression of the polypeptides of the invention.","Inactivation can be carried out using homologous recombination methods described above.","Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression.","The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.","4.10 Uses and Biological Activity The polynucleotides and proteins of the present invention are expected to exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified herein.","Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA).","The mechanism underlying the particular condition or pathology will dictate whether the polypeptides of the invention, the polynucleotides of the invention or modulators (activators or inhibitors) thereof would be beneficial to the subject in need of treatment.","Thus, “therapeutic compositions of the invention” include compositions comprising isolated polynucleotides (including recombinant DNA molecules, cloned genes and degenerate variants thereof) or polypeptides of the invention (including full length protein, mature protein and truncations or domains thereof), or compounds and other substances that modulate the overall activity of the target gene products, either at the level of target gene/protein expression or target protein activity.","Such modulators include polypeptides, analogs, (variants), including fragments and fusion proteins, antibodies and other binding proteins; chemical compounds that directly or indirectly activate or inhibit the polypeptides of the invention (identified, e.g., via drug screening assays as described herein); antisense polynucleotides and polynucleotides suitable for triple helix formation; and in particular antibodies or other binding partners that specifically recognize one or more epitopes of the polypeptides of the invention.","The polypeptides of the present invention may likewise be involved in cellular activation or in one of the other physiological pathways described herein.","4.10.1 Research Uses and Utilities The polynucleotides provided by the present invention can be used by the research community for various purposes.","The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to “subtract-out” known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a “gene chip” or other support, including for examination of expression patterns; to raise anti-protein antibodies using DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response.","Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.","The polypeptides provided by the present invention can similarly be used in assays to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding polypeptide is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands.","Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.","Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products.","Methods for performing the uses listed above are well known to those skilled in the art.","References disclosing such methods include without limitation “Molecular Cloning: A Laboratory Manual”, 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E. F. Fritsch and T. Maniatis eds., 1989, and “Methods in Enzymology: Guide to Molecular Cloning Techniques”, Academic Press, Berger, S. L. and A. R. Kimmel eds., 1987.4.10.2 Nutritional Uses Polynucleotides and polypeptides of the present invention can also be used as nutritional sources or supplements.","Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate.","In such cases the polypeptide or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules.","In the case of microorganisms, the polypeptide or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.","4.10.3 Cytokine and Cell Proliferation/Differentiation Activity A polypeptide of the present invention may exhibit activity relating to cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or inhibiting) activity or may induce production of other cytokines in certain cell populations.","A polynucleotide of the invention can encode a polypeptide exhibiting such attributes.","Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity.","The activity of therapeutic compositions of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+(preB M+), 2E8, RB5, DA1, 123, T1165, HT2, CTLL2, TF-1, Mo7e, CMK, HUVEC, and Caco.","Therapeutic compositions of the invention can be used in the following: Assays for T-cell or thymocyte proliferation include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub.","Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol.","137:3494-3500, 1986; Bertagnolli et al., J. Immunol.","145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al., I. Immunol.","149:3778-3783, 1992; Bowman et al., I. Immunol.","152:1756-1761, 1994.Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T cell stimulation, Kruisbeek, A. M. and Shevach, E. M. In Current Protocols in Immunology.","J. E. e.a.","Coligan eds.","Vol 1 pp.","3.12.1-3.12.14, John Wiley and Sons, Toronto.","1994; and Measurement of mouse and human interleukin-γ, Schreiber, R. D. In Current Protocols in Immunology.","J. E. e.a.","Coligan eds.","Vol 1 pp.","6.8.1-6.8.8, John Wiley and Sons, Toronto.","1994.Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L. S. and Lipsky, P. E. In Current Protocols in Immunology.","J. E. e.a.","Coligan eds.","Vol 1 pp.","6.3.1-6.3.12, John Wiley and Sons, Toronto.","1991; deVries et al., J. Exp.","Med.","173:1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc.","Natl.","Acad.","Sci.","U.S.A. 80:2931-2938, 1983; Measurement of mouse and human interleukin 6-Nordan, R. In Current Protocols in Immunology.","J. E. Coligan eds.","Vol 1 pp.","6.6.1-6.6.5, John Wiley and Sons, Toronto.","1991; Smith et al., Proc.","Natl.","Aced.","Sci.","U.S.A. 83:1857-1861, 1986; Measurement of human Interleukin 11-Bennett, F., Giannotti, J., Clark, S. C. and Turner, K. J.","In Current Protocols in Immunology.","J. E. Coligan eds.","Vol 1 pp.","6.15.1 John Wiley and Sons, Toronto.","1991; Measurement of mouse and human Interleukin 9-Ciarletta, A., Giannotti, J., Clark, S. C. and Turner, K. J.","In Current Protocols in Immunology.","J. E. Coligan eds.","Vol 1 pp.","6.13.1, John Wiley and Sons, Toronto.","1991.Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W Strober, Pub.","Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in Humans); Weinberger et al., Proc.","Natl.","Acad.","Sci.","USA 77:6091-6095, 1980; Weinberger et al., Eur.","J. Immuni.","11:405-411, 1981; Takai et al., J. Immunol.","137:3494-3500, 1986; Takai et al., J. Immunol.","140:508-512, 1988.4.10.4 Stem Cell Growth Factor Activity A polypeptide of the present invention may exhibit stem cell growth factor activity and be involved in the proliferation, differentiation and survival of pluripotent and totipotent stem cells including primordial germ cells, embryonic stem cells, hematopoietic stem cells and/or germ line stem cells.","Administration of the polypeptide of the invention to stem cells in vivo or ex vivo is expected to maintain and expand cell populations in a totipotential or pluripotential state which would be useful for re-engineering damaged or diseased tissues, transplantation, manufacture of bio-pharmaceuticals and the development of bio-sensors.","The ability to produce large quantities of human cells has important working applications for the production of human proteins which currently must be obtained from non-human sources or donors, implantation of cells to treat diseases such as Parkinson's, Alzheimer's and other neurodegenerative diseases; tissues for grafting such as bone marrow, skin, cartilage, tendons, bone, muscle (including cardiac muscle), blood vessels, cornea, neural cells, gastrointestinal cells and others; and organs for transplantation such as kidney, liver, pancreas (including islet cells), heart and lung.","It is contemplated that multiple different exogenous growth factors and/or cytokines may be administered in combination with the polypeptide of the invention to achieve the desired effect, including any of the growth factors listed herein, other stem cell maintenance factors, and specifically including stem cell factor (SCF), leukemia inhibitory factor (LIF), Flt-3 ligand (Flt-3L), any of the interleukins, recombinant soluble IL-6 receptor fused to IL-6, macrophage inflammatory protein I-alpha (MIP-1-alpha), G-CSF, GM-CSF, thrombopoietin (TPO), platelet factor 4 (PF-4), platelet-derived growth factor (PDGF), neural growth factors and basic fibroblast growth factor (bFGF).","Since totipotent stem cells can give rise to virtually any mature cell type, expansion of these cells in culture will facilitate the production of large quantities of mature cells.","Techniques for culturing stem cells are known in the art and administration of polypeptides of the invention, optionally with other growth factors and/or cytokines, is expected to enhance the survival and proliferation of the stem cell populations.","This can be accomplished by direct administration of the polypeptide of the invention to the culture medium.","Alternatively, stroma cells transfected with a polynucleotide that encodes for the polypeptide of the invention can be used as a feeder layer for the stem cell populations in culture or in vivo.","Stromal support cells for feeder layers may include embryonic bone marrow fibroblasts, bone marrow stromal cells, fetal liver cells, or cultured embryonic fibroblasts (see U.S. Pat.","No.","5,690,926).","Stem cells themselves can be transfected with a polynucleotide of the invention to induce autocrine expression of the polypeptide of the invention.","This will allow for generation of undifferentiated totipotential/pluripotential stem cell lines that are useful as is or that can then be differentiated into the desired mature cell types.","These stable cell lines can also serve as a source of undifferentiated totipotential/pluripotential mRNA to create cDNA libraries and templates for polymerase chain reaction experiments.","These studies would allow for the isolation and identification of differentially expressed genes in stem cell populations that regulate stem cell proliferation and/or maintenance.","Expansion and maintenance of totipotent stem cell populations will be useful in the treatment of many pathological conditions.","For example, polypeptides of the present invention may be used to manipulate stem cells in culture to give rise to neuroepithelial cells that can be used to augment or replace cells damaged by illness, autoimmune disease, accidental damage or genetic disorders.","The polypeptide of the invention may be useful for inducing the proliferation of neural cells and for the regeneration of nerve and brain tissue, i.e.","for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders which involve degeneration, death or trauma to neural cells or nerve tissue.","In addition, the expanded stem cell populations can also be genetically altered for gene therapy purposes and to decrease host rejection of replacement tissues after grafting or implantation.","Expression of the polypeptide of the invention and its effect on stem cells can also be manipulated to achieve controlled differentiation of the stem cells into more differentiated cell types.","A broadly applicable method of obtaining pure populations of a specific differentiated cell type from undifferentiated stem cell populations involves the use of a cell-type specific promoter driving a selectable marker.","The selectable marker allows only cells of the desired type to survive.","For example, stem cells can be induced to differentiate into cardiomyocytes (Wobus et al., Differentiation, 48: 173-182, (1991); Klug et al., J. Clin.","Invest., 98(1): 216-224, (1998)) or skeletal muscle cells (Browder, L. W. In: Principles of Tissue Engineering eds.","Lanza et al., Academic Press (1997)).","Alternatively, directed differentiation of stem cells can be accomplished by culturing the stem cells in the presence of a differentiation factor such as retinoic acid and an antagonist of the polypeptide of the invention which would inhibit the effects of endogenous stem cell factor activity and allow differentiation to proceed.","In vitro cultures of stem cells can be used to determine if the polypeptide of the invention exhibits stem cell growth factor activity.","Stem cells are isolated from any one of various cell sources (including hematopoietic stem cells and embryonic stem cells) and cultured on a feeder layer, as described by Thompson et al.","Proc.","Natl.","Acad.","Sci, U.S.A., 92: 7844-7848 (1995), in the presence of the polypeptide of the invention alone or in combination with other growth factors or cytokines.","The ability of the polypeptide of the invention to induce stem cells proliferation is determined by colony formation on semi-solid support e.g.","as described by Bernstein et al., Blood, 77: 2316-2321 (1991).","4.10.5 Hematopoiesis Regulating Activity A polypeptide of the present invention may be involved in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell disorders.","Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g.","in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thrombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above-mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantation, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post irradiation/chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous)) as normal cells or genetically manipulated for gene therapy.","Therapeutic compositions of the invention can be used in the following: Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above.","Assays for embryonic stem cell differentiation (which will identify, among others, proteins that influence embryonic differentiation hematopoiesis) include, without limitation, those described in: Johansson et al.","Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993.Assays for stem cell survival and differentiation (which will identify, among others, proteins that regulate lympho-hematopoiesis) include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M. G. In Culture of Hematopoietic Cells.","R. I. Freshney, et al.","eds.","Vol pp.","265-268, Wiley-Liss, Inc., New York, N.Y. 1994; Hirayama et al., Proc.","Natl.","Acad.","Sci.","USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I. K. and Briddell, R. A.","In Culture of Hematopoietic Cells.","R. I. Freshney, et al.","eds.","Vol pp.","23-39, Wiley-Liss, Inc., New York, N.Y. 1994; Neben et al., Experimental Hematology 22:353-359, 1994; Cobblestone area forming cell assay, Ploemacher, R. E. In Culture of Hematopoietic Cells.","R. I. Freshney, et al.","eds.","Vol pp.","1-21, Wiley-Liss, Inc., New York, N.Y. 1994; Long term bone marrow cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells.","R. I. Freshney, et al.","eds.","Vol pp.","163-179, Wiley-Liss, Inc., New York, N.Y. 1994; Long term culture initiating cell assay, Sutherland, H. J.","In Culture of Hematopoietic Cells.","R. I. Freshney, et al.","eds.","Vol pp.","139-162, Wiley-Liss, Inc., New York, N.Y. 1994.4.10.6 Tissue Growth Activity A polypeptide of the present invention also may be involved in bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as in wound healing and tissue repair and replacement, and in healing of burns, incisions and ulcers.","A polypeptide of the present invention which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals.","Compositions of a polypeptide, antibody, binding partner, or other modulator of the invention may have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints.","De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.","A polypeptide of this invention may also be involved in attracting bone-forming cells, stimulating growth of bone-forming cells, or inducing differentiation of progenitors of bone-forming cells.","Treatment of osteoporosis, osteoarthritis, bone degenerative disorders, or periodontal disease, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.)","mediated by inflammatory processes may also be possible using the composition of the invention.","Another category of tissue regeneration activity that may involve the polypeptide of the present invention is tendon/ligament formation.","Induction of tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals.","Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue.","De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments.","The compositions of the present invention may provide environment to attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair.","The compositions of the invention may also be useful in the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects.","The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art.","The compositions of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e.","for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue.","More specifically, a composition may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome.","Further conditions that may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke.","Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a composition of the invention.","Compositions of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.","Compositions of the present invention may also be involved in the generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues.","Part of the desired effects may be by inhibition or modulation of fibrotic scarring may allow normal tissue to regenerate.","A polypeptide of the present invention may also exhibit angiogenic activity.","A composition of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage.","A composition of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.","Therapeutic compositions of the invention can be used in the following: Assays for tissue generation activity include, without limitation, those described in: International Patent Publication No.","WO95/16035 (bone, cartilage, tendon); International Patent Publication No.","WO95/05846 (nerve, neuronal); International Patent Publication No.","WO91/07491 (skin, endothelium).","Assays for wound healing activity include, without limitation, those described in: Winter, Epidermal Wound Healing, pps.","71-112 (Maibach, H. I. and Rovee, D. T., eds.","), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz J.","Invest.","Dermatol 71:382-84 (1978).","4.10.7 Immune Stimulating or Suppressing Activity A polypeptide of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein.","A polynucleotide of the invention can encode a polypeptide exhibiting such activities.","A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in regulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations.","These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders.","More specifically, infectious diseases causes by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpes viruses, mycobacteria, Leishmania spp., malaria spp.","and various fungal infections such as candidiasis.","Of course, in this regard, proteins of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., in the treatment of cancer.","include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease.","Such a protein (or antagonists thereof, including antibodies) of the present invention may also to be useful in the treatment of allergic reactions and conditions (e.g., anaphylaxis, serum sickness, drug reactions, food allergies, insect venom allergies, mastocytosis, allergic rhinitis, hypersensitivity pneumonitis, urticaria, angioedema, eczema, atopic dermatitis, allergic contact dermatitis, erythema multiforme, Stevens-Johnson syndrome, allergic conjunctivitis, atopic keratoconjunctivitis, venereal keratoconjunctivitis, giant papillary conjunctivitis and contact allergies), such as asthma (particularly allergic asthma) or other respiratory problems.","Other conditions, in which immune suppression is desired (including, for example, organ transplantation), may also be treatable using a protein (or antagonists thereof) of the present invention.","The therapeutic effects of the polypeptides or antagonists thereof on allergic reactions can be evaluated by in vivo animals models such as the cumulative contact enhancement test (Lastbom et al., Toxicology 125: 59-66, 1998), skin prick test (Hoffmann et al., Allergy 54: 446-54, 1999), guinea pig skin sensitization test (Vohr et al., Arch.","Toxocol.","73: 501-9), and murine local lymph node assay (Kimber et al., J. Toxicol.","Environ.","Health 53: 563-79).","Using the proteins of the invention it may also be possible to modulate immune responses, in a number of ways.","Down regulation may be in the form of inhibiting or blocking an immune response already in progress or may involve preventing the induction of an immune response.","The functions of activated T cells may be inhibited by suppressing T cell responses or by inducing specific tolerance in T cells, or both.","Immunosuppression of T cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent.","Tolerance, which involves inducing non-responsiveness or anergy in T cells, is distinguishable from immunosuppression in that it is generally antigen-specific and persists after exposure to the tolerizing agent has ceased.","Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.","Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as, for example, B7)), e.g., preventing high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD).","For example, blockage of T cell function should result in reduced tissue destruction in tissue transplantation.","Typically, in tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys the transplant.","The administration of a therapeutic composition of the invention may prevent cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant.","Moreover, a lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject.","Induction of long-term tolerance by B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents.","To achieve sufficient immunosuppression or tolerance in a subject, it may also be necessary to block the function of a combination of B lymphocyte antigens.","The efficacy of particular therapeutic compositions in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans.","Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc.","Natl.","Acad.","Sci USA, 89:11102-11105 (1992).","In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp.","846-847) can be used to determine the effect of therapeutic compositions of the invention on the development of that disease.","Blocking antigen function may also be therapeutically useful for treating autoimmune diseases.","Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self-tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases.","Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms.","Administration of reagents which block stimulation of T cells can be used to inhibit T cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process.","Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from the disease.","The efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases.","Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/lpr/lpr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp.","840-856).","Upregulation of an antigen function (e.g., a B lymphocyte antigen function), as a means of up regulating immune responses, may also be useful in therapy.","Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting an initial immune response.","For example, enhancing an immune response may be useful in cases of viral infection, including systemic viral diseases such as influenza, the common cold, and encephalitis.","Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro with viral antigen-pulsed APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and reintroducing the in vitro activated T cells into the patient.","Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the protein on their surface, and reintroduce the transfected cells into the patient.","The infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T cells in vivo.","A polypeptide of the present invention may provide the necessary stimulation signal to T cells to induce a T cell mediated immune response against the transfected tumor cells.","In addition, tumor cells which lack MHC class I or MHC class II molecules, or which fail to reexpress sufficient mounts of MHC class I or MHC class II molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I alpha chain protein and β2 microglobulin protein or an MHC class II alpha chain protein and an MHC class II beta chain protein to thereby express MHC class I or MHC class II proteins on the cell surface.","Expression of the appropriate class I or class II MHC in conjunction with a peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T cell mediated immune response against the transfected tumor cell.","Optionally, a gene encoding an antisense construct which blocks expression of an MHC class II associated protein, such as the invariant chain, can also be cotransfected with a DNA encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity.","Thus, the induction of a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject.","The activity of a protein of the invention may, among other means, be measured by the following methods: Suitable assays for thymocyte or splenocyte cytotoxicity include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub.","Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Herrmann et al., Proc.","Natl.","Acad.","Sci.","USA 78:2488-2492, 1981; Herrmann et al., J. Immunol.","128:1968-1974, 1982; Handa et al., J. Immunol.","135:1564-1572, 1985; Takai et al., I. Immunol.","137:3494-3500, 1986; Takai et al., J. Immunol.","140:508-512, 1988; Bowman et al., J. Virology 61:1992-1998; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Brown et al., J. Immunol.","153:3079-3092, 1994.Assays for T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Th1/Th2 profiles) include, without limitation, those described in: Maliszewski, J. Immunol.","144:3028-3033, 1990; and Assays for B cell function: In vitro antibody production, Mond, J. J. and Brunswick, M. In Current Protocols in Immunology.","J. E. e.a.","Coligan eds.","Vol 1 pp.","3.8.1-3.8.16, John Wiley and Sons, Toronto.","1994.Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly Th1 and CTL responses) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub.","Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol.","137:3494-3500, 1986; Takai et al., J. Immunol.","140:508-512, 1988; Bertagnolli et al., J. Immunol.","149:3778-3783, 1992.Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Guery et al., J. Immunol.","134:536-544, 1995; Inaba et al., Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al., Journal of Immunology 154:5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182:255-260, 1995; Nair et al., Journal of Virology 67:4062-4069, 1993; Huang et al., Science 264:961-965, 1994; Macatonia et al., Journal of Experimental Medicine 169:1255-1264, 1989; Bhardwaj et al., Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640, 1990.Assays for lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in: Darzynkiewicz et al., Cytometry 13:795-808, 1992; Gorczyca et al., Leukemia 7:659-670, 1993; Gorczyca et al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1991; Zacharchuk, Journal of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al., International Journal of Oncology 1:639-648, 1992.Assays for proteins that influence early steps of T-cell commitment and development include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular Immunology 155:111-122, 1994; Galy et al., Blood 85:2770-2778, 1995; Toki et al., Proc.","Nat.","Acad.","Sci.","USA 88:7548-7551, 1991.4.10.8 Activin/Inhibin Activity A polypeptide of the present invention may also exhibit activin- or inhibin-related activities.","A polynucleotide of the invention may encode a polypeptide exhibiting such characteristics.","Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH).","Thus, a polypeptide of the present invention, alone or in heterodimers with a member of the inhibin family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals.","Administration of sufficient amounts of other inhibins can induce infertility in these mammals.","Alternatively, the polypeptide of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin group, may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary.","See, for example, U.S. Pat.","No.","4,798,885.A polypeptide of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as, but not limited to, cows, sheep and pigs.","The activity of a polypeptide of the invention may, among other means, be measured by the following methods.","Assays for activin/inhibin activity include, without limitation, those described in: Vale et al., Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986; Vale et al., Nature 321:776-779, 1986; Mason et al., Nature 318:659-663, 1985; Forage et al., Proc.","Natl.","Acad.","Sci.","USA 83:3091-3095, 1986.4.10.9 Chemotactic/Chemokinetic Activity A polypeptide of the present invention may be involved in chemotactic or chemokinetic activity for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells.","A polynucleotide of the invention can encode a polypeptide exhibiting such attributes.","Chemotactic and chemokinetic receptor activation can be used to mobilize or attract a desired cell population to a desired site of action.","Chemotactic or chemokinetic compositions (e.g.","proteins, antibodies, binding partners, or modulators of the invention) provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections.","For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.","A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population.","Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells.","Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis.","Therapeutic compositions of the invention can be used in the following: Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population.","Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Marguiles, E. M. Shevach, W. Strober, Pub.","Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1-6.12.28; Taub et al.","J. Clin.","Invest.","95:1370-1376, 1995; Lind et al.","APMIS 103:140-146, 1995; Muller et al Eur.","J. Immunol.","25:1744-1748; Gruber et al.","J. of Immunol.","152:5860-5867, 1994; Johnston et al.","J. of Immunol.","153:1762-1768, 1994.4.10.10 Hemostatic and Thrombolytic Activity A polypeptide of the invention may also be involved in hemostatis or thrombolysis or thrombosis.","A polynucleotide of the invention can encode a polypeptide exhibiting such attributes.","Compositions may be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes.","A composition of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke).","Therapeutic compositions of the invention can be used in the following: Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin.","Pharmacol.","26:131-140, 1986; Burdick et al., Thrombosis Res.","45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467-474, 1988.4.10.11 Cancer Diagnosis and Therapy Polypeptides of the invention may be involved in cancer cell generation, proliferation or metastasis.","Detection of the presence or amount of polynucleotides or polypeptides of the invention may be useful for the diagnosis and/or prognosis of one or more types of cancer.","For example, the presence or increased expression of a polynucleotide/polypeptide of the invention may indicate a hereditary risk of cancer, a precancerous condition, or an ongoing malignancy.","Conversely, a defect in the gene or absence of the polypeptide may be associated with a cancer condition.","Identification of single nucleotide polymorphisms associated with cancer or a predisposition to cancer may also be useful for diagnosis or prognosis.","Cancer treatments promote tumor regression by inhibiting tumor cell proliferation, inhibiting angiogenesis (growth of new blood vessels that is necessary to support tumor growth) and/or prohibiting metastasis by reducing tumor cell motility or invasiveness.","Therapeutic compositions of the invention may be effective in adult and pediatric oncology including in solid phase tumors/malignancies, locally advanced tumors, human soft tissue sarcomas, metastatic cancer, including lymphatic metastases, blood cell malignancies including multiple myeloma, acute and chronic leukemias, and lymphomas, head and neck cancers including mouth cancer, larynx cancer and thyroid cancer, lung cancers including small cell carcinoma and non-small cell cancers, breast cancers including small cell carcinoma and ductal carcinoma, gastrointestinal cancers including esophageal cancer, stomach cancer, colon cancer, colorectal cancer and polyps associated with colorectal neoplasia, pancreatic cancers, liver cancer, urologic cancers including bladder cancer and prostate cancer, malignancies of the female genital tract including ovarian carcinoma, uterine (including endometrial) cancers, and solid tumor in the ovarian follicle, kidney cancers including renal cell carcinoma, brain cancers including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers including osteomas, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal cell carcinoma, hemangiopericytoma and Karposi's sarcoma.","Polypeptides, polynucleotides, or modulators of polypeptides of the invention (including inhibitors and stimulators of the biological activity of the polypeptide of the invention) may be administered to treat cancer.","Therapeutic compositions can be administered in therapeutically effective dosages alone or in combination with adjuvant cancer therapy such as surgery, chemotherapy, radiotherapy, thermotherapy, and laser therapy, and may provide a beneficial effect, e.g.","reducing tumor size, slowing rate of tumor growth, inhibiting metastasis, or otherwise improving overall clinical condition, without necessarily eradicating the cancer.","The composition can also be administered in therapeutically effective amounts as a portion of an anti-cancer cocktail.","An anticancer cocktail is a mixture of the polypeptide or modulator of the invention with one or more anti-cancer drugs in addition to a pharmaceutically acceptable carrier for delivery.","The use of anti-cancer cocktails as a cancer treatment is routine.","Anti-cancer drugs that are well known in the art and can be used as a treatment in combination with the polypeptide or modulator of the invention include: Actinomycin D, Aminoglutethimide, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin (cis-DDP), Cyclophosphamide, Cytarabine HCl (Cytosine arabinoside), Dacarbazine, Dactinomycin, Daunorubicin HCl, Doxorubicin HCl, Estramustine phosphate sodium, Etoposide (V16-213), Floxuridine, 5-Fluorouracil (5-Fu), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alpha-2a, Interferon Alpha-2b, Leuprolide acetate (LHRH-releasing factor analog), Lomustine, Mechlorethamine HCl (nitrogen mustard), Melphalan, Mercaptopurine, Mesna, Methotrexate (MTX), Mitomycin, Mitoxantrone HCl, Octreotide, Plicamycin, Procarbazine HCl, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Vincristine sulfate, Amsacrine, Azacitidine, Hexamethylmelamine, Interleukin-2, Mitoguazone, Pentostatin, Semustine, Teniposide, and Vindesine sulfate.","In addition, therapeutic compositions of the invention may be used for prophylactic treatment of cancer.","There are hereditary conditions and/or environmental situations (e.g.","exposure to carcinogens) known in the art that predispose an individual to developing cancers.","Under these circumstances, it may be beneficial to treat these individuals with therapeutically effective doses of the polypeptide of the invention to reduce the risk of developing cancers.","In vitro models can be used to determine the effective doses of the polypeptide of the invention as a potential cancer treatment.","These in vitro models include proliferation assays of cultured tumor cells, growth of cultured tumor cells in soft agar (see Freshney, (1987) Culture of Animal Cells: A Manual of Basic Technique, Wily-Liss, New York, N.Y. Ch 18 and Ch 21), tumor systems in nude mice as described in Giovanella et al., J. Natl.","Can.","Inst., 52: 921-30 (1974), mobility and invasive potential of tumor cells in Boyden Chamber assays as described in Pilkington et al., Anticancer Res., 17: 4107-9 (1997), and angiogenesis assays such as induction of vascularization of the chick chorioallantoic membrane or induction of vascular endothelial cell migration as described in Ribatta et al., Intl.","J. Dev.","Biol., 40: 1189-97 (1999) and Li et al., Clin.","Exp.","Metastasis, 17:423-9 (1999), respectively.","Suitable tumor cells lines are available, e.g.","from American Type Tissue Culture Collection catalogs.","4.10.12 Receptor/Ligand Activity A polypeptide of the present invention may also demonstrate activity as receptor, receptor ligand or inhibitor or agonist of receptor/ligand interactions.","A polynucleotide of the invention can encode a polypeptide exhibiting such characteristics.","Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selectins, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses.","Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.","A protein of the present invention (including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor/ligand interactions.","The activity of a polypeptide of the invention may, among other means, be measured by the following methods: Suitable assays for receptor-ligand activity include without limitation those described in: Current Protocols in Immunology; Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub.","Greene Publishing Associates and Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1-7.28.22), Takai et al., Proc.","Natl.","Acad.","Sci.","USA 84:6864-6868, 1987; Bierer et al., J. Exp.","Med.","168:1145-1156, 1988; Rosenstein et al., J. Exp.","Med.","169:149-160 1989; Stoltenborg et al., J. Immunol.","Methods 175:59-68, 1994; Stitt et al., Cell 80:661-670, 1995.By way of example, the polypeptides of the invention may be used as a receptor for a ligand(s) thereby transmitting the biological activity of that ligand(s).","Ligands may be identified through binding assays, affinity chromatography, dihybrid screening assays, BIAcore assays, gel overlay assays, or other methods known in the art.","Studies characterizing drugs or proteins as agonist or antagonist or partial agonists or a partial antagonist require the use of other proteins as competing ligands.","The polypeptides of the present invention or ligand(s) thereof may be labeled by being coupled to radioisotopes, colorimetric molecules or toxin molecules by conventional methods.","(“Guide to Protein Purification” Murray P. Deutscher (ed) Methods in Enzymology Vol.","182 (1990) Academic Press, Inc. San Diego).","Examples of radioisotopes include, but are not limited to, tritium and carbon-14.Examples of colorimetric molecules include, but are not limited to, fluorescent molecules such as fluorescamine, or rhodamine or other colorimetric molecules.","Examples of toxins include, but are not limited, to ricin.","4.10.13 Drug Screening This invention is particularly useful for screening chemical compounds by using the novel polypeptides or binding fragments thereof in any of a variety of drug screening techniques.","The polypeptides or fragments employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly.","One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or a fragment thereof.","Drugs are screened against such transformed cells in competitive binding assays.","Such cells, either in viable or fixed form, can be used for standard binding assays.","One may measure, for example, the formation of complexes between polypeptides of the invention or fragments and the agent being tested or examine the diminution in complex formation between the novel polypeptides and an appropriate cell line, which are well known in the art.","Sources for test compounds that may be screened for ability to bind to or modulate (i.e., increase or decrease) the activity of polypeptides of the invention include (1) inorganic and organic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of either random or mimetic peptides, oligonucleotides or organic molecules.","Chemical libraries may be readily synthesized or purchased from a number of commercial sources, and may include structural analogs of known compounds or compounds that are identified as “hits” or “leads” via natural product screening.","The sources of natural product libraries are microorganisms (including bacteria and fungi), animals, plants or other vegetation, or marine organisms, and libraries of mixtures for screening may be created by: (1) fermentation and extraction of broths from soil, plant or marine microorganisms or (2) extraction of the organisms themselves.","Natural product libraries include polyketides, non-ribosomal peptides, and (non-naturally occurring) variants thereof.","For a review, see Science 282:63-68 (1998).","Combinatorial libraries are composed of large numbers of peptides, oligonucleotides or organic compounds and can be readily prepared by traditional automated synthesis methods, PCR, cloning or proprietary synthetic methods.","Of particular interest are peptide and oligonucleotide combinatorial libraries.","Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries.","For a review of combinatorial chemistry and libraries created therefrom, see Myers, Curr.","Opin.","Biotechnol.","8:701-707 (1997).","For reviews and examples of peptidomimetic libraries, see Al-Obeidi et al., Mol.","Biotechnol, 9(3):205-23 (1998); Hruby et al., Curr Opin Chem Biol, 1 (1): 114-19 (1997); Dorner et al., Bioorg Med Chem, 4(5):709-15 (1996) (alkylated dipeptides).","Identification of modulators through use of the various libraries described herein permits modification of the candidate “hit” (or “lead”) to optimize the capacity of the “hit” to bind a polypeptide of the invention.","The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art.","In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.","The binding molecules thus identified may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells such as radioisotopes.","The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for a polypeptide of the invention.","Alternatively, the binding molecules may be complexed with imaging agents for targeting and imaging purposes.","4.10.14 Assay for Receptor Activity The invention also provides methods to detect specific binding of a polypeptide e.g.","a ligand or a receptor.","The art provides numerous assays particularly useful for identifying previously unknown binding partners for receptor polypeptides of the invention.","For example, expression cloning using mammalian or bacterial cells, or dihybrid screening assays can be used to identify polynucleotides encoding binding partners.","As another example, affinity chromatography with the appropriate immobilized polypeptide of the invention can be used to isolate polypeptides that recognize and bind polypeptides of the invention.","There are a number of different libraries used for the identification of compounds, and in particular small molecules, that modulate (i.e., increase or decrease) biological activity of a polypeptide of the invention.","Ligands for receptor polypeptides of the invention can also be identified by adding exogenous ligands, or cocktails of ligands to two cells populations that are genetically identical except for the expression of the receptor of the invention: one cell population expresses the receptor of the invention whereas the other does not.","The responses of the two cell populations to the addition of ligands(s) are then compared.","Alternatively, an expression library can be co-expressed with the polypeptide of the invention in cells and assayed for an autocrine response to identify potential ligand(s).","As still another example, BIAcore assays, gel overlay assays, or other methods known in the art can be used to identify binding partner polypeptides, including, (1) organic and inorganic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of random peptides, oligonucleotides or organic molecules.","The role of downstream intracellular signaling molecules in the signaling cascade of the polypeptide of the invention can be determined.","For example, a chimeric protein in which the cytoplasmic domain of the polypeptide of the invention is fused to the extracellular portion of a protein, whose ligand has been identified, is produced in a host cell.","The cell is then incubated with the ligand specific for the extracellular portion of the chimeric protein, thereby activating the chimeric receptor.","Known downstream proteins involved in intracellular signaling can then be assayed for expected modifications i.e.","phosphorylation.","Other methods known to those in the art can also be used to identify signaling molecules involved in receptor activity.","4.10.15 Anti-Inflammatory Activity Compositions of the present invention may also exhibit anti-inflammatory activity.","The anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response.","Compositions with such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation intimation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1.Compositions of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material.","Compositions of this invention may be utilized to prevent or treat conditions such as, but not limited to, sepsis, acute pancreatitis, endotoxin shock, cytokine induced shock, rheumatoid arthritis, chronic inflammatory arthritis, pancreatic cell damage from diabetes mellitus type 1, graft versus host disease, inflammatory bowel disease, inflammation associated with pulmonary disease, other autoimmune disease or inflammatory disease, an antiproliferative agent such as for acute or chronic mylegenous leukemia or in the prevention of premature labor secondary to intrauterine infections.","4.10.16 Leukemias Leukemias and related disorders may be treated or prevented by administration of a therapeutic that promotes or inhibits function of the polynucleotides and/or polypeptides of the invention.","Such leukemias and related disorders include but are not limited to acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia).","4.10.17 Nervous System Disorders Nervous system disorders, involving cell types which can be tested for efficacy of intervention with compounds that modulate the activity of the polynucleotides and/or polypeptides of the invention, and which can be treated upon thus observing an indication of therapeutic utility, include but are not limited to nervous system injuries, and diseases or disorders which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination.","Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the invention include but are not limited to the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems: (i) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries; (ii) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia; (iii) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, syphilis; (iv) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to degeneration associated with Parkinson's disease, Alzheimer's disease, Huntington's chorea, or amyotrophic lateral sclerosis; (v) lesions associated with nutritional diseases or disorders, in which a portion of the nervous system is destroyed or injured by a nutritional disorder or disorder of metabolism including but not limited to, vitamin B12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum), and alcoholic cerebellar degeneration; (vi) neurological lesions associated with systemic diseases including but not limited to diabetes (diabetic neuropathy, Bell's palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis; (vii) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and (viii) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including but not limited to multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.","Therapeutics which are useful according to the invention for treatment of a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons.","For example, and not by way of limitation, therapeutics which elicit any of the following effects may be useful according to the invention: (i) increased survival time of neurons in culture; (ii) increased sprouting of neurons in culture or in vivo; (iii) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or (iv) decreased symptoms of neuron dysfunction in vivo.","Such effects may be measured by any method known in the art.","In preferred, non-limiting embodiments, increased survival of neurons may be measured by the method set forth in Arakawa et al.","(1990, J. Neurosci.","10:3507-3515); increased sprouting of neurons may be detected by methods set forth in Pestronk et al.","(1980, Exp.","Neurol.","70:65-82) or Brown et al.","(1981, Ann.","Rev.","Neurosci.","4:17-42); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., depending on the molecule to be measured; and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.","In specific embodiments, motor neuron disorders that may be treated according to the invention include but are not limited to disorders such as infarction, infection, exposure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as disorders that selectively affect neurons such as amyotrophic lateral sclerosis, and including but not limited to progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, infantile and juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).","4.10.18 Other Activities A polypeptide of the invention may also exhibit one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or circadian cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, co-factors or other nutritional factors or component(s); effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects; promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic lineages; hormonal or endocrine activity; in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); immunoglobulin-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein.","4.10.19 Identification of Polymorphisms The demonstration of polymorphisms makes possible the identification of such polymorphisms in human subjects and the pharmacogenetic use of this information for diagnosis and treatment.","Such polymorphisms may be associated with, e.g., differential predisposition or susceptibility to various disease states (such as disorders involving inflammation or immune response) or a differential response to drug administration, and this genetic information can be used to tailor preventive or therapeutic treatment appropriately.","For example, the existence of a polymorphism associated with a predisposition to inflammation or autoimmune disease makes possible the diagnosis of this condition in humans by identifying the presence of the polymorphism.","Polymorphisms can be identified in a variety of ways known in the art which all generally involve obtaining a sample from a patient, analyzing DNA from the sample, optionally involving isolation or amplification of the DNA, and identifying the presence of the polymorphism in the DNA.","For example, PCR may be used to amplify an appropriate fragment of genomic DNA which may then be sequenced.","Alternatively, the DNA may be subjected to allele-specific oligonucleotide hybridization (in which appropriate oligonucleotides are hybridized to the DNA under conditions permitting detection of a single base mismatch) or to a single nucleotide extension assay (in which an oligonucleotide that hybridizes immediately adjacent to the position of the polymorphism is extended with one or more labeled nucleotides).","In addition, traditional restriction fragment length polymorphism analysis (using restriction enzymes that provide differential digestion of the genomic DNA depending on the presence or absence of the polymorphism) may be performed.","Arrays with nucleotide sequences of the present invention can be used to detect polymorphisms.","The array can comprise modified nucleotide sequences of the present invention in order to detect the nucleotide sequences of the present invention.","In the alternative, any one of the nucleotide sequences of the present invention can be placed on the array to detect changes from those sequences.","Alternatively a polymorphism resulting in a change in the amino acid sequence could also be detected by detecting a corresponding change in amino acid sequence of the protein, e.g., by an antibody specific to the variant sequence.","4.10.20 Arthritis and Inflammation The immunosuppressive effects of the compositions of the invention against rheumatoid arthritis are determined in an experimental animal model system.","The experimental model system is adjuvant induced arthritis in rats, and the protocol is described by J. Holoshitz, et at., 1983, Science, 219:56, or by B. Waksman et al., 1963, Int.","Arch.","Allergy Appl.","Immunol., 23:129.Induction of the disease can be caused by a single injection, generally intradermally, of a suspension of killed Mycobacterium tuberculosis in complete Freund's adjuvant (CFA).","The route of injection can vary, but rats may be injected at the base of the tail with an adjuvant mixture.","The polypeptide is administered in phosphate buffered solution (PBS) at a dose of about 1-5 mg/kg.","The control consists of administering PBS only.","The procedure for testing the effects of the test compound would consist of intradermally injecting killed Mycobacterium tuberculosis in CFA followed by immediately administering the test compound and subsequent treatment every other day until day 24.At 14, 15, 18, 20, 22, and 24 days after injection of Mycobacterium CFA, an overall arthritis score may be obtained as described by J. Holoskitz above.","An analysis of the data would reveal that the test compound would have a dramatic affect on the swelling of the joints as measured by a decrease of the arthritis score.","4.11 Therapeutic Methods The compositions (including polypeptide fragments, analogs, variants and antibodies or other binding partners or modulators including antisense polynucleotides) of the invention have numerous applications in a variety of therapeutic methods.","Examples of therapeutic applications include, but are not limited to, those exemplified herein.","4.11.1 Example One embodiment of the invention is the administration of an effective amount of the polypeptides or other composition of the invention to individuals affected by a disease or disorder that can be modulated by regulating the peptides of the invention.","While the mode of administration is not particularly important, parenteral administration is preferred.","An exemplary mode of administration is to deliver an intravenous bolus.","The dosage of the polypeptides or other composition of the invention will normally be determined by the prescribing physician.","It is to be expected that the dosage will vary according to the age, weight, condition and response of the individual patient.","Typically, the amount of polypeptide administered per dose will be in the range of about 0.01 μg/kg to 100 mg/kg of body weight, with the preferred dose being about 0.1 μg/kg to 10 mg/kg of patient body weight.","For parenteral administration, polypeptides of the invention will be formulated in an injectable form combined with a pharmaceutically acceptable parenteral vehicle.","Such vehicles are well known in the art and examples include water, saline, Ringer's solution, dextrose solution, and solutions consisting of small amounts of the human serum albumin.","The vehicle may contain minor amounts of additives that maintain the isotonicity and stability of the polypeptide or other active ingredient.","The preparation of such solutions is within the skill of the art.","4.12 Pharmaceutical Formulations and Routes of Administration A protein or other composition of the present invention (from whatever source derived, including without limitation from recombinant and non-recombinant sources and including antibodies and other binding partners of the polypeptides of the invention) may be administered to a patient in need, by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a variety of disorders.","Such a composition may optionally contain (in addition to protein or other active ingredient and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.","The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).","The characteristics of the carrier will depend on the route of administration.","The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNF0, TNF1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, and erythropoietin.","In further compositions, proteins of the invention may be combined with other agents beneficial to the treatment of the disease or disorder in question.","These agents include various growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), insulin-like growth factor (IGF), as well as cytokines described herein.","The pharmaceutical composition may further contain other agents which either enhance the activity of the protein or other active ingredient or complement its activity or use in treatment.","Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with protein or other active ingredient of the invention, or to minimize side effects.","Conversely, protein or other active ingredient of the present invention may be included in formulations of the particular clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent (such as IL-1Ra, IL-1 Hy1, IL-1 Hy2, anti-TNF, corticosteroids, immunosuppressive agents).","A protein of the present invention may be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins.","As a result, pharmaceutical compositions of the invention may comprise a protein of the invention in such multimeric or complexed form.","As an alternative to being included in a pharmaceutical composition of the invention including a first protein, a second protein or a therapeutic agent may be concurrently administered with the first protein (e.g., at the same time, or at differing times provided that therapeutic concentrations of the combination of agents is achieved at the treatment site).","Techniques for formulation and administration of the compounds of the instant application may be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition.","A therapeutically effective dose further refers to that amount of the compound sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.","When applied to an individual active ingredient, administered alone, a therapeutically effective dose refers to that ingredient alone.","When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.","In practicing the method of treatment or use of the present invention, a therapeutically effective amount of protein or other active ingredient of the present invention is administered to a mammal having a condition to be treated.","Protein or other active ingredient of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors.","When co-administered with one or more cytokines, lymphokines or other hematopoietic factors, protein or other active ingredient of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially.","If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein or other active ingredient of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.","4.12.1 Routes of Administration Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.","Administration of protein or other active ingredient of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection.","Intravenous administration to the patient is preferred.","Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a arthritic joints or in fibrotic tissue, often in a depot or sustained release formulation.","In order to prevent the scarring process frequently occurring as complication of glaucoma surgery, the compounds may be administered topically, for example, as eye drops.","Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a specific antibody, targeting, for example, arthritic or fibrotic tissue.","The liposomes will be targeted to and taken up selectively by the afflicted tissue.","The polypeptides of the invention are administered by any route that delivers an effective dosage to the desired site of action.","The determination of a suitable route of administration and an effective dosage for a particular indication is within the level of skill in the art.","Preferably for wound treatment, one administers the therapeutic compound directly to the site.","Suitable dosage ranges for the polypeptides of the invention can be extrapolated from these dosages or from similar studies in appropriate animal models.","Dosages can then be adjusted as necessary by the clinician to provide maximal therapeutic benefit.","4.12.2 Compositions/Formulations Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.","These pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.","Proper formulation is dependent upon the route of administration chosen.","When a therapeutically effective amount of protein or other active ingredient of the present invention is administered orally, protein or other active ingredient of the present invention will be in the form of a tablet, capsule, powder, solution or elixir.","When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant.","The tablet, capsule, and powder contain from about 5 to 95% protein or other active ingredient of the present invention, and preferably from about 25 to 90% protein or other active ingredient of the present invention.","When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added.","The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol.","When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of protein or other active ingredient of the present invention, and preferably from about 1 to 50% protein or other active-ingredient of the present invention.","When a therapeutically effective amount of protein or other active ingredient of the present invention is administered by intravenous, cutaneous or subcutaneous injection, protein or other active ingredient of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution.","The preparation of such parenterally acceptable protein or other active ingredient solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.","A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to protein or other active ingredient of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art.","The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.","For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.","For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation.","Such penetrants are generally known in the art.","For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.","Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.","Pharmaceutical preparations for oral use can be obtained from a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.","Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).","If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.","Dragee cores are provided with suitable coatings.","For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.","Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.","Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.","The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.","In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.","In addition, stabilizers may be added.","All formulations for oral administration should be in dosages suitable for such administration.","For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.","For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.","In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.","Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.","The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.","Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.","The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.","Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.","Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.","Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.","Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.","Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.","Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.","The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.","In addition to the formulations described previously, the compounds may also be formulated as a depot preparation.","Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.","Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.","A pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.","The co-solvent system may be the VPD co-solvent system.","VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.","The VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution.","This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.","Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.","Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g.","polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.","Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed.","Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.","Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.","Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.","Various types of sustained-release materials have been established and are well known by those skilled in the art.","Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.","Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein or other active ingredient stabilization may be employed.","The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients.","Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.","Many of the active ingredients of the invention may be provided as salts with pharmaceutically compatible counter ions.","Such pharmaceutically acceptable base addition salts are those salts which retain the biological effectiveness and properties of the free acids and which are obtained by reaction with inorganic or organic bases such as sodium hydroxide, magnesium hydroxide, ammonia, trialkylamine, dialkylamine, monoalkylamine, dibasic amino acids, sodium acetate, potassium benzoate, triethanol amine and the like.","The pharmaceutical composition of the invention may be in the form of a complex of the protein(s) or other active ingredient(s) of present invention along with protein or peptide antigens.","The protein and/or peptide antigen will deliver a stimulatory signal to both B and T lymphocytes.","B-lymphocytes will respond to antigen through their surface immunoglobulin receptor.","T lymphocytes will respond to antigen through the T cell receptor (TCR) following presentation of the antigen by MHC proteins.","MHC and structurally related proteins including those encoded by class I and class II MHC genes on host cells will serve to present the peptide antigen(s) to T lymphocytes.","The antigen components could also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules that can directly signal T cells.","Alternatively antibodies able to bind surface immunoglobulin and other molecules on B cells as well as antibodies able to bind the TCR and other molecules on T cells can be combined with the pharmaceutical composition of the invention.","The pharmaceutical composition of the invention may be in the form of a liposome in which protein of the present invention is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution.","Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithins, phospholipids, saponin, bile acids, and the like.","Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Pat.","Nos.","4,235,871; 4,501,728; 4,837,028; and 4,737,323, all of which are incorporated herein by reference.","The amount of protein or other active ingredient of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone.","Ultimately, the attending physician will decide the amount of protein or other active ingredient of the present invention with which to treat each individual patient.","Initially, the attending physician will administer low doses of protein or other active ingredient of the present invention and observe the patient's response.","Larger doses of protein or other active ingredient of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further.","It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 μg to about 100 mg (preferably about 0.1 μg to about 10 mg, more preferably about 0.1 μg to about 1 mg) of protein or other active ingredient of the present invention per kg body weight.","For compositions of the present invention which are useful for bone, cartilage, tendon or ligament regeneration, the therapeutic method includes administering the composition topically, systematically, or locally as an implant or device.","When administered, the therapeutic composition for use in this invention is, of course, in a pyrogen-free, physiologically acceptable form.","Further, the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of bone, cartilage or tissue damage.","Topical administration may be suitable for wound healing and tissue repair.","Therapeutically useful agents other than a protein or other active ingredient of the invention which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention.","Preferably for bone and/or cartilage formation, the composition would include a matrix capable of delivering the protein-containing or other active ingredient-containing composition to the site of bone and/or cartilage damage, providing a structure for the developing bone and cartilage and optimally capable of being resorbed into the body.","Such matrices may be formed of materials presently in use for other implanted medical applications.","The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties.","The particular application of the compositions will define the appropriate formulation.","Potential matrices for the compositions may be biodegradable and chemically defined calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, polyglycolic acid and polyanhydrides.","Other potential materials are biodegradable and biologically well-defined, such as bone or dermal collagen.","Further matrices are comprised of pure proteins or extracellular matrix components.","Other potential matrices are nonbiodegradable and chemically defined, such as sintered hydroxyapatite, bioglass, aluminates, or other ceramics.","Matrices may be comprised of combinations of any of the above-mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalcium phosphate.","The bioceramics may be altered in composition, such as in calcium-aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability.","Presently preferred is a 50:50 (mole weight) copolymer of lactic acid and glycolic acid in the form of porous particles having diameters ranging from 150 to 800 microns.","In some applications, it will be useful to utilize a sequestering agent, such as carboxymethyl cellulose or autologous blood clot, to prevent the protein compositions from disassociating from the matrix.","A preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC).","Other preferred sequestering agents include hyaluronic acid, sodium alginate, poly(ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and poly(vinyl alcohol).","The amount of sequestering agent useful herein is 0.5-20 wt %, preferably 1-10 wt % based on total formulation weight, which represents the amount necessary to prevent desorption of the protein from the polymer matrix and to provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the osteogenic activity of the progenitor cells.","In further compositions, proteins or other active ingredients of the invention may be combined with other agents beneficial to the treatment of the bone and/or cartilage defect, wound, or tissue in question.","These agents include various growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), and insulin-like growth factor (IGF).","The therapeutic compositions are also presently valuable for veterinary applications.","Particularly domestic animals and thoroughbred horses, in addition to humans, are desired patients for such treatment with proteins or other active ingredients of the present invention.","The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g., amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration and other clinical factors.","The dosage may vary with the type of matrix used in the reconstitution and with inclusion of other proteins in the pharmaceutical composition.","For example, the addition of other known growth factors, such as IGF I (insulin like growth factor I), to the final composition, may also effect the dosage.","Progress can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, X-rays, histomorphometric determinations and tetracycline labeling.","Polynucleotides of the present invention can also be used for gene therapy.","Such polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject.","Polynucleotides of the invention may also be administered by other known methods for introduction of nucleic acid into a cell or organism (including, without limitation, in the form of viral vectors or naked DNA).","Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells.","Treated cells can then be introduced in vivo for therapeutic purposes.","4.12.3 Effective Dosage Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose.","More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated.","Determination of the effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.","For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from appropriate in vitro assays.","For example, a dose can be formulated in animal models to achieve a circulating concentration range that can be used to more accurately determine useful doses in humans.","For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in cell culture (i.e., the concentration of A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient.","Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).","The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.Compounds which exhibit high therapeutic indices are preferred.","The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.","The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.","The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.","The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition.","See, e.g., Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.","1 p. 1.Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired effects, or minimal effective concentration (MEC).","The MEC will vary for each compound but can be estimated from in vitro data.","Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration.","However, HPLC assays or bioassays can be used to determine plasma concentrations.","Dosage intervals can also be determined using MEC value.","Compounds should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.","In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.","An exemplary dosage regimen for polypeptides or other compositions of the invention will be in the range of about 0.01 μg/kg to 100 mg/kg of body weight daily, with the preferred dose being about 0.1 μg/kg to 25 mg/kg of patient body weight daily, varying in adults and children.","Dosing may be once daily, or equivalent doses may be delivered at longer or shorter intervals.","The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's age and weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.","4.12.4 Packaging The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.","The pack may, for example, comprise metal or plastic foil, such as a blister pack.","The pack or dispenser device may be accompanied by instructions for administration.","Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.","4.13 Antibodies Also included in the invention are antibodies to proteins, or fragments of proteins of the invention.","The term “antibody” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen.","Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab′ and F(ab′)2 fragments, and an Fab expression library.","In general, an antibody molecule obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule.","Certain classes have subclasses as well, such as IgG1, IgG2, and others.","Furthermore, in humans, the light chain may be a kappa chain or a lambda chain.","Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.","An isolated related protein of the invention may be intended to serve as an antigen, or a portion or fragment thereof, and additionally can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation.","The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens.","An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of any of the full length proteins of the invention, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope.","Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues.","Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.","In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a region on the surface of the protein of the invention, e.g., a hydrophilic region.","A hydrophobicity analysis of the human related protein sequence will indicate which regions of a related protein are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production.","As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation.","See, e.g., Hopp and Woods, 1981, Proc.","Nat.","Acad.","Sci USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mol.","Biol.","157: 105-142, each of which is incorporated herein by reference in its entirety.","Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.","A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.","Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., incorporated herein by reference).","Some of these antibodies are discussed below.","5.13.1 Polyclonal Antibodies For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing.","An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein.","Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized.","Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor.","The preparation can further include an adjuvant.","Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.","), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents.","Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).","The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum.","Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography.","Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia Pa., Vol.","14, No.","8 (Apr.","17, 2000), pp.","25-28).","5.13.2 Monoclonal Antibodies The term “monoclonal antibody” (MAb) or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product.","In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population.","MAbs thus contain an antigen-binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.","Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975).","In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent.","Alternatively, the lymphocytes can be immunized in vitro.","The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof.","Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired.","The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp.","59-103).","Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin.","Usually, rat or mouse myeloma cell lines are employed.","The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.","For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.","Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium.","More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, Calif. and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J.","Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp.","51-63).","The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen.","Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).","Such techniques and assays are known in the art.","The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal.","Biochem., 107:220 (1980).","Preferably, antibodies having a high degree of specificity and a high binding affinity for the target antigen are isolated.","After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods.","Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium.","Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.","The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.","The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Pat.","No.","4,816,567.DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies).","The hybridoma cells of the invention serve as a preferred source of such DNA.","Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.","The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Pat.","No.","4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide.","Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.","5.13.2 Humanized Antibodies The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies.","These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin.","Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin.","Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody.","(See also U.S. Pat.","No.","5,225,539.)","In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.","Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.","In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence.","The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr.","Op.","Struct.","Biol., 2:593-596 (1992)).","5.133 Human Antibodies Fully human antibodies relate to antibody molecules in which essentially the entire sequences of both the light chain and the heavy chain, including the CDRs, arise from human genes.","Such antibodies are termed “human antibodies”, or “fully human antibodies” herein.","Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp.","77-96).","Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983.Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp.","77-96).","In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol.","Biol., 227:381 (1991); Marks et al., J. Mol.","Biol., 222:581 (1991)).","Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated.","Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.","This approach is described, for example, in U.S. Pat.","Nos.","5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et at.","(Bio/Technology 10, 779-783 (1992)); Lonberg et al.","(Nature 368 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al, (Nature Biotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern.","Rev.","Immunol.","13 65-93 (1995)).","Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen.","(See PCT publication WO94/02602).","The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome.","The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments.","An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications.","The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096.This animal produces B cells which secrete fully human immunoglobulins.","The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies.","Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.","An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Pat.","No.","5,939,598.It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.","A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Pat.","No.","5,916,771.It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell.","The hybrid cell expresses an antibody containing the heavy chain and the light chain.","In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.5.13.4 Fab Fragments and Single Chain Antibodies According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Pat.","No.","4,946,778).","In addition, methods can be adapted for the construction of Fab expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof.","Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(ab′)2 fragment produced by pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F(ab′)2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) Fv fragments.","5.13.5 Bispecific Antibodies Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens.","In the present case, one of the binding specificities is for an antigenic protein of the invention.","The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.","Methods for making bispecific antibodies are known in the art.","Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)).","Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure.","The purification of the correct molecule is usually accomplished by affinity chromatography steps.","Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., 1991 EMBO J., 10:3655-3659.Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences.","The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions.","It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions.","DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism.","For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).","According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture.","The preferred interface comprises at least a part of the CH3 region of an antibody constant domain.","In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g tyrosine or tryptophan).","Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g.","alanine or threonine).","This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.","Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g.","F(ab′)2 bispecific antibodies).","Techniques for generating bispecific antibodies from antibody fragments have been described in the literature.","For example, bispecific antibodies can be prepared using chemical linkage.","Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)2 fragments.","These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation.","The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives.","One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody.","The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.","Additionally, Fab′ fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies.","Shalaby et al., J. Exp.","Med.","175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab′)2 molecule.","Each Fab′ fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody.","The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.","Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described.","For example, bispecific antibodies have been produced using leucine zippers.","Kostelny et al., J. Immunol.","148(5):1547-1553 (1992).","The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion.","The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers.","This method can also be utilized for the production of antibody homodimers.","The “diabody” technology described by Hollinger et al., Proc.","Natl.","Acad.","Sci.","USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments.","The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain.","Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites.","Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported.","See, Gruber et al., J. Immunol.","152:5368 (1994).","Antibodies with more than two valencies are contemplated.","For example, trispecific antibodies can be prepared.","Tutt et al., J. Immunol.","147:60 (1991).","Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention.","Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g.","CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen.","Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen.","These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA.","Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).","5.13.6 Heteroconjugate Antibodies Heteroconjugate antibodies are also within the scope of the present invention.","Heteroconjugate antibodies are composed of two covalently joined antibodies.","Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat.","No.","4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089).","It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents.","For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond.","Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat.","No.","4,676,980.5.13.7 Effector Function Engineering It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer.","For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region.","The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC).","See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J.","Immunol., 148: 2918-2922 (1992).","Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al.","Cancer Research, 53: 2560-2565 (1993).","Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities.","See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).","5.13.8 Immunoconjugates The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).","Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above.","Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.","A variety of radionuclides are available for the production of radioconjugated antibodies.","Examples include 212Bi, 131I, 131In, 90Y, and 186Re.","Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene).","For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987).","Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody.","See WO94/1 1026.In another embodiment, the antibody can be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) that is in turn conjugated to a cytotoxic agent.","4.14 Computer Readable Sequences In one application of this embodiment, a nucleotide sequence of the present invention can be recorded on computer readable media.","As used herein, “computer readable media” refers to any medium which can be read and accessed directly by a computer.","Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media.","A skilled artisan can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising computer readable medium having recorded thereon a nucleotide sequence of the present invention.","As used herein, “recorded” refers to a process for storing information on computer readable medium.","A skilled artisan can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the nucleotide sequence information of the present invention.","A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon a nucleotide sequence of the present invention.","The choice of the data storage structure will generally be based on the means chosen to access the stored information.","In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium.","The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and Microsoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like.","A skilled artisan can readily adapt any number of data processor structuring formats (e.g.","text file or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention.","By providing any of the nucleotide sequences SEQ ID NO: 1-8051 or a representative fragment thereof; or a nucleotide sequence at least 95% identical to any of the nucleotide sequences of SEQ ID NO: 1-8051 in computer readable form, a skilled artisan can routinely access the sequence information for a variety of purposes.","Computer software is publicly available which allows a skilled artisan to access sequence information provided in a computer readable medium.","The examples which follow demonstrate how software which implements the BLAST (Altschul et al., J. Mol.","Biol.","215:403-410 (1990)) and BLAZE (Brutlag et al., Comp.","Chem.","17:203-207 (1993)) search algorithms on a Sybase system is used to identify open reading frames (ORFs) within a nucleic acid sequence.","Such ORFs may be protein encoding fragments and may be useful in producing commercially important proteins such as enzymes used in fermentation reactions and in the production of commercially useful metabolites.","As used herein, “a computer-based system” refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention.","The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means.","A skilled artisan can readily appreciate that any one of the currently available computer-based systems are suitable for use in the present invention.","As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein a nucleotide sequence of the present invention and the necessary hardware means and software means for supporting and implementing a search means.","As used herein, “data storage means” refers to memory which can store nucleotide sequence information of the present invention, or a memory access means which can access manufactures having recorded thereon the nucleotide sequence information of the present invention.","As used herein, “search means” refers to one or more programs which are implemented on the computer-based system to compare a target sequence or target structural motif with the sequence information stored within the data storage means.","Search means are used to identify fragments or regions of a known sequence which match a particular target sequence or target motif.","A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention.","Examples of such software includes, but is not limited to, Smith-Waterman, MacPattern (EMBL), BLASTN and BLASTA (NPOLYPEPTIDEIA).","A skilled artisan can readily recognize that any one of the available algorithms or implementing software packages for conducting homology searches can be adapted for use in the present computer-based systems.","As used herein, a “target sequence” can be any nucleic acid or amino acid sequence of six or more nucleotides or two or more amino acids.","A skilled artisan can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database.","The most preferred sequence length of a target sequence is from about 10 to 300 amino acids, more preferably from about 30 to 100 nucleotide residues.","However, it is well recognized that searches for commercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.","As used herein, “a target structural motif,” or “target motif,” refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration which is formed upon the folding of the target motif.","There are a variety of target motifs known in the art.","Protein target motifs include, but are not limited to, enzyme active sites and signal sequences.","Nucleic acid target motifs include, but are not limited to, promoter sequences, hairpin structures and inducible expression elements (protein binding sequences).","4.15 Triple Helix Formation In addition, the fragments of the present invention, as broadly described, can be used to control gene expression through triple helix formation or antisense DNA or RNA, both of which methods are based on the binding of a polynucleotide sequence to DNA or RNA.","Polynucleotides suitable for use in these methods are preferably 20 to 40 bases in length and are designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl.","Acids Res.","6:3073 (1979); Cooney et al., Science 15241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Olmno, J. Neurochem.","56:560, (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)).","Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide.","Both techniques have been demonstrated to be effective in model systems.","Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide.","4.16 Diagnostic Assays and Kits The present invention further provides methods to identify the presence or expression of one of the ORFs of the present invention, or homolog thereof, in a test sample, using a nucleic acid probe or antibodies of the present invention, optionally conjugated or otherwise associated with a suitable label.","In general, methods for detecting a polynucleotide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polynucleotide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polynucleotide of the invention is detected in the sample.","Such methods can also comprise contacting a sample under stringent hybridization conditions with nucleic acid primers that anneal to a polynucleotide of the invention under such conditions, and amplifying annealed polynucleotides, so that if a polynucleotide is amplified, a polynucleotide of the invention is detected in the sample.","In general, methods for detecting a polypeptide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polypeptide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polypeptide of the invention is detected in the sample.","In detail, such methods comprise incubating a test sample with one or more of the antibodies or one or more of the nucleic acid probes of the present invention and assaying for binding of the nucleic acid probes or antibodies to components within the test sample.","Conditions for incubating a nucleic acid probe or antibody with a test sample vary.","Incubation conditions depend on the format employed in the assay, the detection methods employed, and the type and nature of the nucleic acid probe or antibody used in the assay.","One skilled in the art will recognize that any one of the commonly available hybridization, amplification or immunological assay formats can readily be adapted to employ the nucleic acid probes or antibodies of the present invention.","Examples of such assays can be found in Chard, T., An Introduction to Radioimmunoassay and Related Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986); Bullock, G. R. et al., Techniques in Immunocytochemistry, Academic Press, Orlando, Fla. Vol.","1 (1982), Vol.","2 (1983), Vol.","3 (1985); Tijssen, P., Practice and Theory of immunoassays: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1985).","The test samples of the present invention include cells, protein or membrane extracts of cells, or biological fluids such as sputum, blood, serum, plasma, or urine.","The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed.","Methods for preparing protein extracts or membrane extracts of cells are well known in the art and can be readily be adapted in order to obtain a sample which is compatible with the system utilized.","In another embodiment of the present invention, kits are provided which contain the necessary reagents to carry out the assays of the present invention.","Specifically, the invention provides a compartment kit to receive, in close confinement, one or more containers which comprises: (a) a first container comprising one of the probes or antibodies of the present invention; and (b) one or more other containers comprising one or more of the following: wash reagents, reagents capable of detecting presence of a bound probe or antibody.","In detail, a compartment kit includes any kit in which reagents are contained in separate containers.","Such containers include small glass containers, plastic containers or strips of plastic or paper.","Such containers allows one to efficiently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another.","Such containers will include a container which will accept the test sample, a container which contains the antibodies used in the assay, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.","), and containers which contain the reagents used to detect the bound antibody or probe.","Types of detection reagents include labeled nucleic acid probes, labeled secondary antibodies, or in the alternative, if the primary antibody is labeled, the enzymatic, or antibody binding reagents which are capable of reacting with the labeled antibody.","One skilled in the art will readily recognize that the disclosed probes and antibodies of the present invention can be readily incorporated into one of the established kit formats which are well known in the art.","4.17 Medical Imaging The novel polypeptides and binding partners of the invention are useful in medical imaging of sites expressing the molecules of the invention (e.g., where the polypeptide of the invention is involved in the immune response, for imaging sites of inflammation or infection).","See, e.g., Kunkel et al., U.S. Pat.","No.","5,413,778.Such methods involve chemical attachment of a labeling or imaging agent, administration of the labeled polypeptide to a subject in a pharmaceutically acceptable carrier, and imaging the labeled polypeptide in vivo at the target site.","4.18 Screening Assays Using the isolated proteins and polynucleotides of the invention, the present invention further provides methods of obtaining and identifying agents which bind to a polypeptide encoded by an ORF corresponding to any of the nucleotide sequences set forth in SEQ ID NO: 1-8051, or bind to a specific domain of the polypeptide encoded by the nucleic acid.","In detail, said method comprises the steps of: (a) contacting an agent with an isolated protein encoded by an ORF of the present invention, or nucleic acid of the invention; and (b) determining whether the agent binds to said protein or said nucleic acid.","In general, therefore, such methods for identifying compounds that bind to a polynucleotide of the invention can comprise contacting a compound with a polynucleotide of the invention for a time sufficient to form a polynucleotide/compound complex, and detecting the complex, so that if a polynucleotide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.","Likewise, in general, therefore, such methods for identifying compounds that bind to a polypeptide of the invention can comprise contacting a compound with a polypeptide of the invention for a time sufficient to form a polypeptide/compound complex, and detecting the complex, so that if a polypeptide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.","Methods for identifying compounds that bind to a polypeptide of the invention can also comprise contacting a compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a receptor gene sequence in the cell, and detecting the complex by detecting reporter gene sequence expression, so that if a polypeptide/compound complex is detected, a compound that binds a polypeptide of the invention is identified.","Compounds identified via such methods can include compounds which modulate the activity of a polypeptide of the invention (that is, increase or decrease its activity, relative to activity observed in the absence of the compound).","Alternatively, compounds identified via such methods can include compounds which modulate the expression of a polynucleotide of the invention (that is, increase or decrease expression relative to expression levels observed in the absence of the compound).","Compounds, such as compounds identified via the methods of the invention, can be tested using standard assays well known to those of skill in the art for their ability to modulate activity/expression.","The agents screened in the above assay can be, but are not limited to, peptides, carbohydrates, vitamin derivatives, or other pharmaceutical agents.","The agents can be selected and screened at random or rationally selected or designed using protein modeling techniques.","For random screening, agents such as peptides, carbohydrates, pharmaceutical agents and the like are selected at random and are assayed for their ability to bind to the protein encoded by the ORF of the present invention.","Alternatively, agents may be rationally selected or designed.","As used herein, an agent is said to be “rationally selected or designed” when the agent is chosen based on the configuration of the particular protein.","For example, one skilled in the art can readily adapt currently available procedures to generate peptides, pharmaceutical agents and the like, capable of binding to a specific peptide sequence, in order to generate rationally designed antipeptide peptides, for example see Hurby et al., Application of Synthetic Peptides: Antisense Peptides,” In Synthetic Peptides, A User's Guide, W.H.","Freeman, NY (1992), pp.","289-307, and Kaspczak et al., Biochemistry 28:9230-8 (1989), or pharmaceutical agents, or the like.","In addition to the foregoing, one class of agents of the present invention, as broadly described, can be used to control gene expression through binding to one of the ORFs or EMFs of the present invention.","As described above, such agents can be randomly screened or rationally designed/selected.","Targeting the ORF or EMF allows a skilled artisan to design sequence specific or element specific agents, modulating the expression of either a single ORF or multiple ORFs which rely on the same EMF for expression control.","One class of DNA binding agents are agents which contain base residues which hybridize or form a triple helix formation by binding to DNA or RNA.","Such agents can be based on the classic phosphodiester, ribonucleic acid backbone, or can be a variety of sulfhydryl or polymeric derivatives which have base attachment capacity.","Agents suitable for use in these methods preferably contain 20 to 40 bases and are designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl.","Acids Res.","6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Okano, J. Neurochem.","56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)).","Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide.","Both techniques have been demonstrated to be effective in model systems.","Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide and other DNA binding agents.","Agents that bind to a protein encoded by one of the ORFs of the present invention can be used as a diagnostic agent.","Agents which bind to a protein encoded by one of the ORFs of the present invention can be formulated using known techniques to generate a pharmaceutical composition.","4.19 Use of Nucleic Acids as Probes Another aspect of the subject invention is to provide for polypeptide-specific nucleic acid hybridization probes capable of hybridizing with naturally occurring nucleotide sequences.","The hybridization probes of the subject invention may be derived from any of the nucleotide sequences SEQ ID NO: 1-8051.Because the corresponding gene is only expressed in a limited number of tissues, a hybridization probe derived from of any of the nucleotide sequences SEQ ID NO: 1-8051 can be used as an indicator of the presence of RNA of cell type of such a tissue in a sample.","Any suitable hybridization technique can be employed, such as, for example, in situ hybridization.","PCR as described in U.S. Pat.","Nos.","4,683,195 and 4,965,188 provides additional uses for oligonucleotides based upon the nucleotide sequences.","Such probes used in PCR may be of recombinant origin, may be chemically synthesized, or a mixture of both.","The probe will comprise a discrete nucleotide sequence for the detection of identical sequences or a degenerate pool of possible sequences for identification of closely related genomic sequences.","Other means for producing specific hybridization probes for nucleic acids include the cloning of nucleic acid sequences into vectors for the production of mRNA probes.","Such vectors are known in the art and are commercially available and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA polymerase as T7 or SP6 RNA polymerase and the appropriate radioactively labeled nucleotides.","The nucleotide sequences may be used to construct hybridization probes for mapping their respective genomic sequences.","The nucleotide sequence provided herein may be mapped to a chromosome or specific regions of a chromosome using well known genetic and/or chromosomal mapping techniques.","These techniques include in situ hybridization, linkage analysis against known chromosomal markers, hybridization screening with libraries or flow-sorted chromosomal preparations specific to known chromosomes, and the like.","The technique of fluorescent in situ hybridization of chromosome spreads has been described, among other places, in Verma et al (1988) Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York N.Y. Fluorescent in situ hybridization of chromosomal preparations and other physical chromosome mapping techniques may be correlated with additional genetic map data.","Examples of genetic map data can be found in the 1994 Genome Issue of Science (265:1981 f).","Correlation between the location of a nucleic acid on a physical chromosomal map and a specific disease (or predisposition to a specific disease) may help delimit the region of DNA associated with that genetic disease.","The nucleotide sequences of the subject invention may be used to detect differences in gene sequences between normal, carrier or affected individuals.","4.20 Preparation of Support Bound Oligonucleotides Oligonucleotides, i.e., small nucleic acid segments, may be readily prepared by, for example, directly synthesizing the oligonucleotide by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer.","Support bound oligonucleotides may be prepared by any of the methods known to those of skill in the art using any suitable support such as glass, polystyrene or Teflon.","One strategy is to precisely spot oligonucleotides synthesized by standard synthesizers.","Immobilization can be achieved using passive adsorption (Inouye & Hondo, (1990) J. Clin.","Microbiol.","28 (6) 1469-72); using UV light (Nagata et al., 1985; Dahlen et al., 1987; Morrissey & Collins, (1989) Mol.","Cell Probes 3 (2) 189-207) or by covalent binding of base modified DNA (Keller et al., 1988; 1989); all references being specifically incorporated herein.","Another strategy that may be employed is the use of the strong biotin-streptavidin interaction as a linker.","For example, Broude et al.","(1994) Proc.","Natl.","Acad.","Sci.","USA 91 (8) 3072-6, describe the use of biotinylated probes, although these are duplex probes, that are immobilized on streptavidin-coated magnetic beads.","Streptavidin-coated beads may be purchased from Dynal, Oslo.","Of course, this same linking chemistry is applicable to coating any surface with streptavidin.","Biotinylated probes may be purchased from various sources, such as, e.g., Operon Technologies (Alameda, Calif.).","Nunc Laboratories (Naperville, Ill.) is also selling suitable material that could be used.","Nunc Laboratories have developed a method by which DNA can be covalently bound to the microwell surface termed Covalink NH.","CovaLink NH is a polystyrene surface grafted with secondary amino groups (>NH) that serve as bridge-heads for further covalent coupling.","CovaLink Modules may be purchased from Nunc Laboratories.","DNA molecules may be bound to CovaLink exclusively at the 5′-end by a phosphoramidate bond, allowing immobilization of more than 1 pmol of DNA (Rasmussen et al., (1991) Anal.","Biochem.","198 (1) 13842).","The use of CovaLink NH strips for covalent binding of DNA molecules at the 5′-end has been described (Rasmussen et al., (1991).","In this technology, a phosphoramidate bond is employed (Chu et al., (1983) Nucleic Acids Res.","11 (8) 6513-29).","This is beneficial as immobilization using only a single covalent bond is preferred.","The phosphoramidate bond joins the DNA to the CovaLink NH secondary amino groups that are positioned at the end of spacer arms covalently grafted onto the polystyrene surface through a 2 nm long spacer arm.","To link an oligonucleotide to CovaLink NH via an phosphoramidate bond, the oligonucleotide terminus must have a 5′-end phosphate group.","It is, perhaps, even possible for biotin to be covalently bound to CovaLink and then streptavidin used to bind the probes.","More specifically, the linkage method includes dissolving DNA in water (7.5 ng/ul) and denaturing for 10 min.","at 95° C. and cooling on ice for 10 min.","Ice-cold 0.1 M 1-methylimidazole, pH 7.0 (1-MeIm7), is then added to a final concentration of 10 mM 1-MeIM7.A ss DNA solution is then dispensed into CovaLink NH strips (75 ul/well) standing on ice.","Carbodiimide 0.2 M 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), dissolved in 10 mM 1-MeIM7, is made fresh and 25 ul added per well.","The strips are incubated for 5 hours at 50° C. After incubation the strips are washed using, e.g., Nunc-Immuno Wash; first the wells are washed 3 times, then they are soaked with washing solution for 5 min., and finally they are washed 3 times (where in the washing solution is 0.4 N NaOH, 0.25% SDS heated to 50° C.).","It is contemplated that a further suitable method for use with the present invention is that described in PCT Patent Application WO 90/03382 (Southern & Maskos), incorporated herein by reference.","This method of preparing an oligonucleotide bound to a support involves attaching a nucleoside 3′-reagent through the phosphate group by a covalent phosphodiester link to aliphatic hydroxyl groups carried by the support.","The oligonucleotide is then synthesized on the supported nucleoside and protecting groups removed from the synthetic oligonucleotide chain under standard conditions that do not cleave the oligonucleotide from the support.","Suitable reagents include nucleoside phosphoramidite and nucleoside hydrogen phosphorate.","An on-chip strategy for the preparation of DNA probe for the preparation of DNA probe arrays may be employed.","For example, addressable laser-activated photodeprotection may be Fodor et al.","(1991) Science 251 (4995) 767-73, incorporated herein by reference.","Probes may also be immobilized on nylon supports as described by Van Ness et at (1991) Nucleic Acids Res.","19 (12) 3345-50; or linked to Teflon using the method of Duncan & Cavalier (1988) Anal.","Biochem.","169 (1) 104-8; all references being specifically incorporated herein.","To link an oligonucleotide to a nylon support, as described by Van Ness et al.","(1991), requires activation of the nylon surface via alkylation and selective activation of the 5′-amine of oligonucleotides with cyanuric chloride.","One particular way to prepare support bound oligonucleotides is to utilize the light-generated synthesis described by Pease et al., (1994) PNAS USA 91 (11) 5022-6, incorporated herein by reference).","These authors used current photolithographic techniques to generate arrays of immobilized oligonucleotide probes (DNA chips).","These methods, in which light is used to direct the synthesis of oligonucleotide probes in high-density, miniaturized arrays, utilize photolabile 5′-protected N-acyl-deoxynucleoside phosphoramidites, surface linker chemistry and versatile combinatorial synthesis strategies.","A matrix of 256 spatially defined oligonucleotide probes may be generated in this manner.","4.21 Preparation of Nucleic Acid Fragments The nucleic acids may be obtained from any appropriate source, such as cDNAs, genomic DNA, chromosomal DNA, microdissected chromosome bands, cosmid or YAC inserts, and RNA, including mRNA without any amplification steps.","For example, Sambrook et al.","(1989) describes three protocols for the isolation of high molecular weight DNA from mammalian cells (p. 9.14-9.23).","DNA fragments may be prepared as clones in M13, plasmid or lambda vectors and/or prepared directly from genomic DNA or cDNA by PCR or other amplification methods.","Samples may be prepared or dispensed in multiwell plates.","About 100-1000 ng of DNA samples may be prepared in 2-500 ml of final volume.","The nucleic acids would then be fragmented by any of the methods known to those of skill in the art including, for example, using restriction enzymes as described at 9.24-9.28 of Sambrook et al.","(1989), shearing by ultrasound and NaOH treatment.","Low pressure shearing is also appropriate, as described by Schriefer et al.","(1990) Nucleic Acids Res.","18 (24) 7455-6, incorporated herein by reference).","In this method, DNA samples are passed through a small French pressure cell at a variety of low to intermediate pressures.","A lever device allows controlled application of low to intermediate pressures to the cell.","The results of these studies indicate that low-pressure shearing is a useful alternative to sonic and enzymatic DNA fragmentation methods.","One particularly suitable way for fragmenting DNA is contemplated to be that using the two base recognition endonuclease, CviJI, described by Fitzgerald et al.","(1992) Nucleic Acids Res.","20 (14) 3753-62.These authors described an approach for the rapid fragmentation and fractionation of DNA into particular sizes that they contemplated to be suitable for shotgun cloning and sequencing.","The restriction endonuclease CviJI normally cleaves the recognition sequence PuGCPy between the G and C to leave blunt ends.","Atypical reaction conditions, which alter the specificity of this enzyme (CviJI**), yield a quasi-random distribution of DNA fragments form the small molecule pUC19 (2688 base pairs).","Fitzgerald et al.","(1992) quantitatively evaluated the randomness of this fragmentation strategy, using a CviJI** digest of pUC19 that was size fractionated by a rapid gel filtration method and directly ligated, without end repair, to a lac Z minus M13 cloning vector.","Sequence analysis of 76 clones showed that CviJI** restricts pyGCPy and PuGCPu, in addition to PuGCPy sites, and that new sequence data is accumulated at a rate consistent with random fragmentation.","As reported in the literature, advantages of this approach compared to sonication and agarose gel fractionation include: smaller amounts of DNA are required (0.2-0.5 ug instead of 2-5 ug); and fewer steps are involved (no preligation, end repair, chemical extraction, or agarose gel electrophoresis and elution are needed.","Irrespective of the manner in which the nucleic acid fragments are obtained or prepared, it is important to denature the DNA to give single stranded pieces available for hybridization.","This is achieved by incubating the DNA solution for 2-5 minutes at 80-90° C. The solution is then cooled quickly to 2° C. to prevent renaturation of the DNA fragments before they are contacted with the chip.","Phosphate groups must also be removed from genomic DNA by methods known in the art.","4.22 Preparation of DNA Arrays Arrays may be prepared by spotting DNA samples on a support such as a nylon membrane.","Spotting may be performed by using arrays of metal pins (the positions of which correspond to an array of wells in a microtiter plate) to repeated by transfer of about 20 nl of a DNA solution to a nylon membrane.","By offset printing, a density of dots higher than the density of the wells is achieved.","One to 25 dots may be accommodated in 1 mm2, depending on the type of label used.","By avoiding spotting in some preselected number of rows and columns, separate subsets (subarrays) may be formed.","Samples in one subarray may be the same genomic segment of DNA (or the same gene) from different individuals, or may be different, overlapped genomic clones.","Each of the subarrays may represent replica spotting of the same samples.","In one example, a selected gene segment may be amplified from 64 patients.","For each patient, the amplified gene segment may be in one 96-well plate (all 96 wells containing the same sample).","A plate for each of the 64 patients is prepared.","By using a 96-pin device, all samples may be spotted on one 8×12 cm membrane.","Subarrays may contain 64 samples, one from each patient.","Where the 96 subarrays are identical, the dot span may be 1 mm2 and there may be a 1 mm space between subarrays.","Another approach is to use membranes or plates (available from NUNC, Naperville, Ill.) which may be partitioned by physical spacers e.g.","a plastic grid molded over the membrane, the grid being similar to the sort of membrane applied to the bottom of multiwell plates, or hydrophobic strips.","A fixed physical spacer is not preferred for imaging by exposure to flat phosphor-storage screens or x-ray films.","The present invention is illustrated in the following examples.","Upon consideration of the present disclosure, one of skill in the art will appreciate that many other embodiments and variations may be made in the scope of the present invention.","Accordingly, it is intended that the broader aspects of the present invention not be limited to the disclosure of the following examples.","The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention, and compositions and methods which are functionally equivalent are within the scope of the invention.","Indeed, numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the present preferred embodiments.","Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims.","All references cited within the body of the instant specification are hereby incorporated by reference in their entirety.","5.0 EXAMPLES 5.1 Example 1 Novel Nucleic Acid Sequences Obtained From Various Libraries A plurality of novel nucleic acids were obtained from cDNA libraries prepared from various human tissues and in some cases isolated from a genomic library derived from human chromosome using standard PCR, SBH sequence signature analysis and Sanger sequencing techniques.","The inserts of the library were amplified with PCR using primers specific for the vector sequences which flank the inserts.","Clones from cDNA libraries were spotted on nylon membrane filters and screened with oligonucleotide probes (e.g., 7-mers) to obtain signature sequences.","The clones were clustered into groups of similar or identical sequences.","Representative clones were selected for sequencing.","In some cases, the 5′ sequence of the amplified inserts was then deduced using a typical Sanger sequencing protocol.","PCR products were purified and subjected to fluorescent dye terminator cycle sequencing.","Single pass gel sequencing was done using a 377 Applied Biosystems (ABI) sequencer to obtain the novel nucleic acid sequences.","In some cases RACE (Rapid Amplification of cDNA Ends) was performed to further extend the sequence in the 5′ direction.","5.2 Example 2 Novel Contigs The novel contigs of the invention were assembled from sequences that were obtained from a cDNA library by methods described in Example 1 above, and in some cases sequences obtained from one or more public databases.","The sequences for the resulting nucleic acid contigs are designated as SEQ ID NO: 1-8051 and are provided in the attached Sequence Listing.","The contigs were assembled using an EST sequence as a seed.","Then a recursive algorithm was used to extend the seed EST into an extended assemblage, by pulling additional sequences from different databases (i.e., Hyseq's database containing EST sequences, dbEST version 115, gb pri 115, and UniGene version 103, and exons from public domain genomic sequences predicted by GenScan) that belong to this assemblage.","The algorithm terminated when there was no additional sequences from the above databases that would extend the assemblage.","Further, the inclusion of component sequences into the assemblage was based on a BLASTN hit to the extending assemblage with BLAST score greater than 300 and percent identity greater than 95%.","The novel predicted polypeptides (including proteins) encoded by the novel polynucleotides (SEQ ID NO: 1-8051) of the present invention are incorporated in the attached Sequence Listing.","A subset of the predicted polypeptide sequences contain an unknown amino acid; a stop codon; a possible nucleotide deletion; or a possible nucleotide insertion.","These sequences have also been shown in their entirety in Table 2.Table 2 also shows the corresponding start and stop nucleotide locations to each of SEQ ID NO: 1-8051.Table 2 also indicates the method by which the polypeptide was predicted.","Method A refers to a polypeptide obtained by using a software program called FASTY (available from http://fasta.bioch.virginia,edu) which selects a polypeptide based on a comparison of the translated novel polynucleotide to known polynucleotides (W. R. Pearson, Methods in Enzymology, 183:63-98 (1990), herein incorporated by reference).","Method B refers to a polypeptide obtained by using a software program called GenScan for human/vertebrate sequences (available from Stanford University, Office of Technology Licensing) that predicts the polypeptide based on a probabilistic model of gene structure/compositional properties (C. Burge and S. Karlin, J. Mol.","Biol., 268:78-94 (1997), incorporated herein by reference).","Method C refers to a polypeptide obtained by using a Hyseq proprietary software program that translates the novel polynucleotide and its complementary strand into six possible amino acid sequences (forward and reverse frames) and chooses the polypeptide with the longest open reading frame.","The nearest neighbor results for SEQ ID NO: 1-8051 were obtained by a BLASTX version 2.0al 19 MP-WashU search against Genpept release 123 and Geneseq release 200110 (Derwent), using BLAST algorithm.","The nearest neighbor result showed the closest homologue for SEQ ID NO: 1-8051.The nearest neighbor results for SEQ ID NO: 1-8051, having identifiable function(s) are incorporated in the attached Sequence Listing.","Using eMatrix software package (Stanford University, Stanford, Calif.) (Wu et al., J. Comp.","Biol., Vol.","6 pp.","219-235 (1999) herein incorporated by reference), all the polypeptide sequences were examined to determine whether they had identifiable signature regions.","The attached Sequence Listing provides the results obtained by eMatrix analysis for each polypeptide as follows: the signature region found in the indicated polypeptide sequences, the description of the signature, the eMatrix p-value(s) and the position(s) of the signature within the polypeptide sequence.","Using the pFam software program (Sonnhammer et al., Nucleic Acids Res., Vol.","26 (1) pp.","320-322 (1998) herein incorporated by reference) all the polypeptide sequences were examined for domains with homology to certain peptide domains.","The attached Sequence Listing provides the results obtained by pFam analysis for each polypeptide, namely: the name of the domain found, the description, the p-value and the pFam score for the identified domain within the sequence.","Tables 1 and 2 follow.","Table 1 shows the various tissue sources of SEQ ID NO: 1-8051.Table 2 shows the start and stop nucleotides for the translated amino acid sequence for which each assemblage encodes.","Table 2 also provides a correlation between the amino acid sequences set forth in the Sequence Listing, the nucleotide sequences set forth in the Sequence Listing and the SEQ ID NO: in U.S. Ser.","No.","09/577,408.LENGTHY TABLE REFERENCED HERE US20070060743A1-20070315-T00001 Please refer to the end of the specification for access instructions.","LENGTHY TABLE REFERENCED HERE US20070060743A1-20070315-T00002 Please refer to the end of the specification for access instructions.","LENGTHY TABLE The patent application contains a lengthy table section.","A copy of the table is available in electronic form from the USPTO web site ().","An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3)."]],"string":"[\n [\n \"Novel nucleic acids and polypeptides\",\n \"The present invention provides novel nucleic acids, novel polypeptide sequences encoded by these nucleic acids and uses thereof.\"\n ],\n [\n \"1.An isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-8051, a mature protein coding portion of SEQ ID NO: 1-8051, an active domain of SEQ ID NO: 1-8051, and complementary sequences thereof.\",\n \"2.An isolated polynucleotide encoding a polypeptide with biological activity, wherein said polynucleotide hybridizes to the polynucleotide of claim 1 under stringent hybridization conditions.\",\n \"3.An isolated polynucleotide encoding a polypeptide with biological activity, wherein said polynucleotide has greater than about 90% sequence identity with the polynucleotide of claim 1.4.The polynucleotide of claim 1 wherein said polynucleotide is DNA.\",\n \"5.An isolated polynucleotide of claim 1 wherein said polynucleotide comprises the complementary sequences.\",\n \"6.A vector comprising the polynucleotide of claim 1.7.An expression vector comprising the polynucleotide of claim 1.8.A host cell genetically engineered to comprise the polynucleotide of claim 1.9.A host cell genetically engineered to comprise the polynucleotide of claim 1 operatively associated with a regulatory sequence that modulates expression of the polynucleotide in the host cell.\",\n \"10.An isolated polypeptide, wherein the polypeptide is selected from the group consisting of: (a) a polypeptide encoded by any one of the polynucleotides of claim 1; and (b) a polypeptide encoded by a polynucleotide hybridizing under stringent conditions with any one of SEQ ID NO: 1-8051.11.A composition comprising the polypeptide of claim 10 and a carrier.\",\n \"12.An antibody directed against the polypeptide of claim 10.13.A method for detecting the polynucleotide of claim 1 in a sample, comprising: a) contacting the sample with a compound that binds to and forms a complex with the polynucleotide of claim 1 for a period sufficient to form the complex; and b) detecting the complex, so that if a complex is detected, the polynucleotide of claim 1 is detected.\",\n \"14.A method for detecting the polynucleotide of claim 1 in a sample, comprising: a) contacting the sample under stringent hybridization conditions with nucleic acid primers that anneal to the polynucleotide of claim 1 under such conditions; b) amplifying a product comprising at least a portion of the polynucleotide of claim 1; and c) detecting said product and thereby the polynucleotide of claim 1 in the sample.\",\n \"15.The method of claim 14, wherein the polynucleotide is an RNA molecule and the method further comprises reverse transcribing an annealed RNA molecule into a cDNA polynucleotide.\",\n \"16.A method for detecting the polypeptide of claim 10 in a sample, comprising: a) contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex; and b) detecting formation of the complex, so that if a complex formation is detected, the polypeptide of claim 10 is detected.\",\n \"17.A method for identifying a compound that binds to the polypeptide of claim 10, comprising: a) contacting the compound with the polypeptide of claim 10 under conditions sufficient to form a polypeptide/compound complex; and b) detecting the complex, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 10 is identified.\",\n \"18.A method for identifying a compound that binds to the polypeptide of claim 10, comprising: a) contacting the compound with the polypeptide of claim 10, in a cell, under conditions sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and b) detecting the complex by detecting reporter gene sequence expression, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 10 is identified.\",\n \"19.A method of producing the polypeptide of claim 10, comprising, a) culturing a host cell comprising a polynucleotide sequence selected from the group consisting of a polynucleotide sequence of SEQ ID NO: 1-8051, a mature protein coding portion of SEQ ID NO: 1-8051, an active domain of SEQ ID NO: 1-8051, complementary sequences thereof and a polynucleotide sequence hybridizing under stringent conditions to SEQ ID NO: 1-8051, under conditions sufficient to express the polypeptide in said cell; and b) isolating the polypeptide from the cell culture or cells of step (a).\",\n \"20.An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 8052-16102, the mature protein portion thereof, or the active domain thereof.\",\n \"21.The polypeptide of claim 20 wherein the polypeptide is provided on a polypeptide array.\",\n \"22.A collection of polynucleotides, wherein the collection comprises the sequence information of at least one of SEQ ID NO: 1-8051.23.The collection of claim 22, wherein the collection is provided on a nucleic acid array.\",\n \"24.The collection of claim 23, wherein the array detects full-matches to any one of the polynucleotides in the collection.\",\n \"25.The collection of claim 23, wherein the array detects mismatches to any one of the polynucleotides in the collection.\",\n \"26.The collection of claim 22, wherein the collection is provided in a computer-readable format.\",\n \"27.A method of treatment comprising administering to a mammalian subject in need thereof a therapeutic amount of a composition comprising a polypeptide of claim 10 or 20 and a pharmaceutically acceptable carrier.\",\n \"28.A method of treatment comprising administering to a mammalian subject in need thereof a therapeutic amount of a composition comprising an antibody that specifically binds to a polypeptide of claim 10 or 20 and a pharmaceutically acceptable carrier.\"\n ],\n [\n \"<SOH> 2.BACKGROUND <EOH>Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lymphokines, interferons, circulating soluble factors, chemokines, and interleukins) has matured rapidly over the past decade.\",\n \"The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides “directly” in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein in the case of hybridization cloning; activity of the protein in the case of expression cloning).\",\n \"More recent “indirect” cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization-based cloning techniques, have advanced the state of the art by making available large numbers of DNA/amino acid sequences for proteins that are known to have biological activity, for example, by virtue of their secreted nature in the case of leader sequence cloning, by virtue of their cell or tissue source in the case of PCR-based techniques, or by virtue of structural similarity to other genes of known biological activity.\",\n \"Identified polynucleotide and polypeptide sequences have numerous applications in, for example, diagnostics, forensics, gene mapping; identification of mutations responsible for genetic disorders or other traits, to assess biodiversity, and to produce many other types of data and products dependent on DNA and amino acid sequences.\"\n ],\n [\n \"<SOH> 3.SUMMARY OF THE INVENTION <EOH>The compositions of the present invention include novel isolated polypeptides, novel isolated polynucleotides encoding such polypeptides, including recombinant DNA molecules, cloned genes or degenerate variants thereof, especially naturally occurring variants such as allelic variants, antisense polynucleotide molecules, and antibodies that specifically recognize one or more epitopes present on such polypeptides, as well as hybridomas producing such antibodies.\",\n \"The compositions of the present invention additionally include vectors, including expression vectors, containing the polynucleotides of the invention, cells genetically engineered to contain such polynucleotides and cells genetically engineered to express such polynucleotides.\",\n \"The present invention relates to a collection or library of at least one novel nucleic acid sequence assembled from expressed sequence tags (ESTs) isolated mainly by sequencing by hybridization (SBH), and in some cases, sequences obtained from one or more public databases.\",\n \"The invention relates also to the proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins.\",\n \"These nucleic acid sequences are designated as SEQ ID NO: 1-8051.The polypeptides sequences are designated SEQ ID NO: 8052-16102.The nucleic acids and polypeptides are provided in the Sequence Listing.\",\n \"In the nucleic acids provided in the Sequence Listing, A is adenosine; C is cytosine; G is guanine; T is thymine; and N is any of the four bases.\",\n \"In the amino acids provided in the Sequence Listing, * corresponds to the stop codon.\",\n \"The nucleic acid sequences of the present invention also include, nucleic acid sequences that hybridize to the complement of SEQ ID NO: 1-8051 under stringent hybridization conditions; nucleic acid sequences which are allelic variants or species homologues of any of the nucleic acid sequences recited above, or nucleic acid sequences that encode a peptide comprising a specific domain or truncation of the peptides encoded by SEQ ID NO: 1-8051.A polynucleotide comprising a nucleotide sequence having at least 90% identity to an identifying sequence of SEQ ID NO: 1-8051 or a degenerate variant or fragment thereof.\",\n \"The identifying sequence can be 100 base pairs in length.\",\n \"The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-8051.The sequence information can be a segment of any one of SEQ ID NO: 1-8051 that uniquely identifies or represents the sequence information of SEQ ID NO: 1-8051.A collection as used in this application can be a collection of only one polynucleotide.\",\n \"The collection of sequence information or identifying information of each sequence can be provided on a nucleic acid array.\",\n \"In one embodiment, segments of sequence information is provided on a nucleic acid array to detect the polynucleotide that contains the segment.\",\n \"The array can be designed to detect full-match or mismatch to the polynucleotide that contains the segment.\",\n \"The collection can also be provided in a computer-readable format.\",\n \"This invention also includes the reverse or direct complement of any of the nucleic acid sequences recited above; cloning or expression vectors containing the nucleic acid sequences; and host cells or organisms transformed with these expression vectors.\",\n \"Nucleic acid sequences (or their reverse or direct complements) according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology, such as use as hybridization probes, use as primers for PCR, use in an array, use in computer-readable media, use in sequencing full-length genes, use for chromosome and gene mapping, use in the recombinant production of protein, and use in the generation of anti-sense DNA or RNA, their chemical analogs and the like.\",\n \"In a preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-8051 or novel segments or parts of the nucleic acids of the invention are used as primers in expression assays that are well known in the art.\",\n \"In a particularly preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-8051 or novel segments or parts of the nucleic acids provided herein are used in diagnostics for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.\",\n \"The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide comprising any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051; a polynucleotide comprising any of the full length protein coding sequences of SEQ ID NO: 1-8051; and a polynucleotide comprising any of the nucleotide sequences of the mature protein coding sequences of SEQ ID NO: 1-8051.The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent hybridization conditions to (a) the complement of any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051; (b) a nucleotide sequence encoding any one of the amino acid sequences set forth in the Sequence Listing (e.g., SEQ ID NO: 8052-16102); (c) a polynucleotide which is an allelic variant of any polynucleotides recited above; (d) a polynucleotide which encodes a species homolog (e.g.\",\n \"orthologs) of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of any of the polypeptides comprising an amino acid sequence set forth in the Sequence Listing.\",\n \"The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising any of the amino acid sequences set forth in the Sequence Listing; or the corresponding full length or mature protein.\",\n \"Polypeptides of the invention also include polypeptides with biological activity that are encoded by (a) any of the polynucleotides having a nucleotide sequence set forth in SEQ ID NO: 1-8051; or (b) polynucleotides that hybridize to the complement of the polynucleotides of (a) under stringent hybridization conditions.\",\n \"Biologically or immunologically active variants of any of the polypeptide sequences in the Sequence Listing, and “substantial equivalents” thereof (e.g., with at least about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid sequence identity) that preferably retain biological activity are also contemplated.\",\n \"The polypeptides of the invention may be wholly or partially chemically synthesized but are preferably produced by recombinant means using the genetically engineered cells (e.g.\",\n \"host cells) of the invention.\",\n \"The invention also provides compositions comprising a polypeptide of the invention.\",\n \"Polypeptide compositions of the invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.\",\n \"The invention also provides host cells transformed or transfected with a polynucleotide of the invention.\",\n \"The invention also relates to methods for producing a polypeptide of the invention comprising growing a culture of the host cells of the invention in a suitable culture medium under conditions permitting expression of the desired polypeptide, and purifying the polypeptide from the culture or from the host cells.\",\n \"Preferred embodiments include those in which the protein produced by such process is a mature form of the protein.\",\n \"Polynucleotides according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology.\",\n \"These techniques include use as hybridization probes, use as oligomers, or primers, for PCR, use for chromosome and gene mapping, use in the recombinant production of protein, and use in generation of anti-sense DNA or RNA, their chemical analogs and the like.\",\n \"For example, when the expression of an mRNA is largely restricted to a particular cell or tissue type, polynucleotides of the invention can be used as hybridization probes to detect the presence of the particular cell or tissue mRNA in a sample using, e.g., in situ hybridization.\",\n \"In other exemplary embodiments, the polynucleotides are used in diagnostics as expressed sequence tags for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.\",\n \"The polypeptides according to the invention can be used in a variety of conventional procedures and methods that are currently applied to other proteins.\",\n \"For example, a polypeptide of the invention can be used to generate an antibody that specifically binds the polypeptide.\",\n \"Such antibodies, particularly monoclonal antibodies, are useful for detecting or quantitating the polypeptide in tissue.\",\n \"The polypeptides of the invention can also be used as molecular weight markers, and as a food supplement.\",\n \"Methods are also provided for preventing, treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a polypeptide of the present invention and a pharmaceutically acceptable carrier.\",\n \"In particular, the polypeptides and polynucleotides of the invention can be utilized, for example, in methods for the prevention and/or treatment of disorders involving aberrant protein expression or biological activity.\",\n \"The present invention further relates to methods for detecting the presence of the polynucleotides or polypeptides of the invention in a sample.\",\n \"Such methods can, for example, be utilized as part of prognostic and diagnostic evaluation of disorders as recited herein and for the identification of subjects exhibiting a predisposition to such conditions.\",\n \"The invention provides a method for detecting the polynucleotides of the invention in a sample, comprising contacting the sample with a compound that binds to and forms a complex with the polynucleotide of interest for a period sufficient to form the complex and under conditions sufficient to form a complex and detecting the complex such that if a complex is detected, the polynucleotide of interest is detected.\",\n \"The invention also provides a method for detecting the polypeptides of the invention in a sample comprising contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex and detecting the formation of the complex such that if a complex is formed, the polypeptide is detected.\",\n \"The invention also provides kits comprising polynucleotide probes and/or monoclonal antibodies, and optionally quantitative standards, for carrying out methods of the invention.\",\n \"Furthermore, the invention provides methods for evaluating the efficacy of drugs, and monitoring the progress of patients, involved in clinical trials for the treatment of disorders as recited above.\",\n \"The invention also provides methods for the identification of compounds that modulate (i.e., increase or decrease) the expression or activity of the polynucleotides and/or polypeptides of the invention.\",\n \"Such methods can be utilized, for example, for the identification of compounds that can ameliorate symptoms of disorders as recited herein.\",\n \"Such methods can include, but are not limited to, assays for identifying compounds and other substances that interact with (e.g., bind to) the polypeptides of the invention.\",\n \"The invention provides a method for identifying a compound that binds to the polypeptides of the invention comprising contacting the compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and detecting the complex by detecting the reporter gene sequence expression such that if expression of the reporter gene is detected the compound that binds to a polypeptide of the invention is identified.\",\n \"The methods of the invention also provides methods for treatment which involve the administration of the polynucleotides or polypeptides of the invention to individuals exhibiting symptoms or tendencies.\",\n \"In addition, the invention encompasses methods for treating diseases or disorders as recited herein comprising administering compounds and other substances that modulate the overall activity of the target gene products.\",\n \"Compounds and other substances can effect such modulation either on the level of target gene/protein expression or target protein activity.\",\n \"The polypeptides of the present invention and the polynucleotides encoding them are also useful for the same functions known to one of skill in the art as the polypeptides and polynucleotides to which they have homology (set forth in the sequence listing).\",\n \"If no homology is set forth for a sequence, then the polypeptides and polynucleotides of the present invention are useful for a variety of applications, as described herein, including use in arrays for detection.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\"\n ],\n [\n \"1.TECHNICAL FIELD The present invention provides novel polynucleotides and proteins encoded by such polynucleotides, along with uses for these polynucleotides and proteins, for example in therapeutic, diagnostic and research methods.\",\n \"2.BACKGROUND Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lymphokines, interferons, circulating soluble factors, chemokines, and interleukins) has matured rapidly over the past decade.\",\n \"The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides “directly” in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein in the case of hybridization cloning; activity of the protein in the case of expression cloning).\",\n \"More recent “indirect” cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization-based cloning techniques, have advanced the state of the art by making available large numbers of DNA/amino acid sequences for proteins that are known to have biological activity, for example, by virtue of their secreted nature in the case of leader sequence cloning, by virtue of their cell or tissue source in the case of PCR-based techniques, or by virtue of structural similarity to other genes of known biological activity.\",\n \"Identified polynucleotide and polypeptide sequences have numerous applications in, for example, diagnostics, forensics, gene mapping; identification of mutations responsible for genetic disorders or other traits, to assess biodiversity, and to produce many other types of data and products dependent on DNA and amino acid sequences.\",\n \"3.SUMMARY OF THE INVENTION The compositions of the present invention include novel isolated polypeptides, novel isolated polynucleotides encoding such polypeptides, including recombinant DNA molecules, cloned genes or degenerate variants thereof, especially naturally occurring variants such as allelic variants, antisense polynucleotide molecules, and antibodies that specifically recognize one or more epitopes present on such polypeptides, as well as hybridomas producing such antibodies.\",\n \"The compositions of the present invention additionally include vectors, including expression vectors, containing the polynucleotides of the invention, cells genetically engineered to contain such polynucleotides and cells genetically engineered to express such polynucleotides.\",\n \"The present invention relates to a collection or library of at least one novel nucleic acid sequence assembled from expressed sequence tags (ESTs) isolated mainly by sequencing by hybridization (SBH), and in some cases, sequences obtained from one or more public databases.\",\n \"The invention relates also to the proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins.\",\n \"These nucleic acid sequences are designated as SEQ ID NO: 1-8051.The polypeptides sequences are designated SEQ ID NO: 8052-16102.The nucleic acids and polypeptides are provided in the Sequence Listing.\",\n \"In the nucleic acids provided in the Sequence Listing, A is adenosine; C is cytosine; G is guanine; T is thymine; and N is any of the four bases.\",\n \"In the amino acids provided in the Sequence Listing, * corresponds to the stop codon.\",\n \"The nucleic acid sequences of the present invention also include, nucleic acid sequences that hybridize to the complement of SEQ ID NO: 1-8051 under stringent hybridization conditions; nucleic acid sequences which are allelic variants or species homologues of any of the nucleic acid sequences recited above, or nucleic acid sequences that encode a peptide comprising a specific domain or truncation of the peptides encoded by SEQ ID NO: 1-8051.A polynucleotide comprising a nucleotide sequence having at least 90% identity to an identifying sequence of SEQ ID NO: 1-8051 or a degenerate variant or fragment thereof.\",\n \"The identifying sequence can be 100 base pairs in length.\",\n \"The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-8051.The sequence information can be a segment of any one of SEQ ID NO: 1-8051 that uniquely identifies or represents the sequence information of SEQ ID NO: 1-8051.A collection as used in this application can be a collection of only one polynucleotide.\",\n \"The collection of sequence information or identifying information of each sequence can be provided on a nucleic acid array.\",\n \"In one embodiment, segments of sequence information is provided on a nucleic acid array to detect the polynucleotide that contains the segment.\",\n \"The array can be designed to detect full-match or mismatch to the polynucleotide that contains the segment.\",\n \"The collection can also be provided in a computer-readable format.\",\n \"This invention also includes the reverse or direct complement of any of the nucleic acid sequences recited above; cloning or expression vectors containing the nucleic acid sequences; and host cells or organisms transformed with these expression vectors.\",\n \"Nucleic acid sequences (or their reverse or direct complements) according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology, such as use as hybridization probes, use as primers for PCR, use in an array, use in computer-readable media, use in sequencing full-length genes, use for chromosome and gene mapping, use in the recombinant production of protein, and use in the generation of anti-sense DNA or RNA, their chemical analogs and the like.\",\n \"In a preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-8051 or novel segments or parts of the nucleic acids of the invention are used as primers in expression assays that are well known in the art.\",\n \"In a particularly preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-8051 or novel segments or parts of the nucleic acids provided herein are used in diagnostics for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.\",\n \"The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide comprising any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051; a polynucleotide comprising any of the full length protein coding sequences of SEQ ID NO: 1-8051; and a polynucleotide comprising any of the nucleotide sequences of the mature protein coding sequences of SEQ ID NO: 1-8051.The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent hybridization conditions to (a) the complement of any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051; (b) a nucleotide sequence encoding any one of the amino acid sequences set forth in the Sequence Listing (e.g., SEQ ID NO: 8052-16102); (c) a polynucleotide which is an allelic variant of any polynucleotides recited above; (d) a polynucleotide which encodes a species homolog (e.g.\",\n \"orthologs) of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of any of the polypeptides comprising an amino acid sequence set forth in the Sequence Listing.\",\n \"The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising any of the amino acid sequences set forth in the Sequence Listing; or the corresponding full length or mature protein.\",\n \"Polypeptides of the invention also include polypeptides with biological activity that are encoded by (a) any of the polynucleotides having a nucleotide sequence set forth in SEQ ID NO: 1-8051; or (b) polynucleotides that hybridize to the complement of the polynucleotides of (a) under stringent hybridization conditions.\",\n \"Biologically or immunologically active variants of any of the polypeptide sequences in the Sequence Listing, and “substantial equivalents” thereof (e.g., with at least about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid sequence identity) that preferably retain biological activity are also contemplated.\",\n \"The polypeptides of the invention may be wholly or partially chemically synthesized but are preferably produced by recombinant means using the genetically engineered cells (e.g.\",\n \"host cells) of the invention.\",\n \"The invention also provides compositions comprising a polypeptide of the invention.\",\n \"Polypeptide compositions of the invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.\",\n \"The invention also provides host cells transformed or transfected with a polynucleotide of the invention.\",\n \"The invention also relates to methods for producing a polypeptide of the invention comprising growing a culture of the host cells of the invention in a suitable culture medium under conditions permitting expression of the desired polypeptide, and purifying the polypeptide from the culture or from the host cells.\",\n \"Preferred embodiments include those in which the protein produced by such process is a mature form of the protein.\",\n \"Polynucleotides according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology.\",\n \"These techniques include use as hybridization probes, use as oligomers, or primers, for PCR, use for chromosome and gene mapping, use in the recombinant production of protein, and use in generation of anti-sense DNA or RNA, their chemical analogs and the like.\",\n \"For example, when the expression of an mRNA is largely restricted to a particular cell or tissue type, polynucleotides of the invention can be used as hybridization probes to detect the presence of the particular cell or tissue mRNA in a sample using, e.g., in situ hybridization.\",\n \"In other exemplary embodiments, the polynucleotides are used in diagnostics as expressed sequence tags for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.\",\n \"The polypeptides according to the invention can be used in a variety of conventional procedures and methods that are currently applied to other proteins.\",\n \"For example, a polypeptide of the invention can be used to generate an antibody that specifically binds the polypeptide.\",\n \"Such antibodies, particularly monoclonal antibodies, are useful for detecting or quantitating the polypeptide in tissue.\",\n \"The polypeptides of the invention can also be used as molecular weight markers, and as a food supplement.\",\n \"Methods are also provided for preventing, treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a polypeptide of the present invention and a pharmaceutically acceptable carrier.\",\n \"In particular, the polypeptides and polynucleotides of the invention can be utilized, for example, in methods for the prevention and/or treatment of disorders involving aberrant protein expression or biological activity.\",\n \"The present invention further relates to methods for detecting the presence of the polynucleotides or polypeptides of the invention in a sample.\",\n \"Such methods can, for example, be utilized as part of prognostic and diagnostic evaluation of disorders as recited herein and for the identification of subjects exhibiting a predisposition to such conditions.\",\n \"The invention provides a method for detecting the polynucleotides of the invention in a sample, comprising contacting the sample with a compound that binds to and forms a complex with the polynucleotide of interest for a period sufficient to form the complex and under conditions sufficient to form a complex and detecting the complex such that if a complex is detected, the polynucleotide of interest is detected.\",\n \"The invention also provides a method for detecting the polypeptides of the invention in a sample comprising contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex and detecting the formation of the complex such that if a complex is formed, the polypeptide is detected.\",\n \"The invention also provides kits comprising polynucleotide probes and/or monoclonal antibodies, and optionally quantitative standards, for carrying out methods of the invention.\",\n \"Furthermore, the invention provides methods for evaluating the efficacy of drugs, and monitoring the progress of patients, involved in clinical trials for the treatment of disorders as recited above.\",\n \"The invention also provides methods for the identification of compounds that modulate (i.e., increase or decrease) the expression or activity of the polynucleotides and/or polypeptides of the invention.\",\n \"Such methods can be utilized, for example, for the identification of compounds that can ameliorate symptoms of disorders as recited herein.\",\n \"Such methods can include, but are not limited to, assays for identifying compounds and other substances that interact with (e.g., bind to) the polypeptides of the invention.\",\n \"The invention provides a method for identifying a compound that binds to the polypeptides of the invention comprising contacting the compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and detecting the complex by detecting the reporter gene sequence expression such that if expression of the reporter gene is detected the compound that binds to a polypeptide of the invention is identified.\",\n \"The methods of the invention also provides methods for treatment which involve the administration of the polynucleotides or polypeptides of the invention to individuals exhibiting symptoms or tendencies.\",\n \"In addition, the invention encompasses methods for treating diseases or disorders as recited herein comprising administering compounds and other substances that modulate the overall activity of the target gene products.\",\n \"Compounds and other substances can effect such modulation either on the level of target gene/protein expression or target protein activity.\",\n \"The polypeptides of the present invention and the polynucleotides encoding them are also useful for the same functions known to one of skill in the art as the polypeptides and polynucleotides to which they have homology (set forth in the sequence listing).\",\n \"If no homology is set forth for a sequence, then the polypeptides and polynucleotides of the present invention are useful for a variety of applications, as described herein, including use in arrays for detection.\",\n \"4.DETAILED DESCRIPTION OF THE INVENTION 4.1 Definitions It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.\",\n \"The term “active” refers to those forms of the polypeptide which retain the biologic and/or immunologic activities of any naturally occurring polypeptide.\",\n \"According to the invention, the terms “biologically active” or “biological activity” refer to a protein or peptide having structural, regulatory or biochemical functions of a naturally occurring molecule.\",\n \"Likewise “immunologically active” or “immunological activity” refers to the capability of the natural, recombinant or synthetic polypeptide to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.\",\n \"The term “activated cells” as used in this application are those cells which are engaged in extracellular or intracellular membrane trafficking, including the export of secretory or enzymatic molecules as part of a normal or disease process.\",\n \"The terms “complementary” or “complementarity” refer to the natural binding of polynucleotides by base pairing.\",\n \"For example, the sequence 5′-AGT-3′ binds to the complementary sequence 3′-TCA-5′.\",\n \"Complementarity between two single-stranded molecules may be “partial” such that only some of the nucleic acids bind or it may be “complete” such that total complementarity exists between the single stranded molecules.\",\n \"The degree of complementarity between the nucleic acid strands has significant effects on the efficiency and strength of the hybridization between the nucleic acid strands.\",\n \"The term “embryonic stem cells (ES)” refers to a cell that can give rise to many differentiated cell types in an embryo or an adult, including the germ cells.\",\n \"The term “germ line stem cells (GSCs)” refers to stem cells derived from primordial stem cells that provide a steady and continuous source of germ cells for the production of gametes.\",\n \"The term “primordial germ cells (PGCs)” refers to a small population of cells set aside from other cell lineages particularly from the yolk sac, mesenteries, or gonadal ridges during embryogenesis that have the potential to differentiate into germ cells and other cells.\",\n \"PGCs are the source from which GSCs and ES cells are derived The PGCs, the GSCs and the ES cells are capable of self-renewal.\",\n \"Thus these cells not only populate the germ line and give rise to a plurality of terminally differentiated cells that comprise the adult specialized organs, but are able to regenerate themselves.\",\n \"The term “expression modulating fragment,” EMF, means a series of nucleotides which modulates the expression of an operably linked ORF or another EMF.\",\n \"As used herein, a sequence is said to “modulate the expression of an operably linked sequence” when the expression of the sequence is altered by the presence of the EMF.\",\n \"EMFs include, but are not limited to, promoters, and promoter modulating sequences (inducible elements).\",\n \"One class of EMFs are nucleic acid fragments which induce the expression of an operably linked ORF in response to a specific regulatory factor or physiological event.\",\n \"The terms “nucleotide sequence” or “nucleic acid” or “polynucleotide” or “oligonucleotide” are used interchangeably and refer to a heteropolymer of nucleotides or the sequence of these nucleotides.\",\n \"These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA) or to any DNA-like or RNA-like material.\",\n \"In the sequences herein A is adenine, C is cytosine, T is thymine, G is guanine and N is A, C, G or T (U).\",\n \"It is contemplated that where the polynucleotide is RNA, the T (thymine) in the sequences provided herein is substituted with U (uracil).\",\n \"Generally, nucleic acid segments provided by this invention may be assembled from fragments of the genome and short oligonucleotide linkers, or from a series of oligonucleotides, or from individual nucleotides, to provide a synthetic nucleic acid which is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon, or a eukaryotic gene.\",\n \"The terms “oligonucleotide fragment” or a “polynucleotide fragment”, “portion,” or “segment” or “probe” or “primer” are used interchangeably and refer to a sequence of nucleotide residues which are at least about 5 nucleotides, more preferably at least about 7 nucleotides, more preferably at least about 9 nucleotides, more preferably at least about 11 nucleotides and most preferably at least about 17 nucleotides.\",\n \"The fragment is preferably less than about 500 nucleotides, preferably less than about 200 nucleotides, more preferably less than about 100 nucleotides, more preferably less than about 50 nucleotides and most preferably less than 30 nucleotides.\",\n \"Preferably the probe is from about 6 nucleotides to about 200 nucleotides, preferably from about 15 to about 50 nucleotides, more preferably from about 17 to 30 nucleotides and most preferably from about 20 to 25 nucleotides.\",\n \"Preferably the fragments can be used in polymerase chain reaction (PCR), various hybridization procedures or microarray procedures to identify or amplify identical or related parts of mRNA or DNA molecules.\",\n \"A fragment or segment may uniquely identify each polynucleotide sequence of the present invention.\",\n \"Preferably the fragment comprises a sequence substantially similar to any one of SEQ ID NO: 1-8051.Probes may, for example, be used to determine whether specific mRNA molecules are present in a cell or tissue or to isolate similar nucleic acid sequences from chromosomal DNA as described by Walsh et al.\",\n \"(Walsh, P. S. et al., 1992, PCR Methods Appl 1:241-250).\",\n \"They may be labeled by nick translation, Klenow fill-in reaction, PCR, or other methods well known in the art.\",\n \"Probes of the present invention, their preparation and/or labeling are elaborated in Sambrook, J. et al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY; or Ausubel, F. M. et al., 1989, Current Protocols in Molecular Biology, John Wiley & Sons, New York N.Y., both of which are incorporated herein by reference in their entirety.\",\n \"The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-8051.The sequence information can be a segment of any one of SEQ ID NO: 1-8051 that uniquely identifies or represents the sequence information of that sequence of SEQ ID NO: 1-8051.One such segment can be a twenty-mer nucleic acid sequence because the probability that a twenty-mer is fully matched in the human genome is 1 in 300.In the human genome, there are three billion base pairs in one set of chromosomes.\",\n \"Because 420 possible twenty-mers exist, there are 300 times more twenty-mers than there are base pairs in a set of human chromosomes.\",\n \"Using the same analysis, the probability for a seventeen-mer to be fully matched in the human genome is approximately 1 in 5.When these segments are used in arrays for expression studies, fifteen-mer segments can be used.\",\n \"The probability that the fifteen-mer is fully matched in the expressed sequences is also approximately one in five because expressed sequences comprise less than approximately 5% of the entire genome sequence.\",\n \"Similarly, when using sequence information for detecting a single mismatch, a segment can be a twenty-five mer.\",\n \"The probability that the twenty-five mer would appear in a human genome with a single mismatch is calculated by multiplying the probability for a full match (1÷425) times the increased probability for mismatch at each nucleotide position (3×25).\",\n \"The probability that an eighteen mer with a single mismatch can be detected in an array for expression studies is approximately one in five.\",\n \"The probability that a twenty-mer with a single mismatch can be detected in a human genome is approximately one in five.\",\n \"The term “open reading frame,” ORF, means a series of nucleotide triplets coding for amino acids without any termination codons and is a sequence translatable into protein.\",\n \"The terms “operably linked” or “operably associated” refer to functionally related nucleic acid sequences.\",\n \"For example, a promoter is operably associated or operably linked with a coding sequence if the promoter controls the transcription of the coding sequence.\",\n \"While operably linked nucleic acid sequences can be contiguous and in the same reading frame, certain genetic elements e.g.\",\n \"repressor genes are not contiguously linked to the coding sequence but still control transcription/translation of the coding sequence.\",\n \"The term “pluripotent” refers to the capability of a cell to differentiate into a number of differentiated cell types that are present in an adult organism.\",\n \"A pluripotent cell is restricted in its differentiation capability in comparison to a totipotent cell.\",\n \"The terms “polypeptide” or “peptide” or “amino acid sequence” refer to an oligopeptide, peptide, polypeptide or protein sequence or fragment thereof and to naturally occurring or synthetic molecules.\",\n \"A polypeptide “fragment,” “portion,” or “segment” is a stretch of amino acid residues of at least about 5 amino acids, preferably at least about 7 amino acids, more preferably at least about 9 amino acids and most preferably at least about 17 or more amino acids.\",\n \"The peptide preferably is not greater than about 200 amino acids, more preferably less than 150 amino acids and most preferably less than 100 amino acids.\",\n \"Preferably the peptide is from about 5 to about 200 amino acids.\",\n \"To be active, any polypeptide must have sufficient length to display biological and/or immunological activity.\",\n \"The term “naturally occurring polypeptide” refers to polypeptides produced by cells that have not been genetically engineered and specifically contemplates various polypeptides arising from post-translational modifications of the polypeptide including, but not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation and acylation.\",\n \"The term “translated protein coding portion” means a sequence which encodes for the full length protein which may include any leader sequence or any processing sequence.\",\n \"The term “mature protein coding sequence” means a sequence which encodes a peptide or protein without a signal or leader sequence.\",\n \"The “mature protein portion” means that portion of the protein which does not include a signal or leader sequence.\",\n \"The peptide may have been produced by processing in the cell which removes any leader/signal sequence.\",\n \"The mature protein portion may or may not include an initial methionine residue.\",\n \"The methionine residue may be removed from the protein during processing in the cell.\",\n \"The peptide may be produced synthetically or the protein may have been produced using a polynucleotide only encoding for the mature protein coding sequence.\",\n \"The term “derivative” refers to polypeptides chemically modified by such techniques as ubiquitination, labeling (e.g., with radionuclides or various enzymes), covalent polymer attachment such as pegylation (derivatization with polyethylene glycol) and insertion or substitution by chemical synthesis of amino acids such as ornithine, which do not normally occur in human proteins.\",\n \"The term “variant”(or “analog”) refers to any polypeptide differing from naturally occurring polypeptides by amino acid insertions, deletions, and substitutions, created using, e.g., recombinant DNA techniques.\",\n \"Guidance in determining which amino acid residues may be replaced, added or deleted without abolishing activities of interest, may be found by comparing the sequence of the particular polypeptide with that of homologous peptides and minimizing the number of amino acid sequence changes made in regions of high homology (conserved regions) or by replacing amino acids with consensus sequence.\",\n \"Alternatively, recombinant variants encoding these same or similar polypeptides may be synthesized or selected by making use of the “redundancy” in the genetic code.\",\n \"Various codon substitutions, such as the silent changes which produce various restriction sites, may be introduced to optimize cloning into a plasmid or viral vector or expression in a particular prokaryotic or eukaryotic system.\",\n \"Mutations in the polynucleotide sequence may be reflected in the polypeptide or domains of other peptides added to the polypeptide to modify the properties of any part of the polypeptide, to change characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate.\",\n \"Preferably, amino acid “substitutions” are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements.\",\n \"“Conservative” amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.\",\n \"For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.\",\n \"“Insertions” or “deletions” are preferably in the range of about 1 to 20 amino acids, more preferably 1 to 10 amino acids.\",\n \"The variation allowed may be experimentally determined by systematically making insertions, deletions, or substitutions of amino acids in a polypeptide molecule using recombinant DNA techniques and assaying the resulting recombinant variants for activity.\",\n \"Alternatively, where alteration of function is desired, insertions, deletions or non-conservative alterations can be engineered to produce altered polypeptides.\",\n \"Such alterations can, for example, alter one or more of the biological functions or biochemical characteristics of the polypeptides of the invention.\",\n \"For example, such alterations may change polypeptide characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate.\",\n \"Further, such alterations can be selected so as to generate polypeptides that are better suited for expression, scale up and the like in the host cells chosen for expression.\",\n \"For example, cysteine residues can be deleted or substituted with another amino acid residue in order to eliminate disulfide bridges.\",\n \"The terms “purified” or “substantially purified” as used herein denotes that the indicated nucleic acid or polypeptide is present in the substantial absence of other biological macromolecules, e.g., polynucleotides, proteins, and the like.\",\n \"In one embodiment, the polynucleotide or polypeptide is purified such that it constitutes at least 95% by weight, more preferably at least 99% by weight, of the indicated biological macromolecules present (but water, buffers, and other small molecules, especially molecules having a molecular weight of less than 1000 daltons, can be present).\",\n \"The term “isolated” as used herein refers to a nucleic acid or polypeptide separated from at least one other component (e.g., nucleic acid or polypeptide) present with the nucleic acid or polypeptide in its natural source.\",\n \"In one embodiment, the nucleic acid or polypeptide is found in the presence of (if anything) only a solvent, buffer, ion, or other component normally present in a solution of the same.\",\n \"The terms “isolated” and “purified” do not encompass nucleic acids or polypeptides present in their natural source.\",\n \"The term “recombinant,” when used herein to refer to a polypeptide or protein, means that a polypeptide or protein is derived from recombinant (e.g., microbial, insect, or mammalian) expression systems.\",\n \"“Microbial” refers to recombinant polypeptides or proteins made in bacterial or fungal (e.g., yeast) expression systems.\",\n \"As a product, “recombinant microbial” defines a polypeptide or protein essentially free of native endogenous substances and unaccompanied by associated native glycosylation.\",\n \"Polypeptides or proteins expressed in most bacterial cultures, e.g., E. coli, will be free of glycosylation modifications; polypeptides or proteins expressed in yeast will have a glycosylation pattern in general different from those expressed in mammalian cells.\",\n \"The term “recombinant expression vehicle or vector” refers to a plasmid or phage or virus or vector, for expressing a polypeptide from a DNA (RNA) sequence.\",\n \"An expression vehicle can comprise a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA and translated into protein, and (3) appropriate transcription initiation and termination sequences.\",\n \"Structural units intended for use in yeast or eukaryotic expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell.\",\n \"Alternatively, where recombinant protein is expressed without a leader or transport sequence, it may include an amino terminal methionine residue.\",\n \"This residue may or may not be subsequently cleaved from the expressed recombinant protein to provide a final product.\",\n \"The term “recombinant expression system” means host cells which have stably integrated a recombinant transcriptional unit into chromosomal DNA or carry the recombinant transcriptional unit extrachromosomally.\",\n \"Recombinant expression systems as defined herein will express heterologous polypeptides or proteins upon induction of the regulatory elements linked to the DNA segment or synthetic gene to be expressed.\",\n \"This term also means host cells which have stably integrated a recombinant genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers.\",\n \"Recombinant expression systems as defined herein will express polypeptides or proteins endogenous to the cell upon induction of the regulatory elements linked to the endogenous DNA segment or gene to be expressed.\",\n \"The cells can be prokaryotic or eukaryotic.\",\n \"The term “secreted” includes a protein that is transported across or through a membrane, including transport as a result of signal sequences in its amino acid sequence when it is expressed in a suitable host cell.\",\n \"“Secreted” proteins include without limitation proteins secreted wholly (e.g., soluble proteins) or partially (e.g., receptors) from the cell in which they are expressed.\",\n \"“Secreted” proteins also include without limitation proteins that are transported across the membrane of the endoplasmic reticulum.\",\n \"“Secreted” proteins are also intended to include proteins containing non-typical signal sequences (e.g.\",\n \"Interleukin-1 Beta, see Krasney, P. A. and Young, P. R. (1992) Cytokine 4(2):134-143) and factors released from damaged cells (e.g.\",\n \"Interleukin-1 Receptor Antagonist, see Arend, W. P. et. al.\",\n \"(1998) Annu.\",\n \"Rev.\",\n \"Immunol.\",\n \"16:27-55) Where desired, an expression vector may be designed to contain a “signal or leader sequence” which will direct the polypeptide through the membrane of a cell.\",\n \"Such a sequence may be naturally present on the polypeptides of the present invention or provided from heterologous protein sources by recombinant DNA techniques.\",\n \"The term “stringent” is used to refer to conditions that are commonly understood in the art as stringent.\",\n \"Stringent conditions can include highly stringent conditions (i.e., hybridization to filter-bound DNA in 0.5 M NaHPO4, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., and washing in 0.1×SSC/0.1% SDS at 68° C.), and moderately stringent conditions (i.e., washing in 0.2×SSC/0.1% SDS at 42° C.).\",\n \"Other exemplary hybridization conditions are described herein in the examples.\",\n \"In instances of hybridization of deoxyoligonucleotides, additional exemplary stringent hybridization conditions include washing in 6×SSC/0.05% sodium pyrophosphate at 37° C. (for 14-base oligonucleotides), 48° C. (for 17-base oligos), 55° C. (for 20-base oligonucleotides), and 60° C. (for 23-base oligonucleotides).\",\n \"As used herein, “substantially equivalent” can refer both to nucleotide and amino acid sequences, for example a mutant sequence, that varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which does not result in an adverse functional dissimilarity between the reference and subject sequences.\",\n \"Typically, such a substantially equivalent sequence varies from one of those listed herein by no more than about 35% (i.e., the number of individual residue substitutions, additions, and/or deletions in a substantially equivalent sequence, as compared to the corresponding reference sequence, divided by the total number of residues in the substantially equivalent sequence is about 0.35 or less).\",\n \"Such a sequence is said to have 65% sequence identity to the listed sequence.\",\n \"In one embodiment, a substantially equivalent, e.g., mutant, sequence of the invention varies from a listed sequence by no more than 30% (70% sequence identity); in a variation of this embodiment, by no more than 25% (75% sequence identity); and in a further variation of this embodiment, by no more than 20% (80% sequence identity) and in a further variation of this embodiment, by no more than 10% (90% sequence identity) and in a further variation of this embodiment, by no more that 5% (95% sequence identity).\",\n \"Substantially equivalent, e.g., mutant, amino acid sequences according to the invention preferably have at least 80% sequence identity with a listed amino acid sequence, more preferably at least 85% sequence identity, more preferably at least 90% sequence identity, more preferably at least 95% identity, more preferably at least 98% identity, and most preferably at least 99% identity.\",\n \"Substantially equivalent nucleotide sequences of the invention can have lower percent sequence identities, taking into account, for example, the redundancy or degeneracy of the genetic code.\",\n \"Preferably, nucleotide sequence has at least about 65% identity, more preferably at least about 75% identity, more preferably at least about 80% sequence identity, more preferably at least about 85% sequence identity, more preferably at least about 90% sequence identity, and most preferably at least about 95% identity, more preferably at least about 98% sequence identity, and most preferably at least about 99% sequence identity.\",\n \"For the purposes of the present invention, sequences having substantially equivalent biological activity and substantially equivalent expression characteristics are considered substantially equivalent.\",\n \"For the purposes of determining equivalence, truncation of the mature sequence (e.g., via a mutation which creates a spurious stop codon) should be disregarded.\",\n \"Sequence identity may be determined, e.g., using the Jotun Hein method (Hein, J.\",\n \"(1990) Methods Enzymol.\",\n \"183:626-645).\",\n \"Identity between sequences can also be determined by other methods known in the art, e.g.\",\n \"by varying hybridization conditions.\",\n \"The term “totipotent” refers to the capability of a cell to differentiate into all of the cell types of an adult organism.\",\n \"The term “transformation” means introducing DNA into a suitable host cell so that the DNA is replicable, either as an extrachromosomal element, or by chromosomal integration.\",\n \"The term “transfection” refers to the taking up of an expression vector by a suitable host cell, whether or not any coding sequences are in fact expressed.\",\n \"The term “infection” refers to the introduction of nucleic acids into a suitable host cell by use of a virus or viral vector.\",\n \"As used herein, an “uptake modulating fragment,” UMF, means a series of nucleotides which mediate the uptake of a linked DNA fragment into a cell.\",\n \"UMFs can be readily identified using known UMFs as a target sequence or target motif with the computer-based systems described below.\",\n \"The presence and activity of a UMF can be confirmed by attaching the suspected UMF to a marker sequence.\",\n \"The resulting nucleic acid molecule is then incubated with an appropriate host under appropriate conditions and the uptake of the marker sequence is determined.\",\n \"As described above, a UMF will increase the frequency of uptake of a linked marker sequence.\",\n \"Each of the above terms is meant to encompass all that is described for each, unless the context dictates otherwise.\",\n \"4.2 Nucleic Acids of the Invention Nucleotide sequences of the invention are set forth in the Sequence Listing.\",\n \"The isolated polynucleotides of the invention include a polynucleotide comprising the nucleotide sequences of SEQ ID NO: 1-8051; a polynucleotide encoding any one of the peptide sequences of SEQ ID NO: 8052-16102; and a polynucleotide comprising the nucleotide sequence encoding the mature protein coding sequence of the polypeptides of any one of SEQ ID NO: 8052-16102.The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent conditions to (a) the complement of any of the nucleotides sequences of SEQ ID NO: 1-8051; (b) nucleotide sequences encoding any one of the amino acid sequences set forth in the Sequence Listing; (c) a polynucleotide which is an allelic variant of any polynucleotide recited above; (d) a polynucleotide which encodes a species homolog of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of the polypeptides of SEQ ID NO: 8052-16102.Domains of interest may depend on the nature of the encoded polypeptide; e.g., domains in receptor-like polypeptides include ligand-binding, extracellular, transmembrane, or cytoplasmic domains, or combinations thereof; domains in immunoglobulin-like proteins include the variable immunoglobulin-like domains; domains in enzyme-like polypeptides include catalytic and substrate binding domains; and domains in ligand polypeptides include receptor-binding domains.\",\n \"The polynucleotides of the invention include naturally occurring or wholly or partially synthetic DNA, e.g., cDNA and genomic DNA, and RNA, e.g., mRNA.\",\n \"The polynucleotides may include all of the coding region of the cDNA or may represent a portion of the coding region of the cDNA.\",\n \"The present invention also provides genes corresponding to the cDNA sequences disclosed herein.\",\n \"The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein.\",\n \"Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials.\",\n \"Further 5′ and 3′ sequence can be obtained using methods known in the art.\",\n \"For example, full length cDNA or genomic DNA that corresponds to any of the polynucleotides of SEQ ID NO: 1-8051 can be obtained by screening appropriate cDNA or genomic DNA libraries under suitable hybridization conditions using any of the polynucleotides of SEQ ID NO: 1-8051 or a portion thereof as a probe.\",\n \"Alternatively, the polynucleotides of SEQ ID NO: 1-8051 may be used as the basis for suitable primer(s) that allow identification and/or amplification of genes in appropriate genomic DNA or cDNA libraries.\",\n \"The nucleic acid sequences of the invention can be assembled from ESTs and sequences (including cDNA and genomic sequences) obtained from one or more public databases, such as dbEST, gbpri, and UniGene.\",\n \"The EST sequences can provide identifying sequence information, representative fragment or segment information, or novel segment information for the full-length gene.\",\n \"The polynucleotides of the invention also provide polynucleotides including nucleotide sequences that are substantially equivalent to the polynucleotides recited above.\",\n \"Polynucleotides according to the invention can have, e.g., at least about 65%, at least about 70%, at least about 75%, at least about 80%, 81%, 82%, 83%, 84%, more typically at least about 85%, 86%, 87%, 88%, 89%, more typically at least about 90%, 91%, 92%, 93%, 94%, and even more typically at least about 95%, 96%, 97%, 98%, 99%, sequence identity to a polynucleotide recited above.\",\n \"Included within the scope of the nucleic acid sequences of the invention are nucleic acid sequence fragments that hybridize under stringent conditions to any of the nucleotide sequences of SEQ ID NO: 1-8051, or complements thereof, which fragment is greater than about 5 nucleotides, preferably 7 nucleotides, more preferably greater than 9 nucleotides and most preferably greater than 17 nucleotides.\",\n \"Fragments of, e.g.\",\n \"15, 17, or 20 nucleotides or more that are selective for (i.e.\",\n \"specifically hybridize to any one of the polynucleotides of the invention) are contemplated.\",\n \"Probes capable of specifically hybridizing to a polynucleotide can differentiate polynucleotide sequences of the invention from other polynucleotide sequences in the same family of genes or can differentiate human genes from genes of other species, and are preferably based on unique nucleotide sequences.\",\n \"The sequences falling within the scope of the present invention are not limited to these specific sequences, but also include allelic and species variations thereof.\",\n \"Allelic and species variations can be routinely determined by comparing the sequence provided in SEQ ID NO: 1-8051, a representative fragment thereof, or a nucleotide sequence at least 90% identical, preferably 95% identical, to SEQ ID NO: 1-8051 with a sequence from another isolate of the same species.\",\n \"Furthermore, to accommodate codon variability, the invention includes nucleic acid molecules coding for the same amino acid sequences as do the specific ORFs disclosed herein.\",\n \"In other words, in the coding region of an ORF, substitution of one codon for another codon that encodes the same amino acid is expressly contemplated.\",\n \"The nearest neighbor or homology result for the nucleic acids of the present invention, including SEQ ID NO: 1-8051 can be obtained by searching a database using an algorithm or a program.\",\n \"Preferably, a BLAST which stands for Basic Local Alignment Search Tool is used to search for local sequence alignments (Altshul, S. F. J. Mol.\",\n \"Evol.\",\n \"36 290-300 (1993) and Altschul S. F. et al.\",\n \"J. Mol.\",\n \"Biol.\",\n \"21:403-410 (1990)).\",\n \"Alternatively a FASTA version 3 search against Genpept, using Fastxy algorithm.\",\n \"Species homologs (or orthologs) of the disclosed polynucleotides and proteins are also provided by the present invention.\",\n \"Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species.\",\n \"The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous or related to that encoded by the polynucleotides.\",\n \"The nucleic acid sequences of the invention are further directed to sequences which encode variants of the described nucleic acids.\",\n \"These amino acid sequence variants may be prepared by methods known in the art by introducing appropriate nucleotide changes into a native or variant polynucleotide.\",\n \"There are two variables in the construction of amino acid sequence variants: the location of the mutation and the nature of the mutation.\",\n \"Nucleic acids encoding the amino acid sequence variants are preferably constructed by mutating the polynucleotide to encode an amino acid sequence that does not occur in nature.\",\n \"These nucleic acid alterations can be made at sites that differ in the nucleic acids from different species (variable positions) or in highly conserved regions (constant regions).\",\n \"Sites at such locations will typically be modified in series, e.g., by substituting first with conservative choices (e.g., hydrophobic amino acid to a different hydrophobic amino acid) and then with more distant choices (e.g., hydrophobic amino acid to a charged amino acid), and then deletions or insertions may be made at the target site.\",\n \"Amino acid sequence deletions generally range from about 1 to 30 residues, preferably about 1 to 10 residues, and are typically contiguous.\",\n \"Amino acid insertions include amino- and/or carboxyl-terminal fusions ranging in length from one to one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.\",\n \"Intrasequence insertions may range generally from about 1 to 10 amino residues, preferably from 1 to 5 residues.\",\n \"Examples of terminal insertions include the heterologous signal sequences necessary for secretion or for intracellular targeting in different host cells and sequences such as FLAG or poly-histidine sequences useful for purifying the expressed protein.\",\n \"In a preferred method, polynucleotides encoding the novel amino acid sequences are changed via site-directed mutagenesis.\",\n \"This method uses oligonucleotide sequences to alter a polynucleotide to encode the desired amino acid variant, as well as sufficient adjacent nucleotides on both sides of the changed amino acid to form a stable duplex on either side of the site of being changed.\",\n \"In general, the techniques of site-directed mutagenesis are well known to those of skill in the art and this technique is exemplified by publications such as, Edelman et al., DNA 2:183 (1983).\",\n \"A versatile and efficient method for producing site-specific changes in a polynucleotide sequence was published by Zoller and Smith, Nucleic Acids Res.\",\n \"10:6487-6500 (1982).\",\n \"PCR may also be used to create amino acid sequence variants of the novel nucleic acids.\",\n \"When small amounts of template DNA are used as starting material, primer(s) that differs slightly in sequence from the corresponding region in the template DNA can generate the desired amino acid variant.\",\n \"PCR amplification results in a population of product DNA fragments that differ from the polynucleotide template encoding the polypeptide at the position specified by the primer.\",\n \"The product DNA fragments replace the corresponding region in the plasmid and this gives a polynucleotide encoding the desired amino acid variant.\",\n \"A further technique for generating amino acid variants is the cassette mutagenesis technique described in Wells et al., Gene 34:315 (1985); and other mutagenesis techniques well known in the art, such as, for example, the techniques in Sambrook et al., supra, and Current Protocols in Molecular Biology, Ausubel et al.\",\n \"Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be used in the practice of the invention for the cloning and expression of these novel nucleic acids.\",\n \"Such DNA sequences include those which are capable of hybridizing to the appropriate novel nucleic acid sequence under stringent conditions.\",\n \"Polynucleotides encoding preferred polypeptide truncations of the invention can be used to generate polynucleotides encoding chimeric or fusion proteins comprising one or more domains of the invention and heterologous protein sequences.\",\n \"The polynucleotides of the invention additionally include the complement of any of the polynucleotides recited above.\",\n \"The polynucleotide can be DNA (genomic, cDNA, amplified, or synthetic) or RNA.\",\n \"Methods and algorithms for obtaining such polynucleotides are well known to those of skill in the art and can include, for example, methods for determining hybridization conditions that can routinely isolate polynucleotides of the desired sequence identities.\",\n \"In accordance with the invention, polynucleotide sequences comprising the mature protein coding sequences corresponding to any one of SEQ ID NO: 1-8051, or functional equivalents thereof, may be used to generate recombinant DNA molecules that direct the expression of that nucleic acid, or a functional equivalent thereof, in appropriate host cells.\",\n \"Also included are the cDNA inserts of any of the clones identified herein.\",\n \"A polynucleotide according to the invention can be joined to any of a variety of other nucleotide sequences by well-established recombinant DNA techniques (see Sambrook J et al.\",\n \"(1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY).\",\n \"Useful nucleotide sequences for joining to polynucleotides include an assortment of vectors, e.g., plasmids, cosmids, lambda phage derivatives, phagemids, and the like, that are well known in the art.\",\n \"Accordingly, the invention also provides a vector including a polynucleotide of the invention and a host cell containing the polynucleotide.\",\n \"In general, the vector contains an origin of replication functional in at least one organism, convenient restriction endonuclease sites, and a selectable marker for the host cell.\",\n \"Vectors according to the invention include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.\",\n \"A host cell according to the invention can be a prokaryotic or eukaryotic cell and can be a unicellular organism or part of a multicellular organism.\",\n \"The present invention further provides recombinant constructs comprising a nucleic acid having any of the nucleotide sequences of SEQ ID NO: 1-8051 or a fragment thereof or any other polynucleotides of the invention.\",\n \"In one embodiment, the recombinant constructs of the present invention comprise a vector, such as a plasmid or viral vector, into which a nucleic acid having any of the nucleotide sequences of SEQ ID NO: 1-8051 or a fragment thereof is inserted, in a forward or reverse orientation.\",\n \"In the case of a vector comprising one of the ORFs of the present invention, the vector may further comprise regulatory sequences, including for example, a promoter, operably linked to the ORF.\",\n \"Large numbers of suitable vectors and promoters are known to those of skill in the art and are commercially available for generating the recombinant constructs of the present invention.\",\n \"The following vectors are provided by way of example.\",\n \"Bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene); pTrc99A, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia).\",\n \"Eukaryotic: pWLneo, pSV2cat, pOG44, PXTI, pSG (Stratagene) pSVK3, pBPV, pMSG, pSVL (Pharmacia).\",\n \"The isolated polynucleotide of the invention may be operably linked to an expression control sequence such as the pMT2 or pED expression vectors disclosed in Kaufman et al., Nucleic Acids Res.\",\n \"19, 4485-4490 (1991), in order to produce the protein recombinantly.\",\n \"Many suitable expression control sequences are known in the art.\",\n \"General methods of expressing recombinant proteins are also known and are exemplified in R. Kaufman, Methods in Enzymology 185, 537-566 (1990).\",\n \"As defined herein “operably linked” means that the isolated polynucleotide of the invention and an expression control sequence are situated within a vector or cell in such a way that the protein is expressed by a host cell which has been transformed (transfected) with the ligated polynucleotide/expression control sequence.\",\n \"Promoter regions can be selected from any desired gene using CAT (chloramphenicol transferase) vectors or other vectors with selectable markers.\",\n \"Two appropriate vectors are pKK232-8 and pCM7.Particular named bacterial promoters include lacI, lacZ, T3, T7, gpt, lambda PR, and trc.\",\n \"Eukaryotic promoters include CMV immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-I.\",\n \"Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art.\",\n \"Generally, recombinant expression vectors will include origins of replication and selectable markers permitting transformation of the host cell, e.g., the ampicillin resistance gene of E. coli and S. cerevisiae TRP1 gene, and a promoter derived from a highly-expressed gene to direct transcription of a downstream structural sequence.\",\n \"Such promoters can be derived from operons encoding glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), a-factor, acid phosphatase, or heat shock proteins, among others.\",\n \"The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein into the periplasmic space or extracellular medium.\",\n \"Optionally, the heterologous sequence can encode a fusion protein including an amino terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product.\",\n \"Useful expression vectors for bacterial use are constructed by inserting a structural DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter.\",\n \"The vector will comprise one or more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and to, if desirable, provide amplification within the host.\",\n \"Suitable prokaryotic hosts for transformation include E. coli, Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus, although others may also be employed as a matter of choice.\",\n \"As a representative but non-limiting example, useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR322 (ATCC 37017).\",\n \"Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and GEM 1 (Promega Biotech, Madison, Wis., USA).\",\n \"These pBR322 “backbone” sections are combined with an appropriate promoter and the structural sequence to be expressed.\",\n \"Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter is induced or derepressed by appropriate means (e.g., temperature shift or chemical induction) and cells are cultured for an additional period.\",\n \"Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification.\",\n \"Polynucleotides of the invention can also be used to induce immune responses.\",\n \"For example, as described in Fan et al., Nat.\",\n \"Biotech.\",\n \"17:870-872 (1999), incorporated herein by reference, nucleic acid sequences encoding a polypeptide may be used to generate antibodies against the encoded polypeptide following topical administration of naked plasmid DNA or following injection, and preferably intramuscular injection of the DNA.\",\n \"The nucleic acid sequences are preferably inserted in a recombinant expression vector and may be in the form of naked DNA.\",\n \"4.3 Antisense Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 1-8051, or fragments, analogs or derivatives thereof.\",\n \"An “antisense” nucleic acid comprises a nucleotide sequence that is complementary to a “sense” nucleic acid encoding a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence.\",\n \"In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire coding strand, or to only a portion thereof.\",\n \"Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a protein of any of SEQ ID NO: 8052-16102 or antisense nucleic acids complementary to a nucleic acid sequence of SEQ ID NO: 1-8051 are additionally provided.\",\n \"In one embodiment, an antisense nucleic acid molecule is antisense to a “coding region” of the coding strand of a nucleotide sequence of the invention.\",\n \"The term “coding region” refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues.\",\n \"In another embodiment, the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence of the invention.\",\n \"The term “noncoding region” refers to 5′ and 3′ sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5′ and 3′ untranslated regions).\",\n \"Given the coding strand sequences encoding a nucleic acid disclosed herein (e.g., SEQ ID NO: 1-8051), antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing.\",\n \"The antisense nucleic acid molecule can be complementary to the entire coding region of a mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of a mRNA.\",\n \"For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of a mRNA.\",\n \"An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length.\",\n \"An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art.\",\n \"For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.\",\n \"Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.\",\n \"Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).\",\n \"The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a protein according to the invention to thereby inhibit expression of the protein, e.g., by inhibiting transcription and/or translation.\",\n \"The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix.\",\n \"An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site.\",\n \"Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically.\",\n \"For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens.\",\n \"The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein.\",\n \"To achieve sufficient intracellular concentrations of antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.\",\n \"In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule.\",\n \"An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual α-units, the strands run parallel to each other (Gaultier et al.\",\n \"(1987) Nucleic Acids Res 15: 6625-6641).\",\n \"The antisense nucleic acid molecule can also comprise a 2′-o-methylribonucleotide (Inoue et al.\",\n \"(1987) Nucleic Acids Res 15: 6131-6148) or a chimeric RNA-DNA analogue (Inoue et al.\",\n \"(1987) FEBS Lett 215: 327-330).\",\n \"4.4 Ribozymes and PNA Moieties In still another embodiment, an antisense nucleic acid of the invention is a ribozyme.\",\n \"Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as a mRNA, to which they have a complementary region.\",\n \"Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach (1988) Nature 334:585-591)) can be used to catalytically cleave a mRNA transcripts to thereby inhibit translation of a mRNA.\",\n \"A ribozyme having specificity for a nucleic acid of the invention can be designed based upon the nucleotide sequence of a DNA disclosed herein (i.e., SEQ ID NO: 1-8051).\",\n \"For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an mRNA of SEQ ID NO: 1-8051 (see, e.g., Cech et al.\",\n \"U.S. Pat.\",\n \"No.\",\n \"4,987,071; and Cech et al.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,116,742).\",\n \"Alternatively, polynucleotides of the invention can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules.\",\n \"See, e.g., Bartel et al., (1993) Science 261:1411-1418.Alternatively, gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of the gene in target cells.\",\n \"See generally, Helene.\",\n \"(1991) Anticancer Drug Des.\",\n \"6: 569-84; Helene.\",\n \"et al.\",\n \"(1992) Ann.\",\n \"N.Y. Acad.\",\n \"Sci.\",\n \"660:27-36; and Maher (1992) Bioassays 14: 807-15.In various embodiments, the nucleic acids of the invention can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule.\",\n \"For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al.\",\n \"(1996) Bioorg Med Chem 4: 5-23).\",\n \"As used herein, the terms “peptide nucleic acids” or “PNAs” refer to nucleic acid mimics, e.g.\",\n \"DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained.\",\n \"The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength.\",\n \"The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al.\",\n \"(1996) above; Perry-O'Keefe et al.\",\n \"(1996) PNAS 93: 14670-675.PNAs of the invention can be used in therapeutic and diagnostic applications.\",\n \"For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.\",\n \"PNAs of the invention can also be used, e.g., in the analysis of single base pair mutations in a gene by, e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S1 nucleases (Hyrup B.\",\n \"(1996) above); or as probes or primers for DNA sequence and hybridization (Hyrup et al.\",\n \"(1996), above; Perry-O'Keefe (1996), above).\",\n \"In another embodiment, PNAs of the invention can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art.\",\n \"For example, PNA-DNA chimeras can be generated that may combine the advantageous properties of PNA and DNA.\",\n \"Such chimeras allow DNA recognition enzymes, e.g., RNase H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity.\",\n \"PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (Hyrup (1996) above).\",\n \"The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996) above and Finn et al.\",\n \"(1996) Nucl Acids Res 24: 3357-63.For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5′-(4-methoxytrityl)amino-5′-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5′ end of DNA (Mag et al.\",\n \"(1989) Nucl Acid Res 17: 5973-88).\",\n \"PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5′ PNA segment and a 3′ DNA segment (Finn et al.\",\n \"(1996) above).\",\n \"Alternatively, chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNA segment.\",\n \"See, Petersen et al.\",\n \"(1975) Bioorg Med Chem Lett 5: 1119-11124.In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"84:648-652; PCT Publication No.\",\n \"W088/09810) or the blood-brain barrier (see, e.g., PCT Publication No.\",\n \"W089/10134).\",\n \"In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (See, e.g., Krol et al., 1988, BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988, Pharm.\",\n \"Res.\",\n \"5:539-549).\",\n \"To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, etc.\",\n \"4.5 Hosts The present invention further provides host cells genetically engineered to contain the polynucleotides of the invention.\",\n \"For example, such host cells may contain nucleic acids of the invention introduced into the host cell using known transformation, transfection or infection methods.\",\n \"The present invention still further provides host cells genetically engineered to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell.\",\n \"Knowledge of nucleic acid sequences allows for modification of cells to permit, or increase, expression of endogenous polypeptide.\",\n \"Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the polypeptide at higher levels.\",\n \"The heterologous promoter is inserted in such a manner that it is operatively linked to the encoding sequences.\",\n \"See, for example, PCT International Publication No.\",\n \"WO94/12650, PCT International Publication No.\",\n \"WO92/20808, and PCT International Publication No.\",\n \"WO91/09955.It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA.\",\n \"If linked to the coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.\",\n \"The host cell can be a higher eukaryotic host cell, such as a mammalian cell, a lower eukaryotic host cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell.\",\n \"Introduction of the recombinant construct into the host cell can be effected by calcium phosphate transfection, DEAE, dextran mediated transfection, or electroporation (Davis, L. et al., Basic Methods in Molecular Biology (1986)).\",\n \"The host cells containing one of the polynucleotides of the invention, can be used in conventional manners to produce the gene product encoded by the isolated fragment (in the case of an ORF) or can be used to produce a heterologous protein under the control of the EMF.\",\n \"Any host/vector system can be used to express one or more of the ORFs of the present invention.\",\n \"These include, but are not limited to, eukaryotic hosts such as HeLa cells, Cv-1 cell, COS cells, 293 cells, and Sf9 cells, as well as prokaryotic host such as E. coli and B. subtilis.\",\n \"The most preferred cells are those which do not normally express the particular polypeptide or protein or which expresses the polypeptide or protein at low natural level.\",\n \"Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters.\",\n \"Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention.\",\n \"Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook, et al., in Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y. (1989), the disclosure of which is hereby incorporated by reference.\",\n \"Various mammalian cell culture systems can also be employed to express recombinant protein.\",\n \"Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts, described by Gluzman, Cell 23:175 (1981).\",\n \"Other cell lines capable of expressing a compatible vector are, for example, the C127, monkey COS cells, Chinese Hamster Ovary (CHO) cells, human kidney 293 cells, human epidermal A431 cells, human Colo205 cells, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jurkat cells.\",\n \"Mammalian expression vectors will comprise an origin of replication, a suitable promoter and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5′ flanking nontranscribed sequences.\",\n \"DNA sequences derived from the SV40 viral genome, for example, SV40 origin, early promoter, enhancer, splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements.\",\n \"Recombinant polypeptides and proteins produced in bacterial culture are usually isolated by initial extraction from cell pellets, followed by one or more salting-out, aqueous ion exchange or size exclusion chromatography steps.\",\n \"Protein refolding steps can be used, as necessary, in completing configuration of the mature protein.\",\n \"Finally, high performance liquid chromatography (HPLC) can be employed for final purification steps.\",\n \"Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.\",\n \"Alternatively, it may be possible to produce the protein in lower eukaryotes such as yeast or insects or in prokaryotes such as bacteria.\",\n \"Potentially suitable yeast strains include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces strains, Candida, or any yeast strain capable of expressing heterologous proteins.\",\n \"Potentially suitable bacterial strains include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or any bacterial strain capable of expressing heterologous proteins.\",\n \"If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced therein, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein.\",\n \"Such covalent attachments may be accomplished using known chemical or enzymatic methods.\",\n \"In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination.\",\n \"As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods.\",\n \"Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences.\",\n \"Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting.\",\n \"These sequence include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.\",\n \"The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene.\",\n \"Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element.\",\n \"Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements.\",\n \"Here, the naturally occurring sequences are deleted and new sequences are added.\",\n \"In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the host cell genome.\",\n \"The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker.\",\n \"Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.\",\n \"The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Pat.\",\n \"No.\",\n \"5,272,071 to Chappel; U.S. Pat.\",\n \"No.\",\n \"5,578,461 to Sherwin et al.\",\n \"; International Application No.\",\n \"PCT/US92/09627 (WO93/09222) by Selden et al.\",\n \"; and International Application No.\",\n \"PCT/US90/06436 (WO91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.\",\n \"4.6 Polypeptides of the Invention The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising: the amino acid sequences set forth as any one of SEQ ID NO: 8052-16102 or an amino acid sequence encoded by any one of the nucleotide sequences SEQ ID NO: 1-8051 or the corresponding full length or mature protein.\",\n \"Polypeptides of the invention also include polypeptides preferably with biological or immunological activity that are encoded by: (a) a polynucleotide having any one of the nucleotide sequences set forth in SEQ ID NO: 1-8051 or (b) polynucleotides encoding any one of the amino acid sequences set forth as SEQ ID NO: 8052-16102 or (c) polynucleotides that hybridize to the complement of the polynucleotides of either (a) or (b) under stringent hybridization conditions.\",\n \"The invention also provides biologically active or immunologically active variants of any of the amino acid sequences set forth as SEQ ID NO: 8052-16102 or the corresponding full length or mature protein; and “substantial equivalents” thereof (e.g., with at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, 86%, 87%, 88%, 89%, at least about 90%, 91%, 92%, 93%, 94%, typically at least about 95%, 96%, 97%, more typically at least about 98%, or most typically at least about 99% amino acid identity) that retain biological activity.\",\n \"Polypeptides encoded by allelic variants may have a similar, increased, or decreased activity compared to polypeptides comprising SEQ ID NO: 8052-16102.Fragments of the proteins of the present invention which are capable of exhibiting biological activity are also encompassed by the present invention.\",\n \"Fragments of the protein may be in linear form or they may be cyclized using known methods, for example, as described in H. U. Saragovi, et al., Bio/Technology 10, 773-778 (1992) and in R. S. McDowell, et al., J. Amer.\",\n \"Chem.\",\n \"Soc.\",\n \"114, 9245-9253 (1992), both of which are incorporated herein by reference.\",\n \"Such fragments may be fused to carrier molecules such as immunoglobulins for many purposes, including increasing the valency of protein binding sites.\",\n \"The present invention also provides both full-length and mature forms (for example, without a signal sequence or precursor sequence) of the disclosed proteins.\",\n \"The protein coding sequence is identified in the sequence listing by translation of the disclosed nucleotide sequences.\",\n \"The mature form of such protein may be obtained by expression of a full-length polynucleotide in a suitable mammalian cell or other host cell.\",\n \"The sequence of the mature form of the protein is also determinable from the amino acid sequence of the full-length form.\",\n \"Where proteins of the present invention are membrane bound, soluble forms of the proteins are also provided.\",\n \"In such forms, part or all of the regions causing the proteins to be membrane bound are deleted so that the proteins are fully secreted from the cell in which they are expressed.\",\n \"Protein compositions of the present invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.\",\n \"The present invention further provides isolated polypeptides encoded by the nucleic acid fragments of the present invention or by degenerate variants of the nucleic acid fragments of the present invention.\",\n \"By “degenerate variant” is intended nucleotide fragments which differ from a nucleic acid fragment of the present invention (e.g., an ORF) by nucleotide sequence but, due to the degeneracy of the genetic code, encode an identical polypeptide sequence.\",\n \"Preferred nucleic acid fragments of the present invention are the ORFs that encode proteins.\",\n \"A variety of methodologies known in the art can be utilized to obtain any one of the isolated polypeptides or proteins of the present invention.\",\n \"At the simplest level, the amino acid sequence can be synthesized using commercially available peptide synthesizers.\",\n \"The synthetically-constructed protein sequences, by virtue of sharing primary, secondary or tertiary structural and/or conformational characteristics with proteins may possess biological properties in common therewith, including protein activity.\",\n \"This technique is particularly useful in producing small peptides and fragments of larger polypeptides.\",\n \"Fragments are useful, for example, in generating antibodies against the native polypeptide.\",\n \"Thus, they may be employed as biologically active or immunological substitutes for natural, purified proteins in screening of therapeutic compounds and in immunological processes for the development of antibodies.\",\n \"The polypeptides and proteins of the present invention can alternatively be purified from cells which have been altered to express the desired polypeptide or protein.\",\n \"As used herein, a cell is said to be altered to express a desired polypeptide or protein when the cell, through genetic manipulation, is made to produce a polypeptide or protein which it normally does not produce or which the cell normally produces at a lower level.\",\n \"One skilled in the art can readily adapt procedures for introducing and expressing either recombinant or synthetic sequences into eukaryotic or prokaryotic cells in order to generate a cell which produces one of the polypeptides or proteins of the present invention.\",\n \"The invention also relates to methods for producing a polypeptide comprising growing a culture of host cells of the invention in a suitable culture medium, and purifying the protein from the cells or the culture in which the cells are grown.\",\n \"For example, the methods of the invention include a process for producing a polypeptide in which a host cell containing a suitable expression vector that includes a polynucleotide of the invention is cultured under conditions that allow expression of the encoded polypeptide.\",\n \"The polypeptide can be recovered from the culture, conveniently from the culture medium, or from a lysate prepared from the host cells and further purified.\",\n \"Preferred embodiments include those in which the protein produced by such process is a full length or mature form of the protein.\",\n \"In an alternative method, the polypeptide or protein is purified from bacterial cells which naturally produce the polypeptide or protein.\",\n \"One skilled in the art can readily follow known methods for isolating polypeptides and proteins in order to obtain one of the isolated polypeptides or proteins of the present invention.\",\n \"These include, but are not limited to, immunochromatography, HPLC, size-exclusion chromatography, ion-exchange chromatography, and immuno-affinity chromatography.\",\n \"See, e.g., Scopes, Protein Purification: Principles and Practice, Springer-Verlag (1994); Sambrook, et al., in Molecular Cloning: A Laboratory Manual; Ausubel et al., Current Protocols in Molecular Biology.\",\n \"Polypeptide fragments that retain biological/immunological activity include fragments comprising greater than about 100 amino acids, or greater than about 200 amino acids, and fragments that encode specific protein domains.\",\n \"The purified polypeptides can be used in in vitro binding assays which are well known in the art to identify molecules which bind to the polypeptides.\",\n \"These molecules include but are not limited to, for e.g., small molecules, molecules from combinatorial libraries, antibodies or other proteins.\",\n \"The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art.\",\n \"In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.\",\n \"In addition, the peptides of the invention or molecules capable of binding to the peptides may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells.\",\n \"The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for SEQ ID NO: 8052-16102.The protein of the invention may also be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.\",\n \"The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but into which modification are naturally provided or deliberately engineered.\",\n \"For example, modifications in the peptide or DNA sequence can be made by those skilled in the art using known techniques.\",\n \"Modifications of interest in the protein sequences may include the alteration, substitution, replacement, insertion or deletion of a selected amino acid residue in the coding sequence.\",\n \"For example, one or more of the cysteine residues may be deleted or replaced with another amino acid to alter the conformation of the molecule.\",\n \"Techniques for such alteration, substitution, replacement, insertion or deletion are well known to those skilled in the art (see, e.g., U.S. Pat.\",\n \"No.\",\n \"4,518,584).\",\n \"Preferably, such alteration, substitution, replacement, insertion or deletion retains the desired activity of the protein.\",\n \"Regions of the protein that are important for the protein function can be determined by various methods known in the art including the alanine-scanning method which involved systematic substitution of single or strings of amino acids with alanine, followed by testing the resulting alanine-containing variant for biological activity.\",\n \"This type of analysis determines the importance of the substituted amino acid(s) in biological activity.\",\n \"Regions of the protein that are important for protein function may be determined by the eMATRIX program.\",\n \"Other fragments and derivatives of the sequences of proteins which would be expected to retain protein activity in whole or in part and are useful for screening or other immunological methodologies may also be easily made by those skilled in the art given the disclosures herein.\",\n \"Such modifications are encompassed by the present invention.\",\n \"The protein may also be produced by operably linking the isolated polynucleotide of the invention to suitable control sequences in one or more insect expression vectors, and employing an insect expression system.\",\n \"Materials and methods for baculovirus/insect cell expression systems are commercially available in kit form from, e.g., Invitrogen, San Diego, Calif., U.S.A. (the MaxBat™ kit), and such methods are well known in the art, as described in Summers and Smith, Texas Agricultural Experiment Station Bulletin No.\",\n \"1555 (1987), incorporated herein by reference.\",\n \"As used herein, an insect cell capable of expressing a polynucleotide of the present invention is “transformed.” The protein of the invention may be prepared by culturing transformed host cells under culture conditions suitable to express the recombinant protein.\",\n \"The resulting expressed protein may then be purified from such culture (i.e., from culture medium or cell extracts) using known purification processes, such as gel filtration and ion exchange chromatography.\",\n \"The purification of the protein may also include an affinity column containing agents which will bind to the protein; one or more column steps over such affinity resins as concanavalin A-agarose, heparin-toyopearl™ or Cibacrom blue 3GA Sepharose™; one or more steps involving hydrophobic interaction chromatography using such resins as phenyl ether, butyl ether, or propyl ether; or immunoaffinity chromatography.\",\n \"Alternatively, the protein of the invention may also be expressed in a form that will facilitate purification.\",\n \"For example, it may be expressed as a fusion protein, such as those of maltose binding protein (MBP), glutathione-S-transferase (GST) or thioredoxin (TRX), or as a His-tag.\",\n \"Kits for expression and purification of such fusion proteins are commercially available from New England BioLab (Beverly, Mass.\",\n \"), Pharmacia (Piscataway, N.J.) and Invitrogen, respectively.\",\n \"The protein can also be tagged with an epitope and subsequently purified by using a specific antibody directed to such epitope.\",\n \"One such epitope (“FLAG®”) is commercially available from Kodak (New Haven, Conn.).\",\n \"Finally, one or more reverse-phase high performance liquid chromatography (RP-HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, can be employed to further purify the protein.\",\n \"Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a substantially homogeneous isolated recombinant protein.\",\n \"The protein thus purified is substantially free of other mammalian proteins and is defined in accordance with the present invention as an “isolated protein.” The polypeptides of the invention include analogs (variants).\",\n \"This embraces fragments, as well as peptides in which one or more amino acids has been deleted, inserted, or substituted.\",\n \"Also, analogs of the polypeptides of the invention embrace fusions of the polypeptides or modifications of the polypeptides of the invention, wherein the polypeptide or analog is fused to another moiety or moieties, e.g., targeting moiety or another therapeutic agent.\",\n \"Such analogs may exhibit improved properties such as activity and/or stability.\",\n \"Examples of moieties which may be fused to the polypeptide or an analog include, for example, targeting moieties which provide for the delivery of polypeptide to pancreatic cells, e.g., antibodies to pancreatic cells, antibodies to immune cells such as T-cells, monocytes, dendritic cells, granulocytes, etc., as well as receptor and ligands expressed on pancreatic or immune cells.\",\n \"Other moieties which may be fused to the polypeptide include therapeutic agents which are used for treatment, for example, immunosuppressive drugs such as cyclosporin, SK506, azathioprine, CD3 antibodies and steroids.\",\n \"Also, polypeptides may be fused to immune modulators, and other cytokines such as alpha or beta interferon.\",\n \"4.6.1 Determining Polypeptide and Polynucleotide Identity and Similarity Preferred identity and/or similarity are designed to give the largest match between the sequences tested.\",\n \"Methods to determine identity and similarity are codified in computer programs including, but are not limited to, the GCG program package, including GAP (Devereux, J., et al., Nucleic Acids Research 12(1):387 (1984); Genetics Computer Group, University of Wisconsin, Madison, Wis.), BLASTP, BLASTN, BLASTX, FASTA (Altschul, S. F. et al., J. Molec.\",\n \"Biol.\",\n \"215:403-410 (1990), PSI-BLAST (Altschul S. F. et al., Nucleic Acids Res.\",\n \"vol.\",\n \"25, pp.\",\n \"3389-3402, herein incorporated by reference), eMatrix software (Wu et al., J. Comp.\",\n \"Biol., Vol.\",\n \"6, pp.\",\n \"219-235 (1999), herein incorporated by reference), eMotif software (Nevill-Manning et al, ISMB-97, Vol.\",\n \"4, pp.\",\n \"202-209, herein incorporated by reference), pFam software (Sonnhammer et al., Nucleic Acids Res., Vol.\",\n \"26 (1), pp.\",\n \"320-322 (1998), herein incorporated by reference) and the Kyte-Doolittle hydrophobocity prediction algorithm (J. Mol.\",\n \"Biol, 157, pp.\",\n \"105-31 (1982), incorporated herein by reference).\",\n \"The BLAST programs are publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul, S., et al.\",\n \"NCB NLM NIH Bethesda, Md.\",\n \"20894; Altschul, S., et al., J. Mol.\",\n \"Biol.\",\n \"215:403-410 (1990).\",\n \"4.7 Chimeric and Fusion Proteins The invention also provides chimeric or fusion proteins.\",\n \"As used herein, a “chimeric protein” or “fusion protein” comprises a polypeptide of the invention operatively linked to another polypeptide.\",\n \"Within a fusion protein the polypeptide according to the invention can correspond to all or a portion of a protein according to the invention.\",\n \"In one embodiment, a fusion protein comprises at least one biologically active portion of a protein according to the invention.\",\n \"In another embodiment, a fusion protein comprises at least two biologically active portions of a protein according to the invention.\",\n \"Within the fusion protein, the term “operatively linked” is intended to indicate that the polypeptide according to the invention and the other polypeptide are fused in-frame to each other.\",\n \"The polypeptide can be fused to the N-terminus or C-terminus.\",\n \"For example, in one embodiment a fusion protein comprises a polypeptide according to the invention operably linked to the extracellular domain of a second protein.\",\n \"In another embodiment, the fusion protein is a GST-fusion protein in which the polypeptide sequences of the invention are fused to the C-terminus of the GST (i.e., glutathione S-transferase) sequences.\",\n \"In another embodiment, the fusion protein is an immunoglobulin fusion protein in which the polypeptide sequences according to the invention comprises one or more domains are fused to sequences derived from a member of the immunoglobulin protein family.\",\n \"The immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a ligand and a protein of the invention on the surface of a cell, to thereby suppress signal transduction in vivo.\",\n \"The immunoglobulin fusion proteins can be used to affect the bioavailability of a cognate ligand.\",\n \"Inhibition of the ligand/protein interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, e,g., cancer as well as modulating (e.g., promoting or inhibiting) cell survival.\",\n \"Moreover, the immunoglobulin fusion proteins of the invention can be used as immunogens to produce antibodies in a subject, to purify ligands, and in screening assays to identify molecules that inhibit the interaction of a polypeptide of the invention with a ligand.\",\n \"A chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques.\",\n \"For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation.\",\n \"In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers.\",\n \"Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, for example, Ausubel et al.\",\n \"(eds.)\",\n \"CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992).\",\n \"Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide).\",\n \"A nucleic acid encoding a polypeptide of the invention can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the protein of the invention.\",\n \"4.8 Gene Therapy Mutations in the polynucleotides of the invention gene may result in loss of normal function of the encoded protein.\",\n \"The invention thus provides gene therapy to restore normal activity of the polypeptides of the invention; or to treat disease states involving polypeptides of the invention.\",\n \"Delivery of a functional gene encoding polypeptides of the invention to appropriate cells is effected ex vivo, in situ, or in vivo by use of vectors, and more particularly viral vectors (e.g., adenovirus, adeno-associated virus, or a retrovirus), or ex vivo by use of physical DNA transfer methods (e.g., liposomes or chemical treatments).\",\n \"See, for example, Anderson, Nature, supplement to vol.\",\n \"392, no.\",\n \"6679, pp.\",\n \"25-20 (1998).\",\n \"For additional reviews of gene therapy technology see Friedmann, Science, 244: 1275-1281 (1989); Verma, Scientific American: 68-84 (1990); and Miller, Nature, 357: 455-460 (1992).\",\n \"Introduction of any one of the nucleotides of the present invention or a gene encoding the polypeptides of the present invention can also be accomplished with extrachromosomal substrates (transient expression) or artificial chromosomes (stable expression).\",\n \"Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells.\",\n \"Treated cells can then be introduced in vivo for therapeutic purposes.\",\n \"Alternatively, it is contemplated that in other human disease states, preventing the expression of or inhibiting the activity of polypeptides of the invention will be useful in treating the disease states.\",\n \"It is contemplated that antisense therapy or gene therapy could be applied to negatively regulate the expression of polypeptides of the invention.\",\n \"Other methods inhibiting expression of a protein include the introduction of antisense molecules to the nucleic acids of the present invention, their complements, or their translated RNA sequences, by methods known in the art.\",\n \"Further, the polypeptides of the present invention can be inhibited by using targeted deletion methods, or the insertion of a negative regulatory element such as a silencer, which is tissue specific.\",\n \"The present invention still further provides cells genetically engineered in vivo to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell.\",\n \"These methods can be used to increase or decrease the expression of the polynucleotides of the present invention.\",\n \"Knowledge of DNA sequences provided by the invention allows for modification of cells to permit, increase, or decrease, expression of endogenous polypeptide.\",\n \"Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the protein at higher levels.\",\n \"The heterologous promoter is inserted in such a manner that it is operatively linked to the desired protein encoding sequences.\",\n \"See, for example, PCT International Publication No.\",\n \"WO 94/12650, PCT International Publication No.\",\n \"WO 92/20808, and PCT International Publication No.\",\n \"WO 91/09955.It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA.\",\n \"If linked to the desired protein coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.\",\n \"In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination.\",\n \"As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods.\",\n \"Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences.\",\n \"Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting.\",\n \"These sequences include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.\",\n \"The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene.\",\n \"Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element.\",\n \"Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements.\",\n \"Here, the naturally occurring sequences are deleted and new sequences are added.\",\n \"In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the cell genome.\",\n \"The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker.\",\n \"Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.\",\n \"The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Pat.\",\n \"No.\",\n \"5,272,071 to Chappel; U.S. Pat.\",\n \"No.\",\n \"5,578,461 to Sherwin et al.\",\n \"; International Application No.\",\n \"PCT/US92/09627 (WO93/09222) by Selden et al.\",\n \"; and International Application No.\",\n \"PCT/US90/06436 (WO91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.\",\n \"4.9 Transgenic Animals In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)].\",\n \"Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals.\",\n \"Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as “knockout” animals.\",\n \"Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Pat.\",\n \"No.\",\n \"5,557,032, incorporated herein by reference.\",\n \"Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states.\",\n \"Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism.\",\n \"Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Pat.\",\n \"No.\",\n \"5,489,743 and PCT Publication No.\",\n \"WO94/28122, incorporated herein by reference.\",\n \"Transgenic animals can be prepared wherein all or part of a promoter of the polynucleotides of the invention is either activated or inactivated to alter the level of expression of the polypeptides of the invention.\",\n \"Inactivation can be carried out using homologous recombination methods described above.\",\n \"Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression.\",\n \"The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.\",\n \"The polynucleotides of the present invention also make possible the development, through, e.g., homologous recombination or knock out strategies, of animals that fail to express polypeptides of the invention or that express a variant polypeptide.\",\n \"Such animals are useful as models for studying the in vivo activities of polypeptide as well as for studying modulators of the polypeptides of the invention.\",\n \"In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)].\",\n \"Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals.\",\n \"Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as “knockout” animals.\",\n \"Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Pat.\",\n \"No.\",\n \"5,557,032, incorporated herein by reference.\",\n \"Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states.\",\n \"Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism.\",\n \"Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Pat.\",\n \"No.\",\n \"5,489,743 and PCT Publication No.\",\n \"WO94/28122, incorporated herein by reference.\",\n \"Transgenic animals can be prepared wherein all or part of the polynucleotides of the invention promoter is either activated or inactivated to alter the level of expression of the polypeptides of the invention.\",\n \"Inactivation can be carried out using homologous recombination methods described above.\",\n \"Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression.\",\n \"The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.\",\n \"4.10 Uses and Biological Activity The polynucleotides and proteins of the present invention are expected to exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified herein.\",\n \"Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA).\",\n \"The mechanism underlying the particular condition or pathology will dictate whether the polypeptides of the invention, the polynucleotides of the invention or modulators (activators or inhibitors) thereof would be beneficial to the subject in need of treatment.\",\n \"Thus, “therapeutic compositions of the invention” include compositions comprising isolated polynucleotides (including recombinant DNA molecules, cloned genes and degenerate variants thereof) or polypeptides of the invention (including full length protein, mature protein and truncations or domains thereof), or compounds and other substances that modulate the overall activity of the target gene products, either at the level of target gene/protein expression or target protein activity.\",\n \"Such modulators include polypeptides, analogs, (variants), including fragments and fusion proteins, antibodies and other binding proteins; chemical compounds that directly or indirectly activate or inhibit the polypeptides of the invention (identified, e.g., via drug screening assays as described herein); antisense polynucleotides and polynucleotides suitable for triple helix formation; and in particular antibodies or other binding partners that specifically recognize one or more epitopes of the polypeptides of the invention.\",\n \"The polypeptides of the present invention may likewise be involved in cellular activation or in one of the other physiological pathways described herein.\",\n \"4.10.1 Research Uses and Utilities The polynucleotides provided by the present invention can be used by the research community for various purposes.\",\n \"The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to “subtract-out” known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a “gene chip” or other support, including for examination of expression patterns; to raise anti-protein antibodies using DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response.\",\n \"Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.\",\n \"The polypeptides provided by the present invention can similarly be used in assays to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding polypeptide is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands.\",\n \"Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.\",\n \"Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products.\",\n \"Methods for performing the uses listed above are well known to those skilled in the art.\",\n \"References disclosing such methods include without limitation “Molecular Cloning: A Laboratory Manual”, 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E. F. Fritsch and T. Maniatis eds., 1989, and “Methods in Enzymology: Guide to Molecular Cloning Techniques”, Academic Press, Berger, S. L. and A. R. Kimmel eds., 1987.4.10.2 Nutritional Uses Polynucleotides and polypeptides of the present invention can also be used as nutritional sources or supplements.\",\n \"Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate.\",\n \"In such cases the polypeptide or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules.\",\n \"In the case of microorganisms, the polypeptide or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.\",\n \"4.10.3 Cytokine and Cell Proliferation/Differentiation Activity A polypeptide of the present invention may exhibit activity relating to cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or inhibiting) activity or may induce production of other cytokines in certain cell populations.\",\n \"A polynucleotide of the invention can encode a polypeptide exhibiting such attributes.\",\n \"Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity.\",\n \"The activity of therapeutic compositions of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+(preB M+), 2E8, RB5, DA1, 123, T1165, HT2, CTLL2, TF-1, Mo7e, CMK, HUVEC, and Caco.\",\n \"Therapeutic compositions of the invention can be used in the following: Assays for T-cell or thymocyte proliferation include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub.\",\n \"Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol.\",\n \"137:3494-3500, 1986; Bertagnolli et al., J. Immunol.\",\n \"145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al., I. Immunol.\",\n \"149:3778-3783, 1992; Bowman et al., I. Immunol.\",\n \"152:1756-1761, 1994.Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T cell stimulation, Kruisbeek, A. M. and Shevach, E. M. In Current Protocols in Immunology.\",\n \"J. E. e.a.\",\n \"Coligan eds.\",\n \"Vol 1 pp.\",\n \"3.12.1-3.12.14, John Wiley and Sons, Toronto.\",\n \"1994; and Measurement of mouse and human interleukin-γ, Schreiber, R. D. In Current Protocols in Immunology.\",\n \"J. E. e.a.\",\n \"Coligan eds.\",\n \"Vol 1 pp.\",\n \"6.8.1-6.8.8, John Wiley and Sons, Toronto.\",\n \"1994.Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L. S. and Lipsky, P. E. In Current Protocols in Immunology.\",\n \"J. E. e.a.\",\n \"Coligan eds.\",\n \"Vol 1 pp.\",\n \"6.3.1-6.3.12, John Wiley and Sons, Toronto.\",\n \"1991; deVries et al., J. Exp.\",\n \"Med.\",\n \"173:1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"U.S.A. 80:2931-2938, 1983; Measurement of mouse and human interleukin 6-Nordan, R. In Current Protocols in Immunology.\",\n \"J. E. Coligan eds.\",\n \"Vol 1 pp.\",\n \"6.6.1-6.6.5, John Wiley and Sons, Toronto.\",\n \"1991; Smith et al., Proc.\",\n \"Natl.\",\n \"Aced.\",\n \"Sci.\",\n \"U.S.A. 83:1857-1861, 1986; Measurement of human Interleukin 11-Bennett, F., Giannotti, J., Clark, S. C. and Turner, K. J.\",\n \"In Current Protocols in Immunology.\",\n \"J. E. Coligan eds.\",\n \"Vol 1 pp.\",\n \"6.15.1 John Wiley and Sons, Toronto.\",\n \"1991; Measurement of mouse and human Interleukin 9-Ciarletta, A., Giannotti, J., Clark, S. C. and Turner, K. J.\",\n \"In Current Protocols in Immunology.\",\n \"J. E. Coligan eds.\",\n \"Vol 1 pp.\",\n \"6.13.1, John Wiley and Sons, Toronto.\",\n \"1991.Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W Strober, Pub.\",\n \"Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in Humans); Weinberger et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 77:6091-6095, 1980; Weinberger et al., Eur.\",\n \"J. Immuni.\",\n \"11:405-411, 1981; Takai et al., J. Immunol.\",\n \"137:3494-3500, 1986; Takai et al., J. Immunol.\",\n \"140:508-512, 1988.4.10.4 Stem Cell Growth Factor Activity A polypeptide of the present invention may exhibit stem cell growth factor activity and be involved in the proliferation, differentiation and survival of pluripotent and totipotent stem cells including primordial germ cells, embryonic stem cells, hematopoietic stem cells and/or germ line stem cells.\",\n \"Administration of the polypeptide of the invention to stem cells in vivo or ex vivo is expected to maintain and expand cell populations in a totipotential or pluripotential state which would be useful for re-engineering damaged or diseased tissues, transplantation, manufacture of bio-pharmaceuticals and the development of bio-sensors.\",\n \"The ability to produce large quantities of human cells has important working applications for the production of human proteins which currently must be obtained from non-human sources or donors, implantation of cells to treat diseases such as Parkinson's, Alzheimer's and other neurodegenerative diseases; tissues for grafting such as bone marrow, skin, cartilage, tendons, bone, muscle (including cardiac muscle), blood vessels, cornea, neural cells, gastrointestinal cells and others; and organs for transplantation such as kidney, liver, pancreas (including islet cells), heart and lung.\",\n \"It is contemplated that multiple different exogenous growth factors and/or cytokines may be administered in combination with the polypeptide of the invention to achieve the desired effect, including any of the growth factors listed herein, other stem cell maintenance factors, and specifically including stem cell factor (SCF), leukemia inhibitory factor (LIF), Flt-3 ligand (Flt-3L), any of the interleukins, recombinant soluble IL-6 receptor fused to IL-6, macrophage inflammatory protein I-alpha (MIP-1-alpha), G-CSF, GM-CSF, thrombopoietin (TPO), platelet factor 4 (PF-4), platelet-derived growth factor (PDGF), neural growth factors and basic fibroblast growth factor (bFGF).\",\n \"Since totipotent stem cells can give rise to virtually any mature cell type, expansion of these cells in culture will facilitate the production of large quantities of mature cells.\",\n \"Techniques for culturing stem cells are known in the art and administration of polypeptides of the invention, optionally with other growth factors and/or cytokines, is expected to enhance the survival and proliferation of the stem cell populations.\",\n \"This can be accomplished by direct administration of the polypeptide of the invention to the culture medium.\",\n \"Alternatively, stroma cells transfected with a polynucleotide that encodes for the polypeptide of the invention can be used as a feeder layer for the stem cell populations in culture or in vivo.\",\n \"Stromal support cells for feeder layers may include embryonic bone marrow fibroblasts, bone marrow stromal cells, fetal liver cells, or cultured embryonic fibroblasts (see U.S. Pat.\",\n \"No.\",\n \"5,690,926).\",\n \"Stem cells themselves can be transfected with a polynucleotide of the invention to induce autocrine expression of the polypeptide of the invention.\",\n \"This will allow for generation of undifferentiated totipotential/pluripotential stem cell lines that are useful as is or that can then be differentiated into the desired mature cell types.\",\n \"These stable cell lines can also serve as a source of undifferentiated totipotential/pluripotential mRNA to create cDNA libraries and templates for polymerase chain reaction experiments.\",\n \"These studies would allow for the isolation and identification of differentially expressed genes in stem cell populations that regulate stem cell proliferation and/or maintenance.\",\n \"Expansion and maintenance of totipotent stem cell populations will be useful in the treatment of many pathological conditions.\",\n \"For example, polypeptides of the present invention may be used to manipulate stem cells in culture to give rise to neuroepithelial cells that can be used to augment or replace cells damaged by illness, autoimmune disease, accidental damage or genetic disorders.\",\n \"The polypeptide of the invention may be useful for inducing the proliferation of neural cells and for the regeneration of nerve and brain tissue, i.e.\",\n \"for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders which involve degeneration, death or trauma to neural cells or nerve tissue.\",\n \"In addition, the expanded stem cell populations can also be genetically altered for gene therapy purposes and to decrease host rejection of replacement tissues after grafting or implantation.\",\n \"Expression of the polypeptide of the invention and its effect on stem cells can also be manipulated to achieve controlled differentiation of the stem cells into more differentiated cell types.\",\n \"A broadly applicable method of obtaining pure populations of a specific differentiated cell type from undifferentiated stem cell populations involves the use of a cell-type specific promoter driving a selectable marker.\",\n \"The selectable marker allows only cells of the desired type to survive.\",\n \"For example, stem cells can be induced to differentiate into cardiomyocytes (Wobus et al., Differentiation, 48: 173-182, (1991); Klug et al., J. Clin.\",\n \"Invest., 98(1): 216-224, (1998)) or skeletal muscle cells (Browder, L. W. In: Principles of Tissue Engineering eds.\",\n \"Lanza et al., Academic Press (1997)).\",\n \"Alternatively, directed differentiation of stem cells can be accomplished by culturing the stem cells in the presence of a differentiation factor such as retinoic acid and an antagonist of the polypeptide of the invention which would inhibit the effects of endogenous stem cell factor activity and allow differentiation to proceed.\",\n \"In vitro cultures of stem cells can be used to determine if the polypeptide of the invention exhibits stem cell growth factor activity.\",\n \"Stem cells are isolated from any one of various cell sources (including hematopoietic stem cells and embryonic stem cells) and cultured on a feeder layer, as described by Thompson et al.\",\n \"Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci, U.S.A., 92: 7844-7848 (1995), in the presence of the polypeptide of the invention alone or in combination with other growth factors or cytokines.\",\n \"The ability of the polypeptide of the invention to induce stem cells proliferation is determined by colony formation on semi-solid support e.g.\",\n \"as described by Bernstein et al., Blood, 77: 2316-2321 (1991).\",\n \"4.10.5 Hematopoiesis Regulating Activity A polypeptide of the present invention may be involved in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell disorders.\",\n \"Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g.\",\n \"in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thrombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above-mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantation, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post irradiation/chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous)) as normal cells or genetically manipulated for gene therapy.\",\n \"Therapeutic compositions of the invention can be used in the following: Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above.\",\n \"Assays for embryonic stem cell differentiation (which will identify, among others, proteins that influence embryonic differentiation hematopoiesis) include, without limitation, those described in: Johansson et al.\",\n \"Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993.Assays for stem cell survival and differentiation (which will identify, among others, proteins that regulate lympho-hematopoiesis) include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M. G. In Culture of Hematopoietic Cells.\",\n \"R. I. Freshney, et al.\",\n \"eds.\",\n \"Vol pp.\",\n \"265-268, Wiley-Liss, Inc., New York, N.Y. 1994; Hirayama et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I. K. and Briddell, R. A.\",\n \"In Culture of Hematopoietic Cells.\",\n \"R. I. Freshney, et al.\",\n \"eds.\",\n \"Vol pp.\",\n \"23-39, Wiley-Liss, Inc., New York, N.Y. 1994; Neben et al., Experimental Hematology 22:353-359, 1994; Cobblestone area forming cell assay, Ploemacher, R. E. In Culture of Hematopoietic Cells.\",\n \"R. I. Freshney, et al.\",\n \"eds.\",\n \"Vol pp.\",\n \"1-21, Wiley-Liss, Inc., New York, N.Y. 1994; Long term bone marrow cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells.\",\n \"R. I. Freshney, et al.\",\n \"eds.\",\n \"Vol pp.\",\n \"163-179, Wiley-Liss, Inc., New York, N.Y. 1994; Long term culture initiating cell assay, Sutherland, H. J.\",\n \"In Culture of Hematopoietic Cells.\",\n \"R. I. Freshney, et al.\",\n \"eds.\",\n \"Vol pp.\",\n \"139-162, Wiley-Liss, Inc., New York, N.Y. 1994.4.10.6 Tissue Growth Activity A polypeptide of the present invention also may be involved in bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as in wound healing and tissue repair and replacement, and in healing of burns, incisions and ulcers.\",\n \"A polypeptide of the present invention which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals.\",\n \"Compositions of a polypeptide, antibody, binding partner, or other modulator of the invention may have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints.\",\n \"De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.\",\n \"A polypeptide of this invention may also be involved in attracting bone-forming cells, stimulating growth of bone-forming cells, or inducing differentiation of progenitors of bone-forming cells.\",\n \"Treatment of osteoporosis, osteoarthritis, bone degenerative disorders, or periodontal disease, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.)\",\n \"mediated by inflammatory processes may also be possible using the composition of the invention.\",\n \"Another category of tissue regeneration activity that may involve the polypeptide of the present invention is tendon/ligament formation.\",\n \"Induction of tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals.\",\n \"Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue.\",\n \"De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments.\",\n \"The compositions of the present invention may provide environment to attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair.\",\n \"The compositions of the invention may also be useful in the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects.\",\n \"The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art.\",\n \"The compositions of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e.\",\n \"for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue.\",\n \"More specifically, a composition may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome.\",\n \"Further conditions that may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke.\",\n \"Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a composition of the invention.\",\n \"Compositions of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.\",\n \"Compositions of the present invention may also be involved in the generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues.\",\n \"Part of the desired effects may be by inhibition or modulation of fibrotic scarring may allow normal tissue to regenerate.\",\n \"A polypeptide of the present invention may also exhibit angiogenic activity.\",\n \"A composition of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage.\",\n \"A composition of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.\",\n \"Therapeutic compositions of the invention can be used in the following: Assays for tissue generation activity include, without limitation, those described in: International Patent Publication No.\",\n \"WO95/16035 (bone, cartilage, tendon); International Patent Publication No.\",\n \"WO95/05846 (nerve, neuronal); International Patent Publication No.\",\n \"WO91/07491 (skin, endothelium).\",\n \"Assays for wound healing activity include, without limitation, those described in: Winter, Epidermal Wound Healing, pps.\",\n \"71-112 (Maibach, H. I. and Rovee, D. T., eds.\",\n \"), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz J.\",\n \"Invest.\",\n \"Dermatol 71:382-84 (1978).\",\n \"4.10.7 Immune Stimulating or Suppressing Activity A polypeptide of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein.\",\n \"A polynucleotide of the invention can encode a polypeptide exhibiting such activities.\",\n \"A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in regulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations.\",\n \"These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders.\",\n \"More specifically, infectious diseases causes by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpes viruses, mycobacteria, Leishmania spp., malaria spp.\",\n \"and various fungal infections such as candidiasis.\",\n \"Of course, in this regard, proteins of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., in the treatment of cancer.\",\n \"include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease.\",\n \"Such a protein (or antagonists thereof, including antibodies) of the present invention may also to be useful in the treatment of allergic reactions and conditions (e.g., anaphylaxis, serum sickness, drug reactions, food allergies, insect venom allergies, mastocytosis, allergic rhinitis, hypersensitivity pneumonitis, urticaria, angioedema, eczema, atopic dermatitis, allergic contact dermatitis, erythema multiforme, Stevens-Johnson syndrome, allergic conjunctivitis, atopic keratoconjunctivitis, venereal keratoconjunctivitis, giant papillary conjunctivitis and contact allergies), such as asthma (particularly allergic asthma) or other respiratory problems.\",\n \"Other conditions, in which immune suppression is desired (including, for example, organ transplantation), may also be treatable using a protein (or antagonists thereof) of the present invention.\",\n \"The therapeutic effects of the polypeptides or antagonists thereof on allergic reactions can be evaluated by in vivo animals models such as the cumulative contact enhancement test (Lastbom et al., Toxicology 125: 59-66, 1998), skin prick test (Hoffmann et al., Allergy 54: 446-54, 1999), guinea pig skin sensitization test (Vohr et al., Arch.\",\n \"Toxocol.\",\n \"73: 501-9), and murine local lymph node assay (Kimber et al., J. Toxicol.\",\n \"Environ.\",\n \"Health 53: 563-79).\",\n \"Using the proteins of the invention it may also be possible to modulate immune responses, in a number of ways.\",\n \"Down regulation may be in the form of inhibiting or blocking an immune response already in progress or may involve preventing the induction of an immune response.\",\n \"The functions of activated T cells may be inhibited by suppressing T cell responses or by inducing specific tolerance in T cells, or both.\",\n \"Immunosuppression of T cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent.\",\n \"Tolerance, which involves inducing non-responsiveness or anergy in T cells, is distinguishable from immunosuppression in that it is generally antigen-specific and persists after exposure to the tolerizing agent has ceased.\",\n \"Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.\",\n \"Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as, for example, B7)), e.g., preventing high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD).\",\n \"For example, blockage of T cell function should result in reduced tissue destruction in tissue transplantation.\",\n \"Typically, in tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys the transplant.\",\n \"The administration of a therapeutic composition of the invention may prevent cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant.\",\n \"Moreover, a lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject.\",\n \"Induction of long-term tolerance by B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents.\",\n \"To achieve sufficient immunosuppression or tolerance in a subject, it may also be necessary to block the function of a combination of B lymphocyte antigens.\",\n \"The efficacy of particular therapeutic compositions in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans.\",\n \"Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci USA, 89:11102-11105 (1992).\",\n \"In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp.\",\n \"846-847) can be used to determine the effect of therapeutic compositions of the invention on the development of that disease.\",\n \"Blocking antigen function may also be therapeutically useful for treating autoimmune diseases.\",\n \"Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self-tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases.\",\n \"Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms.\",\n \"Administration of reagents which block stimulation of T cells can be used to inhibit T cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process.\",\n \"Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from the disease.\",\n \"The efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases.\",\n \"Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/lpr/lpr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp.\",\n \"840-856).\",\n \"Upregulation of an antigen function (e.g., a B lymphocyte antigen function), as a means of up regulating immune responses, may also be useful in therapy.\",\n \"Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting an initial immune response.\",\n \"For example, enhancing an immune response may be useful in cases of viral infection, including systemic viral diseases such as influenza, the common cold, and encephalitis.\",\n \"Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro with viral antigen-pulsed APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and reintroducing the in vitro activated T cells into the patient.\",\n \"Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the protein on their surface, and reintroduce the transfected cells into the patient.\",\n \"The infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T cells in vivo.\",\n \"A polypeptide of the present invention may provide the necessary stimulation signal to T cells to induce a T cell mediated immune response against the transfected tumor cells.\",\n \"In addition, tumor cells which lack MHC class I or MHC class II molecules, or which fail to reexpress sufficient mounts of MHC class I or MHC class II molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I alpha chain protein and β2 microglobulin protein or an MHC class II alpha chain protein and an MHC class II beta chain protein to thereby express MHC class I or MHC class II proteins on the cell surface.\",\n \"Expression of the appropriate class I or class II MHC in conjunction with a peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T cell mediated immune response against the transfected tumor cell.\",\n \"Optionally, a gene encoding an antisense construct which blocks expression of an MHC class II associated protein, such as the invariant chain, can also be cotransfected with a DNA encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity.\",\n \"Thus, the induction of a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject.\",\n \"The activity of a protein of the invention may, among other means, be measured by the following methods: Suitable assays for thymocyte or splenocyte cytotoxicity include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub.\",\n \"Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Herrmann et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 78:2488-2492, 1981; Herrmann et al., J. Immunol.\",\n \"128:1968-1974, 1982; Handa et al., J. Immunol.\",\n \"135:1564-1572, 1985; Takai et al., I. Immunol.\",\n \"137:3494-3500, 1986; Takai et al., J. Immunol.\",\n \"140:508-512, 1988; Bowman et al., J. Virology 61:1992-1998; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Brown et al., J. Immunol.\",\n \"153:3079-3092, 1994.Assays for T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Th1/Th2 profiles) include, without limitation, those described in: Maliszewski, J. Immunol.\",\n \"144:3028-3033, 1990; and Assays for B cell function: In vitro antibody production, Mond, J. J. and Brunswick, M. In Current Protocols in Immunology.\",\n \"J. E. e.a.\",\n \"Coligan eds.\",\n \"Vol 1 pp.\",\n \"3.8.1-3.8.16, John Wiley and Sons, Toronto.\",\n \"1994.Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly Th1 and CTL responses) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub.\",\n \"Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol.\",\n \"137:3494-3500, 1986; Takai et al., J. Immunol.\",\n \"140:508-512, 1988; Bertagnolli et al., J. Immunol.\",\n \"149:3778-3783, 1992.Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Guery et al., J. Immunol.\",\n \"134:536-544, 1995; Inaba et al., Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al., Journal of Immunology 154:5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182:255-260, 1995; Nair et al., Journal of Virology 67:4062-4069, 1993; Huang et al., Science 264:961-965, 1994; Macatonia et al., Journal of Experimental Medicine 169:1255-1264, 1989; Bhardwaj et al., Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640, 1990.Assays for lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in: Darzynkiewicz et al., Cytometry 13:795-808, 1992; Gorczyca et al., Leukemia 7:659-670, 1993; Gorczyca et al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1991; Zacharchuk, Journal of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al., International Journal of Oncology 1:639-648, 1992.Assays for proteins that influence early steps of T-cell commitment and development include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular Immunology 155:111-122, 1994; Galy et al., Blood 85:2770-2778, 1995; Toki et al., Proc.\",\n \"Nat.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 88:7548-7551, 1991.4.10.8 Activin/Inhibin Activity A polypeptide of the present invention may also exhibit activin- or inhibin-related activities.\",\n \"A polynucleotide of the invention may encode a polypeptide exhibiting such characteristics.\",\n \"Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH).\",\n \"Thus, a polypeptide of the present invention, alone or in heterodimers with a member of the inhibin family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals.\",\n \"Administration of sufficient amounts of other inhibins can induce infertility in these mammals.\",\n \"Alternatively, the polypeptide of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin group, may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary.\",\n \"See, for example, U.S. Pat.\",\n \"No.\",\n \"4,798,885.A polypeptide of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as, but not limited to, cows, sheep and pigs.\",\n \"The activity of a polypeptide of the invention may, among other means, be measured by the following methods.\",\n \"Assays for activin/inhibin activity include, without limitation, those described in: Vale et al., Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986; Vale et al., Nature 321:776-779, 1986; Mason et al., Nature 318:659-663, 1985; Forage et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 83:3091-3095, 1986.4.10.9 Chemotactic/Chemokinetic Activity A polypeptide of the present invention may be involved in chemotactic or chemokinetic activity for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells.\",\n \"A polynucleotide of the invention can encode a polypeptide exhibiting such attributes.\",\n \"Chemotactic and chemokinetic receptor activation can be used to mobilize or attract a desired cell population to a desired site of action.\",\n \"Chemotactic or chemokinetic compositions (e.g.\",\n \"proteins, antibodies, binding partners, or modulators of the invention) provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections.\",\n \"For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.\",\n \"A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population.\",\n \"Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells.\",\n \"Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis.\",\n \"Therapeutic compositions of the invention can be used in the following: Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population.\",\n \"Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Marguiles, E. M. Shevach, W. Strober, Pub.\",\n \"Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1-6.12.28; Taub et al.\",\n \"J. Clin.\",\n \"Invest.\",\n \"95:1370-1376, 1995; Lind et al.\",\n \"APMIS 103:140-146, 1995; Muller et al Eur.\",\n \"J. Immunol.\",\n \"25:1744-1748; Gruber et al.\",\n \"J. of Immunol.\",\n \"152:5860-5867, 1994; Johnston et al.\",\n \"J. of Immunol.\",\n \"153:1762-1768, 1994.4.10.10 Hemostatic and Thrombolytic Activity A polypeptide of the invention may also be involved in hemostatis or thrombolysis or thrombosis.\",\n \"A polynucleotide of the invention can encode a polypeptide exhibiting such attributes.\",\n \"Compositions may be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes.\",\n \"A composition of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke).\",\n \"Therapeutic compositions of the invention can be used in the following: Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin.\",\n \"Pharmacol.\",\n \"26:131-140, 1986; Burdick et al., Thrombosis Res.\",\n \"45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467-474, 1988.4.10.11 Cancer Diagnosis and Therapy Polypeptides of the invention may be involved in cancer cell generation, proliferation or metastasis.\",\n \"Detection of the presence or amount of polynucleotides or polypeptides of the invention may be useful for the diagnosis and/or prognosis of one or more types of cancer.\",\n \"For example, the presence or increased expression of a polynucleotide/polypeptide of the invention may indicate a hereditary risk of cancer, a precancerous condition, or an ongoing malignancy.\",\n \"Conversely, a defect in the gene or absence of the polypeptide may be associated with a cancer condition.\",\n \"Identification of single nucleotide polymorphisms associated with cancer or a predisposition to cancer may also be useful for diagnosis or prognosis.\",\n \"Cancer treatments promote tumor regression by inhibiting tumor cell proliferation, inhibiting angiogenesis (growth of new blood vessels that is necessary to support tumor growth) and/or prohibiting metastasis by reducing tumor cell motility or invasiveness.\",\n \"Therapeutic compositions of the invention may be effective in adult and pediatric oncology including in solid phase tumors/malignancies, locally advanced tumors, human soft tissue sarcomas, metastatic cancer, including lymphatic metastases, blood cell malignancies including multiple myeloma, acute and chronic leukemias, and lymphomas, head and neck cancers including mouth cancer, larynx cancer and thyroid cancer, lung cancers including small cell carcinoma and non-small cell cancers, breast cancers including small cell carcinoma and ductal carcinoma, gastrointestinal cancers including esophageal cancer, stomach cancer, colon cancer, colorectal cancer and polyps associated with colorectal neoplasia, pancreatic cancers, liver cancer, urologic cancers including bladder cancer and prostate cancer, malignancies of the female genital tract including ovarian carcinoma, uterine (including endometrial) cancers, and solid tumor in the ovarian follicle, kidney cancers including renal cell carcinoma, brain cancers including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers including osteomas, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal cell carcinoma, hemangiopericytoma and Karposi's sarcoma.\",\n \"Polypeptides, polynucleotides, or modulators of polypeptides of the invention (including inhibitors and stimulators of the biological activity of the polypeptide of the invention) may be administered to treat cancer.\",\n \"Therapeutic compositions can be administered in therapeutically effective dosages alone or in combination with adjuvant cancer therapy such as surgery, chemotherapy, radiotherapy, thermotherapy, and laser therapy, and may provide a beneficial effect, e.g.\",\n \"reducing tumor size, slowing rate of tumor growth, inhibiting metastasis, or otherwise improving overall clinical condition, without necessarily eradicating the cancer.\",\n \"The composition can also be administered in therapeutically effective amounts as a portion of an anti-cancer cocktail.\",\n \"An anticancer cocktail is a mixture of the polypeptide or modulator of the invention with one or more anti-cancer drugs in addition to a pharmaceutically acceptable carrier for delivery.\",\n \"The use of anti-cancer cocktails as a cancer treatment is routine.\",\n \"Anti-cancer drugs that are well known in the art and can be used as a treatment in combination with the polypeptide or modulator of the invention include: Actinomycin D, Aminoglutethimide, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin (cis-DDP), Cyclophosphamide, Cytarabine HCl (Cytosine arabinoside), Dacarbazine, Dactinomycin, Daunorubicin HCl, Doxorubicin HCl, Estramustine phosphate sodium, Etoposide (V16-213), Floxuridine, 5-Fluorouracil (5-Fu), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alpha-2a, Interferon Alpha-2b, Leuprolide acetate (LHRH-releasing factor analog), Lomustine, Mechlorethamine HCl (nitrogen mustard), Melphalan, Mercaptopurine, Mesna, Methotrexate (MTX), Mitomycin, Mitoxantrone HCl, Octreotide, Plicamycin, Procarbazine HCl, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Vincristine sulfate, Amsacrine, Azacitidine, Hexamethylmelamine, Interleukin-2, Mitoguazone, Pentostatin, Semustine, Teniposide, and Vindesine sulfate.\",\n \"In addition, therapeutic compositions of the invention may be used for prophylactic treatment of cancer.\",\n \"There are hereditary conditions and/or environmental situations (e.g.\",\n \"exposure to carcinogens) known in the art that predispose an individual to developing cancers.\",\n \"Under these circumstances, it may be beneficial to treat these individuals with therapeutically effective doses of the polypeptide of the invention to reduce the risk of developing cancers.\",\n \"In vitro models can be used to determine the effective doses of the polypeptide of the invention as a potential cancer treatment.\",\n \"These in vitro models include proliferation assays of cultured tumor cells, growth of cultured tumor cells in soft agar (see Freshney, (1987) Culture of Animal Cells: A Manual of Basic Technique, Wily-Liss, New York, N.Y. Ch 18 and Ch 21), tumor systems in nude mice as described in Giovanella et al., J. Natl.\",\n \"Can.\",\n \"Inst., 52: 921-30 (1974), mobility and invasive potential of tumor cells in Boyden Chamber assays as described in Pilkington et al., Anticancer Res., 17: 4107-9 (1997), and angiogenesis assays such as induction of vascularization of the chick chorioallantoic membrane or induction of vascular endothelial cell migration as described in Ribatta et al., Intl.\",\n \"J. Dev.\",\n \"Biol., 40: 1189-97 (1999) and Li et al., Clin.\",\n \"Exp.\",\n \"Metastasis, 17:423-9 (1999), respectively.\",\n \"Suitable tumor cells lines are available, e.g.\",\n \"from American Type Tissue Culture Collection catalogs.\",\n \"4.10.12 Receptor/Ligand Activity A polypeptide of the present invention may also demonstrate activity as receptor, receptor ligand or inhibitor or agonist of receptor/ligand interactions.\",\n \"A polynucleotide of the invention can encode a polypeptide exhibiting such characteristics.\",\n \"Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selectins, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses.\",\n \"Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.\",\n \"A protein of the present invention (including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor/ligand interactions.\",\n \"The activity of a polypeptide of the invention may, among other means, be measured by the following methods: Suitable assays for receptor-ligand activity include without limitation those described in: Current Protocols in Immunology; Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub.\",\n \"Greene Publishing Associates and Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1-7.28.22), Takai et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 84:6864-6868, 1987; Bierer et al., J. Exp.\",\n \"Med.\",\n \"168:1145-1156, 1988; Rosenstein et al., J. Exp.\",\n \"Med.\",\n \"169:149-160 1989; Stoltenborg et al., J. Immunol.\",\n \"Methods 175:59-68, 1994; Stitt et al., Cell 80:661-670, 1995.By way of example, the polypeptides of the invention may be used as a receptor for a ligand(s) thereby transmitting the biological activity of that ligand(s).\",\n \"Ligands may be identified through binding assays, affinity chromatography, dihybrid screening assays, BIAcore assays, gel overlay assays, or other methods known in the art.\",\n \"Studies characterizing drugs or proteins as agonist or antagonist or partial agonists or a partial antagonist require the use of other proteins as competing ligands.\",\n \"The polypeptides of the present invention or ligand(s) thereof may be labeled by being coupled to radioisotopes, colorimetric molecules or toxin molecules by conventional methods.\",\n \"(“Guide to Protein Purification” Murray P. Deutscher (ed) Methods in Enzymology Vol.\",\n \"182 (1990) Academic Press, Inc. San Diego).\",\n \"Examples of radioisotopes include, but are not limited to, tritium and carbon-14.Examples of colorimetric molecules include, but are not limited to, fluorescent molecules such as fluorescamine, or rhodamine or other colorimetric molecules.\",\n \"Examples of toxins include, but are not limited, to ricin.\",\n \"4.10.13 Drug Screening This invention is particularly useful for screening chemical compounds by using the novel polypeptides or binding fragments thereof in any of a variety of drug screening techniques.\",\n \"The polypeptides or fragments employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly.\",\n \"One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or a fragment thereof.\",\n \"Drugs are screened against such transformed cells in competitive binding assays.\",\n \"Such cells, either in viable or fixed form, can be used for standard binding assays.\",\n \"One may measure, for example, the formation of complexes between polypeptides of the invention or fragments and the agent being tested or examine the diminution in complex formation between the novel polypeptides and an appropriate cell line, which are well known in the art.\",\n \"Sources for test compounds that may be screened for ability to bind to or modulate (i.e., increase or decrease) the activity of polypeptides of the invention include (1) inorganic and organic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of either random or mimetic peptides, oligonucleotides or organic molecules.\",\n \"Chemical libraries may be readily synthesized or purchased from a number of commercial sources, and may include structural analogs of known compounds or compounds that are identified as “hits” or “leads” via natural product screening.\",\n \"The sources of natural product libraries are microorganisms (including bacteria and fungi), animals, plants or other vegetation, or marine organisms, and libraries of mixtures for screening may be created by: (1) fermentation and extraction of broths from soil, plant or marine microorganisms or (2) extraction of the organisms themselves.\",\n \"Natural product libraries include polyketides, non-ribosomal peptides, and (non-naturally occurring) variants thereof.\",\n \"For a review, see Science 282:63-68 (1998).\",\n \"Combinatorial libraries are composed of large numbers of peptides, oligonucleotides or organic compounds and can be readily prepared by traditional automated synthesis methods, PCR, cloning or proprietary synthetic methods.\",\n \"Of particular interest are peptide and oligonucleotide combinatorial libraries.\",\n \"Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries.\",\n \"For a review of combinatorial chemistry and libraries created therefrom, see Myers, Curr.\",\n \"Opin.\",\n \"Biotechnol.\",\n \"8:701-707 (1997).\",\n \"For reviews and examples of peptidomimetic libraries, see Al-Obeidi et al., Mol.\",\n \"Biotechnol, 9(3):205-23 (1998); Hruby et al., Curr Opin Chem Biol, 1 (1): 114-19 (1997); Dorner et al., Bioorg Med Chem, 4(5):709-15 (1996) (alkylated dipeptides).\",\n \"Identification of modulators through use of the various libraries described herein permits modification of the candidate “hit” (or “lead”) to optimize the capacity of the “hit” to bind a polypeptide of the invention.\",\n \"The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art.\",\n \"In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.\",\n \"The binding molecules thus identified may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells such as radioisotopes.\",\n \"The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for a polypeptide of the invention.\",\n \"Alternatively, the binding molecules may be complexed with imaging agents for targeting and imaging purposes.\",\n \"4.10.14 Assay for Receptor Activity The invention also provides methods to detect specific binding of a polypeptide e.g.\",\n \"a ligand or a receptor.\",\n \"The art provides numerous assays particularly useful for identifying previously unknown binding partners for receptor polypeptides of the invention.\",\n \"For example, expression cloning using mammalian or bacterial cells, or dihybrid screening assays can be used to identify polynucleotides encoding binding partners.\",\n \"As another example, affinity chromatography with the appropriate immobilized polypeptide of the invention can be used to isolate polypeptides that recognize and bind polypeptides of the invention.\",\n \"There are a number of different libraries used for the identification of compounds, and in particular small molecules, that modulate (i.e., increase or decrease) biological activity of a polypeptide of the invention.\",\n \"Ligands for receptor polypeptides of the invention can also be identified by adding exogenous ligands, or cocktails of ligands to two cells populations that are genetically identical except for the expression of the receptor of the invention: one cell population expresses the receptor of the invention whereas the other does not.\",\n \"The responses of the two cell populations to the addition of ligands(s) are then compared.\",\n \"Alternatively, an expression library can be co-expressed with the polypeptide of the invention in cells and assayed for an autocrine response to identify potential ligand(s).\",\n \"As still another example, BIAcore assays, gel overlay assays, or other methods known in the art can be used to identify binding partner polypeptides, including, (1) organic and inorganic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of random peptides, oligonucleotides or organic molecules.\",\n \"The role of downstream intracellular signaling molecules in the signaling cascade of the polypeptide of the invention can be determined.\",\n \"For example, a chimeric protein in which the cytoplasmic domain of the polypeptide of the invention is fused to the extracellular portion of a protein, whose ligand has been identified, is produced in a host cell.\",\n \"The cell is then incubated with the ligand specific for the extracellular portion of the chimeric protein, thereby activating the chimeric receptor.\",\n \"Known downstream proteins involved in intracellular signaling can then be assayed for expected modifications i.e.\",\n \"phosphorylation.\",\n \"Other methods known to those in the art can also be used to identify signaling molecules involved in receptor activity.\",\n \"4.10.15 Anti-Inflammatory Activity Compositions of the present invention may also exhibit anti-inflammatory activity.\",\n \"The anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response.\",\n \"Compositions with such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation intimation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1.Compositions of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material.\",\n \"Compositions of this invention may be utilized to prevent or treat conditions such as, but not limited to, sepsis, acute pancreatitis, endotoxin shock, cytokine induced shock, rheumatoid arthritis, chronic inflammatory arthritis, pancreatic cell damage from diabetes mellitus type 1, graft versus host disease, inflammatory bowel disease, inflammation associated with pulmonary disease, other autoimmune disease or inflammatory disease, an antiproliferative agent such as for acute or chronic mylegenous leukemia or in the prevention of premature labor secondary to intrauterine infections.\",\n \"4.10.16 Leukemias Leukemias and related disorders may be treated or prevented by administration of a therapeutic that promotes or inhibits function of the polynucleotides and/or polypeptides of the invention.\",\n \"Such leukemias and related disorders include but are not limited to acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia).\",\n \"4.10.17 Nervous System Disorders Nervous system disorders, involving cell types which can be tested for efficacy of intervention with compounds that modulate the activity of the polynucleotides and/or polypeptides of the invention, and which can be treated upon thus observing an indication of therapeutic utility, include but are not limited to nervous system injuries, and diseases or disorders which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination.\",\n \"Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the invention include but are not limited to the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems: (i) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries; (ii) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia; (iii) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, syphilis; (iv) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to degeneration associated with Parkinson's disease, Alzheimer's disease, Huntington's chorea, or amyotrophic lateral sclerosis; (v) lesions associated with nutritional diseases or disorders, in which a portion of the nervous system is destroyed or injured by a nutritional disorder or disorder of metabolism including but not limited to, vitamin B12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum), and alcoholic cerebellar degeneration; (vi) neurological lesions associated with systemic diseases including but not limited to diabetes (diabetic neuropathy, Bell's palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis; (vii) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and (viii) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including but not limited to multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.\",\n \"Therapeutics which are useful according to the invention for treatment of a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons.\",\n \"For example, and not by way of limitation, therapeutics which elicit any of the following effects may be useful according to the invention: (i) increased survival time of neurons in culture; (ii) increased sprouting of neurons in culture or in vivo; (iii) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or (iv) decreased symptoms of neuron dysfunction in vivo.\",\n \"Such effects may be measured by any method known in the art.\",\n \"In preferred, non-limiting embodiments, increased survival of neurons may be measured by the method set forth in Arakawa et al.\",\n \"(1990, J. Neurosci.\",\n \"10:3507-3515); increased sprouting of neurons may be detected by methods set forth in Pestronk et al.\",\n \"(1980, Exp.\",\n \"Neurol.\",\n \"70:65-82) or Brown et al.\",\n \"(1981, Ann.\",\n \"Rev.\",\n \"Neurosci.\",\n \"4:17-42); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., depending on the molecule to be measured; and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.\",\n \"In specific embodiments, motor neuron disorders that may be treated according to the invention include but are not limited to disorders such as infarction, infection, exposure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as disorders that selectively affect neurons such as amyotrophic lateral sclerosis, and including but not limited to progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, infantile and juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).\",\n \"4.10.18 Other Activities A polypeptide of the invention may also exhibit one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or circadian cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, co-factors or other nutritional factors or component(s); effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects; promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic lineages; hormonal or endocrine activity; in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); immunoglobulin-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein.\",\n \"4.10.19 Identification of Polymorphisms The demonstration of polymorphisms makes possible the identification of such polymorphisms in human subjects and the pharmacogenetic use of this information for diagnosis and treatment.\",\n \"Such polymorphisms may be associated with, e.g., differential predisposition or susceptibility to various disease states (such as disorders involving inflammation or immune response) or a differential response to drug administration, and this genetic information can be used to tailor preventive or therapeutic treatment appropriately.\",\n \"For example, the existence of a polymorphism associated with a predisposition to inflammation or autoimmune disease makes possible the diagnosis of this condition in humans by identifying the presence of the polymorphism.\",\n \"Polymorphisms can be identified in a variety of ways known in the art which all generally involve obtaining a sample from a patient, analyzing DNA from the sample, optionally involving isolation or amplification of the DNA, and identifying the presence of the polymorphism in the DNA.\",\n \"For example, PCR may be used to amplify an appropriate fragment of genomic DNA which may then be sequenced.\",\n \"Alternatively, the DNA may be subjected to allele-specific oligonucleotide hybridization (in which appropriate oligonucleotides are hybridized to the DNA under conditions permitting detection of a single base mismatch) or to a single nucleotide extension assay (in which an oligonucleotide that hybridizes immediately adjacent to the position of the polymorphism is extended with one or more labeled nucleotides).\",\n \"In addition, traditional restriction fragment length polymorphism analysis (using restriction enzymes that provide differential digestion of the genomic DNA depending on the presence or absence of the polymorphism) may be performed.\",\n \"Arrays with nucleotide sequences of the present invention can be used to detect polymorphisms.\",\n \"The array can comprise modified nucleotide sequences of the present invention in order to detect the nucleotide sequences of the present invention.\",\n \"In the alternative, any one of the nucleotide sequences of the present invention can be placed on the array to detect changes from those sequences.\",\n \"Alternatively a polymorphism resulting in a change in the amino acid sequence could also be detected by detecting a corresponding change in amino acid sequence of the protein, e.g., by an antibody specific to the variant sequence.\",\n \"4.10.20 Arthritis and Inflammation The immunosuppressive effects of the compositions of the invention against rheumatoid arthritis are determined in an experimental animal model system.\",\n \"The experimental model system is adjuvant induced arthritis in rats, and the protocol is described by J. Holoshitz, et at., 1983, Science, 219:56, or by B. Waksman et al., 1963, Int.\",\n \"Arch.\",\n \"Allergy Appl.\",\n \"Immunol., 23:129.Induction of the disease can be caused by a single injection, generally intradermally, of a suspension of killed Mycobacterium tuberculosis in complete Freund's adjuvant (CFA).\",\n \"The route of injection can vary, but rats may be injected at the base of the tail with an adjuvant mixture.\",\n \"The polypeptide is administered in phosphate buffered solution (PBS) at a dose of about 1-5 mg/kg.\",\n \"The control consists of administering PBS only.\",\n \"The procedure for testing the effects of the test compound would consist of intradermally injecting killed Mycobacterium tuberculosis in CFA followed by immediately administering the test compound and subsequent treatment every other day until day 24.At 14, 15, 18, 20, 22, and 24 days after injection of Mycobacterium CFA, an overall arthritis score may be obtained as described by J. Holoskitz above.\",\n \"An analysis of the data would reveal that the test compound would have a dramatic affect on the swelling of the joints as measured by a decrease of the arthritis score.\",\n \"4.11 Therapeutic Methods The compositions (including polypeptide fragments, analogs, variants and antibodies or other binding partners or modulators including antisense polynucleotides) of the invention have numerous applications in a variety of therapeutic methods.\",\n \"Examples of therapeutic applications include, but are not limited to, those exemplified herein.\",\n \"4.11.1 Example One embodiment of the invention is the administration of an effective amount of the polypeptides or other composition of the invention to individuals affected by a disease or disorder that can be modulated by regulating the peptides of the invention.\",\n \"While the mode of administration is not particularly important, parenteral administration is preferred.\",\n \"An exemplary mode of administration is to deliver an intravenous bolus.\",\n \"The dosage of the polypeptides or other composition of the invention will normally be determined by the prescribing physician.\",\n \"It is to be expected that the dosage will vary according to the age, weight, condition and response of the individual patient.\",\n \"Typically, the amount of polypeptide administered per dose will be in the range of about 0.01 μg/kg to 100 mg/kg of body weight, with the preferred dose being about 0.1 μg/kg to 10 mg/kg of patient body weight.\",\n \"For parenteral administration, polypeptides of the invention will be formulated in an injectable form combined with a pharmaceutically acceptable parenteral vehicle.\",\n \"Such vehicles are well known in the art and examples include water, saline, Ringer's solution, dextrose solution, and solutions consisting of small amounts of the human serum albumin.\",\n \"The vehicle may contain minor amounts of additives that maintain the isotonicity and stability of the polypeptide or other active ingredient.\",\n \"The preparation of such solutions is within the skill of the art.\",\n \"4.12 Pharmaceutical Formulations and Routes of Administration A protein or other composition of the present invention (from whatever source derived, including without limitation from recombinant and non-recombinant sources and including antibodies and other binding partners of the polypeptides of the invention) may be administered to a patient in need, by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a variety of disorders.\",\n \"Such a composition may optionally contain (in addition to protein or other active ingredient and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.\",\n \"The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).\",\n \"The characteristics of the carrier will depend on the route of administration.\",\n \"The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNF0, TNF1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, and erythropoietin.\",\n \"In further compositions, proteins of the invention may be combined with other agents beneficial to the treatment of the disease or disorder in question.\",\n \"These agents include various growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), insulin-like growth factor (IGF), as well as cytokines described herein.\",\n \"The pharmaceutical composition may further contain other agents which either enhance the activity of the protein or other active ingredient or complement its activity or use in treatment.\",\n \"Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with protein or other active ingredient of the invention, or to minimize side effects.\",\n \"Conversely, protein or other active ingredient of the present invention may be included in formulations of the particular clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent (such as IL-1Ra, IL-1 Hy1, IL-1 Hy2, anti-TNF, corticosteroids, immunosuppressive agents).\",\n \"A protein of the present invention may be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins.\",\n \"As a result, pharmaceutical compositions of the invention may comprise a protein of the invention in such multimeric or complexed form.\",\n \"As an alternative to being included in a pharmaceutical composition of the invention including a first protein, a second protein or a therapeutic agent may be concurrently administered with the first protein (e.g., at the same time, or at differing times provided that therapeutic concentrations of the combination of agents is achieved at the treatment site).\",\n \"Techniques for formulation and administration of the compounds of the instant application may be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition.\",\n \"A therapeutically effective dose further refers to that amount of the compound sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.\",\n \"When applied to an individual active ingredient, administered alone, a therapeutically effective dose refers to that ingredient alone.\",\n \"When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.\",\n \"In practicing the method of treatment or use of the present invention, a therapeutically effective amount of protein or other active ingredient of the present invention is administered to a mammal having a condition to be treated.\",\n \"Protein or other active ingredient of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors.\",\n \"When co-administered with one or more cytokines, lymphokines or other hematopoietic factors, protein or other active ingredient of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially.\",\n \"If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein or other active ingredient of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.\",\n \"4.12.1 Routes of Administration Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.\",\n \"Administration of protein or other active ingredient of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection.\",\n \"Intravenous administration to the patient is preferred.\",\n \"Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a arthritic joints or in fibrotic tissue, often in a depot or sustained release formulation.\",\n \"In order to prevent the scarring process frequently occurring as complication of glaucoma surgery, the compounds may be administered topically, for example, as eye drops.\",\n \"Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a specific antibody, targeting, for example, arthritic or fibrotic tissue.\",\n \"The liposomes will be targeted to and taken up selectively by the afflicted tissue.\",\n \"The polypeptides of the invention are administered by any route that delivers an effective dosage to the desired site of action.\",\n \"The determination of a suitable route of administration and an effective dosage for a particular indication is within the level of skill in the art.\",\n \"Preferably for wound treatment, one administers the therapeutic compound directly to the site.\",\n \"Suitable dosage ranges for the polypeptides of the invention can be extrapolated from these dosages or from similar studies in appropriate animal models.\",\n \"Dosages can then be adjusted as necessary by the clinician to provide maximal therapeutic benefit.\",\n \"4.12.2 Compositions/Formulations Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.\",\n \"These pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.\",\n \"Proper formulation is dependent upon the route of administration chosen.\",\n \"When a therapeutically effective amount of protein or other active ingredient of the present invention is administered orally, protein or other active ingredient of the present invention will be in the form of a tablet, capsule, powder, solution or elixir.\",\n \"When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant.\",\n \"The tablet, capsule, and powder contain from about 5 to 95% protein or other active ingredient of the present invention, and preferably from about 25 to 90% protein or other active ingredient of the present invention.\",\n \"When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added.\",\n \"The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol.\",\n \"When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of protein or other active ingredient of the present invention, and preferably from about 1 to 50% protein or other active-ingredient of the present invention.\",\n \"When a therapeutically effective amount of protein or other active ingredient of the present invention is administered by intravenous, cutaneous or subcutaneous injection, protein or other active ingredient of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution.\",\n \"The preparation of such parenterally acceptable protein or other active ingredient solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.\",\n \"A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to protein or other active ingredient of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art.\",\n \"The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.\",\n \"For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.\",\n \"For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation.\",\n \"Such penetrants are generally known in the art.\",\n \"For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.\",\n \"Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.\",\n \"Pharmaceutical preparations for oral use can be obtained from a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.\",\n \"Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).\",\n \"If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.\",\n \"Dragee cores are provided with suitable coatings.\",\n \"For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.\",\n \"Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.\",\n \"Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.\",\n \"The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.\",\n \"In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.\",\n \"In addition, stabilizers may be added.\",\n \"All formulations for oral administration should be in dosages suitable for such administration.\",\n \"For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.\",\n \"For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.\",\n \"In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.\",\n \"Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.\",\n \"The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.\",\n \"Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.\",\n \"The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.\",\n \"Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.\",\n \"Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.\",\n \"Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.\",\n \"Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.\",\n \"Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.\",\n \"Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.\",\n \"The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.\",\n \"In addition to the formulations described previously, the compounds may also be formulated as a depot preparation.\",\n \"Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.\",\n \"Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.\",\n \"A pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.\",\n \"The co-solvent system may be the VPD co-solvent system.\",\n \"VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.\",\n \"The VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution.\",\n \"This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.\",\n \"Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.\",\n \"Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g.\",\n \"polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.\",\n \"Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed.\",\n \"Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.\",\n \"Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.\",\n \"Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.\",\n \"Various types of sustained-release materials have been established and are well known by those skilled in the art.\",\n \"Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.\",\n \"Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein or other active ingredient stabilization may be employed.\",\n \"The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients.\",\n \"Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.\",\n \"Many of the active ingredients of the invention may be provided as salts with pharmaceutically compatible counter ions.\",\n \"Such pharmaceutically acceptable base addition salts are those salts which retain the biological effectiveness and properties of the free acids and which are obtained by reaction with inorganic or organic bases such as sodium hydroxide, magnesium hydroxide, ammonia, trialkylamine, dialkylamine, monoalkylamine, dibasic amino acids, sodium acetate, potassium benzoate, triethanol amine and the like.\",\n \"The pharmaceutical composition of the invention may be in the form of a complex of the protein(s) or other active ingredient(s) of present invention along with protein or peptide antigens.\",\n \"The protein and/or peptide antigen will deliver a stimulatory signal to both B and T lymphocytes.\",\n \"B-lymphocytes will respond to antigen through their surface immunoglobulin receptor.\",\n \"T lymphocytes will respond to antigen through the T cell receptor (TCR) following presentation of the antigen by MHC proteins.\",\n \"MHC and structurally related proteins including those encoded by class I and class II MHC genes on host cells will serve to present the peptide antigen(s) to T lymphocytes.\",\n \"The antigen components could also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules that can directly signal T cells.\",\n \"Alternatively antibodies able to bind surface immunoglobulin and other molecules on B cells as well as antibodies able to bind the TCR and other molecules on T cells can be combined with the pharmaceutical composition of the invention.\",\n \"The pharmaceutical composition of the invention may be in the form of a liposome in which protein of the present invention is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution.\",\n \"Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithins, phospholipids, saponin, bile acids, and the like.\",\n \"Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Pat.\",\n \"Nos.\",\n \"4,235,871; 4,501,728; 4,837,028; and 4,737,323, all of which are incorporated herein by reference.\",\n \"The amount of protein or other active ingredient of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone.\",\n \"Ultimately, the attending physician will decide the amount of protein or other active ingredient of the present invention with which to treat each individual patient.\",\n \"Initially, the attending physician will administer low doses of protein or other active ingredient of the present invention and observe the patient's response.\",\n \"Larger doses of protein or other active ingredient of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further.\",\n \"It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 μg to about 100 mg (preferably about 0.1 μg to about 10 mg, more preferably about 0.1 μg to about 1 mg) of protein or other active ingredient of the present invention per kg body weight.\",\n \"For compositions of the present invention which are useful for bone, cartilage, tendon or ligament regeneration, the therapeutic method includes administering the composition topically, systematically, or locally as an implant or device.\",\n \"When administered, the therapeutic composition for use in this invention is, of course, in a pyrogen-free, physiologically acceptable form.\",\n \"Further, the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of bone, cartilage or tissue damage.\",\n \"Topical administration may be suitable for wound healing and tissue repair.\",\n \"Therapeutically useful agents other than a protein or other active ingredient of the invention which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention.\",\n \"Preferably for bone and/or cartilage formation, the composition would include a matrix capable of delivering the protein-containing or other active ingredient-containing composition to the site of bone and/or cartilage damage, providing a structure for the developing bone and cartilage and optimally capable of being resorbed into the body.\",\n \"Such matrices may be formed of materials presently in use for other implanted medical applications.\",\n \"The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties.\",\n \"The particular application of the compositions will define the appropriate formulation.\",\n \"Potential matrices for the compositions may be biodegradable and chemically defined calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, polyglycolic acid and polyanhydrides.\",\n \"Other potential materials are biodegradable and biologically well-defined, such as bone or dermal collagen.\",\n \"Further matrices are comprised of pure proteins or extracellular matrix components.\",\n \"Other potential matrices are nonbiodegradable and chemically defined, such as sintered hydroxyapatite, bioglass, aluminates, or other ceramics.\",\n \"Matrices may be comprised of combinations of any of the above-mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalcium phosphate.\",\n \"The bioceramics may be altered in composition, such as in calcium-aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability.\",\n \"Presently preferred is a 50:50 (mole weight) copolymer of lactic acid and glycolic acid in the form of porous particles having diameters ranging from 150 to 800 microns.\",\n \"In some applications, it will be useful to utilize a sequestering agent, such as carboxymethyl cellulose or autologous blood clot, to prevent the protein compositions from disassociating from the matrix.\",\n \"A preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC).\",\n \"Other preferred sequestering agents include hyaluronic acid, sodium alginate, poly(ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and poly(vinyl alcohol).\",\n \"The amount of sequestering agent useful herein is 0.5-20 wt %, preferably 1-10 wt % based on total formulation weight, which represents the amount necessary to prevent desorption of the protein from the polymer matrix and to provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the osteogenic activity of the progenitor cells.\",\n \"In further compositions, proteins or other active ingredients of the invention may be combined with other agents beneficial to the treatment of the bone and/or cartilage defect, wound, or tissue in question.\",\n \"These agents include various growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), and insulin-like growth factor (IGF).\",\n \"The therapeutic compositions are also presently valuable for veterinary applications.\",\n \"Particularly domestic animals and thoroughbred horses, in addition to humans, are desired patients for such treatment with proteins or other active ingredients of the present invention.\",\n \"The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g., amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration and other clinical factors.\",\n \"The dosage may vary with the type of matrix used in the reconstitution and with inclusion of other proteins in the pharmaceutical composition.\",\n \"For example, the addition of other known growth factors, such as IGF I (insulin like growth factor I), to the final composition, may also effect the dosage.\",\n \"Progress can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, X-rays, histomorphometric determinations and tetracycline labeling.\",\n \"Polynucleotides of the present invention can also be used for gene therapy.\",\n \"Such polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject.\",\n \"Polynucleotides of the invention may also be administered by other known methods for introduction of nucleic acid into a cell or organism (including, without limitation, in the form of viral vectors or naked DNA).\",\n \"Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells.\",\n \"Treated cells can then be introduced in vivo for therapeutic purposes.\",\n \"4.12.3 Effective Dosage Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose.\",\n \"More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated.\",\n \"Determination of the effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.\",\n \"For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from appropriate in vitro assays.\",\n \"For example, a dose can be formulated in animal models to achieve a circulating concentration range that can be used to more accurately determine useful doses in humans.\",\n \"For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in cell culture (i.e., the concentration of A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient.\",\n \"Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).\",\n \"The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.Compounds which exhibit high therapeutic indices are preferred.\",\n \"The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.\",\n \"The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.\",\n \"The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.\",\n \"The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition.\",\n \"See, e.g., Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.\",\n \"1 p. 1.Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired effects, or minimal effective concentration (MEC).\",\n \"The MEC will vary for each compound but can be estimated from in vitro data.\",\n \"Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration.\",\n \"However, HPLC assays or bioassays can be used to determine plasma concentrations.\",\n \"Dosage intervals can also be determined using MEC value.\",\n \"Compounds should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.\",\n \"In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.\",\n \"An exemplary dosage regimen for polypeptides or other compositions of the invention will be in the range of about 0.01 μg/kg to 100 mg/kg of body weight daily, with the preferred dose being about 0.1 μg/kg to 25 mg/kg of patient body weight daily, varying in adults and children.\",\n \"Dosing may be once daily, or equivalent doses may be delivered at longer or shorter intervals.\",\n \"The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's age and weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.\",\n \"4.12.4 Packaging The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.\",\n \"The pack may, for example, comprise metal or plastic foil, such as a blister pack.\",\n \"The pack or dispenser device may be accompanied by instructions for administration.\",\n \"Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.\",\n \"4.13 Antibodies Also included in the invention are antibodies to proteins, or fragments of proteins of the invention.\",\n \"The term “antibody” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen.\",\n \"Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab′ and F(ab′)2 fragments, and an Fab expression library.\",\n \"In general, an antibody molecule obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule.\",\n \"Certain classes have subclasses as well, such as IgG1, IgG2, and others.\",\n \"Furthermore, in humans, the light chain may be a kappa chain or a lambda chain.\",\n \"Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.\",\n \"An isolated related protein of the invention may be intended to serve as an antigen, or a portion or fragment thereof, and additionally can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation.\",\n \"The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens.\",\n \"An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of any of the full length proteins of the invention, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope.\",\n \"Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues.\",\n \"Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.\",\n \"In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a region on the surface of the protein of the invention, e.g., a hydrophilic region.\",\n \"A hydrophobicity analysis of the human related protein sequence will indicate which regions of a related protein are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production.\",\n \"As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation.\",\n \"See, e.g., Hopp and Woods, 1981, Proc.\",\n \"Nat.\",\n \"Acad.\",\n \"Sci USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mol.\",\n \"Biol.\",\n \"157: 105-142, each of which is incorporated herein by reference in its entirety.\",\n \"Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.\",\n \"A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.\",\n \"Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., incorporated herein by reference).\",\n \"Some of these antibodies are discussed below.\",\n \"5.13.1 Polyclonal Antibodies For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing.\",\n \"An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein.\",\n \"Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized.\",\n \"Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor.\",\n \"The preparation can further include an adjuvant.\",\n \"Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.\",\n \"), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents.\",\n \"Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).\",\n \"The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum.\",\n \"Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography.\",\n \"Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia Pa., Vol.\",\n \"14, No.\",\n \"8 (Apr.\",\n \"17, 2000), pp.\",\n \"25-28).\",\n \"5.13.2 Monoclonal Antibodies The term “monoclonal antibody” (MAb) or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product.\",\n \"In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population.\",\n \"MAbs thus contain an antigen-binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.\",\n \"Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975).\",\n \"In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent.\",\n \"Alternatively, the lymphocytes can be immunized in vitro.\",\n \"The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof.\",\n \"Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired.\",\n \"The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp.\",\n \"59-103).\",\n \"Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin.\",\n \"Usually, rat or mouse myeloma cell lines are employed.\",\n \"The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.\",\n \"For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.\",\n \"Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium.\",\n \"More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, Calif. and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J.\",\n \"Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp.\",\n \"51-63).\",\n \"The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen.\",\n \"Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).\",\n \"Such techniques and assays are known in the art.\",\n \"The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal.\",\n \"Biochem., 107:220 (1980).\",\n \"Preferably, antibodies having a high degree of specificity and a high binding affinity for the target antigen are isolated.\",\n \"After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods.\",\n \"Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium.\",\n \"Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.\",\n \"The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.\",\n \"The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Pat.\",\n \"No.\",\n \"4,816,567.DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies).\",\n \"The hybridoma cells of the invention serve as a preferred source of such DNA.\",\n \"Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.\",\n \"The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Pat.\",\n \"No.\",\n \"4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide.\",\n \"Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.\",\n \"5.13.2 Humanized Antibodies The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies.\",\n \"These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin.\",\n \"Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin.\",\n \"Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody.\",\n \"(See also U.S. Pat.\",\n \"No.\",\n \"5,225,539.)\",\n \"In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.\",\n \"Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.\",\n \"In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence.\",\n \"The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr.\",\n \"Op.\",\n \"Struct.\",\n \"Biol., 2:593-596 (1992)).\",\n \"5.133 Human Antibodies Fully human antibodies relate to antibody molecules in which essentially the entire sequences of both the light chain and the heavy chain, including the CDRs, arise from human genes.\",\n \"Such antibodies are termed “human antibodies”, or “fully human antibodies” herein.\",\n \"Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp.\",\n \"77-96).\",\n \"Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983.Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp.\",\n \"77-96).\",\n \"In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol.\",\n \"Biol., 227:381 (1991); Marks et al., J. Mol.\",\n \"Biol., 222:581 (1991)).\",\n \"Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated.\",\n \"Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.\",\n \"This approach is described, for example, in U.S. Pat.\",\n \"Nos.\",\n \"5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et at.\",\n \"(Bio/Technology 10, 779-783 (1992)); Lonberg et al.\",\n \"(Nature 368 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al, (Nature Biotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern.\",\n \"Rev.\",\n \"Immunol.\",\n \"13 65-93 (1995)).\",\n \"Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen.\",\n \"(See PCT publication WO94/02602).\",\n \"The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome.\",\n \"The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments.\",\n \"An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications.\",\n \"The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096.This animal produces B cells which secrete fully human immunoglobulins.\",\n \"The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies.\",\n \"Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.\",\n \"An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Pat.\",\n \"No.\",\n \"5,939,598.It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.\",\n \"A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Pat.\",\n \"No.\",\n \"5,916,771.It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell.\",\n \"The hybrid cell expresses an antibody containing the heavy chain and the light chain.\",\n \"In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.5.13.4 Fab Fragments and Single Chain Antibodies According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Pat.\",\n \"No.\",\n \"4,946,778).\",\n \"In addition, methods can be adapted for the construction of Fab expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof.\",\n \"Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(ab′)2 fragment produced by pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F(ab′)2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) Fv fragments.\",\n \"5.13.5 Bispecific Antibodies Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens.\",\n \"In the present case, one of the binding specificities is for an antigenic protein of the invention.\",\n \"The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.\",\n \"Methods for making bispecific antibodies are known in the art.\",\n \"Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)).\",\n \"Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure.\",\n \"The purification of the correct molecule is usually accomplished by affinity chromatography steps.\",\n \"Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., 1991 EMBO J., 10:3655-3659.Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences.\",\n \"The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions.\",\n \"It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions.\",\n \"DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism.\",\n \"For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).\",\n \"According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture.\",\n \"The preferred interface comprises at least a part of the CH3 region of an antibody constant domain.\",\n \"In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g tyrosine or tryptophan).\",\n \"Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g.\",\n \"alanine or threonine).\",\n \"This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.\",\n \"Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g.\",\n \"F(ab′)2 bispecific antibodies).\",\n \"Techniques for generating bispecific antibodies from antibody fragments have been described in the literature.\",\n \"For example, bispecific antibodies can be prepared using chemical linkage.\",\n \"Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)2 fragments.\",\n \"These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation.\",\n \"The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives.\",\n \"One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody.\",\n \"The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.\",\n \"Additionally, Fab′ fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies.\",\n \"Shalaby et al., J. Exp.\",\n \"Med.\",\n \"175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab′)2 molecule.\",\n \"Each Fab′ fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody.\",\n \"The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.\",\n \"Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described.\",\n \"For example, bispecific antibodies have been produced using leucine zippers.\",\n \"Kostelny et al., J. Immunol.\",\n \"148(5):1547-1553 (1992).\",\n \"The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion.\",\n \"The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers.\",\n \"This method can also be utilized for the production of antibody homodimers.\",\n \"The “diabody” technology described by Hollinger et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments.\",\n \"The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain.\",\n \"Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites.\",\n \"Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported.\",\n \"See, Gruber et al., J. Immunol.\",\n \"152:5368 (1994).\",\n \"Antibodies with more than two valencies are contemplated.\",\n \"For example, trispecific antibodies can be prepared.\",\n \"Tutt et al., J. Immunol.\",\n \"147:60 (1991).\",\n \"Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention.\",\n \"Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g.\",\n \"CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen.\",\n \"Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen.\",\n \"These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA.\",\n \"Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).\",\n \"5.13.6 Heteroconjugate Antibodies Heteroconjugate antibodies are also within the scope of the present invention.\",\n \"Heteroconjugate antibodies are composed of two covalently joined antibodies.\",\n \"Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat.\",\n \"No.\",\n \"4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089).\",\n \"It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents.\",\n \"For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond.\",\n \"Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat.\",\n \"No.\",\n \"4,676,980.5.13.7 Effector Function Engineering It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer.\",\n \"For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region.\",\n \"The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC).\",\n \"See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J.\",\n \"Immunol., 148: 2918-2922 (1992).\",\n \"Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al.\",\n \"Cancer Research, 53: 2560-2565 (1993).\",\n \"Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities.\",\n \"See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).\",\n \"5.13.8 Immunoconjugates The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).\",\n \"Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above.\",\n \"Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.\",\n \"A variety of radionuclides are available for the production of radioconjugated antibodies.\",\n \"Examples include 212Bi, 131I, 131In, 90Y, and 186Re.\",\n \"Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene).\",\n \"For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987).\",\n \"Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody.\",\n \"See WO94/1 1026.In another embodiment, the antibody can be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) that is in turn conjugated to a cytotoxic agent.\",\n \"4.14 Computer Readable Sequences In one application of this embodiment, a nucleotide sequence of the present invention can be recorded on computer readable media.\",\n \"As used herein, “computer readable media” refers to any medium which can be read and accessed directly by a computer.\",\n \"Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media.\",\n \"A skilled artisan can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising computer readable medium having recorded thereon a nucleotide sequence of the present invention.\",\n \"As used herein, “recorded” refers to a process for storing information on computer readable medium.\",\n \"A skilled artisan can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the nucleotide sequence information of the present invention.\",\n \"A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon a nucleotide sequence of the present invention.\",\n \"The choice of the data storage structure will generally be based on the means chosen to access the stored information.\",\n \"In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium.\",\n \"The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and Microsoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like.\",\n \"A skilled artisan can readily adapt any number of data processor structuring formats (e.g.\",\n \"text file or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention.\",\n \"By providing any of the nucleotide sequences SEQ ID NO: 1-8051 or a representative fragment thereof; or a nucleotide sequence at least 95% identical to any of the nucleotide sequences of SEQ ID NO: 1-8051 in computer readable form, a skilled artisan can routinely access the sequence information for a variety of purposes.\",\n \"Computer software is publicly available which allows a skilled artisan to access sequence information provided in a computer readable medium.\",\n \"The examples which follow demonstrate how software which implements the BLAST (Altschul et al., J. Mol.\",\n \"Biol.\",\n \"215:403-410 (1990)) and BLAZE (Brutlag et al., Comp.\",\n \"Chem.\",\n \"17:203-207 (1993)) search algorithms on a Sybase system is used to identify open reading frames (ORFs) within a nucleic acid sequence.\",\n \"Such ORFs may be protein encoding fragments and may be useful in producing commercially important proteins such as enzymes used in fermentation reactions and in the production of commercially useful metabolites.\",\n \"As used herein, “a computer-based system” refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention.\",\n \"The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means.\",\n \"A skilled artisan can readily appreciate that any one of the currently available computer-based systems are suitable for use in the present invention.\",\n \"As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein a nucleotide sequence of the present invention and the necessary hardware means and software means for supporting and implementing a search means.\",\n \"As used herein, “data storage means” refers to memory which can store nucleotide sequence information of the present invention, or a memory access means which can access manufactures having recorded thereon the nucleotide sequence information of the present invention.\",\n \"As used herein, “search means” refers to one or more programs which are implemented on the computer-based system to compare a target sequence or target structural motif with the sequence information stored within the data storage means.\",\n \"Search means are used to identify fragments or regions of a known sequence which match a particular target sequence or target motif.\",\n \"A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention.\",\n \"Examples of such software includes, but is not limited to, Smith-Waterman, MacPattern (EMBL), BLASTN and BLASTA (NPOLYPEPTIDEIA).\",\n \"A skilled artisan can readily recognize that any one of the available algorithms or implementing software packages for conducting homology searches can be adapted for use in the present computer-based systems.\",\n \"As used herein, a “target sequence” can be any nucleic acid or amino acid sequence of six or more nucleotides or two or more amino acids.\",\n \"A skilled artisan can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database.\",\n \"The most preferred sequence length of a target sequence is from about 10 to 300 amino acids, more preferably from about 30 to 100 nucleotide residues.\",\n \"However, it is well recognized that searches for commercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.\",\n \"As used herein, “a target structural motif,” or “target motif,” refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration which is formed upon the folding of the target motif.\",\n \"There are a variety of target motifs known in the art.\",\n \"Protein target motifs include, but are not limited to, enzyme active sites and signal sequences.\",\n \"Nucleic acid target motifs include, but are not limited to, promoter sequences, hairpin structures and inducible expression elements (protein binding sequences).\",\n \"4.15 Triple Helix Formation In addition, the fragments of the present invention, as broadly described, can be used to control gene expression through triple helix formation or antisense DNA or RNA, both of which methods are based on the binding of a polynucleotide sequence to DNA or RNA.\",\n \"Polynucleotides suitable for use in these methods are preferably 20 to 40 bases in length and are designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl.\",\n \"Acids Res.\",\n \"6:3073 (1979); Cooney et al., Science 15241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Olmno, J. Neurochem.\",\n \"56:560, (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)).\",\n \"Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide.\",\n \"Both techniques have been demonstrated to be effective in model systems.\",\n \"Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide.\",\n \"4.16 Diagnostic Assays and Kits The present invention further provides methods to identify the presence or expression of one of the ORFs of the present invention, or homolog thereof, in a test sample, using a nucleic acid probe or antibodies of the present invention, optionally conjugated or otherwise associated with a suitable label.\",\n \"In general, methods for detecting a polynucleotide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polynucleotide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polynucleotide of the invention is detected in the sample.\",\n \"Such methods can also comprise contacting a sample under stringent hybridization conditions with nucleic acid primers that anneal to a polynucleotide of the invention under such conditions, and amplifying annealed polynucleotides, so that if a polynucleotide is amplified, a polynucleotide of the invention is detected in the sample.\",\n \"In general, methods for detecting a polypeptide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polypeptide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polypeptide of the invention is detected in the sample.\",\n \"In detail, such methods comprise incubating a test sample with one or more of the antibodies or one or more of the nucleic acid probes of the present invention and assaying for binding of the nucleic acid probes or antibodies to components within the test sample.\",\n \"Conditions for incubating a nucleic acid probe or antibody with a test sample vary.\",\n \"Incubation conditions depend on the format employed in the assay, the detection methods employed, and the type and nature of the nucleic acid probe or antibody used in the assay.\",\n \"One skilled in the art will recognize that any one of the commonly available hybridization, amplification or immunological assay formats can readily be adapted to employ the nucleic acid probes or antibodies of the present invention.\",\n \"Examples of such assays can be found in Chard, T., An Introduction to Radioimmunoassay and Related Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986); Bullock, G. R. et al., Techniques in Immunocytochemistry, Academic Press, Orlando, Fla. Vol.\",\n \"1 (1982), Vol.\",\n \"2 (1983), Vol.\",\n \"3 (1985); Tijssen, P., Practice and Theory of immunoassays: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1985).\",\n \"The test samples of the present invention include cells, protein or membrane extracts of cells, or biological fluids such as sputum, blood, serum, plasma, or urine.\",\n \"The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed.\",\n \"Methods for preparing protein extracts or membrane extracts of cells are well known in the art and can be readily be adapted in order to obtain a sample which is compatible with the system utilized.\",\n \"In another embodiment of the present invention, kits are provided which contain the necessary reagents to carry out the assays of the present invention.\",\n \"Specifically, the invention provides a compartment kit to receive, in close confinement, one or more containers which comprises: (a) a first container comprising one of the probes or antibodies of the present invention; and (b) one or more other containers comprising one or more of the following: wash reagents, reagents capable of detecting presence of a bound probe or antibody.\",\n \"In detail, a compartment kit includes any kit in which reagents are contained in separate containers.\",\n \"Such containers include small glass containers, plastic containers or strips of plastic or paper.\",\n \"Such containers allows one to efficiently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another.\",\n \"Such containers will include a container which will accept the test sample, a container which contains the antibodies used in the assay, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.\",\n \"), and containers which contain the reagents used to detect the bound antibody or probe.\",\n \"Types of detection reagents include labeled nucleic acid probes, labeled secondary antibodies, or in the alternative, if the primary antibody is labeled, the enzymatic, or antibody binding reagents which are capable of reacting with the labeled antibody.\",\n \"One skilled in the art will readily recognize that the disclosed probes and antibodies of the present invention can be readily incorporated into one of the established kit formats which are well known in the art.\",\n \"4.17 Medical Imaging The novel polypeptides and binding partners of the invention are useful in medical imaging of sites expressing the molecules of the invention (e.g., where the polypeptide of the invention is involved in the immune response, for imaging sites of inflammation or infection).\",\n \"See, e.g., Kunkel et al., U.S. Pat.\",\n \"No.\",\n \"5,413,778.Such methods involve chemical attachment of a labeling or imaging agent, administration of the labeled polypeptide to a subject in a pharmaceutically acceptable carrier, and imaging the labeled polypeptide in vivo at the target site.\",\n \"4.18 Screening Assays Using the isolated proteins and polynucleotides of the invention, the present invention further provides methods of obtaining and identifying agents which bind to a polypeptide encoded by an ORF corresponding to any of the nucleotide sequences set forth in SEQ ID NO: 1-8051, or bind to a specific domain of the polypeptide encoded by the nucleic acid.\",\n \"In detail, said method comprises the steps of: (a) contacting an agent with an isolated protein encoded by an ORF of the present invention, or nucleic acid of the invention; and (b) determining whether the agent binds to said protein or said nucleic acid.\",\n \"In general, therefore, such methods for identifying compounds that bind to a polynucleotide of the invention can comprise contacting a compound with a polynucleotide of the invention for a time sufficient to form a polynucleotide/compound complex, and detecting the complex, so that if a polynucleotide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.\",\n \"Likewise, in general, therefore, such methods for identifying compounds that bind to a polypeptide of the invention can comprise contacting a compound with a polypeptide of the invention for a time sufficient to form a polypeptide/compound complex, and detecting the complex, so that if a polypeptide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.\",\n \"Methods for identifying compounds that bind to a polypeptide of the invention can also comprise contacting a compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a receptor gene sequence in the cell, and detecting the complex by detecting reporter gene sequence expression, so that if a polypeptide/compound complex is detected, a compound that binds a polypeptide of the invention is identified.\",\n \"Compounds identified via such methods can include compounds which modulate the activity of a polypeptide of the invention (that is, increase or decrease its activity, relative to activity observed in the absence of the compound).\",\n \"Alternatively, compounds identified via such methods can include compounds which modulate the expression of a polynucleotide of the invention (that is, increase or decrease expression relative to expression levels observed in the absence of the compound).\",\n \"Compounds, such as compounds identified via the methods of the invention, can be tested using standard assays well known to those of skill in the art for their ability to modulate activity/expression.\",\n \"The agents screened in the above assay can be, but are not limited to, peptides, carbohydrates, vitamin derivatives, or other pharmaceutical agents.\",\n \"The agents can be selected and screened at random or rationally selected or designed using protein modeling techniques.\",\n \"For random screening, agents such as peptides, carbohydrates, pharmaceutical agents and the like are selected at random and are assayed for their ability to bind to the protein encoded by the ORF of the present invention.\",\n \"Alternatively, agents may be rationally selected or designed.\",\n \"As used herein, an agent is said to be “rationally selected or designed” when the agent is chosen based on the configuration of the particular protein.\",\n \"For example, one skilled in the art can readily adapt currently available procedures to generate peptides, pharmaceutical agents and the like, capable of binding to a specific peptide sequence, in order to generate rationally designed antipeptide peptides, for example see Hurby et al., Application of Synthetic Peptides: Antisense Peptides,” In Synthetic Peptides, A User's Guide, W.H.\",\n \"Freeman, NY (1992), pp.\",\n \"289-307, and Kaspczak et al., Biochemistry 28:9230-8 (1989), or pharmaceutical agents, or the like.\",\n \"In addition to the foregoing, one class of agents of the present invention, as broadly described, can be used to control gene expression through binding to one of the ORFs or EMFs of the present invention.\",\n \"As described above, such agents can be randomly screened or rationally designed/selected.\",\n \"Targeting the ORF or EMF allows a skilled artisan to design sequence specific or element specific agents, modulating the expression of either a single ORF or multiple ORFs which rely on the same EMF for expression control.\",\n \"One class of DNA binding agents are agents which contain base residues which hybridize or form a triple helix formation by binding to DNA or RNA.\",\n \"Such agents can be based on the classic phosphodiester, ribonucleic acid backbone, or can be a variety of sulfhydryl or polymeric derivatives which have base attachment capacity.\",\n \"Agents suitable for use in these methods preferably contain 20 to 40 bases and are designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl.\",\n \"Acids Res.\",\n \"6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Okano, J. Neurochem.\",\n \"56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)).\",\n \"Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide.\",\n \"Both techniques have been demonstrated to be effective in model systems.\",\n \"Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide and other DNA binding agents.\",\n \"Agents that bind to a protein encoded by one of the ORFs of the present invention can be used as a diagnostic agent.\",\n \"Agents which bind to a protein encoded by one of the ORFs of the present invention can be formulated using known techniques to generate a pharmaceutical composition.\",\n \"4.19 Use of Nucleic Acids as Probes Another aspect of the subject invention is to provide for polypeptide-specific nucleic acid hybridization probes capable of hybridizing with naturally occurring nucleotide sequences.\",\n \"The hybridization probes of the subject invention may be derived from any of the nucleotide sequences SEQ ID NO: 1-8051.Because the corresponding gene is only expressed in a limited number of tissues, a hybridization probe derived from of any of the nucleotide sequences SEQ ID NO: 1-8051 can be used as an indicator of the presence of RNA of cell type of such a tissue in a sample.\",\n \"Any suitable hybridization technique can be employed, such as, for example, in situ hybridization.\",\n \"PCR as described in U.S. Pat.\",\n \"Nos.\",\n \"4,683,195 and 4,965,188 provides additional uses for oligonucleotides based upon the nucleotide sequences.\",\n \"Such probes used in PCR may be of recombinant origin, may be chemically synthesized, or a mixture of both.\",\n \"The probe will comprise a discrete nucleotide sequence for the detection of identical sequences or a degenerate pool of possible sequences for identification of closely related genomic sequences.\",\n \"Other means for producing specific hybridization probes for nucleic acids include the cloning of nucleic acid sequences into vectors for the production of mRNA probes.\",\n \"Such vectors are known in the art and are commercially available and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA polymerase as T7 or SP6 RNA polymerase and the appropriate radioactively labeled nucleotides.\",\n \"The nucleotide sequences may be used to construct hybridization probes for mapping their respective genomic sequences.\",\n \"The nucleotide sequence provided herein may be mapped to a chromosome or specific regions of a chromosome using well known genetic and/or chromosomal mapping techniques.\",\n \"These techniques include in situ hybridization, linkage analysis against known chromosomal markers, hybridization screening with libraries or flow-sorted chromosomal preparations specific to known chromosomes, and the like.\",\n \"The technique of fluorescent in situ hybridization of chromosome spreads has been described, among other places, in Verma et al (1988) Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York N.Y. Fluorescent in situ hybridization of chromosomal preparations and other physical chromosome mapping techniques may be correlated with additional genetic map data.\",\n \"Examples of genetic map data can be found in the 1994 Genome Issue of Science (265:1981 f).\",\n \"Correlation between the location of a nucleic acid on a physical chromosomal map and a specific disease (or predisposition to a specific disease) may help delimit the region of DNA associated with that genetic disease.\",\n \"The nucleotide sequences of the subject invention may be used to detect differences in gene sequences between normal, carrier or affected individuals.\",\n \"4.20 Preparation of Support Bound Oligonucleotides Oligonucleotides, i.e., small nucleic acid segments, may be readily prepared by, for example, directly synthesizing the oligonucleotide by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer.\",\n \"Support bound oligonucleotides may be prepared by any of the methods known to those of skill in the art using any suitable support such as glass, polystyrene or Teflon.\",\n \"One strategy is to precisely spot oligonucleotides synthesized by standard synthesizers.\",\n \"Immobilization can be achieved using passive adsorption (Inouye & Hondo, (1990) J. Clin.\",\n \"Microbiol.\",\n \"28 (6) 1469-72); using UV light (Nagata et al., 1985; Dahlen et al., 1987; Morrissey & Collins, (1989) Mol.\",\n \"Cell Probes 3 (2) 189-207) or by covalent binding of base modified DNA (Keller et al., 1988; 1989); all references being specifically incorporated herein.\",\n \"Another strategy that may be employed is the use of the strong biotin-streptavidin interaction as a linker.\",\n \"For example, Broude et al.\",\n \"(1994) Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 91 (8) 3072-6, describe the use of biotinylated probes, although these are duplex probes, that are immobilized on streptavidin-coated magnetic beads.\",\n \"Streptavidin-coated beads may be purchased from Dynal, Oslo.\",\n \"Of course, this same linking chemistry is applicable to coating any surface with streptavidin.\",\n \"Biotinylated probes may be purchased from various sources, such as, e.g., Operon Technologies (Alameda, Calif.).\",\n \"Nunc Laboratories (Naperville, Ill.) is also selling suitable material that could be used.\",\n \"Nunc Laboratories have developed a method by which DNA can be covalently bound to the microwell surface termed Covalink NH.\",\n \"CovaLink NH is a polystyrene surface grafted with secondary amino groups (>NH) that serve as bridge-heads for further covalent coupling.\",\n \"CovaLink Modules may be purchased from Nunc Laboratories.\",\n \"DNA molecules may be bound to CovaLink exclusively at the 5′-end by a phosphoramidate bond, allowing immobilization of more than 1 pmol of DNA (Rasmussen et al., (1991) Anal.\",\n \"Biochem.\",\n \"198 (1) 13842).\",\n \"The use of CovaLink NH strips for covalent binding of DNA molecules at the 5′-end has been described (Rasmussen et al., (1991).\",\n \"In this technology, a phosphoramidate bond is employed (Chu et al., (1983) Nucleic Acids Res.\",\n \"11 (8) 6513-29).\",\n \"This is beneficial as immobilization using only a single covalent bond is preferred.\",\n \"The phosphoramidate bond joins the DNA to the CovaLink NH secondary amino groups that are positioned at the end of spacer arms covalently grafted onto the polystyrene surface through a 2 nm long spacer arm.\",\n \"To link an oligonucleotide to CovaLink NH via an phosphoramidate bond, the oligonucleotide terminus must have a 5′-end phosphate group.\",\n \"It is, perhaps, even possible for biotin to be covalently bound to CovaLink and then streptavidin used to bind the probes.\",\n \"More specifically, the linkage method includes dissolving DNA in water (7.5 ng/ul) and denaturing for 10 min.\",\n \"at 95° C. and cooling on ice for 10 min.\",\n \"Ice-cold 0.1 M 1-methylimidazole, pH 7.0 (1-MeIm7), is then added to a final concentration of 10 mM 1-MeIM7.A ss DNA solution is then dispensed into CovaLink NH strips (75 ul/well) standing on ice.\",\n \"Carbodiimide 0.2 M 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), dissolved in 10 mM 1-MeIM7, is made fresh and 25 ul added per well.\",\n \"The strips are incubated for 5 hours at 50° C. After incubation the strips are washed using, e.g., Nunc-Immuno Wash; first the wells are washed 3 times, then they are soaked with washing solution for 5 min., and finally they are washed 3 times (where in the washing solution is 0.4 N NaOH, 0.25% SDS heated to 50° C.).\",\n \"It is contemplated that a further suitable method for use with the present invention is that described in PCT Patent Application WO 90/03382 (Southern & Maskos), incorporated herein by reference.\",\n \"This method of preparing an oligonucleotide bound to a support involves attaching a nucleoside 3′-reagent through the phosphate group by a covalent phosphodiester link to aliphatic hydroxyl groups carried by the support.\",\n \"The oligonucleotide is then synthesized on the supported nucleoside and protecting groups removed from the synthetic oligonucleotide chain under standard conditions that do not cleave the oligonucleotide from the support.\",\n \"Suitable reagents include nucleoside phosphoramidite and nucleoside hydrogen phosphorate.\",\n \"An on-chip strategy for the preparation of DNA probe for the preparation of DNA probe arrays may be employed.\",\n \"For example, addressable laser-activated photodeprotection may be Fodor et al.\",\n \"(1991) Science 251 (4995) 767-73, incorporated herein by reference.\",\n \"Probes may also be immobilized on nylon supports as described by Van Ness et at (1991) Nucleic Acids Res.\",\n \"19 (12) 3345-50; or linked to Teflon using the method of Duncan & Cavalier (1988) Anal.\",\n \"Biochem.\",\n \"169 (1) 104-8; all references being specifically incorporated herein.\",\n \"To link an oligonucleotide to a nylon support, as described by Van Ness et al.\",\n \"(1991), requires activation of the nylon surface via alkylation and selective activation of the 5′-amine of oligonucleotides with cyanuric chloride.\",\n \"One particular way to prepare support bound oligonucleotides is to utilize the light-generated synthesis described by Pease et al., (1994) PNAS USA 91 (11) 5022-6, incorporated herein by reference).\",\n \"These authors used current photolithographic techniques to generate arrays of immobilized oligonucleotide probes (DNA chips).\",\n \"These methods, in which light is used to direct the synthesis of oligonucleotide probes in high-density, miniaturized arrays, utilize photolabile 5′-protected N-acyl-deoxynucleoside phosphoramidites, surface linker chemistry and versatile combinatorial synthesis strategies.\",\n \"A matrix of 256 spatially defined oligonucleotide probes may be generated in this manner.\",\n \"4.21 Preparation of Nucleic Acid Fragments The nucleic acids may be obtained from any appropriate source, such as cDNAs, genomic DNA, chromosomal DNA, microdissected chromosome bands, cosmid or YAC inserts, and RNA, including mRNA without any amplification steps.\",\n \"For example, Sambrook et al.\",\n \"(1989) describes three protocols for the isolation of high molecular weight DNA from mammalian cells (p. 9.14-9.23).\",\n \"DNA fragments may be prepared as clones in M13, plasmid or lambda vectors and/or prepared directly from genomic DNA or cDNA by PCR or other amplification methods.\",\n \"Samples may be prepared or dispensed in multiwell plates.\",\n \"About 100-1000 ng of DNA samples may be prepared in 2-500 ml of final volume.\",\n \"The nucleic acids would then be fragmented by any of the methods known to those of skill in the art including, for example, using restriction enzymes as described at 9.24-9.28 of Sambrook et al.\",\n \"(1989), shearing by ultrasound and NaOH treatment.\",\n \"Low pressure shearing is also appropriate, as described by Schriefer et al.\",\n \"(1990) Nucleic Acids Res.\",\n \"18 (24) 7455-6, incorporated herein by reference).\",\n \"In this method, DNA samples are passed through a small French pressure cell at a variety of low to intermediate pressures.\",\n \"A lever device allows controlled application of low to intermediate pressures to the cell.\",\n \"The results of these studies indicate that low-pressure shearing is a useful alternative to sonic and enzymatic DNA fragmentation methods.\",\n \"One particularly suitable way for fragmenting DNA is contemplated to be that using the two base recognition endonuclease, CviJI, described by Fitzgerald et al.\",\n \"(1992) Nucleic Acids Res.\",\n \"20 (14) 3753-62.These authors described an approach for the rapid fragmentation and fractionation of DNA into particular sizes that they contemplated to be suitable for shotgun cloning and sequencing.\",\n \"The restriction endonuclease CviJI normally cleaves the recognition sequence PuGCPy between the G and C to leave blunt ends.\",\n \"Atypical reaction conditions, which alter the specificity of this enzyme (CviJI**), yield a quasi-random distribution of DNA fragments form the small molecule pUC19 (2688 base pairs).\",\n \"Fitzgerald et al.\",\n \"(1992) quantitatively evaluated the randomness of this fragmentation strategy, using a CviJI** digest of pUC19 that was size fractionated by a rapid gel filtration method and directly ligated, without end repair, to a lac Z minus M13 cloning vector.\",\n \"Sequence analysis of 76 clones showed that CviJI** restricts pyGCPy and PuGCPu, in addition to PuGCPy sites, and that new sequence data is accumulated at a rate consistent with random fragmentation.\",\n \"As reported in the literature, advantages of this approach compared to sonication and agarose gel fractionation include: smaller amounts of DNA are required (0.2-0.5 ug instead of 2-5 ug); and fewer steps are involved (no preligation, end repair, chemical extraction, or agarose gel electrophoresis and elution are needed.\",\n \"Irrespective of the manner in which the nucleic acid fragments are obtained or prepared, it is important to denature the DNA to give single stranded pieces available for hybridization.\",\n \"This is achieved by incubating the DNA solution for 2-5 minutes at 80-90° C. The solution is then cooled quickly to 2° C. to prevent renaturation of the DNA fragments before they are contacted with the chip.\",\n \"Phosphate groups must also be removed from genomic DNA by methods known in the art.\",\n \"4.22 Preparation of DNA Arrays Arrays may be prepared by spotting DNA samples on a support such as a nylon membrane.\",\n \"Spotting may be performed by using arrays of metal pins (the positions of which correspond to an array of wells in a microtiter plate) to repeated by transfer of about 20 nl of a DNA solution to a nylon membrane.\",\n \"By offset printing, a density of dots higher than the density of the wells is achieved.\",\n \"One to 25 dots may be accommodated in 1 mm2, depending on the type of label used.\",\n \"By avoiding spotting in some preselected number of rows and columns, separate subsets (subarrays) may be formed.\",\n \"Samples in one subarray may be the same genomic segment of DNA (or the same gene) from different individuals, or may be different, overlapped genomic clones.\",\n \"Each of the subarrays may represent replica spotting of the same samples.\",\n \"In one example, a selected gene segment may be amplified from 64 patients.\",\n \"For each patient, the amplified gene segment may be in one 96-well plate (all 96 wells containing the same sample).\",\n \"A plate for each of the 64 patients is prepared.\",\n \"By using a 96-pin device, all samples may be spotted on one 8×12 cm membrane.\",\n \"Subarrays may contain 64 samples, one from each patient.\",\n \"Where the 96 subarrays are identical, the dot span may be 1 mm2 and there may be a 1 mm space between subarrays.\",\n \"Another approach is to use membranes or plates (available from NUNC, Naperville, Ill.) which may be partitioned by physical spacers e.g.\",\n \"a plastic grid molded over the membrane, the grid being similar to the sort of membrane applied to the bottom of multiwell plates, or hydrophobic strips.\",\n \"A fixed physical spacer is not preferred for imaging by exposure to flat phosphor-storage screens or x-ray films.\",\n \"The present invention is illustrated in the following examples.\",\n \"Upon consideration of the present disclosure, one of skill in the art will appreciate that many other embodiments and variations may be made in the scope of the present invention.\",\n \"Accordingly, it is intended that the broader aspects of the present invention not be limited to the disclosure of the following examples.\",\n \"The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention, and compositions and methods which are functionally equivalent are within the scope of the invention.\",\n \"Indeed, numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the present preferred embodiments.\",\n \"Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims.\",\n \"All references cited within the body of the instant specification are hereby incorporated by reference in their entirety.\",\n \"5.0 EXAMPLES 5.1 Example 1 Novel Nucleic Acid Sequences Obtained From Various Libraries A plurality of novel nucleic acids were obtained from cDNA libraries prepared from various human tissues and in some cases isolated from a genomic library derived from human chromosome using standard PCR, SBH sequence signature analysis and Sanger sequencing techniques.\",\n \"The inserts of the library were amplified with PCR using primers specific for the vector sequences which flank the inserts.\",\n \"Clones from cDNA libraries were spotted on nylon membrane filters and screened with oligonucleotide probes (e.g., 7-mers) to obtain signature sequences.\",\n \"The clones were clustered into groups of similar or identical sequences.\",\n \"Representative clones were selected for sequencing.\",\n \"In some cases, the 5′ sequence of the amplified inserts was then deduced using a typical Sanger sequencing protocol.\",\n \"PCR products were purified and subjected to fluorescent dye terminator cycle sequencing.\",\n \"Single pass gel sequencing was done using a 377 Applied Biosystems (ABI) sequencer to obtain the novel nucleic acid sequences.\",\n \"In some cases RACE (Rapid Amplification of cDNA Ends) was performed to further extend the sequence in the 5′ direction.\",\n \"5.2 Example 2 Novel Contigs The novel contigs of the invention were assembled from sequences that were obtained from a cDNA library by methods described in Example 1 above, and in some cases sequences obtained from one or more public databases.\",\n \"The sequences for the resulting nucleic acid contigs are designated as SEQ ID NO: 1-8051 and are provided in the attached Sequence Listing.\",\n \"The contigs were assembled using an EST sequence as a seed.\",\n \"Then a recursive algorithm was used to extend the seed EST into an extended assemblage, by pulling additional sequences from different databases (i.e., Hyseq's database containing EST sequences, dbEST version 115, gb pri 115, and UniGene version 103, and exons from public domain genomic sequences predicted by GenScan) that belong to this assemblage.\",\n \"The algorithm terminated when there was no additional sequences from the above databases that would extend the assemblage.\",\n \"Further, the inclusion of component sequences into the assemblage was based on a BLASTN hit to the extending assemblage with BLAST score greater than 300 and percent identity greater than 95%.\",\n \"The novel predicted polypeptides (including proteins) encoded by the novel polynucleotides (SEQ ID NO: 1-8051) of the present invention are incorporated in the attached Sequence Listing.\",\n \"A subset of the predicted polypeptide sequences contain an unknown amino acid; a stop codon; a possible nucleotide deletion; or a possible nucleotide insertion.\",\n \"These sequences have also been shown in their entirety in Table 2.Table 2 also shows the corresponding start and stop nucleotide locations to each of SEQ ID NO: 1-8051.Table 2 also indicates the method by which the polypeptide was predicted.\",\n \"Method A refers to a polypeptide obtained by using a software program called FASTY (available from http://fasta.bioch.virginia,edu) which selects a polypeptide based on a comparison of the translated novel polynucleotide to known polynucleotides (W. R. Pearson, Methods in Enzymology, 183:63-98 (1990), herein incorporated by reference).\",\n \"Method B refers to a polypeptide obtained by using a software program called GenScan for human/vertebrate sequences (available from Stanford University, Office of Technology Licensing) that predicts the polypeptide based on a probabilistic model of gene structure/compositional properties (C. Burge and S. Karlin, J. Mol.\",\n \"Biol., 268:78-94 (1997), incorporated herein by reference).\",\n \"Method C refers to a polypeptide obtained by using a Hyseq proprietary software program that translates the novel polynucleotide and its complementary strand into six possible amino acid sequences (forward and reverse frames) and chooses the polypeptide with the longest open reading frame.\",\n \"The nearest neighbor results for SEQ ID NO: 1-8051 were obtained by a BLASTX version 2.0al 19 MP-WashU search against Genpept release 123 and Geneseq release 200110 (Derwent), using BLAST algorithm.\",\n \"The nearest neighbor result showed the closest homologue for SEQ ID NO: 1-8051.The nearest neighbor results for SEQ ID NO: 1-8051, having identifiable function(s) are incorporated in the attached Sequence Listing.\",\n \"Using eMatrix software package (Stanford University, Stanford, Calif.) (Wu et al., J. Comp.\",\n \"Biol., Vol.\",\n \"6 pp.\",\n \"219-235 (1999) herein incorporated by reference), all the polypeptide sequences were examined to determine whether they had identifiable signature regions.\",\n \"The attached Sequence Listing provides the results obtained by eMatrix analysis for each polypeptide as follows: the signature region found in the indicated polypeptide sequences, the description of the signature, the eMatrix p-value(s) and the position(s) of the signature within the polypeptide sequence.\",\n \"Using the pFam software program (Sonnhammer et al., Nucleic Acids Res., Vol.\",\n \"26 (1) pp.\",\n \"320-322 (1998) herein incorporated by reference) all the polypeptide sequences were examined for domains with homology to certain peptide domains.\",\n \"The attached Sequence Listing provides the results obtained by pFam analysis for each polypeptide, namely: the name of the domain found, the description, the p-value and the pFam score for the identified domain within the sequence.\",\n \"Tables 1 and 2 follow.\",\n \"Table 1 shows the various tissue sources of SEQ ID NO: 1-8051.Table 2 shows the start and stop nucleotides for the translated amino acid sequence for which each assemblage encodes.\",\n \"Table 2 also provides a correlation between the amino acid sequences set forth in the Sequence Listing, the nucleotide sequences set forth in the Sequence Listing and the SEQ ID NO: in U.S. Ser.\",\n \"No.\",\n \"09/577,408.LENGTHY TABLE REFERENCED HERE US20070060743A1-20070315-T00001 Please refer to the end of the specification for access instructions.\",\n \"LENGTHY TABLE REFERENCED HERE US20070060743A1-20070315-T00002 Please refer to the end of the specification for access instructions.\",\n \"LENGTHY TABLE The patent application contains a lengthy table section.\",\n \"A copy of the table is available in electronic form from the USPTO web site ().\",\n \"An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10276817"}}},{"rowIdx":88,"cells":{"text":{"kind":"list like","value":[["Automatic scanning system, shoppers scanpass system","The checkout system described herein is to show a system how to eliminate the lines at the regiters, to eliminate the removal of items from shopping cart in order to “ring” them at the checkout counters.","As clients lowering their goods into shopping carts, an auto scanner mounted at the top of the cart shall trigger a beam to scan the items which are lower into the cart.","Once client completes his shopping he than read the total amount of sale which can be verified at the top of the shopping cart.","The cart with all the intended purchased items is wheeled to a checkout areas, in which the total amount is paid either by cash or credit cards."],["1.Checkout system eliminating the lines at the register, so to eliminate the removal of items from shopping carts in order to “ring” them at the checkout counters As clients lowering their goods into shopping carts, an automatic scanner mounted at the top of the carts shall trigger a beam to scan the items which are lowered into the carts."],["Systematic design for most retail establishments which “ring” their items thru a checkout counter, where clients/shoppers can conduct the process of shopping without the standard waiting on lines in front of cash registers.","DESCRIPTION Items meanning any commodity which can be handled mostly by hand, as a self service method of purchase, within retail establishment such as supermarkets, retail chains stores, retail chain outlets of any type of marketing in a self-service system, can benefit greatly by using this system.","Any items which are for the most part are picked up from the selling offering area and are lower into shopping wagons by clients who wheel the wanted goods to the cash registers counters.","Shopping cart.","Specifically designed as carriers and for an automatic instant scanning for all items which are lowered into them.","An automatically scanning devise installed at the top brim, frame of shopping cart that electronically sensetive to the coded pricing tags attached to every item.","Once an item which carried the coded price tag is passed thru the top frame of the shopping cart and lower onto cart will instantally trigger the pricing scanner installed at their top Wagons O Matic Pricing Scanner.","Wagons, Carts are made of a type of materials, components and designed specifically to be used as a carriers and scanners.","The designed wagons/carts will described in a separate chapter.","Shoppers will have the ability to monitor each item by the unit pricing as well as the price itself thru a scanner window installed at the top of each shopping cart.","In the event of a reversed scanning such as a removal of an item from cart, the scanner installed at the top frame of cart will automatically deduct the amount from the total desired purchase.","(By pressing a botton which says CANCEL).","A processing checkout booths shall be constructed at the location designated to receive all carts filled with goods which are wheeled into specifically designed Cashiers scanning booths.","Each booth equipped with a remote scanner shall beam directly into the “total price” window located at the top of each shopping cart.","A total amount of sale shall be displayed and announced for each individual shopping cart.","Scanning booths shall be equipped with slots machines mounted on their walls to recieve payment for each purchase by cash, credit cards or store cards.","Customers shall be instructed to insert cards at appropriate slot machines.","Once payments accepted a gate/door will be opened for each shopping cart to be wheeled out into a packing booths or a similar packing counter.","At each gate/door a push button shall activate a trigger for the total sale reciept.","Each time door/gate is opened a cc tv system will monitor that individual shopping cart.","All Check—points of entries and exits shall be monitored by a cc tv systems.","An optional checkout cashier counters, “the old system” will still be operational for those who wish to be informed about various store applications as well as the privilege to converse with cashier in general.","The advantage use of the SCANPASS system is to reduce the long lines in front of each cash registers.","Shoppers will not leave unwanted items by registers.","There will be a dramatic reduction in shoplifting, probably not at all.","If store employees are engaged in theft, than any items not accounted for, unscanned will have to exit the back doors, an area which can be easily monitored at all hours.","Produce and related loose food items shall be packed and wrapped accordingly meaning by wanted desired volume, with a protected see thru wrap, bag which eliminate the direct contact of skin.","Each wrapped produced, food bag will carry a scanning tag.","and be protected against an outside contact of foreign bacterias, as well as human breath, speach, cough, hair, etc.","No item could be carried out of the store undetected unpaid or unaccounted for, since the scanned tag attached will always trigger the alarm systematic devise on the way out.","And if any attempt shall be made to carry the item out of the store thru the SCANPASS exit (gate), then simply the gate will not open.","Type of “labels” attached to all products will be of a design that applicable to the size and shape of the item, and be constructed as a wrap around ribbon with a thin cord inserted or attached to it, visible from all directions for scanning detections and if item relatively large in size than 2 or three scanning labels shall be attached.","Once all shopping carts are moved into the bagging counters which shall be supported by store employees or upon shoppers choice to bag their items themselves, A conveyor belt shall be constructed at that area for all carts to be wheeled on and eventually be carried to the the front store entrance.","SCANPASS System An Automatic SCANPASS System.","Specifically designed/Systematic design for retail establishments which “ring” their items thru a checkout counter, where clients/shoppers conduct the process of shopping without the standard of waiting on lines in front of the cash registers.","and use the specifically special designed built shopping cart/wagon equipped with an automatic scanner at the top of its frame to scan/trigger all items which are entering, lowering into wagons/carts.","SCANPASS To be registered as a trade mark.","And said title shall be recognized as a title for the system described herein on page 5 and on exhibit E. Wagon O Matic System Wagon O Matic Pricing Scanner.","Specifically designed shopping wagon equipped with an automatic scanner/trigger, mounted at the top of its frame to scan/trigger all item which are lowered into the wagon.","Wagon O Matic To be registered as a trade mark.","and said title shall be recognized as a title for the system described herein on page 6 and on exhibit F."]],"string":"[\n [\n \"Automatic scanning system, shoppers scanpass system\",\n \"The checkout system described herein is to show a system how to eliminate the lines at the regiters, to eliminate the removal of items from shopping cart in order to “ring” them at the checkout counters.\",\n \"As clients lowering their goods into shopping carts, an auto scanner mounted at the top of the cart shall trigger a beam to scan the items which are lower into the cart.\",\n \"Once client completes his shopping he than read the total amount of sale which can be verified at the top of the shopping cart.\",\n \"The cart with all the intended purchased items is wheeled to a checkout areas, in which the total amount is paid either by cash or credit cards.\"\n ],\n [\n \"1.Checkout system eliminating the lines at the register, so to eliminate the removal of items from shopping carts in order to “ring” them at the checkout counters As clients lowering their goods into shopping carts, an automatic scanner mounted at the top of the carts shall trigger a beam to scan the items which are lowered into the carts.\"\n ],\n [\n \"Systematic design for most retail establishments which “ring” their items thru a checkout counter, where clients/shoppers can conduct the process of shopping without the standard waiting on lines in front of cash registers.\",\n \"DESCRIPTION Items meanning any commodity which can be handled mostly by hand, as a self service method of purchase, within retail establishment such as supermarkets, retail chains stores, retail chain outlets of any type of marketing in a self-service system, can benefit greatly by using this system.\",\n \"Any items which are for the most part are picked up from the selling offering area and are lower into shopping wagons by clients who wheel the wanted goods to the cash registers counters.\",\n \"Shopping cart.\",\n \"Specifically designed as carriers and for an automatic instant scanning for all items which are lowered into them.\",\n \"An automatically scanning devise installed at the top brim, frame of shopping cart that electronically sensetive to the coded pricing tags attached to every item.\",\n \"Once an item which carried the coded price tag is passed thru the top frame of the shopping cart and lower onto cart will instantally trigger the pricing scanner installed at their top Wagons O Matic Pricing Scanner.\",\n \"Wagons, Carts are made of a type of materials, components and designed specifically to be used as a carriers and scanners.\",\n \"The designed wagons/carts will described in a separate chapter.\",\n \"Shoppers will have the ability to monitor each item by the unit pricing as well as the price itself thru a scanner window installed at the top of each shopping cart.\",\n \"In the event of a reversed scanning such as a removal of an item from cart, the scanner installed at the top frame of cart will automatically deduct the amount from the total desired purchase.\",\n \"(By pressing a botton which says CANCEL).\",\n \"A processing checkout booths shall be constructed at the location designated to receive all carts filled with goods which are wheeled into specifically designed Cashiers scanning booths.\",\n \"Each booth equipped with a remote scanner shall beam directly into the “total price” window located at the top of each shopping cart.\",\n \"A total amount of sale shall be displayed and announced for each individual shopping cart.\",\n \"Scanning booths shall be equipped with slots machines mounted on their walls to recieve payment for each purchase by cash, credit cards or store cards.\",\n \"Customers shall be instructed to insert cards at appropriate slot machines.\",\n \"Once payments accepted a gate/door will be opened for each shopping cart to be wheeled out into a packing booths or a similar packing counter.\",\n \"At each gate/door a push button shall activate a trigger for the total sale reciept.\",\n \"Each time door/gate is opened a cc tv system will monitor that individual shopping cart.\",\n \"All Check—points of entries and exits shall be monitored by a cc tv systems.\",\n \"An optional checkout cashier counters, “the old system” will still be operational for those who wish to be informed about various store applications as well as the privilege to converse with cashier in general.\",\n \"The advantage use of the SCANPASS system is to reduce the long lines in front of each cash registers.\",\n \"Shoppers will not leave unwanted items by registers.\",\n \"There will be a dramatic reduction in shoplifting, probably not at all.\",\n \"If store employees are engaged in theft, than any items not accounted for, unscanned will have to exit the back doors, an area which can be easily monitored at all hours.\",\n \"Produce and related loose food items shall be packed and wrapped accordingly meaning by wanted desired volume, with a protected see thru wrap, bag which eliminate the direct contact of skin.\",\n \"Each wrapped produced, food bag will carry a scanning tag.\",\n \"and be protected against an outside contact of foreign bacterias, as well as human breath, speach, cough, hair, etc.\",\n \"No item could be carried out of the store undetected unpaid or unaccounted for, since the scanned tag attached will always trigger the alarm systematic devise on the way out.\",\n \"And if any attempt shall be made to carry the item out of the store thru the SCANPASS exit (gate), then simply the gate will not open.\",\n \"Type of “labels” attached to all products will be of a design that applicable to the size and shape of the item, and be constructed as a wrap around ribbon with a thin cord inserted or attached to it, visible from all directions for scanning detections and if item relatively large in size than 2 or three scanning labels shall be attached.\",\n \"Once all shopping carts are moved into the bagging counters which shall be supported by store employees or upon shoppers choice to bag their items themselves, A conveyor belt shall be constructed at that area for all carts to be wheeled on and eventually be carried to the the front store entrance.\",\n \"SCANPASS System An Automatic SCANPASS System.\",\n \"Specifically designed/Systematic design for retail establishments which “ring” their items thru a checkout counter, where clients/shoppers conduct the process of shopping without the standard of waiting on lines in front of the cash registers.\",\n \"and use the specifically special designed built shopping cart/wagon equipped with an automatic scanner at the top of its frame to scan/trigger all items which are entering, lowering into wagons/carts.\",\n \"SCANPASS To be registered as a trade mark.\",\n \"And said title shall be recognized as a title for the system described herein on page 5 and on exhibit E. Wagon O Matic System Wagon O Matic Pricing Scanner.\",\n \"Specifically designed shopping wagon equipped with an automatic scanner/trigger, mounted at the top of its frame to scan/trigger all item which are lowered into the wagon.\",\n \"Wagon O Matic To be registered as a trade mark.\",\n \"and said title shall be recognized as a title for the system described herein on page 6 and on exhibit F.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10292688"}}},{"rowIdx":89,"cells":{"text":{"kind":"list like","value":[["Thermoplastic Hydraulic Composition, Formed Article Prepared From The Composition By Hydration- Hardening And Method For Preparing The Hydration- Hardened Former Article","The object of the present invention is to produce general machine parts, OA machine part, and the like which can be produced by injection molding and which have excellent mechanical properties, thermal resistance, dimension stability and processability.","The thermoplastic hydraulic composition of the present invention comprises 100 parts by weight of two types of thermoplastic resins differing in melting point and from 500 to 1000 parts by weight of a hydraulic composition.","It is characterized by further comprising from 1 to 200 parts by weight of a fiber and/or from 0.5 to 10.0 parts by weight of a releasing agent added.","It is characterized in that the hydraulic composition preferably is a mixed powder which comprises from 50 to 90 wt % of a hydraulic powder and from 10 to 50 wt % of a non-hydraulic powder having an average particle diameter of 1/10 that of the hydraulic powder or less."],["1.A thermoplastic hydraulic composition that is formed into a given shape and then is hardened by removal of at least a part of a thermoplastic resin from the inside, followed by the introduction of moisture, which is characterized by comprising 100 parts by weight of two types of thermoplastic resins differing in melting point and from 500 to 1000 parts by weight of a hydraulic composition.","2.The thermoplastic hydraulic composition according to claim 1 further comprising at least one of from 1 to 200 parts by weight of a fiber and from 0.5 to 10.0 parts by weight of a releasing agent added.","3.The thermoplastic hydraulic composition according to claim 1, wherein the hydraulic composition is a mixed powder comprising from 50 to 90 wt % of a hydraulic powder and from 10 to 50 wt % of a non-hydraulic powder.","4.The thermoplastic hydraulic composition according to claim 1, wherein the hydraulic powder is at least one powder selected from portland cement, calcium silicate, calcium aluminate, calcium fluoroaluminate, calcium sulphoaluminate, calcium alumino-ferrite, calcium phosphate, hemihydrate or anhydride gypsum and a powder of calcium oxide possessing a self-hardening property.","5.The thermoplastic hydraulic composition according to claim 1, wherein the non-hydraulic powder is at least one powder selected from a potassium hydroxide powder, a dihydrate gypsum powder, a calcium carbonate powder, a slag powder, a flyash powder, a silica powder, a clay powder and a silica fume powder.","6.The thermoplastic hydraulic composition according to claim 1, wherein the thermoplastic resin is constituted of from 50 to 90 wt % of a thermoplastic low molecular compound and 50 to 10 wt % of a thermoplastic high molecular compound.","7.The thermoplastic hydraulic composition according to claim 6, wherein the thermoplastic low molecular compound is selected from low melting point compounds of paraffin wax, montan wax, carnauba wax, a fatty acid ester, glycerite and modified wax.","8.The thermoplastic hydraulic composition according to claim 6, wherein the thermoplastic high molecular compound is a single substance or a copolymer of two or more substances selected from polystyrene, an ethylene-vinyl acetate copolymer, an ethylene-ethyl acrylate copolymer, polypropylene, an acrylonitrile-butadiene-styrene copolymer, an acrylonitrile-styrene copolymer, methyl methacrylate, a vinyl chloride-vinyl chloride acetate copolymer, a vinyl chloride-vinyl acetate-maleic acid copolymer, a vinyl chloride-vinyl acetate copolymer, a vinyl chloride-vinylidene chloride copolymer, a vinyl chloride-acrylonitrile copolymer, an ethylene-vinyl chloride copolymer, a propylene-vinyl chloride copolymer, vinyl acetate, polyvinyl alcohol, polyamide, polyacetal, polyester, polycarbonate, polysulfone, polyether imide, polyamidoimide, and polyphenylene sulfide.","9.A hydration-hardened formed article characterized by being obtained by forming a thermoplastic hydraulic composition comprising 100 parts by weight of a thermoplastic resin and from 500 to 1000 parts by weight of a hydraulic composition into a given shape, subsequently removing the thermoplastic resin from the inside of the resulting formed article, and further introducing moisture into the formed article to harden it.","10.A hydration-hardened formed article characterized by being obtained by forming the hydraulic composition according to claim 1 into a given shape, subsequently removing the thermoplastic resin from the resulting formed article completely or removing only a thermoplastic low molecular compound, and further introducing moisture into the inside of the formed article to harden it.","11.A method for producing a hydrogen-hardened formed article, the method being characterized in that it comprises forming a thermoplastic hydraulic composition comprising 100 parts by weight of a thermoplastic resin and from 500 to 1000 parts by weight of a hydraulic composition into a given shape to obtain an unhardened formed article, subsequently removing only a thermoplastic low molecular compound from the inside of the formed article by degreasing the unhardened formed article at a temperature not lower than the melting point of the thermoplastic low molecular compound, and then hydration-hardening the unhardened formed article by curing it to introduce moisture thereinto.","12.A method for producing a hydration-hardened formed article, the method being characterized in that it comprises forming the hydraulic composition according to claim 1 into a given shape to obtain an unhardened formed article, subsequently removing only a thermoplastic resin from the inside of the formed article by degreasing the unhardened formed article at a temperature not lower than the melting point of the thermoplastic high molecular compound, and then hydration-hardening the unhardened formed article by curing it to introduce moisture thereinto.","13.The method for producing a hydration-hardened formed article according to claim 11, wherein the degreasing step is carried out at a temperature of from 400 to 500° C. for a period of 12 hours or longer.","14.A method for producing a hydration-hardened formed article, the method being characterized in that it comprises forming the hydraulic composition according to claim 1 into a given shape to obtain an unhardened formed article, subsequently removing only a thermoplastic low molecular compound from the inside of the formed article by degreasing the unhardened formed article at a temperature not lower than the melting point of the thermoplastic low molecular compound, and then hydration-hardening the unhardened formed article by curing it to introduce moisture thereinto.","15.The method for producing a hydration-hardened formed article according to claim 14, wherein the degreasing step is carried out at a temperature of 270° C. or lower for a period of 12 hours or shorter.","16.The method for producing a hydration-hardened formed article according to claim 11, wherein said curing step is carried out at a temperature of 80° C. or higher by any one of normal pressure steam curing, high pressure steam curing and hot water curing, or in combination of the normal pressure steam curing and the hot water curing, or in combination of the high pressure steam curing and the hot water curing."],["<SOH> BACKGROUND ART <EOH>As a material for machine parts, metallic materials have conventionally been used widely due to their superior material characteristics.","However, a recent technical progress has diversified needs for machine parts and machine parts in which non-metallic materials such as sintered ceramics or plastics have come to be used for making up for drawbacks of metallic materials The present inventors made a variety of investigations in order to comply with such demands and found that a hydraulic composition comprising a combination of a hydraulic powder, a non-hydraulic powder with an average particle diameter at least one order smaller than that of the hydraulic powder, a workability improver and a formability improver can be applied for machine parts such as paper sheet-feeding rollers through its pressure forming or extrusion forming; they filed patent applications directed thereto (Japanese Patent Application Nos.","Hei-10-177099, Hei-10-177100 and Hei-11-233636.)","However, these hydraulic compositions and methods for forming the same can be easily applied for machine parts of simple shapes but are difficult to be applied for machine parts of complex shapes.","The fact of being restricted in shape which can be produced problematically results directly in the restriction on the application range of the hydraulic compositions."],["TECHNICAL FIELD The present invention relates to a thermoplastic hydraulic composition that allows an injection molding technique mainly employed for production of plastic molded articles and ceramic molded articles to be applicable even for hydraulic compositions, and to formed articles prepared from the hydraulic compositions by hydration-hardening.","The present invention relates more particularly to provide thermoplastic hydraulic compositions, formed articles thereof having excellent mechanical properties, thermal resistance, dimensional stability and processability, as well as being capable of being applied for, e.g., general machine parts and OA machine parts.","BACKGROUND ART As a material for machine parts, metallic materials have conventionally been used widely due to their superior material characteristics.","However, a recent technical progress has diversified needs for machine parts and machine parts in which non-metallic materials such as sintered ceramics or plastics have come to be used for making up for drawbacks of metallic materials The present inventors made a variety of investigations in order to comply with such demands and found that a hydraulic composition comprising a combination of a hydraulic powder, a non-hydraulic powder with an average particle diameter at least one order smaller than that of the hydraulic powder, a workability improver and a formability improver can be applied for machine parts such as paper sheet-feeding rollers through its pressure forming or extrusion forming; they filed patent applications directed thereto (Japanese Patent Application Nos.","Hei-10-177099, Hei-10-177100 and Hei-11-233636.)","However, these hydraulic compositions and methods for forming the same can be easily applied for machine parts of simple shapes but are difficult to be applied for machine parts of complex shapes.","The fact of being restricted in shape which can be produced problematically results directly in the restriction on the application range of the hydraulic compositions.","DISCLOSURE OF THE INVENTION The object of the present invention is to provide a thermoplastic hydraulic composition and a formed article prepared from the composition by hydration-hardening that make it possible to produce machine parts with a shape more complex than those obtained by conventional pressing or extrusion forming by allowing the above-mentioned hydraulic composition for machine parts to have a composition such that the resulting hydraulic composition can be injection molded and forming it.","The present inventors made intensive studies to achieve the above object and found that a thermoplastic hydraulic composition containing a thermoplastic resin, a hydraulic powder, a fiber and a releasing agent respectively in given amounts is of excellent injection moldability and that a molded article obtained by injection molding the thermoplastic hydraulic composition and hardening it by curing is excellent in mechanical properties, thermal properties and formability, thus achieving reproduction of a complex shape.","Specifically, the thermoplastic hydraulic composition of the present invention is characterized by containing 100 parts by weight of two types of thermoplastic resins differing in melting point and from 500 to 1000 parts by weight of a hydraulic composition, and is preferably characterized by further comprising from 1 to 200 parts by weight of a fiber and/or from 0.5 to 10.0 parts by weight of a releasing agent added.","The foregoing hydraulic composition is preferably a mixed powder comprising from 50 to 90 wt % of a hydraulic powder and from 10 to 50 wt % of a non-hydraulic powder.","BEST MODE FOR CARRYING OUT OF THE INVENTION A more detailed description on the thermoplastic hydraulic composition of the present invention will be made below.","(1) Hydraulic Composition (1-1) In the thermoplastic hydraulic composition of the present invention, it is preferable that the hydraulic composition is used in an amount of from 500 to 1000 parts by weight, particularly from 650 to 750 parts by weight, based on 100 parts by weight of the two types of thermoplastic resins differing in melting point.","If less than 500 parts by weight, the strength of formed articles will be reduced, whereas when exceeding 1000 parts by weight, the amount of the thermoplastic resin incorporated will be reduced, resulting in deterioration of formability to cause a problem.","By the hydraulic composition is meant a powder that is hardened by water and preferably comprises at least one powder selected from portland cement, calcium silicate, calcium aluminate, calcium fluoroaluminate, calcium sulphoaluminate, calcium aluminoferrite, calcium phosphate, hemihydrate or anhydride gypsum, and a powder of calcium oxide possessing a self-hardening property.","The hydraulic powder preferably has an average particle diameter of from about 10 to about 40 μm, and preferably has a specific surface area by blaine of 2500 cm2/g or more from the viewpoint of securing a high strength of formed articles.","(1-2) The aforementioned hydraulic composition preferably is a mixed powder comprising from 50 to 90 wt % of a hydraulic powder and from 10 to 50 wt % of a non-hydraulic powder having an average particle diameter of 1/10 that of the hydraulic powder or less.","The aforementioned non-hydraulic powder indicates a powder that is incapable of hardening by itself even by its contact with water and includes a powder such that some of the components thereof are eluted in an alkaline or acid state or under a high-pressure steam atmosphere and then react with other eluted components to form a product.","Preferred as the non-hydraulic powder is at least one powder selected from a calcium hydroxide powder, a dihydrate gypsum powder, a calcium carbonate powder, a slag powder, a fly ash powder, a silica powder, a clay powder and a silica fume powder.","The non-hydraulic powder has an average particle diameter at least one order, preferably at least two order, smaller than that of the hydraulic powder, but no lower limit is set unless the effect of the present invention is damaged.","(2) The thermoplastic resin is a resin which can obtain a plasticity to a degree such that it can be formed by heating and is a resin which can be used for extrusion forming and injection molding.","In the present invention, a hydraulic composition is melt kneaded together with the thermoplastic resin at a temperature not lower than the softening point of the thermoplastic resin to be formed into a pellet form, which is used as a raw material for the subsequent injection molding.","The pellet-formed raw material is melted and kneaded again within a heating cylinder mounted inside an injection molding machine and is filled into a mold by the injection device.","The mixture of the hydraulic composition and the thermoplastic resin filled into the mold is formed into a formed article through cooling and hardening of the thermoplastic resin, which can be removed from the mold.","Hydraulic compositions are generally provided with a flowability by water, but it takes a long time for them to be released from a mold.","Therefore, forming methods such as injection molding can not be applied for them.","Moreover, if the hydraulic compositions come into contact with water, a hydration reaction will proceed and therefore articles defectively formed can not be recycled.","However, a mixture of the aforementioned thermoplastic resin and the hydraulic composition can afford a shape to the hydraulic composition without use of water and can realize releasing from a mold in a short time.","In addition, since no water is used in a stage of forming, no hydration reaction of the hydraulic composition is started and therefore the mixture can be recycled multiple times if it has not been cured yet.","Since the hydraulic composition of the present invention uses no water during its forming, it is necessary to supply moisture after the forming.","The spaces between particles of the hydraulic composition in a formed article after injection molding are filled with a thermoplastic resin.","Therefore, if the formed article is left in such a condition, the supply of water to the inside of the formed article will be inhibited, resulting in an insufficient hydration reaction of the formed article.","For this reason, it is necessary to remove a part or the whole of the resin from the inside of the formed article to form a channel for water supply.","When removing the resin from the inside of a formed article, it is desirable to use two types of resins differing in melting point when considering minimizing the dimensional change of the formed article.","Use of two types of resins differing in melting point makes it possible to injection mold the thermoplastic hydraulic composition and to obtain a formed article with a complex shape because a low molecular resin melts at a relatively low temperature and enables the hydraulic composition to fluidize easily.","Such a low molecular resin starts to decompose at a relatively low temperature (about 100° C. in the case of some resins), but a high molecular resin starts to decompose at a relatively high temperature (about 200° C. in the case of some resins).","Accordingly, if the removal of resin components at an intermediate temperature, only the low molecular resin is removed from the inside of the formed article and the vacant spaces resulting from the removal of the low molecular resin becomes channels for moisture supply, which facilitates a hydration reaction in the inside of the formed article.","On the other hand, the high molecular resin remaining in the inside of the formed article instead of being decomposed exists in the inside of the formed article to inhibit, e.g., dimensional change of the formed article.","In addition, when the resin components are removed at a temperature not lower than the melting point of the high molecular resin, all of the low molecular resin and the high molecular resin are removed and a completely inorganic hardened article will be obtained.","In such a case, since the low molecular resin has a melting point different than that of the high molecular resin, the low molecular resin is removed first and then the high molecular resin is removed.","Such removal of the resin components with a time lag can inhibit dimensional change of formed articles.","The thermoplastic low molecular compound with a lower melting point preferably has a molecular weight of 200 to several thousands.","The thermoplastic high molecular compound with a higher melting point preferably has a molecular weight of 10000 or more.","It is desirable to set upper limits based on appropriate selection from the viewpoint of kneadability and the like, because the increase of molecular weight have a great influence to kneadability.","Regarding blending of the thermoplastic resin, it is preferable to blend a low molecular compound in an amount of from 50 to 90 wt %, as described above, and most preferably from 55 to 65 wt %.","The amount of the thermoplastic high molecular compound is preferably from 50 to 10 wt %, and more preferably from 45 to 35 wt %.","If the amount of the thermoplastic low molecular compound is less than 50 wt %, the channel for moisture supply is reduced and hydration proceeds insufficiently.","On the other hand, if it is more than 90 wt %, the dimensional change during removal from a mold will adversely become large.","(2-1) As the aforementioned thermoplastic low molecular compound, it is preferable to use a single substance or two or more substances selected from low melting point compounds including paraffin wax, montan wax, carnauba wax, fatty acid esters, glycerite, and modified wax.","(2-2) As the thermoplastic high molecular compound, used are a single substance or two or more substances of polystyrene, an ethylene-vinyl acetate copolymer, an ethylene-ethyl acrylate copolymer, polypropylene, an acrylonitrile-butadiene-styrene copolymer, an acrylonitrile-styrene copolymer, methyl methacrylate, a vinyl chloride-vinyl chloride acetate copolymer, a vinyl chloride-vinyl acetate-maleic acid copolymer, a vinyl chloride-vinyl acetate copolymer, a vinyl chloride-vinylidene chloride copolymer, a vinyl chloride-acrylonitrile copolymer, an ethylene-vinyl chloride copolymer, a propylene-vinyl chloride copolymer, vinyl acetate, polyvinyl alcohol, polyamide, polyacetal, polyester, polycarbonate, polysulfone, polyether imide, polyamidoimide, and polyphenylene sulfide.","(3) The fiber is preferably added in an amount of from 1 to 200 parts by weight, and more preferably from 100 to 170 parts by weight based on 100 parts by weight of the thermoplastic resin.","When no fiber is added or when the amount of fiber added is less than 40 parts by weight, it may be impossible to improve the low impact strength and low tensile strength, which are inherent to hydraulic compositions.","If more than 200 parts by weight, it will have much influence to flowability to result in poor formability.","As the fiber, fibers of glass, carbon, aramid, polyamide, boron and the like and potassium titanate whisker can be used.","The length of the fiber is preferably from 0.1 to 6 mm, and more preferably from 3 to 6 mm.","The diameter of the fiber is preferably from 5 to 30 μm.","(4) The releasing agent is added preferably in an amount of from 0.5 to 10.0 parts by weight, and more preferably in an amount of from 2.0 to 3.0 parts by weight.","If less than 0.5 part by weight, the releasability from a mold will be poor.","If exceeding 10.0 parts by weight, the hydration reaction of the hydraulic composition may be inhibited.","As the releasing agent, stearic acid, stearyl alcohol, ethylene bisstearic acid amide, glycerol triester, glycerol monoester and the like can be used.","As other additives, alkylphenols, 2.6-tertialbutylparacresol, bisphenol A and the like for inhibiting oxidation of the thermoplastic resin can be used.","In addition, salicylic acid esters, benzene acid esters or the like may optionally be added as an ultraviolet absorber.","(5) Method for Producing Hardened Articles The hydration-hardened formed article of the present invention is a product produced by forming a thermoplastic hydraulic composition comprising a thermoplastic resin and a hydraulic composition into a given shape to obtain an unhardened formed article, subsequently heating it at a temperature not lower than the melting point of the thermoplastic resin to remove the thermoplastic resin from the inside of the formed article (this operation is also called degreasing), and curing the resulting formed article to introduce moisture, thereby hydration-hardening the formed article.","The thermoplastic resin may be made up of one compound, but it is preferable to use one made up of two types of substances including a thermoplastic low molecular compound and a thermoplastic high molecular compound as described previously.","When the thermoplastic resin is constituted of such two types of compounds, preferred is degreasing at a temperature between the melting point of the thermoplastic low molecular compound having a lower melting point and the melting point of the thermoplastic high molecular compound having a higher melting point (270° C. or less).","This will remove only the thermoplastic low molecular compound from the inside of a formed article.","Introduction of moisture using the vacant spaces resulting from the degreasing as channels for moisture supply will increase the hydration reaction rate to cause hydration hardening.","Specifically, injection molding, extrusion forming, pressure forming and the like can be employed as a forming method.","Furthermore, regarding a degreasing method, when DEP and an ethylene-vinyl acetate copolymer are used as a low molecular compound and a high molecular compound, respectively, decomposition of DEP starts at 100° C. and ends at 190° C.; whereas the ethylene-vinyl acetate copolymer starts to decompose at 210° C. Accordingly, it is possible to selectively remove only DEP by heating formed articles at 200° C. When curing at a temperature of from 400 to 500° C., it is possible to remove these thermoplastic resins completely.","The time required for resin removal can be set optionally depending, for example, on the kind, incorporation amount, pressure and temperature of the resin.","When the combination of the resins described in the above example is degreased at 200° C. under atmospheric pressure, the degreasing ratio will reach about 70% in 3 hours and about 100% in 12 hours.","Further, curing may be carried out by a curing method such as a normal pressure steam curing, a high pressure steam curing and a hot water curing conducted alone at a temperature not lower than 80° C., or in combination of the normal pressure curing and the hot water curing, or in combination of the high pressure steam curing and the hot water curing.","As a degreasing method, methods other than heating can be applied and are exemplified by solvent extraction and a removal method using reduced pressure.","The following is a description on embodiments of the present invention.","EXPERIMENTAL EXAMPLE 1 A thermoplastic hydraulic composition was prepared by blending an ethylene-vinyl acetate copolymer resin (EVA, molecular weight: 30000 to 50000) as a thermoplastic high molecular compound, carnauba wax (molecular weight: 300 to 500) as a thermoplastic low molecular compound and stearic acid as a releasing agent, respectively in the ratios given in Table 1, to a powder resulting from mixing of portland cement (average particle diameter 20 μm) as a hydraulic powder and fly ash and silica powder as non-hydraulic powders, and then was kneaded with a hot roll at 140° C. for 45 minutes to yield pellets.","Subsequently, an injection molded article 120 mm long, 10 mm wide and 3 mm thick was obtained by use of the pellets.","The resulting unhardened molded article was degreased through a degreasing step by heating (1): at 200° C. for 12 hours, 2) at 500° C. for 12 hours) and then a molded article was produced by autoclave curing (175° C., 7 hours, 8.8 atm).","The molded article was tested for its flexural strength, deflection temperature under load, and coefficient of linear expansion and was compared.","The results are shown in Table 1.<Test Method> HDT Test (Test of Deflection Temperature under Load) .",".",".","According to JIS K 7191-2, Method A A specimen 120 mm long, 10 mm wide and 3 mm thick was prepared.","The specimen was held between supporting points with an interval of 100 mm and the temperature thereof was raised at a constant rate while a flexural stress of 1.8 MPa was applied downward to its center.","The temperature at which the deflection reached a standard deflection was used as the deflection temperature under load.","Coefficient of linear expansion .",".",".","According to ASTM D-648 A φ3×20 mm specimen was prepared and the coefficient of linear expansion was measured in the temperature range of from 30 to 80° C. using a push-rod type measuring device.","TABLE 1 Unit: part(s) by weight Compara- Compara- tive tive Example Example Example Example Example Example Example 1 2 3 4 5 1 2 Portland cement 80 80 80 80 80 80 80 Fly ash (average 10 10 10 10 10 10 10 particle diameter 1 to 2 μm) Silica powder 10 10 10 10 10 10 10 Carnauba wax 7.5 8.5 7.5 8.5 4.0 9.0 0 Ethylene-vinyl 3.5 3.5 3.5 3.5 6.0 0 9.0 acetate copolymer Stearic acid 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Carbon fiber 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Degreasing (1) (1) (2) (2) (1) (1) (1) method Flexural strength* 37.0 40.4 105 110 22.5 ** 8.6 (N/mm2) HDT(° C.) 180 178 >280 >280 95 ** 50 Coefficient of 80 80 38 39 150 ** 250 linear expansion (×10−7) *According to JIS K 7171 Bending test **Cracks were formed during curing.","The results shown above reveal that all the molded articles of the present invention are superior in mechanical strength in terms of flexural strength to those of the Comparative Examples.","In addition, it is shown that the molded articles of the present invention have higher deflection temperatures under load and therefore are superior also in thermal resistance.","Moreover, the fact that the molded articles of the present invention have smaller coefficients of linear expansion shows that those molded articles are superior also in dimension stability.","On the other hand, the molded articles of Comparative Examples are inferior in all of these properties to those of the present invention.","In Comparative Example 2, cracks were formed during curing.","EXPERIMENTAL EXAMPLE 2 Using the same materials as those used in Experimental Example 1, a thermoplastic hydraulic composition with the composition shown in Table 2 was kneaded while being heated to 150° C. with a hot roll and formed into a pellet form.","Subsequently, the resultant was formed into a 120 mm long, 10 mm wide, 3 mm thick specimen using an injection machine and then the unhardened molded article was degreased through a degreasing step by heating ((1): at 200° C. for 12 hours, (2) at 500° C. for 12 hours).","A molded article thereafter was produced by normal pressure steam curing (100° C., 7 hours) and then compared its flexural strength, deflection temperature under load, and coefficient of linear expansion in the same way as Experimental Example 1.The results are shown in Table 2.TABLE 2 Unit: part(s) by weight Compara- Compara- tive tive Example Example Example Example Example Example Example 6 7 8 9 10 3 4 Portland cement 80 80 80 80 80 80 80 Fly ash (average 10 10 10 10 10 10 10 particle diameter 1 to 2 μm) Silica powder 10 10 10 10 10 10 10 Carnauba wax 7.5 8.5 7.5 8.5 4.0 9.0 0 Ethylene-vinyl 3.5 3.5 3.5 3.5 6.0 0 9.0 acetate copolymer Stearic acid 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Carbon fiber 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Degreasing (1) (1) (2) (2) (1) (1) (1) method Flexural strength* 31.2 32.3 70.5 80.4 19.6 ** 6.0 (N/mm2) HDT(° C.) 180 178 >280 >280 95 ** 50 Coefficient of 100 100 50 48 179 ** 254 linear expansion (×10−7) *According to JIS K 7171 Bending test **Cracks were formed during curing.","The results shown above reveal that all the formed articles of the present invention are superior in mechanical strength measured as flexural strength to those of Comparative Examples.","Further, it is also shown that the formed articles of the present invention have higher deflection temperature under load and are superior in thermal resistance.","Furthermore, the fact that those formed article have small coefficients of linear expansion shows that those formed articles are also superior in dimensional stability.","On the other hand, the formed articles of the Comparative Examples are inferior in all of such properties to the formed articles of the present invention.","In Comparative Example 3, cracks were formed during curing.","As described above, the thermoplastic hydraulic composition of the present invention can be injection molded without addition of water.","When this composition is cured, general machine parts, OA machine parts and the like with excellent mechanical properties, thermal resistance, dimensional stability and processability can be produced.","By blending two types of thermoplastic resins differing in melting point and removing only a thermoplastic low molecular compound having a low melting point followed by curing, it is possible to promote the hydration reaction to the inside of formed articles and simultaneously to harden the formed articles while maintaining their shapes by the action of the remaining high molecular compounds having high melting points.","In such a manner, machine parts excellent in mechanical characteristics, thermal resistance, dimensional stability or the like can be produced.","Furthermore, curing after complete removal of the thermoplastic resin at higher temperatures makes it possible to further improve such properties of formed articles."]],"string":"[\n [\n \"Thermoplastic Hydraulic Composition, Formed Article Prepared From The Composition By Hydration- Hardening And Method For Preparing The Hydration- Hardened Former Article\",\n \"The object of the present invention is to produce general machine parts, OA machine part, and the like which can be produced by injection molding and which have excellent mechanical properties, thermal resistance, dimension stability and processability.\",\n \"The thermoplastic hydraulic composition of the present invention comprises 100 parts by weight of two types of thermoplastic resins differing in melting point and from 500 to 1000 parts by weight of a hydraulic composition.\",\n \"It is characterized by further comprising from 1 to 200 parts by weight of a fiber and/or from 0.5 to 10.0 parts by weight of a releasing agent added.\",\n \"It is characterized in that the hydraulic composition preferably is a mixed powder which comprises from 50 to 90 wt % of a hydraulic powder and from 10 to 50 wt % of a non-hydraulic powder having an average particle diameter of 1/10 that of the hydraulic powder or less.\"\n ],\n [\n \"1.A thermoplastic hydraulic composition that is formed into a given shape and then is hardened by removal of at least a part of a thermoplastic resin from the inside, followed by the introduction of moisture, which is characterized by comprising 100 parts by weight of two types of thermoplastic resins differing in melting point and from 500 to 1000 parts by weight of a hydraulic composition.\",\n \"2.The thermoplastic hydraulic composition according to claim 1 further comprising at least one of from 1 to 200 parts by weight of a fiber and from 0.5 to 10.0 parts by weight of a releasing agent added.\",\n \"3.The thermoplastic hydraulic composition according to claim 1, wherein the hydraulic composition is a mixed powder comprising from 50 to 90 wt % of a hydraulic powder and from 10 to 50 wt % of a non-hydraulic powder.\",\n \"4.The thermoplastic hydraulic composition according to claim 1, wherein the hydraulic powder is at least one powder selected from portland cement, calcium silicate, calcium aluminate, calcium fluoroaluminate, calcium sulphoaluminate, calcium alumino-ferrite, calcium phosphate, hemihydrate or anhydride gypsum and a powder of calcium oxide possessing a self-hardening property.\",\n \"5.The thermoplastic hydraulic composition according to claim 1, wherein the non-hydraulic powder is at least one powder selected from a potassium hydroxide powder, a dihydrate gypsum powder, a calcium carbonate powder, a slag powder, a flyash powder, a silica powder, a clay powder and a silica fume powder.\",\n \"6.The thermoplastic hydraulic composition according to claim 1, wherein the thermoplastic resin is constituted of from 50 to 90 wt % of a thermoplastic low molecular compound and 50 to 10 wt % of a thermoplastic high molecular compound.\",\n \"7.The thermoplastic hydraulic composition according to claim 6, wherein the thermoplastic low molecular compound is selected from low melting point compounds of paraffin wax, montan wax, carnauba wax, a fatty acid ester, glycerite and modified wax.\",\n \"8.The thermoplastic hydraulic composition according to claim 6, wherein the thermoplastic high molecular compound is a single substance or a copolymer of two or more substances selected from polystyrene, an ethylene-vinyl acetate copolymer, an ethylene-ethyl acrylate copolymer, polypropylene, an acrylonitrile-butadiene-styrene copolymer, an acrylonitrile-styrene copolymer, methyl methacrylate, a vinyl chloride-vinyl chloride acetate copolymer, a vinyl chloride-vinyl acetate-maleic acid copolymer, a vinyl chloride-vinyl acetate copolymer, a vinyl chloride-vinylidene chloride copolymer, a vinyl chloride-acrylonitrile copolymer, an ethylene-vinyl chloride copolymer, a propylene-vinyl chloride copolymer, vinyl acetate, polyvinyl alcohol, polyamide, polyacetal, polyester, polycarbonate, polysulfone, polyether imide, polyamidoimide, and polyphenylene sulfide.\",\n \"9.A hydration-hardened formed article characterized by being obtained by forming a thermoplastic hydraulic composition comprising 100 parts by weight of a thermoplastic resin and from 500 to 1000 parts by weight of a hydraulic composition into a given shape, subsequently removing the thermoplastic resin from the inside of the resulting formed article, and further introducing moisture into the formed article to harden it.\",\n \"10.A hydration-hardened formed article characterized by being obtained by forming the hydraulic composition according to claim 1 into a given shape, subsequently removing the thermoplastic resin from the resulting formed article completely or removing only a thermoplastic low molecular compound, and further introducing moisture into the inside of the formed article to harden it.\",\n \"11.A method for producing a hydrogen-hardened formed article, the method being characterized in that it comprises forming a thermoplastic hydraulic composition comprising 100 parts by weight of a thermoplastic resin and from 500 to 1000 parts by weight of a hydraulic composition into a given shape to obtain an unhardened formed article, subsequently removing only a thermoplastic low molecular compound from the inside of the formed article by degreasing the unhardened formed article at a temperature not lower than the melting point of the thermoplastic low molecular compound, and then hydration-hardening the unhardened formed article by curing it to introduce moisture thereinto.\",\n \"12.A method for producing a hydration-hardened formed article, the method being characterized in that it comprises forming the hydraulic composition according to claim 1 into a given shape to obtain an unhardened formed article, subsequently removing only a thermoplastic resin from the inside of the formed article by degreasing the unhardened formed article at a temperature not lower than the melting point of the thermoplastic high molecular compound, and then hydration-hardening the unhardened formed article by curing it to introduce moisture thereinto.\",\n \"13.The method for producing a hydration-hardened formed article according to claim 11, wherein the degreasing step is carried out at a temperature of from 400 to 500° C. for a period of 12 hours or longer.\",\n \"14.A method for producing a hydration-hardened formed article, the method being characterized in that it comprises forming the hydraulic composition according to claim 1 into a given shape to obtain an unhardened formed article, subsequently removing only a thermoplastic low molecular compound from the inside of the formed article by degreasing the unhardened formed article at a temperature not lower than the melting point of the thermoplastic low molecular compound, and then hydration-hardening the unhardened formed article by curing it to introduce moisture thereinto.\",\n \"15.The method for producing a hydration-hardened formed article according to claim 14, wherein the degreasing step is carried out at a temperature of 270° C. or lower for a period of 12 hours or shorter.\",\n \"16.The method for producing a hydration-hardened formed article according to claim 11, wherein said curing step is carried out at a temperature of 80° C. or higher by any one of normal pressure steam curing, high pressure steam curing and hot water curing, or in combination of the normal pressure steam curing and the hot water curing, or in combination of the high pressure steam curing and the hot water curing.\"\n ],\n [\n \"<SOH> BACKGROUND ART <EOH>As a material for machine parts, metallic materials have conventionally been used widely due to their superior material characteristics.\",\n \"However, a recent technical progress has diversified needs for machine parts and machine parts in which non-metallic materials such as sintered ceramics or plastics have come to be used for making up for drawbacks of metallic materials The present inventors made a variety of investigations in order to comply with such demands and found that a hydraulic composition comprising a combination of a hydraulic powder, a non-hydraulic powder with an average particle diameter at least one order smaller than that of the hydraulic powder, a workability improver and a formability improver can be applied for machine parts such as paper sheet-feeding rollers through its pressure forming or extrusion forming; they filed patent applications directed thereto (Japanese Patent Application Nos.\",\n \"Hei-10-177099, Hei-10-177100 and Hei-11-233636.)\",\n \"However, these hydraulic compositions and methods for forming the same can be easily applied for machine parts of simple shapes but are difficult to be applied for machine parts of complex shapes.\",\n \"The fact of being restricted in shape which can be produced problematically results directly in the restriction on the application range of the hydraulic compositions.\"\n ],\n [\n \"TECHNICAL FIELD The present invention relates to a thermoplastic hydraulic composition that allows an injection molding technique mainly employed for production of plastic molded articles and ceramic molded articles to be applicable even for hydraulic compositions, and to formed articles prepared from the hydraulic compositions by hydration-hardening.\",\n \"The present invention relates more particularly to provide thermoplastic hydraulic compositions, formed articles thereof having excellent mechanical properties, thermal resistance, dimensional stability and processability, as well as being capable of being applied for, e.g., general machine parts and OA machine parts.\",\n \"BACKGROUND ART As a material for machine parts, metallic materials have conventionally been used widely due to their superior material characteristics.\",\n \"However, a recent technical progress has diversified needs for machine parts and machine parts in which non-metallic materials such as sintered ceramics or plastics have come to be used for making up for drawbacks of metallic materials The present inventors made a variety of investigations in order to comply with such demands and found that a hydraulic composition comprising a combination of a hydraulic powder, a non-hydraulic powder with an average particle diameter at least one order smaller than that of the hydraulic powder, a workability improver and a formability improver can be applied for machine parts such as paper sheet-feeding rollers through its pressure forming or extrusion forming; they filed patent applications directed thereto (Japanese Patent Application Nos.\",\n \"Hei-10-177099, Hei-10-177100 and Hei-11-233636.)\",\n \"However, these hydraulic compositions and methods for forming the same can be easily applied for machine parts of simple shapes but are difficult to be applied for machine parts of complex shapes.\",\n \"The fact of being restricted in shape which can be produced problematically results directly in the restriction on the application range of the hydraulic compositions.\",\n \"DISCLOSURE OF THE INVENTION The object of the present invention is to provide a thermoplastic hydraulic composition and a formed article prepared from the composition by hydration-hardening that make it possible to produce machine parts with a shape more complex than those obtained by conventional pressing or extrusion forming by allowing the above-mentioned hydraulic composition for machine parts to have a composition such that the resulting hydraulic composition can be injection molded and forming it.\",\n \"The present inventors made intensive studies to achieve the above object and found that a thermoplastic hydraulic composition containing a thermoplastic resin, a hydraulic powder, a fiber and a releasing agent respectively in given amounts is of excellent injection moldability and that a molded article obtained by injection molding the thermoplastic hydraulic composition and hardening it by curing is excellent in mechanical properties, thermal properties and formability, thus achieving reproduction of a complex shape.\",\n \"Specifically, the thermoplastic hydraulic composition of the present invention is characterized by containing 100 parts by weight of two types of thermoplastic resins differing in melting point and from 500 to 1000 parts by weight of a hydraulic composition, and is preferably characterized by further comprising from 1 to 200 parts by weight of a fiber and/or from 0.5 to 10.0 parts by weight of a releasing agent added.\",\n \"The foregoing hydraulic composition is preferably a mixed powder comprising from 50 to 90 wt % of a hydraulic powder and from 10 to 50 wt % of a non-hydraulic powder.\",\n \"BEST MODE FOR CARRYING OUT OF THE INVENTION A more detailed description on the thermoplastic hydraulic composition of the present invention will be made below.\",\n \"(1) Hydraulic Composition (1-1) In the thermoplastic hydraulic composition of the present invention, it is preferable that the hydraulic composition is used in an amount of from 500 to 1000 parts by weight, particularly from 650 to 750 parts by weight, based on 100 parts by weight of the two types of thermoplastic resins differing in melting point.\",\n \"If less than 500 parts by weight, the strength of formed articles will be reduced, whereas when exceeding 1000 parts by weight, the amount of the thermoplastic resin incorporated will be reduced, resulting in deterioration of formability to cause a problem.\",\n \"By the hydraulic composition is meant a powder that is hardened by water and preferably comprises at least one powder selected from portland cement, calcium silicate, calcium aluminate, calcium fluoroaluminate, calcium sulphoaluminate, calcium aluminoferrite, calcium phosphate, hemihydrate or anhydride gypsum, and a powder of calcium oxide possessing a self-hardening property.\",\n \"The hydraulic powder preferably has an average particle diameter of from about 10 to about 40 μm, and preferably has a specific surface area by blaine of 2500 cm2/g or more from the viewpoint of securing a high strength of formed articles.\",\n \"(1-2) The aforementioned hydraulic composition preferably is a mixed powder comprising from 50 to 90 wt % of a hydraulic powder and from 10 to 50 wt % of a non-hydraulic powder having an average particle diameter of 1/10 that of the hydraulic powder or less.\",\n \"The aforementioned non-hydraulic powder indicates a powder that is incapable of hardening by itself even by its contact with water and includes a powder such that some of the components thereof are eluted in an alkaline or acid state or under a high-pressure steam atmosphere and then react with other eluted components to form a product.\",\n \"Preferred as the non-hydraulic powder is at least one powder selected from a calcium hydroxide powder, a dihydrate gypsum powder, a calcium carbonate powder, a slag powder, a fly ash powder, a silica powder, a clay powder and a silica fume powder.\",\n \"The non-hydraulic powder has an average particle diameter at least one order, preferably at least two order, smaller than that of the hydraulic powder, but no lower limit is set unless the effect of the present invention is damaged.\",\n \"(2) The thermoplastic resin is a resin which can obtain a plasticity to a degree such that it can be formed by heating and is a resin which can be used for extrusion forming and injection molding.\",\n \"In the present invention, a hydraulic composition is melt kneaded together with the thermoplastic resin at a temperature not lower than the softening point of the thermoplastic resin to be formed into a pellet form, which is used as a raw material for the subsequent injection molding.\",\n \"The pellet-formed raw material is melted and kneaded again within a heating cylinder mounted inside an injection molding machine and is filled into a mold by the injection device.\",\n \"The mixture of the hydraulic composition and the thermoplastic resin filled into the mold is formed into a formed article through cooling and hardening of the thermoplastic resin, which can be removed from the mold.\",\n \"Hydraulic compositions are generally provided with a flowability by water, but it takes a long time for them to be released from a mold.\",\n \"Therefore, forming methods such as injection molding can not be applied for them.\",\n \"Moreover, if the hydraulic compositions come into contact with water, a hydration reaction will proceed and therefore articles defectively formed can not be recycled.\",\n \"However, a mixture of the aforementioned thermoplastic resin and the hydraulic composition can afford a shape to the hydraulic composition without use of water and can realize releasing from a mold in a short time.\",\n \"In addition, since no water is used in a stage of forming, no hydration reaction of the hydraulic composition is started and therefore the mixture can be recycled multiple times if it has not been cured yet.\",\n \"Since the hydraulic composition of the present invention uses no water during its forming, it is necessary to supply moisture after the forming.\",\n \"The spaces between particles of the hydraulic composition in a formed article after injection molding are filled with a thermoplastic resin.\",\n \"Therefore, if the formed article is left in such a condition, the supply of water to the inside of the formed article will be inhibited, resulting in an insufficient hydration reaction of the formed article.\",\n \"For this reason, it is necessary to remove a part or the whole of the resin from the inside of the formed article to form a channel for water supply.\",\n \"When removing the resin from the inside of a formed article, it is desirable to use two types of resins differing in melting point when considering minimizing the dimensional change of the formed article.\",\n \"Use of two types of resins differing in melting point makes it possible to injection mold the thermoplastic hydraulic composition and to obtain a formed article with a complex shape because a low molecular resin melts at a relatively low temperature and enables the hydraulic composition to fluidize easily.\",\n \"Such a low molecular resin starts to decompose at a relatively low temperature (about 100° C. in the case of some resins), but a high molecular resin starts to decompose at a relatively high temperature (about 200° C. in the case of some resins).\",\n \"Accordingly, if the removal of resin components at an intermediate temperature, only the low molecular resin is removed from the inside of the formed article and the vacant spaces resulting from the removal of the low molecular resin becomes channels for moisture supply, which facilitates a hydration reaction in the inside of the formed article.\",\n \"On the other hand, the high molecular resin remaining in the inside of the formed article instead of being decomposed exists in the inside of the formed article to inhibit, e.g., dimensional change of the formed article.\",\n \"In addition, when the resin components are removed at a temperature not lower than the melting point of the high molecular resin, all of the low molecular resin and the high molecular resin are removed and a completely inorganic hardened article will be obtained.\",\n \"In such a case, since the low molecular resin has a melting point different than that of the high molecular resin, the low molecular resin is removed first and then the high molecular resin is removed.\",\n \"Such removal of the resin components with a time lag can inhibit dimensional change of formed articles.\",\n \"The thermoplastic low molecular compound with a lower melting point preferably has a molecular weight of 200 to several thousands.\",\n \"The thermoplastic high molecular compound with a higher melting point preferably has a molecular weight of 10000 or more.\",\n \"It is desirable to set upper limits based on appropriate selection from the viewpoint of kneadability and the like, because the increase of molecular weight have a great influence to kneadability.\",\n \"Regarding blending of the thermoplastic resin, it is preferable to blend a low molecular compound in an amount of from 50 to 90 wt %, as described above, and most preferably from 55 to 65 wt %.\",\n \"The amount of the thermoplastic high molecular compound is preferably from 50 to 10 wt %, and more preferably from 45 to 35 wt %.\",\n \"If the amount of the thermoplastic low molecular compound is less than 50 wt %, the channel for moisture supply is reduced and hydration proceeds insufficiently.\",\n \"On the other hand, if it is more than 90 wt %, the dimensional change during removal from a mold will adversely become large.\",\n \"(2-1) As the aforementioned thermoplastic low molecular compound, it is preferable to use a single substance or two or more substances selected from low melting point compounds including paraffin wax, montan wax, carnauba wax, fatty acid esters, glycerite, and modified wax.\",\n \"(2-2) As the thermoplastic high molecular compound, used are a single substance or two or more substances of polystyrene, an ethylene-vinyl acetate copolymer, an ethylene-ethyl acrylate copolymer, polypropylene, an acrylonitrile-butadiene-styrene copolymer, an acrylonitrile-styrene copolymer, methyl methacrylate, a vinyl chloride-vinyl chloride acetate copolymer, a vinyl chloride-vinyl acetate-maleic acid copolymer, a vinyl chloride-vinyl acetate copolymer, a vinyl chloride-vinylidene chloride copolymer, a vinyl chloride-acrylonitrile copolymer, an ethylene-vinyl chloride copolymer, a propylene-vinyl chloride copolymer, vinyl acetate, polyvinyl alcohol, polyamide, polyacetal, polyester, polycarbonate, polysulfone, polyether imide, polyamidoimide, and polyphenylene sulfide.\",\n \"(3) The fiber is preferably added in an amount of from 1 to 200 parts by weight, and more preferably from 100 to 170 parts by weight based on 100 parts by weight of the thermoplastic resin.\",\n \"When no fiber is added or when the amount of fiber added is less than 40 parts by weight, it may be impossible to improve the low impact strength and low tensile strength, which are inherent to hydraulic compositions.\",\n \"If more than 200 parts by weight, it will have much influence to flowability to result in poor formability.\",\n \"As the fiber, fibers of glass, carbon, aramid, polyamide, boron and the like and potassium titanate whisker can be used.\",\n \"The length of the fiber is preferably from 0.1 to 6 mm, and more preferably from 3 to 6 mm.\",\n \"The diameter of the fiber is preferably from 5 to 30 μm.\",\n \"(4) The releasing agent is added preferably in an amount of from 0.5 to 10.0 parts by weight, and more preferably in an amount of from 2.0 to 3.0 parts by weight.\",\n \"If less than 0.5 part by weight, the releasability from a mold will be poor.\",\n \"If exceeding 10.0 parts by weight, the hydration reaction of the hydraulic composition may be inhibited.\",\n \"As the releasing agent, stearic acid, stearyl alcohol, ethylene bisstearic acid amide, glycerol triester, glycerol monoester and the like can be used.\",\n \"As other additives, alkylphenols, 2.6-tertialbutylparacresol, bisphenol A and the like for inhibiting oxidation of the thermoplastic resin can be used.\",\n \"In addition, salicylic acid esters, benzene acid esters or the like may optionally be added as an ultraviolet absorber.\",\n \"(5) Method for Producing Hardened Articles The hydration-hardened formed article of the present invention is a product produced by forming a thermoplastic hydraulic composition comprising a thermoplastic resin and a hydraulic composition into a given shape to obtain an unhardened formed article, subsequently heating it at a temperature not lower than the melting point of the thermoplastic resin to remove the thermoplastic resin from the inside of the formed article (this operation is also called degreasing), and curing the resulting formed article to introduce moisture, thereby hydration-hardening the formed article.\",\n \"The thermoplastic resin may be made up of one compound, but it is preferable to use one made up of two types of substances including a thermoplastic low molecular compound and a thermoplastic high molecular compound as described previously.\",\n \"When the thermoplastic resin is constituted of such two types of compounds, preferred is degreasing at a temperature between the melting point of the thermoplastic low molecular compound having a lower melting point and the melting point of the thermoplastic high molecular compound having a higher melting point (270° C. or less).\",\n \"This will remove only the thermoplastic low molecular compound from the inside of a formed article.\",\n \"Introduction of moisture using the vacant spaces resulting from the degreasing as channels for moisture supply will increase the hydration reaction rate to cause hydration hardening.\",\n \"Specifically, injection molding, extrusion forming, pressure forming and the like can be employed as a forming method.\",\n \"Furthermore, regarding a degreasing method, when DEP and an ethylene-vinyl acetate copolymer are used as a low molecular compound and a high molecular compound, respectively, decomposition of DEP starts at 100° C. and ends at 190° C.; whereas the ethylene-vinyl acetate copolymer starts to decompose at 210° C. Accordingly, it is possible to selectively remove only DEP by heating formed articles at 200° C. When curing at a temperature of from 400 to 500° C., it is possible to remove these thermoplastic resins completely.\",\n \"The time required for resin removal can be set optionally depending, for example, on the kind, incorporation amount, pressure and temperature of the resin.\",\n \"When the combination of the resins described in the above example is degreased at 200° C. under atmospheric pressure, the degreasing ratio will reach about 70% in 3 hours and about 100% in 12 hours.\",\n \"Further, curing may be carried out by a curing method such as a normal pressure steam curing, a high pressure steam curing and a hot water curing conducted alone at a temperature not lower than 80° C., or in combination of the normal pressure curing and the hot water curing, or in combination of the high pressure steam curing and the hot water curing.\",\n \"As a degreasing method, methods other than heating can be applied and are exemplified by solvent extraction and a removal method using reduced pressure.\",\n \"The following is a description on embodiments of the present invention.\",\n \"EXPERIMENTAL EXAMPLE 1 A thermoplastic hydraulic composition was prepared by blending an ethylene-vinyl acetate copolymer resin (EVA, molecular weight: 30000 to 50000) as a thermoplastic high molecular compound, carnauba wax (molecular weight: 300 to 500) as a thermoplastic low molecular compound and stearic acid as a releasing agent, respectively in the ratios given in Table 1, to a powder resulting from mixing of portland cement (average particle diameter 20 μm) as a hydraulic powder and fly ash and silica powder as non-hydraulic powders, and then was kneaded with a hot roll at 140° C. for 45 minutes to yield pellets.\",\n \"Subsequently, an injection molded article 120 mm long, 10 mm wide and 3 mm thick was obtained by use of the pellets.\",\n \"The resulting unhardened molded article was degreased through a degreasing step by heating (1): at 200° C. for 12 hours, 2) at 500° C. for 12 hours) and then a molded article was produced by autoclave curing (175° C., 7 hours, 8.8 atm).\",\n \"The molded article was tested for its flexural strength, deflection temperature under load, and coefficient of linear expansion and was compared.\",\n \"The results are shown in Table 1.<Test Method> HDT Test (Test of Deflection Temperature under Load) .\",\n \".\",\n \".\",\n \"According to JIS K 7191-2, Method A A specimen 120 mm long, 10 mm wide and 3 mm thick was prepared.\",\n \"The specimen was held between supporting points with an interval of 100 mm and the temperature thereof was raised at a constant rate while a flexural stress of 1.8 MPa was applied downward to its center.\",\n \"The temperature at which the deflection reached a standard deflection was used as the deflection temperature under load.\",\n \"Coefficient of linear expansion .\",\n \".\",\n \".\",\n \"According to ASTM D-648 A φ3×20 mm specimen was prepared and the coefficient of linear expansion was measured in the temperature range of from 30 to 80° C. using a push-rod type measuring device.\",\n \"TABLE 1 Unit: part(s) by weight Compara- Compara- tive tive Example Example Example Example Example Example Example 1 2 3 4 5 1 2 Portland cement 80 80 80 80 80 80 80 Fly ash (average 10 10 10 10 10 10 10 particle diameter 1 to 2 μm) Silica powder 10 10 10 10 10 10 10 Carnauba wax 7.5 8.5 7.5 8.5 4.0 9.0 0 Ethylene-vinyl 3.5 3.5 3.5 3.5 6.0 0 9.0 acetate copolymer Stearic acid 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Carbon fiber 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Degreasing (1) (1) (2) (2) (1) (1) (1) method Flexural strength* 37.0 40.4 105 110 22.5 ** 8.6 (N/mm2) HDT(° C.) 180 178 >280 >280 95 ** 50 Coefficient of 80 80 38 39 150 ** 250 linear expansion (×10−7) *According to JIS K 7171 Bending test **Cracks were formed during curing.\",\n \"The results shown above reveal that all the molded articles of the present invention are superior in mechanical strength in terms of flexural strength to those of the Comparative Examples.\",\n \"In addition, it is shown that the molded articles of the present invention have higher deflection temperatures under load and therefore are superior also in thermal resistance.\",\n \"Moreover, the fact that the molded articles of the present invention have smaller coefficients of linear expansion shows that those molded articles are superior also in dimension stability.\",\n \"On the other hand, the molded articles of Comparative Examples are inferior in all of these properties to those of the present invention.\",\n \"In Comparative Example 2, cracks were formed during curing.\",\n \"EXPERIMENTAL EXAMPLE 2 Using the same materials as those used in Experimental Example 1, a thermoplastic hydraulic composition with the composition shown in Table 2 was kneaded while being heated to 150° C. with a hot roll and formed into a pellet form.\",\n \"Subsequently, the resultant was formed into a 120 mm long, 10 mm wide, 3 mm thick specimen using an injection machine and then the unhardened molded article was degreased through a degreasing step by heating ((1): at 200° C. for 12 hours, (2) at 500° C. for 12 hours).\",\n \"A molded article thereafter was produced by normal pressure steam curing (100° C., 7 hours) and then compared its flexural strength, deflection temperature under load, and coefficient of linear expansion in the same way as Experimental Example 1.The results are shown in Table 2.TABLE 2 Unit: part(s) by weight Compara- Compara- tive tive Example Example Example Example Example Example Example 6 7 8 9 10 3 4 Portland cement 80 80 80 80 80 80 80 Fly ash (average 10 10 10 10 10 10 10 particle diameter 1 to 2 μm) Silica powder 10 10 10 10 10 10 10 Carnauba wax 7.5 8.5 7.5 8.5 4.0 9.0 0 Ethylene-vinyl 3.5 3.5 3.5 3.5 6.0 0 9.0 acetate copolymer Stearic acid 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Carbon fiber 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Degreasing (1) (1) (2) (2) (1) (1) (1) method Flexural strength* 31.2 32.3 70.5 80.4 19.6 ** 6.0 (N/mm2) HDT(° C.) 180 178 >280 >280 95 ** 50 Coefficient of 100 100 50 48 179 ** 254 linear expansion (×10−7) *According to JIS K 7171 Bending test **Cracks were formed during curing.\",\n \"The results shown above reveal that all the formed articles of the present invention are superior in mechanical strength measured as flexural strength to those of Comparative Examples.\",\n \"Further, it is also shown that the formed articles of the present invention have higher deflection temperature under load and are superior in thermal resistance.\",\n \"Furthermore, the fact that those formed article have small coefficients of linear expansion shows that those formed articles are also superior in dimensional stability.\",\n \"On the other hand, the formed articles of the Comparative Examples are inferior in all of such properties to the formed articles of the present invention.\",\n \"In Comparative Example 3, cracks were formed during curing.\",\n \"As described above, the thermoplastic hydraulic composition of the present invention can be injection molded without addition of water.\",\n \"When this composition is cured, general machine parts, OA machine parts and the like with excellent mechanical properties, thermal resistance, dimensional stability and processability can be produced.\",\n \"By blending two types of thermoplastic resins differing in melting point and removing only a thermoplastic low molecular compound having a low melting point followed by curing, it is possible to promote the hydration reaction to the inside of formed articles and simultaneously to harden the formed articles while maintaining their shapes by the action of the remaining high molecular compounds having high melting points.\",\n \"In such a manner, machine parts excellent in mechanical characteristics, thermal resistance, dimensional stability or the like can be produced.\",\n \"Furthermore, curing after complete removal of the thermoplastic resin at higher temperatures makes it possible to further improve such properties of formed articles.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10296092"}}},{"rowIdx":90,"cells":{"text":{"kind":"list like","value":[["Combinations of enzyme inhibitor-containing preparations and the use thereof","The invention comprises a process wherein the DNA synthesis and, thus, the proliferation of mononuclear cells (MNZ) and of T cells as well is inhibited by the simultaneous and combined inhibition of the enzyme activity (I) of alanyl aminopeptidase and of dipeptidyl peptidase IV; (II) of dipeptidyl peptidase IV and of the angiotensin-converting enzyme; (III) of dipeptidyl peptidase IV and of prolyl oligopeptidase; and (IV) of dipeptidyl peptidase IV and of X-Pro-aminopeptidase to an extent which cannot be achieved by an application of a single one of said enzyme inhibitors, even at a higher dosage.","Although the said inhibitors exercise an influence on the very same process finally, i.e.","the DNA synthesis and, thus, the proliferation of immune cells, this effect is not complete and is not long lasting when a single inhibitor is applied.","From the functional overlap of enzymatic activities results an additive/superadditive inhibitory effect on the DNA synthesis and proliferation by the simultaneous inhibition of more than one of the above enzymes, as our data show.","Our invention shows that the simultaneous application of substances inhibiting the above enzymes or of corresponding preparations and administration forms, respectively, is well suitable for a therapy of autoimmune diseases and chronic diseases with an inflammatory genesis as well as for a treatment of rejection episodes after a transplantation."],["1.Use of inhibitors of dipeptidyl peptidase IV (DP IV) as well as of enzymes having the same substrate specificity (DP IV-analogous enzyme activity) in combination with inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) as well as of enzymes having the same substrate specificity (APN-analogous enzyme activity), of X-Pro-aminopeptidase (aminopeptidase P, APP), of the angiotensin-converting enzyme (ACE) and/or of prolyl oligopeptidase (POP, prolyl endopeptidase, PEP) for a superadditive inhibition of an activation, DNA synthesis and proliferation of human T lymphocytes and mononuclear cells.","2.Use according to claim 1, wherein the inhibitors of DP IV are preferably Xaa-Pro-dipeptides (Xaa=α-amino acid or side chain-protected derivative), corresponding derivatives, preferably dipeptide phosphonic acid diaryl estates, dipeptide boronic acids (e.g.","Pro-boro-Pro) and salts thereof, Xaa-Xaa-(Trp)-Pro-(Xaa)n-peptides (Xaa=α-amino acid, n=0-10), corresponding derivatives and salts thereof or amino acid (Xaa)-amides, corresponding derivatives and salts thereof, wherein Xaa is an α-amino acid or a side chain-protected derivative, respectively, preferably NE-4-nitrobenzyloxycarbonyl L-lysine, -L-proline, -L-tryptophane, -L-isoleucine, -L-valine and cyclic amines as, for example, pyrrolidine, piperidine, thiazolidine and derivatives thereof act as amide structure.","3.Use according to claim 1, wherein amino acid amides, e.g., NE-4-nitrobenzyloxy-carbonyl-L-lysine-thiazolidid, -pyrrolidid and -piperidid as well as the corresponding 2-cyanothiazolidid, 2-cyanopyrrolidid and 2-cyanopiperidid derivative, are preferably employed as the DP IV inhibitor.","4.Use according to claim 1, wherein Actinonin, Leuhistin, Phebestin, Amastin, Probestin, β-aminothiols, α-amino phosphinic acids, α-amino phosphinic acid derivatives, preferably D-Phe-ψ-[PO(OH)—CH2]-Phe-Phe and salts thereof, preferably act as inhibitors of APN; Apstatin, (2S,3R)-HAMH-L-proline, (2S,3R)-HAPB-L-proline, the corresponding L-proline methyl esters, (2S,3R)-HAMH/(2S,3R)-HAPB-pyrrolidides, -thiazolidides (HAMH=3-amino-2-hydroxy-5-methyl hexanoyl, HAPB=3-amino-2-hydroxy-4-phenyl butanoyl) and salts thereof preferably act as inhibitors of APP; Captopril, Enalapril, Lisinopril, Cilazopril and salts thereof preferably act as inhibitors of ACE; Postatin, Eurystatin A or B, Na-protected peptide aldehydes, preferably benzyloxy-carbonyl-L-prolyl-L-prolinal or benzyloxycarbonyl-L-thioprolyl-L-thioprolinal, Na-protected amino acid (Xaa)-pyrrolidides or -thiazolidides (Xaa=α-amino acid, preferably L-alanine, L-valine, L-isoleucine) as well as the corresponding 2-cyano-pyrrolidid or 2-cyanothiazolidid derivatives, substrate-analogous Na-protected peptide phosphonic acid diaryl esters or peptide diazo methyl ketones or peptide ammonium methyl ketones and salts thereof preferably act as inhibitors of POP (PEP).","5.Use of inhibitor combinations of claim 1 for a prevention and therapy of autoimmune diseases, preferably of Rheumatoid Arthritis, Lupus Erythematodes, Multiple Sclerosis, IDDM, Morbus Crohn, Colitis Ulcerosa, Psoriasis, Neurodermitis, Glomerulonephritis, Interstitial Nephritis, Vasculitis, autoimmune diseases of the thyroid gland or autoimmune hemolytic anemia as well as of other chronic diseases with an inflammatory genesis as, for example, allergies and arteriosclerosis.","6.Use of inhibitor combinations of claim 1 for a suppression of transplant rejection and for a therapy of tumor diseases.","7.Pharmaceutical preparations, comprising inhibitors of dipeptidyl peptidase IV (DP IV) as well as of enzymes having DP IV-analogous enzyme activity in combination with inhibitors of any of the enzymes alanyl aminopeptidase (aminopeptidase N, APN) as well as of enzymes having the same substrate specificity (APN-analogous enzyme activity), of X-Pro aminopeptidase (aminopeptidase P, APP), of the angiotensin-converting enzyme (ACE) and of prolyl oligopeptidase (POP, prolyl endopeptidase, PEP) and in combination with per se known carrier, additive and/or auxiliary substances.","8.Pharmaceutical preparation according to claim 7, comprising preferably Xaa-Pro-dipeptides (Xaa=α-amino acid or side chain-protected derivatives) corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters and salts thereof, Xaa-Xaa-(Trp)-Pro-(Xaa)n-peptides (Xaa=α-amino acid, n=0-10), corresponding derivatives and salts thereof or amino acid (Xaa)-amides, corresponding derivatives and salts thereof, wherein Xaa is an α-amino acid or a side chain-protected derivative, respectively, preferably Ne-4-nitrobenzyloxcarbonyl L-lysine, -L-proline, -L-tryptophane, -L-isoleucine, -L-valine, and cyclic amines as, for example, pyrrolidine, piperidine, thiazolidine and derivatives thereof act as amide structure, as the inhibitors of DP IV.","9.Pharmaceutical preparation according to claim 7, comprising preferably amino acid amides, e.g.","Ne-4-nitrobenzyloxcarbonyl-L-lysine-thiazolidid, -pyrrolidid and -piperidid as well as the corresponding 2-cyanothiazolidid, 2-cyanopyrrolidid and 2-cyanopiperidid derivative as the inhibitors of DP IV.","10.Pharmaceutical preparation according to claim 7, comprising, as the inhibitors of APN, APP, ACE and POP (PEP), preferably Actnonin, Leuhistin, Phebestin, Amastin, Probestin, β-aminothiols, α-amino phosphinic acids, α-amino phoshinic acid derivatives, preferably D-Phe-ψ-[PO(OH)—CH2]-Phe-Phe and salts thereof, as the inhibitors of APN; Apstatin, (2S,3R)-HAMH-L-proline, (2S,3R)-HAPB-pyrrolidides, -thiazolidides (HAMH=3-amino-2-hydroxy-5-methyl hexanoyl, HAPB=3-amino-2-hydroxy-4-phenyl butanoyl) and salts thereof as the inhibitors of APP; Captopril, Enalapril, Lisinopril, Cilazopril and salts thereof as inhibitors of ACE; Postatin, Eurystatin A or B, Naprotected peptide aldehydes, preferably benzyloxycarbonyl-L-prolyl-L-prolinal or benzyloxcarbonyl-L-thioprolyl-L-thioprolinal, Naprotected amino acid (Xaa)-pyrrolidides or -thiazolidides (Xaa=α-amino acid, preferably L-alanine, L-valine, L-isoleucine) as well as the corresponding 2-cyanopyrrolidid or 2-cyanothiazolidid derivatives, substrate-analogous Na-protected peptide phosphonic acid diaryl esters or peptide diazo methyl ketones or peptide ammonium methyl ketones and salts thereof as inhibitors of POP (PEP).","11.Pharmaceutical preparation according to claim 7 comprising two or more of the inhibitors of DP IV or of enzymes having a DP IV-analogous enzyme activity, of APN or of enzymes having an APN-analogous enzyme activity, of ACE, of POP (PEP) and of XPNPEP2 in a spaced apart formulation in combination with per se known carrier, auxiliary and/or additive substances for a simultaneous or a directly consecutive administration with the aim of a combined action.","12.Pharmaceutical preparation according to claim 7 for a systemic use of the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramusclar, rectal, vaginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.","13.Pharmaceutical preparation according to claim 7 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications.","14.Use of inhibitor combinations of claim 2 for a prevention and therapy of autoimmune diseases, preferably of Rheumatoid Arthritis, Lupus Erythematodes, Multiple Sclerosis, IDDM, Morbus Crohn, Colitis Ulcerosa, Psoriasis, Neurodermitis, Glomerulonephritis, Interstitial Nephritis, Vasculitis, autoimmune diseases of the thyroid gland or autoimmune hemolytic anemia as well as of other chronic diseases with an inflammatory genesis as, for example, allergies and arteriosclerosis.","15.Use of inhibitor combinations of claim 2 for a suppression of transplant rejection and for a therapy of tumor diseases.","16.Use of inhibitor combinations of claim 3 for a prevention and therapy of autoimmune diseases, preferably of Rheumatoid Arthritis, Lupus Erythematodes, Multiple Sclerosis, IDDM, Morbus Crohn, Colitis Ulcerosa, Psoriasis, Neurodermitis, Glomerulonephritis, Interstitial Nephritis, Vasculitis, autoimmune diseases of the thyroid gland or autoimmune hemolytic anemia as well as of other chronic diseases with an inflammatory genesis as, for example, allergies and arteriosclerosis.","17.Use of inhibitor combinations of claim 3 for a suppression of transplant rejection and for a therapy of tumor diseases.","18.Use of inhibitor combinations of claim 4 for a prevention and therapy of autoimmune diseases, preferably of Rheumatoid Arthritis, Lupus Erythematodes, Multiple Sclerosis, IDDM, Morbus Crohn, Colitis Ulcerosa, Psoriasis, Neurodermitis, Glomerulonephritis, Interstitial Nephritis, Vasculitis, autoimmune diseases of the thyroid gland or autoimmune hemolytic anemia as well as of other chronic diseases with an inflammatory genesis as, for example, allergies and arteriosclerosis.","19.Use of inhibitor combinations of claim 4 for a suppression of transplant rejection and for a therapy of tumor diseases.","20.Pharmaceutical preparation according to claim 8 comprising two or more of the inhibitors of DP IV or of enzymes having a DP IV-analogous enzyme activity, of APN or of enzymes having an APN-analogous enzyme activity, of ACE, of POP (PEP) and of XPNPEP2 in a spaced apart formulation in combination with per se known carrier, auxiliary and/or additive substances for a simultaneous or a directly consecutive administration with the aim of a combined action.","21.Pharmaceutical preparation according to claim 8 for a systemic use for the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, vaginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.","22.Pharmaceutical preparation according to claim 8 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications.","23.Pharmaceutical preparation according to claim 9 comprising two or more of the inhibitors of DP IV or of enzymes having a DP IV-analogous enzyme activity, of APN or of enzymes having an APN-analogous enzyme activity, of ACE, of POP (PEP) and of XPNPEP2 in a spaced apart formulation in combination with per se known carrier, auxiliary and/or additive substances for a simultaneous or a directly consecutive administration with the aim of a combined action.","24.Pharmaceutical preparation according to claim 9 for a systemic use for the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, vaginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.","25.Pharmaceutical preparation according to claim 9 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications.","26.Pharmaceutical preparation according to claim 10 comprising two or more of the inhibitors of DP IV or of enzymes having a DP IV-analogous enzyme activity, of APN or of enzymes having an APN-analogous enzyme activity, of ACE, of POP (PEP) and of XPNPEP2 in a spaced apart formulation in combination with per se known carrier, auxiliary and/or additive substances for a simultaneous or a directly consecutive administration with the aim of a combined action.","27.Pharmaceutical preparation according to claim 10 for a systemic use for the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, vaginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.","28.Pharmaceutical preparation according to claim 10 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications.","29.Pharmaceutical preparation according to claim 11 for a systemic use for the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, virginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.","30.Pharmaceutical preparation according to claim 11 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications."],["The present invention describes the combined inhibition of the activity of the enzymes Aminopeptidase N (APN; E.C.","3.4.11.2.; CD13), Dipeptidyl peptidase IV (DP IV; E.C.","3.4.14.5; CD26), Prolyl oligopeptidase (POP; Prolyl endopeptidase; PEP; E.C.","3.4.21.26), the membrane-adherent Aminopeptidase P (X-Pro-Aminopeptidase; APP; XPNPEP2; E.C.","3.4.11.9) and Angiotensin-converting Enzyme (Angiotensin-konvertierendes Enzym; ACE; CD156; E.C.","3.4.15.1;CD156) by a simultaneous application of respective specific inhibitors of the above-referenced enzymes on the basis of amino acid derivatives, peptides or peptide derivatives, by which the activation, the DNA synthesis and, thus, the proliferation of immune cells is suppressed.","It is applicable to all diseases showing autoimmune pathogenesis that the disease is based on, or consists of, an activation and proliferation of immune cells, in particular of autoreactive T cells.","The very same mechanisms effect the acute or chronic rejection episodes after a transplantation of organs.","It was shown that membrane-adherent peptidases as, for example, DP IV or APN play a key role in the process of activation and clonal expansion of immune cells, particularly of T lymphocytes [B. Fleischer: “CD26, a surface protease involved in T cell activation”, Immunology Today 1994, 15, 180-184; U. Lendeckel et al.",": “Role of alanyl peptidase in growth and function of human T cells”, International Journal of Molecular Medicine 1999, 4, 17-27; D. Riemann et al.",": “CD13—not just a marker in leukemia typing”, Immunology Today 1999, 20, 83-88].","Several functions of mitogene-stimulated mononuclear cells (mitogen-stimulierte mononukleäre Zellen; MNZ) or of enriched T lymphocytes as, for example, the DNA synthesis, production and secretion of immune-stimulating cytokines (IL2, IL6, IL12, IFN-γ) and helper functions for B cells (synthesis of IgG and IgM) may be inhibited in the presence of specific inhibitors DP IV and APN [E. Schön et al,: “The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes”, Biomed.","Biochim Acta 1985, 2, K9-K15; E. Schön et al.",": “The role of dipeptidyl peptidase IV in humane T lymphocyte activation, inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro”, Eur.","J. Immunol.","1987, 17, 1821-1826; D. Reinhold et al.",": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360; U. Lendeckel et al.",": “Induction of the membrane alanyl peptidase gene and surface expression in human T cells by mitogenic activation”, Biochem.","J.","1996, 319, 817-823; T. Kähne et al.",": “Dipeptidyl peptidase IV: A cell surface peptidase involved in regulating T cell growth (Review)”, Int.","J. Mol.","Med.","1999, 4, 3-15; U. Lendeckel et al.",": “Role of alanyl aminopeptidase in growth and function of human T cells (Review)”, Int.","J. Mol.","Med.","1999, 4, 17-27].","It is already known that the treatment of autoimmune diseases and rejection reactions after transplantations can be effected by an inhibition of dipeptidyl peptidase IV localized on immune cells by means of synthetic inhibitors.","Reference is made, for example, to EP 764 151 A1, WO 09529691, EP 731 789 A1, EP 528 858).","With respect to the enzymes aminopeptidase N, angiotensin-converting enzyme, X-Pro-aminopeptidase and prolyl oligopeptidase, such effects are not known up to now.","The invention is based on the surprising finding that the simultaneous inhibition of the enzymatic activities of (I) dipeptidyl peptidase IV and aminopeptidase N, (II) dipeptidyl peptidase IV and angiotensin-converting enzyme, (III) dipeptidyl peptidase IV and prolyl oligopeptidase, as well as (IV) dipeptidyl peptidase IV and X-Pro-aminopeptidase inhibits the DNA synthesis and, thus, the proliferation of mononuclear cells (MNZ), and of T cells as well, to an extent which cannot be achieved by the application of a single one of these enzyme inhibitors, even at a higher dosage.","Although the above-mentioned inhibitors finally exhibit an effect to the same process, i.e.","the DNA synthesis and, thus, the proliferation of immune cells, said effect is marked to a weaker extent and is not long lasting in the case of an application of single inhibitors.","Due to the functional overlap of the enzymatic activities of said enzymes, there can be observed a superadditive inhibitory effect on the DNA synthesis and proliferation resulting from the simultaneous inhibition of two or more of these enzymes, as can be concluded from our data.","Our invention shows that the simultaneous application of inhibitory substances of the above-mentioned enzymes or, respectively, of corresponding preparations and administration forms is well suitable for the therapy of autoimmune diseases and inflammatory diseases as well as for the treatment of rejection reactions after a transplantation.","In detail, the invention is based on the finding that the DNA synthesis of mononuclear cells (MNZ) and T cells is inhibited, in a superadditive way, by the simultaneous administration of inhibitors of the enzymatic activities of (I) dipeptidyl peptidase IV and aminopeptidase N, (II) dipeptidyl peptidase IV and angiotensin-converting enzyme, (III) dipeptidyl peptidase IV and prolyl oligopeptidase, (IV) dipeptidyl peptidase IV and X-Pro-aminopeptidase.","The application of enzyme inhibitors is a new method and complementary therapy form for the treatment of the above-mentioned diseases.","The inhibitors of dipeptidyl peptidase IV, of aminopeptidase N, of prolyl oligopeptidase, of the angiotensin-converting enzyme and of X-Pro-aminopeptidase applied in accordance with the invention may be employed in pharmaceutically applicable formulation complexes as inhibitors, substrates, pseudo-substrates, peptides and peptide derivatives having inhibitory effect and as antibodies of said enzymes as well.","Preferred effectors for DP IV are, for example, Xaa-Pro-dipeptides, their corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters and their salts, Xaa-Xaa-(Trp)-Pro-(Xaa)n-peptides (n=0-10), their corresponding derivatives and their salts and amino acid (Xaa)-amides, their corresponding derivatives and salts, wherein Xaa is an α-amino acid/imino acid or an α-amino acid/imino acid derivative, respectively, preferably Nε-4-nitrobenzylcarbonyl-L-lysin, -L-prolin, -L-tryptophan, -L-isoleucin, -L-valin, and cyclic amines as, for example, pyrrolidine, piperidine, thiazolidine, and their derivatives serve as the amide structure.","Such compounds and their preparation were described in a prior patent (K. Neubert et al., DD 296 075 A5).","The inhibitors are administered simultaneously with known carrier substances.","The administration is conducted, on one hand, as a topical application in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles, respectively, including instillative applications and, on the other hand, systemic applications for an oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular administration in suitable recipes and in a suitable galenic application form, respectively.","WORKING EXAMPLES Example 1 Inhibition of the DNA Synthesis of Human T Lymphocytes by Incubation with Synthetic Inhibitors of DP IV and of APN Our investigations showed that the DNA synthesis of human peripheric T lymphocytes is inhibited in a superadditive manner by the simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of APN (Actinonin).","The T cells were incubated for 72 h in the presence of said inhibitors and subsequently, the DNA synthesis rate was determined via a measurement of the 3[H]-thymidin incorporation, as was described by Reinhold et al.","[D. Reinhold et al,: “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].","FIG.","1 shows the dose-dependent superadditive inhibition of the DNA synthesis.","FIG.","1 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and aminopeptidase N (actinonine) on the DNA synthesis of human T lymphocytes.","Human peripheric T cells were incubated over 3 days with the concentrations of the inhibitors shown.","Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine inserted into the DNA was measured after further 6 hours.","Example 2 Inhibition of the DNA Synthesis of Human Peripheric Mononuclear Cells by an Incubation with Synthetic Inhibitors of DP IV and of APN Our experiments showed that the DNA synthesis of human peripheric mononuclear cells (MNZ) is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of APN (actinonine).","The MNZ were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.","[D. Reinhold et al.",": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].","FIG.","2 shows the dose-dependent, superadditive inhibition of the DNA synthesis.","FIG.","2 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and APN (actinonine) on the DNA synthesis of human mononuclear cells (MNZ).","Human MNZ were incubated for three days with the concentrations of inhibitors mentioned above.","Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.","Example 3 Inhibition of the DNA Synthesis of Human T Lymphocytes by an Incubation with Synthetic Inhibitors of DP IV and of POP Our experiments showed that the DNA synthesis of human T lymphocytes is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of prolyl oligopeptidase (Boc-Ala-thiazolidid).","The T cells were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.","[D. Reinhold et al.",": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].","FIG.","3 shows the dose-dependent, superadditive inhibition of the DNA synthesis.","FIG.","3 show a the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and of prolyl oligopeptidase (Boc-Ala-Thia) on the DNA synthesis of human peripheric T lymphocytes.","Human T cells were incubated for three days with the concentrations of inhibitors mentioned above.","Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.","Example 4 Inhibition of the DNA Synthesis of Human Peripheric Mononuclear Cells by an Incubation with Synthetic Inhibitors of DP IV and of POP Our experiments showed that the DNA synthesis of human peripheric mononuclear cells (MNZ) is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of prolyl oligopeptidase (Boc-Ala-Thiazolidid).","The MNZ were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.","[D. Reinhold et al.",": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].","FIG.","4 shows the dose-dependent, superadditive inhibition of the DNA synthesis.","FIG.","4 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and of prolyl oligopeptidase (Boc-Ala-Thia) on the DNA synthesis of human mononuclear cells (MNZ).","Human MNZ were incubated for three days with the concentrations of inhibitors mentioned above.","Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.","Example 5 Inhibition of the DNA Synthesis of Human T Lymphocytes by an Incubation with Synthetic Inhibitors of DP IV and of ACE Our experiments showed that the DNA synthesis of human T lymphocytes is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of the angiotensin-converting enzyme (Captopril).","The T cells were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.","[D. Reinhold et al.",": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].","FIG.","5 shows the dose-dependent, superadditive inhibition of the DNA synthesis.","FIG.","5 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) X and of the angiotensin-converting enzyme (Captopril) on the DNA synthesis of human peripheric T lymphocytes.","Human T cells were incubated for three days with the concentrations of inhibitors mentioned above.","Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.","Example 6 Inhibition of the DNA Synthesis of Human Peripheric Mononuclear Cells by an Incubation with Synthetic Inhibitors of DP IV and of ACE Our experiments showed that the DNA synthesis of human peripheric mononuclear cells (MNZ) is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of the angiotensin-converting enzyme (Captopril).","The MNZ were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.","[D. Reinhold et al.","; “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].","FIG.","6 shows the dose-dependent, superadditive inhibition of the DNA synthesis.","FIG.","6 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and of the angiotensin-converting enzyme (Captopril) on the DNA synthesis of human mononuclear cells (MNZ).","Human MNZ were incubated for three days with the concentrations of inhibitors mentioned above.","Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.","Example 7 Inhibition of the Proliferation of Human Peripheric Mononuclear Cells (MNZ) by a Single and Simultaneous Administration of Inhibitory Substances of DP IV (I49=Lys[Z(NO2)]-thiazolidid) and of APN (Actinonin) FIG.","7: The MNZ were incubated for a time period of 72 h without addition (control), with an addition of the mitogenic lectin phytohemagglutinin (PHA), and with the addition of PHA and the inhibitors mentioned above, respectively.","Subsequently, the number amount of metabolically active cells was determined by using the commercially available WST-1 cell proliferation assay (Takara Inc.) in accordance with the provisions of the manufacturer.","Example 8 Inhibition of the Proliferation of the Human T Cell Line KARPAS-299 by a Single and Simultaneous Administration of Inhibitory Substances of DP IV (I49=Lys[Z(NO2)]thiazolidid) and of APN (Actinonin and Probestin) FIG.","8: The KARPAS-299 cells were incubated without addition (control) and in the presence of single inhibitors mentioned above as well as in the presence of combinations thereof, respectively.","Subsequently, the number of metabolically active cells was determined by using the commercially available WST-1 cell proliferation assay (Takara Inc.) in accordance with the provisions of the manufacturer.","Example 9 Inhibition of the Proliferation of Activated Human Peripheric T Cells by a Single or Simultaneous Administration of Inhibitory Substances of DP IV (I49=Lys[Z(NO2)]-thiazolidid) and of APN (Actinonin and Probestin) FIG.","9: The T cells, with the exception of the untreated control, were activated by an addition of phytohemagglutinine and phorbol-12-myristate-13-acetate to the culture medium and were incubated for a time period of 72 h in the presence of the above-mentioned inhibitors single and in combination.","Subsequently, the number of metabolically active cells was determined by using the commercially available WST-1 cell proliferation assay (Takara Inc.) in accordance with the provisions of the manufacturer.","Example 10 Inhibition of the Proliferation of PHA-Activated Human Mononuclear Cells (MNZ) by a Single or Simultaneous Administration of Inhibitory Substances of DP IV (I49=Lys[Z(NO2)]thiazolidid) and of X-Pro-Aminopeptidase (APP) (Apstatin) FIG.","10: The mononuclear cells (MNZ) were incubated for a time period of 72 h in the presence of the inhibitors mentioned above single and in combination.","Subsequently, the number of metabolically active cells was determined by using the commercially available WST-1 cell proliferation assay (Takara Inc.) in accordance with the provisions of the manufacturer."]],"string":"[\n [\n \"Combinations of enzyme inhibitor-containing preparations and the use thereof\",\n \"The invention comprises a process wherein the DNA synthesis and, thus, the proliferation of mononuclear cells (MNZ) and of T cells as well is inhibited by the simultaneous and combined inhibition of the enzyme activity (I) of alanyl aminopeptidase and of dipeptidyl peptidase IV; (II) of dipeptidyl peptidase IV and of the angiotensin-converting enzyme; (III) of dipeptidyl peptidase IV and of prolyl oligopeptidase; and (IV) of dipeptidyl peptidase IV and of X-Pro-aminopeptidase to an extent which cannot be achieved by an application of a single one of said enzyme inhibitors, even at a higher dosage.\",\n \"Although the said inhibitors exercise an influence on the very same process finally, i.e.\",\n \"the DNA synthesis and, thus, the proliferation of immune cells, this effect is not complete and is not long lasting when a single inhibitor is applied.\",\n \"From the functional overlap of enzymatic activities results an additive/superadditive inhibitory effect on the DNA synthesis and proliferation by the simultaneous inhibition of more than one of the above enzymes, as our data show.\",\n \"Our invention shows that the simultaneous application of substances inhibiting the above enzymes or of corresponding preparations and administration forms, respectively, is well suitable for a therapy of autoimmune diseases and chronic diseases with an inflammatory genesis as well as for a treatment of rejection episodes after a transplantation.\"\n ],\n [\n \"1.Use of inhibitors of dipeptidyl peptidase IV (DP IV) as well as of enzymes having the same substrate specificity (DP IV-analogous enzyme activity) in combination with inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) as well as of enzymes having the same substrate specificity (APN-analogous enzyme activity), of X-Pro-aminopeptidase (aminopeptidase P, APP), of the angiotensin-converting enzyme (ACE) and/or of prolyl oligopeptidase (POP, prolyl endopeptidase, PEP) for a superadditive inhibition of an activation, DNA synthesis and proliferation of human T lymphocytes and mononuclear cells.\",\n \"2.Use according to claim 1, wherein the inhibitors of DP IV are preferably Xaa-Pro-dipeptides (Xaa=α-amino acid or side chain-protected derivative), corresponding derivatives, preferably dipeptide phosphonic acid diaryl estates, dipeptide boronic acids (e.g.\",\n \"Pro-boro-Pro) and salts thereof, Xaa-Xaa-(Trp)-Pro-(Xaa)n-peptides (Xaa=α-amino acid, n=0-10), corresponding derivatives and salts thereof or amino acid (Xaa)-amides, corresponding derivatives and salts thereof, wherein Xaa is an α-amino acid or a side chain-protected derivative, respectively, preferably NE-4-nitrobenzyloxycarbonyl L-lysine, -L-proline, -L-tryptophane, -L-isoleucine, -L-valine and cyclic amines as, for example, pyrrolidine, piperidine, thiazolidine and derivatives thereof act as amide structure.\",\n \"3.Use according to claim 1, wherein amino acid amides, e.g., NE-4-nitrobenzyloxy-carbonyl-L-lysine-thiazolidid, -pyrrolidid and -piperidid as well as the corresponding 2-cyanothiazolidid, 2-cyanopyrrolidid and 2-cyanopiperidid derivative, are preferably employed as the DP IV inhibitor.\",\n \"4.Use according to claim 1, wherein Actinonin, Leuhistin, Phebestin, Amastin, Probestin, β-aminothiols, α-amino phosphinic acids, α-amino phosphinic acid derivatives, preferably D-Phe-ψ-[PO(OH)—CH2]-Phe-Phe and salts thereof, preferably act as inhibitors of APN; Apstatin, (2S,3R)-HAMH-L-proline, (2S,3R)-HAPB-L-proline, the corresponding L-proline methyl esters, (2S,3R)-HAMH/(2S,3R)-HAPB-pyrrolidides, -thiazolidides (HAMH=3-amino-2-hydroxy-5-methyl hexanoyl, HAPB=3-amino-2-hydroxy-4-phenyl butanoyl) and salts thereof preferably act as inhibitors of APP; Captopril, Enalapril, Lisinopril, Cilazopril and salts thereof preferably act as inhibitors of ACE; Postatin, Eurystatin A or B, Na-protected peptide aldehydes, preferably benzyloxy-carbonyl-L-prolyl-L-prolinal or benzyloxycarbonyl-L-thioprolyl-L-thioprolinal, Na-protected amino acid (Xaa)-pyrrolidides or -thiazolidides (Xaa=α-amino acid, preferably L-alanine, L-valine, L-isoleucine) as well as the corresponding 2-cyano-pyrrolidid or 2-cyanothiazolidid derivatives, substrate-analogous Na-protected peptide phosphonic acid diaryl esters or peptide diazo methyl ketones or peptide ammonium methyl ketones and salts thereof preferably act as inhibitors of POP (PEP).\",\n \"5.Use of inhibitor combinations of claim 1 for a prevention and therapy of autoimmune diseases, preferably of Rheumatoid Arthritis, Lupus Erythematodes, Multiple Sclerosis, IDDM, Morbus Crohn, Colitis Ulcerosa, Psoriasis, Neurodermitis, Glomerulonephritis, Interstitial Nephritis, Vasculitis, autoimmune diseases of the thyroid gland or autoimmune hemolytic anemia as well as of other chronic diseases with an inflammatory genesis as, for example, allergies and arteriosclerosis.\",\n \"6.Use of inhibitor combinations of claim 1 for a suppression of transplant rejection and for a therapy of tumor diseases.\",\n \"7.Pharmaceutical preparations, comprising inhibitors of dipeptidyl peptidase IV (DP IV) as well as of enzymes having DP IV-analogous enzyme activity in combination with inhibitors of any of the enzymes alanyl aminopeptidase (aminopeptidase N, APN) as well as of enzymes having the same substrate specificity (APN-analogous enzyme activity), of X-Pro aminopeptidase (aminopeptidase P, APP), of the angiotensin-converting enzyme (ACE) and of prolyl oligopeptidase (POP, prolyl endopeptidase, PEP) and in combination with per se known carrier, additive and/or auxiliary substances.\",\n \"8.Pharmaceutical preparation according to claim 7, comprising preferably Xaa-Pro-dipeptides (Xaa=α-amino acid or side chain-protected derivatives) corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters and salts thereof, Xaa-Xaa-(Trp)-Pro-(Xaa)n-peptides (Xaa=α-amino acid, n=0-10), corresponding derivatives and salts thereof or amino acid (Xaa)-amides, corresponding derivatives and salts thereof, wherein Xaa is an α-amino acid or a side chain-protected derivative, respectively, preferably Ne-4-nitrobenzyloxcarbonyl L-lysine, -L-proline, -L-tryptophane, -L-isoleucine, -L-valine, and cyclic amines as, for example, pyrrolidine, piperidine, thiazolidine and derivatives thereof act as amide structure, as the inhibitors of DP IV.\",\n \"9.Pharmaceutical preparation according to claim 7, comprising preferably amino acid amides, e.g.\",\n \"Ne-4-nitrobenzyloxcarbonyl-L-lysine-thiazolidid, -pyrrolidid and -piperidid as well as the corresponding 2-cyanothiazolidid, 2-cyanopyrrolidid and 2-cyanopiperidid derivative as the inhibitors of DP IV.\",\n \"10.Pharmaceutical preparation according to claim 7, comprising, as the inhibitors of APN, APP, ACE and POP (PEP), preferably Actnonin, Leuhistin, Phebestin, Amastin, Probestin, β-aminothiols, α-amino phosphinic acids, α-amino phoshinic acid derivatives, preferably D-Phe-ψ-[PO(OH)—CH2]-Phe-Phe and salts thereof, as the inhibitors of APN; Apstatin, (2S,3R)-HAMH-L-proline, (2S,3R)-HAPB-pyrrolidides, -thiazolidides (HAMH=3-amino-2-hydroxy-5-methyl hexanoyl, HAPB=3-amino-2-hydroxy-4-phenyl butanoyl) and salts thereof as the inhibitors of APP; Captopril, Enalapril, Lisinopril, Cilazopril and salts thereof as inhibitors of ACE; Postatin, Eurystatin A or B, Naprotected peptide aldehydes, preferably benzyloxycarbonyl-L-prolyl-L-prolinal or benzyloxcarbonyl-L-thioprolyl-L-thioprolinal, Naprotected amino acid (Xaa)-pyrrolidides or -thiazolidides (Xaa=α-amino acid, preferably L-alanine, L-valine, L-isoleucine) as well as the corresponding 2-cyanopyrrolidid or 2-cyanothiazolidid derivatives, substrate-analogous Na-protected peptide phosphonic acid diaryl esters or peptide diazo methyl ketones or peptide ammonium methyl ketones and salts thereof as inhibitors of POP (PEP).\",\n \"11.Pharmaceutical preparation according to claim 7 comprising two or more of the inhibitors of DP IV or of enzymes having a DP IV-analogous enzyme activity, of APN or of enzymes having an APN-analogous enzyme activity, of ACE, of POP (PEP) and of XPNPEP2 in a spaced apart formulation in combination with per se known carrier, auxiliary and/or additive substances for a simultaneous or a directly consecutive administration with the aim of a combined action.\",\n \"12.Pharmaceutical preparation according to claim 7 for a systemic use of the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramusclar, rectal, vaginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.\",\n \"13.Pharmaceutical preparation according to claim 7 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications.\",\n \"14.Use of inhibitor combinations of claim 2 for a prevention and therapy of autoimmune diseases, preferably of Rheumatoid Arthritis, Lupus Erythematodes, Multiple Sclerosis, IDDM, Morbus Crohn, Colitis Ulcerosa, Psoriasis, Neurodermitis, Glomerulonephritis, Interstitial Nephritis, Vasculitis, autoimmune diseases of the thyroid gland or autoimmune hemolytic anemia as well as of other chronic diseases with an inflammatory genesis as, for example, allergies and arteriosclerosis.\",\n \"15.Use of inhibitor combinations of claim 2 for a suppression of transplant rejection and for a therapy of tumor diseases.\",\n \"16.Use of inhibitor combinations of claim 3 for a prevention and therapy of autoimmune diseases, preferably of Rheumatoid Arthritis, Lupus Erythematodes, Multiple Sclerosis, IDDM, Morbus Crohn, Colitis Ulcerosa, Psoriasis, Neurodermitis, Glomerulonephritis, Interstitial Nephritis, Vasculitis, autoimmune diseases of the thyroid gland or autoimmune hemolytic anemia as well as of other chronic diseases with an inflammatory genesis as, for example, allergies and arteriosclerosis.\",\n \"17.Use of inhibitor combinations of claim 3 for a suppression of transplant rejection and for a therapy of tumor diseases.\",\n \"18.Use of inhibitor combinations of claim 4 for a prevention and therapy of autoimmune diseases, preferably of Rheumatoid Arthritis, Lupus Erythematodes, Multiple Sclerosis, IDDM, Morbus Crohn, Colitis Ulcerosa, Psoriasis, Neurodermitis, Glomerulonephritis, Interstitial Nephritis, Vasculitis, autoimmune diseases of the thyroid gland or autoimmune hemolytic anemia as well as of other chronic diseases with an inflammatory genesis as, for example, allergies and arteriosclerosis.\",\n \"19.Use of inhibitor combinations of claim 4 for a suppression of transplant rejection and for a therapy of tumor diseases.\",\n \"20.Pharmaceutical preparation according to claim 8 comprising two or more of the inhibitors of DP IV or of enzymes having a DP IV-analogous enzyme activity, of APN or of enzymes having an APN-analogous enzyme activity, of ACE, of POP (PEP) and of XPNPEP2 in a spaced apart formulation in combination with per se known carrier, auxiliary and/or additive substances for a simultaneous or a directly consecutive administration with the aim of a combined action.\",\n \"21.Pharmaceutical preparation according to claim 8 for a systemic use for the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, vaginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.\",\n \"22.Pharmaceutical preparation according to claim 8 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications.\",\n \"23.Pharmaceutical preparation according to claim 9 comprising two or more of the inhibitors of DP IV or of enzymes having a DP IV-analogous enzyme activity, of APN or of enzymes having an APN-analogous enzyme activity, of ACE, of POP (PEP) and of XPNPEP2 in a spaced apart formulation in combination with per se known carrier, auxiliary and/or additive substances for a simultaneous or a directly consecutive administration with the aim of a combined action.\",\n \"24.Pharmaceutical preparation according to claim 9 for a systemic use for the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, vaginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.\",\n \"25.Pharmaceutical preparation according to claim 9 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications.\",\n \"26.Pharmaceutical preparation according to claim 10 comprising two or more of the inhibitors of DP IV or of enzymes having a DP IV-analogous enzyme activity, of APN or of enzymes having an APN-analogous enzyme activity, of ACE, of POP (PEP) and of XPNPEP2 in a spaced apart formulation in combination with per se known carrier, auxiliary and/or additive substances for a simultaneous or a directly consecutive administration with the aim of a combined action.\",\n \"27.Pharmaceutical preparation according to claim 10 for a systemic use for the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, vaginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.\",\n \"28.Pharmaceutical preparation according to claim 10 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications.\",\n \"29.Pharmaceutical preparation according to claim 11 for a systemic use for the oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, virginal, sublingual application, together with per se known carrier, auxiliary and/or additive substances.\",\n \"30.Pharmaceutical preparation according to claim 11 for a topical use in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles including instillative applications.\"\n ],\n [\n \"The present invention describes the combined inhibition of the activity of the enzymes Aminopeptidase N (APN; E.C.\",\n \"3.4.11.2.; CD13), Dipeptidyl peptidase IV (DP IV; E.C.\",\n \"3.4.14.5; CD26), Prolyl oligopeptidase (POP; Prolyl endopeptidase; PEP; E.C.\",\n \"3.4.21.26), the membrane-adherent Aminopeptidase P (X-Pro-Aminopeptidase; APP; XPNPEP2; E.C.\",\n \"3.4.11.9) and Angiotensin-converting Enzyme (Angiotensin-konvertierendes Enzym; ACE; CD156; E.C.\",\n \"3.4.15.1;CD156) by a simultaneous application of respective specific inhibitors of the above-referenced enzymes on the basis of amino acid derivatives, peptides or peptide derivatives, by which the activation, the DNA synthesis and, thus, the proliferation of immune cells is suppressed.\",\n \"It is applicable to all diseases showing autoimmune pathogenesis that the disease is based on, or consists of, an activation and proliferation of immune cells, in particular of autoreactive T cells.\",\n \"The very same mechanisms effect the acute or chronic rejection episodes after a transplantation of organs.\",\n \"It was shown that membrane-adherent peptidases as, for example, DP IV or APN play a key role in the process of activation and clonal expansion of immune cells, particularly of T lymphocytes [B. Fleischer: “CD26, a surface protease involved in T cell activation”, Immunology Today 1994, 15, 180-184; U. Lendeckel et al.\",\n \": “Role of alanyl peptidase in growth and function of human T cells”, International Journal of Molecular Medicine 1999, 4, 17-27; D. Riemann et al.\",\n \": “CD13—not just a marker in leukemia typing”, Immunology Today 1999, 20, 83-88].\",\n \"Several functions of mitogene-stimulated mononuclear cells (mitogen-stimulierte mononukleäre Zellen; MNZ) or of enriched T lymphocytes as, for example, the DNA synthesis, production and secretion of immune-stimulating cytokines (IL2, IL6, IL12, IFN-γ) and helper functions for B cells (synthesis of IgG and IgM) may be inhibited in the presence of specific inhibitors DP IV and APN [E. Schön et al,: “The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes”, Biomed.\",\n \"Biochim Acta 1985, 2, K9-K15; E. Schön et al.\",\n \": “The role of dipeptidyl peptidase IV in humane T lymphocyte activation, inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro”, Eur.\",\n \"J. Immunol.\",\n \"1987, 17, 1821-1826; D. Reinhold et al.\",\n \": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360; U. Lendeckel et al.\",\n \": “Induction of the membrane alanyl peptidase gene and surface expression in human T cells by mitogenic activation”, Biochem.\",\n \"J.\",\n \"1996, 319, 817-823; T. Kähne et al.\",\n \": “Dipeptidyl peptidase IV: A cell surface peptidase involved in regulating T cell growth (Review)”, Int.\",\n \"J. Mol.\",\n \"Med.\",\n \"1999, 4, 3-15; U. Lendeckel et al.\",\n \": “Role of alanyl aminopeptidase in growth and function of human T cells (Review)”, Int.\",\n \"J. Mol.\",\n \"Med.\",\n \"1999, 4, 17-27].\",\n \"It is already known that the treatment of autoimmune diseases and rejection reactions after transplantations can be effected by an inhibition of dipeptidyl peptidase IV localized on immune cells by means of synthetic inhibitors.\",\n \"Reference is made, for example, to EP 764 151 A1, WO 09529691, EP 731 789 A1, EP 528 858).\",\n \"With respect to the enzymes aminopeptidase N, angiotensin-converting enzyme, X-Pro-aminopeptidase and prolyl oligopeptidase, such effects are not known up to now.\",\n \"The invention is based on the surprising finding that the simultaneous inhibition of the enzymatic activities of (I) dipeptidyl peptidase IV and aminopeptidase N, (II) dipeptidyl peptidase IV and angiotensin-converting enzyme, (III) dipeptidyl peptidase IV and prolyl oligopeptidase, as well as (IV) dipeptidyl peptidase IV and X-Pro-aminopeptidase inhibits the DNA synthesis and, thus, the proliferation of mononuclear cells (MNZ), and of T cells as well, to an extent which cannot be achieved by the application of a single one of these enzyme inhibitors, even at a higher dosage.\",\n \"Although the above-mentioned inhibitors finally exhibit an effect to the same process, i.e.\",\n \"the DNA synthesis and, thus, the proliferation of immune cells, said effect is marked to a weaker extent and is not long lasting in the case of an application of single inhibitors.\",\n \"Due to the functional overlap of the enzymatic activities of said enzymes, there can be observed a superadditive inhibitory effect on the DNA synthesis and proliferation resulting from the simultaneous inhibition of two or more of these enzymes, as can be concluded from our data.\",\n \"Our invention shows that the simultaneous application of inhibitory substances of the above-mentioned enzymes or, respectively, of corresponding preparations and administration forms is well suitable for the therapy of autoimmune diseases and inflammatory diseases as well as for the treatment of rejection reactions after a transplantation.\",\n \"In detail, the invention is based on the finding that the DNA synthesis of mononuclear cells (MNZ) and T cells is inhibited, in a superadditive way, by the simultaneous administration of inhibitors of the enzymatic activities of (I) dipeptidyl peptidase IV and aminopeptidase N, (II) dipeptidyl peptidase IV and angiotensin-converting enzyme, (III) dipeptidyl peptidase IV and prolyl oligopeptidase, (IV) dipeptidyl peptidase IV and X-Pro-aminopeptidase.\",\n \"The application of enzyme inhibitors is a new method and complementary therapy form for the treatment of the above-mentioned diseases.\",\n \"The inhibitors of dipeptidyl peptidase IV, of aminopeptidase N, of prolyl oligopeptidase, of the angiotensin-converting enzyme and of X-Pro-aminopeptidase applied in accordance with the invention may be employed in pharmaceutically applicable formulation complexes as inhibitors, substrates, pseudo-substrates, peptides and peptide derivatives having inhibitory effect and as antibodies of said enzymes as well.\",\n \"Preferred effectors for DP IV are, for example, Xaa-Pro-dipeptides, their corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters and their salts, Xaa-Xaa-(Trp)-Pro-(Xaa)n-peptides (n=0-10), their corresponding derivatives and their salts and amino acid (Xaa)-amides, their corresponding derivatives and salts, wherein Xaa is an α-amino acid/imino acid or an α-amino acid/imino acid derivative, respectively, preferably Nε-4-nitrobenzylcarbonyl-L-lysin, -L-prolin, -L-tryptophan, -L-isoleucin, -L-valin, and cyclic amines as, for example, pyrrolidine, piperidine, thiazolidine, and their derivatives serve as the amide structure.\",\n \"Such compounds and their preparation were described in a prior patent (K. Neubert et al., DD 296 075 A5).\",\n \"The inhibitors are administered simultaneously with known carrier substances.\",\n \"The administration is conducted, on one hand, as a topical application in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes, shaked mixtures, hydrocolloid dressings, and other dermatological bases/vehicles, respectively, including instillative applications and, on the other hand, systemic applications for an oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular administration in suitable recipes and in a suitable galenic application form, respectively.\",\n \"WORKING EXAMPLES Example 1 Inhibition of the DNA Synthesis of Human T Lymphocytes by Incubation with Synthetic Inhibitors of DP IV and of APN Our investigations showed that the DNA synthesis of human peripheric T lymphocytes is inhibited in a superadditive manner by the simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of APN (Actinonin).\",\n \"The T cells were incubated for 72 h in the presence of said inhibitors and subsequently, the DNA synthesis rate was determined via a measurement of the 3[H]-thymidin incorporation, as was described by Reinhold et al.\",\n \"[D. Reinhold et al,: “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].\",\n \"FIG.\",\n \"1 shows the dose-dependent superadditive inhibition of the DNA synthesis.\",\n \"FIG.\",\n \"1 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and aminopeptidase N (actinonine) on the DNA synthesis of human T lymphocytes.\",\n \"Human peripheric T cells were incubated over 3 days with the concentrations of the inhibitors shown.\",\n \"Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine inserted into the DNA was measured after further 6 hours.\",\n \"Example 2 Inhibition of the DNA Synthesis of Human Peripheric Mononuclear Cells by an Incubation with Synthetic Inhibitors of DP IV and of APN Our experiments showed that the DNA synthesis of human peripheric mononuclear cells (MNZ) is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of APN (actinonine).\",\n \"The MNZ were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.\",\n \"[D. Reinhold et al.\",\n \": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].\",\n \"FIG.\",\n \"2 shows the dose-dependent, superadditive inhibition of the DNA synthesis.\",\n \"FIG.\",\n \"2 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and APN (actinonine) on the DNA synthesis of human mononuclear cells (MNZ).\",\n \"Human MNZ were incubated for three days with the concentrations of inhibitors mentioned above.\",\n \"Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.\",\n \"Example 3 Inhibition of the DNA Synthesis of Human T Lymphocytes by an Incubation with Synthetic Inhibitors of DP IV and of POP Our experiments showed that the DNA synthesis of human T lymphocytes is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of prolyl oligopeptidase (Boc-Ala-thiazolidid).\",\n \"The T cells were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.\",\n \"[D. Reinhold et al.\",\n \": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].\",\n \"FIG.\",\n \"3 shows the dose-dependent, superadditive inhibition of the DNA synthesis.\",\n \"FIG.\",\n \"3 show a the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and of prolyl oligopeptidase (Boc-Ala-Thia) on the DNA synthesis of human peripheric T lymphocytes.\",\n \"Human T cells were incubated for three days with the concentrations of inhibitors mentioned above.\",\n \"Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.\",\n \"Example 4 Inhibition of the DNA Synthesis of Human Peripheric Mononuclear Cells by an Incubation with Synthetic Inhibitors of DP IV and of POP Our experiments showed that the DNA synthesis of human peripheric mononuclear cells (MNZ) is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of prolyl oligopeptidase (Boc-Ala-Thiazolidid).\",\n \"The MNZ were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.\",\n \"[D. Reinhold et al.\",\n \": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].\",\n \"FIG.\",\n \"4 shows the dose-dependent, superadditive inhibition of the DNA synthesis.\",\n \"FIG.\",\n \"4 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and of prolyl oligopeptidase (Boc-Ala-Thia) on the DNA synthesis of human mononuclear cells (MNZ).\",\n \"Human MNZ were incubated for three days with the concentrations of inhibitors mentioned above.\",\n \"Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.\",\n \"Example 5 Inhibition of the DNA Synthesis of Human T Lymphocytes by an Incubation with Synthetic Inhibitors of DP IV and of ACE Our experiments showed that the DNA synthesis of human T lymphocytes is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of the angiotensin-converting enzyme (Captopril).\",\n \"The T cells were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.\",\n \"[D. Reinhold et al.\",\n \": “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].\",\n \"FIG.\",\n \"5 shows the dose-dependent, superadditive inhibition of the DNA synthesis.\",\n \"FIG.\",\n \"5 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) X and of the angiotensin-converting enzyme (Captopril) on the DNA synthesis of human peripheric T lymphocytes.\",\n \"Human T cells were incubated for three days with the concentrations of inhibitors mentioned above.\",\n \"Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.\",\n \"Example 6 Inhibition of the DNA Synthesis of Human Peripheric Mononuclear Cells by an Incubation with Synthetic Inhibitors of DP IV and of ACE Our experiments showed that the DNA synthesis of human peripheric mononuclear cells (MNZ) is inhibited in a superadditive manner by a simultaneous administration of inhibitors of DP IV (Lys[Z(NO2)]-thiazolidid=I49) and of the angiotensin-converting enzyme (Captopril).\",\n \"The MNZ were incubated for 72 h in the presence of said inhibitors, and the DNA synthesis rate was determined subsequently by the measurement of the 3[H]-thymidine incorporation, as was described by Reinhold et al.\",\n \"[D. Reinhold et al.\",\n \"; “Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells”, Immunology 1997, 91, 354-360].\",\n \"FIG.\",\n \"6 shows the dose-dependent, superadditive inhibition of the DNA synthesis.\",\n \"FIG.\",\n \"6 shows the synergistic and dose-dependent effect of inhibitors of DP IV (I49) and of the angiotensin-converting enzyme (Captopril) on the DNA synthesis of human mononuclear cells (MNZ).\",\n \"Human MNZ were incubated for three days with the concentrations of inhibitors mentioned above.\",\n \"Subsequently, 3[H]-methyl thymidine was added to the culture medium, and the amount of 3[H]-thymidine incorporated into the DNA was measured after further 6 hours.\",\n \"Example 7 Inhibition of the Proliferation of Human Peripheric Mononuclear Cells (MNZ) by a Single and Simultaneous Administration of Inhibitory Substances of DP IV (I49=Lys[Z(NO2)]-thiazolidid) and of APN (Actinonin) FIG.\",\n \"7: The MNZ were incubated for a time period of 72 h without addition (control), with an addition of the mitogenic lectin phytohemagglutinin (PHA), and with the addition of PHA and the inhibitors mentioned above, respectively.\",\n \"Subsequently, the number amount of metabolically active cells was determined by using the commercially available WST-1 cell proliferation assay (Takara Inc.) in accordance with the provisions of the manufacturer.\",\n \"Example 8 Inhibition of the Proliferation of the Human T Cell Line KARPAS-299 by a Single and Simultaneous Administration of Inhibitory Substances of DP IV (I49=Lys[Z(NO2)]thiazolidid) and of APN (Actinonin and Probestin) FIG.\",\n \"8: The KARPAS-299 cells were incubated without addition (control) and in the presence of single inhibitors mentioned above as well as in the presence of combinations thereof, respectively.\",\n \"Subsequently, the number of metabolically active cells was determined by using the commercially available WST-1 cell proliferation assay (Takara Inc.) in accordance with the provisions of the manufacturer.\",\n \"Example 9 Inhibition of the Proliferation of Activated Human Peripheric T Cells by a Single or Simultaneous Administration of Inhibitory Substances of DP IV (I49=Lys[Z(NO2)]-thiazolidid) and of APN (Actinonin and Probestin) FIG.\",\n \"9: The T cells, with the exception of the untreated control, were activated by an addition of phytohemagglutinine and phorbol-12-myristate-13-acetate to the culture medium and were incubated for a time period of 72 h in the presence of the above-mentioned inhibitors single and in combination.\",\n \"Subsequently, the number of metabolically active cells was determined by using the commercially available WST-1 cell proliferation assay (Takara Inc.) in accordance with the provisions of the manufacturer.\",\n \"Example 10 Inhibition of the Proliferation of PHA-Activated Human Mononuclear Cells (MNZ) by a Single or Simultaneous Administration of Inhibitory Substances of DP IV (I49=Lys[Z(NO2)]thiazolidid) and of X-Pro-Aminopeptidase (APP) (Apstatin) FIG.\",\n \"10: The mononuclear cells (MNZ) were incubated for a time period of 72 h in the presence of the inhibitors mentioned above single and in combination.\",\n \"Subsequently, the number of metabolically active cells was determined by using the commercially available WST-1 cell proliferation assay (Takara Inc.) in accordance with the provisions of the manufacturer.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10296102"}}},{"rowIdx":91,"cells":{"text":{"kind":"list like","value":[["Induction heating of rail welds","An apparatus (10) and method for preheating welds uses a centered induction plate (12) having preferably a plurality of induction coils (30, 32) to impart the generation of heat in the materials to be welded (14), being interactively controlled by at least a temperature sensor (90, 92) and power supply control loop (16) so that even preheating can be obtained for a selected length of time given the parameters of the weld desired."],["1.An induction heating system for preheating first and second workpieces to be welded together comprising: a tool having first and second opposing sides, and disposed in a gap defined by facing ends of the workpieces, the tool further including mechanical centering assemblies disposed adjacent the facing ends of the workpieces, wherein the mechanical centering assemblies position the tool longitudinally with respect to the workpieces for proper proximity to the workpieces; a first induction heating element affixed to the first side of the tool and disposed proximate the first and second workpieces; a first heating zone defined by a first temperature sensor positioned proximate the first workpiece and the first heating element; a second induction heating element affixed to the second side of the tool and disposed proximate the first and second workpieces; a second heating zone defined by a second temperature sensor positioned proximate the first workpiece and the second heating element; a controller coupled to the first and second temperature sensors, the controller activating the first and second heating elements independently to achieve a predetermined welding temperature in both first and second heating zones.","2.The induction heating system of claim 1, further comprising a first power supply coupled to the first heating element, and a second power supply coupled to the second heating element, wherein both first and second power supplies are coupled to the controller.","3.The induction heating system of claim 1, wherein the first and second induction heating elements are ferrite core heating elements.","4.The induction heating system of claim 1, wherein the temperature sensors comprise thermocouple temperature sensors.","5.The induction heating system of claim 1, wherein the temperature sensors comprise pyrometer temperature sensors.","6.The induction heating system of claim 1, wherein the controller provides a discernible indication when the workpieces have reached the predetermined welding temperature.","7.The induction heating system of claim 6, wherein the discernible indication is a visual indication.","8.The induction heating system of claim 1, wherein the controller provides positioning information to a positioning robot that adjusts relative position of the tool until the predetermined welding temperature is achieved.","9.The induction heating system of claim 1, wherein cooling fluid is provided proximate each of the heating elements.","10.The induction heating system of claim 9, wherein the controller controls cooling fluid activation.","11.The induction heating system of claim 1, wherein there are three or more heating elements.","12.The induction heating system of claim 1, wherein there are three or more heating zones.","13.The induction heating system of claim 1, wherein the first and second workpieces are railroad rails.","14.An induction heating system for preheating first and second workpieces to be welded together comprising: a tool disposed in a gap defined by facing ends of the workpieces, the tool further including mechanical centering assemblies disposed adjacent the facing ends of the work-pieces, wherein the mechanical centering assemblies position the tool longitudinally with respect to the workpieces for proper proximity to the workpieces; an induction heating element affixed to the tool and disposed proximate the first and second workpieces; a heating zone defined by a temperature sensor positioned proximate the first workpiece and the heating element; a controller coupled to the temperature sensor, the controller activating the heating element to achieve a predetermined welding temperature in the heating zone.","15.An induction heating system for preheating first and second workpieces to be welded together comprising: a tool disposed in a gap defined by facing ends of the workpieces, the tool further including mechanical centering assemblies disposed adjacent the facing ends of the workpieces, wherein the mechanical centering assemblies position the tool longitudinally with respect to the workpieces for proper proximity to the workpieces; a plurality of induction heating elements affixed to the tool and disposed proximate the first and second workpieces; as plurality of heating zones defined by multiple temperature sensors positioned proximate the first workpiece and the heating elements; a controller coupled to the temperature sensors, the controller activating the heating elements to achieve a predetermined welding temperature in the heating zones.","16.An induction heating system for preheating first and second workpieces to be welded together comprising: mounting means having first and second opposing sides, and disposed in a gap defined by facing ends of the workpieces, wherein the mounting means further further includes mechanical centering assemblies disposed adjacent the facing ends of the workpieces, wherein the mechanical centering assemblies position the mounting means longitudinally with respect to the workpieces for proper proximity to the workpieces; a first induction heating means affixed to the first side of the mounting means and disposed proximate the first and second workpieces; a first heating zone defined by a first temperature sensing means positioned proximate the first workpiece and the first heating means; a second induction heating means affixed to the second side of the mounting means and disposed proximate the first and second workpieces; a second heating zone defined by a second temperature sensing means positioned proximate the first workpiece and the second heating means; a controller means coupled to the first and second temperature sensing means, the controller means activating the first and second heating means independently to achieve a predetermined welding temperature in both first and second heating zones.","17.The induction heating system of claim 16, wherein the mounting means comprises a tool having first and second opposing sides.","18.The induction heating system of claim 16, further comprising a first power supply means coupled to the first heating means, and a second power supply means coupled to the second heating means, wherein both first and second power supplies means are coupled to the controller means.","19.The induction heating system of claim 16, wherein the first and second induction heating means comprise ferrite core heating elements.","20.The induction heating system of claim 16, wherein the temperature sensing means comprise thermocouple temperature sensors.","21.The induction heating system of claim 16, wherein the temperature sensing means comprise pyrometer temperature sensors.","22.The induction heating system of claim 16, wherein the controller means provides a discernible indication when the workpieces have reached the predetermined welding temperature.","23.The induction heating system of claim 22, wherein the discernible indication is a visual indication.","24.The induction heating system of claim 16, wherein the controller means provides positioning information to a positioning means that adjusts relative position of the tool until the predetermined welding temperature is achieved.","25.The induction heating system of claim 16, wherein cooling fluid is provided proximate each of the heating means.","26.The induction heating system of claim 25, wherein the controller means controls cooling fluid activation.","27.The induction heating system of claim 16, wherein there are three or more heating means.","28.The induction heating system of claim 16, wherein there are three or more heating zones.","29.The induction heating system of claim 16, wherein the first and second workpieces are railroad rails.","30.A method for preheating first and second workpieces to be welded together, the method comprising the steps of: (a) disposing, within a gap defined by facing ends of the workpieces, mounting means having first and second opposing sides; (b) providing mechanical centering assemblies disposed adjacent the facing ends of the workpieces, wherein the mechanical centering assemblies position the mounting means longitudinally with respect to the workpieces for proper proximity to the workpieces; (c) disposing a first induction heating means affixed to the first side of the mounting means proximate the first and second workpieces; (d) defining a first heating zone by positioning a first temperature sensing means proximate the first workpiece and the first heating means; (e) disposing a second induction heating means affixed to the second side of the mounting means proximate the first and second workpieces; (f) defining a second heating zone by positioning a second temperature sensing means proximate the first workpiece and the second heating means; and (g) activating the first and second heating means independently to achieve a predetermined welding temperature in both first and second heating zones."],["<SOH> BACKGROUND OF THE INVENTION <EOH>1.Summary of Invention The preferred embodiment is adapted to use in welding railroad rails, however, other difficult to weld work pieces could be advantageously preheated with the invention.","The descriptions herein of rail welds should be considered with this more expansive use in mind.","Induction type heat allows for precise heating at ideal locations and can be used to control heat gradients.","This control is possible though use of a feedback system, controller, coil arrangement and a positioning mechanism.","This eliminates the human element, resulting in an automated high quality weld preheat method.","The use of an automated electrically powered and computer controlled induction heating system using the induction heating coils and heating plate with sensitive temperature control and feedback interfaced within the power supply enables higher quality and more consistent welds of difficult to weld pieces such as railroad rails and similar high strength and complex shaped generally ferric items.","One advantage in this regard is the ability to manipulate the heat gradient.","Also included in advantages over prior art methods are the facts that no consumables are required, there is no need for gases or fuel on board or during transportation and cleanliness—in that there are no combustion byproducts.","The invention provides consistent heat through a wide range of ambient temperatures.","Another advantage is that of use in different rail geometry, rail chemistries and welding methods.","In addition to heating, an analogous plate or array can be used to control cooling after welding.","In the preferred and alternative embodiments, the invention envisions the use of independent, single or multiple coils and/or power units.","Independent, single or multiple coils and/or power units enable the precise location of heating, subdivides locations of heating and provides flexibility in the control of heating areas.","An added benefit of using an independent preheating unit, as compared to including the welder or portions of the welder's power supply or the like is that of efficiencies gains due to multi tasking during welding process.","While preheating is occurring, the welder itself can be independently set up for welding operations, or, indeed, one rail may be welded while the adjacent rail is preheated, should the rail gaps be proximate the rail welder's cable runs.","2.Description of Related Art While preheating of metal pieces for welding as a general concept is well known, heretofore generally manual application of heat has been used.","The use of items such as gas or other torches, gas burners or electrically powered devices.","Field welding in the past commonly preheated with torches and gas burners.","Such methods introduce human intervention positioning, timing or estimating heat input and temperature.","Combustion variables including fuel, air, pressure, position and shape of a flame relative to rails, ignition steps, initial temperature of the workpieces and even weather contribute to imprecision in temperature control in the prior art.","Resistance electrical devices have power and conductivity variables including both electrical and thermal limitations that also contribute to imprecision in temperature control."],["<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG.","1 is a schematic view showing the layout of the components of the invention.","FIG.","2 is an elevational view showing the induction plate of the invention.","FIG.","2A is an elevational view showing an induction coil with ferrite core.","FIG.","3 is a wiring diagram showing the control wiring of the invention.","FIG.","4 is a wiring diagram showing the power supply wiring to control separate heating zones.","FIG.","5 is a side elevational view showing the induction plate of the invention.","detailed-description description=\"Detailed Description\" end=\"lead\"?"],["CLAIM OF PRIORITY Priority is claimed based upon Provisional Patent Application Ser.","No.","60/209,030, filed Jun.","2, 2000, which is incorporated by reference as if fully set forth herein.","STATEMENT OF INVENTORSHIP Assignee, Holland Company, believes that the subject matter was the invention of Richard F. Miller.","FIELD OF THE INVENTION Some welding techniques require precise consistent and controlled heating, which is difficult or impossible to obtain with torches, gas burners or other electric devices.","Instead, this is achievable through the use of induction heating wherein a plate or other locating and holding device is placed in a gap between work pieces to be welded, the plate containing an array of induction heating elements which, when energized, produce shaped, varying electromagnetic fields which link with and induce a voltage in the work pieces which in turn results in eddy current flows and subsequent power losses, as well as hysteresis losses, so that the workpiece temperature is raised to a desired, uniform level prior to welding.","BACKGROUND OF THE INVENTION 1.Summary of Invention The preferred embodiment is adapted to use in welding railroad rails, however, other difficult to weld work pieces could be advantageously preheated with the invention.","The descriptions herein of rail welds should be considered with this more expansive use in mind.","Induction type heat allows for precise heating at ideal locations and can be used to control heat gradients.","This control is possible though use of a feedback system, controller, coil arrangement and a positioning mechanism.","This eliminates the human element, resulting in an automated high quality weld preheat method.","The use of an automated electrically powered and computer controlled induction heating system using the induction heating coils and heating plate with sensitive temperature control and feedback interfaced within the power supply enables higher quality and more consistent welds of difficult to weld pieces such as railroad rails and similar high strength and complex shaped generally ferric items.","One advantage in this regard is the ability to manipulate the heat gradient.","Also included in advantages over prior art methods are the facts that no consumables are required, there is no need for gases or fuel on board or during transportation and cleanliness—in that there are no combustion byproducts.","The invention provides consistent heat through a wide range of ambient temperatures.","Another advantage is that of use in different rail geometry, rail chemistries and welding methods.","In addition to heating, an analogous plate or array can be used to control cooling after welding.","In the preferred and alternative embodiments, the invention envisions the use of independent, single or multiple coils and/or power units.","Independent, single or multiple coils and/or power units enable the precise location of heating, subdivides locations of heating and provides flexibility in the control of heating areas.","An added benefit of using an independent preheating unit, as compared to including the welder or portions of the welder's power supply or the like is that of efficiencies gains due to multi tasking during welding process.","While preheating is occurring, the welder itself can be independently set up for welding operations, or, indeed, one rail may be welded while the adjacent rail is preheated, should the rail gaps be proximate the rail welder's cable runs.","2.Description of Related Art While preheating of metal pieces for welding as a general concept is well known, heretofore generally manual application of heat has been used.","The use of items such as gas or other torches, gas burners or electrically powered devices.","Field welding in the past commonly preheated with torches and gas burners.","Such methods introduce human intervention positioning, timing or estimating heat input and temperature.","Combustion variables including fuel, air, pressure, position and shape of a flame relative to rails, ignition steps, initial temperature of the workpieces and even weather contribute to imprecision in temperature control in the prior art.","Resistance electrical devices have power and conductivity variables including both electrical and thermal limitations that also contribute to imprecision in temperature control.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 is a schematic view showing the layout of the components of the invention.","FIG.","2 is an elevational view showing the induction plate of the invention.","FIG.","2A is an elevational view showing an induction coil with ferrite core.","FIG.","3 is a wiring diagram showing the control wiring of the invention.","FIG.","4 is a wiring diagram showing the power supply wiring to control separate heating zones.","FIG.","5 is a side elevational view showing the induction plate of the invention.","DETAILED DESCRIPTION OF THE INVENTION Weld quality and consistency can be improved with precise control of heating (temperatures, location zones and heat gradients).","Heating becomes more critical when dealing with certain alloying, geometry or ambient temperatures.","This is more of an art gained through experience or a routine that must be followed carefully to attempt to produce consistent, quality welds.","An induction heating system 10 uses a tool or plate 12 to heat a railroad rail 14.Power control 16 is operatively connected to a pair of power supplies 18,20.Power supplies 18,20 are in turn operatively connected to a heat zone control unit 22 using control output connections 24, 26.Cables (not shown) interconnect power supplies 18,20 to plate 12, generally, and to heating elements 30, 32 specifically through connectors 34, 36.FIG.","2A shows the heating element 32 in more detail.","Each element 30, 32 is generally broken out into a separate heating module 38, 40 using the elements 30, 32 and other features more fully described below to provide a unitary heating module 38, 40.The heating system 10 is a 5 Kw, 25 Khz induction heating system broken out in the form of two 2.5 Kw modules 38, 40.While this is the preferred capacity of the system, different welding operations could advantageously be accommodated through the use of a heating system with a different heating capacity.","These are capable of independent heating of two heat zones, 42, 44.Each module 38, 40 is connected to a heating element 30, 32 with ferrite cores 46, 48 in a common housing in plate 12 capable of being inserted in an approximate one inch gap between rails 14.It will be understood that the rails 14 are shown in section and in the field there will be to rails 14 with a gap between them intended to be welded.","For preheating of normal section railroad rails 14 for gas shielded arc welding, the preferred heat zones 42, 44 consist of two heating locations 50, 52 generally near the bottom flanges 54, 56.The preferred embodiment will be further described below after general description of the field that requires induction preheating.","Gas shielded arc welding without the preheating taught by the invention in this application has been practiced under controlled laboratory and/or workshop conditions but is believed unsuitable for use in the field.","One method used under controlled conditions is generally taught by U.S. Pat.","Nos.","5,773,779 and 5,877,468, which are incorporated by reference as if fully set forth herein.","It is believed that one reason the method described in these two patents is inoperative in field conditions is inadequate control of preheating.","Delivery of gas shielded arc welding equipment and the alignment and restraint of railroad rails and the deployment of a weld containment unit for application of weld beads is taught in published International Application No.","WO 99/31322 published 16 Dec. 1998 entitled “Mail Welding Apparatus Incorporating Rail Restraining Device, Weld Containment Device and Weld Delivery Unit.” The teachings of this application are also incorporated by reference.","It is believed that the apparatus and method taught herein are essential in effective practice of gas shielded arc welding of rails.","Additionally, other welding methods are believed to be capable of enhancement through the use of the invention taught here.","Other weld methods, such as thermite, on site foundry and even certain flux-based arc welding may prove suitable for high strength welds of complex shapes with adequate and well controlled preheating.","While the preferred embodiment of induction heating for rail welding using gas shielded arc welding anticipates using two heating modules 38, 40, other uses could use fewer, more or differently arranged heating modules.","Thus, for certain rail welding or joining methods it may prove advantageous to heat the entire rail section simultaneously.","The invention is not limited to rail welding using two heating modules.","Plate 12 is formed to fully support and contain heating elements 30, 32.Accordingly plate 12 has a body portion 60 ending in a protective ceramic cover 62 which fully covers ferrite cores 46, 48 and the corresponding conductors of elements 30, 32.Side edges 64, 66 of plate 12 are fitted with centering bar assemblies 68, 70.Assemblies 68, 70 use centering adjustment mechanism 72 to adjust bars 74, 76 outwardly or inwardly to fit the rail gap.","It will be understood that assemblies 68, 70 are symmetric and accordingly only one assembly 70 is shown and illustrated in FIG.","5.Precise cutting of rails in the field is quite difficult, thus there is often variation in the size of gaps and the orientation of their faces.","The adjustable and expandable centering bar assembles enabling side to side and top to bottom centering are important in aligning plate 12 as close to the center of the gap as practicable to maximize the uniform heating of the rail ends.","In this manner the assemblies 68, 70 are aligned for maximum effectiveness and uniformity, being centered between faces that may themselves be non-parallel due to the difficulty of cutting in the field.","Each heating element 30, 32 is fitted with a respective pair of water/power connections 80, 82 illustrated in FIG.","2A.","These enable both the electrical power connection necessary to energize the ferrite core 46, 48 and provide conduits for the transmission of cooling fluid to dissipate the heat radiantly transmitted from the preheated rails 14 to the plate 12.Spring clips 84, 86 are used to retain elements 30, 32 in place in plate 12.Temperature measuring devices such as spring loaded thermocouples 90, 92 are used as an integral part of both plate 12 and heat zone control unit 22.Thermocouples 90, 92 are operatively connected to heat zone control unit 22 which is in turn used to control power supplies 18, 20.Power supplies 18, 20 receive signals from unit 22 interconnected through connections 24, 26 which provide power on or power off control signals depending on the heat measured at thermocouples 90, 92.It will be observed, particularly from FIG.","1 and 2 that thermocouples 90 and 92 are positioned proximate ferrite cores 48, thereby providing an accurate temperature reading from rails 14 which are heated as a result of the energizing of elements 30, 32 and particularly cores 46, 48.The general principles of induction heating will be recognized, namely the providing of a sufficiently large energy output at elements 30, 32 and cores 46, 48 will create heat in adjacent steel rails 14.In this manner heat zones 42, 44 are interactively controlled so that a controlled heat results although a variety of factors, whether an imprecise gap, power, magnetic fluctuations, unequal temperature differential or even environmental factors such as a crosswind, impact the actual temperature and heat distribution in the rails.","As noted above while locating heat zones 42, 44 near the rail flanges is advantageous for gas shielded arc welding other types of welding may require the use of different heat zones such as heating the entire rail section including flanges, web and head, or for the welding of different shapes such as I-beams and the like.","In these other uses and applications, the number of heat zones and their orientation can be controlled consistent with the principles of this invention.","The use of one or more coil elements 30, 32 gives flexibility in applying the two preferred heat zones 46, 48.In other, particularly non-rail welding applications, a single heat zone or multiple heat zones could be used.","A plurality of coil elements, two or more, also provide flexibility in temperature differentials that may be required by particular metallurgical or welding considerations.","The invention enables precision controlling of the heat gradient in the pieces to be welded.","The interactive control between elements 30, 32 and thermocouples 90, 92 in zones 42, 44 enables the ability to manipulate the effects of applied heat to the particular metallurgy of the rails 14 and weld material and method used.","Control unit 22 can also be interconnected to corresponding additional fixtures or controls.","The invention contemplates a feedback system that enables, but is not limited to input from a robot or positioner or a controller/computer that calculates heat soak/rail temperature for particular conditions.","With this data compared to the induction heat inputs directly supplied by unit 22 and temperature measurement enabled by thermocouples 90, 92, control unit can be modified for particular time and energy parameters, given known metallurgical and welding requirements.","This full feedback system maximizes the quality control of the welding process so that it will be repeatable and monitored.","The full feedback system also records actual temperatures and adjusts automatically.","The fill feedback system is further programmable for various materials, conditions and methods.","With greater and better data regarding when the weld pieces reach correct temperature(s) in singular and/or multiple zones fully integrated with weld delivery controls, the user is provided a seamless system with no additional mechanisms, components required, such as the prior art burners or torches, and welding materials requiring multiple unrelated and uncontrolled steps.","Finally, the fully integrated system can be manipulated by robot for deployment, movements during heating process and retractment.","In operation, the steps of the invention are premised on the step in which each heat zone is monitored by a temperature measuring device which checks temperature on one side of the zone.","Even heating is achieved on either side of the zone because the inductor is centered between the rails with a mechanical centering device, which independently and exactly centers the inductor relative to side one and side two.","By so doing each side is brought up to a preferably preheat temperature even though the rails may have a variable gap.","It will be noted that the temperature may, of course, vary based on the materials welded and the method of welding used.","Rail ends are preheated by induction heating for preparation of welding.","The ideal temperature and heat gradient is controlled by a feedback system.","The feedback system uses temperature-measuring devices like thermocouple's, pyrometers, and other heat sensors with or without a controlling device.","During the pre-heating, different zone(s) of rail ends can be simultaneously heated independently of each other.","Frequency, proximity and number of cycles allow for control of the heat gradient.","This is complemented though coil designs in the tool and/or power inputs.","This tool fits between the rail ends in the gap and can be manipulated by a robotic arm or manually.","The gaps between rails are approximately ¼″ and up.","Material and mechanical designs of this tool enhance durability and efficiencies.","Process requirements are monitored and recorded for quality control.","Parameter measurements give a go/no go signal to proceed with welding or intervene with corrections to meet parameters.","In addition post-heating enjoys many of the same benefits.","The complete system is mobile and portable.","In operation, each zone begins heating simultaneously.","Should one zone reach temperature prior to the other the heater output is reduced so as to maintain at temperature until the second zone also achieves required temperature.","Only at this time does the controller send a signal to the weld controller indicating that welding can commence."]],"string":"[\n [\n \"Induction heating of rail welds\",\n \"An apparatus (10) and method for preheating welds uses a centered induction plate (12) having preferably a plurality of induction coils (30, 32) to impart the generation of heat in the materials to be welded (14), being interactively controlled by at least a temperature sensor (90, 92) and power supply control loop (16) so that even preheating can be obtained for a selected length of time given the parameters of the weld desired.\"\n ],\n [\n \"1.An induction heating system for preheating first and second workpieces to be welded together comprising: a tool having first and second opposing sides, and disposed in a gap defined by facing ends of the workpieces, the tool further including mechanical centering assemblies disposed adjacent the facing ends of the workpieces, wherein the mechanical centering assemblies position the tool longitudinally with respect to the workpieces for proper proximity to the workpieces; a first induction heating element affixed to the first side of the tool and disposed proximate the first and second workpieces; a first heating zone defined by a first temperature sensor positioned proximate the first workpiece and the first heating element; a second induction heating element affixed to the second side of the tool and disposed proximate the first and second workpieces; a second heating zone defined by a second temperature sensor positioned proximate the first workpiece and the second heating element; a controller coupled to the first and second temperature sensors, the controller activating the first and second heating elements independently to achieve a predetermined welding temperature in both first and second heating zones.\",\n \"2.The induction heating system of claim 1, further comprising a first power supply coupled to the first heating element, and a second power supply coupled to the second heating element, wherein both first and second power supplies are coupled to the controller.\",\n \"3.The induction heating system of claim 1, wherein the first and second induction heating elements are ferrite core heating elements.\",\n \"4.The induction heating system of claim 1, wherein the temperature sensors comprise thermocouple temperature sensors.\",\n \"5.The induction heating system of claim 1, wherein the temperature sensors comprise pyrometer temperature sensors.\",\n \"6.The induction heating system of claim 1, wherein the controller provides a discernible indication when the workpieces have reached the predetermined welding temperature.\",\n \"7.The induction heating system of claim 6, wherein the discernible indication is a visual indication.\",\n \"8.The induction heating system of claim 1, wherein the controller provides positioning information to a positioning robot that adjusts relative position of the tool until the predetermined welding temperature is achieved.\",\n \"9.The induction heating system of claim 1, wherein cooling fluid is provided proximate each of the heating elements.\",\n \"10.The induction heating system of claim 9, wherein the controller controls cooling fluid activation.\",\n \"11.The induction heating system of claim 1, wherein there are three or more heating elements.\",\n \"12.The induction heating system of claim 1, wherein there are three or more heating zones.\",\n \"13.The induction heating system of claim 1, wherein the first and second workpieces are railroad rails.\",\n \"14.An induction heating system for preheating first and second workpieces to be welded together comprising: a tool disposed in a gap defined by facing ends of the workpieces, the tool further including mechanical centering assemblies disposed adjacent the facing ends of the work-pieces, wherein the mechanical centering assemblies position the tool longitudinally with respect to the workpieces for proper proximity to the workpieces; an induction heating element affixed to the tool and disposed proximate the first and second workpieces; a heating zone defined by a temperature sensor positioned proximate the first workpiece and the heating element; a controller coupled to the temperature sensor, the controller activating the heating element to achieve a predetermined welding temperature in the heating zone.\",\n \"15.An induction heating system for preheating first and second workpieces to be welded together comprising: a tool disposed in a gap defined by facing ends of the workpieces, the tool further including mechanical centering assemblies disposed adjacent the facing ends of the workpieces, wherein the mechanical centering assemblies position the tool longitudinally with respect to the workpieces for proper proximity to the workpieces; a plurality of induction heating elements affixed to the tool and disposed proximate the first and second workpieces; as plurality of heating zones defined by multiple temperature sensors positioned proximate the first workpiece and the heating elements; a controller coupled to the temperature sensors, the controller activating the heating elements to achieve a predetermined welding temperature in the heating zones.\",\n \"16.An induction heating system for preheating first and second workpieces to be welded together comprising: mounting means having first and second opposing sides, and disposed in a gap defined by facing ends of the workpieces, wherein the mounting means further further includes mechanical centering assemblies disposed adjacent the facing ends of the workpieces, wherein the mechanical centering assemblies position the mounting means longitudinally with respect to the workpieces for proper proximity to the workpieces; a first induction heating means affixed to the first side of the mounting means and disposed proximate the first and second workpieces; a first heating zone defined by a first temperature sensing means positioned proximate the first workpiece and the first heating means; a second induction heating means affixed to the second side of the mounting means and disposed proximate the first and second workpieces; a second heating zone defined by a second temperature sensing means positioned proximate the first workpiece and the second heating means; a controller means coupled to the first and second temperature sensing means, the controller means activating the first and second heating means independently to achieve a predetermined welding temperature in both first and second heating zones.\",\n \"17.The induction heating system of claim 16, wherein the mounting means comprises a tool having first and second opposing sides.\",\n \"18.The induction heating system of claim 16, further comprising a first power supply means coupled to the first heating means, and a second power supply means coupled to the second heating means, wherein both first and second power supplies means are coupled to the controller means.\",\n \"19.The induction heating system of claim 16, wherein the first and second induction heating means comprise ferrite core heating elements.\",\n \"20.The induction heating system of claim 16, wherein the temperature sensing means comprise thermocouple temperature sensors.\",\n \"21.The induction heating system of claim 16, wherein the temperature sensing means comprise pyrometer temperature sensors.\",\n \"22.The induction heating system of claim 16, wherein the controller means provides a discernible indication when the workpieces have reached the predetermined welding temperature.\",\n \"23.The induction heating system of claim 22, wherein the discernible indication is a visual indication.\",\n \"24.The induction heating system of claim 16, wherein the controller means provides positioning information to a positioning means that adjusts relative position of the tool until the predetermined welding temperature is achieved.\",\n \"25.The induction heating system of claim 16, wherein cooling fluid is provided proximate each of the heating means.\",\n \"26.The induction heating system of claim 25, wherein the controller means controls cooling fluid activation.\",\n \"27.The induction heating system of claim 16, wherein there are three or more heating means.\",\n \"28.The induction heating system of claim 16, wherein there are three or more heating zones.\",\n \"29.The induction heating system of claim 16, wherein the first and second workpieces are railroad rails.\",\n \"30.A method for preheating first and second workpieces to be welded together, the method comprising the steps of: (a) disposing, within a gap defined by facing ends of the workpieces, mounting means having first and second opposing sides; (b) providing mechanical centering assemblies disposed adjacent the facing ends of the workpieces, wherein the mechanical centering assemblies position the mounting means longitudinally with respect to the workpieces for proper proximity to the workpieces; (c) disposing a first induction heating means affixed to the first side of the mounting means proximate the first and second workpieces; (d) defining a first heating zone by positioning a first temperature sensing means proximate the first workpiece and the first heating means; (e) disposing a second induction heating means affixed to the second side of the mounting means proximate the first and second workpieces; (f) defining a second heating zone by positioning a second temperature sensing means proximate the first workpiece and the second heating means; and (g) activating the first and second heating means independently to achieve a predetermined welding temperature in both first and second heating zones.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>1.Summary of Invention The preferred embodiment is adapted to use in welding railroad rails, however, other difficult to weld work pieces could be advantageously preheated with the invention.\",\n \"The descriptions herein of rail welds should be considered with this more expansive use in mind.\",\n \"Induction type heat allows for precise heating at ideal locations and can be used to control heat gradients.\",\n \"This control is possible though use of a feedback system, controller, coil arrangement and a positioning mechanism.\",\n \"This eliminates the human element, resulting in an automated high quality weld preheat method.\",\n \"The use of an automated electrically powered and computer controlled induction heating system using the induction heating coils and heating plate with sensitive temperature control and feedback interfaced within the power supply enables higher quality and more consistent welds of difficult to weld pieces such as railroad rails and similar high strength and complex shaped generally ferric items.\",\n \"One advantage in this regard is the ability to manipulate the heat gradient.\",\n \"Also included in advantages over prior art methods are the facts that no consumables are required, there is no need for gases or fuel on board or during transportation and cleanliness—in that there are no combustion byproducts.\",\n \"The invention provides consistent heat through a wide range of ambient temperatures.\",\n \"Another advantage is that of use in different rail geometry, rail chemistries and welding methods.\",\n \"In addition to heating, an analogous plate or array can be used to control cooling after welding.\",\n \"In the preferred and alternative embodiments, the invention envisions the use of independent, single or multiple coils and/or power units.\",\n \"Independent, single or multiple coils and/or power units enable the precise location of heating, subdivides locations of heating and provides flexibility in the control of heating areas.\",\n \"An added benefit of using an independent preheating unit, as compared to including the welder or portions of the welder's power supply or the like is that of efficiencies gains due to multi tasking during welding process.\",\n \"While preheating is occurring, the welder itself can be independently set up for welding operations, or, indeed, one rail may be welded while the adjacent rail is preheated, should the rail gaps be proximate the rail welder's cable runs.\",\n \"2.Description of Related Art While preheating of metal pieces for welding as a general concept is well known, heretofore generally manual application of heat has been used.\",\n \"The use of items such as gas or other torches, gas burners or electrically powered devices.\",\n \"Field welding in the past commonly preheated with torches and gas burners.\",\n \"Such methods introduce human intervention positioning, timing or estimating heat input and temperature.\",\n \"Combustion variables including fuel, air, pressure, position and shape of a flame relative to rails, ignition steps, initial temperature of the workpieces and even weather contribute to imprecision in temperature control in the prior art.\",\n \"Resistance electrical devices have power and conductivity variables including both electrical and thermal limitations that also contribute to imprecision in temperature control.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG.\",\n \"1 is a schematic view showing the layout of the components of the invention.\",\n \"FIG.\",\n \"2 is an elevational view showing the induction plate of the invention.\",\n \"FIG.\",\n \"2A is an elevational view showing an induction coil with ferrite core.\",\n \"FIG.\",\n \"3 is a wiring diagram showing the control wiring of the invention.\",\n \"FIG.\",\n \"4 is a wiring diagram showing the power supply wiring to control separate heating zones.\",\n \"FIG.\",\n \"5 is a side elevational view showing the induction plate of the invention.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\"\n ],\n [\n \"CLAIM OF PRIORITY Priority is claimed based upon Provisional Patent Application Ser.\",\n \"No.\",\n \"60/209,030, filed Jun.\",\n \"2, 2000, which is incorporated by reference as if fully set forth herein.\",\n \"STATEMENT OF INVENTORSHIP Assignee, Holland Company, believes that the subject matter was the invention of Richard F. Miller.\",\n \"FIELD OF THE INVENTION Some welding techniques require precise consistent and controlled heating, which is difficult or impossible to obtain with torches, gas burners or other electric devices.\",\n \"Instead, this is achievable through the use of induction heating wherein a plate or other locating and holding device is placed in a gap between work pieces to be welded, the plate containing an array of induction heating elements which, when energized, produce shaped, varying electromagnetic fields which link with and induce a voltage in the work pieces which in turn results in eddy current flows and subsequent power losses, as well as hysteresis losses, so that the workpiece temperature is raised to a desired, uniform level prior to welding.\",\n \"BACKGROUND OF THE INVENTION 1.Summary of Invention The preferred embodiment is adapted to use in welding railroad rails, however, other difficult to weld work pieces could be advantageously preheated with the invention.\",\n \"The descriptions herein of rail welds should be considered with this more expansive use in mind.\",\n \"Induction type heat allows for precise heating at ideal locations and can be used to control heat gradients.\",\n \"This control is possible though use of a feedback system, controller, coil arrangement and a positioning mechanism.\",\n \"This eliminates the human element, resulting in an automated high quality weld preheat method.\",\n \"The use of an automated electrically powered and computer controlled induction heating system using the induction heating coils and heating plate with sensitive temperature control and feedback interfaced within the power supply enables higher quality and more consistent welds of difficult to weld pieces such as railroad rails and similar high strength and complex shaped generally ferric items.\",\n \"One advantage in this regard is the ability to manipulate the heat gradient.\",\n \"Also included in advantages over prior art methods are the facts that no consumables are required, there is no need for gases or fuel on board or during transportation and cleanliness—in that there are no combustion byproducts.\",\n \"The invention provides consistent heat through a wide range of ambient temperatures.\",\n \"Another advantage is that of use in different rail geometry, rail chemistries and welding methods.\",\n \"In addition to heating, an analogous plate or array can be used to control cooling after welding.\",\n \"In the preferred and alternative embodiments, the invention envisions the use of independent, single or multiple coils and/or power units.\",\n \"Independent, single or multiple coils and/or power units enable the precise location of heating, subdivides locations of heating and provides flexibility in the control of heating areas.\",\n \"An added benefit of using an independent preheating unit, as compared to including the welder or portions of the welder's power supply or the like is that of efficiencies gains due to multi tasking during welding process.\",\n \"While preheating is occurring, the welder itself can be independently set up for welding operations, or, indeed, one rail may be welded while the adjacent rail is preheated, should the rail gaps be proximate the rail welder's cable runs.\",\n \"2.Description of Related Art While preheating of metal pieces for welding as a general concept is well known, heretofore generally manual application of heat has been used.\",\n \"The use of items such as gas or other torches, gas burners or electrically powered devices.\",\n \"Field welding in the past commonly preheated with torches and gas burners.\",\n \"Such methods introduce human intervention positioning, timing or estimating heat input and temperature.\",\n \"Combustion variables including fuel, air, pressure, position and shape of a flame relative to rails, ignition steps, initial temperature of the workpieces and even weather contribute to imprecision in temperature control in the prior art.\",\n \"Resistance electrical devices have power and conductivity variables including both electrical and thermal limitations that also contribute to imprecision in temperature control.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 is a schematic view showing the layout of the components of the invention.\",\n \"FIG.\",\n \"2 is an elevational view showing the induction plate of the invention.\",\n \"FIG.\",\n \"2A is an elevational view showing an induction coil with ferrite core.\",\n \"FIG.\",\n \"3 is a wiring diagram showing the control wiring of the invention.\",\n \"FIG.\",\n \"4 is a wiring diagram showing the power supply wiring to control separate heating zones.\",\n \"FIG.\",\n \"5 is a side elevational view showing the induction plate of the invention.\",\n \"DETAILED DESCRIPTION OF THE INVENTION Weld quality and consistency can be improved with precise control of heating (temperatures, location zones and heat gradients).\",\n \"Heating becomes more critical when dealing with certain alloying, geometry or ambient temperatures.\",\n \"This is more of an art gained through experience or a routine that must be followed carefully to attempt to produce consistent, quality welds.\",\n \"An induction heating system 10 uses a tool or plate 12 to heat a railroad rail 14.Power control 16 is operatively connected to a pair of power supplies 18,20.Power supplies 18,20 are in turn operatively connected to a heat zone control unit 22 using control output connections 24, 26.Cables (not shown) interconnect power supplies 18,20 to plate 12, generally, and to heating elements 30, 32 specifically through connectors 34, 36.FIG.\",\n \"2A shows the heating element 32 in more detail.\",\n \"Each element 30, 32 is generally broken out into a separate heating module 38, 40 using the elements 30, 32 and other features more fully described below to provide a unitary heating module 38, 40.The heating system 10 is a 5 Kw, 25 Khz induction heating system broken out in the form of two 2.5 Kw modules 38, 40.While this is the preferred capacity of the system, different welding operations could advantageously be accommodated through the use of a heating system with a different heating capacity.\",\n \"These are capable of independent heating of two heat zones, 42, 44.Each module 38, 40 is connected to a heating element 30, 32 with ferrite cores 46, 48 in a common housing in plate 12 capable of being inserted in an approximate one inch gap between rails 14.It will be understood that the rails 14 are shown in section and in the field there will be to rails 14 with a gap between them intended to be welded.\",\n \"For preheating of normal section railroad rails 14 for gas shielded arc welding, the preferred heat zones 42, 44 consist of two heating locations 50, 52 generally near the bottom flanges 54, 56.The preferred embodiment will be further described below after general description of the field that requires induction preheating.\",\n \"Gas shielded arc welding without the preheating taught by the invention in this application has been practiced under controlled laboratory and/or workshop conditions but is believed unsuitable for use in the field.\",\n \"One method used under controlled conditions is generally taught by U.S. Pat.\",\n \"Nos.\",\n \"5,773,779 and 5,877,468, which are incorporated by reference as if fully set forth herein.\",\n \"It is believed that one reason the method described in these two patents is inoperative in field conditions is inadequate control of preheating.\",\n \"Delivery of gas shielded arc welding equipment and the alignment and restraint of railroad rails and the deployment of a weld containment unit for application of weld beads is taught in published International Application No.\",\n \"WO 99/31322 published 16 Dec. 1998 entitled “Mail Welding Apparatus Incorporating Rail Restraining Device, Weld Containment Device and Weld Delivery Unit.” The teachings of this application are also incorporated by reference.\",\n \"It is believed that the apparatus and method taught herein are essential in effective practice of gas shielded arc welding of rails.\",\n \"Additionally, other welding methods are believed to be capable of enhancement through the use of the invention taught here.\",\n \"Other weld methods, such as thermite, on site foundry and even certain flux-based arc welding may prove suitable for high strength welds of complex shapes with adequate and well controlled preheating.\",\n \"While the preferred embodiment of induction heating for rail welding using gas shielded arc welding anticipates using two heating modules 38, 40, other uses could use fewer, more or differently arranged heating modules.\",\n \"Thus, for certain rail welding or joining methods it may prove advantageous to heat the entire rail section simultaneously.\",\n \"The invention is not limited to rail welding using two heating modules.\",\n \"Plate 12 is formed to fully support and contain heating elements 30, 32.Accordingly plate 12 has a body portion 60 ending in a protective ceramic cover 62 which fully covers ferrite cores 46, 48 and the corresponding conductors of elements 30, 32.Side edges 64, 66 of plate 12 are fitted with centering bar assemblies 68, 70.Assemblies 68, 70 use centering adjustment mechanism 72 to adjust bars 74, 76 outwardly or inwardly to fit the rail gap.\",\n \"It will be understood that assemblies 68, 70 are symmetric and accordingly only one assembly 70 is shown and illustrated in FIG.\",\n \"5.Precise cutting of rails in the field is quite difficult, thus there is often variation in the size of gaps and the orientation of their faces.\",\n \"The adjustable and expandable centering bar assembles enabling side to side and top to bottom centering are important in aligning plate 12 as close to the center of the gap as practicable to maximize the uniform heating of the rail ends.\",\n \"In this manner the assemblies 68, 70 are aligned for maximum effectiveness and uniformity, being centered between faces that may themselves be non-parallel due to the difficulty of cutting in the field.\",\n \"Each heating element 30, 32 is fitted with a respective pair of water/power connections 80, 82 illustrated in FIG.\",\n \"2A.\",\n \"These enable both the electrical power connection necessary to energize the ferrite core 46, 48 and provide conduits for the transmission of cooling fluid to dissipate the heat radiantly transmitted from the preheated rails 14 to the plate 12.Spring clips 84, 86 are used to retain elements 30, 32 in place in plate 12.Temperature measuring devices such as spring loaded thermocouples 90, 92 are used as an integral part of both plate 12 and heat zone control unit 22.Thermocouples 90, 92 are operatively connected to heat zone control unit 22 which is in turn used to control power supplies 18, 20.Power supplies 18, 20 receive signals from unit 22 interconnected through connections 24, 26 which provide power on or power off control signals depending on the heat measured at thermocouples 90, 92.It will be observed, particularly from FIG.\",\n \"1 and 2 that thermocouples 90 and 92 are positioned proximate ferrite cores 48, thereby providing an accurate temperature reading from rails 14 which are heated as a result of the energizing of elements 30, 32 and particularly cores 46, 48.The general principles of induction heating will be recognized, namely the providing of a sufficiently large energy output at elements 30, 32 and cores 46, 48 will create heat in adjacent steel rails 14.In this manner heat zones 42, 44 are interactively controlled so that a controlled heat results although a variety of factors, whether an imprecise gap, power, magnetic fluctuations, unequal temperature differential or even environmental factors such as a crosswind, impact the actual temperature and heat distribution in the rails.\",\n \"As noted above while locating heat zones 42, 44 near the rail flanges is advantageous for gas shielded arc welding other types of welding may require the use of different heat zones such as heating the entire rail section including flanges, web and head, or for the welding of different shapes such as I-beams and the like.\",\n \"In these other uses and applications, the number of heat zones and their orientation can be controlled consistent with the principles of this invention.\",\n \"The use of one or more coil elements 30, 32 gives flexibility in applying the two preferred heat zones 46, 48.In other, particularly non-rail welding applications, a single heat zone or multiple heat zones could be used.\",\n \"A plurality of coil elements, two or more, also provide flexibility in temperature differentials that may be required by particular metallurgical or welding considerations.\",\n \"The invention enables precision controlling of the heat gradient in the pieces to be welded.\",\n \"The interactive control between elements 30, 32 and thermocouples 90, 92 in zones 42, 44 enables the ability to manipulate the effects of applied heat to the particular metallurgy of the rails 14 and weld material and method used.\",\n \"Control unit 22 can also be interconnected to corresponding additional fixtures or controls.\",\n \"The invention contemplates a feedback system that enables, but is not limited to input from a robot or positioner or a controller/computer that calculates heat soak/rail temperature for particular conditions.\",\n \"With this data compared to the induction heat inputs directly supplied by unit 22 and temperature measurement enabled by thermocouples 90, 92, control unit can be modified for particular time and energy parameters, given known metallurgical and welding requirements.\",\n \"This full feedback system maximizes the quality control of the welding process so that it will be repeatable and monitored.\",\n \"The full feedback system also records actual temperatures and adjusts automatically.\",\n \"The fill feedback system is further programmable for various materials, conditions and methods.\",\n \"With greater and better data regarding when the weld pieces reach correct temperature(s) in singular and/or multiple zones fully integrated with weld delivery controls, the user is provided a seamless system with no additional mechanisms, components required, such as the prior art burners or torches, and welding materials requiring multiple unrelated and uncontrolled steps.\",\n \"Finally, the fully integrated system can be manipulated by robot for deployment, movements during heating process and retractment.\",\n \"In operation, the steps of the invention are premised on the step in which each heat zone is monitored by a temperature measuring device which checks temperature on one side of the zone.\",\n \"Even heating is achieved on either side of the zone because the inductor is centered between the rails with a mechanical centering device, which independently and exactly centers the inductor relative to side one and side two.\",\n \"By so doing each side is brought up to a preferably preheat temperature even though the rails may have a variable gap.\",\n \"It will be noted that the temperature may, of course, vary based on the materials welded and the method of welding used.\",\n \"Rail ends are preheated by induction heating for preparation of welding.\",\n \"The ideal temperature and heat gradient is controlled by a feedback system.\",\n \"The feedback system uses temperature-measuring devices like thermocouple's, pyrometers, and other heat sensors with or without a controlling device.\",\n \"During the pre-heating, different zone(s) of rail ends can be simultaneously heated independently of each other.\",\n \"Frequency, proximity and number of cycles allow for control of the heat gradient.\",\n \"This is complemented though coil designs in the tool and/or power inputs.\",\n \"This tool fits between the rail ends in the gap and can be manipulated by a robotic arm or manually.\",\n \"The gaps between rails are approximately ¼″ and up.\",\n \"Material and mechanical designs of this tool enhance durability and efficiencies.\",\n \"Process requirements are monitored and recorded for quality control.\",\n \"Parameter measurements give a go/no go signal to proceed with welding or intervene with corrections to meet parameters.\",\n \"In addition post-heating enjoys many of the same benefits.\",\n \"The complete system is mobile and portable.\",\n \"In operation, each zone begins heating simultaneously.\",\n \"Should one zone reach temperature prior to the other the heater output is reduced so as to maintain at temperature until the second zone also achieves required temperature.\",\n \"Only at this time does the controller send a signal to the weld controller indicating that welding can commence.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10296635"}}},{"rowIdx":92,"cells":{"text":{"kind":"list like","value":[["Carboxylate salts in heat-storage applications","The use of an alkali metal salt or alkaline earth metal salt or of a bring solution of a C1-C16 carboxylic acid, or a mixture thereof, as a medium for the storage and use of thermal energy.","The salts or solution can be used in a heat exchange fluid or a lubricant or hydraulic fluid or soap."],["1-13.","(canceled) 14.A method for the storage and use of thermal energy comprising contacting one or a mixture of anhydrous alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C1-C18 carboxylic acid or hydrated salts of a C1 to C7 carboxylic acid with a source of thermal energy.","15.The method of claim 1 further comprising contacting one or a mixture of anhydrous alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C3-C18 carboxylic acid or hydrated salts of a C3 to C7 carboxylic acid with a source of thermal energy.","16.The method of claim 1 wherein said mixture comprises a salt of one or more C1-C2 carboxylic acids and a salt of one or more C3-C5 carboxylic acids.","17.The method of claim 1 wherein said mixture comprises a salt of one or more C1-C5 carboxylic acids and one or more C6-C18 carboxylic acids.","18.The method of claim 4 wherein said mixture comprises a salt of one or more C3-C5 carboxylic acids and one or more C6-C16 carboxylic acids.","19.The method of claim 1 wherein the temperature range of the thermal energy source is 20 to 180 degrees C. 20.The method of claim 1 further comprising contacting one or a mixture of anhydrous alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C1 carboxylic acid with a source of thermal energy.","21.The method of claim 1 further comprising contacting one or a mixture of hydrated alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C1 carboxylic acid with a source of thermal energy.","22.A method for improving the thermal properties of a fluid comprising dispersing in said fluid one or a mixture of anhydrous alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C1-C18 carboxylic acid or hydrated salts of a C1 to C7 carboxylic acid with a source of thermal energy.","23.The method of claim 9 wherein the fluid is a water soluble alcohol freezing point depressant selected from the group consisting of ethylene glycol, propylene glycol, ethanol and methanol.","24.The method of claim 9 wherein the fluid is a lubricant or hydraulic fluid selected from the group consisting of mineral oil, synthetic oil, mineral soap, synthetic soap, mineral grease and synthetic grease."],["<SOH> BACKGROUND OF THE INVENTION <EOH>Thermal energy originating from any energy source is reusable if it can be stored.","Examples of reusable energy are excess heat from stationary and automotive internal combustion engines, heat generated by electrical motors and generators, process heat and condensation heat (e.g.","in refineries and steam generation plants).","Energy generated in peak load time can be managed and stored for later use.","Examples are solar heating and electrical heating on low tariff hours.","The problem of cold car engine start in wintertime is well known.","Frost and damp on windscreen and windows, difficult engine start, cold in the passenger compartment.","Car manufacturers are aware of this problem and make every possible effort to improve the driver's comfort under such circumstances.","Electrical heating of windshield, rear windows, steering wheel and passenger seats are offered as comfort options.","However these solutions put an extra burden on the vehicle's electrical power system.","Engine manufacturers are looking for solutions that make preferably use of excess heat generated by the engine that can be controllably released to the environment.","Heat-storage salts or functional fluids containing heat-storage salts may find new applications in emerging technologies.","Heat-storage salts could for instance be applied to maintain fuel cells at constant temperatures.","An aspect of this invention is that in automotive and heavy-duty engine applications, excess engine heat can be stored in carboxylic salts or in carboxylic salt solutions integrated into the engine heat-exchange system.","The stored heat can be used to rapidly heat critical engine components, engine fluids and exhaust gas catalyst Heating of these critical components before engine start helps avoids the discomfort, high fuel consumption, high exhaust emissions and increased engine wear linked to cold engine start.","The heat stored in carboxylic salts or in carboxylic salts solutions can also be used to heat the passenger compartment to improve driver and passenger comfort in cold climates."],["This invention relates to the application of carboxylate salts for storing thermal energy.","Melted salts are used for heat-storage because salts absorb heat during the transition from the solid to the liquid phase.","This heat is stored in latent form as long as the liquid state persists and released again during the transition from the liquid to the solid phase when the liquid salt solidifies.","BACKGROUND OF THE INVENTION Thermal energy originating from any energy source is reusable if it can be stored.","Examples of reusable energy are excess heat from stationary and automotive internal combustion engines, heat generated by electrical motors and generators, process heat and condensation heat (e.g.","in refineries and steam generation plants).","Energy generated in peak load time can be managed and stored for later use.","Examples are solar heating and electrical heating on low tariff hours.","The problem of cold car engine start in wintertime is well known.","Frost and damp on windscreen and windows, difficult engine start, cold in the passenger compartment.","Car manufacturers are aware of this problem and make every possible effort to improve the driver's comfort under such circumstances.","Electrical heating of windshield, rear windows, steering wheel and passenger seats are offered as comfort options.","However these solutions put an extra burden on the vehicle's electrical power system.","Engine manufacturers are looking for solutions that make preferably use of excess heat generated by the engine that can be controllably released to the environment.","Heat-storage salts or functional fluids containing heat-storage salts may find new applications in emerging technologies.","Heat-storage salts could for instance be applied to maintain fuel cells at constant temperatures.","An aspect of this invention is that in automotive and heavy-duty engine applications, excess engine heat can be stored in carboxylic salts or in carboxylic salt solutions integrated into the engine heat-exchange system.","The stored heat can be used to rapidly heat critical engine components, engine fluids and exhaust gas catalyst Heating of these critical components before engine start helps avoids the discomfort, high fuel consumption, high exhaust emissions and increased engine wear linked to cold engine start.","The heat stored in carboxylic salts or in carboxylic salts solutions can also be used to heat the passenger compartment to improve driver and passenger comfort in cold climates.","PRIOR ART Hydrated fluoride-, chloride-, sulfate- and nitrate salts or salt combinations have been described as heat-storage media.","U.S. Pat.","No.","4,104,185 describes a heat accumulator in which the heat-energy storage medium consists essentially of a potassium fluoride/water solution having a fluoride content between 44 and 48% by weight.","U.S. Pat.","No.","5,567,346 relates to a latent heat storage material composition comprising 65 to 85 wt % of sodium sulfate decahydrate, 1 to 20 wt % of ammonium chloride and 1 to 20 wt % of sodium bromide, and optionally 1 to 20 wt % of ammonium sulfate.","U.S. Pat.","No.","5,728,316 relates to heat-storage salt mixtures composed of magnesium nitrate hexahydrate and lithium nitrate in mass ratio 86-81:14-19.U.S.","Pat.","No.","5,755,988 relates to a process for moderating the thermal energy content of closed container comprising mixtures of organic acids.","Co-assigned EP 0,229,440, EP 0,251,480, EP 0,308,037 and EP 0,564,721 describe the use of carboxylate salts as corrosion inhibitors in aqueous heat exchange fluids or corrosion-inhibited antifreeze formulations.","EPA No.","99930566.1 describes aqueous solutions of carboxylates that provide frost and corrosion protection.","Aqueous solutions of low carbon (C1-C2) carboxylic acid salts, in combination with higher carbon (C3-C5) carboxylic acid salts, were found to provide eutectic freezing protection.","Improved corrosion protection was found by adding one or more than one C6-C16 carboxylic acids.","The advantage of these carboxylic salts based cooling fluids over ethylene glycol- or propylene glycol cooling fluids is improved heat-transfer due to a higher specific heat and improved fluidity resulting from the higher water content at the same frost protection.","It is another objective of this invention to add heat-storage capacity to the above heat-exchange fluids and other functional fluids and soaps like lubricants and greases.","It is an object of the present invention to provide heat storage salt combinations that are less toxic and less burdensome to the environment than the fluoride-, chloride-, sulfate- and nitrate salts or the acidic salt combinations used in prior art Another object of the invention is to provide heat storage salt combinations that are less corrosive to the metals and materials used in heat transfer- and heat-storage equipment.","FIELD OF THE INVENTION One aspect of the invention relates to the application of alkali metal salts or alkali earth metal salts of carboxylic acids, and combinations of such salts as latent heat-storage media The carboxylate heat-storage salts of this invention are less toxic and more environmentally friendly than the fluoride-, chloride-, sulfate- and nitrate salts or salt combinations used in prior art.","They are also less corrosive to the metals and materials used in heat transfer- and heat-storage equipment.","They are similar to the carboxylates used as corrosion inhibitors in aqueous and glycol based heat-exchange fluids.","They are also compatible with the carboxylates (formates and/or acetates) used as freezing point depressant in aqueous heat-exchange fluids.","In heat storage applications it is important to find media with melting temperatures that are in line with the temperature operating range of the heat source and which have high latent heat capacity.","It is another aspect of this invention that mixtures of carboxylic salts can be tuned to provide melting temperatures that fit the application temperatures.","Similarly, combinations with high heat capacity can be selected to optimize storage capacity.","This can be done by mixing different salts of the same carboxylate (for instance the potassium, lithium and/or sodium salt of the same carboxylate) or by mixing the salts of different carboxylates.","In heat storage applications it is also important that the heat storage salts can withstand unchanged and unlimited cycles of heat storage and heat release.","Hydrated heat-storage salts are particularly susceptible.","Loss of water from hydrolyzed crystals will introduce anhydrous crystalline structures with different melting temperatures and different latent heat capacities that may no longer be suitable for the application.","Dehydration at temperatures above the melting temperature of a hydrated salt can be avoided by using hermetically sealed containers and limiting the free space where water can condense without contact with the heat-storage salts.","These measures limit to some extent the use of hydrated salts in heat-storage applications.","It is another aspect of this invention to disperse carboxylate salts with heat-storage capacity in the heat-transfer fluid.","Heat-storage salts can be selected that have limited solubility in the heat-transfer fluid of choice.","The total amount of heat-storage salts added to the solution can be tuned to the heat capacity required in a particular system.","As the melting temperature of the dispersed heat-storage salts is reached, the salts will start to melt and extract heat from the fluid by phase transmission.","The fluid temperature can only rise again when all the heat-storage salts are in molten state.","In the case where hydrated heat-storage salts are used, the use of an aqueous heat-exchange fluid in which the salts are dispersed ensures hydration.","Heat-storage salts can be selected that have densities that are close in solid and liquid phase so that there is no risk of damage to the container or system due to expansion upon phase transition.","In many heat-exchange applications, however, a fluid phase will be preferred to allow easy transport of heat.","Dual heat-exchange systems can of course be used, in which the primary system contains the heat-storage salts, and the secondary system contains the heat-transport fluid.","It is another aspect of the invention to improve the heat capacity of a heat-exchange fluid by dispersion of heat-storage particles in existing heat exchange fluids or other functional fluids or soaps.","Examples are: 1 Heat-exchange fluids based on water soluble alcohol freezing point depressants such as ethylene glycol, propylene glycol, ethanol or methanol.","2 Heat-exchange fluids based on aqueous solutions of low carbon (C1-C2) carboxylic acid salts (formates, acetates) or mixtures thereof.","3 Heat-exchange fluids, lubricants or hydraulic fluids based on mineral- or synthetic oil, mineral and synthetic soaps or greases.","Suspended particles provide heat-storage capacity in the bulk of the existing exchange medium, lubricant or grease.","The alkali metal salts of carboxylic acids have low toxicity, are biodegradable and are not corrosive towards many materials.","An additional advantage of alkali metal carboxylates is that they are similar and/or compatible with the carboxylates used as freezing point depressant and with the carboxylates used as corrosion inhibitors in aqueous and glycol based heat-exchange fluids.","EXAMPLES The invention will be more specifically described by way of reference to the following examples.","A number of formulations were evaluated, by subjecting known quantities of salts to controlled heating and cooling cycles between 20° C. and 180° C. EXAMPLE COMPOSITION Comparative A Magnesium Chloride Hexahydrate Comparative B Magnesium Nitrate Hexahydrate Invention 1 Potassium Octanoate Invention 2 Potassium Heptanoate Invention 3 Potassium Octanoate (90%)/Potassium Heptanoate (10%) Invention 4 Potassium Propionate Invention 5 Sodium Propionate (30%)/Potassium Formate (70%) Invention 6 Potassium Octanoate (70%)/Potassium Heptanoate (30%) Invention 7 Brine solution of 80 w/w % Potassium Propionate Invention 8 Sodium Propionate (20%)/Potassium Formate (20%)/ Potassium Heptanoate (10%)/Water (50%) FIGURES The Figures show heat transformation curves for the formulations of the examples.","They are more specifically described hereinafter.","DISCLOSURE OF THE INVENTION Application of Carboxylate Salts in Heat-Storage Applications.","One aspect of the invention is that alkali metal salts and alkali earth metal salts of carboxylic acids have been found to have heat-storage capacities which allow these salts to be used in heat-storage applications.","To evaluate the heat-storage capacities, salts were subjected to controlled heating and cooling cycles over a preset temperature range.","For instance, to evaluate possible automotive applications, known quantities of the salts were subjected to controlled heating and cooling cycles between 20° C. and 180° C. When, upon heating, the melting point is reached, the temperature measured within the salt will tend to remain constant until all of the salt is melted.","By measuring the temperature differential between salt and a reference recipient subjected to the same temperature cycles, the melting point can be determined.","By integrating the temperature differential over time, the latent heat capacity of the sample can be measured.","Similarly, when, upon cooling the solidification point is reached, the temperature measured within the salt will tend to remain constant until all of the salt is solidified.","Again, by integrating the temperature differential overtime, the latent heat capacity of the sample can be estimated (differential scanning calorimetric technique).","By repeating the temperature cycles, the stability of the heat-storage salt can be evaluated.","Literature provides information on the melting point and heat capacity of some known heat-storage salts.","For instance, magnesium chloride hexahydrate (comparative example A) has been reported to have a melting point of 117° C. and a latent heat capacity of 165 KJ/kg.","FIG.","1 shows experimental curves for magnesium chloride hexahydrate.","The temperature cycle has been repeated five times.","FIG.","2 shows the temperature differentials versus time.","In FIG.","3, the temperature differentials are plotted in function of temperature.","From these curves it can be derived that the melting point is indeed 117° C. Under-cooling upon solidification is shown.","Repeatability of the melting point in successive temperature cycles or series is good.","Some reduction in heat capacity is however noted, likely the result of partial dehydration of the salt.","More extreme shifts in melting point(s) and heat-storage capacity are shown in FIG.","4 for magnesium nitrate hexahydrate (comparative example B).","In this experiment heat-storage capacity is lost in the second and third temperature cycle (series 2 and 3).","Additional temperature cycles for the sample of magnesium nitrate hexahydrate are shown in FIG.","5.Dehydration of the salt apparently causes further changes and shifts in melting and solidification points towards higher temperatures.","Carboxylate Salts Provide Stable Heat-Storage Properties.","Surprisingly, a much more stable behavior is found for alkali metal salts of carboxylic acids that are also employed as corrosion inhibitors.","For example, FIG.","6 shows five successive temperature cycles for potassium octanoate (invention example 1).","The melting point of the salt is 57° C. An additional example using potassium heptanoate is shown in FIG.","7 (invention example 2).","The melting point for potassium heptanoate is 61° C. The Melting Point of Carboxylate Salts can be Tuned for a Specific Heat-Storage Application.","The melting point can be tuned for a specific application by the selection and mixing ratio of the alkali metal carboxylates.","For example, a mixture of potassium octanoate (90%) and potassium heptanoate (10%) (invention example 3 shown in FIG.","8) was found to have a melting temperature of about 48° C., particularly suited for heat-storage at lower temperatures.","In aqueous solutes these carboxylate salts or salt combinations show excellent corrosion protection properties.","In addition, they are similar and thus fully compatible with the carboxylates used as corrosion inhibitors in ethylene glycol and propylene glycol heat-exchange fluids and water treatment chemicals.","The low carbon (C1-C2) carboxylic acid alkali metal salts and the medium carbon (C3-C5) carboxylic acid alkali metal salts, or combinations of the two can be used as heat-storage salts.","For example, FIG.","9 (invention example 4) shows consecutive heating and cooling cycles for potassium propionate, with melting temperature of 79° C. A mixture of 30% sodium propionate and 70% potassium formate—FIG.","10 (invention example 5)—was found to have a melting temperature of 167° C. Heat-Storage Properties of Wetted or Hydrated Carboxylate Salts are Easily Restored.","It was found that, starting from hydrated or wetted carboxylate salts, stable heat-storage properties can easily be obtained by one or more temperature cycles in which the water is evaporated.","This is illustrated in FIG.","11 (invention example 6) for a mixture of the potassium octanoate (70%) and potassium heptanoate (30%), with a melting temperature of about 42° C.—water is boiled off from a wet sample in the first heatig cycle and latent heat can already be recovered in the first cooling cycle at a solidification temperature of about 45° C. This allows heat-exchange applications in which water is evaporated or added to the heat-storage salts, for instance to remove excess heat efficiently.","Brine Solutions of Carboxylate Salts have Heat-Storage Capacity.","Brine solutions of carboxylate salts can also be used as heat-storage medium.","For example, FIGS.","12 to 14 (invention example 7) shows the different curves for consecutive heating and cooling cycles for a brine solution of 80 w/w % of potassium propionate.","Contrary to the salts, the aqueous brine solution was contained in a closed container, not allowing evaporation of water.","In the experiment, phase transition on the lower temperature range was apparently not completed when the heating cycle was re-started, due to the high heat-storage capacity of the medium.","Silicone oil was used as reference fluid.","Dispersed Carboxylates Salts Provide Heat-Storage Capacity to Fluids or Soaps.","It is another aspect of this invention to disperse the hydrated salts with heat-storage capacity in the heat-transfer fluid.","For example, FIG.","15 (invention example 8) shows the consecutive heating and cooling cycles for a mixture of 20% sodium propionate and 20% potassium formate and 10% potassium heptanoate with 50% water in comparison with a brine solution without the addition of the potassium heptanoate.","The effect of the heptanoate additions is clearly seen.","This is even more evident from the curves in FIG.","16, showing the differential temperatures in function of time.","FIG.","17 shows the effect of the potassium heptanoate.","The effect of solidification at about 73° C. which is also observed for pure potassium heptanoate (FIG.","7) is clearly seen.","Dispersion of carboxylate heat-storage salts in other fluids will have similar effects.","This will particularly be the case for glycol based heat exchange fluids.","Many carboxylate salts have limited solubility in glycol and water and can thus be dispersed in such fluids to add heat-storage capacity.","Similarly, this is possible in other functional products such as lubricants or hydraulic fluids based on mineral- or synthetic oil, and in mineral-and synthetic soaps or greases."]],"string":"[\n [\n \"Carboxylate salts in heat-storage applications\",\n \"The use of an alkali metal salt or alkaline earth metal salt or of a bring solution of a C1-C16 carboxylic acid, or a mixture thereof, as a medium for the storage and use of thermal energy.\",\n \"The salts or solution can be used in a heat exchange fluid or a lubricant or hydraulic fluid or soap.\"\n ],\n [\n \"1-13.\",\n \"(canceled) 14.A method for the storage and use of thermal energy comprising contacting one or a mixture of anhydrous alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C1-C18 carboxylic acid or hydrated salts of a C1 to C7 carboxylic acid with a source of thermal energy.\",\n \"15.The method of claim 1 further comprising contacting one or a mixture of anhydrous alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C3-C18 carboxylic acid or hydrated salts of a C3 to C7 carboxylic acid with a source of thermal energy.\",\n \"16.The method of claim 1 wherein said mixture comprises a salt of one or more C1-C2 carboxylic acids and a salt of one or more C3-C5 carboxylic acids.\",\n \"17.The method of claim 1 wherein said mixture comprises a salt of one or more C1-C5 carboxylic acids and one or more C6-C18 carboxylic acids.\",\n \"18.The method of claim 4 wherein said mixture comprises a salt of one or more C3-C5 carboxylic acids and one or more C6-C16 carboxylic acids.\",\n \"19.The method of claim 1 wherein the temperature range of the thermal energy source is 20 to 180 degrees C. 20.The method of claim 1 further comprising contacting one or a mixture of anhydrous alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C1 carboxylic acid with a source of thermal energy.\",\n \"21.The method of claim 1 further comprising contacting one or a mixture of hydrated alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C1 carboxylic acid with a source of thermal energy.\",\n \"22.A method for improving the thermal properties of a fluid comprising dispersing in said fluid one or a mixture of anhydrous alkali metal salts, alkali metal earth salts, amine salts or ammonium salts of a C1-C18 carboxylic acid or hydrated salts of a C1 to C7 carboxylic acid with a source of thermal energy.\",\n \"23.The method of claim 9 wherein the fluid is a water soluble alcohol freezing point depressant selected from the group consisting of ethylene glycol, propylene glycol, ethanol and methanol.\",\n \"24.The method of claim 9 wherein the fluid is a lubricant or hydraulic fluid selected from the group consisting of mineral oil, synthetic oil, mineral soap, synthetic soap, mineral grease and synthetic grease.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>Thermal energy originating from any energy source is reusable if it can be stored.\",\n \"Examples of reusable energy are excess heat from stationary and automotive internal combustion engines, heat generated by electrical motors and generators, process heat and condensation heat (e.g.\",\n \"in refineries and steam generation plants).\",\n \"Energy generated in peak load time can be managed and stored for later use.\",\n \"Examples are solar heating and electrical heating on low tariff hours.\",\n \"The problem of cold car engine start in wintertime is well known.\",\n \"Frost and damp on windscreen and windows, difficult engine start, cold in the passenger compartment.\",\n \"Car manufacturers are aware of this problem and make every possible effort to improve the driver's comfort under such circumstances.\",\n \"Electrical heating of windshield, rear windows, steering wheel and passenger seats are offered as comfort options.\",\n \"However these solutions put an extra burden on the vehicle's electrical power system.\",\n \"Engine manufacturers are looking for solutions that make preferably use of excess heat generated by the engine that can be controllably released to the environment.\",\n \"Heat-storage salts or functional fluids containing heat-storage salts may find new applications in emerging technologies.\",\n \"Heat-storage salts could for instance be applied to maintain fuel cells at constant temperatures.\",\n \"An aspect of this invention is that in automotive and heavy-duty engine applications, excess engine heat can be stored in carboxylic salts or in carboxylic salt solutions integrated into the engine heat-exchange system.\",\n \"The stored heat can be used to rapidly heat critical engine components, engine fluids and exhaust gas catalyst Heating of these critical components before engine start helps avoids the discomfort, high fuel consumption, high exhaust emissions and increased engine wear linked to cold engine start.\",\n \"The heat stored in carboxylic salts or in carboxylic salts solutions can also be used to heat the passenger compartment to improve driver and passenger comfort in cold climates.\"\n ],\n [\n \"This invention relates to the application of carboxylate salts for storing thermal energy.\",\n \"Melted salts are used for heat-storage because salts absorb heat during the transition from the solid to the liquid phase.\",\n \"This heat is stored in latent form as long as the liquid state persists and released again during the transition from the liquid to the solid phase when the liquid salt solidifies.\",\n \"BACKGROUND OF THE INVENTION Thermal energy originating from any energy source is reusable if it can be stored.\",\n \"Examples of reusable energy are excess heat from stationary and automotive internal combustion engines, heat generated by electrical motors and generators, process heat and condensation heat (e.g.\",\n \"in refineries and steam generation plants).\",\n \"Energy generated in peak load time can be managed and stored for later use.\",\n \"Examples are solar heating and electrical heating on low tariff hours.\",\n \"The problem of cold car engine start in wintertime is well known.\",\n \"Frost and damp on windscreen and windows, difficult engine start, cold in the passenger compartment.\",\n \"Car manufacturers are aware of this problem and make every possible effort to improve the driver's comfort under such circumstances.\",\n \"Electrical heating of windshield, rear windows, steering wheel and passenger seats are offered as comfort options.\",\n \"However these solutions put an extra burden on the vehicle's electrical power system.\",\n \"Engine manufacturers are looking for solutions that make preferably use of excess heat generated by the engine that can be controllably released to the environment.\",\n \"Heat-storage salts or functional fluids containing heat-storage salts may find new applications in emerging technologies.\",\n \"Heat-storage salts could for instance be applied to maintain fuel cells at constant temperatures.\",\n \"An aspect of this invention is that in automotive and heavy-duty engine applications, excess engine heat can be stored in carboxylic salts or in carboxylic salt solutions integrated into the engine heat-exchange system.\",\n \"The stored heat can be used to rapidly heat critical engine components, engine fluids and exhaust gas catalyst Heating of these critical components before engine start helps avoids the discomfort, high fuel consumption, high exhaust emissions and increased engine wear linked to cold engine start.\",\n \"The heat stored in carboxylic salts or in carboxylic salts solutions can also be used to heat the passenger compartment to improve driver and passenger comfort in cold climates.\",\n \"PRIOR ART Hydrated fluoride-, chloride-, sulfate- and nitrate salts or salt combinations have been described as heat-storage media.\",\n \"U.S. Pat.\",\n \"No.\",\n \"4,104,185 describes a heat accumulator in which the heat-energy storage medium consists essentially of a potassium fluoride/water solution having a fluoride content between 44 and 48% by weight.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,567,346 relates to a latent heat storage material composition comprising 65 to 85 wt % of sodium sulfate decahydrate, 1 to 20 wt % of ammonium chloride and 1 to 20 wt % of sodium bromide, and optionally 1 to 20 wt % of ammonium sulfate.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,728,316 relates to heat-storage salt mixtures composed of magnesium nitrate hexahydrate and lithium nitrate in mass ratio 86-81:14-19.U.S.\",\n \"Pat.\",\n \"No.\",\n \"5,755,988 relates to a process for moderating the thermal energy content of closed container comprising mixtures of organic acids.\",\n \"Co-assigned EP 0,229,440, EP 0,251,480, EP 0,308,037 and EP 0,564,721 describe the use of carboxylate salts as corrosion inhibitors in aqueous heat exchange fluids or corrosion-inhibited antifreeze formulations.\",\n \"EPA No.\",\n \"99930566.1 describes aqueous solutions of carboxylates that provide frost and corrosion protection.\",\n \"Aqueous solutions of low carbon (C1-C2) carboxylic acid salts, in combination with higher carbon (C3-C5) carboxylic acid salts, were found to provide eutectic freezing protection.\",\n \"Improved corrosion protection was found by adding one or more than one C6-C16 carboxylic acids.\",\n \"The advantage of these carboxylic salts based cooling fluids over ethylene glycol- or propylene glycol cooling fluids is improved heat-transfer due to a higher specific heat and improved fluidity resulting from the higher water content at the same frost protection.\",\n \"It is another objective of this invention to add heat-storage capacity to the above heat-exchange fluids and other functional fluids and soaps like lubricants and greases.\",\n \"It is an object of the present invention to provide heat storage salt combinations that are less toxic and less burdensome to the environment than the fluoride-, chloride-, sulfate- and nitrate salts or the acidic salt combinations used in prior art Another object of the invention is to provide heat storage salt combinations that are less corrosive to the metals and materials used in heat transfer- and heat-storage equipment.\",\n \"FIELD OF THE INVENTION One aspect of the invention relates to the application of alkali metal salts or alkali earth metal salts of carboxylic acids, and combinations of such salts as latent heat-storage media The carboxylate heat-storage salts of this invention are less toxic and more environmentally friendly than the fluoride-, chloride-, sulfate- and nitrate salts or salt combinations used in prior art.\",\n \"They are also less corrosive to the metals and materials used in heat transfer- and heat-storage equipment.\",\n \"They are similar to the carboxylates used as corrosion inhibitors in aqueous and glycol based heat-exchange fluids.\",\n \"They are also compatible with the carboxylates (formates and/or acetates) used as freezing point depressant in aqueous heat-exchange fluids.\",\n \"In heat storage applications it is important to find media with melting temperatures that are in line with the temperature operating range of the heat source and which have high latent heat capacity.\",\n \"It is another aspect of this invention that mixtures of carboxylic salts can be tuned to provide melting temperatures that fit the application temperatures.\",\n \"Similarly, combinations with high heat capacity can be selected to optimize storage capacity.\",\n \"This can be done by mixing different salts of the same carboxylate (for instance the potassium, lithium and/or sodium salt of the same carboxylate) or by mixing the salts of different carboxylates.\",\n \"In heat storage applications it is also important that the heat storage salts can withstand unchanged and unlimited cycles of heat storage and heat release.\",\n \"Hydrated heat-storage salts are particularly susceptible.\",\n \"Loss of water from hydrolyzed crystals will introduce anhydrous crystalline structures with different melting temperatures and different latent heat capacities that may no longer be suitable for the application.\",\n \"Dehydration at temperatures above the melting temperature of a hydrated salt can be avoided by using hermetically sealed containers and limiting the free space where water can condense without contact with the heat-storage salts.\",\n \"These measures limit to some extent the use of hydrated salts in heat-storage applications.\",\n \"It is another aspect of this invention to disperse carboxylate salts with heat-storage capacity in the heat-transfer fluid.\",\n \"Heat-storage salts can be selected that have limited solubility in the heat-transfer fluid of choice.\",\n \"The total amount of heat-storage salts added to the solution can be tuned to the heat capacity required in a particular system.\",\n \"As the melting temperature of the dispersed heat-storage salts is reached, the salts will start to melt and extract heat from the fluid by phase transmission.\",\n \"The fluid temperature can only rise again when all the heat-storage salts are in molten state.\",\n \"In the case where hydrated heat-storage salts are used, the use of an aqueous heat-exchange fluid in which the salts are dispersed ensures hydration.\",\n \"Heat-storage salts can be selected that have densities that are close in solid and liquid phase so that there is no risk of damage to the container or system due to expansion upon phase transition.\",\n \"In many heat-exchange applications, however, a fluid phase will be preferred to allow easy transport of heat.\",\n \"Dual heat-exchange systems can of course be used, in which the primary system contains the heat-storage salts, and the secondary system contains the heat-transport fluid.\",\n \"It is another aspect of the invention to improve the heat capacity of a heat-exchange fluid by dispersion of heat-storage particles in existing heat exchange fluids or other functional fluids or soaps.\",\n \"Examples are: 1 Heat-exchange fluids based on water soluble alcohol freezing point depressants such as ethylene glycol, propylene glycol, ethanol or methanol.\",\n \"2 Heat-exchange fluids based on aqueous solutions of low carbon (C1-C2) carboxylic acid salts (formates, acetates) or mixtures thereof.\",\n \"3 Heat-exchange fluids, lubricants or hydraulic fluids based on mineral- or synthetic oil, mineral and synthetic soaps or greases.\",\n \"Suspended particles provide heat-storage capacity in the bulk of the existing exchange medium, lubricant or grease.\",\n \"The alkali metal salts of carboxylic acids have low toxicity, are biodegradable and are not corrosive towards many materials.\",\n \"An additional advantage of alkali metal carboxylates is that they are similar and/or compatible with the carboxylates used as freezing point depressant and with the carboxylates used as corrosion inhibitors in aqueous and glycol based heat-exchange fluids.\",\n \"EXAMPLES The invention will be more specifically described by way of reference to the following examples.\",\n \"A number of formulations were evaluated, by subjecting known quantities of salts to controlled heating and cooling cycles between 20° C. and 180° C. EXAMPLE COMPOSITION Comparative A Magnesium Chloride Hexahydrate Comparative B Magnesium Nitrate Hexahydrate Invention 1 Potassium Octanoate Invention 2 Potassium Heptanoate Invention 3 Potassium Octanoate (90%)/Potassium Heptanoate (10%) Invention 4 Potassium Propionate Invention 5 Sodium Propionate (30%)/Potassium Formate (70%) Invention 6 Potassium Octanoate (70%)/Potassium Heptanoate (30%) Invention 7 Brine solution of 80 w/w % Potassium Propionate Invention 8 Sodium Propionate (20%)/Potassium Formate (20%)/ Potassium Heptanoate (10%)/Water (50%) FIGURES The Figures show heat transformation curves for the formulations of the examples.\",\n \"They are more specifically described hereinafter.\",\n \"DISCLOSURE OF THE INVENTION Application of Carboxylate Salts in Heat-Storage Applications.\",\n \"One aspect of the invention is that alkali metal salts and alkali earth metal salts of carboxylic acids have been found to have heat-storage capacities which allow these salts to be used in heat-storage applications.\",\n \"To evaluate the heat-storage capacities, salts were subjected to controlled heating and cooling cycles over a preset temperature range.\",\n \"For instance, to evaluate possible automotive applications, known quantities of the salts were subjected to controlled heating and cooling cycles between 20° C. and 180° C. When, upon heating, the melting point is reached, the temperature measured within the salt will tend to remain constant until all of the salt is melted.\",\n \"By measuring the temperature differential between salt and a reference recipient subjected to the same temperature cycles, the melting point can be determined.\",\n \"By integrating the temperature differential over time, the latent heat capacity of the sample can be measured.\",\n \"Similarly, when, upon cooling the solidification point is reached, the temperature measured within the salt will tend to remain constant until all of the salt is solidified.\",\n \"Again, by integrating the temperature differential overtime, the latent heat capacity of the sample can be estimated (differential scanning calorimetric technique).\",\n \"By repeating the temperature cycles, the stability of the heat-storage salt can be evaluated.\",\n \"Literature provides information on the melting point and heat capacity of some known heat-storage salts.\",\n \"For instance, magnesium chloride hexahydrate (comparative example A) has been reported to have a melting point of 117° C. and a latent heat capacity of 165 KJ/kg.\",\n \"FIG.\",\n \"1 shows experimental curves for magnesium chloride hexahydrate.\",\n \"The temperature cycle has been repeated five times.\",\n \"FIG.\",\n \"2 shows the temperature differentials versus time.\",\n \"In FIG.\",\n \"3, the temperature differentials are plotted in function of temperature.\",\n \"From these curves it can be derived that the melting point is indeed 117° C. Under-cooling upon solidification is shown.\",\n \"Repeatability of the melting point in successive temperature cycles or series is good.\",\n \"Some reduction in heat capacity is however noted, likely the result of partial dehydration of the salt.\",\n \"More extreme shifts in melting point(s) and heat-storage capacity are shown in FIG.\",\n \"4 for magnesium nitrate hexahydrate (comparative example B).\",\n \"In this experiment heat-storage capacity is lost in the second and third temperature cycle (series 2 and 3).\",\n \"Additional temperature cycles for the sample of magnesium nitrate hexahydrate are shown in FIG.\",\n \"5.Dehydration of the salt apparently causes further changes and shifts in melting and solidification points towards higher temperatures.\",\n \"Carboxylate Salts Provide Stable Heat-Storage Properties.\",\n \"Surprisingly, a much more stable behavior is found for alkali metal salts of carboxylic acids that are also employed as corrosion inhibitors.\",\n \"For example, FIG.\",\n \"6 shows five successive temperature cycles for potassium octanoate (invention example 1).\",\n \"The melting point of the salt is 57° C. An additional example using potassium heptanoate is shown in FIG.\",\n \"7 (invention example 2).\",\n \"The melting point for potassium heptanoate is 61° C. The Melting Point of Carboxylate Salts can be Tuned for a Specific Heat-Storage Application.\",\n \"The melting point can be tuned for a specific application by the selection and mixing ratio of the alkali metal carboxylates.\",\n \"For example, a mixture of potassium octanoate (90%) and potassium heptanoate (10%) (invention example 3 shown in FIG.\",\n \"8) was found to have a melting temperature of about 48° C., particularly suited for heat-storage at lower temperatures.\",\n \"In aqueous solutes these carboxylate salts or salt combinations show excellent corrosion protection properties.\",\n \"In addition, they are similar and thus fully compatible with the carboxylates used as corrosion inhibitors in ethylene glycol and propylene glycol heat-exchange fluids and water treatment chemicals.\",\n \"The low carbon (C1-C2) carboxylic acid alkali metal salts and the medium carbon (C3-C5) carboxylic acid alkali metal salts, or combinations of the two can be used as heat-storage salts.\",\n \"For example, FIG.\",\n \"9 (invention example 4) shows consecutive heating and cooling cycles for potassium propionate, with melting temperature of 79° C. A mixture of 30% sodium propionate and 70% potassium formate—FIG.\",\n \"10 (invention example 5)—was found to have a melting temperature of 167° C. Heat-Storage Properties of Wetted or Hydrated Carboxylate Salts are Easily Restored.\",\n \"It was found that, starting from hydrated or wetted carboxylate salts, stable heat-storage properties can easily be obtained by one or more temperature cycles in which the water is evaporated.\",\n \"This is illustrated in FIG.\",\n \"11 (invention example 6) for a mixture of the potassium octanoate (70%) and potassium heptanoate (30%), with a melting temperature of about 42° C.—water is boiled off from a wet sample in the first heatig cycle and latent heat can already be recovered in the first cooling cycle at a solidification temperature of about 45° C. This allows heat-exchange applications in which water is evaporated or added to the heat-storage salts, for instance to remove excess heat efficiently.\",\n \"Brine Solutions of Carboxylate Salts have Heat-Storage Capacity.\",\n \"Brine solutions of carboxylate salts can also be used as heat-storage medium.\",\n \"For example, FIGS.\",\n \"12 to 14 (invention example 7) shows the different curves for consecutive heating and cooling cycles for a brine solution of 80 w/w % of potassium propionate.\",\n \"Contrary to the salts, the aqueous brine solution was contained in a closed container, not allowing evaporation of water.\",\n \"In the experiment, phase transition on the lower temperature range was apparently not completed when the heating cycle was re-started, due to the high heat-storage capacity of the medium.\",\n \"Silicone oil was used as reference fluid.\",\n \"Dispersed Carboxylates Salts Provide Heat-Storage Capacity to Fluids or Soaps.\",\n \"It is another aspect of this invention to disperse the hydrated salts with heat-storage capacity in the heat-transfer fluid.\",\n \"For example, FIG.\",\n \"15 (invention example 8) shows the consecutive heating and cooling cycles for a mixture of 20% sodium propionate and 20% potassium formate and 10% potassium heptanoate with 50% water in comparison with a brine solution without the addition of the potassium heptanoate.\",\n \"The effect of the heptanoate additions is clearly seen.\",\n \"This is even more evident from the curves in FIG.\",\n \"16, showing the differential temperatures in function of time.\",\n \"FIG.\",\n \"17 shows the effect of the potassium heptanoate.\",\n \"The effect of solidification at about 73° C. which is also observed for pure potassium heptanoate (FIG.\",\n \"7) is clearly seen.\",\n \"Dispersion of carboxylate heat-storage salts in other fluids will have similar effects.\",\n \"This will particularly be the case for glycol based heat exchange fluids.\",\n \"Many carboxylate salts have limited solubility in glycol and water and can thus be dispersed in such fluids to add heat-storage capacity.\",\n \"Similarly, this is possible in other functional products such as lubricants or hydraulic fluids based on mineral- or synthetic oil, and in mineral-and synthetic soaps or greases.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10296826"}}},{"rowIdx":93,"cells":{"text":{"kind":"list like","value":[["Stabiliser for radiopharmaceuticals","The present invention provides an improved stabiliser for radiopharmaceuticals which inhibits impurities from being produced by two kinds of decomposition mechanisms and exhibits such an effect that the shelf life of a radiopharmaceutical after its preparation is prolonged as compared with conventional ones.","The improvement comprises a combination of an amino-substituted aromatic carboxylic acid or its salt, ester or amide in combination with a diphosphonic acid or its salt."],["1.A stabilised radiopharmaceutical composition which comprises: (i) a radiopharmaceutical which is susceptible to either reductive degradation or radiolysis; (ii) a first stabiliser for said radiopharmaceutical which includes an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof; (iii) a second stabiliser for said radiopharmaceutical which includes a diphosphonic acid or salt thereof, wherein the radiopharmaceutical is not a metal complex of the diphosphonic acid.","2.The composition of claim 1 wherein the amino-ubstituted aromatic carboxylic acid or its salt, ester or amide is selected from the group consisting of 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 3, 5-diaminobenzoic acid, 4-amino-salicylic acid, and salts, esters and amides thereof.","3.The composition of claim 1, wherein the diphosphonic acid or its salt is selected from the group consisting of methylenediphosphonic acid, hydroxymethanediphosphonic acid, hydroxyethanediphosphonic acid, ethylenediaminetetraphosphonic acid, and salts thereof.","4.The composition of claim 1, wherein the amino-substituted aromatic carboxylic acid or salt, ester or amide thereof is sodium 4-aminobenzoate, and the diphosphonic acid is methylenediphosphonic acid.","5.The composition of claim 1, wherein the radiopharmaceutical includes a γ-ray emitter or a β-ray emitter.","6.The composition of claim 5, wherein the radiopharmaceutical includes Tc-99m, Re-186 or Re-188.7.The composition of claim 1, wherein the radiopharmaceutical includes a metal complex of a radionuclide with a ligand.","8.The composition of claim 7, wherein the ligand is an amine oxime.","9.The composition of claim 8, wherein the amine oxime is selected from the group consisting of d,l-hexamethylpropyleneamine oxime and 4,9-diaza-3, 3, 10, 10-tetramethyldodecane-2, 11-dione dioxime.","10.A non-radioactive kit for the preparation of the stabilised radiopharmaceutical composition of claim 1 which comprises: (i) a first stabiliser which comprises an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof; and (ii) a second stabiliser which comprises a diphosphonic acid or salt thereof, wherein the radiopharmaceutical is not a metal complex of the diphosphonic acid.","11.The kit of claim 10, which includes 0.01 to 10 mg of an amino-substituted aromatic carboxylic acid or its salt, ester or amide, and 0.01 to 1 mg of a diphosphonic acid or its salt.","12.The kit of claim 10, further comprising a tin (II) reductant, wherein the molar ratio of the diphosphonic acid or its salt to tin (II) is in the range 1 to 10.13.The kit of claim 10, further comprising an amine oxime ligand.","14.The kit of claim 13 wherein the amine oxime is selected from the group consisting of d, l-hexamethylpropyleneamine oxime and 4,9-diaza-3, 3, 10, 10-tetramethyldodecane-2, 11-dione dioxime.","15.The kit of claim 10, wherein the first and second stabilzers are lyophilised.","16.In a method of preparing a radiopharmaceutical composition which includes adding stabilizers to a radiopharmaceutical, wherein the radiopharmaceutical is not a metal complex of diphosphonic acid, the improvement comprising using a diphosphonic acid or a salt thereof as a stabiliser.","17.Cancelled 18.The method of claim 16, wherein the radiopharmaceutical comprises Tc-99m.","19.The method of claim 16, wherein the diphosphonic acid is selected from the group consisting of methylenediphosphonic acid, hydroxymethanediphosphonic acid, hydroxyethanediphosphonic acid, ethylenediaminetetraphosphonic acid, and salts thereof."],["<SOH> BACKGROUND TO THE INVENTION <EOH>Some radiopharmaceuticals undergo decomposition due to either radiolysis or redox reactions, and hence exhibit undesirable instability.","Non-radioactive kits for the preparation of radiopharmaceuticals, especially Tc-99m radiopharmaceuticals, may suffer from two types of instability: (i) shelf-life instability of the non-radioactive composition over time, (ii) instability of the radiopharmaceutical post-formation.","In the case of Tc-99m, the latter is referred to as post-reconstitution instability.","U.S. Pat.","No.","4,451,451 discloses that para-aminobenzoic acid (pABA) and analogues are useful stabilisers for technetium non-radioactive kits, including kits for the preparation of 99m Tc-complexes of diphosphonic acids.","Tc-99m-hexamethylpropyleneamine oxime (referred to hereinafter as 99m Tc-HMPAO), is a radiopharmaceutical commercially available as a regional cerebral blood flow imaging agent.","99m Tc-HMPAO is particularly unstable with respect to post-reconstitution stability.","99m Tc-HMPAO is usually prepared from a lyophilised, non-radioactive kit which contains HMPAO and stannous ion.","The function of the stannous ion is to reduce the 99m Tc-pertechnetate ( 99m TcO 4 − ), ie.","technetium in oxidation state Tc(VII), to the Tc(V) oxidation state of the 99m Tc-HMPAO metal complex.","The radiochemical purity (Rcp) of 99m Tc-HMPAO one hour after Tc-99m labelling is only about 80%, so that it must be used within 30 minutes of 99m Tc labelling.","After Tc-99m radiolabelling, the Rcp of 99m Tc-HMPAO decreases with time due to the growth of three different radioactive impurities, namely: a hydrophilic secondary 99m Tc complex of unknown structure derived from 99m Tc-HMPAO, 99m Tc-pertechnetate ( 99m TcO 4 − ) and reduced-hydrolysed-technetium [ 99m Tc].","Of these impurities, both the secondary complex and 99m Tc-pertechnetate are decomposition products of 99m Tc-HMPAO; however, it is reported that the decomposition mechanisms are different (J. Nucl.","Med.","29, 1568-1576, 1988).","The secondary complex is believed to be produced when the lipophilic 99m Tc-HMPAO complex is exposed to excess unoxidised tin(II) (ie.","stannous) remaining from the pertechnetate reduction step.","On the other hand, the 99m Tc-pertechnetate impurity is produced when 99m Tc-HMPAO and the secondary complex are oxidised by the free radicals produced in solution by the action of radiation, ie.","radiolysis of the solvent.","Accordingly, in order to inhibit the production of both the 99m Tc-pertechnetate and secondary complex impurities, the addition of stabilisers has been disclosed.","Thus, Nucl.","Med.","Biol.","7, 675-680 (1989); Eur.","J. Nucl.","Med.","16, 541 (1990); Eur.","J. Nucl.","Med.","20, 661-666 (1993) and Eur.","J. Nucl.","Med.","22, 1163-1172 (1995) all report attempts to stabilise 99m Tc-HMPAO by the addition of either: gentisic acid, sodium decahydroxypyrophosphate, methylene blue, cobalt chloride or the like.","In particular, the post-radiolabelling addition of methylene blue improves the Rcp of 99m Tc-HMPAO to at least 80% at 4 hours post reconstitution.","Similarly, the post-radiolabelling addition of cobalt chloride has been found to improve the Rcp of 99m Tc-HMPAO at 6 hours post reconstitution to at least 80%.","The stabilisation mechanisms of 99m Tc-HMPAO by methylene blue and cobalt chloride are believed to be essentially the same.","Both are in redox equilibrium in solution, and oxidise excess tin(II), thus stabilising 99m Tc-HMPAO.","However, when the reducing tin(II) and methylene blue or cobalt chloride coexist in solution before the Tc-99m radiolabelling step, the tin(II) reductant is completely oxidised, so that the Tc-99m labelling becomes impossible because there is no longer any reducing agent present to reduce the Tc(VII) 99m Tc-blue or cobalt chloride is used as a stabiliser for 99m Tc-HMPAO, it must be added after the Tc-99m radiolabelling step and cannot be pre-mixed with the ligand (HMPAO) and 99m Tc-pertechnetate.","Accordingly, any kit for the preparation of 99m Tc-HMPAO employing such stabilisers, must be composed of two vials (referred to hereinafter as a 2-vial kit).","One vial is a freeze-dried vial containing the HMPAO ligand together with the tin(II) reductant and other excipients.","The other is a vial containing the stabiliser (methylene blue or cobalt chloride).","Thus, the most successful prior art methods of stabilising 99m Tc-HMPAO to date all require the use of 2-vial kits.","When the kit for preparing 99m Tc-HMPAO is a 2-vial kit, the radiolabelling operation is more complicated than for a single vial kit and comprises two steps: (1) 99m Tc-pertechnetate solution is added to the vial containing the HMPAO ligand and the resulting mixture is mixed by shaking; (2) a stabiliser solution from the second vial (eg.","methylene blue or cobalt chloride) is added to the reconstituted mixture from step (1) in the first vial.","It is necessary that the time between the first and second steps is controlled so as to be as close as possible to two minutes.","Too short a time, and 99m Tc-HMPAO complex formation may be incomplete and hence addition of the stabiliser may adversely affect the Rcp by oxidising the stannous ion before the reduction of the pertechnetate starting material is complete.","Too long a time, and the stabilising effect is delayed.","In such a procedure it is also necessary that care be taken with respect to the amounts of the solutions added.","The operator must also take due care to ensure that the vials are not inadvertently mixed up at any stage.","In addition, there is an increased risk of radiation dose to the operator due to the increased number of manipulations.","Moreover, when methylene blue is added to 99m Tc-HMPAO, a precipitate is produced, so that a filtration step becomes necessary, and thus the procedure becomes more complicated.","There is therefore a need for a single vial kit for the preparation of 99m Tc-HMPAO which has both shelf-life and post-radiolabelling stability.","The present invention provides a kit which solves this problem, and is straightforward to use.","The Present Invention.","The present invention relates to a stabiliser for radiopharmaceuticals which comprises a combination of an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof, with a diphosphonic acid or a salt thereof with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid."],["FIELD OF THE INVENTION The present invention relates to a stabilised radiopharmaceutical composition, together with non-radioactive kits for the preparation of the stabilised radiopharmaceutical composition.","BACKGROUND TO THE INVENTION Some radiopharmaceuticals undergo decomposition due to either radiolysis or redox reactions, and hence exhibit undesirable instability.","Non-radioactive kits for the preparation of radiopharmaceuticals, especially Tc-99m radiopharmaceuticals, may suffer from two types of instability: (i) shelf-life instability of the non-radioactive composition over time, (ii) instability of the radiopharmaceutical post-formation.","In the case of Tc-99m, the latter is referred to as post-reconstitution instability.","U.S. Pat.","No.","4,451,451 discloses that para-aminobenzoic acid (pABA) and analogues are useful stabilisers for technetium non-radioactive kits, including kits for the preparation of 99mTc-complexes of diphosphonic acids.","Tc-99m-hexamethylpropyleneamine oxime (referred to hereinafter as 99mTc-HMPAO), is a radiopharmaceutical commercially available as a regional cerebral blood flow imaging agent.","99mTc-HMPAO is particularly unstable with respect to post-reconstitution stability.","99mTc-HMPAO is usually prepared from a lyophilised, non-radioactive kit which contains HMPAO and stannous ion.","The function of the stannous ion is to reduce the 99mTc-pertechnetate (99mTcO4−), ie.","technetium in oxidation state Tc(VII), to the Tc(V) oxidation state of the 99mTc-HMPAO metal complex.","The radiochemical purity (Rcp) of 99mTc-HMPAO one hour after Tc-99m labelling is only about 80%, so that it must be used within 30 minutes of 99mTc labelling.","After Tc-99m radiolabelling, the Rcp of 99mTc-HMPAO decreases with time due to the growth of three different radioactive impurities, namely: a hydrophilic secondary 99mTc complex of unknown structure derived from 99mTc-HMPAO, 99mTc-pertechnetate (99mTcO4−) and reduced-hydrolysed-technetium [99mTc].","Of these impurities, both the secondary complex and 99mTc-pertechnetate are decomposition products of 99mTc-HMPAO; however, it is reported that the decomposition mechanisms are different (J. Nucl.","Med.","29, 1568-1576, 1988).","The secondary complex is believed to be produced when the lipophilic 99mTc-HMPAO complex is exposed to excess unoxidised tin(II) (ie.","stannous) remaining from the pertechnetate reduction step.","On the other hand, the 99mTc-pertechnetate impurity is produced when 99mTc-HMPAO and the secondary complex are oxidised by the free radicals produced in solution by the action of radiation, ie.","radiolysis of the solvent.","Accordingly, in order to inhibit the production of both the 99mTc-pertechnetate and secondary complex impurities, the addition of stabilisers has been disclosed.","Thus, Nucl.","Med.","Biol.","7, 675-680 (1989); Eur.","J. Nucl.","Med.","16, 541 (1990); Eur.","J. Nucl.","Med.","20, 661-666 (1993) and Eur.","J. Nucl.","Med.","22, 1163-1172 (1995) all report attempts to stabilise 99mTc-HMPAO by the addition of either: gentisic acid, sodium decahydroxypyrophosphate, methylene blue, cobalt chloride or the like.","In particular, the post-radiolabelling addition of methylene blue improves the Rcp of 99mTc-HMPAO to at least 80% at 4 hours post reconstitution.","Similarly, the post-radiolabelling addition of cobalt chloride has been found to improve the Rcp of 99mTc-HMPAO at 6 hours post reconstitution to at least 80%.","The stabilisation mechanisms of 99mTc-HMPAO by methylene blue and cobalt chloride are believed to be essentially the same.","Both are in redox equilibrium in solution, and oxidise excess tin(II), thus stabilising 99mTc-HMPAO.","However, when the reducing tin(II) and methylene blue or cobalt chloride coexist in solution before the Tc-99m radiolabelling step, the tin(II) reductant is completely oxidised, so that the Tc-99m labelling becomes impossible because there is no longer any reducing agent present to reduce the Tc(VII) 99mTc-blue or cobalt chloride is used as a stabiliser for 99mTc-HMPAO, it must be added after the Tc-99m radiolabelling step and cannot be pre-mixed with the ligand (HMPAO) and 99mTc-pertechnetate.","Accordingly, any kit for the preparation of 99mTc-HMPAO employing such stabilisers, must be composed of two vials (referred to hereinafter as a 2-vial kit).","One vial is a freeze-dried vial containing the HMPAO ligand together with the tin(II) reductant and other excipients.","The other is a vial containing the stabiliser (methylene blue or cobalt chloride).","Thus, the most successful prior art methods of stabilising 99mTc-HMPAO to date all require the use of 2-vial kits.","When the kit for preparing 99mTc-HMPAO is a 2-vial kit, the radiolabelling operation is more complicated than for a single vial kit and comprises two steps: (1) 99mTc-pertechnetate solution is added to the vial containing the HMPAO ligand and the resulting mixture is mixed by shaking; (2) a stabiliser solution from the second vial (eg.","methylene blue or cobalt chloride) is added to the reconstituted mixture from step (1) in the first vial.","It is necessary that the time between the first and second steps is controlled so as to be as close as possible to two minutes.","Too short a time, and 99mTc-HMPAO complex formation may be incomplete and hence addition of the stabiliser may adversely affect the Rcp by oxidising the stannous ion before the reduction of the pertechnetate starting material is complete.","Too long a time, and the stabilising effect is delayed.","In such a procedure it is also necessary that care be taken with respect to the amounts of the solutions added.","The operator must also take due care to ensure that the vials are not inadvertently mixed up at any stage.","In addition, there is an increased risk of radiation dose to the operator due to the increased number of manipulations.","Moreover, when methylene blue is added to 99mTc-HMPAO, a precipitate is produced, so that a filtration step becomes necessary, and thus the procedure becomes more complicated.","There is therefore a need for a single vial kit for the preparation of 99mTc-HMPAO which has both shelf-life and post-radiolabelling stability.","The present invention provides a kit which solves this problem, and is straightforward to use.","The Present Invention.","The present invention relates to a stabiliser for radiopharmaceuticals which comprises a combination of an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof, with a diphosphonic acid or a salt thereof with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid.","DETAILED DESCRIPTION OF THE INVENTION In a first aspect, the present invention provides: a stabilised radiopharmaceutical composition which comprises: (i) a radiopharmaceutical; (ii) an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof; (iii) a diphosphonic acid or salt thereof, is with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid.","By the term ‘amino-substituted aromatic carboxylic acid’ is meant a compound in which at least one hydrogen atom on the aromatic ring of an aromatic carboxylic acid is substituted with at least one amino group.","The aromatic group is preferably benzene.","Preferred amino-substituted aromatic carboxylic acids are: 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid (pABA), 3,5-diaminobenzoic acid and 4-aminosalicylic acid.","4-aminobenzoic acid (pABA) is especially preferred.","The salt of the amino-substituted aromatic carboxylic acid is suitably a salt with a biocompatible cation.","By the term “biocompatible cation” is meant a positively charged counterion which forms a salt with an ionised, negatively charged group (here a carboxylate group), where said positively charged counterion is also non-toxic and hence suitable for administration to the mammalian body, especially the human body.","Examples of suitable biocompatible cations include: the alkali metals (eg.","sodium or potassium); the alkaline earth metals (eg.","calcium, magnesium and barium); and the ammonium ion.","A preferred biocompatible cation is sodium.","Preferred salts of the present invention include: sodium 2-aminobenzoate, sodium 3-aminobenzoate, sodium 4-aminobenzoate (NapABA), sodium 3,5-diaminobenzoate, sodium 4-aminosalicylate, potassium 2-aminobenzoate, potassium 3-aminobenzoate, potassium 4-aminobenzoate, potassium 3,5-diaminobenzoate and potassium 4-aminosalicylate.","Sodium 4-aminobenzoate (NapABA) is especially preferred.","Suitable esters of the aromatic carboxylic acid include methyl, ethyl or propyl esters.","Preferred esters are: methyl 2-aminobenzoate, methyl 3-aminobenzoate, methyl 4-aminobenzoate, methyl 3,5-diaminobenzoate, methyl 4-aminosalicylate, ethyl 2-aminobenzoate, ethyl 3-aminobenzoate, ethyl 4-aminobenzoate, ethyl 3,5-diaminobenzoate, ethyl 4-aminosalicylate, propyl 2-aminobenzoate, propyl 3-aminobenzoate, propyl 4-aminobenzoate, propyl 3,5-diaminobenzoate and propyl 4-aminosalicylate.","Suitable amides of the amino-substituted aromatic carboxylic acid are amides formed by derivatising the carboxyl group of the aromatic carboxylic acid with either ammonia or a compound having at least one amino group, and include such compounds as 2-aminobenzamide, 3-aminobenzamide and 4-aminobenzamide.","The diphosphonic acid of the present invention is suitably a 1,1- or a 1,2-diphosphonic acid, or a diphosphonic acid derivative of an amine such as ethylenediaminetetraphosphonic acid (EDTMP).","1,1-diphosphonic acids are preferred, such as methylenediphosphonic acid (MDP), hydroxymethanediphosphonic acid (HMDP), hydroxyethanediphosphonic acid (HEDP).","Methylenediphosphonic acid (MDP) and hydroxymethanediphosphonic acid (HMDP) are especially preferred.","Suitable salts of the diphosphonic acid are with a ‘biocompatible cation’ as defined above.","Preferred such diphosphonate salts include: sodium methylenediphosphonate, sodium hydroxymethanediphosphonate, sodium hydroxyethanediphosphonate, sodium ethylenediamine-tetraphosphonate, ammonium methylenediphosphonate, ammonium hydroxymethanediphosphonate, ammonium hydroxyethanediphosphonate and ammonium ethylenediamine-tetraphosphonate.","The combination of compounds in the stabiliser for radiopharmaceuticals of the present invention is preferably a combination of sodium 4-aminobenzoate (NapABA) with methylenediphosphonic acid (MDP) or hydroxymethanediphosphonic acid (HMDP).","Without wishing to be bound by theory, it is believed that the stabilisers of the present invention act as follows: The amino-substituted aromatic carboxylic acid or its salt, ester or amide has a reducing ability and removes any oxidising free radicals which result from the radiolysis of the solution, and hence inhibits the oxidative destruction of the radiopharmaceutical by free radical attack.","On the other hand, when excess tin(II) reductant remains after completion of the radiolabelling, the diphosphonic acid or its salt inhibits the excess stannous ion from reductively degrading the radiopharmaceutical.","It is a surprising finding of the present invention that such stabilisers can be present in a single step radiopharmaceutical preparation without either: (i) preventing or hindering the stannous reduction of the radiopharmaceutical precursor, with consequent adverse effect on Rcp; (ii) complexing with the radiometal to form undesirable radioactive impurities (eg.","diphosphonic acid complexes of the radionuclide).","Accordingly, the amount of the diphosphonic acid or its salt to be added to the radiopharmaceutical depends upon the amount of the reducing tin(II) contained in the radiopharmaceutical preparation or kit.","The amount of the diphosphonic acid or its salt effective to stabilise the radiopharmaceutical is 1 to 10 moles per mole of stannous, preferably 2 to 8 moles per mole of stannous, most preferably 4 to 6 moles per mole of stannous.","The radionuclide of the radiopharmaceutical of the present invention is a γ-ray or β-ray emitter, preferably Tc-99m, Re-186 or Re-188, most preferably Tc-99m.","γ-ray emitters are mainly used for radiodiagnosis and β-ray emitters are mainly used for radiotherapy.","When a radiodiagnostic radiopharmaceutical of this invention is intracorporeally administered to a human being, the level of radioactivity used is in the range of from 370 to 1,480 MBq, preferably from 370 to 1,110 MBq.","When a radiotherapeutic agent of the radiopharmaceuticals of this invention is intracorporeally administered to a human being, the radioactivity level is in the range of from 37 to 18,500 MBq, preferably from 370 to 7,400 MBq.","The radiopharmaceutical comprises an active ingredient which is susceptible to either degradation by the reducing action of the reductant (present to help effect labelling of the radionuclide), or radiolysis.","By using the stabiliser composition of the present invention to stabilise such active ingredients, it is possible to prolong the useful lifetime post-radiolabelling to at least twice that of the prior art.","The stabilisers of the present invention are particularly useful when the active ingredient comprises a ligand having a tetradentate diaminedioxime donor set, especially d,l-hexamethylpropyleneamine oxime or HMPAO (exametazime), 4,9-diaza-3,3,10,10-tetramethyldodecane-2,11-dione dioxime (PnAO), and similar compounds.","In a second aspect, the present invention provides a non-radioactive kit for the preparation of the stabilised radiopharmaceutical composition described above which comprises: (i) an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof; (ii) a diphosphonic acid or salt thereof, with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid.","Thus, the stabiliser for radiopharmaceuticals of the present invention can be pre-mixed with the ligand prior to radiolabelling, so that the formulation of a single vial, non-radioactive kit for the preparation of a stabilised radiopharmaceutical (which is not a radionuclide complex of the diphosphonic acid stabilizer) is possible.","This simplifies the labelling procedure of the prior art 2-vial kit, shortens the labelling time and diminishes the risk of operator exposure to harmful radiation.","The single vial kit of the present invention also has an extended stability post radioactive preparation, which in turn extends the useful lifetime for the user of the kit, eg.","a clinician.","Suitable non-radioactive kits of the present invention comprise 0.01 to 10 mg of an amino-substituted aromatic carboxylic acid or its salt, ester or amide, and 0.01 to 1 mg of a diphosphonic acid or its salt.","When the kit contains stannous, the amount of the diphosphonic acid or its salt effective to stabilise is 1 to 10 moles per mole of stannous.","Preferably, the ratio of diphosphonic acid or its salt is 2 to 8 moles per mole of stannous, most preferably 4 to 6 moles per mole of stannous.","In a third aspect, the present invention discloses the use of a diphosphonic acid or a salt thereof as a stabiliser for radiopharmaceuticals, with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid suitable diphosphonic acid salts are those with a biocompatible cation as described above.","Preferably the radiopharmaceutical also comprises stannous in the formulation.","Most preferably, the radiopharmaceutical comprises 99mTc.","Preferably, the diphosphonic acid or salt thereof used as a stabiliser is methylenediphosphonic acid (MDP), hydroxymethanediphosphonic acid (HMDP), hydroxyethanediphosphonic acid (HEDP), ethylenediaminetetraphosphonic acid (EDTMP), and salts thereof.","In a fourth aspect, the present invention discloses the use of a diphosphonic acid or a salt thereof as a stabiliser for non-radioactive kits for the preparation of radiopharmaceuticals, with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid.","Suitable diphosphonic acid salts are those with a biocompatible cation as described above.","Preferably the non-radioactive kit further comprises stannous in the formulation.","Most preferably, the non-radioactive kit is for the preparation of a 99mTc radiopharmaceutical.","Preferably, the diphosphonic acid or salt thereof used as a stabiliser is methylenediphosphonic acid (MDP), hydroxymethanediphosphonic acid (HMDP), hydroxyethanediphosphonic acid (HEDP), ethylenediaminetetraphosphonic acid (EDTMP), and salts thereof.","DESCRIPTION OF THE DRAWINGS FIG.","1 compares the change in Rcp of 99mTc-HMPAO prepared from Composition III, Composition III+lactose and a commercially available kit for preparing 99mTc-HMPAO, each of which had been stored for 6 months prior to reconstitution.","The present invention is explained in more detail with reference to the following Examples: Example 1 is a comparative example for a two step process (including prior art stabilisers such as cobalt chloride).","An Rcp of 99mTc-HMPAO of at least 80% 3 hours after the addition is judged as effective stabilisation.","However, as is clear from Table 1, the only single stabiliser which meets this criterion is cobalt chloride.","Example 2 shows that 99mTc-HMPAO can be effectively stabilised in a single-step process, using a mixture of two compounds as stabilisers, and that the stability is significantly increased over that achieved using the 2-step process of Example 1.Example 3 provides further data on optimising the combinations of MDP/NapABA and HMDP/NapABA in a single step process.","The molar ratio of Sn2+ to MDP/HMDP was kept constant (1:5), and the amounts added were varied.","Example 4 shows that lyophilised non-radioactive kits for the preparation of 99mTc radiopharmaceuticals can be prepared using the compositions of the present invention.","Lactose (a known cryoprotectant excipient in freeze-dried formulations), is shown to be useful to preserve stannous levels for extended shelf-life periods.","Example 5 shows that the combination HMDP/NapABA is also effective as a stabiliser for 99mTc-HMPAO.","Example 6 provides data on the stannous or tin(II) content of the freeze-dried kits, as a function of shelf-life storage in the dark at 4° C., and shows that the amount of reducing tin(II) in Composition III+lactose is higher than that in Composition III.","Moreover, the amount of the reducing tin(II) in Composition III shows some tendency to decrease with increasing storage time.","Accordingly, when the freeze-dried kit is stored for a prolonged period of time, lactose may be used in the kit composition to maintain the amount of the tin(II) reductant constant.","Example 7 compares the Rcp after 6-months storage of the freeze-dried kits of the present invention, with the Rcp for 99mTc-HMPAO prepared from a commercially available kit.","The Rcp decreases as a function of time post-reconstitution for the commercial kit, but for Composition III and Composition III+lactose, the Rcp's at 6 hours post-reconstitution were at least 80%.","This shows that, whilst the stannous levels without lactose do show some modest decrease (Example 5), the decrease does not impair the performance of the kit.","Example 8 shows that freeze-dried kits containing the stabiliser composition HMDP/NapABA have an effective shelf-life.","Example 9 compares the biodistribution in rats of 99mTc-HMPAO prepared using kit Composition III and kit Composition III+lactose of the present invention, with a commercial 99mTc-HMPAO kit preparation.","No significant difference in uptake in target organs was found.","This includes the brain, which is the diagnostic imaging application of the present commercial 99mTc-HMPAO agent.","These results show that the added compounds (MDP, NapABA and lactose), which are not present in the commercially available kit, do not adversely affect the biological behaviour of the 99mTc radiopharmaceutical.","Example 10 describes various lyophilisation methods suitable for freeze-dried kit preparation of formulations of the present invention.","Example 11 compares the Rcp of the various freeze-dried kits of Example 10.Example 1 The Rcp of 99mTc-HMPAO Using a Single Stabiliser: Two Step Process (Comparative Example) The radiochemical purity (Rcp) of 99mTc-HMPAO prepared using a commercially available kit (CERETEC™) for preparing 99mTc-HMPAO is 80% at one hour post-reconstitution, and the Rcp decreases thereafter with time.","On the other hand, in the case of 99mTc-HMPAO stabilised with cobalt chloride, the Rcp 6 hours after radiolabelling is 80%.","The following known medically acceptable compounds and additives were studied: ascorbic acid, sodium ascorbate, gentisic acid, gentisic acid ethanolamide, methylenediphosphonic acid (MDP), succinic acid, 4-aminobenzoic acid (pABA) and sodium 4-aminobenzoate (NapABA).","To each of ten vials each containing 0.5 mg of HMPAO and 4.0 μg of Sn2+ (stannous), was added sodium pertechnetate (1.48 GBq in 5 ml of saline) to carry out the radiolabelling.","To each of 9 of the ten reconstituted vials was individually added the compound shown in Table 1 at a time of 2 minutes post-radiolabelling.","Nothing was added to the remaining vial.","At 1 minute and 3 hours after the addition, an aliquot was taken from each vial and the Rcp measured by a combination of three chromatographic systems (stationary phase/developing solvent: silica gel/methyl ethyl ketone, silica gel/saline, filter paper/50% aqueous acetonitrile).","The results are given in Table 1: TABLE 1 Radiochemical purity (Rcp) of 99mTc-HMPAO after the addition of a single stabiliser (%, n = 3).","Name of Additive Rcp 1 min from Rcp 3 hours from (amount) addition (%) addition (%) No additive 87 ± 4 38 ± 15 Cobalt chloride 94 ± 3 89 ± 2 (200 μg) Ascorbic acid 83* 41* (4.5 μg) Sodium ascorbate 90* 51* (10 mg) Gentisic acid 87 ± 2 77 ± 3 30 μg) Gentisic acid ethanolamide 61 ± 3 29 ± 13 (30 μg) Methylene diphosphonic acid 79* 30* (10 μg) 4-Aminobenzoic acid 80 ± 8 67 ± 5 (30 μg) Sodium4-amino-benzoate 69 ± 5 39 ± 11 (30 μg) Succinic acid 51* 14* (30 μg) Note: *n = 1 Example 2 Examination of Stabilisation of 99mTc-HMPAO by a Combination of Two Compounds: Single Step Process The combinations studied were: (i) ascorbic acid and hydroxymethanediphosphonic acid (HMDP); (ii) sodium 4-aminobenzoate (NapABA) and methylenediphosphonic acid (MDP).","A composition comprising 0.5 mg of HMPAO, 4.0 μg of Sn2+, 1.0 μg of HMDP and 0.5 μg of ascorbic acid (Composition A), and a composition comprising 0.5 mg of HMPAO, 5.4 μg of Sn2+, 40.5 μg of MDP and 0.5 mg of NapABA (Composition B) were prepared.","To each of A and B was added sodium pertechnetate (1.48 GBq in 5 ml) to carry out the labelling.","After 3 hours, an aliquot was taken from each, and the Rcp measured by a combination of three chromatographic systems (stationary phase/developing solvent: silica gel/methyl ethyl ketone, silica gel/saline, filter paper/50% aqueous acetonitrile).","The Rcp of 99mTc-HMPAO 3 hours after Tc-99m labelling was about 62% in the case of Composition A and about 80% in the case of Composition B.","Example 3 Optimisation of Stabiliser Composition: Single Step Process As shown in Table 2, six different sample compositions were prepared and stored in the dark at 4° C. One vial of each formulation was taken out at each time point (1, 7, 31 and 32-days storage), and sodium pertechnetate (1.48 GBq in 5 ml) was added.","At 6 hours post addition of pertechnetate, an aliquot was taken from each vial and the Rcp measured by a combination of three chromatographic systems (stationary phase/developing solvent: silica gel/methyl ethyl ketone, silica gel/saline, filter paper/50% aqueous acetonitrile).","The results are shown in Table 2: TABLE 2 Sample Compositions and Rcp of 99mTc-HMPAO 6 hours post-radiolabelling (n = 1, *n = 3).","Composition I II III IV V VI Preparation HMPAO 0.5 0.5 0.5 0.5 0.5 0.5 Conditions (mg) NapABA 0.5 0.1 0.1 0.1 0.5 — Sn2+ 5.4 5.4 8.1 8.1 8.1 8.1 (μg) MDP 40.5 40.5 61.0 61.0 — — (μg) HMPD — — — — 66.0 66.0 (μg) Rcp (%) - 1 day 86.4 79.5 82.2 73.8 84.8 ± 2.7* 77.3 ± 5.5* after storage 7 days 80.8 80.9 82.1 81.1 — — time 32 days 79.0 81.8 84.3 66.5 — — 31 days — — — — 83.5 ± 2.2* 72.0 ± 0.2* Note: *n = 3.Compositions II, III and V show that, even in the case of samples stored for 32 days in the dark at 4° C., the Rcp at 6 hours post-reconstitution was at least 80%.","Compositions III and V, which exhibited a higher Rcp, 5 were therefore used as the basis for subsequent tests.","Example 4 Stabilisation of 99mTc-HMPAO by a Combination of MDP and NapABA: Single Step Process using a Freeze-Dried Kit Composition III of Example 3, and a composition prepared by adding lactose to Composition III (referred to hereinafter as Composition III+lactose) were used to prepare four lots of freeze-dried kit in each case.","The amounts of compounds shown below correspond to the scale for a production batch of about 100 freeze-dried kit vials.","First, anhydrous stannous chloride (25.8 mg) and MDP (122 mg) were dissolved in 0.1 M hydrochloric acid (1,000 ml).","The resulting solution is referred to hereinafter as Solution 1.d,l-HMPAO (100 mg) and NapABA (100 mg) were dissolved in Solution 1 (100 ml), to give a solution referred to hereinafter as Solution 2.Solution 2 was divided into two 50 ml portions, one of which was adjusted to a pH of 8.5-9.0 with sodium hydroxide and thereafter the total volume was adjusted to 10.0 ml with water by use of a measuring cylinder.","In the other 50 ml portion was dissolved 300 mg of lactose monohydrate, the resulting solution was adjusted to a pH of 8.5 to 9.0 with sodium hydroxide, and thereafter, the total volume was adjusted to 100 ml with water by use of a measuring cylinder.","1.0 ml of each of the solutions obtained was placed in each vial, which was then frozen at −50 to −78° C. and then freeze-dried for about 24 hours.","After completion of the freeze-drying, the vials were sealed and the freeze-dried kit was stored in the dark at 4° C. The same procedure was repeated four times to prepare four separate lots of each of, Composition III and Composition III+lactose.","Lot Nos.","ID-01 to ID-04 were of Composition III and Lot Nos.","ID-05 to ID-08 were of Composition III+lactose.","The production conditions and results of each lot are shown in Table 3.TABLE 3 Production conditions and results of each lot Freezing Number of pH before temperature Vials Lot No.","freezing (° C.) Produced Property# ID-01 9.0 −50 99 Fair ID-02 9.0 −78 90 Bad ID-03 8.5 −78 39 Bad ID-04 9.0 −50 99 Fair ID-05 9.0 −50 91 Good ID-06 9.0 −78 92 Good ID-07 8.5 −78 94 Good ID-08 8.5 −50 91 Good #where ’property' refers to the behaviour during lyophilisation: Good = the cake in the freeze-dried kits kept well-formed; Fair = the cake in the freeze-dried kits was partly broken, but there was no loss of powder from the vials during lyophilisation; Bad = the cake in the freeze-dried kits was completely broken, and some of the powder was lost from the vials during lyophilisation.","In all the lots other than ID-03 (which is of Composition III), at least 90 vials were produced.","Among the four lots of Composition III, only ID-03 was adjusted to a pH of 8.5 before freezing.","Moreover, in the case of Composition III+lactose, even when the pH was adjusted to 8.5 before freezing (ID-07, ID-08), at least 90 vials could be produced.","Accordingly, when a freeze-dried kit is produced, it is desirable to adjust the pH to 9.0 in the case of lactose-free Composition III.","Example 5 Stabilisation of 99mTc-HMPAO by a Combination of HMDP and NapABA: Single Step Process using a Freeze-Dried Kit Composition V of Example 3, and a composition prepared by adding lactose to Composition V (referred to hereinafter as Composition V+lactose) were used to prepare one lot of freeze-dried kits in each case.","The freeze-dried kits were prepared in much the same manner as that of Example 4, except that Solution 1 was slightly different—in this case anhydrous stannous chloride (25.8 mg) and HMDP-2Na (132.0 mg) were dissolved in 0.1M hydrochloric acid (1,000 mL).","Lot Nos.","ID-09 was of Composition V and Lot Nos.","ID-10 was of Composition V+lactose.","The production conditions and results of each lot are shown in Table 4.TABLE 4 Production conditions and results of each lot.","Freezing Number of pH before Temperature Vials freezing (° C.) Produced Property# ID-09 8.8 −50° C. 49 Fair ID-10 8.8 −50° C. 45 Good #defined in Example 4.Example 6 Determination of the Amount of tin(II) in the Freeze-Dried Kit as a Function of Storage Time Vials of Composition III (ID-01, O2, 03 and 04), Composition III+lactose (ID-05, 06, 07 and 08), Composition V (ID-09) and Composition V+lactose (ID-10) which had been stored in the dark at 4° C. for periods of 1 day, 3-months and 6-months, were allowed to warm to room temperature.","The amount of tin(II) was then determined by an absorbance method.","The results obtained are shown in Table 5.TABLE 5 Amounts of reducing tin(II) determined (μg/vial, n = 2).","1-day storage 3-month storage 6-month storage Composition III 9.5 ± 0.2 9.1 ± 0.5 8.7 ± 0.5 Composition III + 10.3 ± 0.5 10.5 ± 0.5 10.8 ± 0.4 lactose Composition V 10.1 ± 0.0 — — Composition V + 10.3 ± 0.3 — — lactose Note Each value was an average value of 4 lots.","Example 7 Radiochemical Purity of Freeze-Dried Kits Containing MDP and NapABA Studied over a 6-Month Shelf-Life Storage Period Four lots of each of Composition III and Composition III+lactose produced in Example 4 were subjected to examination of radiochemical purity after 6 -months storage in the dark at 4° C. Vials of freeze-dried Composition III (ID-01, O2, 03 and 04) and Composition III+lactose (ID-OS, 06, 07 and 08) were stored for 6 months in the dark at 4° C. After a storage period of 1 day, 1, 3 and 6 months, the vials were allowed to warm to room temperature, and Tc-99m labelling was carried out.","Thus, to one vial of each lot was added sodium pertechnetate (1.48 GBq in 5 ml).","Aliquots were taken after times of 2 minutes, one hour, 3 hours and 6 hours and the Rcp was measured by a combination of three chromatographic systems (stationary phase/developing solvent: silica gel/methyl ethyl ketone, silica gel/saline and filter paper/50% aqueous acetonitrile).","The results obtained at 6 hours are shown in Table 6.When Composition III and Composition III+lactose were radiolabelled after 6-month shelf-life storage, simultaneously, sodium pertechnetate (1.48 GBq/5 ml) was added to a commercially available kit for preparing 99mTc-HMPAO (containing 0.5 mg of HMPAO and 4.0 μg of Sn2+) as a control.","An aliquot thereof was taken after times of one minute, one hour, 3 hours and 6 hours, and then the Rcp was measured in the same manner.","The results obtained are shown in FIG.","1.TABLE 6 Rcp of 99mTc-HMPAO at 6 hr post reconstitution by a combination of MDP and NapABA as a function of storage time.","STORAGE PERIOD 1-day 1-month 3-months 6-months Rcp Composition III 86.4 ± 2.2 87.4 ± 1.5 86.5± 2.7 88.4 ± 3.4 (%) Composition III + 86.2 ± 2.3 86.2 ± 2.4 87.9 ± 2.6 85.6 ± 2.7 Lactose Example 8 Radiochemical Purity of Freeze-Dried Kits Containing HMDP and NapABA for 1-Month Shelf-Life Storage One lot of each of Composition V and Composition V+lactose produced in Example 5 were subjected to examination of radiochemical purity for 1-month storage in the dark at 4° C. The Rcp was measured in the same manner.","The results obtained are shown in Table 7.TABLE 7 Rcp of 99mTc-HMPAO at 6 hr post-reconstitution stabilised by a combination of HMDP and NapABA as a function of storage time.","Storage Time 1-day 1-month Rcp Composition V 84.8 ± 2.7 83.5 ± 2.2 (%) Composition V + 87.3 ± 2.8 86.0 ± 1.0 Lactose Example 9 Biodistribution in the Rat To one vial of each of Composition III (ID-O2) and Composition III+lactose (ID-06) obtained in Example 4 was added sodium pertechnetate in a proportion of 1.48 GBq/5 ml to carry out the radiolabelling.","After 2 hours, 3.0 to 3.7 MBq of the reconstituted solution was administered to a female Sprague-Dawley strain rat (body weight 140-170 g) which had been previously anaesthetised with sodium thiopentobarbital in the tail vein.","At one hour post-administration, the animal was sacrificed and the radioactivity in each organ was measured using a NaI single channel analyser.","Separately, sodium pertechnetate was added in a proportion of 1.48 GBq/5 ml to the commercially available kit for preparing 99mTc-HMPAO.","In the same manner, at 15 minutes post-reconstitution, 3.0-3.7 MBq of the solution was administered to the same kind of rat, and the biodistribution of radioactivity in each organ measured.","The results obtained are shown in Table 8: TABLE 8 Biodistribution of Commercial 99mTc-HMPAO, Composition III (ID-02) and Composition III + lactose (ID-06) in the female rat at one hour post administration (upper row: % ID/organ, lower row: % ID/g, n = 5).","Composition III + Commercial Composition lactose 99mTc-HMPAO III (ID-02) (ID-06) Brain 1.66 ± 0.13 1.65 ± 0.10 1.73 ± 0.15 0.96 ± 0.07 0.96 ± 0.15 1.01 ± 0.07 Blood 15.38 ± 0.72 14.41 ± 1.68 14.07 ± 1.51 1.56 ± 0.04 1.64 ± 0.06 1.45 ± 0.18 Heart 0.81 ± 0.04 0.85 ± 0.03 0.90 ± 0.10 1.61 ± 0.08 1.75 ± 0.10 1.72 ± 0.03 Lung 3.41 ± 0.20 3.15 ± 0.18 3.39 ± 0.38 4.05 ± 0.28 4.26 ± 0.29 4.14 ± 0.36 Liver 5.91 ± 0.20 6.49 ± 0.48 7.68 ± 0.38 1.10 ± 0.07 1.36 ± 0.13 1.44 ± 0.14 Spleen 0.78 ± 0.10 0.79 ± 0.18 0.86 ± 0.12 2.17 ± 0.12 2.24 ± 0.12 2.25 ± 0.21 Kidney 4.27 ± 0.27 5.04 ± 0.48 4.81 ± 0.31 4.39 ± 0.16 4.78 ± 0.64 4.46 ± 0.21 Stomach 1.41 ± 0.54 2.15 ± 0.46 1.70 ± 0.79 0.49 ± 0.17 1.24 ± 0.43 0.93 ± 0.54 Small 17.27 ± 0.85 17.61 ± 0.87 20.23 ± 1.50 Intestine 2.86 ± 0.17 3.47 ± 0.33 3.94 ± 0.46 Large 2.08 ± 0.25 2.14 ± 0.34 2.05 ± 0.24 Intestine 0.35 ± 0.03 0.40 ± 0.04 0.34 ± 0.03 Skin 0.78 ± 0.61 0.68 ± 0.55 0.51 ± 0.34 0.39 ± 0.04 0.37 ± 0.09 0.31 ± 0.09 Muscle 0.91 ± 0.49 0.67 ± 0.41 0.49 ± 0.21 0.28 ± 0.03 0.29 ± 0.03 0.16 ± 0.02 Urine 12.36 ± 1.18 11.78 ± 2.18 12.07 ± 1.11 Carcass 36.96 ± 0.83 37.76 ± 2.18 33.95 ± 1.37 0.34 ± 0.02 0.37 ± 0.02 0.31 ± 0.01 Example 10 Methods of Freeze-Dried Kit Preparation The freeze-dried kit (Composition V+lactose of Example 5) was prepared by two methods.","The first method (ID-11) was similar to that of Example 5, but with a modified Solution 2—thus, d,l-HMPAO (250 mg),NapABA (250 mg) and lactose monohydrate (1.5 g) were dissolved in Solution 1 (250 mL).","The solution was added to water (250 mL) and adjusted to pH 8.9.The production conditions and results for ID-11 are shown in Table 9.The second method (ID-12) is described below.","Thus, lactose monohydrate (3.03 g), NapABA (505 mg), d,l-HMPAO (505 mg), HMDP (66.6 mg) and anhydrous stannous chloride (13.1 mg) were dissolved in 0.1M hydrochloric acid (1000 mL) in the order given.","The solution was then adjusted to pH 9.4.The production conditions and results for ID-12 are shown in Table 9.TABLE 9 Production conditions and results of each lot Freezing Number pH before Temperature of Vials freezing ° ( C.) Produced Property# ID-11 8.9 −40° C. 290 Good ID-12 9.4 −40° C. 240 Good #as defined in Example 4.Example 11 RCP of Freeze-Dried Kits Prepared by Different Methods The freeze-dried kits in Example 10 were used to examine the RCP.","The RCP was measured in the same manner as in Example 7.The results obtained are shown in Table 10.TABLE 10 Rcp of 99mTc-HMPAO at the time after reconstitution 2 min 1 hour 3 hours 6 hours ID-11 90.2 ± 0.4 89.3 ± 1.8 85.9 ± 1.7 85.7 ± 1.7 ID-12 87.1 ± 2.1 81.4 ± 2.4 70.6 ± 1.7 60.7 ± 4.0"]],"string":"[\n [\n \"Stabiliser for radiopharmaceuticals\",\n \"The present invention provides an improved stabiliser for radiopharmaceuticals which inhibits impurities from being produced by two kinds of decomposition mechanisms and exhibits such an effect that the shelf life of a radiopharmaceutical after its preparation is prolonged as compared with conventional ones.\",\n \"The improvement comprises a combination of an amino-substituted aromatic carboxylic acid or its salt, ester or amide in combination with a diphosphonic acid or its salt.\"\n ],\n [\n \"1.A stabilised radiopharmaceutical composition which comprises: (i) a radiopharmaceutical which is susceptible to either reductive degradation or radiolysis; (ii) a first stabiliser for said radiopharmaceutical which includes an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof; (iii) a second stabiliser for said radiopharmaceutical which includes a diphosphonic acid or salt thereof, wherein the radiopharmaceutical is not a metal complex of the diphosphonic acid.\",\n \"2.The composition of claim 1 wherein the amino-ubstituted aromatic carboxylic acid or its salt, ester or amide is selected from the group consisting of 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 3, 5-diaminobenzoic acid, 4-amino-salicylic acid, and salts, esters and amides thereof.\",\n \"3.The composition of claim 1, wherein the diphosphonic acid or its salt is selected from the group consisting of methylenediphosphonic acid, hydroxymethanediphosphonic acid, hydroxyethanediphosphonic acid, ethylenediaminetetraphosphonic acid, and salts thereof.\",\n \"4.The composition of claim 1, wherein the amino-substituted aromatic carboxylic acid or salt, ester or amide thereof is sodium 4-aminobenzoate, and the diphosphonic acid is methylenediphosphonic acid.\",\n \"5.The composition of claim 1, wherein the radiopharmaceutical includes a γ-ray emitter or a β-ray emitter.\",\n \"6.The composition of claim 5, wherein the radiopharmaceutical includes Tc-99m, Re-186 or Re-188.7.The composition of claim 1, wherein the radiopharmaceutical includes a metal complex of a radionuclide with a ligand.\",\n \"8.The composition of claim 7, wherein the ligand is an amine oxime.\",\n \"9.The composition of claim 8, wherein the amine oxime is selected from the group consisting of d,l-hexamethylpropyleneamine oxime and 4,9-diaza-3, 3, 10, 10-tetramethyldodecane-2, 11-dione dioxime.\",\n \"10.A non-radioactive kit for the preparation of the stabilised radiopharmaceutical composition of claim 1 which comprises: (i) a first stabiliser which comprises an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof; and (ii) a second stabiliser which comprises a diphosphonic acid or salt thereof, wherein the radiopharmaceutical is not a metal complex of the diphosphonic acid.\",\n \"11.The kit of claim 10, which includes 0.01 to 10 mg of an amino-substituted aromatic carboxylic acid or its salt, ester or amide, and 0.01 to 1 mg of a diphosphonic acid or its salt.\",\n \"12.The kit of claim 10, further comprising a tin (II) reductant, wherein the molar ratio of the diphosphonic acid or its salt to tin (II) is in the range 1 to 10.13.The kit of claim 10, further comprising an amine oxime ligand.\",\n \"14.The kit of claim 13 wherein the amine oxime is selected from the group consisting of d, l-hexamethylpropyleneamine oxime and 4,9-diaza-3, 3, 10, 10-tetramethyldodecane-2, 11-dione dioxime.\",\n \"15.The kit of claim 10, wherein the first and second stabilzers are lyophilised.\",\n \"16.In a method of preparing a radiopharmaceutical composition which includes adding stabilizers to a radiopharmaceutical, wherein the radiopharmaceutical is not a metal complex of diphosphonic acid, the improvement comprising using a diphosphonic acid or a salt thereof as a stabiliser.\",\n \"17.Cancelled 18.The method of claim 16, wherein the radiopharmaceutical comprises Tc-99m.\",\n \"19.The method of claim 16, wherein the diphosphonic acid is selected from the group consisting of methylenediphosphonic acid, hydroxymethanediphosphonic acid, hydroxyethanediphosphonic acid, ethylenediaminetetraphosphonic acid, and salts thereof.\"\n ],\n [\n \"<SOH> BACKGROUND TO THE INVENTION <EOH>Some radiopharmaceuticals undergo decomposition due to either radiolysis or redox reactions, and hence exhibit undesirable instability.\",\n \"Non-radioactive kits for the preparation of radiopharmaceuticals, especially Tc-99m radiopharmaceuticals, may suffer from two types of instability: (i) shelf-life instability of the non-radioactive composition over time, (ii) instability of the radiopharmaceutical post-formation.\",\n \"In the case of Tc-99m, the latter is referred to as post-reconstitution instability.\",\n \"U.S. Pat.\",\n \"No.\",\n \"4,451,451 discloses that para-aminobenzoic acid (pABA) and analogues are useful stabilisers for technetium non-radioactive kits, including kits for the preparation of 99m Tc-complexes of diphosphonic acids.\",\n \"Tc-99m-hexamethylpropyleneamine oxime (referred to hereinafter as 99m Tc-HMPAO), is a radiopharmaceutical commercially available as a regional cerebral blood flow imaging agent.\",\n \"99m Tc-HMPAO is particularly unstable with respect to post-reconstitution stability.\",\n \"99m Tc-HMPAO is usually prepared from a lyophilised, non-radioactive kit which contains HMPAO and stannous ion.\",\n \"The function of the stannous ion is to reduce the 99m Tc-pertechnetate ( 99m TcO 4 − ), ie.\",\n \"technetium in oxidation state Tc(VII), to the Tc(V) oxidation state of the 99m Tc-HMPAO metal complex.\",\n \"The radiochemical purity (Rcp) of 99m Tc-HMPAO one hour after Tc-99m labelling is only about 80%, so that it must be used within 30 minutes of 99m Tc labelling.\",\n \"After Tc-99m radiolabelling, the Rcp of 99m Tc-HMPAO decreases with time due to the growth of three different radioactive impurities, namely: a hydrophilic secondary 99m Tc complex of unknown structure derived from 99m Tc-HMPAO, 99m Tc-pertechnetate ( 99m TcO 4 − ) and reduced-hydrolysed-technetium [ 99m Tc].\",\n \"Of these impurities, both the secondary complex and 99m Tc-pertechnetate are decomposition products of 99m Tc-HMPAO; however, it is reported that the decomposition mechanisms are different (J. Nucl.\",\n \"Med.\",\n \"29, 1568-1576, 1988).\",\n \"The secondary complex is believed to be produced when the lipophilic 99m Tc-HMPAO complex is exposed to excess unoxidised tin(II) (ie.\",\n \"stannous) remaining from the pertechnetate reduction step.\",\n \"On the other hand, the 99m Tc-pertechnetate impurity is produced when 99m Tc-HMPAO and the secondary complex are oxidised by the free radicals produced in solution by the action of radiation, ie.\",\n \"radiolysis of the solvent.\",\n \"Accordingly, in order to inhibit the production of both the 99m Tc-pertechnetate and secondary complex impurities, the addition of stabilisers has been disclosed.\",\n \"Thus, Nucl.\",\n \"Med.\",\n \"Biol.\",\n \"7, 675-680 (1989); Eur.\",\n \"J. Nucl.\",\n \"Med.\",\n \"16, 541 (1990); Eur.\",\n \"J. Nucl.\",\n \"Med.\",\n \"20, 661-666 (1993) and Eur.\",\n \"J. Nucl.\",\n \"Med.\",\n \"22, 1163-1172 (1995) all report attempts to stabilise 99m Tc-HMPAO by the addition of either: gentisic acid, sodium decahydroxypyrophosphate, methylene blue, cobalt chloride or the like.\",\n \"In particular, the post-radiolabelling addition of methylene blue improves the Rcp of 99m Tc-HMPAO to at least 80% at 4 hours post reconstitution.\",\n \"Similarly, the post-radiolabelling addition of cobalt chloride has been found to improve the Rcp of 99m Tc-HMPAO at 6 hours post reconstitution to at least 80%.\",\n \"The stabilisation mechanisms of 99m Tc-HMPAO by methylene blue and cobalt chloride are believed to be essentially the same.\",\n \"Both are in redox equilibrium in solution, and oxidise excess tin(II), thus stabilising 99m Tc-HMPAO.\",\n \"However, when the reducing tin(II) and methylene blue or cobalt chloride coexist in solution before the Tc-99m radiolabelling step, the tin(II) reductant is completely oxidised, so that the Tc-99m labelling becomes impossible because there is no longer any reducing agent present to reduce the Tc(VII) 99m Tc-blue or cobalt chloride is used as a stabiliser for 99m Tc-HMPAO, it must be added after the Tc-99m radiolabelling step and cannot be pre-mixed with the ligand (HMPAO) and 99m Tc-pertechnetate.\",\n \"Accordingly, any kit for the preparation of 99m Tc-HMPAO employing such stabilisers, must be composed of two vials (referred to hereinafter as a 2-vial kit).\",\n \"One vial is a freeze-dried vial containing the HMPAO ligand together with the tin(II) reductant and other excipients.\",\n \"The other is a vial containing the stabiliser (methylene blue or cobalt chloride).\",\n \"Thus, the most successful prior art methods of stabilising 99m Tc-HMPAO to date all require the use of 2-vial kits.\",\n \"When the kit for preparing 99m Tc-HMPAO is a 2-vial kit, the radiolabelling operation is more complicated than for a single vial kit and comprises two steps: (1) 99m Tc-pertechnetate solution is added to the vial containing the HMPAO ligand and the resulting mixture is mixed by shaking; (2) a stabiliser solution from the second vial (eg.\",\n \"methylene blue or cobalt chloride) is added to the reconstituted mixture from step (1) in the first vial.\",\n \"It is necessary that the time between the first and second steps is controlled so as to be as close as possible to two minutes.\",\n \"Too short a time, and 99m Tc-HMPAO complex formation may be incomplete and hence addition of the stabiliser may adversely affect the Rcp by oxidising the stannous ion before the reduction of the pertechnetate starting material is complete.\",\n \"Too long a time, and the stabilising effect is delayed.\",\n \"In such a procedure it is also necessary that care be taken with respect to the amounts of the solutions added.\",\n \"The operator must also take due care to ensure that the vials are not inadvertently mixed up at any stage.\",\n \"In addition, there is an increased risk of radiation dose to the operator due to the increased number of manipulations.\",\n \"Moreover, when methylene blue is added to 99m Tc-HMPAO, a precipitate is produced, so that a filtration step becomes necessary, and thus the procedure becomes more complicated.\",\n \"There is therefore a need for a single vial kit for the preparation of 99m Tc-HMPAO which has both shelf-life and post-radiolabelling stability.\",\n \"The present invention provides a kit which solves this problem, and is straightforward to use.\",\n \"The Present Invention.\",\n \"The present invention relates to a stabiliser for radiopharmaceuticals which comprises a combination of an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof, with a diphosphonic acid or a salt thereof with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid.\"\n ],\n [\n \"FIELD OF THE INVENTION The present invention relates to a stabilised radiopharmaceutical composition, together with non-radioactive kits for the preparation of the stabilised radiopharmaceutical composition.\",\n \"BACKGROUND TO THE INVENTION Some radiopharmaceuticals undergo decomposition due to either radiolysis or redox reactions, and hence exhibit undesirable instability.\",\n \"Non-radioactive kits for the preparation of radiopharmaceuticals, especially Tc-99m radiopharmaceuticals, may suffer from two types of instability: (i) shelf-life instability of the non-radioactive composition over time, (ii) instability of the radiopharmaceutical post-formation.\",\n \"In the case of Tc-99m, the latter is referred to as post-reconstitution instability.\",\n \"U.S. Pat.\",\n \"No.\",\n \"4,451,451 discloses that para-aminobenzoic acid (pABA) and analogues are useful stabilisers for technetium non-radioactive kits, including kits for the preparation of 99mTc-complexes of diphosphonic acids.\",\n \"Tc-99m-hexamethylpropyleneamine oxime (referred to hereinafter as 99mTc-HMPAO), is a radiopharmaceutical commercially available as a regional cerebral blood flow imaging agent.\",\n \"99mTc-HMPAO is particularly unstable with respect to post-reconstitution stability.\",\n \"99mTc-HMPAO is usually prepared from a lyophilised, non-radioactive kit which contains HMPAO and stannous ion.\",\n \"The function of the stannous ion is to reduce the 99mTc-pertechnetate (99mTcO4−), ie.\",\n \"technetium in oxidation state Tc(VII), to the Tc(V) oxidation state of the 99mTc-HMPAO metal complex.\",\n \"The radiochemical purity (Rcp) of 99mTc-HMPAO one hour after Tc-99m labelling is only about 80%, so that it must be used within 30 minutes of 99mTc labelling.\",\n \"After Tc-99m radiolabelling, the Rcp of 99mTc-HMPAO decreases with time due to the growth of three different radioactive impurities, namely: a hydrophilic secondary 99mTc complex of unknown structure derived from 99mTc-HMPAO, 99mTc-pertechnetate (99mTcO4−) and reduced-hydrolysed-technetium [99mTc].\",\n \"Of these impurities, both the secondary complex and 99mTc-pertechnetate are decomposition products of 99mTc-HMPAO; however, it is reported that the decomposition mechanisms are different (J. Nucl.\",\n \"Med.\",\n \"29, 1568-1576, 1988).\",\n \"The secondary complex is believed to be produced when the lipophilic 99mTc-HMPAO complex is exposed to excess unoxidised tin(II) (ie.\",\n \"stannous) remaining from the pertechnetate reduction step.\",\n \"On the other hand, the 99mTc-pertechnetate impurity is produced when 99mTc-HMPAO and the secondary complex are oxidised by the free radicals produced in solution by the action of radiation, ie.\",\n \"radiolysis of the solvent.\",\n \"Accordingly, in order to inhibit the production of both the 99mTc-pertechnetate and secondary complex impurities, the addition of stabilisers has been disclosed.\",\n \"Thus, Nucl.\",\n \"Med.\",\n \"Biol.\",\n \"7, 675-680 (1989); Eur.\",\n \"J. Nucl.\",\n \"Med.\",\n \"16, 541 (1990); Eur.\",\n \"J. Nucl.\",\n \"Med.\",\n \"20, 661-666 (1993) and Eur.\",\n \"J. Nucl.\",\n \"Med.\",\n \"22, 1163-1172 (1995) all report attempts to stabilise 99mTc-HMPAO by the addition of either: gentisic acid, sodium decahydroxypyrophosphate, methylene blue, cobalt chloride or the like.\",\n \"In particular, the post-radiolabelling addition of methylene blue improves the Rcp of 99mTc-HMPAO to at least 80% at 4 hours post reconstitution.\",\n \"Similarly, the post-radiolabelling addition of cobalt chloride has been found to improve the Rcp of 99mTc-HMPAO at 6 hours post reconstitution to at least 80%.\",\n \"The stabilisation mechanisms of 99mTc-HMPAO by methylene blue and cobalt chloride are believed to be essentially the same.\",\n \"Both are in redox equilibrium in solution, and oxidise excess tin(II), thus stabilising 99mTc-HMPAO.\",\n \"However, when the reducing tin(II) and methylene blue or cobalt chloride coexist in solution before the Tc-99m radiolabelling step, the tin(II) reductant is completely oxidised, so that the Tc-99m labelling becomes impossible because there is no longer any reducing agent present to reduce the Tc(VII) 99mTc-blue or cobalt chloride is used as a stabiliser for 99mTc-HMPAO, it must be added after the Tc-99m radiolabelling step and cannot be pre-mixed with the ligand (HMPAO) and 99mTc-pertechnetate.\",\n \"Accordingly, any kit for the preparation of 99mTc-HMPAO employing such stabilisers, must be composed of two vials (referred to hereinafter as a 2-vial kit).\",\n \"One vial is a freeze-dried vial containing the HMPAO ligand together with the tin(II) reductant and other excipients.\",\n \"The other is a vial containing the stabiliser (methylene blue or cobalt chloride).\",\n \"Thus, the most successful prior art methods of stabilising 99mTc-HMPAO to date all require the use of 2-vial kits.\",\n \"When the kit for preparing 99mTc-HMPAO is a 2-vial kit, the radiolabelling operation is more complicated than for a single vial kit and comprises two steps: (1) 99mTc-pertechnetate solution is added to the vial containing the HMPAO ligand and the resulting mixture is mixed by shaking; (2) a stabiliser solution from the second vial (eg.\",\n \"methylene blue or cobalt chloride) is added to the reconstituted mixture from step (1) in the first vial.\",\n \"It is necessary that the time between the first and second steps is controlled so as to be as close as possible to two minutes.\",\n \"Too short a time, and 99mTc-HMPAO complex formation may be incomplete and hence addition of the stabiliser may adversely affect the Rcp by oxidising the stannous ion before the reduction of the pertechnetate starting material is complete.\",\n \"Too long a time, and the stabilising effect is delayed.\",\n \"In such a procedure it is also necessary that care be taken with respect to the amounts of the solutions added.\",\n \"The operator must also take due care to ensure that the vials are not inadvertently mixed up at any stage.\",\n \"In addition, there is an increased risk of radiation dose to the operator due to the increased number of manipulations.\",\n \"Moreover, when methylene blue is added to 99mTc-HMPAO, a precipitate is produced, so that a filtration step becomes necessary, and thus the procedure becomes more complicated.\",\n \"There is therefore a need for a single vial kit for the preparation of 99mTc-HMPAO which has both shelf-life and post-radiolabelling stability.\",\n \"The present invention provides a kit which solves this problem, and is straightforward to use.\",\n \"The Present Invention.\",\n \"The present invention relates to a stabiliser for radiopharmaceuticals which comprises a combination of an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof, with a diphosphonic acid or a salt thereof with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid.\",\n \"DETAILED DESCRIPTION OF THE INVENTION In a first aspect, the present invention provides: a stabilised radiopharmaceutical composition which comprises: (i) a radiopharmaceutical; (ii) an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof; (iii) a diphosphonic acid or salt thereof, is with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid.\",\n \"By the term ‘amino-substituted aromatic carboxylic acid’ is meant a compound in which at least one hydrogen atom on the aromatic ring of an aromatic carboxylic acid is substituted with at least one amino group.\",\n \"The aromatic group is preferably benzene.\",\n \"Preferred amino-substituted aromatic carboxylic acids are: 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid (pABA), 3,5-diaminobenzoic acid and 4-aminosalicylic acid.\",\n \"4-aminobenzoic acid (pABA) is especially preferred.\",\n \"The salt of the amino-substituted aromatic carboxylic acid is suitably a salt with a biocompatible cation.\",\n \"By the term “biocompatible cation” is meant a positively charged counterion which forms a salt with an ionised, negatively charged group (here a carboxylate group), where said positively charged counterion is also non-toxic and hence suitable for administration to the mammalian body, especially the human body.\",\n \"Examples of suitable biocompatible cations include: the alkali metals (eg.\",\n \"sodium or potassium); the alkaline earth metals (eg.\",\n \"calcium, magnesium and barium); and the ammonium ion.\",\n \"A preferred biocompatible cation is sodium.\",\n \"Preferred salts of the present invention include: sodium 2-aminobenzoate, sodium 3-aminobenzoate, sodium 4-aminobenzoate (NapABA), sodium 3,5-diaminobenzoate, sodium 4-aminosalicylate, potassium 2-aminobenzoate, potassium 3-aminobenzoate, potassium 4-aminobenzoate, potassium 3,5-diaminobenzoate and potassium 4-aminosalicylate.\",\n \"Sodium 4-aminobenzoate (NapABA) is especially preferred.\",\n \"Suitable esters of the aromatic carboxylic acid include methyl, ethyl or propyl esters.\",\n \"Preferred esters are: methyl 2-aminobenzoate, methyl 3-aminobenzoate, methyl 4-aminobenzoate, methyl 3,5-diaminobenzoate, methyl 4-aminosalicylate, ethyl 2-aminobenzoate, ethyl 3-aminobenzoate, ethyl 4-aminobenzoate, ethyl 3,5-diaminobenzoate, ethyl 4-aminosalicylate, propyl 2-aminobenzoate, propyl 3-aminobenzoate, propyl 4-aminobenzoate, propyl 3,5-diaminobenzoate and propyl 4-aminosalicylate.\",\n \"Suitable amides of the amino-substituted aromatic carboxylic acid are amides formed by derivatising the carboxyl group of the aromatic carboxylic acid with either ammonia or a compound having at least one amino group, and include such compounds as 2-aminobenzamide, 3-aminobenzamide and 4-aminobenzamide.\",\n \"The diphosphonic acid of the present invention is suitably a 1,1- or a 1,2-diphosphonic acid, or a diphosphonic acid derivative of an amine such as ethylenediaminetetraphosphonic acid (EDTMP).\",\n \"1,1-diphosphonic acids are preferred, such as methylenediphosphonic acid (MDP), hydroxymethanediphosphonic acid (HMDP), hydroxyethanediphosphonic acid (HEDP).\",\n \"Methylenediphosphonic acid (MDP) and hydroxymethanediphosphonic acid (HMDP) are especially preferred.\",\n \"Suitable salts of the diphosphonic acid are with a ‘biocompatible cation’ as defined above.\",\n \"Preferred such diphosphonate salts include: sodium methylenediphosphonate, sodium hydroxymethanediphosphonate, sodium hydroxyethanediphosphonate, sodium ethylenediamine-tetraphosphonate, ammonium methylenediphosphonate, ammonium hydroxymethanediphosphonate, ammonium hydroxyethanediphosphonate and ammonium ethylenediamine-tetraphosphonate.\",\n \"The combination of compounds in the stabiliser for radiopharmaceuticals of the present invention is preferably a combination of sodium 4-aminobenzoate (NapABA) with methylenediphosphonic acid (MDP) or hydroxymethanediphosphonic acid (HMDP).\",\n \"Without wishing to be bound by theory, it is believed that the stabilisers of the present invention act as follows: The amino-substituted aromatic carboxylic acid or its salt, ester or amide has a reducing ability and removes any oxidising free radicals which result from the radiolysis of the solution, and hence inhibits the oxidative destruction of the radiopharmaceutical by free radical attack.\",\n \"On the other hand, when excess tin(II) reductant remains after completion of the radiolabelling, the diphosphonic acid or its salt inhibits the excess stannous ion from reductively degrading the radiopharmaceutical.\",\n \"It is a surprising finding of the present invention that such stabilisers can be present in a single step radiopharmaceutical preparation without either: (i) preventing or hindering the stannous reduction of the radiopharmaceutical precursor, with consequent adverse effect on Rcp; (ii) complexing with the radiometal to form undesirable radioactive impurities (eg.\",\n \"diphosphonic acid complexes of the radionuclide).\",\n \"Accordingly, the amount of the diphosphonic acid or its salt to be added to the radiopharmaceutical depends upon the amount of the reducing tin(II) contained in the radiopharmaceutical preparation or kit.\",\n \"The amount of the diphosphonic acid or its salt effective to stabilise the radiopharmaceutical is 1 to 10 moles per mole of stannous, preferably 2 to 8 moles per mole of stannous, most preferably 4 to 6 moles per mole of stannous.\",\n \"The radionuclide of the radiopharmaceutical of the present invention is a γ-ray or β-ray emitter, preferably Tc-99m, Re-186 or Re-188, most preferably Tc-99m.\",\n \"γ-ray emitters are mainly used for radiodiagnosis and β-ray emitters are mainly used for radiotherapy.\",\n \"When a radiodiagnostic radiopharmaceutical of this invention is intracorporeally administered to a human being, the level of radioactivity used is in the range of from 370 to 1,480 MBq, preferably from 370 to 1,110 MBq.\",\n \"When a radiotherapeutic agent of the radiopharmaceuticals of this invention is intracorporeally administered to a human being, the radioactivity level is in the range of from 37 to 18,500 MBq, preferably from 370 to 7,400 MBq.\",\n \"The radiopharmaceutical comprises an active ingredient which is susceptible to either degradation by the reducing action of the reductant (present to help effect labelling of the radionuclide), or radiolysis.\",\n \"By using the stabiliser composition of the present invention to stabilise such active ingredients, it is possible to prolong the useful lifetime post-radiolabelling to at least twice that of the prior art.\",\n \"The stabilisers of the present invention are particularly useful when the active ingredient comprises a ligand having a tetradentate diaminedioxime donor set, especially d,l-hexamethylpropyleneamine oxime or HMPAO (exametazime), 4,9-diaza-3,3,10,10-tetramethyldodecane-2,11-dione dioxime (PnAO), and similar compounds.\",\n \"In a second aspect, the present invention provides a non-radioactive kit for the preparation of the stabilised radiopharmaceutical composition described above which comprises: (i) an amino-substituted aromatic carboxylic acid or a salt, ester or amide thereof; (ii) a diphosphonic acid or salt thereof, with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid.\",\n \"Thus, the stabiliser for radiopharmaceuticals of the present invention can be pre-mixed with the ligand prior to radiolabelling, so that the formulation of a single vial, non-radioactive kit for the preparation of a stabilised radiopharmaceutical (which is not a radionuclide complex of the diphosphonic acid stabilizer) is possible.\",\n \"This simplifies the labelling procedure of the prior art 2-vial kit, shortens the labelling time and diminishes the risk of operator exposure to harmful radiation.\",\n \"The single vial kit of the present invention also has an extended stability post radioactive preparation, which in turn extends the useful lifetime for the user of the kit, eg.\",\n \"a clinician.\",\n \"Suitable non-radioactive kits of the present invention comprise 0.01 to 10 mg of an amino-substituted aromatic carboxylic acid or its salt, ester or amide, and 0.01 to 1 mg of a diphosphonic acid or its salt.\",\n \"When the kit contains stannous, the amount of the diphosphonic acid or its salt effective to stabilise is 1 to 10 moles per mole of stannous.\",\n \"Preferably, the ratio of diphosphonic acid or its salt is 2 to 8 moles per mole of stannous, most preferably 4 to 6 moles per mole of stannous.\",\n \"In a third aspect, the present invention discloses the use of a diphosphonic acid or a salt thereof as a stabiliser for radiopharmaceuticals, with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid suitable diphosphonic acid salts are those with a biocompatible cation as described above.\",\n \"Preferably the radiopharmaceutical also comprises stannous in the formulation.\",\n \"Most preferably, the radiopharmaceutical comprises 99mTc.\",\n \"Preferably, the diphosphonic acid or salt thereof used as a stabiliser is methylenediphosphonic acid (MDP), hydroxymethanediphosphonic acid (HMDP), hydroxyethanediphosphonic acid (HEDP), ethylenediaminetetraphosphonic acid (EDTMP), and salts thereof.\",\n \"In a fourth aspect, the present invention discloses the use of a diphosphonic acid or a salt thereof as a stabiliser for non-radioactive kits for the preparation of radiopharmaceuticals, with the proviso that the radiopharmaceutical is not a metal complex of the diphosphonic acid.\",\n \"Suitable diphosphonic acid salts are those with a biocompatible cation as described above.\",\n \"Preferably the non-radioactive kit further comprises stannous in the formulation.\",\n \"Most preferably, the non-radioactive kit is for the preparation of a 99mTc radiopharmaceutical.\",\n \"Preferably, the diphosphonic acid or salt thereof used as a stabiliser is methylenediphosphonic acid (MDP), hydroxymethanediphosphonic acid (HMDP), hydroxyethanediphosphonic acid (HEDP), ethylenediaminetetraphosphonic acid (EDTMP), and salts thereof.\",\n \"DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 compares the change in Rcp of 99mTc-HMPAO prepared from Composition III, Composition III+lactose and a commercially available kit for preparing 99mTc-HMPAO, each of which had been stored for 6 months prior to reconstitution.\",\n \"The present invention is explained in more detail with reference to the following Examples: Example 1 is a comparative example for a two step process (including prior art stabilisers such as cobalt chloride).\",\n \"An Rcp of 99mTc-HMPAO of at least 80% 3 hours after the addition is judged as effective stabilisation.\",\n \"However, as is clear from Table 1, the only single stabiliser which meets this criterion is cobalt chloride.\",\n \"Example 2 shows that 99mTc-HMPAO can be effectively stabilised in a single-step process, using a mixture of two compounds as stabilisers, and that the stability is significantly increased over that achieved using the 2-step process of Example 1.Example 3 provides further data on optimising the combinations of MDP/NapABA and HMDP/NapABA in a single step process.\",\n \"The molar ratio of Sn2+ to MDP/HMDP was kept constant (1:5), and the amounts added were varied.\",\n \"Example 4 shows that lyophilised non-radioactive kits for the preparation of 99mTc radiopharmaceuticals can be prepared using the compositions of the present invention.\",\n \"Lactose (a known cryoprotectant excipient in freeze-dried formulations), is shown to be useful to preserve stannous levels for extended shelf-life periods.\",\n \"Example 5 shows that the combination HMDP/NapABA is also effective as a stabiliser for 99mTc-HMPAO.\",\n \"Example 6 provides data on the stannous or tin(II) content of the freeze-dried kits, as a function of shelf-life storage in the dark at 4° C., and shows that the amount of reducing tin(II) in Composition III+lactose is higher than that in Composition III.\",\n \"Moreover, the amount of the reducing tin(II) in Composition III shows some tendency to decrease with increasing storage time.\",\n \"Accordingly, when the freeze-dried kit is stored for a prolonged period of time, lactose may be used in the kit composition to maintain the amount of the tin(II) reductant constant.\",\n \"Example 7 compares the Rcp after 6-months storage of the freeze-dried kits of the present invention, with the Rcp for 99mTc-HMPAO prepared from a commercially available kit.\",\n \"The Rcp decreases as a function of time post-reconstitution for the commercial kit, but for Composition III and Composition III+lactose, the Rcp's at 6 hours post-reconstitution were at least 80%.\",\n \"This shows that, whilst the stannous levels without lactose do show some modest decrease (Example 5), the decrease does not impair the performance of the kit.\",\n \"Example 8 shows that freeze-dried kits containing the stabiliser composition HMDP/NapABA have an effective shelf-life.\",\n \"Example 9 compares the biodistribution in rats of 99mTc-HMPAO prepared using kit Composition III and kit Composition III+lactose of the present invention, with a commercial 99mTc-HMPAO kit preparation.\",\n \"No significant difference in uptake in target organs was found.\",\n \"This includes the brain, which is the diagnostic imaging application of the present commercial 99mTc-HMPAO agent.\",\n \"These results show that the added compounds (MDP, NapABA and lactose), which are not present in the commercially available kit, do not adversely affect the biological behaviour of the 99mTc radiopharmaceutical.\",\n \"Example 10 describes various lyophilisation methods suitable for freeze-dried kit preparation of formulations of the present invention.\",\n \"Example 11 compares the Rcp of the various freeze-dried kits of Example 10.Example 1 The Rcp of 99mTc-HMPAO Using a Single Stabiliser: Two Step Process (Comparative Example) The radiochemical purity (Rcp) of 99mTc-HMPAO prepared using a commercially available kit (CERETEC™) for preparing 99mTc-HMPAO is 80% at one hour post-reconstitution, and the Rcp decreases thereafter with time.\",\n \"On the other hand, in the case of 99mTc-HMPAO stabilised with cobalt chloride, the Rcp 6 hours after radiolabelling is 80%.\",\n \"The following known medically acceptable compounds and additives were studied: ascorbic acid, sodium ascorbate, gentisic acid, gentisic acid ethanolamide, methylenediphosphonic acid (MDP), succinic acid, 4-aminobenzoic acid (pABA) and sodium 4-aminobenzoate (NapABA).\",\n \"To each of ten vials each containing 0.5 mg of HMPAO and 4.0 μg of Sn2+ (stannous), was added sodium pertechnetate (1.48 GBq in 5 ml of saline) to carry out the radiolabelling.\",\n \"To each of 9 of the ten reconstituted vials was individually added the compound shown in Table 1 at a time of 2 minutes post-radiolabelling.\",\n \"Nothing was added to the remaining vial.\",\n \"At 1 minute and 3 hours after the addition, an aliquot was taken from each vial and the Rcp measured by a combination of three chromatographic systems (stationary phase/developing solvent: silica gel/methyl ethyl ketone, silica gel/saline, filter paper/50% aqueous acetonitrile).\",\n \"The results are given in Table 1: TABLE 1 Radiochemical purity (Rcp) of 99mTc-HMPAO after the addition of a single stabiliser (%, n = 3).\",\n \"Name of Additive Rcp 1 min from Rcp 3 hours from (amount) addition (%) addition (%) No additive 87 ± 4 38 ± 15 Cobalt chloride 94 ± 3 89 ± 2 (200 μg) Ascorbic acid 83* 41* (4.5 μg) Sodium ascorbate 90* 51* (10 mg) Gentisic acid 87 ± 2 77 ± 3 30 μg) Gentisic acid ethanolamide 61 ± 3 29 ± 13 (30 μg) Methylene diphosphonic acid 79* 30* (10 μg) 4-Aminobenzoic acid 80 ± 8 67 ± 5 (30 μg) Sodium4-amino-benzoate 69 ± 5 39 ± 11 (30 μg) Succinic acid 51* 14* (30 μg) Note: *n = 1 Example 2 Examination of Stabilisation of 99mTc-HMPAO by a Combination of Two Compounds: Single Step Process The combinations studied were: (i) ascorbic acid and hydroxymethanediphosphonic acid (HMDP); (ii) sodium 4-aminobenzoate (NapABA) and methylenediphosphonic acid (MDP).\",\n \"A composition comprising 0.5 mg of HMPAO, 4.0 μg of Sn2+, 1.0 μg of HMDP and 0.5 μg of ascorbic acid (Composition A), and a composition comprising 0.5 mg of HMPAO, 5.4 μg of Sn2+, 40.5 μg of MDP and 0.5 mg of NapABA (Composition B) were prepared.\",\n \"To each of A and B was added sodium pertechnetate (1.48 GBq in 5 ml) to carry out the labelling.\",\n \"After 3 hours, an aliquot was taken from each, and the Rcp measured by a combination of three chromatographic systems (stationary phase/developing solvent: silica gel/methyl ethyl ketone, silica gel/saline, filter paper/50% aqueous acetonitrile).\",\n \"The Rcp of 99mTc-HMPAO 3 hours after Tc-99m labelling was about 62% in the case of Composition A and about 80% in the case of Composition B.\",\n \"Example 3 Optimisation of Stabiliser Composition: Single Step Process As shown in Table 2, six different sample compositions were prepared and stored in the dark at 4° C. One vial of each formulation was taken out at each time point (1, 7, 31 and 32-days storage), and sodium pertechnetate (1.48 GBq in 5 ml) was added.\",\n \"At 6 hours post addition of pertechnetate, an aliquot was taken from each vial and the Rcp measured by a combination of three chromatographic systems (stationary phase/developing solvent: silica gel/methyl ethyl ketone, silica gel/saline, filter paper/50% aqueous acetonitrile).\",\n \"The results are shown in Table 2: TABLE 2 Sample Compositions and Rcp of 99mTc-HMPAO 6 hours post-radiolabelling (n = 1, *n = 3).\",\n \"Composition I II III IV V VI Preparation HMPAO 0.5 0.5 0.5 0.5 0.5 0.5 Conditions (mg) NapABA 0.5 0.1 0.1 0.1 0.5 — Sn2+ 5.4 5.4 8.1 8.1 8.1 8.1 (μg) MDP 40.5 40.5 61.0 61.0 — — (μg) HMPD — — — — 66.0 66.0 (μg) Rcp (%) - 1 day 86.4 79.5 82.2 73.8 84.8 ± 2.7* 77.3 ± 5.5* after storage 7 days 80.8 80.9 82.1 81.1 — — time 32 days 79.0 81.8 84.3 66.5 — — 31 days — — — — 83.5 ± 2.2* 72.0 ± 0.2* Note: *n = 3.Compositions II, III and V show that, even in the case of samples stored for 32 days in the dark at 4° C., the Rcp at 6 hours post-reconstitution was at least 80%.\",\n \"Compositions III and V, which exhibited a higher Rcp, 5 were therefore used as the basis for subsequent tests.\",\n \"Example 4 Stabilisation of 99mTc-HMPAO by a Combination of MDP and NapABA: Single Step Process using a Freeze-Dried Kit Composition III of Example 3, and a composition prepared by adding lactose to Composition III (referred to hereinafter as Composition III+lactose) were used to prepare four lots of freeze-dried kit in each case.\",\n \"The amounts of compounds shown below correspond to the scale for a production batch of about 100 freeze-dried kit vials.\",\n \"First, anhydrous stannous chloride (25.8 mg) and MDP (122 mg) were dissolved in 0.1 M hydrochloric acid (1,000 ml).\",\n \"The resulting solution is referred to hereinafter as Solution 1.d,l-HMPAO (100 mg) and NapABA (100 mg) were dissolved in Solution 1 (100 ml), to give a solution referred to hereinafter as Solution 2.Solution 2 was divided into two 50 ml portions, one of which was adjusted to a pH of 8.5-9.0 with sodium hydroxide and thereafter the total volume was adjusted to 10.0 ml with water by use of a measuring cylinder.\",\n \"In the other 50 ml portion was dissolved 300 mg of lactose monohydrate, the resulting solution was adjusted to a pH of 8.5 to 9.0 with sodium hydroxide, and thereafter, the total volume was adjusted to 100 ml with water by use of a measuring cylinder.\",\n \"1.0 ml of each of the solutions obtained was placed in each vial, which was then frozen at −50 to −78° C. and then freeze-dried for about 24 hours.\",\n \"After completion of the freeze-drying, the vials were sealed and the freeze-dried kit was stored in the dark at 4° C. The same procedure was repeated four times to prepare four separate lots of each of, Composition III and Composition III+lactose.\",\n \"Lot Nos.\",\n \"ID-01 to ID-04 were of Composition III and Lot Nos.\",\n \"ID-05 to ID-08 were of Composition III+lactose.\",\n \"The production conditions and results of each lot are shown in Table 3.TABLE 3 Production conditions and results of each lot Freezing Number of pH before temperature Vials Lot No.\",\n \"freezing (° C.) Produced Property# ID-01 9.0 −50 99 Fair ID-02 9.0 −78 90 Bad ID-03 8.5 −78 39 Bad ID-04 9.0 −50 99 Fair ID-05 9.0 −50 91 Good ID-06 9.0 −78 92 Good ID-07 8.5 −78 94 Good ID-08 8.5 −50 91 Good #where ’property' refers to the behaviour during lyophilisation: Good = the cake in the freeze-dried kits kept well-formed; Fair = the cake in the freeze-dried kits was partly broken, but there was no loss of powder from the vials during lyophilisation; Bad = the cake in the freeze-dried kits was completely broken, and some of the powder was lost from the vials during lyophilisation.\",\n \"In all the lots other than ID-03 (which is of Composition III), at least 90 vials were produced.\",\n \"Among the four lots of Composition III, only ID-03 was adjusted to a pH of 8.5 before freezing.\",\n \"Moreover, in the case of Composition III+lactose, even when the pH was adjusted to 8.5 before freezing (ID-07, ID-08), at least 90 vials could be produced.\",\n \"Accordingly, when a freeze-dried kit is produced, it is desirable to adjust the pH to 9.0 in the case of lactose-free Composition III.\",\n \"Example 5 Stabilisation of 99mTc-HMPAO by a Combination of HMDP and NapABA: Single Step Process using a Freeze-Dried Kit Composition V of Example 3, and a composition prepared by adding lactose to Composition V (referred to hereinafter as Composition V+lactose) were used to prepare one lot of freeze-dried kits in each case.\",\n \"The freeze-dried kits were prepared in much the same manner as that of Example 4, except that Solution 1 was slightly different—in this case anhydrous stannous chloride (25.8 mg) and HMDP-2Na (132.0 mg) were dissolved in 0.1M hydrochloric acid (1,000 mL).\",\n \"Lot Nos.\",\n \"ID-09 was of Composition V and Lot Nos.\",\n \"ID-10 was of Composition V+lactose.\",\n \"The production conditions and results of each lot are shown in Table 4.TABLE 4 Production conditions and results of each lot.\",\n \"Freezing Number of pH before Temperature Vials freezing (° C.) Produced Property# ID-09 8.8 −50° C. 49 Fair ID-10 8.8 −50° C. 45 Good #defined in Example 4.Example 6 Determination of the Amount of tin(II) in the Freeze-Dried Kit as a Function of Storage Time Vials of Composition III (ID-01, O2, 03 and 04), Composition III+lactose (ID-05, 06, 07 and 08), Composition V (ID-09) and Composition V+lactose (ID-10) which had been stored in the dark at 4° C. for periods of 1 day, 3-months and 6-months, were allowed to warm to room temperature.\",\n \"The amount of tin(II) was then determined by an absorbance method.\",\n \"The results obtained are shown in Table 5.TABLE 5 Amounts of reducing tin(II) determined (μg/vial, n = 2).\",\n \"1-day storage 3-month storage 6-month storage Composition III 9.5 ± 0.2 9.1 ± 0.5 8.7 ± 0.5 Composition III + 10.3 ± 0.5 10.5 ± 0.5 10.8 ± 0.4 lactose Composition V 10.1 ± 0.0 — — Composition V + 10.3 ± 0.3 — — lactose Note Each value was an average value of 4 lots.\",\n \"Example 7 Radiochemical Purity of Freeze-Dried Kits Containing MDP and NapABA Studied over a 6-Month Shelf-Life Storage Period Four lots of each of Composition III and Composition III+lactose produced in Example 4 were subjected to examination of radiochemical purity after 6 -months storage in the dark at 4° C. Vials of freeze-dried Composition III (ID-01, O2, 03 and 04) and Composition III+lactose (ID-OS, 06, 07 and 08) were stored for 6 months in the dark at 4° C. After a storage period of 1 day, 1, 3 and 6 months, the vials were allowed to warm to room temperature, and Tc-99m labelling was carried out.\",\n \"Thus, to one vial of each lot was added sodium pertechnetate (1.48 GBq in 5 ml).\",\n \"Aliquots were taken after times of 2 minutes, one hour, 3 hours and 6 hours and the Rcp was measured by a combination of three chromatographic systems (stationary phase/developing solvent: silica gel/methyl ethyl ketone, silica gel/saline and filter paper/50% aqueous acetonitrile).\",\n \"The results obtained at 6 hours are shown in Table 6.When Composition III and Composition III+lactose were radiolabelled after 6-month shelf-life storage, simultaneously, sodium pertechnetate (1.48 GBq/5 ml) was added to a commercially available kit for preparing 99mTc-HMPAO (containing 0.5 mg of HMPAO and 4.0 μg of Sn2+) as a control.\",\n \"An aliquot thereof was taken after times of one minute, one hour, 3 hours and 6 hours, and then the Rcp was measured in the same manner.\",\n \"The results obtained are shown in FIG.\",\n \"1.TABLE 6 Rcp of 99mTc-HMPAO at 6 hr post reconstitution by a combination of MDP and NapABA as a function of storage time.\",\n \"STORAGE PERIOD 1-day 1-month 3-months 6-months Rcp Composition III 86.4 ± 2.2 87.4 ± 1.5 86.5± 2.7 88.4 ± 3.4 (%) Composition III + 86.2 ± 2.3 86.2 ± 2.4 87.9 ± 2.6 85.6 ± 2.7 Lactose Example 8 Radiochemical Purity of Freeze-Dried Kits Containing HMDP and NapABA for 1-Month Shelf-Life Storage One lot of each of Composition V and Composition V+lactose produced in Example 5 were subjected to examination of radiochemical purity for 1-month storage in the dark at 4° C. The Rcp was measured in the same manner.\",\n \"The results obtained are shown in Table 7.TABLE 7 Rcp of 99mTc-HMPAO at 6 hr post-reconstitution stabilised by a combination of HMDP and NapABA as a function of storage time.\",\n \"Storage Time 1-day 1-month Rcp Composition V 84.8 ± 2.7 83.5 ± 2.2 (%) Composition V + 87.3 ± 2.8 86.0 ± 1.0 Lactose Example 9 Biodistribution in the Rat To one vial of each of Composition III (ID-O2) and Composition III+lactose (ID-06) obtained in Example 4 was added sodium pertechnetate in a proportion of 1.48 GBq/5 ml to carry out the radiolabelling.\",\n \"After 2 hours, 3.0 to 3.7 MBq of the reconstituted solution was administered to a female Sprague-Dawley strain rat (body weight 140-170 g) which had been previously anaesthetised with sodium thiopentobarbital in the tail vein.\",\n \"At one hour post-administration, the animal was sacrificed and the radioactivity in each organ was measured using a NaI single channel analyser.\",\n \"Separately, sodium pertechnetate was added in a proportion of 1.48 GBq/5 ml to the commercially available kit for preparing 99mTc-HMPAO.\",\n \"In the same manner, at 15 minutes post-reconstitution, 3.0-3.7 MBq of the solution was administered to the same kind of rat, and the biodistribution of radioactivity in each organ measured.\",\n \"The results obtained are shown in Table 8: TABLE 8 Biodistribution of Commercial 99mTc-HMPAO, Composition III (ID-02) and Composition III + lactose (ID-06) in the female rat at one hour post administration (upper row: % ID/organ, lower row: % ID/g, n = 5).\",\n \"Composition III + Commercial Composition lactose 99mTc-HMPAO III (ID-02) (ID-06) Brain 1.66 ± 0.13 1.65 ± 0.10 1.73 ± 0.15 0.96 ± 0.07 0.96 ± 0.15 1.01 ± 0.07 Blood 15.38 ± 0.72 14.41 ± 1.68 14.07 ± 1.51 1.56 ± 0.04 1.64 ± 0.06 1.45 ± 0.18 Heart 0.81 ± 0.04 0.85 ± 0.03 0.90 ± 0.10 1.61 ± 0.08 1.75 ± 0.10 1.72 ± 0.03 Lung 3.41 ± 0.20 3.15 ± 0.18 3.39 ± 0.38 4.05 ± 0.28 4.26 ± 0.29 4.14 ± 0.36 Liver 5.91 ± 0.20 6.49 ± 0.48 7.68 ± 0.38 1.10 ± 0.07 1.36 ± 0.13 1.44 ± 0.14 Spleen 0.78 ± 0.10 0.79 ± 0.18 0.86 ± 0.12 2.17 ± 0.12 2.24 ± 0.12 2.25 ± 0.21 Kidney 4.27 ± 0.27 5.04 ± 0.48 4.81 ± 0.31 4.39 ± 0.16 4.78 ± 0.64 4.46 ± 0.21 Stomach 1.41 ± 0.54 2.15 ± 0.46 1.70 ± 0.79 0.49 ± 0.17 1.24 ± 0.43 0.93 ± 0.54 Small 17.27 ± 0.85 17.61 ± 0.87 20.23 ± 1.50 Intestine 2.86 ± 0.17 3.47 ± 0.33 3.94 ± 0.46 Large 2.08 ± 0.25 2.14 ± 0.34 2.05 ± 0.24 Intestine 0.35 ± 0.03 0.40 ± 0.04 0.34 ± 0.03 Skin 0.78 ± 0.61 0.68 ± 0.55 0.51 ± 0.34 0.39 ± 0.04 0.37 ± 0.09 0.31 ± 0.09 Muscle 0.91 ± 0.49 0.67 ± 0.41 0.49 ± 0.21 0.28 ± 0.03 0.29 ± 0.03 0.16 ± 0.02 Urine 12.36 ± 1.18 11.78 ± 2.18 12.07 ± 1.11 Carcass 36.96 ± 0.83 37.76 ± 2.18 33.95 ± 1.37 0.34 ± 0.02 0.37 ± 0.02 0.31 ± 0.01 Example 10 Methods of Freeze-Dried Kit Preparation The freeze-dried kit (Composition V+lactose of Example 5) was prepared by two methods.\",\n \"The first method (ID-11) was similar to that of Example 5, but with a modified Solution 2—thus, d,l-HMPAO (250 mg),NapABA (250 mg) and lactose monohydrate (1.5 g) were dissolved in Solution 1 (250 mL).\",\n \"The solution was added to water (250 mL) and adjusted to pH 8.9.The production conditions and results for ID-11 are shown in Table 9.The second method (ID-12) is described below.\",\n \"Thus, lactose monohydrate (3.03 g), NapABA (505 mg), d,l-HMPAO (505 mg), HMDP (66.6 mg) and anhydrous stannous chloride (13.1 mg) were dissolved in 0.1M hydrochloric acid (1000 mL) in the order given.\",\n \"The solution was then adjusted to pH 9.4.The production conditions and results for ID-12 are shown in Table 9.TABLE 9 Production conditions and results of each lot Freezing Number pH before Temperature of Vials freezing ° ( C.) Produced Property# ID-11 8.9 −40° C. 290 Good ID-12 9.4 −40° C. 240 Good #as defined in Example 4.Example 11 RCP of Freeze-Dried Kits Prepared by Different Methods The freeze-dried kits in Example 10 were used to examine the RCP.\",\n \"The RCP was measured in the same manner as in Example 7.The results obtained are shown in Table 10.TABLE 10 Rcp of 99mTc-HMPAO at the time after reconstitution 2 min 1 hour 3 hours 6 hours ID-11 90.2 ± 0.4 89.3 ± 1.8 85.9 ± 1.7 85.7 ± 1.7 ID-12 87.1 ± 2.1 81.4 ± 2.4 70.6 ± 1.7 60.7 ± 4.0\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10296952"}}},{"rowIdx":94,"cells":{"text":{"kind":"list like","value":[["METHODS FOR MEDIATING GENE SUPPRESSION","The present invention is concerned with methods for enhancing gene suppression in cells and in particular it is concerned with improved methods for enhancing RNAi-mediated gene silencing by manipulation of factors associated with RNAi.","The present invention is also concerned with methods for identifying factors which down-regulate as well as those which up-regulate RNAi.","It is also concerned with genetic constructs useful for enhancing or modulating gene silencing and cells harbouring such constructs."],["1.A method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) elevating in the cell the level of an RNAi factor, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","2.A method of increasing cellular susceptibility to anti-sense-mediated inhibition of target nucleic acid expression, which method comprises elevating the level of an RNAi factor in a cell that expresses said target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","3.A method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.","4.A method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.","5.A method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) elevating the level of an RNAi factor in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.","6.A method according to any one of claims 1 to 5, wherein the target nucleic acid is an exogenous nucleic acid or a part thereof.","7.A method according to any one of claims 1 to 6, wherein the level of the RNAi factor is elevated by introducing into the cell additional copies of, or agents which give rise to, the RNAi factor.","8.A method according to any one of claims 1 to 7, wherein the factor is selected from the group consisting of a gene, cDNA, RNA or a protein.","9.A method according to any one of claims 1 to 8, wherein the factor is selected from the group consisting of a transcriptional activator of the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.","10.A method according to any one of claims 1 to 9, wherein the RNAi factor is an res sequence.","11.A method according to claim 10, wherein the factor is selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.","12.A method according to claim 11, wherein the res sequence is obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.13.A method according to claim 11, wherein the res sequence is represented by Seq ID Nos 1 to 4.14.A method according to any one of claims 1 to 13, wherein the cell is a eukaryotic cell.","15.A method according to 14, wherein the eukaryotic cell is a mammalian.","16.A method according to claim 1 or claim 2, wherein the cell is a Schizosaccharomyces pombe cell.","17.A method according to any one of claims 1 to 16, wherein the antisense nucleic acid corresponds to a part of the target nucleic acid.","18.A pharmaceutical composition for use in performing the method of any one of claims 2 to 17 comprising (i) an expressible nucleic acid encoding, or capable of increasing or decreasing the expression of, an RNAi factor; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.","19.A pharmaceutical composition for use in performing the method of any one of claims 2 to 17 comprising (i) an nucleic acid which is the target nucleic acid or a part thereof, or an expressible nucleic acid encoding a factor capable of elevating the intracellular level of the target nucleic acid; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.","20.A cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses a target nucleic acid and (ii) comprises an elevated level of an RNAi factor, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","21.A cell according to claim 20, wherein the cell is a eukaryotic cell.","22.A cell according to claim 20 or claim 21, wherein the cell is a Schizosaccharomyces pombe cell.","23.A method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the cell, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of said target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of said target nucleic acid.","24.A method of increasing cellular susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which method comprises augmenting the level of the target nucleic acid or a part thereof in a cell expressing the target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","25.A method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of said target nucleic acid or a part thereof in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.","26.A method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.","27.A method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.","28.A method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) augmenting the level of the target nucleic acid in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.","29.A method according to any one of claims 23 to 28, wherein the target nucleic acid is an exogenous nucleic acid or a part thereof.","30.A method according to any one of claims 23 to 29, wherein the level of the target nucleic acid is augmented by introducing into the cell additional copies of, or agents which are capable of inducing intracellular over-expression of, the target nucleic acid.","31.A method according to any one of claims 23 to 30, wherein the cell is a eukaryotic cell.","32.A method according to 31, wherein the eukaryotic cell is a mammalian.","33.A method according to claim 23 or claim 24, wherein the cell is a Schizosaccharomyces pombe cell.","34.A method according to any one of claims 23 to 33, wherein the antisense nucleic acid corresponds to a part of the target nucleic acid.","35.A cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses said target nucleic acid and (ii) comprises an elevated level of said target nucleic acid, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","36.A cell according to claim 35, wherein the cell is a eukaryotic cell.","37.A cell according to claim 35 or claim 36, wherein the cell is a Schizosaccharomyces pombe cell.","38.Method of identifying a cellular factor capable of effecting and/or modulating expression of a target nucleic acid in a cell having the target nucleic acid and a nucleic acid which is an antisense of the target nucleic acid or part thereof, which method comprises over-expressing said factor in the cell and wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.","39.A factor identified by the method of claim 38.40.A factor according to claim 39, wherein the factor is selected from the group consisting of a gene, cDNA, RNA or a protein.","41.A factor according to claim 39 or claim 40, wherein the factor is selected from the group consisting of a transcriptional activator or the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.","42.A factor according to any one of claims 39 to 41, wherein the factor is an res sequence.","43.A factor according to claim 42, wherein the factor is selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.","44.An RNAi factor which is an res sequence obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.45.An RNAi factor which is an res sequence represented by Seq ID Nos 1 to 4.46.A Schizosaccharomyces pombe cell having a target nucleic acid or a part thereof and a antisense nucleic acid or a part thereof which corresponds to the target nucleic acid or a part thereof, wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed."],["<SOH> BACKGROUND OF THE INVENTION <EOH>The use of double-stranded RNA (dsRNA) to specifically interfere with gene expression has received considerable attention because of its demonstrated potency in a range of organisms, including some which have so far been genetically intractable.","Termed RNA interference (RNAi), it has been implicated in viral defense, control of transpositional elements, genetic imprinting and endogenous gene regulation.","It has been hypothesised to be the central mechanism in post-transcriptional gene silencing (PTGS), co-suppression, quelling, and antisense RNA-mediated gene suppression.","One model that has been proposed is that dsRNA is fragmented into 21-25 nt species by dsRNA-specific nucleases, amplified by RNA-dependent RNA polymerase, and then dissociated and free to attack homologous mRNA by RNA nuclease-mediated degradation.","The application of this technique will greatly facilitate the dissection of gene function and the validation of genes involved in disease states.","Recently at least two different strategies have been undertaken to identify the cellular proteins composing a proposed multi-protein complex involved in the recognition of dsRNA and the activation of dsRNA-mediated gene interference.","The first involves the use of classical chemical mutagenesis or insertional mutagenesis to isolate mutants completely defective for RNAi and cloning of the relevant genes using complementation.","These studies have been carried out in genetically tractable organisms such as plants, worms and fungi.","The genetic screens described involve the use of RNAi systems in which the degree of suppression is complete.","The mutagenesis produces mutants in which the RNAi effect is completely reversed indicating the loss of a cellular factor (function) required for the RNAi effect.","Thus these genetic screens would most likely miss factors that have subtle effects or rate limiting or rate determining roles in RNAi.","The second strategy for finding key players in RNAi has involved the use of cell free assays.","These in vitro reconstitution assays, on the other hand, identify cellular factors that impact on RNAi outside of the cellular context and therefore the cellular role of these factors must always be tested.","However, the major disadvantages of these strategies are that genes will not be identified if they are essential to the organism, nor will they directly identify gene activities which will enhance RNAi when overexpressed.","Thus there is a need for models which can demonstrate a range of RNAi efficacies, with both increasing and decreasing quantitative activities being selectable.","This would enable the identification of factors which can enhance or reduce the gene silencing effect.","It is therefore an object of the present invention to overcome or at least ameliorate one or more disadvantages of the prior art, or provide a useful alternative."],["<SOH> SUMMARY OF THE INVENTION <EOH>Through the use of a fission yeast model for the study of dsRNA-mediated gene silencing and in the search for factors involved in this process, it was surprisingly found that the natural level of RNAi activity can be enhanced by manipulating factors associated with RNAi activity or efficacy.","Thus, it has been found that by increasing the steady-state levels of a target nucleic acid sequence in the presence of the same pool of the corresponding antisense sequence, or a part thereof, the antisense-mediated suppression was not only maintained, but enhanced.","This is indicative of an RNAi-like mechanism of gene suppression.","It has also been found that overexpression of certain sequences, named herein RNAi enhancing sequences (res), (also referred to herein as anti-sense enhancing sequences—aes), also had the ability to enhance RNAi.","This ability of RNAi activity to be enhanced in S. pombe provides a model system which enables the analysis of RNAi processes and the identification and study of factors which either up-regulate or down-regulate its activity.","The system has been further used to identify RNAi enhancing gene sequences which increase PTGS efficacy when their resulting protein activities are augmented in vivo.","The model used to exemplify the present invention and the methods described are also applicable to treatment of disorders in which gene expression requires more efficient modulation or silencing.","According to a first aspect there is provided a method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) elevating in the cell the level of an RNAi factor, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","According to a second aspect there is provided a method of increasing cellular susceptibility to anti-sense-mediated inhibition of target nucleic acid expression, which method comprises elevating the level of an RNAi factor in a cell that expresses said target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","According to a third aspect there is provided a method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.","According to a fourth aspect there is provided a method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.","According to a fifth aspect there is provided a method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) elevating the level of an RNAi factor in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.","In a preferred embodiment the target nucleic acid is an endogenous nucleic acid or a part thereof, but it may also be an exogenous sequence or part thereof.","Preferably the level of the RNAi factor is elevated by introducing into the cell additional copies of, or agents which give rise to, the RNAi factor.","It will be understood therefore that up-regulating the expression of an endogenous RNAi factor will also achieve the same result and is contemplated herein as part of the invention.","Preferably the factor is selected from the group consisting of a gene, cDNA, RNA or a protein.","More preferred is a factor selected from the group consisting of a transcriptional activator of the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.","Even more preferred is an RNAi factor which is an res sequence.","Also for preference the factor can be selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.","Further preferred factors are represented by the res sequences which are obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.Preferably the res sequence is represented by any one of Seq ID Nos 1 to 4.The preferred cell is a eukaryotic cell and even more preferred is a mammalian cell.","In certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.","Preferably the antisense nucleic acid corresponds to a part only of the target nucleic acid.","According to a sixth aspect there is provided a pharmaceutical composition for use in performing the method of any one of the previous aspects comprising (i) an expressible nucleic acid encoding, or capable of increasing or decreasing the expression of, an RNAi factor; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.","According to a seventh aspect there is provided a pharmaceutical composition for use in performing the method of any one of claims 2 to 17 comprising (i) an nucleic acid which is the target nucleic acid or a part thereof, or an expressible nucleic acid encoding a factor capable of elevating the intracellular level of the target nucleic acid; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.","According to an eighth aspect there is provided a cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses a target nucleic acid and (ii) comprises an elevated level of an RNAi factor, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","For preference the cell is a eukaryotic cell but more preferred is a mammalian cell.","As indicated above, in certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.","According to a ninth aspect there is provided a method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the cell, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of said target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of said target nucleic acid.","According to a tenth aspect there is provided a method of increasing cellular susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which method comprises augmenting the level of the target nucleic acid or a part thereof in a cell expressing the target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","According to an eleventh aspect there is provided a method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of said target nucleic acid or a part thereof in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.","According to a twelfth aspect there is provided a method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.","According to a thirteenth aspect there is provided a method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) augmenting the level of the target nucleic acid in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.","In a preferred embodiment the target nucleic acid is an endogenous nucleic acid or a part thereof, but it may also be an exogenous sequence or part thereof.","Preferably the level of the target nucleic acid is augmented by introducing into the cell additional copies of, or agents which are capable of inducing intracellular over-expression of, the target nucleic acid.","Over-expression can be achieved for an endogenous as well as an exogenous target nucleic acid.","Preferably the nucleic acid used for augmenting content of the target nucleic acid is a fragment, derivative or analogue of the target nucleic acid.","However it will be understood that the entire native sequence of the target nucleic acid may be employed.","Conveniently, the target nucleic acid may be coupled to a selectable marker.","The preferred cell is a eukaryotic cell and even more preferred is a mammalian cell.","In certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.","Preferably the antisense nucleic acid corresponds to a part only of the target nucleic acid.","According to a fourteenth aspect there is provided a cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses said target nucleic acid and (ii) comprises an elevated level of said target nucleic acid, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","The preferred cell is a eukaryotic cell and even more preferred is a Schizosaccharomyces pombe cell.","According to a fifteenth aspect there is provided a method of identifying a cellular factor capable of effecting and/or modulating expression of a target nucleic acid in a cell having the target nucleic acid and a nucleic acid which is an antisense of the target nucleic acid or part thereof, which method comprises over-expressing said factor in the cell and wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.","According to a sixteenth aspect there is provided a factor identified by the method of the fifteenth aspect.","The preferred factors can be selected from the group consisting of a gene, cDNA, RNA or a protein.","More preferred are factors selected from the group consisting of a transcriptional activator or the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.","Even more preferred is a factor having an res sequence.","Preferred factors can also be selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.","According to a seventeenth aspect there is provided an RNAi factor which is an res sequence obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.According to an eighteenth aspect there is provided an RNAi factor which is an res sequence represented by Seq ID Nos 1 to 4.According to a nineteenth aspect there is provided a Schizosaccharomyces pombe cell having a target nucleic acid or a part thereof and a antisense nucleic acid or a part thereof which corresponds to the target nucleic acid or a part thereof, wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.","The term “inhibiting expression of a target nucleic acid” as used in the context of the present invention is intended to encompass, but not be limited to, reduction or elimination of gene expression, whether or not the target nucleic acid is a gene, or a part thereof, introduced into the cell or it is an endogenous gene.","The term “RNAi factor” is intended to include in its scope any naturally occurring, modified or synthetic molecule capable of enhancing RNAi activity.","This definition includes in its scope the factors referred to herein as RNAi enhancing sequences (res).","The term res may be used herein interchangeably with the term aes (anti-sense enhancing sequences).","It will be understood by those skilled in the art that “elevating RNAi factor level” can be achieved by transfection, upregulation or other means known in the art.","The term “anti-sense nucleic acid molecule” as used in the context of the present invention is intended to encompass RNA or DNA and contain region(s) related to a specific target RNA transcript or its gene.","It is also intended to include molecules giving rise to antisense sequences, including inverted repeat, sense RNA, etc.","The term “conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid molecule inhibits expression of the gene” is intended to include the concept of inhibition of gene expression which is high enough to be effective, but not so high as to harm the cell.","The effective concentration range can be determined using routine methodology known in the art.","Reference to a “subject” is intended to include human, animal (mouse), plant, or other life forms.","Reference to a “cell” is intended to encompass eukaryotic cells such as yeast, mammalian, plant, etc The term “disorder” will be understood to include viral infection (HIV, HPV, etc), cancer, autoimmune disease and other chronic and acute diseases.","The term “phenotype” as used in the context of the present invention is intended to include cell staining, morphology, growth, and similar characteristics."],["TECHNICAL FIELD The present invention is concerned with methods for enhancing gene suppression in cells and in particular it is concerned with improved methods for enhancing RNAi-mediated gene silencing by manipulation of factors associated with RNAi.","The present invention is also concerned with methods for identifying factors which down-regulate as well as those which up-regulate RNAi.","It is also concerned with genetic constructs useful for enhancing or modulating gene silencing and cells harbouring such constructs.","BACKGROUND OF THE INVENTION The use of double-stranded RNA (dsRNA) to specifically interfere with gene expression has received considerable attention because of its demonstrated potency in a range of organisms, including some which have so far been genetically intractable.","Termed RNA interference (RNAi), it has been implicated in viral defense, control of transpositional elements, genetic imprinting and endogenous gene regulation.","It has been hypothesised to be the central mechanism in post-transcriptional gene silencing (PTGS), co-suppression, quelling, and antisense RNA-mediated gene suppression.","One model that has been proposed is that dsRNA is fragmented into 21-25 nt species by dsRNA-specific nucleases, amplified by RNA-dependent RNA polymerase, and then dissociated and free to attack homologous mRNA by RNA nuclease-mediated degradation.","The application of this technique will greatly facilitate the dissection of gene function and the validation of genes involved in disease states.","Recently at least two different strategies have been undertaken to identify the cellular proteins composing a proposed multi-protein complex involved in the recognition of dsRNA and the activation of dsRNA-mediated gene interference.","The first involves the use of classical chemical mutagenesis or insertional mutagenesis to isolate mutants completely defective for RNAi and cloning of the relevant genes using complementation.","These studies have been carried out in genetically tractable organisms such as plants, worms and fungi.","The genetic screens described involve the use of RNAi systems in which the degree of suppression is complete.","The mutagenesis produces mutants in which the RNAi effect is completely reversed indicating the loss of a cellular factor (function) required for the RNAi effect.","Thus these genetic screens would most likely miss factors that have subtle effects or rate limiting or rate determining roles in RNAi.","The second strategy for finding key players in RNAi has involved the use of cell free assays.","These in vitro reconstitution assays, on the other hand, identify cellular factors that impact on RNAi outside of the cellular context and therefore the cellular role of these factors must always be tested.","However, the major disadvantages of these strategies are that genes will not be identified if they are essential to the organism, nor will they directly identify gene activities which will enhance RNAi when overexpressed.","Thus there is a need for models which can demonstrate a range of RNAi efficacies, with both increasing and decreasing quantitative activities being selectable.","This would enable the identification of factors which can enhance or reduce the gene silencing effect.","It is therefore an object of the present invention to overcome or at least ameliorate one or more disadvantages of the prior art, or provide a useful alternative.","SUMMARY OF THE INVENTION Through the use of a fission yeast model for the study of dsRNA-mediated gene silencing and in the search for factors involved in this process, it was surprisingly found that the natural level of RNAi activity can be enhanced by manipulating factors associated with RNAi activity or efficacy.","Thus, it has been found that by increasing the steady-state levels of a target nucleic acid sequence in the presence of the same pool of the corresponding antisense sequence, or a part thereof, the antisense-mediated suppression was not only maintained, but enhanced.","This is indicative of an RNAi-like mechanism of gene suppression.","It has also been found that overexpression of certain sequences, named herein RNAi enhancing sequences (res), (also referred to herein as anti-sense enhancing sequences—aes), also had the ability to enhance RNAi.","This ability of RNAi activity to be enhanced in S. pombe provides a model system which enables the analysis of RNAi processes and the identification and study of factors which either up-regulate or down-regulate its activity.","The system has been further used to identify RNAi enhancing gene sequences which increase PTGS efficacy when their resulting protein activities are augmented in vivo.","The model used to exemplify the present invention and the methods described are also applicable to treatment of disorders in which gene expression requires more efficient modulation or silencing.","According to a first aspect there is provided a method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) elevating in the cell the level of an RNAi factor, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","According to a second aspect there is provided a method of increasing cellular susceptibility to anti-sense-mediated inhibition of target nucleic acid expression, which method comprises elevating the level of an RNAi factor in a cell that expresses said target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","According to a third aspect there is provided a method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.","According to a fourth aspect there is provided a method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.","According to a fifth aspect there is provided a method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) elevating the level of an RNAi factor in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.","In a preferred embodiment the target nucleic acid is an endogenous nucleic acid or a part thereof, but it may also be an exogenous sequence or part thereof.","Preferably the level of the RNAi factor is elevated by introducing into the cell additional copies of, or agents which give rise to, the RNAi factor.","It will be understood therefore that up-regulating the expression of an endogenous RNAi factor will also achieve the same result and is contemplated herein as part of the invention.","Preferably the factor is selected from the group consisting of a gene, cDNA, RNA or a protein.","More preferred is a factor selected from the group consisting of a transcriptional activator of the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.","Even more preferred is an RNAi factor which is an res sequence.","Also for preference the factor can be selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.","Further preferred factors are represented by the res sequences which are obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.Preferably the res sequence is represented by any one of Seq ID Nos 1 to 4.The preferred cell is a eukaryotic cell and even more preferred is a mammalian cell.","In certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.","Preferably the antisense nucleic acid corresponds to a part only of the target nucleic acid.","According to a sixth aspect there is provided a pharmaceutical composition for use in performing the method of any one of the previous aspects comprising (i) an expressible nucleic acid encoding, or capable of increasing or decreasing the expression of, an RNAi factor; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.","According to a seventh aspect there is provided a pharmaceutical composition for use in performing the method of any one of claims 2 to 17 comprising (i) an nucleic acid which is the target nucleic acid or a part thereof, or an expressible nucleic acid encoding a factor capable of elevating the intracellular level of the target nucleic acid; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.","According to an eighth aspect there is provided a cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses a target nucleic acid and (ii) comprises an elevated level of an RNAi factor, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","For preference the cell is a eukaryotic cell but more preferred is a mammalian cell.","As indicated above, in certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.","According to a ninth aspect there is provided a method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the cell, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of said target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of said target nucleic acid.","According to a tenth aspect there is provided a method of increasing cellular susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which method comprises augmenting the level of the target nucleic acid or a part thereof in a cell expressing the target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","According to an eleventh aspect there is provided a method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of said target nucleic acid or a part thereof in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.","According to a twelfth aspect there is provided a method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.","According to a thirteenth aspect there is provided a method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) augmenting the level of the target nucleic acid in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.","In a preferred embodiment the target nucleic acid is an endogenous nucleic acid or a part thereof, but it may also be an exogenous sequence or part thereof.","Preferably the level of the target nucleic acid is augmented by introducing into the cell additional copies of, or agents which are capable of inducing intracellular over-expression of, the target nucleic acid.","Over-expression can be achieved for an endogenous as well as an exogenous target nucleic acid.","Preferably the nucleic acid used for augmenting content of the target nucleic acid is a fragment, derivative or analogue of the target nucleic acid.","However it will be understood that the entire native sequence of the target nucleic acid may be employed.","Conveniently, the target nucleic acid may be coupled to a selectable marker.","The preferred cell is a eukaryotic cell and even more preferred is a mammalian cell.","In certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.","Preferably the antisense nucleic acid corresponds to a part only of the target nucleic acid.","According to a fourteenth aspect there is provided a cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses said target nucleic acid and (ii) comprises an elevated level of said target nucleic acid, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.","The preferred cell is a eukaryotic cell and even more preferred is a Schizosaccharomyces pombe cell.","According to a fifteenth aspect there is provided a method of identifying a cellular factor capable of effecting and/or modulating expression of a target nucleic acid in a cell having the target nucleic acid and a nucleic acid which is an antisense of the target nucleic acid or part thereof, which method comprises over-expressing said factor in the cell and wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.","According to a sixteenth aspect there is provided a factor identified by the method of the fifteenth aspect.","The preferred factors can be selected from the group consisting of a gene, cDNA, RNA or a protein.","More preferred are factors selected from the group consisting of a transcriptional activator or the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.","Even more preferred is a factor having an res sequence.","Preferred factors can also be selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.","According to a seventeenth aspect there is provided an RNAi factor which is an res sequence obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.According to an eighteenth aspect there is provided an RNAi factor which is an res sequence represented by Seq ID Nos 1 to 4.According to a nineteenth aspect there is provided a Schizosaccharomyces pombe cell having a target nucleic acid or a part thereof and a antisense nucleic acid or a part thereof which corresponds to the target nucleic acid or a part thereof, wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.","The term “inhibiting expression of a target nucleic acid” as used in the context of the present invention is intended to encompass, but not be limited to, reduction or elimination of gene expression, whether or not the target nucleic acid is a gene, or a part thereof, introduced into the cell or it is an endogenous gene.","The term “RNAi factor” is intended to include in its scope any naturally occurring, modified or synthetic molecule capable of enhancing RNAi activity.","This definition includes in its scope the factors referred to herein as RNAi enhancing sequences (res).","The term res may be used herein interchangeably with the term aes (anti-sense enhancing sequences).","It will be understood by those skilled in the art that “elevating RNAi factor level” can be achieved by transfection, upregulation or other means known in the art.","The term “anti-sense nucleic acid molecule” as used in the context of the present invention is intended to encompass RNA or DNA and contain region(s) related to a specific target RNA transcript or its gene.","It is also intended to include molecules giving rise to antisense sequences, including inverted repeat, sense RNA, etc.","The term “conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid molecule inhibits expression of the gene” is intended to include the concept of inhibition of gene expression which is high enough to be effective, but not so high as to harm the cell.","The effective concentration range can be determined using routine methodology known in the art.","Reference to a “subject” is intended to include human, animal (mouse), plant, or other life forms.","Reference to a “cell” is intended to encompass eukaryotic cells such as yeast, mammalian, plant, etc The term “disorder” will be understood to include viral infection (HIV, HPV, etc), cancer, autoimmune disease and other chronic and acute diseases.","The term “phenotype” as used in the context of the present invention is intended to include cell staining, morphology, growth, and similar characteristics.","BRIEF DESCRIPTION OF THE FIGURES FIG.","1.Target genes and antisense fragments.","a, The strain KC4-6 expresses low levels of lacZ RNA.","The lacZ expression cassette is integrated at the ura4 locus on chromosome III and is composed of the SV40 early promoter, the E. coli lacZ gene and the SV40 3′ processing signal.","The 5′ and 3′ flanking DNA sequences of the ura4 locus are as indicated.","b, The strain RB3-2, which expresses high levels of lacZ RNA, contains an expression cassette containing the S. pombe adh1 promoter, the lacZ coding region, and the S. pombe ura4 3′ processing signal.","c, The full-length 3.5 kb antisense lacZ fragment is shown.","The crippled sense fragment was generated by end-filling the ClaI cut lacZ vector and religating on itself.","d, The AML1 strain contains a c-myc-lacZ fusion cassette integrated at the ura4 locus.","Exons 2 and 3 of the human c-myc gene were employed as a target.","The relative position of the c-myc antisense fragment is shown.","Transcription initiation sites are indicated by the bent arrows.","The straight arrows represent the normal direction of transcription for a particular DNA fragment.","FIG.","2.dsRNA-mediated gene silencing in fission yeast.","a, A fission yeast strain containing the integrated lacZ gene under control of the strong adh1 promoter was transformed with lacZ antisense vectors.","The antisense gene was under control of the weak nmt41 promoter (low antisense), the strong nmt1 promoter in single copy (15) (medium antisense), or the nmt1 promoter in multi-copy (high antisense).","For the strain expressing maximum antisense RNA two episomal nmt1-driven antisense vectors containing different selectable markers were co-transformed into the target strain.","b, A fission yeast strain containing the integrated lacZ gene under control of the weak SV40 promoter (low target) or strong adh1 promoter (high target) was transformed with the antisense lacZ vector or antisense lacZ and sense lacZ vectors.","Strains were co-transformed with vectors containing appropriate selectable markers to complement auxotrophy.","c, The lacZ inverted repeat vector was expressed in the high-expressing lacZ target strain.","The strain expressing the antisense construct only is also indicated.","d, A fission yeast strain containing an integrated c-myc-lacZ fusion gene was transformed with the sense construct, the antisense construct, or both.","Antisense and sense constructs were also expressed in the high-expressing lacZ strain.","All strains were transformed with appropriate control plasmids to complement auxotrophy.","FIG.","3.Effect of co-expressing single copies of sense and antisense genes.","Strains containing target lacZ alone (RB3-2), the target and a single copy of the antisense gene (K40-7), and the target and both the antisense and frameshifted lacZ genes (M62-1) were assayed for β-galactosidase activity.","pREP2 and pREP4 are parental plasmids containing the LEU2 and ura4 selectable markers respectively.","Strains were transformed with the appropriate control plasmids to complement auxotrophy.","For each sample three independent colonies were assayed in triplicate.","FIG.","4.RNA expression profiles in fission yeast strains a, The target strain RB3-2 was transformed with the lacZ inverted repeat vector (pM53-1) or co-transformed with antisense (pGT2) and sense (pM54-3) vectors and grown to mid-log in the absence of thiamine.","Total RNA from each strain was separated on a 1% denaturing agarose gel, transferred to a nylon membrane and probed with the radioactively labeled 2.2 kb nmt1 fragment.","The episomal lacZ signal was normalized with the endogenous nmt1 transcript and quantitated by phosphorimage analysis.","The relative level of episomal lacZ expression is shown.","b, The strain M38-1 which contains a single copy stably integrated lacZ inverted repeat gene was grown to mid-log in the absence of thiamine, its RNA isolated and analyzed by Northern hybridization.","The relative steady-state level of the “panhandle” lacZ RNA is indicated in comparison to episomally expressed antisense lacZ RNA.","FIG.","5.In vivo dsRNA assay.","a, The constructs employed for assaying the ability of the lacZ inverted repeat to form an intramolecular RNA duplex are shown.","Each vector contains a functional lacZ fragment which gives the transformed strain a blue color phenotype when grown in the presence of X-GAL.","The predicted secondary structure of the pM81-2 generated transcript is indicated.","b, The strain 2037 was transformed with the vectors pM85-1, pM91-1 and pM81-2 in the absence of thiamine Single colonies were streaked on minimal media plates and overlayed with 0.5% agarose medium containing 500 μg/ml X-gal and 0.01% SDS.","FIG.","6.The effect of ded1 on dsRNA-mediated gene regulation.","a, The ded1 gene was co-expressed in a fission yeast strain containing the integrated lacZ gene.","β-galactosidase activity of the strain transformed with and without the antisense lacZ vector is shown.","b, The target strain was transformed with a vector expressing a short lacZ antisense gene or with both the short lacZ antisense vector and the ded1-expressing vector.","Strains were transformed with appropriate control plasmids to complement auxotrophy.","FIG.","7.Over-expression of thi1 in an antisense lacZ expressing strain.","β-galactosidase activity of the target strain RB3-2 transformed with and without the antisense lacZ vector is shown.","Over-expression of the thi1 gene in the antisense expressing strain is also indicated.","Strains were transformed with appropriate control plasmids to complement auxotrophy.","FIG.","8.Over-expression screening strategy for RNAi modulating factors.","A target strain containing the integrated lacZ gene under control of the adh1 promoter and the episomal vector containing the nmt1-driven lacZ antisense gene is transformed with an S. pombe cDNA library.","Library fragments are driven by the nmt1 promoter.","Transformants are individually screened for a change in the lacZ-encoded blue colony colour phenotype.","These transformants are then quantitatively assayed for β-galactosidase activity in the presence and absence of thiamine.","The antisense vector is then segregated out of transformants showing a cDNA dependent modification of lacZ suppression.","A tertiary β-galactosidase assay is performed to determine if the effect is dependent on the presence of dsRNA.","cDNA vectors are recovered from strains of interest, sequenced, and subjected to BLASTN analysis.","FIG.","9.Over-expression screen of a S. pombe cDNA library.","a, Transformants were grown on minimal media plates and over-layed with X-GAL-containing medium.","Those which showed a reduced blue colour-phenotype (black arrow) were analysed further.","Transformants demonstrating an enhanced blue-colour phenotype were also identified (white arrow).","b, Transformants which showed a visual reduction in the blue phenotype were assayed for β-galactosidase activity in liquid culture in the absence of thiamine.","Thiamine was added to the medium to demonstrate that the enhanced lacZ suppression was dependent on RNA expression.","Transformants were again assayed for β-galactosidase activity following antisense vector segregation.","c, Over-expression of unique res genes in dsRNA-expressing strains.","FIG.","10.lacZ panhandle-mediated gene silencing.","(A) The lacZ panhandle construct contains the full-length crippled lacZ gene which is followed by the inverted 5′ 2.5 kb lacZ fragment.","Intramolecular hybridization generates an RNA with 2.5 kb RNA duplex and a 1 kb loop.","(B) The relative steady-state level of the episomally expressed panhandle lacZ RNA (7.0 kb) is shown in comparison to episomally expressed antisense lacZ RNA (4.5 kb).","The lacZ signals were normalized to the endogenous nmt1 transcript (1.3 kb) and quantitated by phosphorimage analysis.","(C) The target strain was transformed with the episomally expressed lacZ panhandle and analyzed for b-galactosidase activity.","The appropriate plasmids were co-introduced to complement auxotrophy.","At least three independent colonies were assayed in triplicate for each strain.","Transformants were assayed in the presence of thiamine to abrogate expression of the panhandle RNA (hatched).","(D) The target lacZ strain was transformed with the panhandle vector only or both the panhandle and aes2 vector.","FIG.","11.Co-expression of ded1 and lacZ antisense genes.","b-galactosidase activity of the target strain co-transformed with the ded1 gene and the antisense lacZ vectors is shown.","Ded1 was expressed from the ura4-based plasmid pREP4 while the antisense genes were expressed from the LEU2-based plasmid pREP2.Strains expressing antisense RNAs or ded1 RNA alone are also indicated.","Strains were transformed with appropriate control plasmids to complement auxotrophy.","Three independent colonies were assayed in triplicate for each strain.","FIG.","12.DNA sequence for aes1 factor FIG.","13.DNA sequence for aes2 factor FIG.","14.DNA sequence for aes3 factor FIG.","15.DNA sequence for aes4 factor DESCRIPTION OF THE PREFERRED EMBODIMENTS Using the lacZ fission yeast model to investigate features of antisense-RNA technology in vivo (1-4), it has been shown that the degree of target gene suppression is dependent on the level of antisense RNA (FIG.","2A)(1).","During the course of developing this model it was surprisingly found that by increasing the steady-state levels of the lacZ target mRNA 20-fold in the presence of the same pool of antisense RNA that antisense-mediated suppression was not only maintained, but enhanced (FIG.","2B).","To verify that this effect was independent of the target mRNA a lacZ gene containing a frameshift mutation (leading to an inability to translate the β-galactosidase enzyme) was co-expressed in antisense-expressing strains.","Again, additional stimulation of lacZ inhibition was observed (FIG.","2B).","These observations are consistent with the potential formation of additional dsRNA and consequent stimulation of gene silencing.","They also indicate that the dsRNA-mediated gene silencing is dose-dependent in this system.","To further show that dsRNA was the key component in target gene inhibition in fission yeast dsRNA was generated by expressing a lacZ inverted repeat with 2.5 kb of internal complementarity in the presence of lacZ target mRNA.","Expression of this construct also reduced β-galactosidase activity in a lacZ expressing strain to a similar level to the full-length antisense RNA (FIG.","2C).","Overall, these data suggested that increasing the potential formation of dsRNA, but not necessarily an antisense RNA:target mRNA hybrid, resulted in efficient interference of target gene expression in S. pombe.","To test the ability of dsRNA to specifically interfere with another target sequence in fission yeast, sense and antisense c-myc sequences were co-expressed in a strain containing an integrated c-myc-lacZ fusion cassette (3).","A 792 bp antisense c-myc fragment from exon 2 of the human c-myc gene was previously found to suppress β-galactosidase activity within the c-myc-lacZ fusion target strain by 47% (3).","β-galactosidase assays demonstrated that co-expression of the antisense and sense c-myc constructs in the target strain enhanced c-myc suppression compared with the antisense c-myc vector alone (FIG.","2D).","Transformation of the strain expressing only the lacZ target with the antisense and sense c-myc constructs resulted in no down-regulation of β-galactosidase activity indicating that the action of dsRNA is sequence-specific (FIG.","2D).","All of the above observations, as well as the reduction in target mRNA levels in response to additional dsRNA (data not shown), are consistent with features associated with RNAi.","This is the first example of dsRNA-mediated gene regulation in yeast and, unlike RNAi in all other organisms except zebrafish, appears to be dependent on the concentration of intracellular dsRNA.","The variation in RNAi efficacy between organisms may be due to the absence or under-expression of some components of the RNAi pathway or the presence of RNAi inhibitors.","We have now further developed this genetic model for identification of factors involved in RNAi.","Without wishing to be bound by any particular mechanism, it is probable that a multi-protein complex exists which mediates the post-transcriptional degradation of target mRNA in RNAi.","Several genes which are involved in the RNAi phenomenon have been identified through genetic screens in Neurospora and nematodes.","These genes include an RNA-dependent RNA polymerase (qde-1, ego-1) a RecQ DNA helicase (qde-3), an RNase D homologue (mut-7), and a putative translation initiation factor (rde-1, qde-2).","The genes mut-2, rde-2, rde-4, and rde-7 have also been identified as being involved in either the initiation or maintenance of RNAi.","Additionally, Drosophila cell free assays have shown that RNAi is mediated by nuclease degradation of the targeted mRNA while a 21-25 nt RNA species appears to be integral to specific post-transcriptional genetic interference.","RNAi has also been shown to be dependent on ATP which may be required for strand dissociation of dsRNA.","However, a missing component of the proposed multi-protein complex in the RNAi pathway is the implied RNA helicase.","The dose-dependency of dsRNA-mediated gene silencing in fission yeast described above has allowed us to use an over-expression strategy to identify genes involved in RNAi.","In comparison to mutagenesis strategies, over-expression can enable the identification of genes which are otherwise essential for cell viability.","Also, cellular factors that quantitatively enhance or reduce RNAi activity can be determined.","The first gene that was tested in mediating RNAi activity in the present model was the nmt1 transcription factor thi1.This gene has been shown to specifically up regulate nmt1 expression when overexpressed in fission yeast.","As we have previously shown that antisense RNA-mediated gene suppression is dose dependent in S. pombe (1) it was hypothesized that over-expression of thi1 would result in increased production of nmt1-driven antisense lacZ RNA and a consequent enhancement in target gene suppression.","The thi1 open reading frame was PCR amplified and subcloned into pREP4 as a BamHI fragment.","This vector was then transformed into RB3-2/pGT2 and β-galactosidase assays performed.","As predicted, lacZ suppression was enhanced when compared to a strain expressing antisense RNA alone (FIG.","7).","This result indicated that host-encoded factors are present which affect the robustness of dsRNA-mediated gene suppression in fission yeast and also validated the overexpression strategy.","The second gene investigated has been the S. pombe ATP-dependent RNA helicase gene, ded1.Ded1 is an essential gene which has previously been characterized as a suppressor of sterility, a suppressor of checkpoint and stress response, and a general translation initiation factor.","According to current models of dsRNA-mediated gene regulation an ATP-dependent RNA helicase may be required in conjunction with a dsRNA-dependent RNA polymerase for the formation of short single-stranded RNA fragments which specifically degrades target mRNA.","It was therefore reasoned that over-expression of this gene in fission yeast could enhance the efficiency of dsRNA-mediated gene silencing by stimulating the unwinding of dsRNA.","Co-expression of the ded1 vector with the antisense lacZ vector significantly enhanced dsRNA-mediated lacZ inhibition by a further 50% compared to the antisense expressing strain (FIG.","6A).","When ded1 was over-expressed in the absence of the antisense lacZ vector, β-galactosidase activity was comparable to control strains indicating that its effect was dependent on the presence of dsRNA (FIG.","6A).","The ded1 vector was also co-expressed with a short antisense lacZ vector which has previously been shown to be less effective than the full-length antisense gene (16).","Again, the over-expression of ded1 stimulated dsRNA-mediated lacZ inhibition (FIG.","6B).","It was thus shown that over-expression of an ATP-dependent RNA helicase greatly enhances RNAi in fission yeast.","By over-expressing a cDNA library in a dsRNA fission yeast model we have identified four novel, genes with potential roles in the RNAi pathway.","All of the known genes identified are essential and have natural associations with DNA, RNA or nucleic acid binding proteins, consistent with the expectation of RNAi cellular factors.","In addition, two of the three known cDNAs encoded proteins involved in the process of translation.","These findings along with our previous identification of an ATP-dependent RNA helicase (Raponi & Arndt, submitted) and reports of the involvement of a translation initiation factor in RNAi and the co-purification of ribonuclease activity with ribosomal fractions, suggests that this may be one site at which RNAi functions.","Alternatively, the identification of such varied proteins as DNA helicases and translational components as part of the RNAi machinery implies that particular cellular proteins may be recruited into more than one multiprotein complex.","Under the latter conditions, over-expression of these specific proteins may result in the generation of an RNAi complex that recognises dsRNA and mediates target gene suppression.","Certain of these proteins may be rate-limiting or rate-determining in RNAi and only through supplementation of these factors are their roles in RNAi uncovered.","It is proposed, without wishing to be bound by any particular mechanism, that in addition to the previously identified core proteins in the RNAi multiprotein complex(es), additional factors such as EF Tu, L7a, sna41 and res1 may be enlisted for a role in dsRNA-mediated gene suppression.","The over-expression strategy described overcomes some limitations associated with mutagenesis by identifying essential genes with a role in RNAi.","In addition, this strategy complements these other systems by allowing the isolation of cellular factors that modify the efficacy of RNAi in vivo.","The roles of these modulators of RNAi may be varied and include recognition and amplification of the dsRNA, delivery of the small 21-25 nt dsRNAs to the target mRNA, association between the antisense and target mRNA strands, and RNAi complex formation.","Alternatively, these modulators may control the rate of RNAi or the formation of different complexes within cell types or for different forms of post-transcriptional gene silencing.","The fact that over-expression of specific RNAi modulators enhanced dsRNA-mediated gene regulation in fission yeast indicates that a similar approach could be used to identify RNAi modulators in other organisms.","In addition, the co-expression of these factors with different forms of post-transcriptional gene silencing including co-suppression, quelling, and antisense RNA could be one way of enhancing the efficacy of these methods.","This may be especially important for application of RNAi to mammalian cells and tissues or to genes which have been somewhat recalcitrant to this form of regulation.","The present invention demonstrates for the first time the intrinsic involvement of an ATP-dependent RNA helicase as a key component in RNAi.","Further, it can be rate limiting, as the over-expression leads to increased RNAi activity in this system.","This ability of the ded1-encoded RNA helicase is consistent with its activities as a member of the DEAD box family of helicases, with their three core domains of ATPase, RNA helicase, and RNA binding activities.","These could allow the enzyme to enhance gene suppression as follows: (i) in a dissociative mechanism it could mediate either the unwinding of dsRNA to generate a cRNA in conjunction with an RNA-dependent RNA polymerase or strand separation of fragmented dsRNA to enhance binding to homologous transcripts, and/or (ii) in an associative mechanism it could catalyse the ATP-dependent exchange of the sense strand of the short dsRNA with the target mRNA.","The presence of ded1 homologues in other organisms displaying RNAi further supports the general involvement of this component in the RNAi machinery.","The present invention also provides for the first time a novel and quantitative genetic system based on S.pombe, for rapidly identifying essential cellular factors involved in RNAi.","The use of this model has enabled verification of RNA helicase activity as a critical contributor to efficient RNAi activity and isolated novel RNAi factors including EF Tu, L7a, sna41, and an unidentified gene res1.The present invention also demonstrates that gene silencing may be enhanced by concomitant expression of such RNAi factors.","The invention will now be described more particularly with reference to non-limiting examples of certain preferred embodiments of the invention.","Example 1 Materials and Methods Used to Exemplify the Invention S. pombe Media and Manipulations.","All yeast strains were maintained on standard YES or EMM media (6).","Repression of nmt1 transcription was achieved by the addition of thiamine to EMM media at a final concentration of 4 μM (7).","Yeast cells were transformed with plasmid DNA by electroporation (8) and stable integrants were identified as previously described (6).","A glass bead procedure (9) was used to isolate genomic DNA which was used for Southern analysis and PCR diagnosis.","Total RNA was extracted as previously described (10).","S. pombe Strain and Plasmid Construction.","Construction of the low expressing lacZ strain, KC4-6 (h−, ura4::SV40-lacZ, leu1-32), has been previously described (2).","The strain RB3-2 (h−, ura4::adh1-lacZ, leu1-32) which expresses higher levels β-galactosidase has also been previously described (1).","The target strain which contains the c-myc:lacZ fusion has previously been described (3).","The construction of the long lacZ antisense containing episomal plasmid, pGT2, and corresponding control plasmids have been described (2).","Plasmid pREP4-As was generated by subcloning the lacZ BamHI fragment contained in pGT2 into the plasmid pREP4 (11).","pREP4 is identical to pREP1 except that the S. cerevisiae LEU2 gene has been replaced with the S. pombe ura4 selectable marker.","To decrease the steady-state level of episomally expressed antisense lacZ, plasmids pREP42-As and pREP82-As were constructed by subcloning the lacZ BamHI fragment from pGT2 into pREP42 and pREP82, respectively.","These plasmids are derivatives of pREP4 with mutations in the TATA box of the nmt1 promoter (12).","The crippled lacZ vector, pGT62, was generated by end-filling the ClaI site of pGT2 and re-ligating (2).","This frameshifted fragment was then subcloned into the BamHI site of pREP4 to generate the plasmid pM54-3.The lacZ panhandle integration vector, pM30-8, was generated by first introducing a NotI site into the XmaI site of pRIP1/s (11) using the self-complementary linker 5′ CCG GGC GGC CGC 3′ to generate pL121-14.The 2.5 kb sequence of the 5′ end of the frameshifted lacZ gene (2) was then PCR-amplified to give it NotI ends using the forward primer 5′ ATGCGGCCGCAATTCCCGGGGATCGAAAGA 3′ and reverse primer 5′ ATGCGGCCGCAATGGGGTCGCTTCACTTA 3′.","This product was cloned using a TA cloning kit (TOPO: Invitrogen, San Diego, Calif., USA) and then subcloned into the NotI site of pL121-14 in the antisense orientation.","The integrating vector was introduced into target strains in single copy by using the sup3-5/ade6-704 complementation system (13).","The full-length frameshifted lacZ fragment was then introduced into the BamHI site of this vector in the sense orientation upstream of the 2.5 kb antisense fragment to generate pM30-8.The episomal version of this vector (pM53-1) was made by removing the Pst1 sup3-5 fragment and introducing the autonomous replicating sequence as an EcoRI fragment (11).","For testing the ability of the panhandle construct to form dsRNA in vivo, the frameshifted lacZ fragment was replaced with the functional lacZ fragment in the vectors pM54-3 and pM53-1, to generate the vectors pM85-1 and pM81-2, respectively.","The vector pM91-1, which is unable to form a lacZ panhandle transcript, was generated by removing the 2.5 kb NotI lacZ fragment from pM81-2 and reintroducing it in the sense orientation.","Generation of the c-myc antisense construct, pCM-17, has been described elsewhere (3).","The 792 by BglII c-myc fragment from pCM-17 was subcloned into the BamHI site of pREP4 in the sense orientation to generate pN12-1.The ded1, and thi1, open reading frames were amplified from fission yeast genomic DNA (strain 1913).","ded1 was amplified to give it BamHI ends using the forward primer 5′ ATGGGATCCCAACCAAACACTTCAACTCAG 3′ and the reverse primer 5′ ATGGGATCCTCAGAAGCCTGTGCATAACAC 3′.","thi1 was amplified to give it BglII ends using the forward primer 5′ ATGAGATCTGTGGTTGGTATTCTAGAGAGA 3′ and the reverse primer 5′ ATGAGATCTAACAAAGACCTGCAAAAAACC 3′.","PCR products were purified (Qiagen PCR purification kit), digested with either BamHI or BglII, gel-purified (Qiagen), and subcloned into the BamHI site of pREP4 in the sense orientation.","Southern and Northern Analysis.","Nucleic acid electrophoresis and membrane transfer was performed as described (14).","Southern and Northern blots were hybridized using ExpressHyb solution according to the manufacturer's instructions (Clontech Laboratories).","DNA probes were 32P-labelled using the Megaprime labelling kit (Amersham).","Probes included a 960 bp BamHI/ClaI lacZ fragment from pI2-1 (1), a 570 by HindIII/EcoRI ura4-3′ fragment from pGT113 (15), and a 2.2 kb PstI/SacI nmt1 fragment from pRIP1/s.","Radioactive signals were detected by autoradiography and quantitated by phosphorimage analysis (ImageQuant; Molecular Dynamics).","Plasmid Distribution Analysis.","Plasmid co-transformants of strain RB3-2 were grown under selective conditions to a cell density of 1-2×107 cells/ml.","A serial dilution of each culture was performed and cells plated for single colonies in triplicate onto each of YES, EMM, EMM+leucine, and EMM+uracil agar media.","The number of colonies grown on YES was taken as the total number of viable cells, while colonies growing on EMM represented the cells in the sampled population that contained both the ura4-containing (pREP4-based) and the LEU2-containing (pREP1-based) plasmids.","Cells containing either the ura4-containing plasmid or the LEU2-containing plasmid were identified from the EMM+leucine and EMM+uracil plates respectively.","The ratio of the number of colonies grown on selective media to the total number of viable colonies was used as the quantitative measure of the proportion of cells in the population, grown under selection, which contained plasmids.","β-galactosidase Assays.","The expression of the lacZ gene-encoded product, β-galactosidase, was quantitated using a cell permeabilization protocol as previously described (Raponi et al., 2000).","A semi-quantitative overlay assay was also employed for rapid screening of yeast transformants (3).","Isolation of S. pombe cDNA Clones That Alter Antisense RNA Efficacy.","The S. pombe cDNA library was originally constructed in pREP3Xho by Bruce Edgar and Chris Norbury (5).","The vector pREP3Xho is derived from pREP3 which contains the LEU2 marker and inserts are under control of the nmt1 promoter (11).","A total of 5 μg of library DNA was transformed into the strain RB3-2 containing the episomal antisense lacZ vector pREP4-lacZAS and grown in EMM liquid media to the mid-logarithmic phase.","Transformants were then plated on EMM solid media and grown at 30° C. for 3 days.","Colonies were over-layed with medium containing 0.5 M sodium phosphate, 0.5% agarose, 2% dimethylformamide, 0.01% SDS, and 500 μg/ml X-GAL (Progen, Australia).","Plates were then incubated at 37° C. for 3 hrs, colonies of interest recovered and assayed for β-galactosidase activity.","Plasmid Segregation.","Strains were plated on EMM containing limiting uracil and 1 mg/ml 5-fluoroorotic acid (6).","Strains were then replica plated on both selective and non-selective media.","Those colonies that did not grow on selective media were identified as having lost the ura4-containing antisense plasmid.","To determine the mitotic stability of pREP-based plasmids we used the plasmid segregation method previously described (16).","This method indicated that up to 30% of the cells grown in selective media did not contain the resident plasmid.","Example 2 Effect of Steady-State Level of Target mRNA and Antisense RNA on Antisense Efficacy To determine the role of target mRNA steady-state levels in antisense-mediated gene suppression, we investigated the ability of a long lacZ antisense RNA (2) to regulate lacZ target genes under control of both weak and strong constitutive promoters.","The low-level expressing strain, KC4-6, contained the lacZ gene driven by the SV40 early promoter integrated at the ura4 locus in chromosome III (FIG.","1A; (2)).","The high-level lacZ expressing strain, RB3-2, was constructed by placing the lacZ gene under control of the strong fission yeast adh1 promoter and the 3′ processing signal from the ura4 gene and integrating this expression cassette at the ura4 locus (FIG.","1B; (1)).","Characterization of both strains indicated that RB3-2 expressed 20-fold more lacZ mRNA than KC4-6 while an approximate 40-fold increase in β-galactosidase was also detected (data not shown).","Both strains were transformed with the lacZ antisense gene-containing plasmid (pGT2) and its corresponding sense control plasmid (pGT62).","β-galactosidase assays indicated that the antisense RNA suppressed β-galactosidase activity by 45% in KC4-6 while the same RNA reduced β-galactosidase activity by 52% in RB3-2 (FIG.","2B).","No reduction in β-galactosidase activity was seen in either strain when transformed with the control plasmid pGT62 which expresses a crippled version of lacZ.","These results indicated that despite a 20-fold increase in the steady state level of the lacZ target mRNA in RB3-2 the efficacy of antisense-mediated down regulation was not only maintained, but enhanced.","The increase in gene suppression demonstrated with strain RB3-2 was also seen when antisense molecules targeted to subregions of the lacZ target gene were used, but was not as pronounced.","These data suggested an increase in target mRNA can result in enhanced target gene suppression.","It has previously, been demonstrated that a stably integrated antisense lacZ gene acts in a dose dependent fashion with the steady-state levels of antisense RNA being dependent on genomic position effects and transgene copy number (1).","Here the role of the steady-state level of episomally expressed antisense RNA in both the low lacZ expressing target strain, KC4-6, and the high lacZ expressing target strain, RB3-2, was investigated.","The expression of lacZ antisense RNA was increased by co-transforming KC4-6 and RB3-2 with plasmids pGT2 and pREP4-As, each of which contains the lacZ antisense gene under control of the nmt1 promoter, but different selectable markers.","To decrease the steady-state level of antisense RNA, the plasmids pREP42-As and pREP82-AS were employed.","The nmt1 promoter in these vectors contain deletions in the TATA box sequence which affect the level of transcription, but have no impact on the site of transcription initiation or thiamine repressibility (12).","Each of the different antisense gene-containing plasmids was co-transformed with a control plasmid to complement auxotrophy where appropriate.","This resulted in a set of co-transformants of both RB3-2 and KC4-6 each containing the same lacZ antisense gene, but with different promoter capacities.","Each co-transformant was analyzed for antisense RNA steady-state levels and β-galactosidase activity.","Table 1 indicates that with both strains the degree of target suppression is enhanced with the increase of antisense lacZ RNA expression.","TABLE 1 Effects of varying the level of antisense RNA in strains expressing both low and high level target.","Relative β-gal.","activity antisense Strain Plasmids Descriptions (units) % suppressiona RNA levelb KC4-6 pREP2, pREP4 Vector 1.07 0 0 pREP2, pREP82-AS Low As 1.10 0 0.04 pREP2, pREP42-AS Medium As 1.07 0.1 0.14 pREP2, pREP4-AS Full As-ura4 0.75 30 1.0 pGT2, pREP4 Full As-LEU2 0.70 34.6 2.2 pGT2, pREP4-AS Double-As 0.54 49.2 5.6 RB3-2 pREP2, pREP4 Vector 48.5 0 0 pREP2, pREP82-AS Low As 44.0 9.4 0.05 pREP2, pREP42-AS Medium As 43.9 9.6 0.18 pREP2, pREP4-AS Full As-ura4 27.2 43.9 1.0 pGT2, pREP4 Full As-LEU2 24.9 48.7 1.9 pGT2, pREP4-AS Double-As 16.6 65.8 5.4 aThe % suppression of β-galactosidase activity was determined by expressing each β-galactosidase activity as a percentage of the activity found in the pREP2, pREP4 co-transformant.","bWithin each strain the steady-state level of long lacZ antisense RNA was normalized to nmt1 mRNA and then expressed relative to the level observed in the pREP2, pREP4-As co-transformant.","These data agree with the previous report that antisense RNA-mediated gene inhibition is dose dependent in S. pombe (1).","However, for each co-transformant the degree of β-galactosidase suppression was greater by 10-15% in the high lacZ expressing strain, RB3-2, than the low lacZ expressing strain, KC4-6, again demonstrating that low levels of target mRNA can limit antisense efficacy.","Example 3 Effect of Increasing Sense RNA on Antisense RNA-Mediated Target Gene Suppression To determine whether the increase in gene suppression was due to formation of an antisense RNA:target mRNA hybrid or an antisense RNA:sense RNA hybrid, a version of lacZ which is unable to be translated into functional β-galactosidase was co-expressed in strains expressing the lacZ antisense gene.","If antisense RNA was required to hybridize to target mRNA for inhibition of the gene expression pathway, then over-expression of the sense RNA would compete with the target for the available antisense molecules and a decrease in lacZ gene suppression would result.","Initially, both antisense and sense lacZ vectors were integrated in single copy into separate target strains and then crossed with each other.","In strains containing the antisense gene alone, β-galactosidase activity was reduced by approximately 40% (FIG.","3; (1)) while there was no reduction in the strain expressing sense lacZ alone (data not shown).","However, in the strain expressing both complementary transcripts (M62-1), β-galactosidase activity was reduced by 50% (FIG.","3).","These results suggested that increasing the intracellular concentration of sense RNA in the presence of antisense RNA, and therefore potentially generating more dsRNA, stimulates target gene suppression.","To further increase the potential formation of intracellular dsRNA an episomal sense lacZ plasmid (pM54-3; FIG.","2B) was co-transformed with the episomal antisense lacZ plasmid, pGT2, into the target strain R133-2.Both of these sequences were expressed by the strong conditional nmt1 promoter and RNA analysis showed that each transcript was being expressed at high levels when grown in the absence of thiamine (FIG.","4A).","When both RNAs were co-expressed in RB3-2, the target lacZ was suppressed by 65% compared to 50% in the strain expressing the antisense plasmid alone (FIG.","2B).","Northern analysis demonstrated that the total relative level of episomally expressed nmt1-driven transgenes was approximately 60% higher than when either vector was expressed alone (FIG.","4A).","Although expression of these complementary RNA transcripts is at a high level compared with single copy integrants only an additional 15% suppression was observed.","One explanation for the absence of higher levels of target gene suppression is plasmid segregation.","S. pombe undergoes asymmetric segregation, with the result that mitosis produces a daughter cell which lacks the segregating plasmid (17).","Therefore, when the 65% suppression level seen in the total population is corrected for only those cells containing the ura4-based and LEU2-based plasmids the level of suppression approaches approximately 100% (data not shown).","Overall these data suggest that increasing the potential formation of dsRNA, but not necessarily an antisense RNA:target mRNA hybrid, is required for efficient interference of target gene expression in S. pombe.","However, unlike the phenomenon of RNAi seen in plants and nematodes, the dsRNA-mediated gene suppression demonstrated in fission yeast seems to be dependent on the concentration of intracellular dsRNA or a threshold level of dsRNA is required to invoke potent gene silencing.","Example 4 Effect of a lacZ Inverted Repeat on lacZ Gene Expression To further investigate the ability of dsRNA to inhibit gene expression in fission yeast we generated a vector containing the full-length 3.5 kb frameshifted lacZ sequence with a 2.5 kb inverted repeat.","This construct generates a transcript of approximately 7 kb in length with 2.5 kb of self-complementarity which, predictably, will form a strong intramolecular RNA duplex.","This gene was initially integrated into a fission yeast strain in single copy and then crossed with the strain RB3-2.The resulting strain which contained the single copy inverted repeat gene and target lacZ showed no reduction in β-galactosidase activity when transcription of the inverted repeat was activated.","Southern analysis confirmed that the cassette was intact (data not shown) while RNA analysis indicated that the 7 kb transcript was being generated but approximately 10-fold less than episomally expressed antisense lacZ (FIG.","4A&B).","To increase the steady-state level of the inverted repeat RNA we generated the episomal plasmid pM53-1 containing this cassette.","RNA analysis demonstrated that this vector is expressed at a similar level to episomally expressed antisense lacZ (FIG.","4A).","When expressed in RB3-2 pM53-1 inhibited β-galactosidase activity by 40% (FIG.","2C), while addition of thiamine to the culture medium returned β-galactosidase activity to control level.","To confirm that gene inhibition was due to this construct forming an RNA duplex, an in vivo assay for dsRNA was developed.","To this end, a series of vectors were generated which contained functional lacZ sequences including lacZ alone (pM85-1), a lacZ inverted repeat (pM81-2), and the lacZ repeat with both sequences in the sense orientation (pM91-1) (FIG.","5A).","These vectors were then introduced into a strain lacking the integrated target sequence (NCYC2037; h+, ura4-D18) and resulting transformants were overlayed with X-GAL-containing agarose.","Both strains containing control vectors generated high levels of β-galactosidase while the strain expressing the lacZ inverted repeat did not (FIG.","5B).","In each case Northern analysis demonstrated that strains were expressing the transgene.","These results indicate that the inverted repeat RNA could not be efficiently translated to produce β-galactosidase, most probably due to the formation of a strong intramolecular hairpin structure.","Taken together, these results show that a construct which has the ability to form dsRNA by intramolecular hybridization will interfere with target gene expression when expressed at high levels, again indicating that dsRNA mediates target gene suppression in a dose-dependent manner in fission yeast.","Example 5 Gene-Specificity of dsRNA-Meditated Gene Silencing in Fission Yeast To test the ability of dsRNA to specifically interfere with other target sequences in fission yeast, sense and antisense c-myc sequences were co-expressed in a strain containing an integrated c-myc-lacZ fusion cassette (FIG.","1D; (3)).","A 792 bp antisense c-myc fragment from exon 2 of the human c-myc gene (named CM-17) was previously found to suppress β-galactosidase activity within a c-myc-lacZ fusion target strain (AML1) by 47% (3).","CM-17 was subsequently subcloned into pREP4 in the sense orientation to generate pN12-1.The antisense c-myc vector (pCM-17) and the sense c-myc vector were transformed into AML1 both independently and together.","β-galactosidase assays demonstrated that co-expression of the antisense and sense constructs enhanced c-myc suppression by an additional 13% compared with the antisense c-myc vector alone (FIG.","2D).","Transformation of RB3-2 with the antisense and sense c-myc constructs resulted in no down-regulation of β-galactosidase activity indicating that the action of dsRNA is gene-specific (FIG.","2D).","These results demonstrate that dsRNA can specifically interfere with multiple targets in fission yeast including one of human origin.","Example 6 Over-Expression of a Translation Factor can Enhance RNAi in Fission Yeast The dose-dependency of dsRNA-mediated gene silencing in fission yeast described above has allowed us to use an over-expression strategy to identify genes involved in RNAi.","In comparison to mutagenesis strategies, over-expression can enable the identification of genes which are otherwise essential for cell viability.","Also, cellular factors that quantitatively enhance or reduce RNAi activity can be determined.","The first gene that we have tested in mediating RNAi activity in the present model has been the S. pombe ATP-dependent RNA helicase gene, ded1.Ded1 is an essential gene which has previously been characterized as a suppressor of sterility, a suppressor of checkpoint and stress response, and a general translation initiation factor.","According to current models of dsRNA-mediated gene regulation an ATP-dependent RNA helicase may be required in conjunction with a dsRNA-dependent RNA polymerase for the formation of short single-stranded RNA fragments which specifically degrades target mRNA.","We therefore reasoned that over-expression of this gene in fission yeast could enhance the efficiency of dsRNA-mediated gene silencing by stimulating the unwinding of dsRNA.","Co-expression of the ded1 vector with the antisense lacZ vector significantly enhanced dsRNA-mediated lacZ inhibition by a further 50% compared to the antisense expressing strain (FIG.","6A).","When ded1 was over-expressed in the absence of the antisense lacZ vector, β-galactosidase activity was comparable to control strains indicating that its effect was dependent on the presence of dsRNA (FIG.","6A).","The ded1 vector was also co-expressed with a short antisense lacZ vector which has previously been shown to be less effective than the full-length antisense gene (2).","Again, the over-expression of ded1 stimulated dsRNA-mediated lacZ inhibition (FIG.","6B).","We have thus shown that over-expression of an ATP-dependent RNA helicase greatly enhances RNAi in fission yeast.","Although an ATP-dependent RNA helicase has recently been suggested to be a key component in RNAi, this is the first demonstration of its intrinsic involvement.","Further, it can clearly be rate limiting, as the over-expression leads to increased RNAi activity in this system.","This ability of the ded1-encoded RNA helicase is consistent with its activities as a member of the DEAD box family of helicases, with their three core domains of ATPase, RNA helicase, and RNA binding activities.","These could allow the enzyme to enhance gene suppression as follows: (i) in a dissociative mechanism it could mediate either the unwinding of dsRNA to generate a cRNA in conjunction with an RNA-dependent RNA polymerase or strand separation of fragmented dsRNA to enhance binding to homologous transcripts, and/or (ii) in an associative mechanism it could catalyse the ATP-dependent exchange of the sense strand of the short dsRNA with the target mRNA.","The presence of ded1 homologues in other organisms displaying RNAi further supports the general involvement of this component in the RNAi machinery.","Example 7 Over-Expression of a Transcription Factor can Enhance RNAi in Fission Yeast The second gene investigated was the nmt1 transcription factor thi1.This gene has been shown to specifically up regulate nmt1 expression when overexpressed in fission yeast.","As we have previously shown that antisense RNA-mediated gene suppression is dose-dependent in S. pombe (1) it was hypothesized that over-expression of thi1 would result in increased production of nmt1-driven antisense lacZ RNA and a consequent enhancement in target gene suppression.","The thi1 open reading frame was PCR-amplified and subcloned into pREP4 as a BamHI fragment.","This vector was then transformed into RB3-2/pGT2 and β-galactosidase assays performed.","As predicted, lacZ suppression was enhanced when compared to a strain expressing antisense RNA alone (FIG.","7).","This result indicated that host-encoded factors are present which modulate the efficacy of dsRNA-mediated gene suppression in fission yeast and also validated the over-expression strategy.","Example 8 Screening for Novel RNAi Modulating Factors Over-expression of a fission yeast cDNA library (5) in an antisense lacZ expressing strain, revealed a series of transformants in which β-galactosidase activity was significantly reduced from that demonstrated in antisense RNA-expressing strains alone.","The screening strategy is shown in FIG.","8.Transformants were grown on selective plates and overlayed with X-GAL-containing media to generate a blue phenotype which could be analysed visually in a semi-quantitative manner (FIG.","9A)(3).","From 12,000 transformants screened, 48 were initially identified as having a reduced blue phenotype compared with background transformants.","Of these, 25 demonstrated a reproducible enhancement in antisense RNA-mediated lacZ suppression when quantified by a liquid β-galactosidase assay (FIG.","9B).","To demonstrate that the observed effects were due to transcription of the cDNA insert, transformants were grown in the presence of thiamine.","This repression of the nmt1 promoter resulted in a return to control levels of β-galactosidase activity in all transformants (FIG.","9B).","This indicated that the enhanced suppression was due to expression of the cDNA rather than other genetic events such as lacZ reporter mutations.","To determine if the effect was dependent on the presence of dsRNA, the antisense plasmid was segregated out of the transformants and the strains were again assayed for β-galactosidase activity.","Nine of the 25 transformants demonstrated a return to the level of β-galactosidase seen in the parental strain indicating that the effect was dsRNA-dependent (FIG.","9B).","The cDNAs being expressed in these transformants were named RNAi enhancing sequences (res).","All transformants displayed normal growth phenotypes indicating that over-expression of the resident cDNAs did not affect general biology of the cell.","In the absence of antisense RNA the remaining 16 transformants retained a reduced β-galactosidase activity indicating that the enhanced gene silencing was not dependent on the presence of dsRNA.","This suggests that the cDNA-encoded proteins in these strains could have been affecting lacZ at the level of transcription or the stability or function of the protein.","The library plasmids were recovered from the aes-containing strains (also referred to as res-containing strains) and their cDNA inserts sequenced.","BLASTN and BLASTP analysis identified clones W18, W20, and W30 (named aes2) as homologues of domains 2 and 3 of the mitochondrial elongation factor Tu (EF Tu).","EF Tu is an essential protein which plays a role in transporting tRNA to the A site in the ribosome for peptide elongation.","The cDNA in transformants W21, W23, and W32 (named aes3) was homologous to a putative protein that was identified in a screen for fission yeast ORFs.","Interestingly, the cDNA insert was also homologous to the antisense strand of the 3′ UTR of the fission yeast gene sna41 which has previously been shown to be involved in DNA replication.","It is thus possible that aes3 may operate through more than one mechanism in enhancing antisense RNA activity.","The cDNA in transformant W47 (named aes4) was homologous to the antisense strand of the ribosomal protein L7a, a component of the 60S ribosomal subunit.","aes4 also contained a small ORF of unknown biological function.","The inserts in transformants W27 and W28 (named aes1) shared homology with a putative protein from C. albicans that was identified in a screen for genes essential for cell growth.","A tertiary quantitative β-galactosidase assay was performed to obtain accurate levels of gene silencing augmentation in the antisense lacZ strains co-expressing these unique factors (FIG.","9C).","This analysis showed that these co-factors enhanced antisense suppression by up to 50%.","These results demonstrated that over-expression of a cDNA library was an effective way of identifying novel co-factors that magnify the suppressive effect mediated by antisense RNA.","aes1 shared 43% identity with amino acids 4 to 202 of a C. albicans hypothetical protein (AJ390519).","aes2 shared 99% identity with nucleotides 10452 to 9484 of the translation elongation factor EF Tu (AL049769).","aes3 shared 94% identity with nucleotides 776 to 1145 of D89239 S. pombe ORF (D89239) and 93% identity with nucleotides 3246 to 2876 of the antisense strand of the DNA replication factor sna41 (AB001379).","aes3 also contained a 220 nt stretch of a GA repeat sequence at its 3′ end.","aes4 shared 99% identity with nucleotides 9678 to 8897 of the antisense strand of ribosomal protein L7a (AJ001133) and 99% identity with nucleoStides 1365 to 584 of the antisense strand of ribosomal protein L4 (AB005750).","The reference numerals in brackets refer to accession numbers in the GeneBank database (the GeneBank database can be accessed from the following web site: http://www.ncbi.nlm.nih.gov/).","EF Tu is analogous to the eukaryotic EF1α and acts by transporting tRNA to the A site in the ribosome for peptide elongation.","EF1α is an essential protein which has also been implicated in a large array of cellular activities including actin binding, microtubule severing, cellular transformation, cell senescence, protein ubiquitination, and protein folding.","Detailed analysis of the EF Tu-expressing strain showed that it enhanced antisense RNA-mediated lacZ silencing by an additional 15% (FIG.","9C).","It has been proposed that dsRNA is fragmented into 21-25 nt species by dsRNA-specific nucleases, amplified by RNA-dependent RNA polymerase, and dissociated by an ATP-dependent RNA helicase.","The small antisense fragments are then free to attack homologous mRNA by RNA nuclease-mediated degradation.","It has recently been suggested that an associative mechanism could catalyse the ATP-dependent exchange of the sense strand of the short dsRNA with the target mRNA.","This may involve the transport of fragmented dsRNA to the ribosome where, in a competitive reaction with tRNA complexes, the complementary antisense strand binds to the mRNA.","This would permit the association of the antisense strand of the dsRNA with the target mRNA when the latter is in a structurally exposed state and both inhibit translation and target the mRNA for ribonuclease degradation.","Without wishing to be bound by any particular mechanism of action, EF Tu could act by binding to RNAi-dependent short dsRNA species and bring them to the site of action.","The protein encoded by sna41 has previously been shown to be involved in DNA replication.","sna41 has low homology with CDC45 and might have DNA helicase properties which could facilitate the expression of complementary sequences.","It is conceivable that the antisense plasmid and target DNA sequences may ectopically pair by intermolecular complementarity.","Such pairing may inhibit RNA expression and consequently reduce the level of intracellular dsRNA.","Similarly the intramolecular pairing of inverted repeat DNA sequences may also interfere with RNA expression.","The over-expression of a protein with DNA helicase properties could facilitate the generation of more dsRNA which could in turn enhance the RNAi effect.","Furthermore, CDC45 mutants show an increased rate of plasmid segregation.","If plasmid loss is inhibited by over-expression of sna41 then more dsRNA may be generated leading to more effective RNAi in this system.","In this light it is not unreasonable to expect that other proteins normally involved in DNA and/or RNA metabolism and function could also have a role in RNAi modulation and/or enhancement.","The L7a protein is part of the 60s ribosomal sub-unit.","Without wishing to be bound by any particular mechanism of action, RNAi augmentation by over-expression of this protein is reasonable as it is hypothesised that the short dsRNA species may undergo strand displacement with target mRNA at the ribosome.","The L7a ribosomal protein may act in RNAi by i) mediating docking of dsRNA or its unwound form into the A site of the ribosome, assisting in association of the antisense strand with the target mRNA, and/or shuttling of dsRNA to the ribosomal complex.","Nucleotide sequences representative of the aes factors referred to above are provided below and identified as Seq ID Nos 1 to 4: DNA sequence for aes1 factor (Seq ID No 1) TTTAACTTAGTTCGCTTTGTTAAATTGGCCTCGAGGTCGACGTTAATTAA GCCGCAATTGTAACAGTAGATTTTTTGCATCATTATTACTCTCCGAAACA TGACTGAACACTCATTTAAGCAAATAGACGTGTTTTCTAATAAAGGTTTT CGAGGTAATCCTGTTGCAGTTTTTTTTGATGCAGATAATTTATCACAAAA GGAAATGCAGCAGATTGCCAAGTGGACAAATTTATCTGAGACAACATTTG TTCAAAAGCCGACAATCGATAAAGCAGATTACAGACTTCGTATATTTACC CCAGAATGTGAATTAAGCTTTGCTGGTCACCCAACAATTGGATCGTGCTT TGCTGTTGTTGAAAGTGGATATTGTACTCCAAAAAACTGTAAAATTATTC AGGAATGTTTAGCCGGTTTAGTTGAATTAACTATCGATGGGGAAAAGGAT GAAGACACTTGGATTTCTTTCAAACTTCCGTATTACAAAATTTTACAGAC TTCTGAAACTGCAATTTCAGAAGTAGAAAATGCATTGGGTATTCCTCTGA ATTATAGTTCTCAAGTTTCTCCTCCTGTGTTAATAGATGATGGACCAAAG TGGCTTGTAATTCAACTTCCAAACGCTACAGATGTGCTCAACCTCGTTCC GAAATTTCAGTCCCTTTCCCAAGTTTGTAAAAACAATGATTGGATAGGCG TCACCCGTCTTTGGTGAATTAGAAAAGACTCGTTTGAAAGCCCGAAGCTT TGCGCCTTTAATACATGTCAATGAGGATCCGGCTTGCGGTAGTGGTGCAG GAGCTGTCGGTGTGTATATTGGAAGCTCTCAAAAAACTCCAACTTCTCTA TCATTTACGATTTCTCAAGGTACAAAATTAAGTAGACAAGCAATTTCCAA AGTCAGCGTAGACGTTTCCTCCAATAAATCAATTGCTGTTTTTGTCGGTG GACAGGCAAAAACTTGTATTTCTGGAAAATCGTTTATTTAATGTTTTTAT TACAAATATTCACTTGCGAGTTTATTTTCCAATACTGAAGACTTTCAATC AATAGCAAATATGCTACTCAAGGAAGTTCACTCATTCAAAAGCAATTGGT TTACTATATCGTTTTTTCTAACTAGTTACTAGTCATTGAACAATCTACCG AATGATAAAATGAAATTTTGGTTTTTCCCCGGGTAAAAGGAATGTCTCCC TTGCCAGTACTGCTAGGGTTTTTCTTTCGAACTATAAGA DNA sequence for aes2 factor (Seq ID No 2) AGTCCGCTTTGTTAAATTGGCCTCGAGGTCGACGTTAATTAAGCCTGATA TGATCGAGCTTGTCGAAATGGAAATGCGTGAGCTACTCTCCGAATACGGA TTTGATGGTGACAATACTCCAATTGTTAGCGGCAGTGCTTTATGTGCCTT AGAGGGTCGTGAGCCTGAGATTGGTCTCAATAGTATTACTAAATTGATGG AAGCTGTTGATAGTTATATTACTCTTCCTGAAAGAAAAACGGATGTCCCT TTCTTGATGGCCATCGAGGACGTTTTTTCAATTTCAGGTCGCGGAACTGT AGTCACTGGCCGTGTCGAGCGCGGTACTTTAAAGAAGGGTGCTGAAATCG AAATCGTCGGTTATGGTAGCCATTTAAAGACTACCGTTACTGGAATTGAA ATGTTCAAAAAGCAGCTTGATGCCGCCGTTGCCGGTGACAATTGTGGCCT TTTACTTCGTTCTATCAAGCGAGAGCAATTAAAACGTGGAATGATTGTCG CTCAACCAGGAACCGTTGCTCCTCATCAGAAATTCAAGGCATCATTCTAT ATTTTGACAAAAGAGGAAGGAGGTCGTCGTACCCGGTTTCGTTGACAAGT ATCGTCCCCAACTGTACAGTCCGTACTTCCGACGTTACTGTCGAACTTAC CCACCCTGATCCTAACGACTCAACAAAATGGTTATGCCTGGAGACAATGT CGAGATGATCTGTACGCTTATTCACCCCATTGTCATCGAAAAAGGACAAC GCTTCACAGTTCGTGAGGGTGGAAGCACTGTAGGCACAGCTTTGGTTACT GAACTTTTGGATTAGTGCATTTATGAACTTATTGGCTTTAAAAATTTTGC ATGCTGAATACCAATATTATGTCCCTTCTCAGAATTCTATAACTACAGTG TCATTATTGTAATAAGACTTTTGCATCCATTGACAATGGTATTTGATACT TTTATAGTTTCTACTATTGTTAGCCAAAGTTATAAAACAAATAATAAAAT AACGTTGAATCAAAAAAAAAAAAAAAAAAAGCGGCCGCGGATCCCCGGGT AAAAGGAATGTCTCCCTTGCCAGTACTGCTAGGGTTTTTCTTTCAAACTA TGGGA DNA sequence for aes3 factor (Seq ID No 3) ATTTCAGACGCAATTCACATGGCTTTTGACTGTATTGCTATTCTTGTCGG TTTAGTTGCTACGACGCTTGCCAAGATGCCTCTAAATTATGCTTACCCCT TTGGATTTGCAAAAATTGAGGCTCTTTCGGGTTTCACTAATGGTATTTTT TTAGTTTTGATTTCATTTTCTATCGTCGGCGAGGCATTATATAGGTTATT TCATCCGCCCCAAATGAATACCGACCAATTGTTGTTGGTTAGTTTTTTGG GCCTTGTTGTGAATTTGGTAGGTATCCTAGCGTTCAATCATGGGCATAAT CATGATCATGGGTCTCATCACCATCATTCCCATAGTAATCATAGTATGTG TCTGCCTAACACTACAAATGATATAAATATTTTTGAAGAGTTTGAAGAAG AAAAAGATAATGTTGAAGCCCAGAAAATGGGCTATACGAATGACGATCAC GTATCCCAACATGAACATACCCATGAGAATAGTCAGGAACATCACCATGA GCATAACCACAATCATGATCACATCCATAAATACAATGAAAAATGCGACC ATGAAAGCATAAGTCTCCAGAATTTAGACAATGATCATCACTGTCATCAT CACCATGAAAATCATAATATGCATGGCATATTTCTGCATATTATCGCAGA TACTATGGGCTCTGTTGGAGTTATTGTCTCTACTATATTAATACAGTGGT TTTCATGGACCGGTTTTGATCCTTCGGCATCTCTAATAATTGCTGCATTA ATATTTGTTTCTGTACTTCCATTAATTAAAGATTCGGCGAAGAATTTGCT CTCTGTGACTGATCCAGAATCGGAATATTTATTGAAGCAGTGTTTGTCGA ACATCAGTTTAAGTCACTCCGTTGTCAGTTTATCCAACCCTAAGTTCTGG ACAAACGAAAGAGGTGAAGTGTATGGAATACTCCATATTCAGGTGAGCAT AGACGGTGATTTAAACGTGGTTCGTAATGAAGTATTTAGGAAGCTCTCAA TCGCTGTACCAAATTTAAAACACATTTGTATACAATCTGAACGGCCAAAC AATTGCTGGTGTGGAAAATAGTTCTTACATCAGTTGATATCCATACTTAT TTACGTGTAATTTTAATTAGATGAATTAATATTTTCTTTATTAGC DNA sequence for aes4 factor (Seq ID No 4) TTTACTTTAGTCGCTTTGTTAAATTGGCCTCGAGGTCGACGTTAATTAAG CTTTTTTTTTAAGAGATATAACATATGTCAACGCGTCATTGATTAACTAC ATAACACGCCAATTATAAACTTCTCCCAAAAGAACTTAAGAATTTCCATT TTCAATCCAGATGAATTTATTTAAGAGACGAACAGTAGCGGCAGCAGCCT TAGCACGCTTAGCGAGCAAAGCTTGGGTCTTACCACCCATGATACCCACC ACCCCACTTACGACGGGCTTTCGTCGTACTTAGCAGAGAAGTTAGCATCA ACGGCGGAGACAATAGAAGCGAGTTCGTTCTTGTCTTCCTCACGGACCTC AGTGACAGCTAAAACAGCAGCAGTCTTTTGGTGAATGACAGTACCAAGGC GGGCCTTGTTCTTGACAATGGCATAAGGAACACCCATCTTCTTGCACAAA GCAGGCAAGAAAACGACGAGTTCAATGGGGTCGACATCGCTGGCAATGAG AACCAACTTAGCCTTCTTGGCCTCAATGAGAGCTACAACATGGTTCAAAC CATATTTAACATTGTAAGGCTTCTTAGAGACGTCTTGAGCAGACTTGCCG TTGGCAACAGCCTCGGCTTCAGCAACCAAACGTTGCTTCTTTTCAGCAGC AGTCTCAGGACGGTACTTGTTAAGCAACTTGAAGACCTGAGTAGCAGTGT TTTTGTCCAAAGTCTTCTGGAACTGAGCAATGGCAGGAGGAACCTTCAAA CGCAAGTTCAAAATCTTGCGACGGCGTTGAAGGCGGATATACTCAGGCCA CTTAACAAAACGGCTCAAGTCACGCTTAGGTTGGATGTCTTGTCCCCCGG GTAAAAGGAATGTCTCCCTTGCCAGTACTGCTAGGGTTTTTCGTTCGAAT AAGGCC Example 9 Effect of Novel RNAi Factors on Antisense RNA and dsRNA-Mediated Gene Regulation With recent studies on PTGS suggesting that antisense RNA, co-suppression, and dsRNA-mediated interference may share similar mechanisms, we wanted to determine whether over-expression of an aes factor would also enhance dsRNA-mediated regulation.","Having demonstrated that dsRNA could mediate gene suppression in this fission yeast model, the effect of an antisense enhancing sequence on dsRNA-mediated regulation was tested.","To this end, the aes2 gene was co-expressed with the lacZ panhandle construct in a yeast strain containing the lacZ target gene.","Under these conditions, this transformant displayed an additional 30% suppression of β-galactosidase activity when compared to the transformant expressing only the panhandle lacZ RNA (see FIG.","10).","This result shows that the aes2 gene, encoding the two domains of the mitochondrial elongation factor EF Tu, stimulated not only antisense RNA but also dsRNA-mediated gene inhibition.","Further it was shown that these two forms of regulation are related by over-expressing the ATP-dependent RNA helicase ded1 in the presence of lacZ antisense RNA and showing that this helicase enhanced gene suppression by a further 50% compared to the control strain (example 6).","ded1 was tested on both active and inactive antisense plasmids and demonstrated that ded1 augmentation of gene silencing was dependent on an active antisense RNA (see FIG.","11).","This could be due to the absence of RNA duplex formation with the inactive antisense RNA and the consequent lack of a substrate for the RNA helicase.","The methods of the present invention have utility in demonstrating a range of RNAi efficacies, in identifying new factors which enhance or reduce gene silencing, in inhibiting gene expression or increasing sensitivity to antisense inhibition of gene expression, in the treatment or prevention of disorders which require inhibition or down-regulation of gene expression.","Although the present invention has been described with reference to specific examples and preferred embodiments it will be clear to those skilled in the art that variations and modifications which do not depart from the concept and the spirit of the invention described herein are also contemplated as being within the scope of the present invention.","REFERENCES 1.Raponi, M., Atkins, D., Dawes, I.","& Arndt, G. (2000) Antisense and Nucleic Acid Drug Development 10, 29-34.2.Arndt, G., Atkins, D., Patrikakis, M. & Izant, J.","(1995) Molecular and General Genetics 248, 293-300.3.Arndt, G., Patrikakis, M. & Atkins, D. (2000) Nucleic Acids Research 28, e15.4.Clarke, M., Patrikakis, M. & Atkins, D. (2000) Biochemical and Biophysical Research Communications 268, 8-13.5.Moreno, S. & Nurse, P. (1994) Nature 367, 236-242.6.Moreno, S., Klar, A.","& Nurse, P. (1991) Methods in Enzymology 194, 795-823.7.Maundrell, K. (1990) Journal of Biological Chemistry 265, 10857-10864.8.Prentice, H. (1992) Nucleic Acids Research 20, 621.9.Hoffman, C. & Winston, F. (1987) Gene 57, 267-272.10.Rose, M., Winston, F. & Hieter, P. (1990) Methods in yeast genetics: A laboratory course manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor).","11.Maundrell, K. (1993) Gene 123, 127-1390.12.Basi, G., Schmid, E. & Maundrell, K. (1993) Gene 123, 131-136.13.Carr, A., MacNeill, S., Hayles, J.","& Nurse, P. (1989) Molecular and General Genetics 218, 41-49.14.Sambrook, J., Fritsch, E. & Maniatis, T. (1989) (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).","15.Patrikakis, M., Izant, J.","& Atkins, D. (1996) Current Genetics 30, 151-158.16.Brun, C., Dubey, D. & Huberman, J.","(1995) Gene 164, 173-177.17.Heyer, W.-D., Sipiczki, M. & Kohli, J.","(1986) Molecular and Cellular Biology 6, 80-89."]],"string":"[\n [\n \"METHODS FOR MEDIATING GENE SUPPRESSION\",\n \"The present invention is concerned with methods for enhancing gene suppression in cells and in particular it is concerned with improved methods for enhancing RNAi-mediated gene silencing by manipulation of factors associated with RNAi.\",\n \"The present invention is also concerned with methods for identifying factors which down-regulate as well as those which up-regulate RNAi.\",\n \"It is also concerned with genetic constructs useful for enhancing or modulating gene silencing and cells harbouring such constructs.\"\n ],\n [\n \"1.A method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) elevating in the cell the level of an RNAi factor, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"2.A method of increasing cellular susceptibility to anti-sense-mediated inhibition of target nucleic acid expression, which method comprises elevating the level of an RNAi factor in a cell that expresses said target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"3.A method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.\",\n \"4.A method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.\",\n \"5.A method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) elevating the level of an RNAi factor in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.\",\n \"6.A method according to any one of claims 1 to 5, wherein the target nucleic acid is an exogenous nucleic acid or a part thereof.\",\n \"7.A method according to any one of claims 1 to 6, wherein the level of the RNAi factor is elevated by introducing into the cell additional copies of, or agents which give rise to, the RNAi factor.\",\n \"8.A method according to any one of claims 1 to 7, wherein the factor is selected from the group consisting of a gene, cDNA, RNA or a protein.\",\n \"9.A method according to any one of claims 1 to 8, wherein the factor is selected from the group consisting of a transcriptional activator of the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.\",\n \"10.A method according to any one of claims 1 to 9, wherein the RNAi factor is an res sequence.\",\n \"11.A method according to claim 10, wherein the factor is selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.\",\n \"12.A method according to claim 11, wherein the res sequence is obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.13.A method according to claim 11, wherein the res sequence is represented by Seq ID Nos 1 to 4.14.A method according to any one of claims 1 to 13, wherein the cell is a eukaryotic cell.\",\n \"15.A method according to 14, wherein the eukaryotic cell is a mammalian.\",\n \"16.A method according to claim 1 or claim 2, wherein the cell is a Schizosaccharomyces pombe cell.\",\n \"17.A method according to any one of claims 1 to 16, wherein the antisense nucleic acid corresponds to a part of the target nucleic acid.\",\n \"18.A pharmaceutical composition for use in performing the method of any one of claims 2 to 17 comprising (i) an expressible nucleic acid encoding, or capable of increasing or decreasing the expression of, an RNAi factor; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.\",\n \"19.A pharmaceutical composition for use in performing the method of any one of claims 2 to 17 comprising (i) an nucleic acid which is the target nucleic acid or a part thereof, or an expressible nucleic acid encoding a factor capable of elevating the intracellular level of the target nucleic acid; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.\",\n \"20.A cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses a target nucleic acid and (ii) comprises an elevated level of an RNAi factor, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"21.A cell according to claim 20, wherein the cell is a eukaryotic cell.\",\n \"22.A cell according to claim 20 or claim 21, wherein the cell is a Schizosaccharomyces pombe cell.\",\n \"23.A method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the cell, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of said target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of said target nucleic acid.\",\n \"24.A method of increasing cellular susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which method comprises augmenting the level of the target nucleic acid or a part thereof in a cell expressing the target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"25.A method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of said target nucleic acid or a part thereof in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.\",\n \"26.A method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.\",\n \"27.A method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.\",\n \"28.A method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) augmenting the level of the target nucleic acid in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.\",\n \"29.A method according to any one of claims 23 to 28, wherein the target nucleic acid is an exogenous nucleic acid or a part thereof.\",\n \"30.A method according to any one of claims 23 to 29, wherein the level of the target nucleic acid is augmented by introducing into the cell additional copies of, or agents which are capable of inducing intracellular over-expression of, the target nucleic acid.\",\n \"31.A method according to any one of claims 23 to 30, wherein the cell is a eukaryotic cell.\",\n \"32.A method according to 31, wherein the eukaryotic cell is a mammalian.\",\n \"33.A method according to claim 23 or claim 24, wherein the cell is a Schizosaccharomyces pombe cell.\",\n \"34.A method according to any one of claims 23 to 33, wherein the antisense nucleic acid corresponds to a part of the target nucleic acid.\",\n \"35.A cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses said target nucleic acid and (ii) comprises an elevated level of said target nucleic acid, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"36.A cell according to claim 35, wherein the cell is a eukaryotic cell.\",\n \"37.A cell according to claim 35 or claim 36, wherein the cell is a Schizosaccharomyces pombe cell.\",\n \"38.Method of identifying a cellular factor capable of effecting and/or modulating expression of a target nucleic acid in a cell having the target nucleic acid and a nucleic acid which is an antisense of the target nucleic acid or part thereof, which method comprises over-expressing said factor in the cell and wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.\",\n \"39.A factor identified by the method of claim 38.40.A factor according to claim 39, wherein the factor is selected from the group consisting of a gene, cDNA, RNA or a protein.\",\n \"41.A factor according to claim 39 or claim 40, wherein the factor is selected from the group consisting of a transcriptional activator or the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.\",\n \"42.A factor according to any one of claims 39 to 41, wherein the factor is an res sequence.\",\n \"43.A factor according to claim 42, wherein the factor is selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.\",\n \"44.An RNAi factor which is an res sequence obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.45.An RNAi factor which is an res sequence represented by Seq ID Nos 1 to 4.46.A Schizosaccharomyces pombe cell having a target nucleic acid or a part thereof and a antisense nucleic acid or a part thereof which corresponds to the target nucleic acid or a part thereof, wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>The use of double-stranded RNA (dsRNA) to specifically interfere with gene expression has received considerable attention because of its demonstrated potency in a range of organisms, including some which have so far been genetically intractable.\",\n \"Termed RNA interference (RNAi), it has been implicated in viral defense, control of transpositional elements, genetic imprinting and endogenous gene regulation.\",\n \"It has been hypothesised to be the central mechanism in post-transcriptional gene silencing (PTGS), co-suppression, quelling, and antisense RNA-mediated gene suppression.\",\n \"One model that has been proposed is that dsRNA is fragmented into 21-25 nt species by dsRNA-specific nucleases, amplified by RNA-dependent RNA polymerase, and then dissociated and free to attack homologous mRNA by RNA nuclease-mediated degradation.\",\n \"The application of this technique will greatly facilitate the dissection of gene function and the validation of genes involved in disease states.\",\n \"Recently at least two different strategies have been undertaken to identify the cellular proteins composing a proposed multi-protein complex involved in the recognition of dsRNA and the activation of dsRNA-mediated gene interference.\",\n \"The first involves the use of classical chemical mutagenesis or insertional mutagenesis to isolate mutants completely defective for RNAi and cloning of the relevant genes using complementation.\",\n \"These studies have been carried out in genetically tractable organisms such as plants, worms and fungi.\",\n \"The genetic screens described involve the use of RNAi systems in which the degree of suppression is complete.\",\n \"The mutagenesis produces mutants in which the RNAi effect is completely reversed indicating the loss of a cellular factor (function) required for the RNAi effect.\",\n \"Thus these genetic screens would most likely miss factors that have subtle effects or rate limiting or rate determining roles in RNAi.\",\n \"The second strategy for finding key players in RNAi has involved the use of cell free assays.\",\n \"These in vitro reconstitution assays, on the other hand, identify cellular factors that impact on RNAi outside of the cellular context and therefore the cellular role of these factors must always be tested.\",\n \"However, the major disadvantages of these strategies are that genes will not be identified if they are essential to the organism, nor will they directly identify gene activities which will enhance RNAi when overexpressed.\",\n \"Thus there is a need for models which can demonstrate a range of RNAi efficacies, with both increasing and decreasing quantitative activities being selectable.\",\n \"This would enable the identification of factors which can enhance or reduce the gene silencing effect.\",\n \"It is therefore an object of the present invention to overcome or at least ameliorate one or more disadvantages of the prior art, or provide a useful alternative.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>Through the use of a fission yeast model for the study of dsRNA-mediated gene silencing and in the search for factors involved in this process, it was surprisingly found that the natural level of RNAi activity can be enhanced by manipulating factors associated with RNAi activity or efficacy.\",\n \"Thus, it has been found that by increasing the steady-state levels of a target nucleic acid sequence in the presence of the same pool of the corresponding antisense sequence, or a part thereof, the antisense-mediated suppression was not only maintained, but enhanced.\",\n \"This is indicative of an RNAi-like mechanism of gene suppression.\",\n \"It has also been found that overexpression of certain sequences, named herein RNAi enhancing sequences (res), (also referred to herein as anti-sense enhancing sequences—aes), also had the ability to enhance RNAi.\",\n \"This ability of RNAi activity to be enhanced in S. pombe provides a model system which enables the analysis of RNAi processes and the identification and study of factors which either up-regulate or down-regulate its activity.\",\n \"The system has been further used to identify RNAi enhancing gene sequences which increase PTGS efficacy when their resulting protein activities are augmented in vivo.\",\n \"The model used to exemplify the present invention and the methods described are also applicable to treatment of disorders in which gene expression requires more efficient modulation or silencing.\",\n \"According to a first aspect there is provided a method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) elevating in the cell the level of an RNAi factor, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"According to a second aspect there is provided a method of increasing cellular susceptibility to anti-sense-mediated inhibition of target nucleic acid expression, which method comprises elevating the level of an RNAi factor in a cell that expresses said target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"According to a third aspect there is provided a method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.\",\n \"According to a fourth aspect there is provided a method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.\",\n \"According to a fifth aspect there is provided a method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) elevating the level of an RNAi factor in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.\",\n \"In a preferred embodiment the target nucleic acid is an endogenous nucleic acid or a part thereof, but it may also be an exogenous sequence or part thereof.\",\n \"Preferably the level of the RNAi factor is elevated by introducing into the cell additional copies of, or agents which give rise to, the RNAi factor.\",\n \"It will be understood therefore that up-regulating the expression of an endogenous RNAi factor will also achieve the same result and is contemplated herein as part of the invention.\",\n \"Preferably the factor is selected from the group consisting of a gene, cDNA, RNA or a protein.\",\n \"More preferred is a factor selected from the group consisting of a transcriptional activator of the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.\",\n \"Even more preferred is an RNAi factor which is an res sequence.\",\n \"Also for preference the factor can be selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.\",\n \"Further preferred factors are represented by the res sequences which are obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.Preferably the res sequence is represented by any one of Seq ID Nos 1 to 4.The preferred cell is a eukaryotic cell and even more preferred is a mammalian cell.\",\n \"In certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.\",\n \"Preferably the antisense nucleic acid corresponds to a part only of the target nucleic acid.\",\n \"According to a sixth aspect there is provided a pharmaceutical composition for use in performing the method of any one of the previous aspects comprising (i) an expressible nucleic acid encoding, or capable of increasing or decreasing the expression of, an RNAi factor; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.\",\n \"According to a seventh aspect there is provided a pharmaceutical composition for use in performing the method of any one of claims 2 to 17 comprising (i) an nucleic acid which is the target nucleic acid or a part thereof, or an expressible nucleic acid encoding a factor capable of elevating the intracellular level of the target nucleic acid; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.\",\n \"According to an eighth aspect there is provided a cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses a target nucleic acid and (ii) comprises an elevated level of an RNAi factor, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"For preference the cell is a eukaryotic cell but more preferred is a mammalian cell.\",\n \"As indicated above, in certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.\",\n \"According to a ninth aspect there is provided a method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the cell, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of said target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of said target nucleic acid.\",\n \"According to a tenth aspect there is provided a method of increasing cellular susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which method comprises augmenting the level of the target nucleic acid or a part thereof in a cell expressing the target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"According to an eleventh aspect there is provided a method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of said target nucleic acid or a part thereof in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.\",\n \"According to a twelfth aspect there is provided a method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.\",\n \"According to a thirteenth aspect there is provided a method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) augmenting the level of the target nucleic acid in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.\",\n \"In a preferred embodiment the target nucleic acid is an endogenous nucleic acid or a part thereof, but it may also be an exogenous sequence or part thereof.\",\n \"Preferably the level of the target nucleic acid is augmented by introducing into the cell additional copies of, or agents which are capable of inducing intracellular over-expression of, the target nucleic acid.\",\n \"Over-expression can be achieved for an endogenous as well as an exogenous target nucleic acid.\",\n \"Preferably the nucleic acid used for augmenting content of the target nucleic acid is a fragment, derivative or analogue of the target nucleic acid.\",\n \"However it will be understood that the entire native sequence of the target nucleic acid may be employed.\",\n \"Conveniently, the target nucleic acid may be coupled to a selectable marker.\",\n \"The preferred cell is a eukaryotic cell and even more preferred is a mammalian cell.\",\n \"In certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.\",\n \"Preferably the antisense nucleic acid corresponds to a part only of the target nucleic acid.\",\n \"According to a fourteenth aspect there is provided a cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses said target nucleic acid and (ii) comprises an elevated level of said target nucleic acid, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"The preferred cell is a eukaryotic cell and even more preferred is a Schizosaccharomyces pombe cell.\",\n \"According to a fifteenth aspect there is provided a method of identifying a cellular factor capable of effecting and/or modulating expression of a target nucleic acid in a cell having the target nucleic acid and a nucleic acid which is an antisense of the target nucleic acid or part thereof, which method comprises over-expressing said factor in the cell and wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.\",\n \"According to a sixteenth aspect there is provided a factor identified by the method of the fifteenth aspect.\",\n \"The preferred factors can be selected from the group consisting of a gene, cDNA, RNA or a protein.\",\n \"More preferred are factors selected from the group consisting of a transcriptional activator or the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.\",\n \"Even more preferred is a factor having an res sequence.\",\n \"Preferred factors can also be selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.\",\n \"According to a seventeenth aspect there is provided an RNAi factor which is an res sequence obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.According to an eighteenth aspect there is provided an RNAi factor which is an res sequence represented by Seq ID Nos 1 to 4.According to a nineteenth aspect there is provided a Schizosaccharomyces pombe cell having a target nucleic acid or a part thereof and a antisense nucleic acid or a part thereof which corresponds to the target nucleic acid or a part thereof, wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.\",\n \"The term “inhibiting expression of a target nucleic acid” as used in the context of the present invention is intended to encompass, but not be limited to, reduction or elimination of gene expression, whether or not the target nucleic acid is a gene, or a part thereof, introduced into the cell or it is an endogenous gene.\",\n \"The term “RNAi factor” is intended to include in its scope any naturally occurring, modified or synthetic molecule capable of enhancing RNAi activity.\",\n \"This definition includes in its scope the factors referred to herein as RNAi enhancing sequences (res).\",\n \"The term res may be used herein interchangeably with the term aes (anti-sense enhancing sequences).\",\n \"It will be understood by those skilled in the art that “elevating RNAi factor level” can be achieved by transfection, upregulation or other means known in the art.\",\n \"The term “anti-sense nucleic acid molecule” as used in the context of the present invention is intended to encompass RNA or DNA and contain region(s) related to a specific target RNA transcript or its gene.\",\n \"It is also intended to include molecules giving rise to antisense sequences, including inverted repeat, sense RNA, etc.\",\n \"The term “conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid molecule inhibits expression of the gene” is intended to include the concept of inhibition of gene expression which is high enough to be effective, but not so high as to harm the cell.\",\n \"The effective concentration range can be determined using routine methodology known in the art.\",\n \"Reference to a “subject” is intended to include human, animal (mouse), plant, or other life forms.\",\n \"Reference to a “cell” is intended to encompass eukaryotic cells such as yeast, mammalian, plant, etc The term “disorder” will be understood to include viral infection (HIV, HPV, etc), cancer, autoimmune disease and other chronic and acute diseases.\",\n \"The term “phenotype” as used in the context of the present invention is intended to include cell staining, morphology, growth, and similar characteristics.\"\n ],\n [\n \"TECHNICAL FIELD The present invention is concerned with methods for enhancing gene suppression in cells and in particular it is concerned with improved methods for enhancing RNAi-mediated gene silencing by manipulation of factors associated with RNAi.\",\n \"The present invention is also concerned with methods for identifying factors which down-regulate as well as those which up-regulate RNAi.\",\n \"It is also concerned with genetic constructs useful for enhancing or modulating gene silencing and cells harbouring such constructs.\",\n \"BACKGROUND OF THE INVENTION The use of double-stranded RNA (dsRNA) to specifically interfere with gene expression has received considerable attention because of its demonstrated potency in a range of organisms, including some which have so far been genetically intractable.\",\n \"Termed RNA interference (RNAi), it has been implicated in viral defense, control of transpositional elements, genetic imprinting and endogenous gene regulation.\",\n \"It has been hypothesised to be the central mechanism in post-transcriptional gene silencing (PTGS), co-suppression, quelling, and antisense RNA-mediated gene suppression.\",\n \"One model that has been proposed is that dsRNA is fragmented into 21-25 nt species by dsRNA-specific nucleases, amplified by RNA-dependent RNA polymerase, and then dissociated and free to attack homologous mRNA by RNA nuclease-mediated degradation.\",\n \"The application of this technique will greatly facilitate the dissection of gene function and the validation of genes involved in disease states.\",\n \"Recently at least two different strategies have been undertaken to identify the cellular proteins composing a proposed multi-protein complex involved in the recognition of dsRNA and the activation of dsRNA-mediated gene interference.\",\n \"The first involves the use of classical chemical mutagenesis or insertional mutagenesis to isolate mutants completely defective for RNAi and cloning of the relevant genes using complementation.\",\n \"These studies have been carried out in genetically tractable organisms such as plants, worms and fungi.\",\n \"The genetic screens described involve the use of RNAi systems in which the degree of suppression is complete.\",\n \"The mutagenesis produces mutants in which the RNAi effect is completely reversed indicating the loss of a cellular factor (function) required for the RNAi effect.\",\n \"Thus these genetic screens would most likely miss factors that have subtle effects or rate limiting or rate determining roles in RNAi.\",\n \"The second strategy for finding key players in RNAi has involved the use of cell free assays.\",\n \"These in vitro reconstitution assays, on the other hand, identify cellular factors that impact on RNAi outside of the cellular context and therefore the cellular role of these factors must always be tested.\",\n \"However, the major disadvantages of these strategies are that genes will not be identified if they are essential to the organism, nor will they directly identify gene activities which will enhance RNAi when overexpressed.\",\n \"Thus there is a need for models which can demonstrate a range of RNAi efficacies, with both increasing and decreasing quantitative activities being selectable.\",\n \"This would enable the identification of factors which can enhance or reduce the gene silencing effect.\",\n \"It is therefore an object of the present invention to overcome or at least ameliorate one or more disadvantages of the prior art, or provide a useful alternative.\",\n \"SUMMARY OF THE INVENTION Through the use of a fission yeast model for the study of dsRNA-mediated gene silencing and in the search for factors involved in this process, it was surprisingly found that the natural level of RNAi activity can be enhanced by manipulating factors associated with RNAi activity or efficacy.\",\n \"Thus, it has been found that by increasing the steady-state levels of a target nucleic acid sequence in the presence of the same pool of the corresponding antisense sequence, or a part thereof, the antisense-mediated suppression was not only maintained, but enhanced.\",\n \"This is indicative of an RNAi-like mechanism of gene suppression.\",\n \"It has also been found that overexpression of certain sequences, named herein RNAi enhancing sequences (res), (also referred to herein as anti-sense enhancing sequences—aes), also had the ability to enhance RNAi.\",\n \"This ability of RNAi activity to be enhanced in S. pombe provides a model system which enables the analysis of RNAi processes and the identification and study of factors which either up-regulate or down-regulate its activity.\",\n \"The system has been further used to identify RNAi enhancing gene sequences which increase PTGS efficacy when their resulting protein activities are augmented in vivo.\",\n \"The model used to exemplify the present invention and the methods described are also applicable to treatment of disorders in which gene expression requires more efficient modulation or silencing.\",\n \"According to a first aspect there is provided a method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) elevating in the cell the level of an RNAi factor, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"According to a second aspect there is provided a method of increasing cellular susceptibility to anti-sense-mediated inhibition of target nucleic acid expression, which method comprises elevating the level of an RNAi factor in a cell that expresses said target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"According to a third aspect there is provided a method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.\",\n \"According to a fourth aspect there is provided a method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) elevating the level of an RNAi factor in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.\",\n \"According to a fifth aspect there is provided a method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) elevating the level of an RNAi factor in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.\",\n \"In a preferred embodiment the target nucleic acid is an endogenous nucleic acid or a part thereof, but it may also be an exogenous sequence or part thereof.\",\n \"Preferably the level of the RNAi factor is elevated by introducing into the cell additional copies of, or agents which give rise to, the RNAi factor.\",\n \"It will be understood therefore that up-regulating the expression of an endogenous RNAi factor will also achieve the same result and is contemplated herein as part of the invention.\",\n \"Preferably the factor is selected from the group consisting of a gene, cDNA, RNA or a protein.\",\n \"More preferred is a factor selected from the group consisting of a transcriptional activator of the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.\",\n \"Even more preferred is an RNAi factor which is an res sequence.\",\n \"Also for preference the factor can be selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.\",\n \"Further preferred factors are represented by the res sequences which are obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.Preferably the res sequence is represented by any one of Seq ID Nos 1 to 4.The preferred cell is a eukaryotic cell and even more preferred is a mammalian cell.\",\n \"In certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.\",\n \"Preferably the antisense nucleic acid corresponds to a part only of the target nucleic acid.\",\n \"According to a sixth aspect there is provided a pharmaceutical composition for use in performing the method of any one of the previous aspects comprising (i) an expressible nucleic acid encoding, or capable of increasing or decreasing the expression of, an RNAi factor; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.\",\n \"According to a seventh aspect there is provided a pharmaceutical composition for use in performing the method of any one of claims 2 to 17 comprising (i) an nucleic acid which is the target nucleic acid or a part thereof, or an expressible nucleic acid encoding a factor capable of elevating the intracellular level of the target nucleic acid; (ii) a nucleic acid encoding a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid; and (iii) a pharmaceutically acceptable carrier, wherein the nucleic acids of (i) and (ii) may be situated on the same or different molecules.\",\n \"According to an eighth aspect there is provided a cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses a target nucleic acid and (ii) comprises an elevated level of an RNAi factor, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"For preference the cell is a eukaryotic cell but more preferred is a mammalian cell.\",\n \"As indicated above, in certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.\",\n \"According to a ninth aspect there is provided a method for inhibiting the expression of a target nucleic acid in a cell, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the cell, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of said target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of said target nucleic acid.\",\n \"According to a tenth aspect there is provided a method of increasing cellular susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which method comprises augmenting the level of the target nucleic acid or a part thereof in a cell expressing the target nucleic acid, with the proviso that the cell is to have prior, concurrently or subsequently introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"According to an eleventh aspect there is provided a method for treating a subject suffering from a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of said target nucleic acid or a part thereof in the subject's cells where the target nucleic acid is expressed, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid, thereby treating the subject.\",\n \"According to a twelfth aspect there is provided a method for inhibiting in a subject the onset of a disorder whose alleviation is mediated by inhibiting the expression of a target nucleic acid, which method comprises the steps of (i) augmenting the level of the target nucleic acid or a part thereof in the subject's cells where the target nucleic acid would be expressed if the subject were suffering from the disorder, and (ii) prior, concurrently with or subsequent to performing step (i), introducing into such cells a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid, under conditions permitting an increase in the degree to which the anti-sense nucleic acid would inhibit expression of the target nucleic acid were such expression to occur, thereby inhibiting in the subject the onset of the disorder.\",\n \"According to a thirteenth aspect there is provided a method of determining whether inhibiting the expression of a particular target nucleic acid or the activity of its product may alleviate a disorder, which method comprises the steps of (i) augmenting the level of the target nucleic acid in a cell whose phenotype correlates with that of a cell from a subject having the disorder; (ii) prior, concurrently with or subsequent to performing step (i), introducing into the cell a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting an increase in the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid; and (iii) determining whether the cell's phenotype now correlates with that of a cell from a subject in whom the disorder has been alleviated or the disorder is not evident, thereby determining whether inhibiting the expression of the target nucleic acid or the activity of its product may alleviate the disorder.\",\n \"In a preferred embodiment the target nucleic acid is an endogenous nucleic acid or a part thereof, but it may also be an exogenous sequence or part thereof.\",\n \"Preferably the level of the target nucleic acid is augmented by introducing into the cell additional copies of, or agents which are capable of inducing intracellular over-expression of, the target nucleic acid.\",\n \"Over-expression can be achieved for an endogenous as well as an exogenous target nucleic acid.\",\n \"Preferably the nucleic acid used for augmenting content of the target nucleic acid is a fragment, derivative or analogue of the target nucleic acid.\",\n \"However it will be understood that the entire native sequence of the target nucleic acid may be employed.\",\n \"Conveniently, the target nucleic acid may be coupled to a selectable marker.\",\n \"The preferred cell is a eukaryotic cell and even more preferred is a mammalian cell.\",\n \"In certain embodiments of the invention described herein the preferred cell is a Schizosaccharomyces pombe cell.\",\n \"Preferably the antisense nucleic acid corresponds to a part only of the target nucleic acid.\",\n \"According to a fourteenth aspect there is provided a cell having increased susceptibility to anti-sense-mediated inhibition of a target nucleic acid expression, which cell (i) expresses said target nucleic acid and (ii) comprises an elevated level of said target nucleic acid, with the proviso that the cell is to have introduced thereinto a molecule which is, or gives rise to, an anti-sense nucleic acid directed toward at least a portion of the RNA transcript of the target nucleic acid under conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid inhibits expression of the target nucleic acid.\",\n \"The preferred cell is a eukaryotic cell and even more preferred is a Schizosaccharomyces pombe cell.\",\n \"According to a fifteenth aspect there is provided a method of identifying a cellular factor capable of effecting and/or modulating expression of a target nucleic acid in a cell having the target nucleic acid and a nucleic acid which is an antisense of the target nucleic acid or part thereof, which method comprises over-expressing said factor in the cell and wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.\",\n \"According to a sixteenth aspect there is provided a factor identified by the method of the fifteenth aspect.\",\n \"The preferred factors can be selected from the group consisting of a gene, cDNA, RNA or a protein.\",\n \"More preferred are factors selected from the group consisting of a transcriptional activator or the antisense nucleic acid, a component of the RNAi machinery, a component of the DNA replication machinery and a component of translational machinery.\",\n \"Even more preferred is a factor having an res sequence.\",\n \"Preferred factors can also be selected from the group consisting of ATP-dependent RNA helicase (ded1), transcriptional factor thi1, DNA replication protein sna41, ribosomal protein L7a, elongation factor EF-Tu and res1 as herein defined.\",\n \"According to a seventeenth aspect there is provided an RNAi factor which is an res sequence obtainable from transformed cells designated herein W18, W20, W21, W23, W27, W28, W30, W32 and W47.According to an eighteenth aspect there is provided an RNAi factor which is an res sequence represented by Seq ID Nos 1 to 4.According to a nineteenth aspect there is provided a Schizosaccharomyces pombe cell having a target nucleic acid or a part thereof and a antisense nucleic acid or a part thereof which corresponds to the target nucleic acid or a part thereof, wherein the expression of the target nucleic acid is capable of being enhanced or only partially suppressed.\",\n \"The term “inhibiting expression of a target nucleic acid” as used in the context of the present invention is intended to encompass, but not be limited to, reduction or elimination of gene expression, whether or not the target nucleic acid is a gene, or a part thereof, introduced into the cell or it is an endogenous gene.\",\n \"The term “RNAi factor” is intended to include in its scope any naturally occurring, modified or synthetic molecule capable of enhancing RNAi activity.\",\n \"This definition includes in its scope the factors referred to herein as RNAi enhancing sequences (res).\",\n \"The term res may be used herein interchangeably with the term aes (anti-sense enhancing sequences).\",\n \"It will be understood by those skilled in the art that “elevating RNAi factor level” can be achieved by transfection, upregulation or other means known in the art.\",\n \"The term “anti-sense nucleic acid molecule” as used in the context of the present invention is intended to encompass RNA or DNA and contain region(s) related to a specific target RNA transcript or its gene.\",\n \"It is also intended to include molecules giving rise to antisense sequences, including inverted repeat, sense RNA, etc.\",\n \"The term “conditions permitting the RNAi factor to increase the degree to which the anti-sense nucleic acid molecule inhibits expression of the gene” is intended to include the concept of inhibition of gene expression which is high enough to be effective, but not so high as to harm the cell.\",\n \"The effective concentration range can be determined using routine methodology known in the art.\",\n \"Reference to a “subject” is intended to include human, animal (mouse), plant, or other life forms.\",\n \"Reference to a “cell” is intended to encompass eukaryotic cells such as yeast, mammalian, plant, etc The term “disorder” will be understood to include viral infection (HIV, HPV, etc), cancer, autoimmune disease and other chronic and acute diseases.\",\n \"The term “phenotype” as used in the context of the present invention is intended to include cell staining, morphology, growth, and similar characteristics.\",\n \"BRIEF DESCRIPTION OF THE FIGURES FIG.\",\n \"1.Target genes and antisense fragments.\",\n \"a, The strain KC4-6 expresses low levels of lacZ RNA.\",\n \"The lacZ expression cassette is integrated at the ura4 locus on chromosome III and is composed of the SV40 early promoter, the E. coli lacZ gene and the SV40 3′ processing signal.\",\n \"The 5′ and 3′ flanking DNA sequences of the ura4 locus are as indicated.\",\n \"b, The strain RB3-2, which expresses high levels of lacZ RNA, contains an expression cassette containing the S. pombe adh1 promoter, the lacZ coding region, and the S. pombe ura4 3′ processing signal.\",\n \"c, The full-length 3.5 kb antisense lacZ fragment is shown.\",\n \"The crippled sense fragment was generated by end-filling the ClaI cut lacZ vector and religating on itself.\",\n \"d, The AML1 strain contains a c-myc-lacZ fusion cassette integrated at the ura4 locus.\",\n \"Exons 2 and 3 of the human c-myc gene were employed as a target.\",\n \"The relative position of the c-myc antisense fragment is shown.\",\n \"Transcription initiation sites are indicated by the bent arrows.\",\n \"The straight arrows represent the normal direction of transcription for a particular DNA fragment.\",\n \"FIG.\",\n \"2.dsRNA-mediated gene silencing in fission yeast.\",\n \"a, A fission yeast strain containing the integrated lacZ gene under control of the strong adh1 promoter was transformed with lacZ antisense vectors.\",\n \"The antisense gene was under control of the weak nmt41 promoter (low antisense), the strong nmt1 promoter in single copy (15) (medium antisense), or the nmt1 promoter in multi-copy (high antisense).\",\n \"For the strain expressing maximum antisense RNA two episomal nmt1-driven antisense vectors containing different selectable markers were co-transformed into the target strain.\",\n \"b, A fission yeast strain containing the integrated lacZ gene under control of the weak SV40 promoter (low target) or strong adh1 promoter (high target) was transformed with the antisense lacZ vector or antisense lacZ and sense lacZ vectors.\",\n \"Strains were co-transformed with vectors containing appropriate selectable markers to complement auxotrophy.\",\n \"c, The lacZ inverted repeat vector was expressed in the high-expressing lacZ target strain.\",\n \"The strain expressing the antisense construct only is also indicated.\",\n \"d, A fission yeast strain containing an integrated c-myc-lacZ fusion gene was transformed with the sense construct, the antisense construct, or both.\",\n \"Antisense and sense constructs were also expressed in the high-expressing lacZ strain.\",\n \"All strains were transformed with appropriate control plasmids to complement auxotrophy.\",\n \"FIG.\",\n \"3.Effect of co-expressing single copies of sense and antisense genes.\",\n \"Strains containing target lacZ alone (RB3-2), the target and a single copy of the antisense gene (K40-7), and the target and both the antisense and frameshifted lacZ genes (M62-1) were assayed for β-galactosidase activity.\",\n \"pREP2 and pREP4 are parental plasmids containing the LEU2 and ura4 selectable markers respectively.\",\n \"Strains were transformed with the appropriate control plasmids to complement auxotrophy.\",\n \"For each sample three independent colonies were assayed in triplicate.\",\n \"FIG.\",\n \"4.RNA expression profiles in fission yeast strains a, The target strain RB3-2 was transformed with the lacZ inverted repeat vector (pM53-1) or co-transformed with antisense (pGT2) and sense (pM54-3) vectors and grown to mid-log in the absence of thiamine.\",\n \"Total RNA from each strain was separated on a 1% denaturing agarose gel, transferred to a nylon membrane and probed with the radioactively labeled 2.2 kb nmt1 fragment.\",\n \"The episomal lacZ signal was normalized with the endogenous nmt1 transcript and quantitated by phosphorimage analysis.\",\n \"The relative level of episomal lacZ expression is shown.\",\n \"b, The strain M38-1 which contains a single copy stably integrated lacZ inverted repeat gene was grown to mid-log in the absence of thiamine, its RNA isolated and analyzed by Northern hybridization.\",\n \"The relative steady-state level of the “panhandle” lacZ RNA is indicated in comparison to episomally expressed antisense lacZ RNA.\",\n \"FIG.\",\n \"5.In vivo dsRNA assay.\",\n \"a, The constructs employed for assaying the ability of the lacZ inverted repeat to form an intramolecular RNA duplex are shown.\",\n \"Each vector contains a functional lacZ fragment which gives the transformed strain a blue color phenotype when grown in the presence of X-GAL.\",\n \"The predicted secondary structure of the pM81-2 generated transcript is indicated.\",\n \"b, The strain 2037 was transformed with the vectors pM85-1, pM91-1 and pM81-2 in the absence of thiamine Single colonies were streaked on minimal media plates and overlayed with 0.5% agarose medium containing 500 μg/ml X-gal and 0.01% SDS.\",\n \"FIG.\",\n \"6.The effect of ded1 on dsRNA-mediated gene regulation.\",\n \"a, The ded1 gene was co-expressed in a fission yeast strain containing the integrated lacZ gene.\",\n \"β-galactosidase activity of the strain transformed with and without the antisense lacZ vector is shown.\",\n \"b, The target strain was transformed with a vector expressing a short lacZ antisense gene or with both the short lacZ antisense vector and the ded1-expressing vector.\",\n \"Strains were transformed with appropriate control plasmids to complement auxotrophy.\",\n \"FIG.\",\n \"7.Over-expression of thi1 in an antisense lacZ expressing strain.\",\n \"β-galactosidase activity of the target strain RB3-2 transformed with and without the antisense lacZ vector is shown.\",\n \"Over-expression of the thi1 gene in the antisense expressing strain is also indicated.\",\n \"Strains were transformed with appropriate control plasmids to complement auxotrophy.\",\n \"FIG.\",\n \"8.Over-expression screening strategy for RNAi modulating factors.\",\n \"A target strain containing the integrated lacZ gene under control of the adh1 promoter and the episomal vector containing the nmt1-driven lacZ antisense gene is transformed with an S. pombe cDNA library.\",\n \"Library fragments are driven by the nmt1 promoter.\",\n \"Transformants are individually screened for a change in the lacZ-encoded blue colony colour phenotype.\",\n \"These transformants are then quantitatively assayed for β-galactosidase activity in the presence and absence of thiamine.\",\n \"The antisense vector is then segregated out of transformants showing a cDNA dependent modification of lacZ suppression.\",\n \"A tertiary β-galactosidase assay is performed to determine if the effect is dependent on the presence of dsRNA.\",\n \"cDNA vectors are recovered from strains of interest, sequenced, and subjected to BLASTN analysis.\",\n \"FIG.\",\n \"9.Over-expression screen of a S. pombe cDNA library.\",\n \"a, Transformants were grown on minimal media plates and over-layed with X-GAL-containing medium.\",\n \"Those which showed a reduced blue colour-phenotype (black arrow) were analysed further.\",\n \"Transformants demonstrating an enhanced blue-colour phenotype were also identified (white arrow).\",\n \"b, Transformants which showed a visual reduction in the blue phenotype were assayed for β-galactosidase activity in liquid culture in the absence of thiamine.\",\n \"Thiamine was added to the medium to demonstrate that the enhanced lacZ suppression was dependent on RNA expression.\",\n \"Transformants were again assayed for β-galactosidase activity following antisense vector segregation.\",\n \"c, Over-expression of unique res genes in dsRNA-expressing strains.\",\n \"FIG.\",\n \"10.lacZ panhandle-mediated gene silencing.\",\n \"(A) The lacZ panhandle construct contains the full-length crippled lacZ gene which is followed by the inverted 5′ 2.5 kb lacZ fragment.\",\n \"Intramolecular hybridization generates an RNA with 2.5 kb RNA duplex and a 1 kb loop.\",\n \"(B) The relative steady-state level of the episomally expressed panhandle lacZ RNA (7.0 kb) is shown in comparison to episomally expressed antisense lacZ RNA (4.5 kb).\",\n \"The lacZ signals were normalized to the endogenous nmt1 transcript (1.3 kb) and quantitated by phosphorimage analysis.\",\n \"(C) The target strain was transformed with the episomally expressed lacZ panhandle and analyzed for b-galactosidase activity.\",\n \"The appropriate plasmids were co-introduced to complement auxotrophy.\",\n \"At least three independent colonies were assayed in triplicate for each strain.\",\n \"Transformants were assayed in the presence of thiamine to abrogate expression of the panhandle RNA (hatched).\",\n \"(D) The target lacZ strain was transformed with the panhandle vector only or both the panhandle and aes2 vector.\",\n \"FIG.\",\n \"11.Co-expression of ded1 and lacZ antisense genes.\",\n \"b-galactosidase activity of the target strain co-transformed with the ded1 gene and the antisense lacZ vectors is shown.\",\n \"Ded1 was expressed from the ura4-based plasmid pREP4 while the antisense genes were expressed from the LEU2-based plasmid pREP2.Strains expressing antisense RNAs or ded1 RNA alone are also indicated.\",\n \"Strains were transformed with appropriate control plasmids to complement auxotrophy.\",\n \"Three independent colonies were assayed in triplicate for each strain.\",\n \"FIG.\",\n \"12.DNA sequence for aes1 factor FIG.\",\n \"13.DNA sequence for aes2 factor FIG.\",\n \"14.DNA sequence for aes3 factor FIG.\",\n \"15.DNA sequence for aes4 factor DESCRIPTION OF THE PREFERRED EMBODIMENTS Using the lacZ fission yeast model to investigate features of antisense-RNA technology in vivo (1-4), it has been shown that the degree of target gene suppression is dependent on the level of antisense RNA (FIG.\",\n \"2A)(1).\",\n \"During the course of developing this model it was surprisingly found that by increasing the steady-state levels of the lacZ target mRNA 20-fold in the presence of the same pool of antisense RNA that antisense-mediated suppression was not only maintained, but enhanced (FIG.\",\n \"2B).\",\n \"To verify that this effect was independent of the target mRNA a lacZ gene containing a frameshift mutation (leading to an inability to translate the β-galactosidase enzyme) was co-expressed in antisense-expressing strains.\",\n \"Again, additional stimulation of lacZ inhibition was observed (FIG.\",\n \"2B).\",\n \"These observations are consistent with the potential formation of additional dsRNA and consequent stimulation of gene silencing.\",\n \"They also indicate that the dsRNA-mediated gene silencing is dose-dependent in this system.\",\n \"To further show that dsRNA was the key component in target gene inhibition in fission yeast dsRNA was generated by expressing a lacZ inverted repeat with 2.5 kb of internal complementarity in the presence of lacZ target mRNA.\",\n \"Expression of this construct also reduced β-galactosidase activity in a lacZ expressing strain to a similar level to the full-length antisense RNA (FIG.\",\n \"2C).\",\n \"Overall, these data suggested that increasing the potential formation of dsRNA, but not necessarily an antisense RNA:target mRNA hybrid, resulted in efficient interference of target gene expression in S. pombe.\",\n \"To test the ability of dsRNA to specifically interfere with another target sequence in fission yeast, sense and antisense c-myc sequences were co-expressed in a strain containing an integrated c-myc-lacZ fusion cassette (3).\",\n \"A 792 bp antisense c-myc fragment from exon 2 of the human c-myc gene was previously found to suppress β-galactosidase activity within the c-myc-lacZ fusion target strain by 47% (3).\",\n \"β-galactosidase assays demonstrated that co-expression of the antisense and sense c-myc constructs in the target strain enhanced c-myc suppression compared with the antisense c-myc vector alone (FIG.\",\n \"2D).\",\n \"Transformation of the strain expressing only the lacZ target with the antisense and sense c-myc constructs resulted in no down-regulation of β-galactosidase activity indicating that the action of dsRNA is sequence-specific (FIG.\",\n \"2D).\",\n \"All of the above observations, as well as the reduction in target mRNA levels in response to additional dsRNA (data not shown), are consistent with features associated with RNAi.\",\n \"This is the first example of dsRNA-mediated gene regulation in yeast and, unlike RNAi in all other organisms except zebrafish, appears to be dependent on the concentration of intracellular dsRNA.\",\n \"The variation in RNAi efficacy between organisms may be due to the absence or under-expression of some components of the RNAi pathway or the presence of RNAi inhibitors.\",\n \"We have now further developed this genetic model for identification of factors involved in RNAi.\",\n \"Without wishing to be bound by any particular mechanism, it is probable that a multi-protein complex exists which mediates the post-transcriptional degradation of target mRNA in RNAi.\",\n \"Several genes which are involved in the RNAi phenomenon have been identified through genetic screens in Neurospora and nematodes.\",\n \"These genes include an RNA-dependent RNA polymerase (qde-1, ego-1) a RecQ DNA helicase (qde-3), an RNase D homologue (mut-7), and a putative translation initiation factor (rde-1, qde-2).\",\n \"The genes mut-2, rde-2, rde-4, and rde-7 have also been identified as being involved in either the initiation or maintenance of RNAi.\",\n \"Additionally, Drosophila cell free assays have shown that RNAi is mediated by nuclease degradation of the targeted mRNA while a 21-25 nt RNA species appears to be integral to specific post-transcriptional genetic interference.\",\n \"RNAi has also been shown to be dependent on ATP which may be required for strand dissociation of dsRNA.\",\n \"However, a missing component of the proposed multi-protein complex in the RNAi pathway is the implied RNA helicase.\",\n \"The dose-dependency of dsRNA-mediated gene silencing in fission yeast described above has allowed us to use an over-expression strategy to identify genes involved in RNAi.\",\n \"In comparison to mutagenesis strategies, over-expression can enable the identification of genes which are otherwise essential for cell viability.\",\n \"Also, cellular factors that quantitatively enhance or reduce RNAi activity can be determined.\",\n \"The first gene that was tested in mediating RNAi activity in the present model was the nmt1 transcription factor thi1.This gene has been shown to specifically up regulate nmt1 expression when overexpressed in fission yeast.\",\n \"As we have previously shown that antisense RNA-mediated gene suppression is dose dependent in S. pombe (1) it was hypothesized that over-expression of thi1 would result in increased production of nmt1-driven antisense lacZ RNA and a consequent enhancement in target gene suppression.\",\n \"The thi1 open reading frame was PCR amplified and subcloned into pREP4 as a BamHI fragment.\",\n \"This vector was then transformed into RB3-2/pGT2 and β-galactosidase assays performed.\",\n \"As predicted, lacZ suppression was enhanced when compared to a strain expressing antisense RNA alone (FIG.\",\n \"7).\",\n \"This result indicated that host-encoded factors are present which affect the robustness of dsRNA-mediated gene suppression in fission yeast and also validated the overexpression strategy.\",\n \"The second gene investigated has been the S. pombe ATP-dependent RNA helicase gene, ded1.Ded1 is an essential gene which has previously been characterized as a suppressor of sterility, a suppressor of checkpoint and stress response, and a general translation initiation factor.\",\n \"According to current models of dsRNA-mediated gene regulation an ATP-dependent RNA helicase may be required in conjunction with a dsRNA-dependent RNA polymerase for the formation of short single-stranded RNA fragments which specifically degrades target mRNA.\",\n \"It was therefore reasoned that over-expression of this gene in fission yeast could enhance the efficiency of dsRNA-mediated gene silencing by stimulating the unwinding of dsRNA.\",\n \"Co-expression of the ded1 vector with the antisense lacZ vector significantly enhanced dsRNA-mediated lacZ inhibition by a further 50% compared to the antisense expressing strain (FIG.\",\n \"6A).\",\n \"When ded1 was over-expressed in the absence of the antisense lacZ vector, β-galactosidase activity was comparable to control strains indicating that its effect was dependent on the presence of dsRNA (FIG.\",\n \"6A).\",\n \"The ded1 vector was also co-expressed with a short antisense lacZ vector which has previously been shown to be less effective than the full-length antisense gene (16).\",\n \"Again, the over-expression of ded1 stimulated dsRNA-mediated lacZ inhibition (FIG.\",\n \"6B).\",\n \"It was thus shown that over-expression of an ATP-dependent RNA helicase greatly enhances RNAi in fission yeast.\",\n \"By over-expressing a cDNA library in a dsRNA fission yeast model we have identified four novel, genes with potential roles in the RNAi pathway.\",\n \"All of the known genes identified are essential and have natural associations with DNA, RNA or nucleic acid binding proteins, consistent with the expectation of RNAi cellular factors.\",\n \"In addition, two of the three known cDNAs encoded proteins involved in the process of translation.\",\n \"These findings along with our previous identification of an ATP-dependent RNA helicase (Raponi & Arndt, submitted) and reports of the involvement of a translation initiation factor in RNAi and the co-purification of ribonuclease activity with ribosomal fractions, suggests that this may be one site at which RNAi functions.\",\n \"Alternatively, the identification of such varied proteins as DNA helicases and translational components as part of the RNAi machinery implies that particular cellular proteins may be recruited into more than one multiprotein complex.\",\n \"Under the latter conditions, over-expression of these specific proteins may result in the generation of an RNAi complex that recognises dsRNA and mediates target gene suppression.\",\n \"Certain of these proteins may be rate-limiting or rate-determining in RNAi and only through supplementation of these factors are their roles in RNAi uncovered.\",\n \"It is proposed, without wishing to be bound by any particular mechanism, that in addition to the previously identified core proteins in the RNAi multiprotein complex(es), additional factors such as EF Tu, L7a, sna41 and res1 may be enlisted for a role in dsRNA-mediated gene suppression.\",\n \"The over-expression strategy described overcomes some limitations associated with mutagenesis by identifying essential genes with a role in RNAi.\",\n \"In addition, this strategy complements these other systems by allowing the isolation of cellular factors that modify the efficacy of RNAi in vivo.\",\n \"The roles of these modulators of RNAi may be varied and include recognition and amplification of the dsRNA, delivery of the small 21-25 nt dsRNAs to the target mRNA, association between the antisense and target mRNA strands, and RNAi complex formation.\",\n \"Alternatively, these modulators may control the rate of RNAi or the formation of different complexes within cell types or for different forms of post-transcriptional gene silencing.\",\n \"The fact that over-expression of specific RNAi modulators enhanced dsRNA-mediated gene regulation in fission yeast indicates that a similar approach could be used to identify RNAi modulators in other organisms.\",\n \"In addition, the co-expression of these factors with different forms of post-transcriptional gene silencing including co-suppression, quelling, and antisense RNA could be one way of enhancing the efficacy of these methods.\",\n \"This may be especially important for application of RNAi to mammalian cells and tissues or to genes which have been somewhat recalcitrant to this form of regulation.\",\n \"The present invention demonstrates for the first time the intrinsic involvement of an ATP-dependent RNA helicase as a key component in RNAi.\",\n \"Further, it can be rate limiting, as the over-expression leads to increased RNAi activity in this system.\",\n \"This ability of the ded1-encoded RNA helicase is consistent with its activities as a member of the DEAD box family of helicases, with their three core domains of ATPase, RNA helicase, and RNA binding activities.\",\n \"These could allow the enzyme to enhance gene suppression as follows: (i) in a dissociative mechanism it could mediate either the unwinding of dsRNA to generate a cRNA in conjunction with an RNA-dependent RNA polymerase or strand separation of fragmented dsRNA to enhance binding to homologous transcripts, and/or (ii) in an associative mechanism it could catalyse the ATP-dependent exchange of the sense strand of the short dsRNA with the target mRNA.\",\n \"The presence of ded1 homologues in other organisms displaying RNAi further supports the general involvement of this component in the RNAi machinery.\",\n \"The present invention also provides for the first time a novel and quantitative genetic system based on S.pombe, for rapidly identifying essential cellular factors involved in RNAi.\",\n \"The use of this model has enabled verification of RNA helicase activity as a critical contributor to efficient RNAi activity and isolated novel RNAi factors including EF Tu, L7a, sna41, and an unidentified gene res1.The present invention also demonstrates that gene silencing may be enhanced by concomitant expression of such RNAi factors.\",\n \"The invention will now be described more particularly with reference to non-limiting examples of certain preferred embodiments of the invention.\",\n \"Example 1 Materials and Methods Used to Exemplify the Invention S. pombe Media and Manipulations.\",\n \"All yeast strains were maintained on standard YES or EMM media (6).\",\n \"Repression of nmt1 transcription was achieved by the addition of thiamine to EMM media at a final concentration of 4 μM (7).\",\n \"Yeast cells were transformed with plasmid DNA by electroporation (8) and stable integrants were identified as previously described (6).\",\n \"A glass bead procedure (9) was used to isolate genomic DNA which was used for Southern analysis and PCR diagnosis.\",\n \"Total RNA was extracted as previously described (10).\",\n \"S. pombe Strain and Plasmid Construction.\",\n \"Construction of the low expressing lacZ strain, KC4-6 (h−, ura4::SV40-lacZ, leu1-32), has been previously described (2).\",\n \"The strain RB3-2 (h−, ura4::adh1-lacZ, leu1-32) which expresses higher levels β-galactosidase has also been previously described (1).\",\n \"The target strain which contains the c-myc:lacZ fusion has previously been described (3).\",\n \"The construction of the long lacZ antisense containing episomal plasmid, pGT2, and corresponding control plasmids have been described (2).\",\n \"Plasmid pREP4-As was generated by subcloning the lacZ BamHI fragment contained in pGT2 into the plasmid pREP4 (11).\",\n \"pREP4 is identical to pREP1 except that the S. cerevisiae LEU2 gene has been replaced with the S. pombe ura4 selectable marker.\",\n \"To decrease the steady-state level of episomally expressed antisense lacZ, plasmids pREP42-As and pREP82-As were constructed by subcloning the lacZ BamHI fragment from pGT2 into pREP42 and pREP82, respectively.\",\n \"These plasmids are derivatives of pREP4 with mutations in the TATA box of the nmt1 promoter (12).\",\n \"The crippled lacZ vector, pGT62, was generated by end-filling the ClaI site of pGT2 and re-ligating (2).\",\n \"This frameshifted fragment was then subcloned into the BamHI site of pREP4 to generate the plasmid pM54-3.The lacZ panhandle integration vector, pM30-8, was generated by first introducing a NotI site into the XmaI site of pRIP1/s (11) using the self-complementary linker 5′ CCG GGC GGC CGC 3′ to generate pL121-14.The 2.5 kb sequence of the 5′ end of the frameshifted lacZ gene (2) was then PCR-amplified to give it NotI ends using the forward primer 5′ ATGCGGCCGCAATTCCCGGGGATCGAAAGA 3′ and reverse primer 5′ ATGCGGCCGCAATGGGGTCGCTTCACTTA 3′.\",\n \"This product was cloned using a TA cloning kit (TOPO: Invitrogen, San Diego, Calif., USA) and then subcloned into the NotI site of pL121-14 in the antisense orientation.\",\n \"The integrating vector was introduced into target strains in single copy by using the sup3-5/ade6-704 complementation system (13).\",\n \"The full-length frameshifted lacZ fragment was then introduced into the BamHI site of this vector in the sense orientation upstream of the 2.5 kb antisense fragment to generate pM30-8.The episomal version of this vector (pM53-1) was made by removing the Pst1 sup3-5 fragment and introducing the autonomous replicating sequence as an EcoRI fragment (11).\",\n \"For testing the ability of the panhandle construct to form dsRNA in vivo, the frameshifted lacZ fragment was replaced with the functional lacZ fragment in the vectors pM54-3 and pM53-1, to generate the vectors pM85-1 and pM81-2, respectively.\",\n \"The vector pM91-1, which is unable to form a lacZ panhandle transcript, was generated by removing the 2.5 kb NotI lacZ fragment from pM81-2 and reintroducing it in the sense orientation.\",\n \"Generation of the c-myc antisense construct, pCM-17, has been described elsewhere (3).\",\n \"The 792 by BglII c-myc fragment from pCM-17 was subcloned into the BamHI site of pREP4 in the sense orientation to generate pN12-1.The ded1, and thi1, open reading frames were amplified from fission yeast genomic DNA (strain 1913).\",\n \"ded1 was amplified to give it BamHI ends using the forward primer 5′ ATGGGATCCCAACCAAACACTTCAACTCAG 3′ and the reverse primer 5′ ATGGGATCCTCAGAAGCCTGTGCATAACAC 3′.\",\n \"thi1 was amplified to give it BglII ends using the forward primer 5′ ATGAGATCTGTGGTTGGTATTCTAGAGAGA 3′ and the reverse primer 5′ ATGAGATCTAACAAAGACCTGCAAAAAACC 3′.\",\n \"PCR products were purified (Qiagen PCR purification kit), digested with either BamHI or BglII, gel-purified (Qiagen), and subcloned into the BamHI site of pREP4 in the sense orientation.\",\n \"Southern and Northern Analysis.\",\n \"Nucleic acid electrophoresis and membrane transfer was performed as described (14).\",\n \"Southern and Northern blots were hybridized using ExpressHyb solution according to the manufacturer's instructions (Clontech Laboratories).\",\n \"DNA probes were 32P-labelled using the Megaprime labelling kit (Amersham).\",\n \"Probes included a 960 bp BamHI/ClaI lacZ fragment from pI2-1 (1), a 570 by HindIII/EcoRI ura4-3′ fragment from pGT113 (15), and a 2.2 kb PstI/SacI nmt1 fragment from pRIP1/s.\",\n \"Radioactive signals were detected by autoradiography and quantitated by phosphorimage analysis (ImageQuant; Molecular Dynamics).\",\n \"Plasmid Distribution Analysis.\",\n \"Plasmid co-transformants of strain RB3-2 were grown under selective conditions to a cell density of 1-2×107 cells/ml.\",\n \"A serial dilution of each culture was performed and cells plated for single colonies in triplicate onto each of YES, EMM, EMM+leucine, and EMM+uracil agar media.\",\n \"The number of colonies grown on YES was taken as the total number of viable cells, while colonies growing on EMM represented the cells in the sampled population that contained both the ura4-containing (pREP4-based) and the LEU2-containing (pREP1-based) plasmids.\",\n \"Cells containing either the ura4-containing plasmid or the LEU2-containing plasmid were identified from the EMM+leucine and EMM+uracil plates respectively.\",\n \"The ratio of the number of colonies grown on selective media to the total number of viable colonies was used as the quantitative measure of the proportion of cells in the population, grown under selection, which contained plasmids.\",\n \"β-galactosidase Assays.\",\n \"The expression of the lacZ gene-encoded product, β-galactosidase, was quantitated using a cell permeabilization protocol as previously described (Raponi et al., 2000).\",\n \"A semi-quantitative overlay assay was also employed for rapid screening of yeast transformants (3).\",\n \"Isolation of S. pombe cDNA Clones That Alter Antisense RNA Efficacy.\",\n \"The S. pombe cDNA library was originally constructed in pREP3Xho by Bruce Edgar and Chris Norbury (5).\",\n \"The vector pREP3Xho is derived from pREP3 which contains the LEU2 marker and inserts are under control of the nmt1 promoter (11).\",\n \"A total of 5 μg of library DNA was transformed into the strain RB3-2 containing the episomal antisense lacZ vector pREP4-lacZAS and grown in EMM liquid media to the mid-logarithmic phase.\",\n \"Transformants were then plated on EMM solid media and grown at 30° C. for 3 days.\",\n \"Colonies were over-layed with medium containing 0.5 M sodium phosphate, 0.5% agarose, 2% dimethylformamide, 0.01% SDS, and 500 μg/ml X-GAL (Progen, Australia).\",\n \"Plates were then incubated at 37° C. for 3 hrs, colonies of interest recovered and assayed for β-galactosidase activity.\",\n \"Plasmid Segregation.\",\n \"Strains were plated on EMM containing limiting uracil and 1 mg/ml 5-fluoroorotic acid (6).\",\n \"Strains were then replica plated on both selective and non-selective media.\",\n \"Those colonies that did not grow on selective media were identified as having lost the ura4-containing antisense plasmid.\",\n \"To determine the mitotic stability of pREP-based plasmids we used the plasmid segregation method previously described (16).\",\n \"This method indicated that up to 30% of the cells grown in selective media did not contain the resident plasmid.\",\n \"Example 2 Effect of Steady-State Level of Target mRNA and Antisense RNA on Antisense Efficacy To determine the role of target mRNA steady-state levels in antisense-mediated gene suppression, we investigated the ability of a long lacZ antisense RNA (2) to regulate lacZ target genes under control of both weak and strong constitutive promoters.\",\n \"The low-level expressing strain, KC4-6, contained the lacZ gene driven by the SV40 early promoter integrated at the ura4 locus in chromosome III (FIG.\",\n \"1A; (2)).\",\n \"The high-level lacZ expressing strain, RB3-2, was constructed by placing the lacZ gene under control of the strong fission yeast adh1 promoter and the 3′ processing signal from the ura4 gene and integrating this expression cassette at the ura4 locus (FIG.\",\n \"1B; (1)).\",\n \"Characterization of both strains indicated that RB3-2 expressed 20-fold more lacZ mRNA than KC4-6 while an approximate 40-fold increase in β-galactosidase was also detected (data not shown).\",\n \"Both strains were transformed with the lacZ antisense gene-containing plasmid (pGT2) and its corresponding sense control plasmid (pGT62).\",\n \"β-galactosidase assays indicated that the antisense RNA suppressed β-galactosidase activity by 45% in KC4-6 while the same RNA reduced β-galactosidase activity by 52% in RB3-2 (FIG.\",\n \"2B).\",\n \"No reduction in β-galactosidase activity was seen in either strain when transformed with the control plasmid pGT62 which expresses a crippled version of lacZ.\",\n \"These results indicated that despite a 20-fold increase in the steady state level of the lacZ target mRNA in RB3-2 the efficacy of antisense-mediated down regulation was not only maintained, but enhanced.\",\n \"The increase in gene suppression demonstrated with strain RB3-2 was also seen when antisense molecules targeted to subregions of the lacZ target gene were used, but was not as pronounced.\",\n \"These data suggested an increase in target mRNA can result in enhanced target gene suppression.\",\n \"It has previously, been demonstrated that a stably integrated antisense lacZ gene acts in a dose dependent fashion with the steady-state levels of antisense RNA being dependent on genomic position effects and transgene copy number (1).\",\n \"Here the role of the steady-state level of episomally expressed antisense RNA in both the low lacZ expressing target strain, KC4-6, and the high lacZ expressing target strain, RB3-2, was investigated.\",\n \"The expression of lacZ antisense RNA was increased by co-transforming KC4-6 and RB3-2 with plasmids pGT2 and pREP4-As, each of which contains the lacZ antisense gene under control of the nmt1 promoter, but different selectable markers.\",\n \"To decrease the steady-state level of antisense RNA, the plasmids pREP42-As and pREP82-AS were employed.\",\n \"The nmt1 promoter in these vectors contain deletions in the TATA box sequence which affect the level of transcription, but have no impact on the site of transcription initiation or thiamine repressibility (12).\",\n \"Each of the different antisense gene-containing plasmids was co-transformed with a control plasmid to complement auxotrophy where appropriate.\",\n \"This resulted in a set of co-transformants of both RB3-2 and KC4-6 each containing the same lacZ antisense gene, but with different promoter capacities.\",\n \"Each co-transformant was analyzed for antisense RNA steady-state levels and β-galactosidase activity.\",\n \"Table 1 indicates that with both strains the degree of target suppression is enhanced with the increase of antisense lacZ RNA expression.\",\n \"TABLE 1 Effects of varying the level of antisense RNA in strains expressing both low and high level target.\",\n \"Relative β-gal.\",\n \"activity antisense Strain Plasmids Descriptions (units) % suppressiona RNA levelb KC4-6 pREP2, pREP4 Vector 1.07 0 0 pREP2, pREP82-AS Low As 1.10 0 0.04 pREP2, pREP42-AS Medium As 1.07 0.1 0.14 pREP2, pREP4-AS Full As-ura4 0.75 30 1.0 pGT2, pREP4 Full As-LEU2 0.70 34.6 2.2 pGT2, pREP4-AS Double-As 0.54 49.2 5.6 RB3-2 pREP2, pREP4 Vector 48.5 0 0 pREP2, pREP82-AS Low As 44.0 9.4 0.05 pREP2, pREP42-AS Medium As 43.9 9.6 0.18 pREP2, pREP4-AS Full As-ura4 27.2 43.9 1.0 pGT2, pREP4 Full As-LEU2 24.9 48.7 1.9 pGT2, pREP4-AS Double-As 16.6 65.8 5.4 aThe % suppression of β-galactosidase activity was determined by expressing each β-galactosidase activity as a percentage of the activity found in the pREP2, pREP4 co-transformant.\",\n \"bWithin each strain the steady-state level of long lacZ antisense RNA was normalized to nmt1 mRNA and then expressed relative to the level observed in the pREP2, pREP4-As co-transformant.\",\n \"These data agree with the previous report that antisense RNA-mediated gene inhibition is dose dependent in S. pombe (1).\",\n \"However, for each co-transformant the degree of β-galactosidase suppression was greater by 10-15% in the high lacZ expressing strain, RB3-2, than the low lacZ expressing strain, KC4-6, again demonstrating that low levels of target mRNA can limit antisense efficacy.\",\n \"Example 3 Effect of Increasing Sense RNA on Antisense RNA-Mediated Target Gene Suppression To determine whether the increase in gene suppression was due to formation of an antisense RNA:target mRNA hybrid or an antisense RNA:sense RNA hybrid, a version of lacZ which is unable to be translated into functional β-galactosidase was co-expressed in strains expressing the lacZ antisense gene.\",\n \"If antisense RNA was required to hybridize to target mRNA for inhibition of the gene expression pathway, then over-expression of the sense RNA would compete with the target for the available antisense molecules and a decrease in lacZ gene suppression would result.\",\n \"Initially, both antisense and sense lacZ vectors were integrated in single copy into separate target strains and then crossed with each other.\",\n \"In strains containing the antisense gene alone, β-galactosidase activity was reduced by approximately 40% (FIG.\",\n \"3; (1)) while there was no reduction in the strain expressing sense lacZ alone (data not shown).\",\n \"However, in the strain expressing both complementary transcripts (M62-1), β-galactosidase activity was reduced by 50% (FIG.\",\n \"3).\",\n \"These results suggested that increasing the intracellular concentration of sense RNA in the presence of antisense RNA, and therefore potentially generating more dsRNA, stimulates target gene suppression.\",\n \"To further increase the potential formation of intracellular dsRNA an episomal sense lacZ plasmid (pM54-3; FIG.\",\n \"2B) was co-transformed with the episomal antisense lacZ plasmid, pGT2, into the target strain R133-2.Both of these sequences were expressed by the strong conditional nmt1 promoter and RNA analysis showed that each transcript was being expressed at high levels when grown in the absence of thiamine (FIG.\",\n \"4A).\",\n \"When both RNAs were co-expressed in RB3-2, the target lacZ was suppressed by 65% compared to 50% in the strain expressing the antisense plasmid alone (FIG.\",\n \"2B).\",\n \"Northern analysis demonstrated that the total relative level of episomally expressed nmt1-driven transgenes was approximately 60% higher than when either vector was expressed alone (FIG.\",\n \"4A).\",\n \"Although expression of these complementary RNA transcripts is at a high level compared with single copy integrants only an additional 15% suppression was observed.\",\n \"One explanation for the absence of higher levels of target gene suppression is plasmid segregation.\",\n \"S. pombe undergoes asymmetric segregation, with the result that mitosis produces a daughter cell which lacks the segregating plasmid (17).\",\n \"Therefore, when the 65% suppression level seen in the total population is corrected for only those cells containing the ura4-based and LEU2-based plasmids the level of suppression approaches approximately 100% (data not shown).\",\n \"Overall these data suggest that increasing the potential formation of dsRNA, but not necessarily an antisense RNA:target mRNA hybrid, is required for efficient interference of target gene expression in S. pombe.\",\n \"However, unlike the phenomenon of RNAi seen in plants and nematodes, the dsRNA-mediated gene suppression demonstrated in fission yeast seems to be dependent on the concentration of intracellular dsRNA or a threshold level of dsRNA is required to invoke potent gene silencing.\",\n \"Example 4 Effect of a lacZ Inverted Repeat on lacZ Gene Expression To further investigate the ability of dsRNA to inhibit gene expression in fission yeast we generated a vector containing the full-length 3.5 kb frameshifted lacZ sequence with a 2.5 kb inverted repeat.\",\n \"This construct generates a transcript of approximately 7 kb in length with 2.5 kb of self-complementarity which, predictably, will form a strong intramolecular RNA duplex.\",\n \"This gene was initially integrated into a fission yeast strain in single copy and then crossed with the strain RB3-2.The resulting strain which contained the single copy inverted repeat gene and target lacZ showed no reduction in β-galactosidase activity when transcription of the inverted repeat was activated.\",\n \"Southern analysis confirmed that the cassette was intact (data not shown) while RNA analysis indicated that the 7 kb transcript was being generated but approximately 10-fold less than episomally expressed antisense lacZ (FIG.\",\n \"4A&B).\",\n \"To increase the steady-state level of the inverted repeat RNA we generated the episomal plasmid pM53-1 containing this cassette.\",\n \"RNA analysis demonstrated that this vector is expressed at a similar level to episomally expressed antisense lacZ (FIG.\",\n \"4A).\",\n \"When expressed in RB3-2 pM53-1 inhibited β-galactosidase activity by 40% (FIG.\",\n \"2C), while addition of thiamine to the culture medium returned β-galactosidase activity to control level.\",\n \"To confirm that gene inhibition was due to this construct forming an RNA duplex, an in vivo assay for dsRNA was developed.\",\n \"To this end, a series of vectors were generated which contained functional lacZ sequences including lacZ alone (pM85-1), a lacZ inverted repeat (pM81-2), and the lacZ repeat with both sequences in the sense orientation (pM91-1) (FIG.\",\n \"5A).\",\n \"These vectors were then introduced into a strain lacking the integrated target sequence (NCYC2037; h+, ura4-D18) and resulting transformants were overlayed with X-GAL-containing agarose.\",\n \"Both strains containing control vectors generated high levels of β-galactosidase while the strain expressing the lacZ inverted repeat did not (FIG.\",\n \"5B).\",\n \"In each case Northern analysis demonstrated that strains were expressing the transgene.\",\n \"These results indicate that the inverted repeat RNA could not be efficiently translated to produce β-galactosidase, most probably due to the formation of a strong intramolecular hairpin structure.\",\n \"Taken together, these results show that a construct which has the ability to form dsRNA by intramolecular hybridization will interfere with target gene expression when expressed at high levels, again indicating that dsRNA mediates target gene suppression in a dose-dependent manner in fission yeast.\",\n \"Example 5 Gene-Specificity of dsRNA-Meditated Gene Silencing in Fission Yeast To test the ability of dsRNA to specifically interfere with other target sequences in fission yeast, sense and antisense c-myc sequences were co-expressed in a strain containing an integrated c-myc-lacZ fusion cassette (FIG.\",\n \"1D; (3)).\",\n \"A 792 bp antisense c-myc fragment from exon 2 of the human c-myc gene (named CM-17) was previously found to suppress β-galactosidase activity within a c-myc-lacZ fusion target strain (AML1) by 47% (3).\",\n \"CM-17 was subsequently subcloned into pREP4 in the sense orientation to generate pN12-1.The antisense c-myc vector (pCM-17) and the sense c-myc vector were transformed into AML1 both independently and together.\",\n \"β-galactosidase assays demonstrated that co-expression of the antisense and sense constructs enhanced c-myc suppression by an additional 13% compared with the antisense c-myc vector alone (FIG.\",\n \"2D).\",\n \"Transformation of RB3-2 with the antisense and sense c-myc constructs resulted in no down-regulation of β-galactosidase activity indicating that the action of dsRNA is gene-specific (FIG.\",\n \"2D).\",\n \"These results demonstrate that dsRNA can specifically interfere with multiple targets in fission yeast including one of human origin.\",\n \"Example 6 Over-Expression of a Translation Factor can Enhance RNAi in Fission Yeast The dose-dependency of dsRNA-mediated gene silencing in fission yeast described above has allowed us to use an over-expression strategy to identify genes involved in RNAi.\",\n \"In comparison to mutagenesis strategies, over-expression can enable the identification of genes which are otherwise essential for cell viability.\",\n \"Also, cellular factors that quantitatively enhance or reduce RNAi activity can be determined.\",\n \"The first gene that we have tested in mediating RNAi activity in the present model has been the S. pombe ATP-dependent RNA helicase gene, ded1.Ded1 is an essential gene which has previously been characterized as a suppressor of sterility, a suppressor of checkpoint and stress response, and a general translation initiation factor.\",\n \"According to current models of dsRNA-mediated gene regulation an ATP-dependent RNA helicase may be required in conjunction with a dsRNA-dependent RNA polymerase for the formation of short single-stranded RNA fragments which specifically degrades target mRNA.\",\n \"We therefore reasoned that over-expression of this gene in fission yeast could enhance the efficiency of dsRNA-mediated gene silencing by stimulating the unwinding of dsRNA.\",\n \"Co-expression of the ded1 vector with the antisense lacZ vector significantly enhanced dsRNA-mediated lacZ inhibition by a further 50% compared to the antisense expressing strain (FIG.\",\n \"6A).\",\n \"When ded1 was over-expressed in the absence of the antisense lacZ vector, β-galactosidase activity was comparable to control strains indicating that its effect was dependent on the presence of dsRNA (FIG.\",\n \"6A).\",\n \"The ded1 vector was also co-expressed with a short antisense lacZ vector which has previously been shown to be less effective than the full-length antisense gene (2).\",\n \"Again, the over-expression of ded1 stimulated dsRNA-mediated lacZ inhibition (FIG.\",\n \"6B).\",\n \"We have thus shown that over-expression of an ATP-dependent RNA helicase greatly enhances RNAi in fission yeast.\",\n \"Although an ATP-dependent RNA helicase has recently been suggested to be a key component in RNAi, this is the first demonstration of its intrinsic involvement.\",\n \"Further, it can clearly be rate limiting, as the over-expression leads to increased RNAi activity in this system.\",\n \"This ability of the ded1-encoded RNA helicase is consistent with its activities as a member of the DEAD box family of helicases, with their three core domains of ATPase, RNA helicase, and RNA binding activities.\",\n \"These could allow the enzyme to enhance gene suppression as follows: (i) in a dissociative mechanism it could mediate either the unwinding of dsRNA to generate a cRNA in conjunction with an RNA-dependent RNA polymerase or strand separation of fragmented dsRNA to enhance binding to homologous transcripts, and/or (ii) in an associative mechanism it could catalyse the ATP-dependent exchange of the sense strand of the short dsRNA with the target mRNA.\",\n \"The presence of ded1 homologues in other organisms displaying RNAi further supports the general involvement of this component in the RNAi machinery.\",\n \"Example 7 Over-Expression of a Transcription Factor can Enhance RNAi in Fission Yeast The second gene investigated was the nmt1 transcription factor thi1.This gene has been shown to specifically up regulate nmt1 expression when overexpressed in fission yeast.\",\n \"As we have previously shown that antisense RNA-mediated gene suppression is dose-dependent in S. pombe (1) it was hypothesized that over-expression of thi1 would result in increased production of nmt1-driven antisense lacZ RNA and a consequent enhancement in target gene suppression.\",\n \"The thi1 open reading frame was PCR-amplified and subcloned into pREP4 as a BamHI fragment.\",\n \"This vector was then transformed into RB3-2/pGT2 and β-galactosidase assays performed.\",\n \"As predicted, lacZ suppression was enhanced when compared to a strain expressing antisense RNA alone (FIG.\",\n \"7).\",\n \"This result indicated that host-encoded factors are present which modulate the efficacy of dsRNA-mediated gene suppression in fission yeast and also validated the over-expression strategy.\",\n \"Example 8 Screening for Novel RNAi Modulating Factors Over-expression of a fission yeast cDNA library (5) in an antisense lacZ expressing strain, revealed a series of transformants in which β-galactosidase activity was significantly reduced from that demonstrated in antisense RNA-expressing strains alone.\",\n \"The screening strategy is shown in FIG.\",\n \"8.Transformants were grown on selective plates and overlayed with X-GAL-containing media to generate a blue phenotype which could be analysed visually in a semi-quantitative manner (FIG.\",\n \"9A)(3).\",\n \"From 12,000 transformants screened, 48 were initially identified as having a reduced blue phenotype compared with background transformants.\",\n \"Of these, 25 demonstrated a reproducible enhancement in antisense RNA-mediated lacZ suppression when quantified by a liquid β-galactosidase assay (FIG.\",\n \"9B).\",\n \"To demonstrate that the observed effects were due to transcription of the cDNA insert, transformants were grown in the presence of thiamine.\",\n \"This repression of the nmt1 promoter resulted in a return to control levels of β-galactosidase activity in all transformants (FIG.\",\n \"9B).\",\n \"This indicated that the enhanced suppression was due to expression of the cDNA rather than other genetic events such as lacZ reporter mutations.\",\n \"To determine if the effect was dependent on the presence of dsRNA, the antisense plasmid was segregated out of the transformants and the strains were again assayed for β-galactosidase activity.\",\n \"Nine of the 25 transformants demonstrated a return to the level of β-galactosidase seen in the parental strain indicating that the effect was dsRNA-dependent (FIG.\",\n \"9B).\",\n \"The cDNAs being expressed in these transformants were named RNAi enhancing sequences (res).\",\n \"All transformants displayed normal growth phenotypes indicating that over-expression of the resident cDNAs did not affect general biology of the cell.\",\n \"In the absence of antisense RNA the remaining 16 transformants retained a reduced β-galactosidase activity indicating that the enhanced gene silencing was not dependent on the presence of dsRNA.\",\n \"This suggests that the cDNA-encoded proteins in these strains could have been affecting lacZ at the level of transcription or the stability or function of the protein.\",\n \"The library plasmids were recovered from the aes-containing strains (also referred to as res-containing strains) and their cDNA inserts sequenced.\",\n \"BLASTN and BLASTP analysis identified clones W18, W20, and W30 (named aes2) as homologues of domains 2 and 3 of the mitochondrial elongation factor Tu (EF Tu).\",\n \"EF Tu is an essential protein which plays a role in transporting tRNA to the A site in the ribosome for peptide elongation.\",\n \"The cDNA in transformants W21, W23, and W32 (named aes3) was homologous to a putative protein that was identified in a screen for fission yeast ORFs.\",\n \"Interestingly, the cDNA insert was also homologous to the antisense strand of the 3′ UTR of the fission yeast gene sna41 which has previously been shown to be involved in DNA replication.\",\n \"It is thus possible that aes3 may operate through more than one mechanism in enhancing antisense RNA activity.\",\n \"The cDNA in transformant W47 (named aes4) was homologous to the antisense strand of the ribosomal protein L7a, a component of the 60S ribosomal subunit.\",\n \"aes4 also contained a small ORF of unknown biological function.\",\n \"The inserts in transformants W27 and W28 (named aes1) shared homology with a putative protein from C. albicans that was identified in a screen for genes essential for cell growth.\",\n \"A tertiary quantitative β-galactosidase assay was performed to obtain accurate levels of gene silencing augmentation in the antisense lacZ strains co-expressing these unique factors (FIG.\",\n \"9C).\",\n \"This analysis showed that these co-factors enhanced antisense suppression by up to 50%.\",\n \"These results demonstrated that over-expression of a cDNA library was an effective way of identifying novel co-factors that magnify the suppressive effect mediated by antisense RNA.\",\n \"aes1 shared 43% identity with amino acids 4 to 202 of a C. albicans hypothetical protein (AJ390519).\",\n \"aes2 shared 99% identity with nucleotides 10452 to 9484 of the translation elongation factor EF Tu (AL049769).\",\n \"aes3 shared 94% identity with nucleotides 776 to 1145 of D89239 S. pombe ORF (D89239) and 93% identity with nucleotides 3246 to 2876 of the antisense strand of the DNA replication factor sna41 (AB001379).\",\n \"aes3 also contained a 220 nt stretch of a GA repeat sequence at its 3′ end.\",\n \"aes4 shared 99% identity with nucleotides 9678 to 8897 of the antisense strand of ribosomal protein L7a (AJ001133) and 99% identity with nucleoStides 1365 to 584 of the antisense strand of ribosomal protein L4 (AB005750).\",\n \"The reference numerals in brackets refer to accession numbers in the GeneBank database (the GeneBank database can be accessed from the following web site: http://www.ncbi.nlm.nih.gov/).\",\n \"EF Tu is analogous to the eukaryotic EF1α and acts by transporting tRNA to the A site in the ribosome for peptide elongation.\",\n \"EF1α is an essential protein which has also been implicated in a large array of cellular activities including actin binding, microtubule severing, cellular transformation, cell senescence, protein ubiquitination, and protein folding.\",\n \"Detailed analysis of the EF Tu-expressing strain showed that it enhanced antisense RNA-mediated lacZ silencing by an additional 15% (FIG.\",\n \"9C).\",\n \"It has been proposed that dsRNA is fragmented into 21-25 nt species by dsRNA-specific nucleases, amplified by RNA-dependent RNA polymerase, and dissociated by an ATP-dependent RNA helicase.\",\n \"The small antisense fragments are then free to attack homologous mRNA by RNA nuclease-mediated degradation.\",\n \"It has recently been suggested that an associative mechanism could catalyse the ATP-dependent exchange of the sense strand of the short dsRNA with the target mRNA.\",\n \"This may involve the transport of fragmented dsRNA to the ribosome where, in a competitive reaction with tRNA complexes, the complementary antisense strand binds to the mRNA.\",\n \"This would permit the association of the antisense strand of the dsRNA with the target mRNA when the latter is in a structurally exposed state and both inhibit translation and target the mRNA for ribonuclease degradation.\",\n \"Without wishing to be bound by any particular mechanism of action, EF Tu could act by binding to RNAi-dependent short dsRNA species and bring them to the site of action.\",\n \"The protein encoded by sna41 has previously been shown to be involved in DNA replication.\",\n \"sna41 has low homology with CDC45 and might have DNA helicase properties which could facilitate the expression of complementary sequences.\",\n \"It is conceivable that the antisense plasmid and target DNA sequences may ectopically pair by intermolecular complementarity.\",\n \"Such pairing may inhibit RNA expression and consequently reduce the level of intracellular dsRNA.\",\n \"Similarly the intramolecular pairing of inverted repeat DNA sequences may also interfere with RNA expression.\",\n \"The over-expression of a protein with DNA helicase properties could facilitate the generation of more dsRNA which could in turn enhance the RNAi effect.\",\n \"Furthermore, CDC45 mutants show an increased rate of plasmid segregation.\",\n \"If plasmid loss is inhibited by over-expression of sna41 then more dsRNA may be generated leading to more effective RNAi in this system.\",\n \"In this light it is not unreasonable to expect that other proteins normally involved in DNA and/or RNA metabolism and function could also have a role in RNAi modulation and/or enhancement.\",\n \"The L7a protein is part of the 60s ribosomal sub-unit.\",\n \"Without wishing to be bound by any particular mechanism of action, RNAi augmentation by over-expression of this protein is reasonable as it is hypothesised that the short dsRNA species may undergo strand displacement with target mRNA at the ribosome.\",\n \"The L7a ribosomal protein may act in RNAi by i) mediating docking of dsRNA or its unwound form into the A site of the ribosome, assisting in association of the antisense strand with the target mRNA, and/or shuttling of dsRNA to the ribosomal complex.\",\n \"Nucleotide sequences representative of the aes factors referred to above are provided below and identified as Seq ID Nos 1 to 4: DNA sequence for aes1 factor (Seq ID No 1) TTTAACTTAGTTCGCTTTGTTAAATTGGCCTCGAGGTCGACGTTAATTAA GCCGCAATTGTAACAGTAGATTTTTTGCATCATTATTACTCTCCGAAACA TGACTGAACACTCATTTAAGCAAATAGACGTGTTTTCTAATAAAGGTTTT CGAGGTAATCCTGTTGCAGTTTTTTTTGATGCAGATAATTTATCACAAAA GGAAATGCAGCAGATTGCCAAGTGGACAAATTTATCTGAGACAACATTTG TTCAAAAGCCGACAATCGATAAAGCAGATTACAGACTTCGTATATTTACC CCAGAATGTGAATTAAGCTTTGCTGGTCACCCAACAATTGGATCGTGCTT TGCTGTTGTTGAAAGTGGATATTGTACTCCAAAAAACTGTAAAATTATTC AGGAATGTTTAGCCGGTTTAGTTGAATTAACTATCGATGGGGAAAAGGAT GAAGACACTTGGATTTCTTTCAAACTTCCGTATTACAAAATTTTACAGAC TTCTGAAACTGCAATTTCAGAAGTAGAAAATGCATTGGGTATTCCTCTGA ATTATAGTTCTCAAGTTTCTCCTCCTGTGTTAATAGATGATGGACCAAAG TGGCTTGTAATTCAACTTCCAAACGCTACAGATGTGCTCAACCTCGTTCC GAAATTTCAGTCCCTTTCCCAAGTTTGTAAAAACAATGATTGGATAGGCG TCACCCGTCTTTGGTGAATTAGAAAAGACTCGTTTGAAAGCCCGAAGCTT TGCGCCTTTAATACATGTCAATGAGGATCCGGCTTGCGGTAGTGGTGCAG GAGCTGTCGGTGTGTATATTGGAAGCTCTCAAAAAACTCCAACTTCTCTA TCATTTACGATTTCTCAAGGTACAAAATTAAGTAGACAAGCAATTTCCAA AGTCAGCGTAGACGTTTCCTCCAATAAATCAATTGCTGTTTTTGTCGGTG GACAGGCAAAAACTTGTATTTCTGGAAAATCGTTTATTTAATGTTTTTAT TACAAATATTCACTTGCGAGTTTATTTTCCAATACTGAAGACTTTCAATC AATAGCAAATATGCTACTCAAGGAAGTTCACTCATTCAAAAGCAATTGGT TTACTATATCGTTTTTTCTAACTAGTTACTAGTCATTGAACAATCTACCG AATGATAAAATGAAATTTTGGTTTTTCCCCGGGTAAAAGGAATGTCTCCC TTGCCAGTACTGCTAGGGTTTTTCTTTCGAACTATAAGA DNA sequence for aes2 factor (Seq ID No 2) AGTCCGCTTTGTTAAATTGGCCTCGAGGTCGACGTTAATTAAGCCTGATA TGATCGAGCTTGTCGAAATGGAAATGCGTGAGCTACTCTCCGAATACGGA TTTGATGGTGACAATACTCCAATTGTTAGCGGCAGTGCTTTATGTGCCTT AGAGGGTCGTGAGCCTGAGATTGGTCTCAATAGTATTACTAAATTGATGG AAGCTGTTGATAGTTATATTACTCTTCCTGAAAGAAAAACGGATGTCCCT TTCTTGATGGCCATCGAGGACGTTTTTTCAATTTCAGGTCGCGGAACTGT AGTCACTGGCCGTGTCGAGCGCGGTACTTTAAAGAAGGGTGCTGAAATCG AAATCGTCGGTTATGGTAGCCATTTAAAGACTACCGTTACTGGAATTGAA ATGTTCAAAAAGCAGCTTGATGCCGCCGTTGCCGGTGACAATTGTGGCCT TTTACTTCGTTCTATCAAGCGAGAGCAATTAAAACGTGGAATGATTGTCG CTCAACCAGGAACCGTTGCTCCTCATCAGAAATTCAAGGCATCATTCTAT ATTTTGACAAAAGAGGAAGGAGGTCGTCGTACCCGGTTTCGTTGACAAGT ATCGTCCCCAACTGTACAGTCCGTACTTCCGACGTTACTGTCGAACTTAC CCACCCTGATCCTAACGACTCAACAAAATGGTTATGCCTGGAGACAATGT CGAGATGATCTGTACGCTTATTCACCCCATTGTCATCGAAAAAGGACAAC GCTTCACAGTTCGTGAGGGTGGAAGCACTGTAGGCACAGCTTTGGTTACT GAACTTTTGGATTAGTGCATTTATGAACTTATTGGCTTTAAAAATTTTGC ATGCTGAATACCAATATTATGTCCCTTCTCAGAATTCTATAACTACAGTG TCATTATTGTAATAAGACTTTTGCATCCATTGACAATGGTATTTGATACT TTTATAGTTTCTACTATTGTTAGCCAAAGTTATAAAACAAATAATAAAAT AACGTTGAATCAAAAAAAAAAAAAAAAAAAGCGGCCGCGGATCCCCGGGT AAAAGGAATGTCTCCCTTGCCAGTACTGCTAGGGTTTTTCTTTCAAACTA TGGGA DNA sequence for aes3 factor (Seq ID No 3) ATTTCAGACGCAATTCACATGGCTTTTGACTGTATTGCTATTCTTGTCGG TTTAGTTGCTACGACGCTTGCCAAGATGCCTCTAAATTATGCTTACCCCT TTGGATTTGCAAAAATTGAGGCTCTTTCGGGTTTCACTAATGGTATTTTT TTAGTTTTGATTTCATTTTCTATCGTCGGCGAGGCATTATATAGGTTATT TCATCCGCCCCAAATGAATACCGACCAATTGTTGTTGGTTAGTTTTTTGG GCCTTGTTGTGAATTTGGTAGGTATCCTAGCGTTCAATCATGGGCATAAT CATGATCATGGGTCTCATCACCATCATTCCCATAGTAATCATAGTATGTG TCTGCCTAACACTACAAATGATATAAATATTTTTGAAGAGTTTGAAGAAG AAAAAGATAATGTTGAAGCCCAGAAAATGGGCTATACGAATGACGATCAC GTATCCCAACATGAACATACCCATGAGAATAGTCAGGAACATCACCATGA GCATAACCACAATCATGATCACATCCATAAATACAATGAAAAATGCGACC ATGAAAGCATAAGTCTCCAGAATTTAGACAATGATCATCACTGTCATCAT CACCATGAAAATCATAATATGCATGGCATATTTCTGCATATTATCGCAGA TACTATGGGCTCTGTTGGAGTTATTGTCTCTACTATATTAATACAGTGGT TTTCATGGACCGGTTTTGATCCTTCGGCATCTCTAATAATTGCTGCATTA ATATTTGTTTCTGTACTTCCATTAATTAAAGATTCGGCGAAGAATTTGCT CTCTGTGACTGATCCAGAATCGGAATATTTATTGAAGCAGTGTTTGTCGA ACATCAGTTTAAGTCACTCCGTTGTCAGTTTATCCAACCCTAAGTTCTGG ACAAACGAAAGAGGTGAAGTGTATGGAATACTCCATATTCAGGTGAGCAT AGACGGTGATTTAAACGTGGTTCGTAATGAAGTATTTAGGAAGCTCTCAA TCGCTGTACCAAATTTAAAACACATTTGTATACAATCTGAACGGCCAAAC AATTGCTGGTGTGGAAAATAGTTCTTACATCAGTTGATATCCATACTTAT TTACGTGTAATTTTAATTAGATGAATTAATATTTTCTTTATTAGC DNA sequence for aes4 factor (Seq ID No 4) TTTACTTTAGTCGCTTTGTTAAATTGGCCTCGAGGTCGACGTTAATTAAG CTTTTTTTTTAAGAGATATAACATATGTCAACGCGTCATTGATTAACTAC ATAACACGCCAATTATAAACTTCTCCCAAAAGAACTTAAGAATTTCCATT TTCAATCCAGATGAATTTATTTAAGAGACGAACAGTAGCGGCAGCAGCCT TAGCACGCTTAGCGAGCAAAGCTTGGGTCTTACCACCCATGATACCCACC ACCCCACTTACGACGGGCTTTCGTCGTACTTAGCAGAGAAGTTAGCATCA ACGGCGGAGACAATAGAAGCGAGTTCGTTCTTGTCTTCCTCACGGACCTC AGTGACAGCTAAAACAGCAGCAGTCTTTTGGTGAATGACAGTACCAAGGC GGGCCTTGTTCTTGACAATGGCATAAGGAACACCCATCTTCTTGCACAAA GCAGGCAAGAAAACGACGAGTTCAATGGGGTCGACATCGCTGGCAATGAG AACCAACTTAGCCTTCTTGGCCTCAATGAGAGCTACAACATGGTTCAAAC CATATTTAACATTGTAAGGCTTCTTAGAGACGTCTTGAGCAGACTTGCCG TTGGCAACAGCCTCGGCTTCAGCAACCAAACGTTGCTTCTTTTCAGCAGC AGTCTCAGGACGGTACTTGTTAAGCAACTTGAAGACCTGAGTAGCAGTGT TTTTGTCCAAAGTCTTCTGGAACTGAGCAATGGCAGGAGGAACCTTCAAA CGCAAGTTCAAAATCTTGCGACGGCGTTGAAGGCGGATATACTCAGGCCA CTTAACAAAACGGCTCAAGTCACGCTTAGGTTGGATGTCTTGTCCCCCGG GTAAAAGGAATGTCTCCCTTGCCAGTACTGCTAGGGTTTTTCGTTCGAAT AAGGCC Example 9 Effect of Novel RNAi Factors on Antisense RNA and dsRNA-Mediated Gene Regulation With recent studies on PTGS suggesting that antisense RNA, co-suppression, and dsRNA-mediated interference may share similar mechanisms, we wanted to determine whether over-expression of an aes factor would also enhance dsRNA-mediated regulation.\",\n \"Having demonstrated that dsRNA could mediate gene suppression in this fission yeast model, the effect of an antisense enhancing sequence on dsRNA-mediated regulation was tested.\",\n \"To this end, the aes2 gene was co-expressed with the lacZ panhandle construct in a yeast strain containing the lacZ target gene.\",\n \"Under these conditions, this transformant displayed an additional 30% suppression of β-galactosidase activity when compared to the transformant expressing only the panhandle lacZ RNA (see FIG.\",\n \"10).\",\n \"This result shows that the aes2 gene, encoding the two domains of the mitochondrial elongation factor EF Tu, stimulated not only antisense RNA but also dsRNA-mediated gene inhibition.\",\n \"Further it was shown that these two forms of regulation are related by over-expressing the ATP-dependent RNA helicase ded1 in the presence of lacZ antisense RNA and showing that this helicase enhanced gene suppression by a further 50% compared to the control strain (example 6).\",\n \"ded1 was tested on both active and inactive antisense plasmids and demonstrated that ded1 augmentation of gene silencing was dependent on an active antisense RNA (see FIG.\",\n \"11).\",\n \"This could be due to the absence of RNA duplex formation with the inactive antisense RNA and the consequent lack of a substrate for the RNA helicase.\",\n \"The methods of the present invention have utility in demonstrating a range of RNAi efficacies, in identifying new factors which enhance or reduce gene silencing, in inhibiting gene expression or increasing sensitivity to antisense inhibition of gene expression, in the treatment or prevention of disorders which require inhibition or down-regulation of gene expression.\",\n \"Although the present invention has been described with reference to specific examples and preferred embodiments it will be clear to those skilled in the art that variations and modifications which do not depart from the concept and the spirit of the invention described herein are also contemplated as being within the scope of the present invention.\",\n \"REFERENCES 1.Raponi, M., Atkins, D., Dawes, I.\",\n \"& Arndt, G. (2000) Antisense and Nucleic Acid Drug Development 10, 29-34.2.Arndt, G., Atkins, D., Patrikakis, M. & Izant, J.\",\n \"(1995) Molecular and General Genetics 248, 293-300.3.Arndt, G., Patrikakis, M. & Atkins, D. (2000) Nucleic Acids Research 28, e15.4.Clarke, M., Patrikakis, M. & Atkins, D. (2000) Biochemical and Biophysical Research Communications 268, 8-13.5.Moreno, S. & Nurse, P. (1994) Nature 367, 236-242.6.Moreno, S., Klar, A.\",\n \"& Nurse, P. (1991) Methods in Enzymology 194, 795-823.7.Maundrell, K. (1990) Journal of Biological Chemistry 265, 10857-10864.8.Prentice, H. (1992) Nucleic Acids Research 20, 621.9.Hoffman, C. & Winston, F. (1987) Gene 57, 267-272.10.Rose, M., Winston, F. & Hieter, P. (1990) Methods in yeast genetics: A laboratory course manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor).\",\n \"11.Maundrell, K. (1993) Gene 123, 127-1390.12.Basi, G., Schmid, E. & Maundrell, K. (1993) Gene 123, 131-136.13.Carr, A., MacNeill, S., Hayles, J.\",\n \"& Nurse, P. (1989) Molecular and General Genetics 218, 41-49.14.Sambrook, J., Fritsch, E. & Maniatis, T. (1989) (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).\",\n \"15.Patrikakis, M., Izant, J.\",\n \"& Atkins, D. (1996) Current Genetics 30, 151-158.16.Brun, C., Dubey, D. & Huberman, J.\",\n \"(1995) Gene 164, 173-177.17.Heyer, W.-D., Sipiczki, M. & Kohli, J.\",\n \"(1986) Molecular and Cellular Biology 6, 80-89.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10297167"}}},{"rowIdx":95,"cells":{"text":{"kind":"list like","value":[["Ligands of Integrin Receptors","The invention relates to the use of cyclic compounds as ligands of integrin receptors, in particular as ligands of the αVβ3 integrin receptor, the novel compounds themselves, their use, and pharmaceutical preparations comprising these compounds."],["1.The use of compounds of the formula I B-G-L I as ligand of integrin receptors, where B, G and L have the following meanings: L is a structural element of the formula IL —U-T IL where T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and —U— is —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1—, where a is 0 or 1, b is 0, 1 or 2 XL is CRL3RL4, NRL5, oxygen or sulfur, RL1, RL2, RL3, RL4 independently of one another are hydrogen, -T, —OH, —NRL6RL7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL1 and RL2 or RL3 and RL4, or optionally RL1 and RL3, together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three identical or different heteroatoms O, N, S, RL5, RL6, RL7 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, G is a structural element of the formula IG where the structural element B is bonded to the structural element G via the ring nitrogen and the structural element L is bonded via WG, YG is CO, CS, C═NRG2 or CRG3RG4, RG2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical, RG3, RG4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG3 and RG4 together a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG3 and RG4 together are an optionally substituted C3-C7-cycloalkyl radical, RG5 and RG6 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, an optionally substituted aryl or arylalkyl radical or both radicals RG5 and RG6 together are an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S, WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4 RG1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, RG7, RG8, RG9, RG10 independently of one another are hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —C1-NRG12RG13—NRG12RG13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical or in each case independently of one another two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 together are an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group O, N, S and up to two double bonds, RG11 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, RG12, RG13 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 and RG11* is a radical RG11 which is independent of RG11 B is a structural element containing at least one atom which, under physiological conditions, as a hydrogen acceptor can form hydrogen bridges, where at least one hydrogen acceptor atom has a distance of 5 to 14 atomic bonds from structural element G along the shortest possible route along the structural element skeleton, and the physiologically tolerable salts, prodrugs and the enantiomerically pure or diastereomerically pure and tautomeric forms.","2.The use as claimed in claim 1, wherein the structural element B is a structural element of the formula IB A-E- IB where A and E have the following meanings: A is a structural element selected from the group: a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon which can contain up to 4 heteroatoms selected from the group O, N and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, or a 9- to 14-membered polycyclic, saturated, unsaturated or aromatic hydrocarbon which can contain up to 6 heteroatoms selected from the group N, O and S, where, in each case independently of one another, the ring nitrogen optionally contained or the carbon atoms can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, a radical where ZA1 is oxygen, sulfur or optionally substituted nitrogen and ZA2 is optionally substituted nitrogen, oxygen or sulfur, and a radical where RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11, and E is a spacer structural element which covalently bonds the structural element A to the structural element G, where the number of atomic bonds along the shortest possible route along the structural element skeleton E is 5 to 14.3.The use as claimed in one of claims 1 or 2, wherein the structural element A used is a structural element selected from the group of structural elements of the formulae IA1 to IA18, where m, p, q independently of one another are 1, 2 or 3, RA1, RA2 independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or SO2NRA15RA16 or both radicals RA1 and RA2 together are a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N, and S, RA13, RA13* independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, where RA14 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkylene-C3-C7-cycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RA15, RA16, independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, CO—Cl1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, arylalkyl, COO-alkylenearyl, SO2-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, CO-aryl, CO—NH-aryl, SO2-aryl, hetaryl, CO—NH-hetaryl or CO-hetaryl radical, RA3, RA4 independently of one another are hydrogen, —(CH2)n—(XA)j—RA12, or both radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle is optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, where n is 0, 1, 2 or 3, j is 0 or 1, XA is —CO—, —CO—N(RX1)—, —N(RX1)—CO—, —N(RX1)—CO—N(RX1*)—, —N(RX1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX1)—, —N(RX1)— or —N(RX1)—SO2—, RA12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally C1-C4-alkyl- or aryl-substituted C2-C6-alkynyl or C2-C6-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocycle, substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, a C3-C7-cycloalkyl, aryl or hetaryl radical, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RA12, together with RX1 or RX1* forms a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RX1, RX1* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, RA6, RA6* are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, —CO—O—C1-C4-alkyl, arylalkyl, —CO—O-alkylenearyl, —CO—O-allyl, —CO—C1-C4-alkyl, —CO-alkylenearyl, C3-C7-cycloalkyl or —CO-allyl radical or in the structural element IA7 both radicals RA6 and RA6* together are an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—CO—C1-C4-alkyl radical, or an optionally substituted arylalkyl, —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical, or both radicals RA6 and RA7 together are an optionally substituted, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms-O, N, S, RA8 is hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—C1-C4-alkyl, SO2—C1-C4-alkyl or CO—O—C1-C4-alkyl radical or an optionally substituted aryl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl, CO—O-alkylenearyl or alkylenearyl radical, RA9, RA10 independently of one another are hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, or both: radicals RA9 and RA10 together in the structural element IA14 are a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA11 is hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, RA17 is hydrogen or, in the structural element IA16, both radicals RA9 and RA17 together are a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA1, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 which is independent of RG11 Z1, Z2, Z3, Z4 independently of one another are nitrogen, C—H, C-halogen or a branched or unbranched, optionally substituted C—C1-C4-alkyl or C—C1-C4-alkoxy radical, Z5 is NRA8, oxygen or sulfur.","4.The use as claimed in one of claims 1 to 3, wherein the spacer structural element E is composed of two to four substructural elements, selected from the group consisting of E1 and E2, where the sequence of linkage of the substructural elements is arbitrary and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE9RE10)g—(XE)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 1-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, or independently of one another in each case two radicals RE1 and RE2 or RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N and S x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms, together with RW2 or RW2*, a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NHC1-C6-alkoxyalkyl, CO—NHC1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an, optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical.","5.The use as claimed in one of claims 1 to 4, wherein the spacer structural-element E used is a structural element of the formula IE1E2 -E2-E1- IE1E2 and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(XE)k5—(CRE9RE10)h—(NRE11*)k6—IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 11-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14 (ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical or independently of one another are in each case two radicals RE1 and RE2 or RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle, which can contain up to three heteroatoms selected from the group O, N and S, x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms together with RW2 or RW2* a saturated or unsaturated C3-C7-heterocycle, which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical.","6.The use of the structural element of the formula IGL -G-L, IGL for the preparation of compounds which bind to integrin receptors, where G and L have the following meanings: L is a structural element of the formula IL —U-T IL where T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and —U— is —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1—, where a is 0 or 1, b is 0, 1 or 2 XL is CRL3RL4, NRL5, oxygen or sulfur, RL1, RL2, RL3, RL4 independently of one another are hydrogen, -T, —OH, —NRL6RL7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL1 and RL2 or RL3 and RL4, or optionally RL1 und RL3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, RL5, RL6, RL7 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, G is a structural element of the formula IG where the structural element B is bonded to the structural element G via the ring nitrogen and the structural element L is bonded via WG, YG is CO, CS, C═NRG2 or CRG3RG4, RG2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical, RG3, RG4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG3 and RG4 together are a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG3 and RG4 together are an optionally substituted, C3-C7-cycloalkyl radical, RG5 and RG6 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, an optionally substituted aryl or arylalkyl radical or both radicals RG5 and RG6 together are an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S, with the proviso that in the case of this fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle substituents are excluded which contain a structural element —V—CO—R8, where V is an optionally substituted C1-C2-alkylene radical R8 is a hydroxyl group, a C1-C8-alkoxy, aryl-C0-C6-alkoxy, C1-C8-alkylcarbonyloxy-C1-C4-alkoxy or aryl-C1-C8-alkylcarbonyloxy-C1-C4-alkoxy group or an L- or D-amino acid, which is bonded by an amide bond and in which the carboxylic acid component of said amino acid is present as a free acid or esterified with C1-C6-alkyl, WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4, RG1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, RG7, RG8, RG9, RG10 independently of one another are hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, —O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —CO—N12RG13, —NRG12RG13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical or in each case independently of one another two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 together are an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group O, N, S and which can contain up to two double bonds, RG11 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, RG12, RG13 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 and RG11* is a radical RG11 which is independent of RG11.7.The use of the compounds as claimed in one of claims 1 to 5 as ligands of the αVβ3 integrin receptor.","8.The use of the compounds as claimed in one of claims 1 to 5 for the production of drugs for treating diseases in which the interaction between integrins and their natural ligands is excessive or decreased.","9.The use of the compounds as claimed in one of claims 1 to 5 as claimed in claim 8 for the treatment of diseases in which the interaction between αVβ3 ingegrin and its natural ligands is excessive or decreased.","10.The use of the compounds as claimed in one of claims 1 to 5 as claimed in claim 9 for the treatment of atherosclerosis, rheumatoid arthritis, restenosis after vascular injury or stent implantation, angioplasty, acute kidney failure, angiogenesis-associated microangiopathies, diabetic angiopathies, blood platelet-mediated vascular occlusion, arterial thrombosis, congestive heart failure, myocardial infarct, stroke, cancer, osteoporosis, high blood pressure, psoriasis or viral, parasitic or bacterial conditions, inflammation, wound healing, hyperparathyroidism, Paget's disease, malignant hypercalcemia or metastatic osteolytic lesions.","11.A compound of the formula I′ A-E′-G′-L I′ where A, E′, G′ and L have the following meanings: L is a structural element of the formula IL —U-T IL where T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and —U— is —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1—, where a is 0 or 1, b is 0, 1 or 2 XL is CRL3RL4, NRL5, oxygen or sulfur, RL1, RL2, RL3, RL4 independently of one another are hydrogen, -T, —OH, —NRL6RL7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL1 and RL2 or RL3 and RL4, or optionally RL1 and RL3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three identical or different heteroatoms O, N, S, RL5, RL6, RL7 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, G′ is a structural element of the formula IG where the structural element A-E′ is bonded to the structural element G′ via the ring nitrogen and the structural element L is bonded via WG, YG is CO, CS, C═NRG2 or CRG3RG4, RG2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical, RG3, RG4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG3 and RG4 together are a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG3 and RG4 together are an optionally substituted C3-C7-cycloalkyl radical, RG5 and RG6 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, an optionally substituted aryl or arylalkyl radical or both radicals RG5 and RG6 together are an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S, WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4, RG1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, RG7, RG8, RG9, RG10 independently of one another are hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG′12RG′13, C1-C4-alkylene-CO—NRG′12RG′13, C1-C4-alkylene-O—CO—NRG′12RG′13, C1-C4-alkylene-NRG′12RG′13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, —O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG′12RG′13, —SO2—NRG′12RG′13, —CO—NRG′12RG′13, —NRG′12RG′13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical or in each case independently of one another two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 together are an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group O, N, S and up to two double bonds, RG11 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, RG′12, RG′13 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11, and RG11* is a radical RG11 which is independent of RG11, RG14 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-heterocycloalkyl, C1-C4-alkylene-heterocycloalkenyl or hetarylalkyl radical, E′ is a structural element, composed of two to four substructural elements, selected from the group E1 and E2, where the sequence of linkage of the substructural elements is arbitrary and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(XE)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 11-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO-o, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, or independently of one another in each case two radicals RE1 and RE2 or RE3 and RE4 or RE8 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N and S, x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—C—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW12)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms, together with RW2 or RW2*, a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical, with the proviso that in the case where YE or ZE=CO and a radical XE or QE or an aromatic or heteroaromatic radical from the structural element A is bonded directly to YE or ZE, a direct atomic bond from YE or ZE to the structural element G is excluded, A is a structural element selected from the group: a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon, which can contain up to 4 heteroatoms selected from the group O, N and S, where, in each case independently of one another, the ring nitrogen optionally present or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, or a 9- to 14-membered polycyclic saturated, unsaturated or aromatic hydrocarbon which can contain up to 6 heteroatoms selected from the group N, O and S, where, in each case independently of one another, the ring nitrogen optionally present or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, a radical where ZA1 is oxygen, sulfur or optionally substituted nitrogen and ZA2 is optionally substituted nitrogen, oxygen or sulfur, and a radical where RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11, and the physiologically tolerable salts, prodrugs and the enantiomerically pure or diastereomerically pure and tautomeric forms.","12.A compound as claimed in claim 11, wherein the structural element A used is a structural element selected from the group of structural elements of the formulae IA1 to IA18 where m, p, q independently of one another are 1, 2 or 3, RA1, RA2 independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or SO2NRA15RA16 or both radicals RA1 and RA2 together are a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N, and S, RA13, RA13* independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, where RA14 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkylene-C3-C7-cycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RA15, RA16, independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, CO—C1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, arylalkyl, COO-alkylenearyl, SO2-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, CO-aryl, CO—NH-aryl, SO2-aryl, hetaryl, CO—NH-hetaryl or CO-hetaryl radical, RA3, RA4 independently of one another are hydrogen, —(CH2)n—(XA)j—RA12, or both radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N-heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle is optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, where n is 0, 1, 2 or 3, j is 0 or 1, XA —CO—, —CO—N(RX1)—, —N(RX1)—CO—, —N(RX1)—CO—N(RX1*)—, —N(RX1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX1)—, —N(RX1)— or —N(RX1)—SO2—, RA12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally C1-C4-alkyl or aryl-substituted C2-C6-alkynyl or C2-C6-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocycle, substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, a C3-C7-cycloalkyl, aryl or hetaryl radical, where both radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RA12, together with RX1 or RX1* is a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RX1, RX1* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, RA6, RA6 are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, —CO—O—C1-C4-alkyl, arylalkyl, —CO—O-alkylenearyl, —CO—O-allyl, —CO—C1-C4-alkyl, —CO-alkylenearyl, C3-C7-cycloalkyl or —CO-allyl radical or in the structural element IA7 both radicals RA6 and RA6* together are an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—CO—C1-C4-alkyl radical, or an optionally substituted arylalkyl, —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical, or both radicals RA6 and RA7 together are an optionally substituted, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA8 is hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—C1-C4-alkyl, SO2—C1-C4-alkyl or CO—O—C1-C4-alkyl radical or an optionally substituted aryl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl, CO—O-alkylenearyl or alkylenearyl radical, RA9, RA10 independently of one another are hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, or both radicals RA9 and RA10 together in the structural element IA14 are a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms Q, N, S and is optionally substituted by up to three identical or different radicals, RA11 is hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, RA17 is hydrogen or, in the structural element IA16, both radicals RA9 and RA17 together are a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 which is independent of RG11, Z1, Z2, Z3, Z4 independently of one another are nitrogen, C—H, C-halogen or a branched or unbranched, optionally substituted C—C1-C4-alkyl or C—C1-C4-alkoxy radical, Z5 is NRA8, oxygen or sulfur.","13.A compound as claimed in claim 11 or 12, wherein the structural element E′ used is a structural element of the formula IE1E2 -E2-E1- IE1E2 and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 (NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(XE)k—(CRE9RE10)h—(NRE11*)k6— IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 11-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon, which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O, and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, or independently of one another in each case two radicals RE1 and RE2 or RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group-O, N and S, x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms, together with RW2 or RW2*, a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical, with the proviso that in the case where YE═CO, k1 and k5=1 and h and k6=0 the sum of the indices c, k2 and d must be other than 0 and in the case where an aromatic or heteroaromatic radical from the structural element A is bonded directly to YE or ZE, a direct atomic bond from YE or ZE to the structural element G is excluded.","14.A compound as claimed in one of claims 11 to 13 for use as a drug.","15.The use of the compounds as claimed in one of claims 11 to 13 for the production of drugs for treating diseases.","16.A pharmaceutical preparation comprising, in addition to the customary pharmaceutical excipients, at least one compound as claimed in one of claims 11 to 13.17.A pharmaceutical preparation, comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group inhibitors of blood platelet adhesion, activation or aggregation, anticoagulants which prevent thrombin activity or formation, antagonists of blood platelet-activating compounds or selectin antagonists.","18.The use of the pharmaceutical preparation as claimed in claim 17 for the production of a drug for treating blood platelet-mediated vascular occlusion or thrombosis.","19.A pharmaceutical preparation, comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group inhibitors of blood platelet activation or aggregation, serine protease inhibitors, fibrinogen-lowering compounds, selectin antagonists, antagonists of ICAM-1 or VCAM-1 inhibitors of leukocyte adhesion inhibitors of vascular wall transmigration, fibrinolysis-modulating compounds, inhibitors of complement factors, endothelin receptor antagonists, tyrosine kinase inhibitors, antioxidants and interleukin 8 antagonists.","20.The use of the pharmaceutical preparation as claimed in claim 19 for the production of a drug for treating myocardial infarct or stroke.","21.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group endothelin antagonists, ACE inhibitors, angiotensin receptor antagonists, endopeptidase inhibitors, beta-blockers, calcium channel antagonists, phosphodiesterase inhibitors and caspase inhibitors.","22.The use of the pharmaceutical preparation as claimed in claim 21 for the production of a drug for treating congestive heart failure.","23.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group thrombin inhibitors, inhibitors of factor Xa, inhibitors of the coagulation pathway which leads to thrombin formation, inhibitors of blood platelet adhesion, activation or aggregation, endothelin receptor antagonists, nitrogen oxide synthase inhibitors, CD44 antagonists, selectin antagonists, MCP-1 antagonists, inhibitors of signal transduction in proliferating cells, antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF and antioxidants.","24.The use of the pharmaceutical preparation as claimed in claim 23 for the production of a drug for treating restenosis after vascular injury or stent implantation.","25.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF, heparin or low-molecular weight heparins or further GAGs, inhibitors of MMPs, selectin antagonists, endothelin antagonists, ACE inhibitors, angiotensin receptor antagonists, glycosylation inhibitors and AGE formation inhibitors or AGE breakers and antagonists of their receptors.","26.The use of the pharmaceutical preparation as claimed in claim 25 for the production of a drug for treating diabetic angiopathies.","27.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group lipid-lowering compounds, selectin antagonists, antagonists of ICAM-1 or VCAM-1 heparin or low-molecular weight heparins or further GAGs, inhibitors of MMPs, endothelin antagonists, apolipoprotein A1 antagonists, cholesterol antagonists, HMG CoA reductase inhibitors, ACAT inhibitors, ACE inhibitors, angiotensin receptor antagonists, tyrosine kinase inhibitors, protein kinase C inhibitors, calcium channel antagonists, LDL receptor function stimulants, antioxidants LCAT mimetics and free radical scavengers.","28.The use of the pharmaceutical preparation as claimed in claim 27 for the production of a drug for treating atherosclerosis.","29.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group cytostatic or antineoplastic compounds, compounds which inhibit proliferation and heparin or low-molecular weight heparins or further GAGs.","30.The use of the pharmaceutical preparation as claimed in claim 29 for the production of a drug for the treatment of cancer.","31.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group compounds for antiresorptive therapy, compounds for hormone exchange therapy, recombinant human growth hormone, bisphosphonates, compounds for calcitonin therapy, calcitonin stimulants, calcium channel antagonists, bone formation stimulants, interleukin-6 antagonists and Src tyrosine kinase inhibitors.","32.The use of the pharmaceutical preparation as claimed in claim 31 for the production of a drug for the treatment of osteoporosis.","33.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group TNF antagonists, antagonists of VLA-4 or VCAM-1, antagonists of LFA-1, Mac-1 or ICAMs, complement inhibitors, immunosuppressants, interleukin-1, -5 or -8 antagonists and dihydrofolate reductase inhibitors.","34.The use of the pharmaceutical preparation as claimed in claim 33 for the production of a drug for treating rheumatoid arthritis.","35.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group collagenase, PDGF antagonists and MMPs.","36.The use of the pharmaceutical preparation as claimed in claim 35 for the production of a drug for improving wound healing."],["The present invention relates to the use of cyclic compounds as ligands of integrin receptors, in particular as ligands of the αVβ3 integrin receptor, the novel compounds themselves, their use, and pharmaceutical preparations comprising these compounds.","Integrins are cell surface glycoprotein receptors which mediate interactions between similar and different cells as well as between cells and extracellular matrix proteins.","They are involved in physiological processes, such as embryogenesis, hemostasis, wound healing, immune response and formation/maintenance of the tissue architecture.","Disturbances in the gene expression of cell adhesion molecules and functional disorders of the receptors can contribute to the pathogenesis of many disorders, such as tumors, thromboembolic events, cardiovascular disorders, lung diseases, disorders of the CNS, the kidney, the gastrointestinal tract or inflammation.","Integrins are heterodimers of an α- and a β-transmembrane subunit in each case, which are noncovalently bonded.","Up to now, 16 different α- and 8 different β-subunits and 22 different combinations have been identified.","Integrin αvβ3, also called the vitronectin receptor, mediates adhesion to a multiplicity of ligands—plasma proteins, extracellular matrix proteins, cell surface proteins, of which the majority contain the amino acid sequence RGD (Cell, 1986, 44, 517-518; Science 1987, 238, 491-497), such as vitronectin, fibrinogen, fibronectin, von Willebrand factor, thrombospondin, osteopontin, laminin, collagen, thrombin, tenascin, MMP-2, bone sialoprotein II, various viral, fungal, parasitic and bacterial proteins, natural integrin antagonists such as disintegrins, neurotoxins—mambin—and blood fluke proteins—decorsin, ornatin—and also some non-RGD ligands, such as Cyr-61 and PECAM-1 (L. Piali, J.","Cell Biol.","1995, 130, 451-460; Buckley, J.","Cell Science 1996, 109, 437-445, J. Biol.","Chem.","1998, 273, 3090-3096).","A number of integrin receptors show cross-reactivity with ligands which contain the RGD motif.","Thus integrin αIIbβ3, also called the platelet fibrinogen receptor, recognizes fibronectin, vitronectin, thrombospondin, von Willebrand factor and fibrinogen.","Integrin αvβ3 is expressed, inter alia, on endothelial cells, blood platelets, monocytes/macrophages, smooth muscle cells, some B cells, fibroblasts, osteoclasts and various tumor cells, such as melanoma, glioblastoma, lung, breast, prostate and bladder carcinomas, osteosarcomas or neuroblastomas.","Increased expression is observed under various pathological conditions, such as in the prothrombotic state, in vascular injury, tumor growth or metastasis or reperfusion and on activated cells, in particular on endothelial cells, smooth muscle cells or macrophages.","An involvement of integrin αvβ3 has been demonstrated, inter alia, in the following syndromes: cardiovascular disorders such as atherosclerosis, restenosis after vascular injury, and angioplasty (neointima formation, smooth muscle cell migration and proliferation) (J. Vasc.","Surg.","1994, 19, 125-134; Circulation 1994, 90, 2203-2206), acute kidney failure (Kidney Int.","1994, 46, 1050-1058; Proc.","Natl.","Acad.","Sci.","1993, 90, 5700-5704; Kidney Int.","1995, 48, 1375-1385), angiogenesis-associated microangiopathies such as diabetic retinopathy or rheumatoid arthritis (Ann.","Rev.","Physiol 1987, 49, 453-464; Int.","Opthalmol.","1987, 11, 41-50; Cell 1994, 79, 1157-1164; J. Biol.","Chem.","1992, 267, 1093.1-10934), arterial thrombosis, stroke (phase II studies with ReoPro, Centocor Inc., 8th annual European Stroke Meeting), carcinomatous disorders, such as in tumor metastasis or in tumor growth (tumor-induced angiogenesis) (Cell 1991, 64, 327-336; Nature 1989, 339, 58-61; Science 1995, 270, 1500-1502), osteoporosis (bone resorption after proliferation, chemotaxis and adhesion of osteoclasts to bone matrix) (FASEB J.","1993, 7, 1475-1482; Exp.","Cell Res.","1991, 195, 368-375, Cell 1991, 64, 327-336), high blood pressure (Am.","J. Physiol.","1998, 275, H1449-H1454), psoriasis (Am.","J. Pathol.","1995, 147, 1661-1667), hyperparathyroidism, Paget's disease (J. Clin.","Endocrinol.","Metab.","1996, 81, 1810-1820), malignant hypercalcemia (Cancer Res.","1998, 58, 1930-1935), metastatic osteolytic lesions (Am.","J. Pathol.","1997, 150, 1383-1393), pathogenic protein (e.g.","HIV-1 tat)-induced processes (e.g.","angiogenesis, Kaposi's sarcoma) (Blood 1999, 94, 663-672) inflammation (J.","Allergy Clin.","Immunol.","1998, 102, 376-381), cardiac insufficiency, CHF, and also in antiviral, antiparasitic, antifungal or antibacterial therapy and prophylaxis (adhesion and internalization) (J. Infect.","Dis.","1999, 180, 156-166; J. Virology 1995, 69, 2664-2666; Cell 1993, 73, 309-319).","On account of its key role, pharmaceutical preparations which contain low-molecular weight integrin αvβ3 ligands are of high therapeutic or diagnostic benefit, inter alia, in the indications mentioned.","Advantageous αvβ3 integrin receptor ligands bind to the integrin αvβ3 receptor with an increased affinity.","In contrast to integrin αvβ3, particularly advantageous αvβ3 integrin receptor ligands additionally have an increased selectivity and are less active with respect to the integrin αIIbβ3 by at least a factor of 10, preferably at least a factor of 100.For a multiplicity of compounds, such as anti-αvβ3 monoclonal antibodies, peptides which contain the RGD binding sequence, natural, RGD-containing proteins (e.g.","disintegrins) and low-molecular weight compounds, an integrin αvβ3 antagonistic action has been shown and a positive in vivo effect demonstrated (FEBS Letts 1991, 291, 50-54; J. Biol.","Chem.","1990, 265, 12267-12271; J. Biol.","Chem.","1994, 269, 20233-20238; J.","Cell Biol 1993, 51, 206-218; J. Biol.","Chem.","1987, 262, 17703-17711; Bioorg.","Med.","Chem.","1998, 6, 1185-1208).","Antagonists of the αVβ3 integrin receptor based on a bicyclic structural element are described in WO 9906049, WO 9905107, WO 9814192, WO 9724124, WO 9724122 and WO 9626190.EP 540 334 and WO 9308174 describe bicyclic antagonists of the αIIbβ3 integrin receptor.","WO 9407488 A1 describes compounds having a bicyclic molecular structure and which accelerate the release of growth hormone.","Further, vasopressin antagonists having a bicyclic molecular structure are described in the specifications EP 620216, WO 9534540, WO 9408582, WO 9802432, WO 9420473, JP 09221476 A1, JP 11060488 A1, WO 9404525, JP 04321669 A1, WO 9722591, as well as in Matsuhisa et al., Chem.","Pharm.","Bull.","1999, 47, 3, 329-339.It is an object of the present invention to make available novel integrin receptor ligands having advantageous properties.","We have found that this object is achieved by the use of compounds of the formula I B-G-L I as ligands of integrin receptors, where B, G and L have the following meanings: L is a structural element of the formula IL —U-T IL where T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and —U— is —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1—, where a is 0 or 1, b is 0, 1 or 2 XL is CRL3RL4, NRL5, oxygen or sulfur, RL1, RL2, RL3, RL4 independently of one another are hydrogen, -T, —OH, —NRL6RL7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL1 and RL2 or RL3 and RL4, or optionally RL1 and RL3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three identical or different heteroatoms O, N, S, RL5, RL6, RL7 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, G is a structural element of the formula IG where the structural element B is bonded to the structural element G via the ring nitrogen and the structural element L is bonded via WG, YG is CO, CS, C═NRG2 or CRG3RG4, RG2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical, RG3, RG4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG3 and RG4 together are a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG3 and RG4 together are an optionally substituted C3-C7-cycloalkyl radical, RG5 and RG6 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, an optionally substituted aryl or arylalkyl radical or both radicals RG5 and RG6 together are an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S, WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4, RG1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, RG7, RG8, RG9, RG10 independently of one another are hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, —O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —CO—NRG12RG13, —NRG12RG13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical or in each case independently of one another two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 together are an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group O, N, S and up to two double bonds, RG11 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, RG12, RG13 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11, and RG11* is a radical RG11 which is independent of RG11, B is a structural element containing at least one atom which, under physiological conditions, as a hydrogen acceptor can form hydrogen bridges, where at least one hydrogen acceptor atom has a distance of 5 to 14 atomic bonds from structural element G along the shortest possible route along the structural element skeleton, and the physiologically tolerable salts, prodrugs and the enantiomerically pure or diastereomerically pure and tautomeric forms.","In the structural element L, T is understood as meaning a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH.","A radical hydrolyzable to COOH is understood as meaning a radical which changes into a group COOH after hydrolysis.","A group which may be mentioned by way of example as a radical T hydrolyzable to COOH is in which R1 has the following meanings: a) OM, where M can be a metal cation, such as an alkali metal cation, such as lithium, sodium, potassium, the equivalent of an alkaline earth metal cation, such as calcium, magnesium and barium, or an environmentally tolerable organic ammonium ion such as primary, secondary, tertiary or quaternary C1-C4-alkylammonium or ammonium ion, such as ONa, OK or OLi, b) a branched or unbranched, optionally halogen-substituted C1-C8-alkoxy radical, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particular methoxy, ethoxy, 1-methylethoxy, pentoxy, hexoxy, heptoxy, octoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy or pentafluoroethoxy c) a branched or unbranched, optionally halogen-substituted C1-C4-alkylthio radical such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio radical d) an optionally substituted —O-alkylenearyl radical, such as —O-benzyl e) R1 is further a radical —(O)m—N(R18)(R19), in which m is 0 or 1 and R18 and R19, which can be identical or different, have the following meanings: hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl or the corresponding substituted radicals, preferably methyl, ethyl, propyl, butyl or i-butyl, C2-C6-alkenyl radical, such as vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl or the corresponding substituted radicals, C2-C6-alkynyl radical, such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl or the corresponding substituted radicals, C3-C8-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl und cycloheptyl, cyclooctyl or the corresponding substituted radicals, or a phenyl radical, optionally mono- or polysubstituted, for example mono- to trisubstituted, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl, C1-C4-alkoxy, C1-C4-halogenoalkoxy or C1-C4-alkylthio such as 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methylphenyl, 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl, or R18 and R19 together form an optionally substituted, e.g.","C1-C4-alkyl-substituted, C4-C7-alkylene chain closed to give a cycle, which can contain a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, such as —(CH2)4—, —(CH2)5—, —(CH2)6—, —(CH2)7—, —(CH2)2—O—(CH2)2—, —CH2—S—(CH2)3—, —(CH2)2—O—(CH2)3—, —NH—(CH2)3—, —CH2—NH—(CH2)2—, —CH2—CH═CH—CH2—, —CH═CH—(CH2)3—, —CO— (CH2)2—CO— or —CO— (CH2)3—CO—.","A radical bioisosteric to COOH is understood as meaning radicals which can replace the function of a group COOH in active compounds by equivalent bond donor/acceptor capabilities or by equivalent charge distribution.","Radicals which may be mentioned by way of example as radicals bioisosteric to —COOH are those such as described in “The Practice of Medicinal Chemistry, Editor: C. G. Wermuth, Academic Press 1996, pages 125 and 216, in particular the radicals —P═O(OH)2, —SO3H, tetrazole or acylsulfonamides.","Preferred radicals T are —COOH, —CO—O—C1-C8-alkyl or —CO—O-benzyl.","The radical —U— in the structural element L is a spacer selected from the group —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1-.","In the case of the radical ═CRL1—, the structural element L is linked to the structural element G via a double bond.","XL is a radical CRL3RL4, NRL5, oxygen or sulfur.","Preferred radicals —U— are the radicals —CRL1═CRL2—, ethynylene or —(XL)a—(CRL1RL2)b—, where XL is preferably CRL3RL4 (a=0 or 1) or oxygen (a=1).","Particularly preferred radicals —U— are the radicals —(XL)a—(CRL1RL2)b—, where XL is preferably CRL3RL4 (a=0 or 1) or oxygen (a 1).","Under RL11, RL2, RL3 or RL4 in the structural element L, a halogen radical is understood as meaning, for example, F, Cl, Br or I, preferably F. Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C1-C6-alkyl radical is understood as meaning, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl, preferably branched or unbranched C1-C4-alkyl radicals such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, particularly preferably methyl.","Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C2-C6-alkenyl radical is understood as meaning, for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl.","Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C2-C6-alkynyl radical is understood as meaning, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably ethynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl.","Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C3-C7-cycloalkyl radical is understood as meaning, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.","Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C1-C4-alkoxy radical is understood as meaning, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.","The radicals —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 are secondary or tertiary amides and are composed of the amide bond and the corresponding C1-C6-alkyl radicals such as described above for RL1, RL2, RL3 or RL4.The radicals RL1, RL2, RL3 or RL4 can furthermore be a radical C1-C2-alkylene-T, such as methylene-T or ethylene-T, C2-alkenylene-T, such as ethenylene-T or C2-alkynylene-T, such as ethynylene-T, an aryl radical, such as phenyl, 1-naphthyl or 2-naphthyl or an arylalkyl radical, such as benzyl or ethylenephenyl (homobenzyl), where the radicals can optionally be substituted.","Furthermore, two radicals RL1 and RL2 or RL3 and RL4 or optionally RL1 and RL3 can in each case independently of one another together be an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S. All radicals for RL1, RL2, RL3 or RL4 can be optionally substituted.","For the radicals RL1, RL2, RL3 oder RL4 and all further substituted radicals of the description below, suitable substituents, if the substituents are not specified in greater detail, are independently of one another up to 5 substituents, for example selected from the following group: —NO2, —NH2, —OH, —CN, —COOH, —O—CH2—COOH, halogen, a branched or unbranched, optionally substituted C1-C4-alkyl radical, such as methyl, CF3, C2F5 or CH2F, —CO—O—C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, C1-C4-thioalkyl, —NH—CO—O—C1-C4-alkyl, —O—CH2—COO—C1-C4-alkyl, —NH—CO—C1-C4-alkyl, —CO—NH—C1-C4-alkyl, —NH—SO2—C1-C4-alkyl, —SO2—NH—C1-C4-alkyl, —N(C1-C4-alkyl)2, —NH—C1-C4-alkyl, or —SO2—C1-C4-alkyl radical, such as —SO2—CF3, an optionally substituted —NH—CO-aryl, —CO—NH-aryl, —NH—CO—O-aryl, —NH—CO—O-alkylenearyl, —NH—SO2-aryl, —SO2—NH-aryl, —CO—NH-benzyl, —NH—SO2-benzyl or —SO2—NH-benzyl radical, an optionally substituted radical —SO2—NR2R3 or —CO—NR2R3 where the radicals R2 and R3 independently of one another can have the meaning RL5 as below or both radicals R2 and R3 together can be a 3- to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three further different or identical heteroatoms O, N, S, and optionally two radicals substituted on this heterocycle can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can be optionally substituted or a further, optionally substituted cycle can be fused to this cycle.","If not specified in greater detail, in all terminally bonded, substituted-hetaryl radicals of the description, two substituents can form a fused 5- to 7-membered, unsaturated or aromatic carbocycle.","Preferred radicals RL1, RL2, RL3 or RL4 are independently of one another hydrogen, halogen, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy or C3-C7-cycloalkyl radical or the radical —NRL6RL7.Particularly preferred radicals RL1, RL2, RL3 or RL4 are independently of one another hydrogen, fluorine or a branched or unbranched, optionally substituted C1-C4-alkyl radical, preferably methyl.","The radicals RL5, RL6, RL7 in structural element L are independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, for example as described above for RL1, C3-C7-cycloalkyl radical, for example as described above for RL1, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical, which is composed of the group CO—O, SO2 and CO and, for example, of the C1-C6-alkyl radicals described above for RL1, or an optionally substituted CO—O-alkylenearyl, SO2-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, which is composed of the group CO—O, SO2 and CO and, for example, of the aryl or arylalkyl radicals described above for RL1.Preferred radicals for RL6 in structural element L are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—O—C1-C4-alkyl, CO—C1-C4-alkyl or SO2—C1-C4-alkyl radical or an optionally substituted CO—O-benzyl, SO2-aryl, SO2-alkylenearyl or CO-aryl radical.","Preferred radicals for RL7 in structural element L are hydrogen or a branched or unbranched, optionally substituted C1-C4-alkyl radical.","Preferred structural elements L are composed of the preferred radicals of the structural element.","Particularly preferred structural elements L are composed of the particularly preferred radicals of the structural element.","G is a structural element of the formula IG where the structural element B is bonded via the ring nitrogen and the structural element L is bonded via WG to the structural element G, optionally via a double bond.","YG in structural element G is CO, CS, C═NRG2 or CRG3RG4, preferably CO, C═NRG2 or CRG3RG4, particularly preferably CO or CRG3RG4.RG2 in structural element G is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy or C3-C7-cycloalkyl radical, for example as described above for RL1 in each case, an optionally substituted —O—C3-C7-cycloalkyl radical, which is composed of an ether group and, for example, of the C3-C7-cycloalkyl radical described above for RL1, an optionally substituted aryl or arylalkyl radical, for example as described above for RL1 in each case or an optionally substituted —O-aryl or —O-alkylenearyl radical, which is composed of a group —O— and, for example, of the aryl or arylalkyl radicals described above for RL1.Branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radicals for RG3 or RG4 in structural element G independently of one another are understood as meaning, for example, the corresponding radicals in each case described above for RL1.Further, both radicals RG3 and RG4 can together form a cyclic acetal, such as —O—CH2—CH2—O— or —O—CH2—O—.","Furthermore, both radicals RG3 and RG4 can together form an optionally substituted C3-C7-cycloalkyl radical.","Preferred radicals for RG3 or RG4 are independently of one another hydrogen, C1-C4-alkyl or C1-C4-alkoxy.","Branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radicals and optionally substituted aryl or arylalkyl radicals for RG5 and RG6 in structural element G independently of one another are, for example, the corresponding radicals in each case described above for RL1.Further, both radicals RG5 and RG6 can together form an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S. Preferred radicals for RG5 and RG6 are independently of one another hydrogen or optionally substituted aryl radicals, preferably phenyl or arylalkyl radicals, preferably benzyl, and in each case both radicals RG5 and RG6 together can contain an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S. In particularly preferred radicals for RG5 and RG6, both radicals RG5 and RG6 together form an optionally substituted, fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle, for example selected from one of the following doubly bonded structural formulae: in particular selected from one of the following, doubly bonded structural formulae: Suitable substituents of these fused, unsaturated or aromatic 3- to 10-membered carbocycles or heterocycles which together can form RG5 and RG6 are in particular substituents such as generally described above.","Particularly preferred substituents of these fused, unsaturated or aromatic 3- to 10-membered carbocycles or heterocycles which together can form RG5 and RG6 are independently of one another up to four substituents selected from the following group: hydroxyl, —CN, F or Cl or a branched or unbranched, optionally substituted C1-C4-alkoxy or C1-C4-alkyl radical, such as methoxy, methyl, CF3, C2F5 or CH2F.","WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4, where the dashed lines intersect the atomic bonds within the structural element G and the carbon atom substituted by RG7 and RG8 is bonded to YG.","In a preferred embodiment, WG is a structural element selected from the group of structural elements of the formulae IWG2 and IWG3, in particular the structural element of the formula IWG2.RG1 in structural element WG is hydrogen, halogen, such as Cl, F, Br or I, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl radical, preferably C1-C4-alkyl or C1-C4-alkoxy radical such as in each case described above for RL1.Particularly preferred radicals for RG1 are hydrogen, methoxy or hydroxyl.","RG7, RG8, RG9 and RG10 in structural element G are independently of one another hydrogen, a hydroxyl group, CN, halogen, such as F, Cl, Br, I, a branched or unbranched, optionally substituted C1-C6-alkyl radical, such as optionally substituted methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl, C2-C6-alkenyl radical, such as optionally substituted vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl or 1-ethyl-2-methyl-2-propenyl, C2-C6-alkynyl radical, such as optionally substituted ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl or 1-ethyl-1-methyl-2-propynyl, an optionally substituted C3-C7-cycloalkyl radical, such as optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, C3-C7-heterocycloalkyl radical, such as optionally substituted aziridinyl, diaziridinyl, oxiranyl, oxaziridinyl, oxetanyl, thiiranyl, thietanyl, pyrrolidinyl, piperazinyl, morpholinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, hexahydroazepinyl, oxepanyl, 1,2-oxathiolanyl or oxazolidinyl, C3-C7-heterocycloalkenyl radical, such as optionally substituted azirinyl, diazirinyl, thiirenyl, thietyl, pyrrolinyls, oxazolinyls, azepinyl, oxepinyl, α-pyranyl, β-pyranyl, γ-pyranyl, dihydropyranyls, 2,5-dihydropyrrolinyl or 4,5-dihydrooxazolyl, a branched or unbranched, optionally substituted C1-C4-alkylene-C3-C7-cycloalkyl radical, which is composed, for example, of branched or unbranched C1-C4-alkylene radicals such as methylene, ethylene, propylene, n-butylene, isobutylene or t-butylene and, for example, the abovementioned C3-C7-cycloalkyl radicals, a branched or unbranched optionally substituted C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, which is composed of optionally substituted C1-C4-alkylene radicals, such as methylene, ethylene, propylene, n-butylene, isobutylene or t-butylene and, for example, the abovementioned C3-C7-heterocycloalkyl or C3-C7-heterocycloalkenyl radicals, the radicals being preferred which in the cyclic moiety contain one or two heteroatoms selected from the group consisting of N, O and S and up to two double bonds, a branched or unbranched, optionally substituted radical C1-C4-alkylene-O—RG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13, C1-C4-alkylene-SRG11 or C1-C4-alkylene-SO—RG11, which is composed of branched or unbranched, optionally substituted C1-C4-alkylene radicals, such as methylene, ethylene, propylene, n-butylene, isobutylene or t-butylene, the corresponding groups —O—, —CO—, —S—, —N and the terminal radicals RG11, RG12 and RG13 described below, an optionally substituted aryl radical, preferably optionally substituted phenyl, 1-naphthyl or 2-naphthyl, arylalkyl radical, preferably optionally substituted benzyl or ethylenephenyl (homobenzyl), hetaryl radical, preferably optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, thiadiazolyl, oxadiazolyl or triazinyl or their fused derivatives such as indazolyl, indolyl, benzothiophenyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl or isoquinolinyl, hetarylalkyl radical, preferably optionally substituted —CH2-2-pyridyl, —CH2-3-pyridyl, —CH2-4-pyridyl, —CH2-2-thienyl, —CH2-3-thienyl, —CH2-2-thiazolyl, —CH2-4-thiazolyl, CH2-5-thiazolyl, —CH2—CH2-2-pyridyl, —CH2—CH2-3-pyridyl, —CH2—CH2-4-pyridyl, —CH2—CH2-2-thienyl, —CH2—CH2-3-thienyl, —CH2—CH2-2-thiazolyl, —CH2—CH2-4-thiazolyl or —CH2—CH2-5-thiazolyl or a radical —S—RG11, —O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —CO—NRG12RG13, —NRG12RG13, CO—RG11.Further, two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 can in each case independently of one another together form an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group consisting of O, N, S and up to two double bonds.","Preferred radicals for RG7, RG8, RG9 and RG10 in the structural element G are independently of one another hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, —O—RG11, —SO—RG11, SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —CO—NRG12RG13, —NRG12RG13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical, as described above in each case.","Particularly preferred radicals for RG7, RG8, RG9 and RG10 in the structural element G are independently of one another hydrogen, F or a branched or unbranched, optionally substituted C1-C4-alkyl radical, as described above.","A branched or unbranched, optionally substituted C1-C8-alkyl radical for RG11, RG12 and RG13 is understood as meaning independently of one another, for example, the C1-C6-alkyl radicals mentioned above for RG1, plus the radicals heptyl and octyl.","Preferred substituents of the branched or unbranched, optionally substituted C1-C8-alkyl radicals for RG11, RG12 and RG13 independently of one another are the radicals halogen, hydroxyl, C1-C4-alkoxy, —CN, —COOH and —CO—O—C1-C4-alkyl.","A branched or unbranched, optionally substituted C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkylene-C3-C7-cycloalkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for RG11, RG12 and RG13 independently of one another is understood as meaning, for example, the corresponding radicals mentioned above for RG1.Preferred, branched or unbranched, optionally substituted —C1-C5-alkylene-C1-C4-alkoxy radicals for RG11, RG12 and RG13 are independently of one another methoxymethylene, ethoxymethylene, t-butoxymethylene, methoxyethylene or ethoxyethylene.","Preferred, branched or unbranched, optionally substituted mono- and bis-alkylaminoalkylene or acylaminoalkylene radicals for RG11, RG12 and RG13 are independently of one another branched or unbranched, optionally substituted radicals —C1-C4-alkylene-NH(C1-C4-alkyl), —C1-C4-alkylene-N(C1-C4-alkyl)2 or —C1-C4-alkylene-NH—CO—C1-C4-alkyl.","Preferred optionally substituted heterocycloalkyl, heterocycloalkenyl, C1-C4-alkyleneheterocycloalkyl or C1-C4-alkyleneheterocycloalkenyl radicals for RG11, RG12 and RG13 are independently of one another the C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radicals described above for RG1.Particularly preferred, optionally substituted heterocycloalkyl, heterocycloalkenyl, C1-C4-alkyleneheterocycloalkyl or C1-C4-alkyleneheterocycloalkenyl radicals for RG11, RG12 and RG13 are independently of one another the C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radicals described above for RG1, one or two heteroatoms selected from the group consisting of N, O and S and up to two double bonds being contained in the cyclic moiety.","Further, RG12 and RG13 can independently of one another be a radical —SO2—RG11, —CO—O—RG11, —CO—NRG11RG11* or —CO—RG11, RG11* being a radical RG11 which is independent of RG11.Preferred structural elements G are composed of at least one preferred radical of the structural element G, while the remaining radicals are widely variable.","Particularly preferred structural elements G are composed of the preferred radicals of the structural element G. Very particularly preferred structural elements G are composed of the particularly preferred radicals of the structural element G. Structural element B is understood as meaning a structural element comprising at least one atom which under physiological conditions can form hydrogen bridges as a hydrogen acceptor, at least one hydrogen acceptor atom having a distance of 5 to 14 atomic bonds from structural element G along the shortest possible route along the structural element skeleton.","The arrangement of the structural skeleton of structural element B is widely variable.","Suitable atoms which under physiological conditions can form hydrogen bridges as hydrogen acceptors are, for example, atoms having Lewis base properties, such as the heteroatoms nitrogen, oxygen or sulfur.","Physiological conditions is understood as meaning a pH which prevails at the site in a body at which the ligands interact with the receptors.","In the present case, the physiological conditions have a pH of, for example, 5 to 9.In a preferred embodiment, structural element B is a structural element of the formula IB A-E- IB where A and E have the following meanings: A is a structural element selected from the group: a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon which can contain up to 4 heteroatoms selected from the group O, N and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, or a 9- to 14-membered polycyclic, saturated, unsaturated or aromatic hydrocarbon which can contain up to 6 heteroatoms selected from the group N, O and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, a radical where ZA1 is oxygen, sulfur or optionally substituted nitrogen and ZA2 is optionally substituted nitrogen, oxygen or sulfur and a radical where RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—R11, and E is a spacer structural element which covalently bonds the structural element A to the structural element G, where the number of atomic bonds along the shortest possible route along the structural element skeleton E is 5 to 14.In a particularly preferred embodiment, the structural element A is a structural element selected from the group of structural elements of the formulae IA1 to IA18 where m, p, g independently of one another are 1, 2 or 3, RA1, RA2 independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or SO2NRA15RA16 or both radicals RA1 and RA2 together are a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N, and S, RA13, RA13* independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, where RA14 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkylene-C3-C7-cycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RA15, RA16, independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, CO—C1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, arylalkyl, COO-alkylenearyl, SO2-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, CO-aryl, CO—NH-aryl, SO2-aryl, hetaryl, CO—NH-hetaryl or CO-hetaryl radical, RA3, RA4 independently of one another are hydrogen, —(CH2)n—(XA)j—RA12, or both radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N-heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle is optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, where n is 0, 1, 2 or 3, j is 0 or 1, XA is —CO—, —CO—N(RX1)—, —N(RX1)—CO—, —N(RX1)—CO—N(RX1*)—, —N(RX1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX1), —N(RX1)— or —N(RX1)—SO2—, RA12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally C1-C4-alkyl- or aryl-substituted C2-C6-alkynyl or C2-C6-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocycle, substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, a C3-C7-cycloalkyl, aryl or hetaryl radical, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RA12, together with RX1 or RX1* forms a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RX1, RX1* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, RA6, RA6* are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, —CO—O—C1-C4-alkyl, arylalkyl, —CO—O-alkylenearyl, —CO—O-allyl, —CO—C1-C4-alkyl, —CO-alkylenearyl, C3-C7-cycloalkyl or —CO-allyl radical or in the structural element IA7 both radicals RA6 and RA6* together are an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—CO—C1-C4-alkyl radical, or an optionally substituted arylalkyl, —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical, or both radicals RA6 and RA7 together are an optionally substituted, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA8 is hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—C1-C4-alkyl, SO2—C1-C4-alkyl or CO—O—C1-C4-alkyl radical or an optionally substituted aryl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl, CO—O-alkylenearyl or alkylenearyl radical, RA9, RA10 independently of one another are hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, or both radicals RA9 and RA10 together in the structural element IA14 are a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA11 is hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, RA17 is hydrogen or, in the structural element IA16, both radicals RA9 and RA17 together are a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 which is independent of RG11, Z1, Z2, Z3, Z4 independently of one another are nitrogen, C—H, C-halogen or a branched or unbranched, optionally substituted C—C1-C4-alkyl or C—C1-C4-alkoxy radical, Z5 is NRA8, oxygen or sulfur.","In a further very particularly preferred embodiment, the structural element A is a structural element of the formula IA1, IA4, IA7, IA8 or IA9.For RA1 or RA2 independently of one another a branched or unbranched, optionally substituted C1-C6-alkyl radical is understood as meaning, for example, the corresponding radicals described above for RG1, preferably methyl or trifluoromethyl.","For RA1 or RA2 in the structural elements IA1, IA2, IA3 or IA17, the branched or unbranched, optionally substituted radical CO—C1-C6-alkyl is composed, for example, of the group CO and the branched or unbranched, optionally substituted C1-C6-alkyl radicals described above for RA1 or RA2.Optionally substituted hetaryl, hetarylalkyl, aryl, arylalkyl or C3-C7-cycloalkyl radicals for RA1 or RA2 independently of one another are understood as meaning, for example, the corresponding radicals described above for RG7.For RA1 or RA2, the optionally substituted radicals CO—O—RA14, O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or SO2NRA15RA16 are composed, for example, of the groups CO—O, O, S, N, CO—N or SO2—N and the radicals RA14, RA15 or RA16 described in greater detail below.","Further, both radicals RA1 and RA2 can together form a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S. RA13 and RA13* are independently of one another hydrogen, CN, halogen, such as fluorine, chlorine, bromine or iodine, a branched or unbranched, optionally substituted C1-C6-alkyl radical, such as described above for RG1, preferably methyl or trifluoromethyl or an optionally substituted aryl, arylalkyl, hetaryl or C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2NRA15RA16 or CO—NRA15RA16 as in each case described above for RA1.Preferred radicals for RA13 and RA13* are the radicals hydrogen, F, Cl, a branched or unbranched, optionally substituted C1-C6-alkyl radical, optionally substituted aryl or arylalkyl or a radical CO—O—RA14, O—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16.A branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, alkylenecycloalkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl or C2-C6-alkynyl radical for RA14 in structural element A is understood as meaning, for example, the corresponding radicals described above for RG7.Optionally substituted aryl, arylalkyl, hetaryl or alkylhetaryl radicals for RA14 in structural element A are understood as meaning, for example, the corresponding radicals described above for RG7.Preferred radicals for RA14 are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical and optionally substituted benzyl.","A branched or unbranched, optionally substituted C1-C6-alkyl or arylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or hetarylalkyl radical for RA15 or RA16 independently of one another is understood as meaning, for example, the corresponding radicals described above for RA14.The branched or unbranched, optionally substituted CO—C1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, COO-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or SO2-alkylenearyl radicals or the optionally substituted CO-aryl, SO2-aryl, CO—NH-aryl, CO—NH-hetaryl or CO-hetaryl radicals for RA15 or RA16 are composed, for example, of the corresponding groups —CO—, —SO2—, —CO—O—, —CO—NH— and the corresponding branched or unbranched, optionally substituted C1-C6-alkyl, hetarylalkyl or arylalkyl radicals or the corresponding optionally substituted aryl or hetaryl radicals described above.","A radical —(CH2)n—(XA)j—RA12 for RA3 or RA4 independently of one another is understood as meaning a radical which is composed of the corresponding radicals —(CH2)n—, (XA)j and RA12.Here, n can be: 0, 1, 2 or 3 and j can be: 0 or 1.XA is a doubly bonded radical selected from the group —CO—, —CO—N(RX1)—, —N(RX1)—CO—, —N(RX1)—CO—N(RX1*)—, —N(RX1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX1)—, —N(RX1)— and —N(RX1)—SO2—.","RA12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, as described above for RG7.a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, or a 3- to 6-membered, saturated or unsaturated heterocycle which is substituted by up to three identical or different radicals and can contain up to three different or identical heteroatoms O, N, S, such as optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-(1,3,4-thiadiazolyl), 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, triazinyl.","Further, RA12 and RX1 or RX1* can together form a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N. Preferably, the radical RA12 together with the radical RX1 or RX1* forms a cyclic amine as the C3-C7-heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl, where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amine protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO2—C1-C4-alkyl, —SO2-phenyl or —SO2-benzyl.","A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C12-alkynyl, preferably C2-C6-alkynyl or C2-C6-alkenyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl or hetaryl radical for RX1 and RX1* independently of one another is understood as meaning, for example, the corresponding radicals described above for RG7.Preferred, branched or unbranched, optionally substituted C1-C6-alkoxyalkyl for RX1 and RX1* are independently of one another methoxymethylene, ethoxymethylene, t-butoxymethylene, methoxyethylene or ethoxyethylene.","Preferred, branched or unbranched, optionally substituted radicals CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl are preferably composed of the C1-C6-alkyl, arylalkyl, aryl or hetaryl radicals and the radicals —CO—, —O—, —SO2— described above.","Preferred radicals for RX1 and RX1* are independently of one another hydrogen, methyl, cyclopropyl, allyl and propargyl.","RA3 and RA4 can further together form a 3- to 8-membered saturated, unsaturated or aromatic N heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle can be optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, RA5 is a branched or unbranched, optionally substituted C1-C6-alkyl, arylalkyl, C1-C4-alkyl-C3-C7-cycloalkyl or C3-C7-cycloalkyl radical or an optionally substituted aryl, hetaryl, heterocycloalkyl or heterocycloalkenyl radical, such as described above for RG7.RA6 and RA6* are independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl radical, such as optionally substituted methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, —CO—O—C1-C4-alkyl or —CO—C1-C4-alkyl radical such as composed of the group —CO—O— or —CO— and the C1-C4-alkyl radicals described above, arylalkyl radical, as described above for RG7, —CO—O-alkylenearyl or —CO-alkylenearyl radical such as composed of the group —CO—O— or —CO— and the arylalkyl radicals described above, —CO—O-allyl or —CO-allyl radical, or C3-C7-cycloalkyl radical, such as described above for RG7.Further, both radicals RA6 and RA6* in structural element IA7 can together form an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S. RA7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl radical, for example as described above for RA6, C1-C4-alkoxy, arylalkyl or C3-C7-cycloalkyl radical, for example as described above for RL14, a branched or unbranched, optionally substituted —O—CO—C1-C4-alkyl radical, which is composed of the group —O—CO— and, for example, of the C1-C4-alkyl radicals mentioned above or an optionally substituted —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical which is composed of the groups —O— or —O—CO— and, for example, of the corresponding radicals described above for RG7.Further, both radicals RA6 and RA7 can together form an optionally substituted unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S. For RAS in structural element A, the branched or unbranched, optionally substituted C1-C4-alkyl radical or an optionally substituted aryl or arylalkyl radical is understood as meaning, for example, the corresponding radicals described above for RA15, where the radicals CO—C1-C4-alkyl, SO2—C1-C4-alkyl, CO—O—C1-C4-alkyl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl or CO—O-alkylenearyl are composed analogously to the other composed radicals of the group consisting of CO, SO2 and COO and, for example, of the corresponding C1-C4-alkyl, aryl or arylalkyl radicals described above for RA15 and these radicals can be optionally substituted.","In each case, for RA9 or RA10 independently of one another, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl or C3-C7-cycloalkyl radical is understood as meaning, for example, the corresponding radicals described above for RA14, preferably methyl or trifluoromethyl.","In each case, for RA9 or RA10 independently of one another, a radical CO—O—RA14, O—RA14, S—RA14, SO2—NRA15RA16, NRA15RA16 or CO—NRA15RA16 is understood as meaning, for example, the corresponding radicals described above for RA13.Further, both radicals RA9 and RA10 together in structural element IA14 can form a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals.","Substituents in this case are in particular understood as meaning halogen, CN, a branched or unbranched, optionally substituted C1-C4-alkyl radical, such as methyl or trifluoromethyl or the radicals O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or —((RA8)HN)C═N—RA7.A branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16 for RA11 is understood, for example, as meaning the corresponding radicals described above for RA9.Further, in structural element IA16, both radicals RA9 and RA17 together can form a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals.","A branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 for RA18 and RA19 independently of one another is understood as meaning, for example, the radicals described above for RG12, preferably hydrogen or a branched or unbranched, optionally substituted C1-C8-alkyl radical.","Z1, Z2, Z3, Z4 are independently of one another nitrogen, C—H, C-halogen, such as C—F, C—Cl, C—Br or C—I or a branched or unbranched, optionally substituted C—C1-C4-alkyl radical which is composed of a carbon radical and, for example, a C1-C4-alkyl radical described above for RA6 or a branched or unbranched optionally substituted C—C1-C4-alkoxy radical which is composed of a carbon radical and, for example, a C1-C4-alkoxy radical described above for RA7.Z5 is oxygen, sulfur or a radical NRA8.Preferred structural elements A are composed of at least one preferred radical of the radicals belonging to the structural element A, while the remaining radicals are widely variable.","Particularly preferred structural elements A are composed of the preferred radicals of the structural element A.","In a preferred embodiment, the spacer structural element E is understood as meaning a structural element that consists of a branched or unbranched aliphatic C2-C30-hydrocarbon radical which is optionally substituted and contains heteroatoms and/or of a 4- to 20-membered aliphatic or aromatic mono- or polycyclic hydrocarbon radical which is optionally substituted and contains heteroatoms.","In a further preferred embodiment, the spacer structural element E is composed of two to four substructural elements, selected from the group consisting of E1 and E2, where the sequence of linkage of the substructural elements is arbitrary and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(XE)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 11-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently, of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, or independently of one another in each case two radicals RE1 and RE2 or RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N and S, x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms, together with RW2 or RW2*, a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical.","The coefficient c is preferably 0 or 1, the coefficient d is preferably 1 or 2, and the coefficients f, g, h independently of one another are preferably 0 or 1.An optionally substituted 4- to 11-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O, S, where the ring carbons or ring nitrogens can optionally be substituted, for QE and XE independently of one another is preferably understood as meaning optionally substituted arylene, such as optionally substituted phenylene or naphthylene, or optionally substituted hetarylene such as the radicals and their substituted or fused derivatives, or radicals of the formulae IE1 to IE11, where the incorporation of the radicals can take place in both orientations.","Aliphatic hydrocarbons are understood as meaning, for example, saturated and unsaturated hydrocarbons.","Z6 and Z7 are independently of one another CH or nitrogen.","Z8 is oxygen, sulfur or NH.","Z9 is oxygen, sulfur or NRE20.r1, r2, r3 and t are independently of one another 0, 1, 2 or 3.s and u are independently of one another 0, 1 or 2.Particularly preferably, XE and QE independently of one another are optionally substituted phenylene, a radical and their substituted or fused derivatives, or radicals of the formulae IE1, IE2, IE3, IE4 and IE7, where the incorporation of the radicals can take place in both orientations.","RE18 and RE19 are independently of one another hydrogen, —NO2, —NH2, —CN, —COOH, a hydroxyl group, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, as in each case described above.","RE20 is independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C3-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, preferably hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl radical.","YE and ZE are independently of one another CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, preferably CO, SO2 and oxygen.","RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl or C2-C8-alkynyl radical or an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical, such as correspondingly described above for RG7 or a radical CO—RE16, COORE16 or SO2—RE16, preferably hydrogen, methyl, allyl, propargyl and cyclopropyl.","A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for RE13, RE14 or RE15 independently of one another is understood as meaning, for example, the corresponding radicals described above for RG7.A branched or unbranched, optionally substituted C1-C4-alkoxy radical for RE13 or RE14 independently of one another is understood as meaning, for example, the C1-C4-alkoxy radicals described above for RA14.Preferred alkylenecycloalkyl radicals for RE13, RE14 or RE15 independently of one another are, for example, the C1-C4-alkylene-C3-C7-cycloalkyl radicals described above for RG7.A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical for RE16 is understood as meaning, for example, the corresponding radicals described above for RG11.A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9 or RE10 independently of one another is understood as meaning, for example, the corresponding radicals mentioned above for RG1.Further, two radicals RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 can in each case independently of one another together form a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle which can contain up to three heteroatoms from the group O, N and S. The radical —(CH2)x—(WE)z—RE17 is composed of a C0-C4-alkylene radical, optionally a bonding element WE selected from the group —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, preferably selected from the group —CO—N(RW2)—, —N(RW2)—CO—, —O—, —SO2—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, and the radical RE17, where RW2 and RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, preferably independently of one another are hydrogen, methyl, cyclopropyl, allyl, propargyl, and RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3 to 8-membered, saturated or unsaturated heterocycle which is substituted by up to three identical or different radicals and can contain up to three different or identical heteroatoms O, N, S, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can be optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, such as optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-(1,3,4-thiadiazolyl), 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl or triazinyl.","Further, RE17 and RW2 or RW2* can together form a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N. Preferably, the radicals RE17 and RW2 or RW2* together form a cyclic amine as the C3-C7-heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amine protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO2—C1-C4-alkyl, —SO2-phenyl or —SO2-benzyl.","Preferred radicals for RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9 or RE10 are independently of one another hydrogen, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, optionally substituted aryl or the radical —(CH2)x—(WE)z—RE17.Particularly preferred radicals for RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9 or RE10 are independently of one another hydrogen, F, a branched or unbranched, optionally substituted C1-C4-alkyl radical, in particular methyl.","A branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl or arylalkyl radical or an optionally substituted aryl, hetaryl or C3-C7-cycloalkyl for RE11 and RE11* in structural element E independently of one another is understood as meaning, for example, the corresponding radicals described above for RG7.The branched or unbranched, optionally substituted radicals CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or the optionally substituted radicals CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl for RE11 and RE11* independently of one another are composed, for example, of the corresponding groups CO, COO, CONH or SO2 and the corresponding radicals mentioned above.","Preferred radicals for RE11 or RE11* are independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C12-alkynyl or arylalkyl radical, or an optionally substituted hetaryl or C3-C7-cycloalkyl radical.","Particularly preferred radicals for RE11 or RE11* are hydrogen, methyl, cyclopropyl, allyl or propargyl.","In a particularly preferred embodiment of structural element E1, structural element E1 is a radical —CH2—CH2—CO—, —CH2—CH2—CH2—CO— or a C1-C5-alkylene radical.","In a particularly preferred embodiment of structural element E, the spacer structural element E used is a structural element of the formula IE1E2 -E2-E1- IE1E2 where the structural elements E2 and E1 have the meanings described above.","Preferred structural elements E are composed of at least one preferred radical of the radicals belonging to structural element E, while the remaining radicals are widely variable.","Particularly preferred structural elements E are composed of the preferred radicals of structural element E. Preferred structural elements B are composed either of the preferred structural element A, while E is widely variable, or of the preferred structural element E, while A is widely variable.","In a further preferred embodiment, the structural element E used is the structural element E′ described below for the novel compounds of the formula I′.","In a further preferred embodiment, the structural element G used is the structural element G′ described below for the novel compounds of the formula I′.","The compounds of the formula I, and also the intermediates for their preparation, can have one or more asymmetric substituted carbon atoms.","The compounds can be present as pure enantiomers or pure diastereomers or as a mixture thereof.","The use of an enantiomerically pure compound as the active compound is preferred.","The compounds of the formula I can also be present in other tautomeric forms.","The compounds of the formula I can also be present in the form of physiologically tolerable salts.","The compounds of the formula I can also be present as prodrugs in a form in which the compounds of the formula I are liberated under physiological conditions.","By way of example, reference may be made here to the group T in structural element L, which in some cases contains groups which are hydrolyzable to the free carboxylic acid group under physiological conditions.","Derivatized structural elements B or A are also suitable which liberate the structural element B or A respectively under physiological conditions.","In preferred compounds of the formula I, in each case one of the three structural elements B, G or L has the preferred range, while the remaining structural elements are widely variable.","In particularly preferred compounds of the formula I, in each case two of the three structural elements B, G and L have the preferred range, while the remaining structural elements are widely variable.","In very particularly preferred compounds of the formula I, in each case all three structural elements B, G and L have the preferred range, while the remaining structural element is widely variable.","Preferred compounds of the formula I contain, for example, the preferred structural element G, while the structural elements B and L are widely variable.","In particularly preferred compounds of the formula I, for example, B is replaced by the structural element A-E- and the compounds contain, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L are widely variable.","Further particularly preferred compounds of the formula I contain, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L are widely variable.","The invention further relates to the use of the structural element of the formula IGL -G-L IGL for the preparation of compounds which bind to integrin receptors.","The compounds of the formula I bind to integrin receptors.","The compounds of the formula I are therefore preferably suitable as integrin receptor ligands and for the production of drugs for treating diseases in which an integrin receptor is involved, in particular for treating diseases in which the interaction between integrins and their natural ligands is dysregulated, i.e.","excessive or decreased.","Integrin receptor ligands are understood as meaning agonists and antagonists.","An excessive or decreased interaction is understood as meaning both an excessive or decreased expression of the natural ligand and/or of the integrin receptor and thus an excessive or decreased amount of natural ligand and/or integrin receptor or an increased or decreased affinity of the natural ligand for the integrin receptor.","The interaction between integrins and their natural ligands is dysregulated compared with the normal state, i.e.","excessive or decreased, if this dysregulation does not correspond to the physiological state.","An increased or decreased interaction can lead to pathophysiological situations.","The level of dysregulation which leads to a pathophysiological situation is dependent on the individual organism and on the site and nature of the disorder.","Preferred integrin receptors for which the compounds of the formula I according to the invention can be used are the α5β1, α4β1, αVβ5 and αVβ3 integrin receptors.","The compounds of the formula I particularly preferably bind to the αVβ3 integrin receptor and can thus be particularly preferably used as ligands of the αVβ3 integrin receptor and for the treatment of illnesses in which the interaction between αVβ3 integrin receptor and its natural ligand is excessive or reduced.","The compounds of the formula I are preferably used for the treatment of the following illnesses: cardiovascular disorders such as atherosclerosis, restenosis after vascular injury or stent implantation, and angioplasty (neointima formation, smooth muscle cell migration and proliferation), acute kidney failure, angiogenesis-associated microangiopathies such as diabetic angiopathies or retinopathy or rheumatoid arthritis, blood platelet-mediated vascular occlusion, arterial thrombosis, stroke, reperfusion damage after myocardial infarct or stroke, carcinomatous disorders, such as in tumor metastasis or in tumor growth (tumor-induced angiogenesis), osteoporosis (bone resorption after chemotaxis and adhesion of osteoclasts to the bone matrix), high blood pressure, psoriasis, hyperparathyroidism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, inflammation, wound healing, cardiac insufficiency, congestive heart failure CHF, as well as in antiviral, antimycotic, antiparasitic or antibacterial therapy and prophylaxis (adhesion and internalization).","Furthermore, the invention relates in particular to the use of the compounds of the formula I as ligands of the αVβ3 integrin receptor.","The invention furthermore relates to the novel compounds of the formula I′ A-E′-G′-L I′ where the structural elements A and L have the meanings described above.","Preferred structural elements A and L are described.","Structural element E′ is composed of two to four substructural elements selected from the group consisting of E1 and E2, the linkage sequence of the substructural elements being arbitrary and E1 and E2 having the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(X)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where all radicals and coefficients of structural element E′ have the meanings of structural element E described above, with the proviso that in the case in which YE or ZE=CO and a radical XE or QE or an aromatic or heteroaromatic radical of the structural element A is bonded directly to YE or ZE, a direct atomic bond from YE or ZE to the structural element G′ is excluded.","In a further preferred embodiment of structural element E′, the structural element E′ used is a structural element of the formula IE1E2 -E2-E1- IE1E2 where E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)—(XE)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where all radicals and coefficients of structural element E′ have the meanings of structural element E described above, with the proviso that in the case where YE═CO, k1 and k5=1 and h and k6=0 the sum of the indices c, k2 and d must be other than 0 and in the case where an aromatic or heteroaromatic radical from the structural element A is bonded directly to YE or ZE, a direct atomic bond from YE or ZE to the structural element G′ is excluded.","Further preferred embodiments of structural element E′ correspond to the preferred embodiments of structural element E with the proviso described above.","Structural element G′ is identical to structural element G, as described above, except for the radicals RG12 and RG13.In structural element G′, the radicals RG12 and RG13 of structural element G are replaced by the radicals RG′12 and RG′13.The radicals RG12 and RG′13 in structural element G′ have the following meanings: independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG14, where RG14 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical.","Preferred radicals of RG′12 and RG13 are the corresponding radicals described above for RG12 and RG13.Further preferred embodiments of the structural element G′ correspond to the preferred embodiments of structural element G. The compounds of the formula I′, and also the intermediates for their preparation, can have one or more asymmetric substituted carbon atoms.","The compounds can be present as pure enantiomers or pure diastereomers or as a mixture thereof.","The use of an enantiomerically pure compound as active compound is preferred.","The compounds of the formula I′ can also be present in other tautomeric forms.","The compounds of the formula I′ can also be present in the form of physiologically tolerable salts.","The compounds of the formula I′ can also be present as prodrugs in a form in which the compounds of the formula I′ are liberated under physiological conditions.","By way of example, reference may be made here to the group T in structural element L, which in some cases contains groups which are hydrolyzable to the free carboxylic acid group under physiological conditions.","Derivatized structural elements A which liberate the structural element A under physiological conditions are also suitable.","Analogously to the compounds of the formula I, the following applies for the compounds of the formula I′ as mentioned above: In preferred compounds of the formula I′, one of the four structural elements A, E′, G′ or L in each case have the preferred range, while the remaining structural elements are widely variable.","In particularly preferred compounds of the formula I′, two of the four structural elements A, E′, G′ or L in each case have the preferred range, while the remaining structural elements are widely variable.","In further particularly preferred compounds of the formula I′, three of the four structural elements A, E′, G′ or L in each case have the preferred range, while the remaining structural element is widely variable.","In very particularly preferred compounds of the formula I′, all four structural elements A, E′, G′ or L have the preferred range.","Preferred compounds of the formula I, have, for example, the preferred structural element G′, while the structural elements A, E′ and L are widely variable.","Further particularly preferred compounds of the formula I′ have, for example, the preferred structural element G′ and the preferred structural element A, while the structural elements E′ and L are widely variable.","Very particularly preferred compounds of the formula I′ are listed below, the number before the text block being the number of an individualized compound of the formula I′, and in the text block A-E′-G′-L the abbreviations separated by a bonding dash in each case being an individual structural element A, E′, G′ or L and the meaning of the abbreviations of the structural elements being explained after the table.","No.","A-E′-G′-L 1 bhs-edia3-phen-es 2 2py-inda2-phen-es 3 bhs-35thirna2-meph-es 4 bim-dibema2-dmeph-es 5 2py-bam2-4-clph-es 6 2py-dibema2-dmeph-es 7 bhs-a24thima2-dmeph-es 8 bhs-aaf-phen-es 9 bhs-a24thima2-4-clph-es 10 bim-me42thiaz2-phen-es 11 2py-edia2-phen-es 12 bim-a24thima2-hdb-es 13 2py-apma2-4-clph-es 14 gua-chex2-phen-es 15 bhs-dibema2-4-clph-es 16 bhs-bam2-phen-es 17 bim-a23thima2-4-clph-es 18 bim-dibema2-phen-es 19 bim-bam2-4-clph-es 20 2py-pipa2-4-clph-es 21 2py-me25thima2-phen-es 22 gua-a24thima2-ioph-es 23 imhs-apma2-phen-es 24 2py-apma2-ioph-es 25 gua-edia3-phen-es 26 bhs-a23thima2-4-clph-es 27 2py-a24thima2-2pyph-es 28 2py-bam2-thoph-es 29 gua-apma2-phen-es 30 2py-a24thima2-reph-es 31 gua-hexa-phen-es 32 dimethpym-apma2-phen-es 33 2py-dibema2-meph-es 34 bhs-apma2-phen-es 35 bim-edia3-phen-es 36 gua-apma2-meph-es 37 bim-apma2-reph-es 38 2py-a24thima2-dmeph-es 39 gua-aaf-phen-es 40 gua-apma2-yrph-es 41 gua-pipeme2-phen-es 42 2py-35thima2-phen-es 43 gua-a24thima2-reph-es 44 bim-bam2-phen-es 45 gua-a24thima2-phen-ms 46 gua-apma2-reph-es 47 mam2py-a24thima2-phen-es 48 2py-a24thima2-phen-gs 49 2py-apma2-phen-nes 50 2py-a24thima2-4-clph-es 51 bhs-penta-phen-es 52 gua-35thima2-dmeph-es 53 bim-dibema2-thoph-es 54 bim-a24thima2-reph-es 55 2py-a23thima2-4-clph-es 56 gua-a23thima2-phen-es 57 dhim-a24thima2-phen-es 58 gua-penta-phen-es 59 bhs-a24thima2-reph-es 60 2py-a23thima2-meph-es 61 gua-prodia2-phen-es 62 bhs-apma2-reph-es 63 2py-apma2-meph-es 64 gua-bam2-4-clph-es 65 2py-me35thima2-phen-es 66 gua-apma2-2pyph-es 67 2py-35thima2-thoph-es 68 clim-a24thima2-phen-es 69 2py-buta-phen-es 70 am2py-apma2-phen-es 71 gua-a24thima2-dmeph-es 72 bhs-apma2-hdb-es 73 bhs-dibema2-thoph-es 74 bim-dibema2-meph-es 75 bhs-bam2-meph-es 76 bhs-apma2-yrph-es 77 bhs-apma2-dmeph-es 78 gua-me25thima2-phen-es 79 2py-a24thima2-meph-es 80 gua-inda2-phen-es 81 bhs-mepipe2-phen-es 82 bhs-a24thima2-phen-as 83 bim-pipa2-thoph-es 84 bhs-bam2-4-clph-es 85 bhs-a24thima2-phen-es 86 bhs-35thima2-phen-es 87 bim-penta-phen-es 88 bhs-apma2-dbph-es 89 gua-42thiaz2-phen-es 90 bhs-a24thima2-24pym-es 91 2py-dibema2-phen-es 92 bim-a24thima2-dm-es 93 bhs-pipa2-4-clph-es 94 2py-apma2-phen-ps 95 2py-apma2-dmeph-es 96 2py-mepipe2-phen-es 97 bhs-35thima2-4-clph-es 98 gua-apma2-phen-mals 99 gua-35thima2-4-clph-es 100 mam2py-apma2-phen-es 101 gua-buta-phen-es 102 2py-a23thima2-thoph-es 103 2py-pyma2-phen-es 104 gua-apma2-phen-gs 105 bim-apma2-phen-as 106 bhs-apma2-4-clph-es 107 bhs-a24thima2-4-pyph-es 108 thpym-apma2-phen-es 109 gua-pipa2-dmeph-es 110 amim-a24thima2-phen-es 111 bim-aepi2-phen-es 112 bim-a23thima2-thoph-es 113 bhs-a23thima2-thoph-es 114 gua-pdagk-phen-es 115 2py-hexa-phen-es 116 bhs-a24thima2-meph-es 117 gua-bam2-meph-es 118 2py-35thima2-meph-es 119 2py-pipa2-meph-es 120 bhs-a23thima2-phen-es 121 bim-pipeme2-phen-es 122 bhs-buta-phen-es 123 bhs-pipa2-dmeph-es 124 bhs-pipa2-meph-es 125 2py-35thima2-dmeph-es 126 bim-bam2-thoph-es 127 gua-35thima2-thoph-es 128 bim-edia2-phen-es 129 bim-apma2-phen-nes 130 gua-bam2-thoph-es 131 gua-bam2-phen-es 132 pippy-a24thima2-phen-es 133 gua-35thima2-phen-es 134 bim-a23thima2-phen-es 135 gua-dibema2-dmeph-es 136 bhs-apma2-phen-gs 137 bhs-apma2-thoph-es 138 2py-apma2-phen-es 139 im-a24thima2-phen-es 140 gua-aepi2-phen-es 141 2py-mea2-phen-es 142 gua-a24thima2-phen-es 143 2py-a24thima2-thaph-es 144 gua-apma2-4-clph-es 145 bhs-apma2-phen-f2es 146 bhs-inda2-phen-es 147 bim-a24thima2-dbph-es 148 bim-apma2-phen-ms 149 gua-a23thima2-thoph-es 150 pippy-apma2-phen-es 151 bhs-apma2-meph-es 152 2py-apma2-phen-as 153 gua-mea2-phen-es 154 bhs-me35thima2-phen-es 155 bhs-pdagk-phen-es 156 bim-42thiaz2-phen-es 157 2py-pipeme2-phen-es 158 bim-me25thima2-phen-es 159 gua-dibema2-phen-es 160 2py-apma2-oxph-es 161 bhs-a24thima2-3clph-es 162 bim-pyma2-phen-es 163 bhs-edia2-phen-es 164 imhs-a24thima2-phen-es 165 gua-dibema2-thoph-es 166 bim-a24thima2-4-clph-es 167 bim-apma2-phen-ps 168 gua-apma2-dm-es 169 2py-a24thima2-phen-mals 170 2py-dibema2-4-clph-es 171 bhs-dibema2-meph-es 172 bim-aof-phen-es 173 bhs-pipeme2-phen-es 174 gua-35thima2-meph-es 175 bim-aaf-phen-es 176 bim-dibema2-4-clph-es 177 bim-a24thima2-2pyph-es 178 bim-a24thima2-yrph-es 179 bim-35thima2-4-clph-es 180 bhs-aepi2-phen-es 181 bim-pipa2-phen-es 182 gua-a23thima2-dmeph-es 183 2py-a24thima2-yrph-es 184 gua-a24thima2-dmeoph-es 185 bhs-42thiaz2-phen-es 186 bim-mepipe2-phen-es 187 2py-chex2-phen-es 188 bhs-prodia2-phen-es 189 gua-bam2-dmeph-es 190 bhs-me25thima2-phen-es 191 thpym-a2.4thima2-phen-es 192 bim-pipa2-dmeph-es 193 bhs-dibema2-phen-es 194 gua-a24thima2-thoph-es 195 2py-pipa2-thoph-es 196 clim-apma2-phen-es 197 bhs-chex2-phen-es 198 gua-a24thima2-phen-nes 199 gua-a24thima2-meph-es 200 bhs-a24thima2-dmeoph-es 201 2py-apma2-24pym-es 202 2py-a24thima2-phen-pms 203 gua-a24thima2-4-piph-es 204 bim-apma2-3clph-es 205 gua-apma2-hdb-es 206 2py-bam2-meph-es 207 bhs-a24thima2-phen-nes 208 gua-pyma2-phen-es 209 bim-a24thima2-thoph-es 210 gua-mepipe2-phen-es 211 bim-apma2-4-clph-es 212 2py-42thiaz2-phen-es 213 bim-apma2-24pym-es 214 bhs-a23thima2-dmeph-es 215 gua-apma2-dbph-es 216 gua-me35thima2-phen-es 217 bim-35thima2-phen-es 218 gua-apma2-thaph-es 219 bim-35thima2-thoph-es 220 gua-apma2-phen-f2es 221 2py-apma2-3clph-es 222 gua-apma2-thoph-es 223 bim-pipa2-meph-es 224 2py-aof-phen-es 225 bhs-35thima2-dmeph-es 226 bhs-hexa-phen-es 227 bim-pipa2-4-clph-es 228 bhs-apma2-phen-pms 229 bim-a23thima2-dmeph-es 230 2py-me42thiaz2-phen-es 231 bim-a24thima2-phen-gs 232 bim-apma2-dmeph-es 233 gua-a23thima2-4-clph-es 234 bim-a24thima2-phen-mals 235 2py-apma2-phen-ms 236 bhs-a24thima2-ioph-es 237 bim-a24thima2-phen-es 238 2py-pdagk-phen-es 239 gua-a24thima2-phen-ps 240 2py-pipa2-phen-es 241 2py-aepi2-phen-es 242 2py-a24thima2-thoph-es 243 bhs-bam2-dmeph-es 244 bim-hexa-phen-es 245 bim-a24thima2-meph-es 246 bhs-me42thiaz2-phen-es 247 am2py-a24thima2-phen-es 248 bim-apma2-meph-es 249 bim-me35thima2-phen-es 250 gua-pipa2-phen-es 251 bhs-a24thima2-oxph-es 252 2py-pipa2-dmeph-es 253 2py-apma2-4-pyph-es 254 bhs-35thima2-thoph-es 255 gua-me42thiaz2-phen-es 256 bim-a24thima2-thaph-es 257 gua-a24thima2-phen-as 258 2py-a24thima2-phen-f2es 259 2py-a24thima2-dbph-es 260 bim-35thima2-meph-es 261 bim-apma2-phen-es 262 bim-a24thima2-phen-pms 263 bim-chex2-phen-es 264 bim-a24thima2-dmeph-es 265 bim-mea2-phen-es 266 2py-apma2-thoph-es 267 dimethpym-a24thima2-phen-es 268 2py-dibema2-thoph-es 269 2py-apma2-dmeoph-es 270 gua-dibema2-4-clph-es 271 bhs-pipa2-phen-es 272 gua-edia2-phen-es 273 gua-apma2-dmeph-es 274 2py-edia3-phen-es 275 gua-a23thima2-meph-es 276 bim-pdagk-phen-es 277 gua-apma2-phen-pms 278 bhs-mea2-phen-es 279 bim-35thima2-dmeph-es 280 bhs-aof-phen-es 281 2py-prodia2-phen-es 282 bim-inda2-phen-es 283 bhs-bam2-thoph-es 284 bim-apma2-4-pyph-es 285 2py-aaf-phen-es 286 2py-bam2-phen-es 287 bhs-apma2-dm-es 288 2py-penta-phen-es 289 gua-aof-phen-es 290 im-apma2-phen-es 291 gua-pipa2-4-clph-es 292 bim-apma2-ioph-es 293 bim-bam2-meph-es 294 gua-pipa2-meph-es 295 bhs-apma2-thaph-es 296 bhs-apma2-2pyph-es 297 bim-apma2-dmeoph-es 298 amim-apma2-phen-es 299 dhim-apma2-phen-es 300 bhs-a24thima2-phen-ps 301 2py-a23thima2-dmeph-es 302 gua-pipa2-thoph-es 303 bim-a23thima2-meph-es 304 2py-bam2-dmeph-es 305 bhs-a24thima2-thoph-es 306 bhs-apma2-phen-mals 307 bhs-a23thima2-meph-es 308 bim-buta-phen-es 309 2py-apma2-reph-es 310 gua-dibema2-meph-es 311 2py-a24thima2-hdb-es 312 gua-a24thima2-4-clph-es 313 bhs-pipa2-thoph-es 314 gua-a24thima2-3clph-es 315 gua-a24thima2-oxph-es 316 bim-bam2-dmeph-es 317 bim-apma2-thoph-es 318 bim-apma2-oxph-es 319 2py-a24thima2-phen-es 320 bhs-a24thima2-phen-ms 321 bim-prodia2-phen-es 322 2py-a24thima2-dm-es 323 bhs-pyma2-phen-es 324 bim-a24thima2-phen-f2es 325 2py-a23thima2-phen-es 326 gua-a24thima2-24pym-es 327 2py-35thima2-4-clph-es 328 bhs-dibema2-dmeph-es In the above list, the following abbreviations are used for the structural units A, E′, G′ and L. A= Abbreviation 2py dhim bim imhs dimethpym mam2py am2py thpym bhs gua amim clim im pippy E′= Abbreviation edia2 pyma2 pipa2 aepi2 me35thima2 dibema2 edia3 buta aaf 42thiaz2 chex2 bam2 apma2 pdagk mepipe2 prodia2 inda2 35thima2 me25thima2 penta aof hexa mea2 pipeme2 me42thiaz2 a23thima2 a24thima2 The bond to the structural unit L should be understood as meaning a double bond in the compound where L=as.","G′= Abbreviation 24pym dmeph dm thoph thaph 2pyph 4clph phen dbph hdb dmeoph meph 3clph oxph ioph yrph 4pyph reph L= Abbreviation es gs pms f2es mals ps ms nes as The compounds of the general formula I and thus also the compounds of the formula I′ as well as the starting substances used for their preparation can be prepared by methods of organic chemistry known to the person skilled in the art, such as are described in standard works such as Houben-Weyl, “Methoden der Organischen Chemie” [Methods of Organic Chemistry], Thieme-verlag, Stuttgart, or March “Advanced Organic Chemistry”, 4th Edition, Wiley & Sons.","Further preparation methods are also described in R. Larock, “Comprehensive Organic Transformations”, Weinheim 1989, in particular the preparation of alkenes, alkynes, halides, amines, ethers, alcohols, phenols, aldehydes, ketones, nitrites, carboxylic acids, esters, amides and acid chlorides.","The synthesis of compounds of the formula I can be carried out either according to the “classical” method in solution or on a polymeric support, in each case reaction conditions as are known and suitable for the respective reactions being used.","Use can also be made in this case of variants which are known per se but not mentioned here.","The general synthesis of compounds of the formula I is described in schemes 1-7.If not stated otherwise, all starting materials and reagents are commercially available, or can be prepared from commercially obtainable precursors by customary methods.","Fused 2,3,4,5-tetrahydro-1H-azepinediones of type II are known and can be prepared by known methods, e.g.","starting from anthranilic acid esters or the corresponding heterocyclic analogs via Dieckmann condensation and subsequent decarboxylation, as is described in the following publications: J.","Am.","Chem.","Soc.","80, 1958, 2172-2178; J. Chem.","Soc.","1959, 3111; J. Chem.","Soc.","1934, 1326; Arch.","Pharm.","324, 1991, 579-581.The preparation of 3,4-dihydro-1H-azepine-2,5-dione is described in Heterocycles 8, 1977, 345-350.The conversion into compounds of the type III is generally carried out by methods known to the person skilled in the art, such as are described, for example, in Larock, “Comprehensive Organic Transformations”, Weinheim 1989, pp.","167ff, although methods which are not mentioned here can also be used.","Preferably, compounds of the general formula III can be prepared by reaction of the ketones II with a phosphonic ester of the general formula (EtO)2P(═O)(XL)a(CRL1RL2)b—COOSG1 in the presence of a base.","The reaction preferably takes place in a polar aprotic solvent, such as tetrahydrofuran, dioxane; dimethylformamide (DMF), dimethylacetamide or acetamide; dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone; in a temperature range depending on the nature of the solvent used from −40° C. up to the boiling point of the corresponding solvent.","The base used can be an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g.","sodium carbonate or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkoxide such as sodium methoxide, potassium tert-butoxide, an organometallic compound such as butyllithium or alkali metal amides such lithium diisopropylamide, or lithium, sodium or potassium bis(trimethylsilyl)amide.","The reaction to give IV is carried out by hydrogenation of the double bond under standard conditions.","Use can also be made here of variants which are known per se but not mentioned.","Preferably, the hydrogenation is carried out in the presence of a noble metal catalyst, such as Pd on activated carbon, Pt, PtO2, Rh on Al2O3 in an inert solvent at a temperature of 0-150° C. and a pressure of 1-200 bar; the addition of an acid such as acetic acid or hydrochloric acid can be advantageous.","Hydrogenation in the presence of 5-10% Pd on activated carbon is particularly preferred.","Solvents which can be used are all customary inert solvents, such as hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; sulfoxides such as dimethyl sulfoxide, sulfolane; pyridine, N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, water or mixtures of the solvents mentioned.","Compounds of type V are prepared by reaction with compounds of the general formula A-E-X1 (VI), the radical X1 being a customary leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl, trifluoromethanesulfonyl and methylsulfonyl or another equivalent leaving group.","The reaction preferably takes place in an inert solvent (such as previously described) with addition of a suitable base, i.e.","of a base which brings about deprotonation of the intermediate IV, in a temperature range from −40° C. up to the boiling point of the corresponding solvent.","The base used can be an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g.","sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkoxide such as sodium methoxide, potassium tert-butoxide, an organometallic compound such as butyllithium or alkali metal amides such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide.","Removal of the protective group SG1 according to standard conditions (see below) leads to the compounds of the general formula I.","If SG1 is C1-C4-alkyl or benzyl, the compounds of the general formula V correspond directly to the compounds of type I. Alternatively to this synthesis strategy, compounds of type I can also be prepared via VII as an intermediate, here too reaction conditions being used such as are known to the person skilled in the art and described in standard works.","Compound VII is prepared by reaction of compounds of type IV having radio of the general formula DE-E-X2 (VIII) under reaction conditions such as have already been described for the preparation of V from IV and VI.","X2 here is a suitable leaving group, as has already been described for X1, and DE is CN, N3 or a protected amino or acid function of the general formula NSG3 or COOSG2.The synthesis of the fragments DE-E or A-E is carried out—depending on the actual structure of E—by removal of the protective groups and coupling of the remaining fragments according to standard methods, e.g.","amide couplings.","The introduction of A is then carried out analogously to the reactions described in schemes 3-7.Compounds of the formula I in which WG in structural element G is a structural element of the formula IWG1 can be prepared according to scheme 2.The starting point of the synthesis is compounds of type IX, which are either known or are accessible by methods known to the person skilled in the art, such as are described, for example, in J.","Am.","Chem.","Soc.","71, 1949, 1985.Alkylation with a compound of the general formula XIII (X3, X4=a customary leaving group) under customary reaction conditions leads to X.","The further reactions to give I then proceed analogously to scheme 1 via compounds of type XI.","In the case in which WG in structural element G is a structural element of the formula IWG3, compounds of type III can be converted into compounds of type XII and then into I analogously to the preparation of V (scheme 2).","The coupling of the individual fragments and the removal of the protective groups can be carried out according to known processes (see Larock, “Comprehensive Organic Transformations; protective groups: Greene, T., “Protective Groups in Organic Synthesis”, New York 1991), in the case of amide bonds also analogously to the methods of peptide synthesis, such as are described in standard works, e.g.","in Bodanszky “The Practice of Peptide Synthesis”, 2nd Edition, Springer-Verlag 1994, and Bodanszky “Principles of Peptide Synthesis”, Springer-Verlag 1984.A general survey of the customary methods for peptide synthesis and a listing of suitable reagents can furthermore be found in NOVABIOCHEM 1999 “Catalog and Peptide Synthesis Handbook”.","The amide couplings mentioned can be carried out with the aid of customary coupling reagents using suitably protected amino and carboxylic acid derivatives.","Another method consists in the use of preactivated carboxylic acid derivatives, preferably of carboxylic acid halides, symmetrical or mixed anhydrides or so-called active esters, which are customarily used for the acylation of amines.","These activated carboxylic acid derivatives can also be prepared in situ.","As a rule, the couplings can be carried out in inert solvents in the presence of an acid-binding agent, preferably of an organic base such as triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, quinoline; the addition of an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogencarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or cesium, can also be favorable.","Depending on the conditions used, the reaction time is between minutes and 14 days, the reaction temperature between −40° C. and 140° C., preferably between −20° C. and 100° C. Suitable inert solvents are, for example, hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; water; or mixtures of the solvents mentioned.","Protective groups SG which can be used are all protective groups which are known from peptide synthesis and customary to the person skilled in the art, such as are also described in the abovementioned standard works.","The protective groups in the compounds of the formulae V, VII, XI and XII are likewise removed according to conditions such as are known to the person skilled in the art and are described by Greene and Wuts in “Protective Groups in organic Synthesis”, 2nd Edition, Wiley & Sons, 1991.Protective groups such as SG3 are so-called N-terminal amino protective groups; Boc, Fmoc, benzyloxycarbonyl (Z), acetyl, Mtr are preferred here.","SG1 and SG2 are acid protective groups; C1-C4-alkyl is preferred here, such as methyl, ethyl, tert-butyl, or alternatively benzyl or trityl, or alternatively polymer-bonded protective groups in the form of the commercially available polystyrene resins such as 2-chlorotrityl chloride resin or Wang resin (Bachem, Novabiochem).","Acid-labile protective groups (e.g.","Boc, tert-butyl, Mtr, trityl) can be removed—depending on the protective group used—using organic acids such as trifluoroacetic acid (TFA), trichloroacetic acid, perchloric acid, trifluoroethanol; but also inorganic acids such as hydrochloric acid or sulfuric acid, sulfonic acids such as benzene- or p-toluenesulfonic acid, the acids generally being employed in an excess.","HCl or TFA is preferably used.","In the case of trityl, the addition of thiols such as thioanisole or thiophenol can be advantageous.","The presence of an additional inert solvent is possible, but not always necessary.","Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid; ethers such as THF or dioxane; amides such as DMF or dimethylacetamide; halogenated hydrocarbons such as dichloromethane; alcohols such as methanol, isopropanol; or water.","Suitable solvents are also mixtures of those mentioned.","The reaction temperature for these reactions is between −10° C. and 50° C.; the reaction is preferably carried out in a range between 0° C. and 30° C. Base-labile protective groups such as Fmoc are cleaved by treatment with organic amines such as dimethylamine, diethylamine, morpholine or piperidine as 5-50% solutions in CH2Cl2 or DMF.","The reaction temperature for these reactions is between −10° C. and 50° C.; the reaction is preferably carried out in a range between 0° C. and 30° C. Acid protective groups such as methyl or ethyl are preferably cleaved by basic hydrolysis in an inert solvent.","The bases used are preferably alkali metal or alkaline earth metal hydroxides, preferably NaOH, KOH or LiOH; the solvents used are all customary inert solvents, such as hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyltert-butyl ether, diisopropyl-ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone; nitro compounds such as nitromethane or nitrobenzene; water or mixtures of the solvents mentioned.","The addition of a phase-transfer catalyst—depending on the solvent or solvent mixture used—may be advantageous.","The reaction temperature for these reactions is generally between −10° C. and 100° C. Hydrogenolytically removable protective groups such as benzyloxycarbonyl (Z) or benzyl can be removed, for example, by hydrogenolysis in the presence of a catalyst (e.g.","of a noble metal catalyst on activated carbon as support).","Suitable solvents are those mentioned above, in particular alcohols such as methanol, ethanol; amides such as DMF or dimethylacetamide; esters such as ethyl acetate.","As a rule, the hydrogenolysis is carried out at a pressure of 1-200 bar and temperatures between 0° and 100° C.; the addition of an acid such as acetic acid or hydrochloric acid may be advantageous.","The catalyst used is preferably 5-10% Pd on activated carbon.","The synthesis of structural units of type E is generally carried out by methods known to the person skilled in the art; the structural units used are either commercially available or accessible by methods known from the literature.","The synthesis of some of these structural units is described by way of example in the experimental section.","In the case in which the fragments QE or XE contained in the compounds of type VI and VIII are a hetaryl radical, the structural units used are either commercially available or accessible by methods known to the person-skilled in the art.","A multiplicity of preparation methods are described in detail in Houben-Weyl's “Methoden der organischen Chemie” (Vol.","E6: furans, thiophenes, pyrroles, indoles, benzothiophenes, -furans, -pyrroles; Vol.","E7: quinolines, pyridines, Vol.","E8: isoxazoles, oxazoles, thiazoles, pyrazoles, imidazoles and their benzo-fused representatives, as well as oxadiazoles, thiadiazoles and triazoles; Vol.","E9: pyridazines, pyrimidines, triazines, azepines and their benzo-fused representatives as well as purines).","The linkage of these fragments to E, depending on the structure of E, can also take place via the amino or acid function according to methods which are known to the person skilled in the art.","Structures of the general formula A-E-DE are synthesized according to methods known to the person skilled in the art, which are described, for example, in WO 97/08145.Examples of these are the conversion of compounds of the general formula: HNRE11EA1-DE (XIV) NC-EA2-DE (XV) into compounds of the general formula: A-HNRE11-EA1-DE (XVI) A-E-DE (XVII) The groups EA1 and EA in the formulae XIV-XVIII represent structural fragments which, after an appropriate modification (e.g.","reaction with suitable reagents or coupling with appropriate structural units) as a whole form the structural fragment A-E.","These structural units can then be reacted either directly—in the case of the corresponding free amines or carboxylic acids—or after removal of the protective groups—to give compounds of the general formula I (scheme 1 and 2).","In principle, A, however, can also be introduced into compounds of the type IV, as described in scheme 1, where the reaction conditions mentioned can be used just as variants which are not described here.","In schemes 3-7, a number of the methods for the introduction of A are described by way of example, in each case reaction conditions being used which are known and suitable for the respective reactions.","Use can also be made in this case of variants which are known per se but not mentioned here.","Ureas and thioureas (AE-1 to AE-3) can be prepared by customary methods of organic chemistry, e.g.","by reaction of an isocyanate or of an isothiocyanate with an amine, if appropriate in an inert solvent with heating (Houben-Weyl Volume VIII, 157ff.)","(scheme 3): Scheme 4 shows, by way of example, the preparation of compounds of the type AE-4, as is described, for example, by Blakemoore et al.","in Eur.","J. Med.","Chem.","1987 (22) 2, 91-100, or Misra et al.","in Bioorg.","Ned.","Chem.","Lett.","1994 4 (18), 2165-2170.Unsubstituted or cyclic guanidine derivatives of the general formulae AE-5 and AE-6 can be prepared by means of commercially available or simply accessible reagents, such as are described, for example, in Synlett 1990, 745, J. Org.","Chem.","1992, 57, 2497, Bioorg.","Ned.","Chem.","1996, 6, 1185-1208; Bioorg.","Med.","Chem.","1998, 1185, or Synth.","Comm.","1998, 28, 741-746 (scheme 5).","The preparation of compounds of the general formula AE-7 can be carried out analogously to U.S. Pat.","No.","3,202,660, compounds of the formulae AE-9, AE-10, AE-11 and AE-12 analogously to WO 97/08145.Compounds of the formula AE-8 can be prepared, as shown in scheme 6, e.g.","according to the method described by Perkins et al., Tetrahedron Lett.","1999, 40, 1103-1106.Scheme 5 gives a survey of the synthesis of the compounds mentioned, the circle in AE-8 representing a fused cycle, such as aryl or hetaryl.","Compounds of the general formula AE-13 can be prepared analogously to Froeyen et al., Phosphorus Sulfur silicon Relat.","Elem.","1991, 63, 283-293; AE-14 analogously to Yoneda et al., Heterocycles 1998, 15 N′-1, Spec.","Issue, 341-344 (scheme 6).","The preparation of corresponding compounds can also be carried out analogously to WO 97/36859.Compounds of the general formula AE-15 can be prepared according to Synthesis 1981, 963-965 or Synth.","Comm.","1997, 27 (15), 2701-2707; AE-16 analogously to J. Org.","Chem.","1991, 56 (6), 2260-2262 (scheme 7), the circle being a fused cycle, such as aryl, hetaryl or cycloalkyl.","The invention further relates to pharmaceutical preparations, comprising at least one compound of the formula I′ in addition to the customary pharmaceutical excipients.","The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in the customary manner.","Administration can also be carried out through the nasopharynx using vapors or sprays.","Further, the compounds according to the invention can be introduced by direct contact with the affected tissue.","The dose depends on the age, condition and weight of the patient and on the manner of administration.","As a rule, the daily dose of active compound is between approximately 0.5 and 50 mg/kg of body weight in the case of oral administration and between approximately 0.1 and 10 mg/kg of body weight in the case of parenteral administration.","The novel compounds can be administered in solid or liquid form in the customary pharmaceutical administration forms, e.g.","as tablets, film-coated tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays.","These are prepared in a customary manner.","The active compounds can in this case be processed using the customary pharmaceutical excipients such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-delaying agents, antioxidants and/or propellants (cf.","H. Sucker et al.",": Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991).","The administration forms thus obtained normally contain the active compound in an amount from 0.1 to 90% by weight.","The invention further relates to the use of compounds of the formula I′ for the production of drugs for treating illnesses.","The compounds of the formula I′ can be used for treating human and animal illnesses.","The compounds of the formula I′ which represent the novel compounds of the formula I bind, as mentioned above, to integrin receptors.","They are therefore suitable, as mentioned above, preferably as integrin receptor ligands and for the production of drugs for treating illnesses in which an integrin receptor is involved, in particular for the treatment of illnesses in which the interaction between integrins and their natural ligands is dysregulated, i.e.","excessive or reduced, as described above.","Advantageously, the compounds of the formula I, preferably the compounds of the formula I′, can be administered in combination with at least one further compound in order to achieve an improved curative action in a number of indications.","These further compounds can have the same or a different mechanism of action as/from the compounds of the formula I.","In addition to the compounds of the formula I, preferably in addition to the compounds of the formula I′ and the customary pharmaceutical excipients, the pharmaceutical preparations can therefore contain at least one further compound, depending on the indication, in each case selected from one of the 10 groups below.","Group 1: inhibitors of blood platelelet adhesion, activation or aggregation, such as acetylsalicylic acid, lysine acetylsalicylate, piracetam, dipyridamol, abciximab, thromboxane antagonists, fibrinogen antagonists, such as tirofiban, or inhibitors of ADP-induced aggregation such as ticlopidine or clopidogrel, anticoagulants which prevent thrombin activity or formation, such as inhibitors of IIa, Xa, XIa, IXa or VIIa, antagonists of blood platelet-activating compounds and selectin antagonists for the treatment of blood platelet-mediated vascular occlusion or thrombosis, or Group 2: inhibitors of blood platelet activation or aggregation, such as GPIIb/IIIa antagonists, thrombin or factor Xa inhibitors or ADP receptor antagonists, serine protease inhibitors, fibrinogen-lowering compounds, selectin antagonists, antagonists of ICAM-1 or VCAM-1 inhibitors of leukocyte adhesion inhibitors of vessel wall transmigration, fibrinolysis-modulating compounds, such as streptokinase, tPA, plasminogen-activating stimulants, TAFI inhibitors, XIa inhibitors or PAI-1 antagonists, inhibitors of complement factors, endothelin receptor antagonists, tyrosine kinase inhibitors, antioxidants and interleukin 8 antagonists for the treatment of myocardial infarct or stroke, or Group 3: endothelin antagonists, ACE inhibitors, angiotensin receptor antagonists, endopeptidase inhibitors, beta-blockers, calcium channel antagonists, phosphodiesterase inhibitors and caspase inhibitors for the treatment of congestive heart failure, or Group 4: thrombin inhibitors, inhibitors of factor Xa, inhibitors of the coagulation pathway which leads to thrombin formation, such as heparin or low-molecular weight heparins, inhibitors of blood platelet adhesion, activation or aggregation, such as GPIIb-IIIa antagonists or antagonists of the blood platelet adhesion and activation mediated by vWF or GPIb, endothelin receptor antagonists, nitrogen oxide synthase inhibitors, CD44 antagonists, selectin antagonists, MCP-1 antagonists, inhibitors of signal transduction in proliferating cells, antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF and antioxidants for the treatment of restenosis after vascular injury or stent implantation, or Group 5: antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF, heparin or low-molecular weight heparins or further GAGs, inhibitors of MMPs, selectin antagonists, endothelin antagonists, ACE inhibitors, angiotensin receptor antagonists and glycosylation inhibitors or AGE formation inhibitors or AGE breakers and antagonists of their receptors, such as RAGE, for the treatment of diabetic angiopathies, or Group 6: lipid-lowering compounds, selectin antagonists, antagonists of ICAM-1 or VCAM-1 heparin or low-molecular weight heparins or further GAGs, inhibitors of MMPs, endothelin antagonists, apolipoprotein A1 antagonists, cholesterol antagonists, HMG CoA reductase inhibitors, ACAT inhibitors, ACE inhibitors, angiotensin receptor antagonists, tyrosine kinase inhibitors, protein kinase C inhibitors, calcium channel antagonists, LDL receptor function stimulants, antioxidants LCAT mimetics and free radical scavengers for the treatment of atherosclerosis, or Group 7: cytostatic or antineoplastic compounds, compounds which inhibit proliferation, such as kinase inhibitors and heparin or low-molecular weight heparins or further GAGS for the treatment of cancer, preferably for the inhibition of tumor growth or metastasis, or Group 8: compounds for antiresorptive therapy, compounds for hormone exchange therapy, such as estrogen or progesterone antagonists, recombinant human growth hormone, bisphosphonates, such as alendronates compounds for calcitonin therapy, calcitonin stimulants, calcium channel antagonists, bone formation stimulants, such as growth factor antagonists, interleukin-6 antagonists and Src tyrosine kinase inhibitors for the treatment of osteoporosis, or Group 9: TNF antagonists, antagonists of VLA-4 or VCAM-1, antagonists of LFA-1, Mac-1 or ICAMs, complement inhibitors, immunosuppressants, interleukin-1, -5 or -8 antagonists and dihydrofolate reductase inhibitors for the treatment of rheumatoid arthritis, or Group 10: collagenase, PDGF antagonists and MMPs for improved wound healing.","A pharmaceutical preparation comprising at least one compound of the formula I, preferably comprising at least one compound of the formula I′, if appropriate pharmaceutical excipients and at least one further compound, depending on the indication, in each case selected from one of the above groups, is understood as meaning a combined administration of at least one of the compounds of the formula I, preferably of one of the compounds of the formula I′, with at least one further compound in each case selected from one of the groups described above and, if appropriate, pharmaceutical excipients.","Combined administration can be carried out by means of a substance mixture comprising at least one compound of the formula I, preferably of the formula I′, if appropriate pharmaceutical excipients and at least one further compound, depending on the indication, in each case selected from one of the above groups, but also spatially and/or chronologically separate.","In the case of the spatially and/or chronologically separate administration, the administration of the components of the pharmaceutical preparation, the compounds of the formula I, preferably of the formula I′ and the compounds selected from one of the abovementioned groups, takes place spatially and/or chronologically separately.","For the treatment of restenosis after vascular injury or stenting, the administrations of the compounds of the formula I, preferably of the formula I′, can be carried out locally at the affected sites, on their own or in combination with at least one compound selected from group 4.It may also be advantageous to coat the stents with these compounds.","For the treatment of osteoporosis, it may be advantageous to carry out the administration of the compounds of the formula I, preferably of the formula I′, in combination with an antiresorptive or hormone exchange therapy.","The invention accordingly relates to the use of the abovementioned pharmaceutical preparations for the production of drugs for treating illnesses.","In a preferred embodiment, the invention relates to the use of the abovementioned combined pharmaceutical preparations for the production of drugs for treating blood platelet-mediated vascular occlusion or thrombosis when using compounds of group 1, myocardial infarct or stroke when using compounds of group 2, congestive heart failure when using compounds of group 3, restenosis after vascular injury or stent implantation when using compounds of group 4, diabetic angiopathies when using compounds of group 5, atherosclerosis when using compounds of group 6, cancer when using compounds of group 7, osteoporosis when using compounds of group 8, rheumatoid arthritis when using compounds of group 9, wound healing when using compounds of group 10.The following examples illustrate the invention, the selection of these examples being non-limiting.","I. SYNTHESIS EXAMPLES I.A Precursors Example 1 t-Butyl (2-oxo-2,3-dihydro-1H-1-benzazepin-5-yl)acetate (1) 22.3 g (80 mmol) of t-butyl diethylphosphonate (95%) were added dropwise at 0° C. to a suspension of 3.27 g of NaH (60%; deoiled) in ml of DMF.","The mixture was stirred until a clear solution was formed and then 12.4 g (70.9 mmol) of 3,4-dihydro-1H-1-benzazepine-2,5-dione (preparation according to Arch.","Pharm.","1991, 324, 579) in 90 ml of DMF were added dropwise at 0° C. The reaction mixture then remained standing at RT for about 3 days.","For workup, the mixture was poured into 700 ml of cold 5% NaCl solution, and the resulting yellow precipitate was filtered off with suction and washed with H2O.","The moist residue was taken up in CH2Cl2, washed with 5% NaHCO3 solution and dried over Na2SO4.The residue which remained after evaporation was treated with 150 ml of cyclohexane in the presence of heat, and after cooling, filtering off with suction and washing with n-hexane 17.5 g (90.5%) of white crystals remained; m.p.",": 136-138° C. Example 2 t-Butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)acetate (2) A suspension of 3 g of 10% Pd/C in 50 ml of ethanol was prehydrogenated, then a solution of compound 1 (14.7 g; 53.8 mmol) in 125 ml of ethanol and 75 ml of dioxane was added, and the mixture was hydrogenated under standard conditions until the absorption of hydrogen was complete.","After filtering off the catalyst with suction and washing it with ethanol, the filtrate was concentrated in vacuo, the oily residue was dissolved in diethyl ether and the crystallization commencing was completed by addition of n-hexane.","After filtering off the precipitate with suction and washing it with n-hexane, 14.2 g (96%) of white crystals remained; m.p.",": 101-103° C. Example 3 [5-(2-t-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-5-yl]acetic acid (3) a.)","A solution of compound 2 (16.8 g; 61.1 mmol) in 60 ml of DMF was added dropwise at 10-20° C. to a suspension of 2.6 g of NaH (60%, deoiled) in 35 ml of DMF and the mixture was stirred until the appearance of an almost clear yellowish solution.","t-Methyl bromoacetate (10 g; 63.4 mmol) was then added dropwise and the mixture was stirred overnight.","For workup, the reaction mixture was poured into 400 ml of 5% cold NaCl solution and extracted 3× with 100 ml each of a diethyl ether/n-hexane mixture.","The combined extracts were then washed with H2O, 10% NaHCO3 solution and NaCl solution, dried over Na2SO4, filtered and evaporated.","The residual yellowish oil was reacted further without further purification; FAB-MS: 348 [M−H+].","b.)","Crude product 3a was dissolved in 100 ml of dioxane and 65 ml of 1N NaOH were added dropwise at RT with stirring.","After about 45′, the reaction mixture was adjusted to pH 7 using 1N KHSO4 solution, the dioxane was largely distilled off in vacuo, and the residue was diluted with H2O, adjusted to pH 9 using 1N NaOH and extracted 3× with diethyl ether.","The aqueous phase was then rendered acidic using 1N KHSO4 solution, the acid precipitating was extracted with a mixture of diethyl ether/n-hexane 4:1, and the organic phase was washed with H2O, 1N NaOH solution and NaCl solution and dried over Na2SO4.Filtration and evaporation afforded an oily residue, which could be crystallized by treatment with diethyl ether/n-hexane 1:4 (water-saturated).","Filtering with suction, washing with n-hexane and drying afforded 17.8 g (87.5%) of white crystals: m.p.",": 117-119° C. Example 4 N-[4-(Aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) a.)","20 g of tert-butyl-4-aminobenzyl carbamate (89.97 mmol)—dissolved in 100 ml of CH3CN—were added dropwise at 0° C. to a solution of 24.5 g of thiocarbonyldiimidazole and 1.56 g of imidazole in 600 ml of CH3CN and the mixture was stirred at RT overnight.","19.5 g of 1,2-phenylenediamine were then added and the mixture was again stirred at RT for 2 h. For workup, the reaction mixture was evaporated in vacuo, the residue was taken up in CH2Cl2, and the solution was washed 7× with 10% citric acid solution and 2× with satd.","NaCl solution, dried over Na2SO4, filtered and concentrated.","The crude product thus obtained (31.78 g; brown foam) was reacted directly without further purification; ESI-MS [M+H+]=373.15.1H-NMR (360 MHz, DMSO) δ ppm: 9.5 and 9.05 (each s, 1H), 7.45 (d, 2H), 7.35 (m, 1H), 7.20 (d, 1H), 7.15, 6.95, 6.75, 6.60 (each m, 1H), 4.85 (s, 2H), 4.10 (d, 2H), 1.35 (s, 9H).","b.)","Crude product 4a was dissolved in 750 ml of ethanol together with 36.7 g of HgO (yellow) and 0.4 g of sulfur and heated to reflux for 2 h. The reaction mixture was then filtered twice through Celite and evaporated to dryness; 20.7 g, ESI-MS [M+H+]=339.15.c.)","7 g of the crude product 4b were introduced into 70 ml of CH2Cl2, 35 ml of HCl in diethyl ether (satd.","at 0° C.) were added and the mixture was stirred at RT for 2 h. The resulting precipitate was filtered off with suction, washed with CH2Cl2 and dried.","6.7 g of brown amorphous solid; ESI-MS [M+H+]=239.15 1H-NMR (360 MHz, DMSO) δ ppm: 11.6 (s broad, 1H), 8.4 (s broad, 3H), 8.25 (s broad, 1H), 7.65 and 7.55 (each d, 2H), 7.45 and 7.3 (each m, 2H), 4.19 (m, 2H).","Example 5 N-[5-(Aminomethyl)-1,3-thiazol-2-yl]guanidine (dihydrochloride) (5) a.)","31 g (130 mmol) of 2-chloro-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanal (preparation according to THL 39 (1998), 8085-8088) and 15.4 g of amidinothiourea were heated at 110° C. for 75′ in 200 ml of n-butanol, then the mixture was evaporated and the residue was treated with CH2Cl2 and conc.","NH3.Evaporation of the organic phase, purification of the residue by chromatography on silica gel (CH2Cl2/CH3OH 0-5%) and crystallization from acetone afforded 12.3 g of N-{5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazol-2-yl}guanidine.","b.)","1 g of 5a in 20 ml of CH3OH was treated with 0.81 ml of hydrazine hydrate and stirred at RT for 2 h. The mixture was then cooled to 0° C., filtered, and the filtrate was concentrated and stirred with dilute HCl.","This process was repeated a number of times, and the crude product obtained in this way was then stirred with ethanol; 0.92 g of white solid, ESI-MS [M+H+]=172.05.Example 6 N-[4-(Aminomethyl)phenyl]-N′-benzylurea (6) a.)","4-Aminobenzylamine (10.0 g, 81.85 mmol) in 150 ml CH2Cl2 was treated with triethylamine (6.8 g, 67.12 mmol) and then treated at 0° C. with di-t-butyl dicarbonate (18.6 g, 85.0 mmol).","The mixture was stirred at 0° C. for 1 h and then at RT for 2 h. For workup, 150 ml of a 1%-aqueous citric acid solution were added, the phases were separated and the aqueous phase was reextracted 2 times with CH2Cl2 (150 ml).","Fresh washing with H2O, drying of the combined organic phases using Na2SO4 and evaporation afforded a solid, which was washed with stirring with a little diisopropyl ether, filtered off with suction and dried.","13.0 g; ESI-MS [M+H+-tBu]=167.05.1H-NMR (360 MHz, CDCl3) δ (ppm): 7.04 (2H, d), 6.61 (2H, d), 4.78 (1H, s br.","), 4.17 (2H, d), 3.67 (2H, s br.","), 1.46 (9H, s).","b.)","Benzyl isocyanate (2.40 g, 18.0 mmol) was added with ice-cooling to a solution of the protected amine 6a (4.0 g, 17.99 mmol) and triethylamine (1.82 g, 18.0 mmol) in 220 ml of toluene/DMF 10:1.The reaction mixture was stirred at RT overnight.","It was possible to filter off some of the urea formed directly as a precipitate and dry it.","The filtrate was washed 2× with H2O, with dilute tartaric acid to pH 3 and again 2 times with H2O to pH 5, and the organic phase was then dried and evaporated.","Altogether, 6.0 g were thus obtained; ESI-MS [M+H+-tBu]=300.15.c.)","The urea 6b thus obtained was introduced in 90 ml of CH2Cl2, and TFA (2.24 g, 196.25 mmol)—dissolved in 90 ml of CH2Cl2—was added dropwise at 0° C. After 3 h, 1 ml of TFA was added again, then the mixture was stirred at RT overnight.","After fresh addition of 1 ml of TFA, the mixture was stirred for a further 5 h, then poured onto ice water and extracted with ethyl acetate (2×50 ml).","The water phase was rendered basic with 2N NaOH solution and extracted with CH2Cl2 (2×50 ml).","The insoluble portion between the phases was filtered off and dried.","4 g; ESI-MS [2M+H+]=511.35 1H-NMR (200 MHz, DMSO) δ (ppm): 8.52 (1H, s), 7.39-7.07 (9H, m), 6.62 (1H, t), 4.27 (2H, d), 3.61 (2H, s).","Example 7 [4-(1H-Benzimidazol-2-yl)phenyl]methaneamine (hydrochloride) (7) a.)","Di(tert-butyl) 4-cyanobenzylimidodicarbonate (10 g, 30.08 mmol; preparation according to Synth.","Comm.","28, 23, 1998, 4419ff) in 200 ml of pyridine was treated with 45 ml of triethylamine and saturated at 0° C. with H2S for 1.5 h. The reaction mixture was allowed to stand at RT overnight and then evaporated.","The residue thus obtained was then stirred with diethyl ether, filtered off with suction and dried (8.5 g).","b.)","6 g of the thioamide 7a (16.37 mmol) in 40 ml of dry CH2Cl2 were alkylated at RT overnight using 23.2 g of CH3I and the mixture was then evaporated.","The residue thus obtained was taken up in 40 ml of CH3OH, 1.95 g of 1,2-phenylenediamine were added and it was again stirred overnight.","Evaporating the reaction mixture and stirring the solid with n-pentane afforded 6.9 g of the desired benzimidazole.","M.p.",": >170° C. (decomposition); ESI-MS: [M+H+]=424.25 c.) 1 g of the bis-Boc compound 7b was dissolved in 5 ml of CH2Cl2, 5 ml of TFA were added at 0° C. and the mixture was stirred at room temperature for 1 h. Evaporating the reaction mixture, treating with HCl in diethyl ether and stirring the isolated solid with diethyl ether afforded 0.6 g of the amine as the hydrochloride; ESI-MS: [M+H+]=224.05.Example 8 N1-(1H-Benzimidazol-2-yl)pentane-1,5-diamine (hydrochloride) (8) Preparation was carried out analogously to the preparation of compound 4 starting from 7 g of N-Boc-1,5-diaminopentane hydrochloride (29.3 mmol).","After reaction analogously to 4a, 10.3 g of N-Boc 5-{[(2-aminoanilino)carbothioyl]amino}pentane-1-amine were obtained; ESI-MS [M+H+]=353.25.Cyclodesulfurization and subsequent removal of the Boc group with TFA afforded an oily crude product, which was taken up in CH3OH and converted into the corresponding hydrochloride using 250 ml of ethereal HCl (saturated at 0° C.).","Stirring the solid obtained with a mixture of CH3OH/methyl t-butyl ether afforded 1.8 g of a reddish amorphous solid.","1H-NMR (360 MHz, DMSO) δ ppm: 9.30 (t, 1H), 8.15 (s broad, 3H), 7.40 and 7.25 (each m, 2H), 3.35 (m, 2H superimposed with H2O peak), 2.80 (m, 2H), 1.65 (m, 4H), 1.45 (m, 2H).","Example 9 N1-(1H-Benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (9) Preparation was carried out analogously to the preparation of compound 4 starting from 9.87 g of N-Boc-1,4-diaminobutane (52.3 mmol).","After reaction analogously to 4a, 17.08 g of N-Boc 4-{[(2-aminoanilino)carbothioyl]amino}butane-1-amine were obtained; ESI-MS [M+H+]=338.99.Subsequent cyclodesulfurization and Boc removal using TFA afforded a brown solid, which was stirred a number of times with n-pentane and then recrystallized from a mixture of CH3OH/methyl t-butyl ether; 14.35 g, ESI-MS [M+H+]=205.15.1H-NMR (360 MHz, DMSO) δ ppm: 9.20 (t, 1H), 7.80 (s broad, 3H), 7.35 and 7.20 (each m, 2H), 3.40 (m, 2H partially superimposed with H2O peak), 2.80 (m, 2H), 1.65 (m, 4H).","Example 10 trans-N-[(4-Aminocyclohexyl)methyl]-1H-benzimidazole-2-amine (dihydrochloride) (10) Preparation was carried out analogously to compound 4 starting from 5.4 g of tert-butyl-4-(aminomethyl)cyclohexylamine carbamate (WO 9603374; Bioorg.","Med.","Chem.","Lett.","1997, 7 (1), 67).","After removal of the Boc group, 3.3 g of white dihydrochloride were obtained; FAB-MS [M+H+]: 245.Example 11 trans-N-{[4-(Aminomethyl)cyclohexyl]-1H-benzimidazole-2-amine (dihydrochloride) (11) Preparation was carried out analogously to compound 4 starting from 10 g of benzyl {4-[(tert-butoxycarbonyl)amino]cyclohexyl}-methylcarbamate (EP 669317) by removal of the Boc group using 4N HCl in dioxane, synthesis of the benzimidazole and subsequent hydrogenolysis.","3.6 g of white dihydrochloride were isolated; FAB-MS [M+H+]: 245.Example 12 [6-(1H-Benzimidazol-2-yl)pyridin-3-yl]methaneamine (trifluoroacetate) (12) a.)","Preparation was carried out analogously to 7 starting from tert-butyl (6-cyanopyridin-3-yl)methylcarbamate (6.0 g, 25.72 mmol); crystallization of the crude product from ethanol afforded 5.15 g; ESI-MS [M+H+]=325.b.)","0.55 g of the Boc-protected amine 12a in 10 ml of CH2Cl2 was treated with 5 ml of TFA and stirred at RT for 2 h. Evaporation of the reaction mixture afforded 0.95 g of a white solid; ESI-MS [M+H+]: 225.25.Example 13 N-[4-(Aminomethyl)phenyl]-2-pyridineamine (13) tert-Butyl 4-aminobenzylcarbamate (2 g; 9 mmol) was heated to reflux for 32 h with 8.74 g of 2-fluoropyridine.","The reaction mixture was evaporated in vacuo and the residue obtained was stirred with n-pentane (1.9 g).","The Boc group was cleaved using TFA, and the crude product obtained was precipitated from diethyl ether as the hydrochloride and then converted into the free-base (0.8 g) using NH3; ESI-MS [M+H+]: 200.25.N-[4-(Aminomethyl)benzyl]-2-pyridineamine (14) a.)","20 g 2-Aminopyridine were dissolved in 100 ml CH3OH, adjusted to pH 6 with isopropanolic HCl and 36 g p-cyanobenzaldehyde were added.","9.35 g Sodium cyanoborohydride were added portionwise over one hour and stirred overnight.","For workup, the suspension was evaporated, the residue taken up in 100 ml water and with KOH adjusted to pH>10.The watery phase was saturated with NaCl and extracted 3× with diethylether.","The ether phase was washed after filtration of a precipitate 3× with a FeSO4 solution, dried and evaporated.","Purification of the residue by chromatography on silica gel (heptane/ethyl acetate 1:1) afforded 28.15 g 4-[2-pyridinyl-amino)methyl]benzonitrile.","b.)","10 g 4-[2-Pyridinyl-amino)methyl]benzonitrile were dissolved in 280 ml ammonia-alkali CH3OH, 10 g Raney-nickel added and it was hydrogenated for 24 h. It was filtered, evaporated and the residue purified by chromatography on silica gel (ethyl acetate/ethyl alcohol 1:3).","5.18 g, ESI-MS: [M+H+]=214.","[5-(1H-Benzimidazole-2-yl(thiene-2-yl]methaneamine (15) Preparation was carried out starting from 5-(aminomethyl)thiophene-2-carbonitrile (preparation according to WO 95/23609), which was reacted to the respective Boc-derivative according to standard methods.","1.1 eq.","Sodium methanolate solution was added to t-butyl-5-cyanothiene-2-ylcarbamate (25 g; 104.9 mmol) in 330 ml CH3OH and stirred overnight at RT, then for 2 h at 40-50°.","18.95 g Phenylenediaminebihydrochloride were then added and again stirred at RT.","For workup, water was added, the resulting precipitate filtered off and carefully dried.","19.6 yellow solid; ESI-MS: [M+H+]=330.The following cleavage of the Boc-group with TFA afforded a raw product, which was dissolved in water, 2× extracted with diethyl ether, the watery phase adjusted to pH 10-11 and then extracted 2× with ethyl acetate.","The watery phase was saturated with NaCl and again extracted with ethyl acetate.","The combined organic phases were dried and evaporated (6.3 g); ESI-MS [M+H+]=230.1.tert-Butyl-2-[4-(1H-benzimidazole-2-yl)phenyl]ethylcarbamate (16) Preparation was carried out analogously to the preparation of [4-(1H-benzimidazole-2-yl)phenyl]methaneamine (hydrochloride) (7) starting from tert-butyl-2-(4-cyanophenyl)ethylcarbamate.","The raw product obtained after reaction with H2S, alkylation with CH3I and reaction with 1,2-phenylenediamine was purified by chromatography on silica gel (CH2Cl2/CH3OH 4-50%) (4.8 g); ESI-MS [M+H+]=338.15.The amine required for the further reaction was obtained by cleavage of the Boc-group with TFA (under standard conditions); the isolated TFA-salt was then directly utilized in the respective couplings.","N-(Piperidine-4-ylmethyl)-1H-benzimidazole-2-amine (trifluoroacetate) (17) a) A solution of tert-butyloxycarbonyl-4-(aminomethyl)-1-piperidine (5.39 g; 25 mmol) in 25 ml CH3CN was added dropwise to 6.75 g thiocarbonyldiimidazole and 0.5 g imidazole in 100 ml CH3CN at 0° C. and then stirred for 3 h at RT.","1,2-Phenylenediamine (5.5 g; 50.86 mmol) was then added and heated for about 1 h to 60° C. The solid obtained upon cooling was filtered off with suction and dried.","6.79 g; ESI-MS [M+H+-tBu]=309.15 b) tert-Butyoxycarbonyl-4-({[(2-aminoanilino)carbothioyl]amino}methyl)1-piperidine (5 g; 13.72 mmol), 5.94 g HgO (yellow) and 0.6 g sulfur in 150 ml ethyl alcohol were heated under reflux for 1 h. The mixture was filtered 2× over Celite, evaporated and the obtained raw product purified by chromatography on silica gel (CH2Cl2/CH3OH 5-25%).","2.65 g; ESI-MS [M+H+]=331.25 1H-NMR (360 MHz, DMSO) δ ppm: 7.15 and 6.9 (each m, 2H), 3.95 (d, 2H) 3.2 (m, 2H, 2.7 (br m; 2H), 1.8 (m, 1H), 1.7 (m, 2H), 1.35 (s, 9H), 1.05 (m, 2H).","c) tert-Butyloxycarbonyl-4-[(1H-benzimidazole-2-ylamino)methyl]-1-piperidine (2.65 g; 8.02 mmol) was treated with 10 ml TFA according to standard conditions.","Evaporation and mixing the raw product with n-pentane afforded 2.39; ESI-MS [M+H+]=231.15.1H-NMR (360 MHz, DMSO δ ppm: 13.25 (s, 1H), 9.35 (m, 1H), 8.8 and 8.5 (each br s, 1H), 7.4 and 7.20 (each m, 2H), 3.3 (m, 4H), 2.85 (m, 2H), 1.9 (m, 3H), 1.35 (m, 2H).","N-{[5-(Aminomethyl)thiene-3-yl]methyl}pyridine-2-amine (trifluoroacetate) (18) a) A solution of tert-butyl-(4-cyanothiene-2-yl)methylcarbamate (7 g; 29.4 mmol) in 120 ml ethyl alcohol was saturated with NH3 and then hydrogenated under standard conditions in the presence of Ra—Ni (9 g watery suspension; decanted with ethyl alcohol).","Filtration of the reaction mixture, evaporation and chromatography of the obtained residue on silica gel (CH2Cl2/CH3OH plus watery NH3) afforded 4.4 g of the amine as a yellow oil.","b) 1.2.of the amine 18a (4.3 mmol), 06.g ethyldiisopropylamine and 15 g 2-fluoropyridine were heated for 20 h to reflux.","The residue obtained after evaporation of the mixture was taken up in CH2Cl2, washed with 0.1n HCl and saturated NaCl solution, dried and again evaporated.","1 g; ESI-MS [M+H+]=320.15 c) 0.9 of the Boc-protected amine 18b were dissolved in 10 ml CH2Cl2, 5 ml TFA was added at 0° C. and it was stirred at room temperature for 1 h. Evaporation of the reaction mixture afforded 1.65 g of a brownish oil which was reacted directly without further purification (ESI-MS [M+H+]=220.05).","3-Amino-N-(1H-imidazole-2-yl)propaneamide (19) a) Z-β-Alanine (10 g; 44.8 mmol) was dissolved in 200 ml DMF and 15.86 g (3.5 eq) N-methylmorpholine and 5.9 g (0.5 eq) 2-aminoimidazolesulfate were added.","7.87 g (1.3.eq) HOBt and 11.16 g (1.3 eq) N′-(dimethylaminopropyl)-N-ethylcarbodiimide were added at −10° C. and stirred for 1 h whilst to RT and then for 18 h. 150 ml diethyl ether were added whereupon a wide residue precipitated which was filtered with suction.","The residue was washed with cold diethyl ether, suspended in ethyl acetate and 1n HCl was added up to an acid reaction.","The watery solution was extracted 1× with ethyl acetate, the watery phase was then adjusted to a basic pH with 10% NaOH at 4° C. The resulting precipitate was filtered with suction and washed with water.","5.4 g; ESI-MS [M+H+]=289.05.b) 5.3 g of the Z-compound 19a were suspended in 250 ml ethyl alcohol and 530 mg 10% Pd on activated carbon was added.","It was hydrogenated with H2 for 18 h at RT, then diluted with CH3OH and the suspension was boiled up whereon the precipitate of the product disintegrated.","Filtering and evaporation of the solution afforded 1.5 g; ESI-MS [M+H+]=155.05.N-[4-(Aminomethyl)phenyl]-4,5-dihydro-1H-imidazole-2-amine (hydrochloride) (20) tert-Butyl-4-aminobenzylcarbamate (2 g; 9 mmol), 2.2 g ethyldiisopropylamine and 4.4 g (2-(3,5-dimethylpyrazole)-4,5-dihydroimidazole×HBr in 15 ml DMF were stirred at 110° C. After the reaction had completed, the mixture was evaporated, the residue taken up in ethyl acetate, each 2× washed with saturated NaHCO3 and NaCl solution, dried and again evaporated.","The basic watery phase was also evaporated, mixed with acetone, the precipitate filtered with suction and the mother liquor evaporated.","The combined residues were purified by means of MPLC (silica gel: Fa.","Bischoff Prontoprep 60-2540-C18E, 32 μm; solvent: CH3CN/H2O+0.1% acetic acid).","0.22 g; ESI-MS [M+H+]=291.15.The product thus obtained was treated with 4n HCl in dioxane for 2 h at RT.","The resulting precipitate was filtered with suction, washed with pentane and dried.","110 mg; ESI-MS [M+H+]=191.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 11.85 (s, 1H), 8.45 (s broad, 3H), 8.40 (s, 1H), 7.60 and 7.30 (each d, 2H), 4.05 (m, 2H), 3.70 (s, 4H).","N-{[5-Aminomethyl)thiene-3-yl]methyl}-1H-benzimidazole-2-amine (hydrochloride) (21) Amine 18a (6.5 g; 23.31 mmol) was reacted to the respective aminobenzimidazole by reaction with thiocarbonyldiimidazole, imidazole and then phenylenediamine analogously to the preparation of 17.1.6 g: ESI-MS [M+H+]=359.15.The subsequent cleavage of the Boc-group by means of 4n HCl in dioxane afforded 1.3 g of slightly yellow solids: ESI-MS [M+H+]=191.15.N1-Pyridine-2-ylpentane-1,5-diamine (hydrochloride) (22) Preparation analogously to 18b by reaction of N-1-Boc-1,5-diaminopentane×HCl (5 g; 20.94 mmol) and 20.3 g 2-fluoropyridine, 5.64 g clear oil; ESI-MS [M+H+]=280.15.Cleavage of the Boc-group with 4n HCl in dioxane afforded 3.46 g white solids; ESI-MS [M+H+]=180.20.1H-NMR (360 MHz, d6-DMSO) δ ppm: 9.10 (s broad, 1H), 8.05 (s broad, 3H), 7.85 (m, 2H), 7.20 (m, 2H), 6.80 (m, 1H), 3.45 (m, superimposed by H2O), 2.80 (m, 2H), 1.65 (m, 4H), 1.45 (m, 2H).","N1-(4,5-Dihydro-1H-imidazole-2-yl)pentane-1,5-diamine (hydrochloride) (23) N-1-Boc-1,5-diaminopentane×HCl (5 g; 20.94 mmol), 5.4 g ethyldiisopropylamine and 5.11 g 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole×HI in 30 ml DMF were stirred overnight at RT.","The reaction mixture was evaporated, taken up in CH2Cl2, washed with water and saturated NaCl solution, dried and again evaporated.","5.05 g clear oil, ESI-MS [M+H+]: 271.18.Cleavage of the Boc-group with 4n HCl in dioxane and purification of the raw product by means of MPLC afforded 2.57 g; ESI-MS [M+H+]: 171.15.13C-NMR (90.55 MHz, d6-DMSO) δ ppm: 160.3, 43.3 (2 signals superimposed).","42.85, 39.70, 28.90, 27.2, 23.60.N-[4-(Aminomethyl)phenyl]-1H-imidazole-2-amine (24) a) 5.24 g BrCN—dissolved in 50 ml CH3OH-were added dropwise to a mixture of tert-butyl-4-aminobenzylcarbamate (10 g; 44.99 mmol) and 11.07 g sodium acetate in 100 ml CH3OH at 0° C., and it was stirred for 3 hours at 0° C. and overnight at RT.","The mixture was evaporated, the obtained residue taken up in water and 2× extracted with methyl-tert-butylether.","Drying and evaporation of the organic phases afforded 12.99 of a yellow-orange oil.","b) 28.6 g triethylamine were added to 7 g tert-butyl-4-[(iminomethylene)amino]benzyl carbamate in 50 ml pyridine, H2S was introduced for 1 hour at 0° C. and the mixture was allowed to stand for 48 hours.","Evaporation afforded 9.79 g of a rosa foam; ESI-MS [M+H+]: 282.05.1H-NMR (360 MHz.","D6DMSO) δ ppm: 9.70 (s, 1H), 7.35 (m, 4H), 7.20 (m, 2H), 4.15 (d, 2H), 1.45 (s, 9H).","c) 5 g of the thioamide in 50 ml CH3OH where methylated with 5.05 g CH3I and the obtained raw product was directly reacted with 1.73 g aminoacetaldehyde-diethylacetal in 7.5 ml CH3CN for 3 hours at RT.","Evaporation of the reaction mixture afforded 6.36 g of a reddish oil (ESI-MS [M+H+]: 381.25) which was dissolved in 50 ml 6n HCl and stirred for 3 hours at 0° C. A pH of 12 was then adjusted with a 25% NaOH solution and it was again stirred for 48 hours at RT.","The mixture was extracted 4× with ethyl acetate, the combined organic phases dried and evaporated.","The oil thus obtained was stirred 2× with methyl-tert-butylether, the obtained solids filtered with suction and dried.","0.6 g red solid; ESI-MS [M+H+]: 189.15.13C-NMR (90.55 MHz, d6-DMSO) δ ppm: 145.5, 141.60, 130.75, 128.4, 119.8, 115.6, 44.85.N1-(1,4,5,6-Tetrahydropyrimidine-2-yl)pentane-1,5-diamine (hydrochloride) (25) Preparation was carried out analogously to 23 starting from N-1-Boc-1,5-diaminopentane×HCl (5 g; 20.94 mmol) and 5.4 g 2-(methylsulfanyl)-1,4,5,6-tetrahydropyrimidine×HI.","After workup, 1.3 g of a yellowish oil was obtained; [M+H+]: 282.2.Cleavage of the Boc-group with 4n HCl in dioxane and purification by means of MPLC afforded 0.46 g; ESI-MS [M+H+]: 185.15.N-[4-(Aminomethyl)cyclohexyl]pyridine-2-amine (hydrochloride) (26) Benzyl (4-aminocyclohexyl)methylcarbamate (TFA-salt) (5 g; 13.28 mmol)-preparation by TFA cleavage starting from benzyl-{4-[(tert-butoxycarbonyl)amino]cyclohexyl}methylcarbamate (EP 669317)-was heated to reflux analogously to 18 with 1.71 g ethyldiisopropylamine in 50 ml 2-fluoropyridine.","Usual workup and crystallization of the raw products from methyl-tert-butylether/methanol afforded 4.15 g; ESI-MS [M+H+]: 340.29.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.75 (d broad, 1H), 7.85 (m, 2H), 7.35 (m, 5H), 7.05 (d, 1H), 6.85 (m, 1H), 5.05 (s, 2H), 2.90 (m, 2H), 1.95 and 1.75 (each m, 2H), 1.45-0.90 (m, 6H).","Cleavage of the Z group under standard conditions (H2; Pd-activated carbon), precipitation of the resulting amine as hydrochloride and drying of the obtained precipitates afforded 1.5 g; ESI-MS [M+H+]: 206.15.tert-Butyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-ylacetate (27) 75 ml of a 1.0 m BH3-THF solution were added to a solution of tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (2) (10 g; 36.32 mmol) in 100 ml THF and it was stirred at RT.","For workup, water was carefully added, it was 2× extracted with diethyl ether and then the organic phases were washed 2× with water.","Evaporation and drying afforded 9.3 g; ESI-MS [M+H+]: 262.04.","[5-(2-tert-Butoxy-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (28) a) 3 g K2CO3, 0.05 g KI and 5 g methylbromoacetate were added to a solution of tert-butyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl acetate (27) in 50 ml DMF and it was stirred for 12 hours at 90° C. Thereafter, 4 g methylbromoacetate were added and it was stirred for further 5 hours at 120° C. For workup, the mixture was concentrated, diluted with CH2Cl2, washed with saturated NaCl solution, dried and again evaporated.","Chromatography on silica gel (CH2Cl2/CH3OH 1-5%) afforded 4.6 g of a bright yellow oil; ESI-MS [M+H+]: 334.12.b) 4.19 of the methylester in 20 ml dioxane/15 ml H2O were saponified with 19 KOH at RT.","For workup, the mixture was concentrated, adjusted to a pH of 2 with 2n HCl and extracted with CH2Cl2.The combined organic phases were dried, evaporated and the obtained raw product purified by chromatography on silica gel (CH2Cl2/CH3OH 2-7%).","2.4 g oil, ESI-MS [M+H+]: 320.15.1H-NMR (360 MHz, CDCl3) δ ppm: 7.20-7.10 (m, 1H), 6.90 and 6.80 (each m, 1H), 4.0 (s, 2H), 3.55 (m, 1H), 3.10 (m, 2H), 2.85 and 2.70 (each m, 1H), 2.90-2.50 (m, 4H), 1.35 (s, 9H).","N-[4-(Aminomethyl)cyclohexyl]-1H-imidazole-2-amine (hydrobromide) (29) Preparation analogously to the preparation of N-[4-(aminomethyl)phenyl]-1H-imidazole-2-amine (23) starting from benzyl-(4-aminocyclohexyl)methylcarbamate (TFA salt) (3 g; 7.97 mmol).","a) Reaction with BrCN and subsequent purification (1.52 g; ESI-MS [M+H+]: 288.15).","1H-NMR (360 MHz, d6-DMSO) δ ppm: 7.45-7.25 (m, 5H), 6.75 (d, 1H), 5.05 (d, 2H), 2.85 (m, 3H), 1.85 and 1.70 (each m, 2H), 1.35 (m, 1H), 1.20 and 0.95 (each m, 2H).","b) Conversion to the corresponding thiourea and subsequent methylation (1.489; ESI-MS [M+H+]: 336.15.c) Reaction with aminoacetaldehyde-diethylacetal and subsequent cyclization afforded 0.79 g; ESI-MS [M+H+]: 329.15.1H-NMR (360 MHz, DMSO) δ ppm: 7.45-7.25 (m, 5H), 6.45 (s, 2H), 5.35 (d, 1H), 5.05 (s, 2H), 2.90 (m, 2H), 1.95 and 1.70 (each m, 2H), 1.35 (m, 1H), 1.15 and 0.95 (each m, 2H).","d) For cleavage of the Z-group it was dissolved in 30 ml HBr/glacial acidic acid and stirred for 3 h at RT.","For workup, the mixture was evaporated and several times co-evaporated with acetone.","0.89 g; ESI-MS [M+H+]: 195.15.tert-Butyloxycarbonyl-4-[(2-pyridinylamino)methyl]-1-piperidine (30) tert-Butyloxycarbonyl-4-(aminomethyl)-1-piperidine (3 g; 14 mmol) and 10 ml 2-fluoropyridine were heated for 4 h to reflux.","Evaporation and mixing the raw product in n-pentane afforded 3 g of a wide solid, mp: 126-130° C.; ESI-MS [M+H+]=292.15.The amine required for the further reaction was obtained by cleavage of the Boc-group with HCl in dioxane (under standard conditions); the isolated HCl-salt was then directly utilized.","Ethyl-2-{[5-(2-tert-butoxy-2-oxoethyl)-oxo-2,3,4,6-tetrahydro H-1-benzazepine-1-yl]methyl}-1,3-thiazole-4-carboxylate (31) a) A solution of t-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (2) in 20 ml DMF was added dropwise to a suspension of 1.28 g NaH (60%; deoiled) in 10 ml DMF at 5° C. and it was stirred for 1 h. 3.49 g Bromoacetonitrile-dissolved in 20 ml DMF-were then added dropwise and it was stirred for 4 h at RT.","For workup, water was added carefully, it was diluted with CH2Cl2, washed several times with H2O and saturated NaCl solution, dried and evaporated.","Purification of the raw product by chromatography on silica gel (CH2Cl2/CH3OH 5%) afforded 7.61 g; ESI-MS [M+H+-tBu]: 259.05.b) 5 g tert-Butyl-[1-(cyanomethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate in 70 ml pyridine were saturated for 1 h with H2S and then allowed to stand overnight at RT.","Evaporation of the mixture and mixing of the obtained residue with pentane afforded 5.5 g of a rosa solid which was directly reacted.","c) A mixture of 2 g tert-butyl-[1-(2-amino-2-thioxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate, 1.62 g ethylpyruvate and 0.86 g KHCO3 in 30 ml dioxane was stirred for 2.5 h at RT.","Dilution with CH2Cl2, washing with saturated NaCl solution, drying and evaporation afforded 2.65 g of a yellow oil; ESI-MS [M+H+]: 445.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.50 (s, 1H), 7.50 and 7.35 (each m, 1H), 7.30-7.20 (m, 2H), 7.35 (d, 1H), 5.20 (broad, 1H), 4.30 (q, 2H), 4.20 (m, 1H), 3.65-3.50 (m, 2H), 2.70 (m, 2H), 2.35-2.10 (m, 3H), 1.70-1.50 (m, 2H), 1.30 (s, 9H; superimposed by t, 3H).","2-{[5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]methyl}-1,3-thiazole-4-carbonic acid (32) 2.6 g Ethyl-2-{[5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]methyl}-1,3-thiazole-4-carboxylate (31) was provided in a mixture of 31 ml dioxane and 4 ml H2O, 1.5 eq.","KOH was added and it was heated to reflux.","After 5 h, again 1 eq.","KOH was added and it was further stirred for 12 h at RT.","For workup, it was concentrated, the residue was taken up in water, a pH of 4-5 was adjusted with 2n HCl and it was extracted several times with CH2Cl2.The combined org.","phases were washed with saturated NaCl solution, dried and evaporated.","Mixing with n-pentane afforded 2.1 g of a white solid; ESI-MS [M+H+]: 417.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.40 (broad, 1H), 7.5 (m, 1H), 7.35 (m, 1H), 7.30-7.20 (m, 3H), 5.25 (m, 2H), 2.70 (m, 2H), 2.35-2.10 (m, 6H), 1.70 (m, 1H), 1.30 (s, 9H).","2-Ammonio-6-(ammoniomethyl)pyridinium trichloride (33) a) 2-Amino-6-methylpyridine (0.14 mol, 15.0 g) and phthalanhydride (0.14 mol, 20.55 g) were heated to 190° C. at the water separator.","Distributing between H2O and CH2Cl2, evaporation of the org.","phase and recrystallisation of the residue (diethyl ether) afforded 28.25 g of a slightly yellowish solid; ESI-MS [M+H+]=239.15.1H-NMR (270 MHz, CDCl3) δ (ppm): 7.95 (2H, m), 7.78 (3H, m), 7.23 (2H, m), 2.64 (3H, s).","b.)","N-bromosuccimide (25.18 mmol, 4.48 g) was added portionwise to a boiling suspension of 2-(6-methyl-2-pyridinyl)-1H-isoindole-1,3(2H)-dione (33a, 20.99 mmol, 5.0 g), AIBN (2.10 mmol, 0.35 g) and dibenzoylperoxide (2.10 mmol, 0.51 g) in CCl4.The reaction mixture was boiled for 20 h, filtered and the filtrate evaporated.","Chromatography (CH2Cl2) afforded 3.12 g of the target product and 1.20 g of the dibromo compound; ESI-MS 318.95, 316.95.1H-NMR (270 MHz, CDCl3) δ (ppm): 7.98 (2H, m), 7.95 (1H, t), 7.81 (2H, m), 7.58 (1H, d), 7.35 (1H, d), 4.60 (2H, s).","c) Potassium phthalimide (9.46 mmol, 1.75 g) was added to a solution of 2-[6-(bromomethyl)-2-pyridinyl]-1H-isoindole-1,3(2H)-dione (33b, 6.31 mmol, 2.0 g) in DMF (30 ml), the reaction mixture was heated for 15 h to 60° C., stirred for 24 h at RT, water (60 ml) was added and it was stirred for 2 h at 0° C. The residue was filtrated and washed with a mixture of H2O-DMF and then with diethyl ether; 2.12 g; ESI-MS [M+H+]=384.05.1H-NMR (270 MHz, CDCl3) δ (ppm): 7.98-7.91 (4H, m), 7.88 (1H, t), 7.85-7.75 (4H, m), 7.38-7.32 (2H, m), 5.10 (2H, s).","d) 2-{6-[(1,3-Dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]-2-pyridinyl}-1H-isoindole-1,3(2H)-dione (33c, 5.22 mmol, 2.09) was heated to reflux for 3 h with hydrazinium hydroxide (13.04 mmol, 0.65 g) in methanol (50 ml).","For workup, water was added, it was evaporated and the watery phase acidified with conc.","HCl.","Anew evaporation and recrystallising (ethyl alcohol) afforded 1.20 g of a white solid; ESI-MS [M+H+]=124.05.1H-NMR (270 MHz, D2O) δ (ppm): 7.94 (1H, t), 7.08 (1H, d), 6.99 (1H, d), 4.33 (2H, s).","trans-N-[4-(Aminomethyl)cyclohexyl]-N′-benzylurea (34) Preparation was carried out analogously to compound 6 starting from benzyl-{4-[(tert-butoxycarbonyl)amino]cyclohexyl}methylcarbamate (EP 669317) by cleavage of the boc-group with 4n HCl in dioxane.","Build-up of the benzyl urea by reaction with benzyl isocyanate and triethylamine in DMF and subsequent hydrogenolysis afforded 0.55 g of the target product; ESI-MS [M+H+]=262.20.7-(4-Aminobutyl)-1,2,3,4-tetrahydro[1,8]naphthyridine (bitrifluoroacetate) (35) a.)","A solution of 5-tert-butoxycarbonylaminovaleric acid (50.0 mmol, 10.86 g), O,N-dimethylhydroxylamine hydrochloride (50 mmol, 4.88 g), N-Methylmorpholine (0.30 mol, 30.35 g), HOBT (53.90 mmol, 8.42 g) and EDCI*HCl (55.0 mmol, 10.54 g) in CH3CN (200 ml) were stirred for 2 days at RT.","After evaporation the residue was taken up in ethyl acetate, and then washed with water, a 10% KHSO4-solution, a saturated watery NaHCO3 solution and a saturated watery NaCl-solution, subsequently.","Drying and evaporation of the organic phase afforded 6.96 g of a yellowish oil; ESI-MS: [2M+Na+]=543.3, [M+Na+]=283.1, 205.1, 161.1.1H-NMR (270 MHz, CDCl3) δ (ppm): 4.63 (1H, s.","br.","), 3.68 (3H, s), 3.21-3.05 (3+2H, m), 2.44 (2H, t), 1.76-1.48 (2+2H, m), 1.43 (9H, s).","b.)","Methyl magnesia bromide (60.0 mmol, 17.30 ml of a 3M solution in Et2O) at 0° C. was added dropwise to a solution of tert-butyl 5-[methoxy(methyl)amino]-5-oxopentylcarbamate (35a, 30.0 mmol, 6.9 g) in THF (120 ml) and stirred for 5 h at 0° C. The reaction mixture was then carefully acidified with a 10% KHSO4-solution, extracted with ethyl acetate and the organic phase then washed with saturated watery NaHCO3— and saturated watery NaCl-solution, dried and evaporated: 5.5 g yellowish oil; ESI-MS: [M-BOC+H+]=116.15.c.)","A mixture of tert-butyl 5-oxohexylcarbamate (35b, 9.29 mmol, 2.0 g), 2-aminonicotinaldehyde (Heterocycl.","1993, 36, 2518; 11.20 mmol, 1.379) and KOH (0.37 ml of a 20% watery solution) was heated to reflux for 8 h. Evaporation and column chromatography afforded 1.60 g of the target product; ESI-MS: [M+H+]=302.15.d.)","A suspension of tert-butyl 4-[1,8]naphthyridine-2-ylbutylcarbamate (35c, 5.31 mmol, 1.60 g) and Pd/C (10%, 1.59) in ethyl alcohol (40 ml) were stirred overnight under H2 atmosphere, then filtered over celite and washed with ethyl alcohol.","Column chromatography afforded 290 mg; ESI-MS: [M+H+]=306.25.1H-NMR (360 MHz, CDCl3) δ (ppm): 7.04 (1H, d), 6.29 (1H, d), 4.97 (1H, s.br.","), 4.81 (1H, s.br.","), 3.37 (2H, m sym.","), 3.12 (2H, q br.","), 2.65 (2H, t), 2.53 (2H, t), 1.89 (2H, quint.","), 1.67 (2H, quint.","), 1.51 (2H, quint.","), 1.43 (9H, s).","e.) TFA (18.30 mmol, 2.099) was added to a solution of tert-butyl 4-(5,6,7,8-tetrahydro[1,8]naphthyridine-2-yl)butylcarbamate (35d, 0.92 mmol, 0.289) in CH2Cl2 (8 ml), the solution was stirred for 20 h and evaporated: 380 mg; ESI-MS: 206.1, 130.7.1H-NMR (400 MHz, CDCl3) δ (ppm): 7.07 (1H, d), 6.31 (1H, d), 5.58 (1H, s.br.","), 3.39 (2H, m sym.","), 2.96 (2H, s br.","), 2.76 (2H, t), 2.68 (2H, t), 2.56 (2H, t), 1.88 (2H, quint.","), 1.69 (2H, quint.","), 1.51 (2H, quint.).","tert-Butyl [1-(2-hydroxyethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (36) Tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (2) (10.9 mmol, 3.0 g)—dissolved in THF—was added at 0° C. to a solution of diisopropylamine (11.0 mmol, 1.119) and butyl lithium (11.0 mmol, 6.91 ml of a 15% solution in hexane) in THF (100 ml) and the solution further stirred for 1 h. About 100 ml ethylene oxide were then added and the mixture was stirred overnight at RT.","The solution was distributed between saturated NH4Cl and ethyl acetate, the organic phase was washed with water and evaporated; 2.7 g; ESI-MS: [2M+Na+]=661.3, [M+K+]=358.1, 321.1, [M+H+]=320.1, 264.0.tert-Butyl [2-oxo-1-(2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (37) tert-Butyl [1-(2-hydroxyethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (36, 6.26 mmol, 2.00 g) dissolved in CH2Cl2 was added dropwise within 10 minutes to a solution of oxalyl chloride (7.93 mmol, 1.0 g) and DMSO (16.59 mmol, 1.26 g) in little CH2Cl2.After 30 min.","triethyl amine (38.22 mmol, 3.87 g) was added, stirred for 5 min., left to reach RT and stirred overnight at RT.","For workup, water was added, the mixture extracted with CH2Cl2 and the organic phase washed with saturated NaCl—, 1%-H2SO4— and with 5%-NaHCO3-solution.","Evaporation afforded 1.8 g of the target product; ESI-MS: 693.2, [M+K+]=358.1, 319.1, [M+H+]=318.1, 262.0.Methyl-2-amino-5-chlorobenzoic acid (38) Thionyl chloride (0.47 mmol, 55.46 g) was added dropwise at 0° C. to a solution of 2-chloro-5-aminobenzoic acid (0.23 mmol, 40.09) in methanol (400 ml) and the mixture heated to 50-60° C. After the reaction had finished, water was added and it was extracted with ethyl acetate.","Then the organic phase was washed with 1n NaOH and diluted HCl solution (pH 1-2), subsequently, and evaporated; 23.0 g; ESI-MS: [M+H+]=186.05.Methyl 4-chloro-2-[(4-ethoxy-4-oxobutanoyl)amino]benzoic acid (39) Ethyl succinic acid-chloride (0.14 mol, 22.44 g) in toluen (15 ml) was added dropwise at 0° C. to a solution of methyl 2-amino-5-chloro-benzoic acid (38, 123.9 mmol, 23.0 g) and pyridine (0.26 mol, 20.58 g) in toluen (40 ml).","The solution was stirred overnight at RT, water was added and it was extracted with ethyl acetate.","The organic phase was washed with 1N HCl-solution, with water, with a saturated NaHCO3-solution and with a saturated NaCl-solution.","Evaporation, recrystallisation (methanol) afforded 34.1 g of the target product; ESI-MS: [2M+Na+]=649.0, [M+K+]=352.0, [M+H+]=314.05; 1H-NMR (270.MHz, CDCl3) δ (ppm): 11.06 (1H, s br.","), 8.68 (1H, d), 7.99 (1H, m), 7.47 (1H, dd), 4.16 (2H, q), 3.92 (3H, s), 2.74 (4H, m), 1.24 (3H, t).","Ethyl-7-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (40) Methyl 4-chloro-2-[(4-ethoxy-4-oxobutanoyl)amino]benzoic acid (39, 0.16 mol, 50.20 g) in DMSO (250 ml) was added dropwise at 15° C. to a suspension of deoiled NaH (0.27 mol) in THF (50 ml) and DMSO (80 ml) and the mixture was stirred for 2 h at RT.","At 0° C. glacial acetic acid (24 ml) was added and stirred for 20 min.","Water (25 ml) was added, the resulting precipitate filtered off, washed with water, taken up in CH2Cl2, extracted with water and the organic phase evaporated.","The residue was then stirred with diethyl ether (50 ml), filtered and dried; 32 g of a 6:4-mixture methyl/ethyl ester, which was not separated; ESI-MS (Me-ester): [M+K+]=307.9, [M+Na+]=290.0, [M+H+]=268.0; ESI-MS (Et-ester): [M+K+]=321.9, [M+Na+]=304.0, [M+H+]=282.0.7-Chloro-3,4-dihydro-1H-1-benzazepine-2,5-dione (41) Ethyl-7-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (40, 0.11 mol, 32.0 g) was heated to 150° C. in DMSO (500 ml) and water (0.23 mol, 4.09 g) and stirred for 2 h. Water was added at 100° C., the mixture cooled to 0° C. and the resulting precipitate filtered off.","Drying afforded 19.09; ESI-MS: [M+Na+]=251.1, [M+H+]=211.9, 209.95, 130.1.tert-Butyl (2E,Z)-(7-Chloro-2-oxo-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene) ethane acid (42) t-Butyl diethylphosphono acetic acid (0.10 mol, 25.849) was added dropwise at 0° C. to a solution of deoiled NaH (0.10 mol) in DMF (40 ml) and stirred until a clear solution develops.","7-Chloro-3,4-dihydro-1H-1-benzazepine-2,5-dione (41, 90.63 mmol, 19.09) in DMF (185 ml) was added dropwise at 0° C. and stirred at RT.","Water was added to the reaction mixture, it was stirred for 1 h and the resulting yellow residue filtered off with suction, washed with water and taken up in CH2Cl2.The organic phase was washed with a 5%-NaHCO3-solution and evaporated.","Recrystallisation afforded 23.5 g of the target product; ESI-MS: [2M+H+]=615.2, [M+Na+]=330.0, 293.0, 254.1, 252.1.1H-NMR (400 MHz, CDCl3) δ (ppm): 9.59 (1H, s br.","), 7.45 (1H, m), 7.25 (1H, m), 7.06 (1H, m), 5.99 (1H, t), 3.43 (2H, s), 2.84 (2H, d), 1.32 (9H, s).","t-Butyl (7-chloro-2-oxo-2,3,4,4-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (43) tert-Butyl (2E,Z)-(7-chloro-2-oxo-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)ethane acid (42, 75.0 mmol, 23.089) in ethyl alcohol/dioxane (250 ml/100 ml) was hydrogenated for 4 days with Pt/carbon (5%, 4.1 g) under standard conditions.","Water was added to the reaction mixture, stirred for 1 h, the yellow residue filtered off with suction, washed with water and taken up in CH2Cl2.The organic phase was washed with a 5%-NaHCO3-solution and evaporated.","Recrystallisation afforded 23.5 g of a solid (mixture of target product and the corresponding dechlorinated compound; the mixture was reacted directly); ESI-MS: [2M+H+]=618.94, [M+K+]=350.66, 309.75, 254.11.Methyl [5-(2-tert-butoxy-2-oxo ethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (44) tert-Butyl (7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (43, 60.00 mmol, 18.59 g) in DMF (10 ml) was added dropwise at 15° C. to deoiled NaH (69.00 mmol) in DMF (5 ml) and the mixture was stirred overnight at RT.","Ice water was added to the reaction mixture, extracted (2×) with ethyl acetate and the organic phase washed with a 10% CH3COOH-solution, with water and then with 1n NaOH.","Evaporation afforded 20.4 g of a raw product, which was reacted without further purification.","[5-(2-tert-Butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) KOH (80.45 mmol, 4.51 g) in water (150 ml) was added to methyl [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (44, 50.28 mmol, 19.29) dissolved in dioxane (250 ml) and stirred for 1 h at RT.","The reaction mixture was evaporated, water (100 ml) was added and it was extracted with ethyl acetate (2×).","After the evaporation, the residue was taken up in diethyl ether and precipitated by addition of n-pentane.","Recrystallisation (diisopropyl ether, 2×) afforded 4.8 g (comprises about 15% of the corresponding dechloro compound); ESI-MS: [M+Na+]=390.0, 314.0, 312.0.","[4-(Aminomethyl)phenyl]guanidine (Bihydrochloride) (46) p-Aminobenzylamine (6.7 g; 54.84 mmol) was suspended in 20 ml 6n HCl and 5.3 g cyanamide—dissolved in 5 ml H20—added slowly under reflux.","After the reaction had completed, 50% NaOH-solution was added at 0° C. to the solution, the resulting precipitate filtered with suction, boiled up in 50 ml ethyl alcohol and filtered off.","Evaporation of the mother liquor and mixing of the obtained residue with diethyl ether afforded 1.4 g of yellow solids; Fp.",": 255° C. 7,8-Dimethoxy-3,4-dihydro-1H-1-benzazepine-2,5-dione (47) Analogously to the preparation of the corresponding building blocks 39, 40 and 41 first ethyl-2-amino-4,5-dimethoxybenzoate (20 g; 88.8 mmol) was reacted with ethyl succinic acid-chloride to the respective amide.","After mixing with n-pentane 30.4 g of a solid was obtained; ESI-MS [M+H+]: 354.15.1H-NMR (400 MHz, DMSO) δ (ppm): 10.65 (s, 1H), 8.10 and 7.40 (each s, 1H), 4.30 and 4.10 (each q, 2H), 3.85 and 3.80 (each s, 3H), 2.70 (m, 4H), 1.30 and 1.20 (each t, 3H).","Subsequent cyclization with 25 g of the obtained amide under utilization of NaH analogously to 40 and usual workup afforded 19.5 g of a white solid; ESI-MS [M+H+]: 308.05.1H-NMR (400 MHz, DMSO) δ (ppm): 13.3 (s, 1H), 10.10 (s, 1H), 7.25 and 6.75 (each s, 1H), 4.30 (q, 2H), 3.80 (s, 6H), 2.95 (s, 2H), 1.35 (t, 3H).","Decarboxylation analogously to 41 starting from 17 g afforded 10.5 g of the target product as a solid; ESI-MS [M+H+]: 236.15.1H-NMR (400 MHz, DMSO) δ (ppm): 9.90 (s, 1H), 7.35 and 6.80 (each s, 1H), 3.80 and 3.75 (each s, 3H), 2.85 and 2.65 (each m, 2H).","tert-Butyl (7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate (48) Preparation analogously to building blocks 42 and 43 by Wittig-Homer-reaction and subsequent hydrogenation; after mixing with n-pentane 8.16 g of solids were obtained; ESI-MS [M+H+-tBu]: 280.15.","[5-(2-tert-Butoxy-2-oxoethyl)-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetate (49) Analogously to 44 and 45, starting from 4 g tert-butyl-(7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate 2.6 g of the target product were isolated as a bright foam; [M+H+-tBu]: 338.15.1H-NMR (400 MHz, DMSO) δ (ppm): 6.85 and 6.75 (each s, 1H), 4.35 (s broad, 2H), 3.80 and 3.75 (each s, 3H), 3.60 (s, 2H), 2.70 (m, 2H), 2.25 (m, 1H), 2.15 (m, 2H), 1.60 (m, 1H), 1.35 (s, 9H).","[1-(2-Methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) a.)","56.1 g (406 mmol) powdered K2CO3 were added at room temperature to a solution of 37 g (135.3 mmol) t-butyl (2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl)acetic acid (1) and 3.7 g tetrabutylammoniumbromide in 370 ml DMF, 22.7 g (148.9 mmol) methylbromoacetic acid was added dropwise, then it was stirred for 3 h at 40° C. and overnight at room temperature.","The reaction mixture was poured into 1000 ml of a water-ice-mixture, and 2× extracted with each 200 ml methyl-tert.butyl ether.","The combined extracts were washed with H2O, 5% NaHCO3— and NaCl-solution, dried over Na2SO4, filtered off and evaporated.","The remaining yellow oil (about 52 g, purity about 90%) was reacted without further purification; ESI-MS [M+H+]: 346.b.)","9.2 g (26.6 mmol) of the raw product 50a were dissolved in 66.6 ml 4n HCl in dioxane and stirred for 24 h at 50° C., then the dioxane was extensively distilled off, 5% NaHCO3-solution and diethyl ether added to the residue, the watery phase again washed with diethyl ether and acidified with 1n KHSO4-solution.","The precipitating acid was extracted with diethyl ether, the ether phase washed with a NaCl-solution, dried over Na2SO4, filtered off with suction and evaporated.","It remained 3.2 g of a slightly yellow oil; ESI-MS [M+H+]: 290.trans-[4-(1H-Benzimidazole-2-yl)cyclohexyl]methaneamine (hydrochloride) (51) 39.3 g (0.25 mol) trans-4-(Aminomethyl)cyclohexanecarbonic acid and 27.0 g (0.25 mol) 1,2-phenylene diamine were heated to reflux for 18 h in a mixture of 167 ml conc.","hydrochloric acid and 333 ml H2O analogously to J. Heterocycl.","Chem.","26, 541 (1989).","The green reaction solution was concentrated until the occurrence of a yellow crystalline pulp and stirred with 400 ml isopropanol, filtered off, washed with 90% isopropanol and finally with diethyl ether.","After 2 times recrystallisation from a isopropanol-water mixture (70/30), 30 g of a white monohydrochloride remained; ESI-MS [M+H+]: 230.Methyl (2-oxo-2,3,4,5-tetrahydro-1H-1,5benzodiazepine-1-yl)acetic acid (52) 1.99 (79.8 mmol) NaH (60% dispersion in mineral oil) were added to an ice cooled solution of 12.2 g (75.3 mmol) 1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-2-One (preparation: J.","Am.","Chem.","Soc.","1949, 71, 1985) in 350 ml DMF, stirred for 30 min.","at 0-5° C. and for 10 min.","at room temperature.","Then 11.5 g (75.3 mmol) methyl bromo acetic acid were added dropwise at 0° C. and it was then stirred for 30 min.","at the same temperature.","The reaction solution was poured onto 600 ml ice water and 3× extracted with each 150 ml ethyl acetate.","The organic phase was washed with a NaCl-solution, dried over MgSO4 and ethyl acetate was distilled off.","The residue was purified by column chromatography (eluent: CH2Cl2/CH3OH 9/1).","9.6 g of a yellowish oil were isolated; ESI-MS [M+H+]: 235.tert-butyl (2-oxo-2,3,4,6-tetrahydro-1H-1,5-benzodiazepine-1-yl)acetic acid (53) Preparation was carried out analogously to building block 52 by reaction of 11.99 (73 mmol) 1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-2-one with 14.3 g (73 mmol) tert-butyl bromo acetic acid.","17 g of a slightly yellowish oil were isolated; ESI-MS [M+H+]: 277.","[5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (54) a.)","14.2 g (102 mmol) powdered K2CO3 were added at 0° C. to a solution of 9.6 g (41 mmol) compound 52 and 8.09 (41 mmol) tert-butyl bromo acetic acid in 90 ml DMF, and stirred for 1 h at 0° C. and then for 14 h at room temperature.","The reaction mixture was poured onto 300 ml ice water and 3× extracted with each 100 ml methyl-tert.butyl ether.","The combined organic phases were washed several times with a NaCl-solution, dried over MgSO4 and evaporated to dryness.","The residue was purified by column chromatography (eluent: ethyl acetate/cyclohexane 7/3).","7.0 g of a slightly yellowish oil were isolated; ESI-MS [M+H+]: 349.b.)","The alkaline saponification of the methyl ester was carried out analogously to 3b.","3.8 g white crystals were obtained; Fp.",": 140-142° C.; ESI-MS [M+H+]: 335.","[5-(2-tert-Butoxy-2 oxoethyl)-4-oxo-2,3,4,6-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (55) Analogously to building block 54a tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl)acetic acid (53) was reacted with methyl bromoacetic acid and then alkaline saponified analogously to 3b.","After purification by column chromatography 2.9 g white crystals were obtained; Fp.",": 82-84° C.; ESI-MS [M+H+]: 335.","[1-(2-Methoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (56) 14.5 g (42 mmol) building block 3a were dissolved in 105 ml 4n HCl in dioxane and stirred for 2 days at 50° C. After evaporation of the solvent, the residue was dissolved in 5% NaHCO3-solution, 2× extracted with methyl-tert.butyl ether, then the watery phase was acidified with a 1n KHSO4-solution and the precipitating acid extracted with methyl-tert.butyl ether.","After drying over MgSO4, evaporation of the solvent and purification by column chromatography (eluent: CH2Cl2/CH3OH/glacial acetic acid 451511) 1.6 g of a viscous, slightly yellowish oil remained; ESI-MS [M+H+]: 292.","[(5R)-5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (57) 14.2 g (42.6 mmol) [5-(2-t.Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) were suspended in 170 ml diethylether and dissolved by addition of 7.3 g (42.64 mmol) (1S)-(−)-1-napthyl)ethylamine.","The yellow solution was inoculated with (1S)-1-napthyl)ethaneaminium[(5R)-5-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetate—prepared by preparative HPLC-separation of compound 3 by means of a chiral column (Chiralpak AD 500×; 50 mm; 20 μm) and subsequent salification-, the deposited precipitate filtered off with suction after 3.5 h and 3× recrystallized from a ethyl acetate/isopropanol mixture.","The purity of enantiomers was checked by means of a chiral HPLC.","3.5 g. of the salt were suspended in 30 ml of a diethylether/hexane-mixture 10/3 and after addition of 50 ml of a 5% watery amidosulfonic acid solution stirred until occurrence of a clear phase.","After separation of the watery phase, the organic phase was washed 3× with 5 ml amidosulfonic acid- and then with a NaCl-solution, dried over Na2SO4 and evaporated.","2.25 g amorphous residue; ESI-MS [M+H+]: 505.","[(5S)-5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (58) From the combined mother liquors of building block 57, 8 g of the acid were isolated as a yellowish amorphous residue as described with a amidosulfonic acid solution, said acid was reacted with (1R)-(+)-1-napthyl)ethyl amine into the diastereomeric salt and recrystallized until the achievement of enantiomeric purity.","Analogously to example 57, 2.5 g of the dextrorotatory acid were isolated as an amorphous solid, ESI-MS [M+H+]: 505.A sample of the acid was reacted with 4-bromobenzylamine into the good crystallizing amide and the absolute configuration figured out by means of a x-ray structure analysis.","tert-Butyl-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]azepine-8-yl)acetate (59) A solution of 5.3 g (29.2 mmol) 6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-dione (Arch.","Pharm.","1991 324, 579) and 12 g (32.2 mmol) (tert-butoxycarbonylmethylene)-triphenyl phosphorane in 15 ml toluen was heated to reflux for 10 h, then toluen was distilled off and the black residue purified by chromatography (eluent: ethyl acetate/cyclohexane 7/3).","The consistent fraction was again digested with 40 ml boiling cyclohexane, cooled and filtered with suction.","3 g yellowish crystals; ESI-MS [M+H+]: 280.tert-Butyl-(5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-8-yl)acetate (60) 39 (11 mol) tert-Butyl-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]azepine-8-yl)acetate were hydrogenated analogously to building block 2 in the presence of 10% Pd/C.","Since educt was still present after 6 h according to HPLC, the catalyst was filtered with suction and after addition of new catalyst it was again hydrogenated for 6 h. After workup and chromatographic purification (eluent: ethyl acetate/cyclohexane 7/3), 1.4 g yellowish crystals were isolated, which comprised according to HPLC still about 2.5% educt; ESI-MS [M+H+]: 282.","[8-(2-tert-Butoxy-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-4-yl]acetic acid (61) Preparation was carried out analogously to building block 50.Ester stage: 1.5 g yellowish crystals; ESI-MS [M+H+]: 354.Target product: 1.2 g yellowish crystals; ESI-MS [M+H+]: 340.I.B Compounds of the Formula I or I′ Example I t-Butyl [1-(2-{[(2-{[amino(imino)methyl]amino}-1,3-thiazol-5-yl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetate 1.1 g of N-methylmorpholine were added dropwise at 0° C. to 1.5 g (4.65 mmol) of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) and 1.22 g (4.8 mmol) of N-[5-(aminomethyl)-1,3-thiazol-2-yl]guanidine dihydrochloride (5) in 20 ml of DMF, and 1.55 g (4.7 mmol) of TOTU (O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetrafluoroborate) were then introduced in portions over the course of 35′.","The yellow reaction solution was stirred at 0° C. for 1 h and then largely evaporated in vacuo.","The residue was then digested a number of times with H2O, taken up in a mixture of 120 ml of ethyl acetate and 40 ml of diethyl ether, washed with 10% K2CO3 and NaCl solution, dried over Na2SO4 and concentrated, the crude product thoroughly crystallizing.","Purification by chromatography on silica gel (CH2Cl2/CH3OH/NH3 42:8:0.1) and crystallization from ethyl acetate/n-hexane afforded 1.45 g (65%) of white crystals.","M.p.",": 190-193° C. (dec.); FAB-MS [M+H+]: 487.Example II [1-(2-{[(2-{[Amino(imino)methyl]amino}-1,3-thiazol-5-yl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid 1.2 g of the t-butyl ester from Example I were suspended in 70 ml of CH2Cl2, treated with 45 ml of 4N HCl in dioxane and stirred overnight at RT.","The solution was evaporated, and the residue was digested a number of times with CH2Cl2 and then dried.","In this way, 1.07 g of a slightly yellowish amorphous powder were isolated; FAB-MS [M−H+]: 432.Example III [1-(2-{[4-(1H-Benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine hydrochloride (4) and subsequent removal of the t-butyl group analogously to Example II.","A slightly yellowish amorphous residue was obtained, FAB-MS [M−H+]: 554.Example IV t-Butyl [1-(2-{[(2-{[amino(imino)methyl]amino}-1,3-thiazol-5-yl)methyl]amino}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepin-5-yl]acetate Analogously to the preparation of compound 3a, 0.9 g (3.3 mmol) of t-butyl (2-oxo-2,3-dihydro-1H-1-benzazepin-5-yl)acetate (1) was alkylated with methyl bromoacetate (FAB-MS [M−H+]: 346) and then hydrolyzed analogously to 3b (0.44 g; FAB-MS [M−H+]: 332).","Coupling of 0.57 g (1.72 mmol) of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepin-1-yl]acetic acid with N-[5-(aminomethyl)-1,3-thiazol-2-yl]guanidine dihydrochloride (5) analogously to Example I afforded the title compound as a slightly yellowish powder; FAB-MS [M−H+]: 485.Example V [1-(2-{[(2-{[Amino(imino)methyl]amino}-1,3-thiazol-5-yl)methyl]amino}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepin-5-yl]acetic acid The t-butyl ester was removed analogously to Example II and afforded 0.42 g of the title compound as a slightly yellowish powder; FAB-MS [M−H+]: 429.Example VI (1-{2-[(4-{[(Benzylamino)carbonyl]amino}benzyl)amino]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-5-yl]acetic acid (3) with N-[4-(aminomethyl)phenyl]-N′-benzylurea (6) and subsequent removal of the t-butyl group analogously to Example II.","Purification of the crude product by elution through a silica gel cartridge (Chromasorb; CH2Cl2/CH3OH 0-20%) afforded 27 mg as an amorphous solid; ESI-MS [M+H+]: 515.2; [M+K+]: 553.2.Example VII [1-(2-{[4-(1H-Benzimidazol-2-yl)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with [4-(1H-benzimidazol-2-yl)phenyl]methaneamine (7) and subsequent cleavage of the t-butyl group analogously to Example II.","Purification of the crude product by elution through a silica gel cartridge (Chromasorb; CH2Cl2/CH3OH 0-20%) afforded 9 mg as an amorphous solid; ESI-MS [M+H+]: 485.2.Example VIII [1-(2-{[4-(1H-Benzimidazol-2-ylamino)butyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-5-yl]acetic acid (3) with N1-(1H-benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (9) and subsequent cleavage of the t-butyl group analogously to Example II.","After chromatographic purification on silica gel (eluent: CH2Cl2/CH3OH/50% acetic acid 42:8:0.7), 0.5 g was isolated as a slightly yellowish amorphous powder; FAB-MS [M−H+]: 464.Example IX [1-(2-{[5-(1H-Benzimidazol-2-ylamino)pentyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with N1-(1H-benzimidazol-2-yl)pentane-1,5-diamine (hydrochloride) (8) and subsequent cleavage of the t-butyl group analogously to Example II.","After chromatographic purification on silica gel (eluent: CH2Cl2/CH3OH/50% acetic acid 42:8:0.7), 0.48 g was isolated as a slightly yellowish amorphous powder; FAB-MS [M−H+]: 478.Example X {1-[2-({4-[(1H-Benzimidazol-2-ylamino)methyl]cyclohexyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl}acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with trans-N-[(4-aminocyclohexyl)methyl]-1H-benzimidazole-2-amine (dihydrochloride) (10) and subsequent cleavage of the t-butyl group analogously to Example II.","After chromatographic purification on silica gel, 0.7 g of slightly yellowish amorphous powder was isolated; FAB-MS [M+H+]: 504.Example XI {1-[2-({[4-(1H-Benzimidazol-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl}acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-5-yl]acetic acid (3) with trans-N-{[4-(aminomethyl)cyclohexyl]-1H-benzimidazole-2-amine (dihydrochloride) (11) and subsequent cleavage of the t-butyl group analogously to Example II.","After chromatographic purification on silica gel, 0.5 g of slightly yellowish amorphous powder was isolated; FAB-MS [M+H+]: 504.Example XII [2-Oxo-1-(2-oxo-2-{[4-(pyridin-2-ylamino)benzyl]amino}ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with N-[4-(aminomethyl)phenyl]-2-pyridineamine (13) and subsequent cleavage of the t-butyl group analogously to Example II (14 mg); ESI-MS [M+H+]: 459.15.Example XIII {1-[2-({[6-(1H-Benzimidazol-2-yl)pyridin-3-yl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl}acetic acid (bishydrochloride) Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with [6-(1H-benzimidazol-2-yl)pyridin-3-yl]methaneamine (trifluoroacetate) (12) and subsequent cleavage of the t-butyl group analogously to Example II.","(13 mg); ESI-MS [M+H+]: 484.15.Compounds of the general formula I analogously to example II were prepared: Example 14 {2-Oxo-1-[2-oxo-2-({4-[(pyridine-2-ylamino)methyl]benzyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Under utilization of N-[4-(aminomethyl)benzyl]-2-pyridine amine (14) as educt, 207 mg as an amorphous solid were obtained according to MPLC 207 mg; ESI-MS [M+H+]: 473.28.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.5 (m, 1H), 7.95 (d, 1H), 7.45 (m, 1H), 7.35-72.0 (m, 9H), 6.60 (m, 2H), 4.45 (m, 3H), 4.25 (m, 3H), 3.55 (m, 1H), 2.70 (m, 2H), 2.35 (m, 1H), 2.20 (m, 2H), 1.65 (m 1H).","Example 15 {1-[2-({[5-(1H-Benzimidazole-2-yl)thiene-2-yl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Under utilization of [5-(1H-benzimidazole-2-yl)thiene-2-yl]methaneamine (15) as educt, 210 mg as amorphous white solids were obtained according to MPLC; ESI-MS [M+H+]: 489.27.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.80 (m, 1H), 7.70 (m, 1H), 7.65 (m, 2H), 7.35-7.15 (m, 6H), 7.05 (m, 1H), 4.55 (m, 3H), 4.20 (m, 1H), 3.55 (m, 1H), 2.75 (m, 2H), 2.35 (m, 1H), 2.15 (m, 2H), 1.65 (m, 1H).","Example 16 {1-[2-({2-[4-(1H-Benzimidazole-2-yl)phenyl]ethyl}amino)-2-oxoethyl]-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Under utilization of tert-butyl-2-[4-(1H-benzimidazole-2-yl)phenyl]ethylcarbamate (16) as educt, 190 mg as amorphous white solids were obtained according to MPLC; ESI-MS [M+H+]: 497.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.15 (d, 2H), 7.65 (d, 2H), 7.45 (m, 2H), 7.30-7.15 (m, 6H), 4.45 and 4.15 (each m, 1H), 3.6-3.25 (m, superimposed by H2O), 2.80 (m, 2H), 2.70 (m, 2H), 2.35 (m, 1H), 2.20 (m, 2H), 1.70 (m, 1H).","Example 17 [1-(2-{4-[(1H-Benzimidazole-2-ylamino)methyl]piperidine-1-yl}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Under utilization of (3 N-(piperidine-4-ylmethyl)-1H-benzimidazole-2-amine (trifluoro acetate) (17) as educt, 134 mg as amorphous white solids were obtained according to MPLC; ESI-MS [M+H+]: 490.29.Example 18 [2-Oxo-1-(2-oxo-2-{[2-(pyridine-2-ylamino)ethyl]amino}ethyl)-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Under utilization of N1-pyridine-2-ylethane-1,2-diamine, the subsequent MPLC afforded 278 mg as amorphous white solids; ESI-MS [M+H+]: 397.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.20 (m, 1H), 7.95 (m, 1H), 7.70 (m, 2H), 7.35-7.20 (m, 4H) 6.80 and 6.70 (each m, 1H), 4.45 and 4.15 (each m, 1H), 3.70-3.0 (m, superimposed by H2O), 2.70 (m, 2H), 2.30 (m, 1H), 2.15 (m, 2H), 1.60 (m, 1H).","Example 19 (2-Oxo-1-{2-oxo-2-[({4-[(pyridine-2-ylamino)methyl]thiene-2-yl}methyl)amino]ethyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Under utilization of N-{[5-(aminomethyl)thiene-3-yl]methyl}pyridine-2-amine (trifluoro acetate) (18), the subsequent MPLC afforded 135 mg as amorphous white solids; ESI-MS [M+H+]: 479.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.65 (m, 1H), 8.0 (m, 1H), 7.45 (m, 1H), 7.35-7.15 (m, 6H), 6.95 (s, 1H), 6.60 and 6.55 (each m, 1H), 4.60-4.30 (m, 5H), 4.15 (m 1H), 3.50 (m, 1H), 2.80-2.60 (m, 2H), 2.35 (m, 1H), 2.15 (m, 2H), 1.70 (m, 1H).","Example 20 [1-(2-{[3-(1H-imidazole-2-ylamino)-3-oxopropyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Under utilization of 3-amino-N-(1H-imidazole-2-yl)propane amide (19) and following purification of the raw product by MPLC 50 mg were obtained as amorphous white solids; ESI-MS [M+H+]: 414.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.20 (m, 1H), 7.30-7.20 (m, 7H), 4.45 and 4.15 (each m, 1H), 3.75-3.25 (m, superimposed by H2O), 2.80-2.65 (m, 4H), 2.35 (m, 1H), 2.15 (m, 2H), 1.60 (m, 1H).","Example 21 [1-(2-{[4-(4,5-Dihydro-1H-imidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Under utilization of N-[4-(aminomethyl)-phenyl]-4,5-dihydro-1H-imidazole-2-amine (hydrochloride) (20) as educt, 12 mg were obtained as amorphous white solids after MPLC; ESI-MS [M+H+]: 450.3.Example 22 (1-{2-[({4-[(1H-Benzimidazole-2-ylamino)methyl]thiene-2-yl}methyl)amino]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-6-yl)acetic acid Utilization of N-{[5-(aminomethyl)thiene-3-yl]methyl}-1H-benzimidazole-2-amine (hydrochloride) (21) as educt; purification by MPLC afforded 90 mg; ESI-MS [M+H+]: 518.29.Example 23 [2-Oxo-1-(2-oxo-2-{[5-(pyridine-2-ylamino)pentyl]amino}ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Utilization of N1-pyridine-2-ylpentane-1,5-diamine (hydrochloride) (22) as educt; after MPLC, 210 mg white solids were obtained; ESI-MS [M+H+]: 439.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.05 (m, 1H), 7.95 (m, 1H), 7.75 (m broad, 1H), 7.65 (m, 1H), 7.30-7.15 (m, 4H), 6.75 and 6.60 (each m, 1H), 4.45 and 4.15 (each m, 1H), 3.70-3.20 (m, superimposed by H2O), 2.70 (m, 2H), 2.35 (m, 1H), 2.15 (m, 2H), 1.60, 1.45 and 1.30 (each m, 2H).","Example 24 N-[5-({[5-(Carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)pentyl]-4,5-dihydro-1H-imidazole-2-amine (acetate) Utilization of N1-(4,5-Dihydro-1H-imidazole-2-yl)pentane-1,5-diamine (hydrochloride) (23) as educt; 22 mg were obtained after MPLC; ESI-MS [M+H+]: 430.15.Example 25 [1-(2-{[4-(1H-imidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Utilization of N-[4-(aminomethyl)phenyl]-1H-imidazole-2-amine (24) as educt; purification by means of MPLC afforded 40 mg; ESI-MS [M+H+]: 448.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.95 (s, 1H), 8.45 (m, 1H), 7.35-7.10 (m, 8H), 6.75 (s, 2H), 4.50 (m, 1H), 4.20 (m, 3H), 3.5-3.1 (m, superimposed by H2O).","2.70 (m, 1H), 2.35 (m 1H), 2.20 (m, 2H), 1.65 (m, 1H).","Example 26 [2-Oxo-1-(2-oxo-2-{[1-(1,4,6,6-tetrahydropyrimidine-2-ylamino)pentyl]amino}ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Utilization of N1-(1,4,5,6-tetrahydropyrimidine-2-yl)pentane-1,5-diamine (hydrochloride) (26) as educt; 40 mg were obtained after MPLC; ESI-MS [M+H+]: 444.9.Example 27 {2-Oxo-1-[2-oxo-2-({[4-(pyridine-2-ylamino)cyclohexyl]methyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Utilization of N-[4-(aminomethyl)cyclohexyl]pyridine-2-amine (hydrochloride) (26), purification by means of an elution over a Chromabond-C18-cartridge afforded 85 mg; ESI-MS [M+H+]: 465.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.55 (s broad, 1H), 8.05 (m, 1H), 7.90 (d, 1H), 7.85 (m, 1H), 7.35 (m, 2H), 7.25 (m, 2H), 6.95 (d, 1H), 6.80 (m, 1H), 4.40 and 4.20 (each m 1H), 3.55 (m, superimposed by H2O), 2.95 (m, 2H), 2.70 (m, 2H), 2.35 (m, 1H), 2.15, 1.95 and 1.75 (each m, 2H), 1.60 and 1.40 (each m, 1H), 1.25 (m, 2H), 1.05 (m, 2H).","Example 28 Ethyl-{2-oxo-1-[2-oxo-2-({[4-(pyridine-2-ylamino)cyclohexyl]methyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 30 ml 4n HCl in dioxane were added to 100 mg {2-oxo-1-[2-oxo-2-({[4-(pyridine-2-ylamino)cyclohexyl]methyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid in 10 ml EtOH and it was stirred for 48 h at RT.","Evaporation and elution over a Chromabond-C8-cartridge afforded 26 mg; ESI-MS [M+H+]: 493.25.Example 29 (1-{4-[4-(1H-Benzimidazole-2-ylamino)phenyl]butyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid a.)","A solution of t-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (2) (0.8 g; 2.91 mmol) in 20 ml DMF was added dropwise at 0° C. to a suspension of 0.169 NaH (60%; deoiled) in 10 ml DMF and stirred for 1 h. A spatula tip full of KI was then added likewise at 0° C., 1 g 1-(4-bromo butyl)-4-nitrobenzene (preparation according to J. Med.","Chem.","38, 13 (1995), 2418-2420)—dissolved in 10 ml DMF—was slowly added dropwise and stirred for 2 h at RT.","For workup, water was carefully added to the reaction mixture, it was diluted with CH2Cl2 and several times extracted with a saturated NaCl-solution.","After drying and evaporation, the obtained raw product was purified by chromatography on silica gel (CH2Cl2/CH3OH 2-10%); 0.429 yellow oil, ESI-MS [M+H+-Boc]: 397.15.b.)","Hydrogenation of the nitro group in 75 ml CH3OH with 100 mg 10% Pd on activated carbon under standard conditions afforded 0.36 mg of a bright oil; ESI-MS [M+H+]: 423.25.c.)","The build-up of the corresponding aminobenzimidazole was carried out analogously to the preparation of 17 by reaction with thiocarbonyldiimidazole, imidazole and then phenylene diamine.","Chromatography on silica gel (CH2Cl2/CH3OH 2-4%) afforded 220 mg of a bright foam; ESI-MS [M+H+]: 539.25.d.)","200 mg tert-Butyl-(1-(4-[4-(1H-benzimidazole-2-ylamino)phenyl]butyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate was treated at RT with 10 ml TFA.","Evaporation and lyophilizing the obtained oil afforded 213 mg of a solid; ESI-MS [M+H+]: 483.25.Example 30 2-(4-{[{[5-(Carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}(methyl)amino]methyl}anilino)-1H-benzimidazole (trifluoro acetate) a.)","Standard coupling of [5-(2-t.Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) (2.2 g; 6.6 mmol) with 1.32 g N-methyl(4-nitrophenyl)methane amine (J.","Am.","Chem.","Soc.","65 (1943), 1984-1990) in 40 ml CH2Cl2 under utilization of HATU as a coupling reagent and ethyldiisopropylamine as a base.","Subsequent chromatography of the raw product on silica gel (CH2Cl2/CH3OH 2-4%) afforded 2.269 of a slightly yellow oil; ESI-MS [M+H+]: 482.03.1H-NMR (360 MHz, d6-DMSO) δ ppm (Rotamers): 8.25/8.20 (d, 2H), 7.60/7.50 (d, 2H), 7.35-7.20 (m, 4H), 4.85-4.5 (m, 4H), 3.05/2.85 (s, 3H), 2.70 (m, 1H), 2.30 (m, 1H), 2.15 (m, 2H), 1.65 (m, 1H), 1.30 (s, 9H).","b.)","5 ml Hydrazine hydrate were added at 60° C. to 1.26 g nitro compound a and 15 mg FeCl3×6H2O in 20 ml CH3OH and for 1 h stirred at 60° C. The mixture was filtered over Celite and the filtrate evaporated.","1.17 g; ESI-MS [M+H+]: 452.17.c.)","The build-up of the respective aminobenzimidazole was carried out analogously to the preparation of 17 by reaction with thiocarbonyldiimidazole, imidazole and phenylene diamine, subsequently.","Chromatography on silica gel (CH2Cl2/CH3OH 4-7.5%) afforded 0.9 g of a slightly beige foam; ESI-MS [M+H+]: 568.25.d.)","Cleavage of the t-butylester with 50 ml TFA and subsequent purification by chromatography on silica gel (CH2Cl2/CH3OH 8-10%) afforded 0.88 g; ESI-MS [M+H+]: 512.25.1H-NMR (360 MHz, d6-DMSO) δ ppm (Rotamers): 11.05 (broad, 1H), 7.60-7.20 (m, 1.2H), 4.85 (m, 1H), 4.75-4.45 (m, 3H), 3.65 (m, 1H), 3.20 (s, 3H), 2.70 (m, 2H), 2.35 (m, 1H), 2.20 (m, 2H), 1.65 (m, 1H).","Example 31 tert-Butyl-[1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate Coupling of [5-(2-tert-butoxy-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (28) with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) analogously to I and purification by chromatography on silica gel (CH2Cl2/CH3OH 2-3%) afforded 200 mg of a beige foam; ESI-MS [M+H+]: 540.25.Example 32 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) TFA-cleavage of tert-butyl-[1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate afforded 240 mg; ESI-MS [M+H+]: 484.36.1H-NMR (360 MHz, d6-DMSO) δ ppm (Rotamers): 11.10 (s, 1H), 8.30 (t, 1H), 7.5-7.25 (m, 8H), 7.15 (m, 2H), 6.85 (m, 2H), 4.40 (m, 2H), 3.75-3.55 (m, superimposed by H2O), 3.5 (m, 1H), 3.0 (m, 1H), 2.70 (m, 2H), 1.70 (m, 2H), 1.45 (m, 1H).","Example 33 tert-Butyl-{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate Preparation analogously to example 31 starting from [5-(2-tert-butoxy-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (28) and trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11).","410 mg of a white foam; ESI-MS [M+H+]: 546.35.Example 34 {1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (trifluoro acetate) Analogously to example 32; 420 mg of white solids; ESI-MS [M+H+]: 490.47.1H-NMR (360 MHz, d6-DMSO) δ ppm: 9.0 (d, 1H), 7.65 (m, 1H), 7.40 and 7.30 (each m, 2H), 7.15 and 6.85 (each m, 2H), 3.80 (m, 2H), 3.50 (m, 1H), 3.0 (m, 4H), 2.75 (m, 2H), 2.0 (m, 2H), 1.75-1.50 (m, 5H), 1.50-1.20 (m, 5H), 0.95 (m, 2H).","Example 35 tert-Butyl-[1-(2-{[5-(1H-benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetate Preparation analogously to example 31 starting from [5-(2-tert-butoxy-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (28) and N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8).","300 mg of a foam; ESI-MS [M+H+]: 520.39.Example 36 [1-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Cleavage of the t-butyl ester from example 35 with 15 ml 4nHCl in dioxane afforded 300 mg solid; ESI-MS [M+H+]: 464.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 9.10 (m, 1H), 7.70 (m, 1H), 7.35, 7.25, 7.10 and 6.85 (each m, 2H), 4.75 (m 2H), 3.30, 3.15, 2.95, 2.70 (each m, 2H), 1.65 (m, 5H), 1.45 and 1.30 (each m, 2H).","Example 37 tert-Butyl-{1-[2-({[4-(1H-imidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate Preparation analogously to example I under utilization of N-[4-(aminomethyl)cyclohexyl]-1H-imidazole-2-amine (hydrobromide) (29) as educt; chromatography on silica gel (CH2Cl2/CH3OH 4-15%) afforded 530 mg of a solid foam; ESI-MS [M+H+]: 510.35.Example 38 {1-[2-({[4-(1H-Imidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (acetate) Cleavage of the t-butyl ester from example 37 mit TFA and subsequent purification by means of chromatography on silica gel (CH2Cl2/CH3OH 10-15%+2% glacial acetic acid) afforded 570 mg; ESI-MS [M+H+]: 454.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.0 (broad, 1H), 7.30 and 7.25 (each m, 2H), 6.80 (broad, 1H), 6.70 (s, 2H), 4.40 and 4.20 (each broad, 1H), 4.75-4.25 (superimposed by H2O), 3.0 (m, 2H), 2.65 (m, 2H), 2.35 (m, 1H), 2.15 (m, 2H), 1.95 (m, 1H), 1.75 (m, 2H), 1.60 and 1.35 (each m, 1H), 1.20 (m, 4H), 0.95 (m, 2H).","Example 39 tert-Butyl-(2-oxo-1-{[4-({4-[(pyridine-2-ylamino)methyl]piperidine-1-yl}carbonyl)-1,3-thiazole-2-yl]methyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate Standard coupling of 2-{[5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]methyl}-1,3-thiazole-4-carbonic acid (32) (0.5 g; 1.2 mmol) with N-(piperidine-4-ylmethyl)pyridine-2-amine (hydrochloride; accessibly from 29) in 15 ml CH2Cl2 under utilization of HATU as a coupling reagent and ethyldiisopropylamine as a base.","Subsequent chromatography of the raw product on silica gel (CH2Cl2/CH3OH 3-20%) afforded 0.44 g of a slightly yellow oil; ESI-MS [M+H+]: 590.35.Example 40 (2-Oxo-1-{[4-({4-[(pyridine-2-ylamino)methyl]piperidine-1-yl}carbonyl)-1,3-thiazole-2-yl]methyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Cleavage of the t-butylester of example 31 with TFA afforded 385 mg; ESI-MS [M+H+]: 534.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.05 (s, 1H), 7.90 (m, 2H), 7.55 (m, 1H), 7.35 (m, 1H), 7.25 (m, 2H), 7.05 and 6.80 (each m, 1H), 5.40-5.20 (m, 2H), 4.20 and 4.0 (each m, 1H), 3.25 (m, 2H), 2.95 (m, 1H), 2.80-2.60 (m, 3H), 2.30 (m, 1H), 2.25-2.05 (m, 2H), 1.80 and 1.65 (each m, 2H), 1.20-1.10 (m, 3H).","Example 41 tert-Butyl-[1-({4-[({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino) carbonyl]-1,3-thiazole-2-yl}methyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetate Analogously to example 29 under utilization of trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11) as educt; chromatography of the raw product on silica gel (CH2Cl2/CH3OH 5-8%) afforded 350 mg of a bright yellow oil; ESI-MS [M+H+]: 643.45.Example 42 [1-({4-[({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)carbonyl]-1,3-thiazole-2-yl}methyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Cleavage of the t-butylester of example 31 and purification by elution over Chromabond-C18 (acetonitrile/H2O 10-80%+0.1% glacial acetic acid) afforded 300 mg; ESI-MS [M+H+]: 587.35.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.40 (broad, 1H), 8.20 (m, 1H), 8.20 (s, 1H), 7.35-7.20 (m, 5H), 7.15 (m, 2H), 5.40 and 5.25 (each d, 1H), 3.15 (m, superimposed by H2O), 2.80-2.60 (m, 2H), 2.35 (m, 1H), 2.20 (m, 2H), 2.05 and 1.80 (each m, 2H), 1.65, 1.30 and 1.15 (each m, 2H).","Example 43 tert-Butyl-(1-{[4 ({4-[(1H-benzimidazole-2-ylamino)methyl]piperidine-1-yl}carbonyl)-1,3-thiazole-2-yl]methyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate 430 mg were obtained analogously to example 29 under utilization of N-(piperidine-4-ylmethyl)-1H-benzimidazole-2-amine (trifluoro acetate) (17) and subsequent purification; ESI-MS [M+H+]: 629.45.Example 44 (1-{[4-({4-[(1H-Benzimidazole-2-ylamino)methyl]piperidine-1-yl}carbonyl)-1,3-thiazole-2-yl]methyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Cleavage of the t-butylester of example 43 and purification by elution over Chromabond-C18 (acetonitrile/H2O 10-80%+0.1% glacial acetic acid) afforded 340 mg; ESI-MS [M+H+]: 573.35.1H-NMR (360 MHz, d-DMSO) δ ppm: 9.20 (m, 1H), 7.95 (s, 1H), 7.45 (m, 1H), 7.40 (m, 2H), 7.30-7.15 (m, 5H), 5.35-5.10 (m, 2H), 4.45 (m, 1H), 4.0-3.25 (m, superimposed by H2O), 2.95 (m, 1H), 2.8-2.60 (m, 2H), 2.30 and 2.20 (each m, 1H), 2.0-1.75 (m, 3H), 1.70-1.50 (m, 2H), 1.20 (m, 3H).","Example 45 tert-Butyl-{2-oxo-1-[(4-{[({4-[(pyridine-2-ylamino)methyl]thiene-2-yl}methyl)amino]carbonyl}-1,3-thiazole-2-yl)methyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 330 mg were obtained analogously to example 39 under utilization of N-{[5-(aminomethyl)thiene-3-yl]methyl}pyridine-2-amine (trifluoro acetate) (18) and purification; ESI-MS [M+H+]: 618.25.Example 46 {2-Oxo-1-[(4-{([{4-[(pyridine-2-ylamino)methyl]thiene-2-yl}methyl)amino]carbonyl}-1,3-thiazole-2-yl)methyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Cleavage of the t-butylesters of example 45 and purification by means of MPLC afforded 150 mg; ESI-MS [M+H+]: 562.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.80 (m, 1H), 8.20 (m, 1H), 8.0 (d, 1H), 7.50 (d, 1H), 7.30-7.20 (m, 4H), 7.10 and 6.95 (each s, 1H), 6.85 (m, 1H), 6.50 (m, 2H), 5.40 and 5.20 (each d, 1H), 4.55 and 4.35 (each m, 2H), 2.80-2.55 (m, 2H), 2.30 (m, 1H), 2.20 (m, 2H), 1.65 (m, 1H).","Example 47 tert-Butyl-[1-({4-[4-(1H-benzimidazole-2-ylamino)phenyl]-1,3-thiazole-2-yl}methyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate a.)","A mixture of 1.5 g tert-butyl-[1-(2-amino-2-thioxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate, 1.36 g 2-bromo-4-nitroacetophenone and 0.65 g KHCO3 in 30 ml dioxane were stirred for 12 h at RT.","Workup analogously to building block 30c and mixing of the raw product with n-pentane afforded 2.1 g of a brown solid; ESI-MS [M+H+]: 494.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.40 (s, 1H), 8.30 and 8.20 (each m, 2H), 7.60 and 7.35 (each m, 1H), 7.25 (m, 2H), 5.50 and 5.30 (each d, 1H), 2.70 (m, 2H), 2.30 (m, 1H), 2.20 (m, 3H), 1.65 (m, 1H), 1.25 (s, 9H).","b.)","Reduction of the nitro group analogously to example 30b (1.6 g; ESI-MS [M+H+]: 464.15) and build-up of the aminobenzimidazole as already described afforded after chromatography on silica gel (CH2Cl2/CH3OH 24%) 0.58 g of a slightly yellow foam; ESI-MS [M+H+]: 614.35.Example 48 [1-({4-[4-(1H-Benzimidazole-2-ylamino)phenyl]-1,3-thiazole-2-yl}methyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Cleavage of the t-butylester of example XXXXVII and purification by means of MPLC afforded 40 mg; ESI-MS [M+H+]: 524.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 11.95 and 9.60 (each broad, 1H), 7.85-7.75 (m, 4H), 7.65 (m, 1H), 7.40-7.25 (m, 5H), 7.0 (m, 2H), 5.40 and 5.30 (each d, 1H), 3.50 (m, 1H), 2.75 (m, 1H), 2.45 (m, 2H), 2.20 (m, 2H), 1.70 (m, 1H).","Example 49 tert-Butyl (1-{2-[(4{[amino(imino)methyl]amino}benzyl)amino]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Ethyldiisopropylamine (0.42 mmol, 54.50 mg) and HATU (0.50 mmol, 190.11 mg) were added at 0° C. to a solution of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) (0.42 mmol, 140.59 mg) in CH2Cl2 (10 ml), the mixture was stirred for 1 h at 0° C. and [4-(aminomethyl)phenyl]guanidine (bihydrochloride) (46) (0.42 mmol, 100 mg), ethyldiisopropylamine (0.63 mmol, 81.76 mg) added.","The mixture was stirred for 1 h at 0° C. and overnight at RT.","After evaporation, the residue was taken up in CH2Cl2/water, washed with watery NaHCO3—, 5%-citric acid- and finally with watery saturated NaCl-solution.","Evaporation and chromatography on silica gel (CH2Cl2/CH3OH 0-100%) afforded 6.0 mg target product; ESI-MS [M+H+]: 426.1, 425.1.Example 50 {4-[({[5-(Carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)methyl]anilino}(imino)methaneamine (trifluoro acetate) tert-Butyl-({2-[(4{[amino(imino)methyl]amino}benzyl)amino]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (example 49, 0.01 mmol, 6 mg) was dissolved in 5 ml CH2Cl2, TFA (1.25 mmol, 142.53 mg) added at 0° C. and stirred overnight at room temperature.","After evaporation, the residue was taken up in CHCl3/water and the watery phase washed with CHCl3; evaporation of the watery phase affords 4.8 mg target product; ESI-MS [M+H+]=425.1.Example 51 tert-Butyl [1-(2-{[(6-amino-2-pyridinyl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Analogously to example 49, under utilization of 2-ammonio-6-(ammonio methyl)pyridinium trichloride (33) (0.30 mmol, 69.76 mg) and following purification and subsequent purification (chromatography; CH2Cl2/MeOH 0-100%) afforded 120 mg of the target product; ESI-MS: [M+H+]=439.28, 383.36.Example 52 [1-(2-{([(6-Amino-2-pyridinyl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (hydrochloride) Cleavage of the t-butylester, chromatography of the raw product (CHCl3/MeOH 0-5%) and ester interchange with HCl in diethyl ether afforded 15.0 mg; the target product as hydrochloride; ESI-MS [M+H+]=383.1.Example 53 tert-Butyl [1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid 2 Drops of a solution of HCl in diethylether were added to N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) (0.63 mmol, 196.10 mg) in methanol (40 mL) and stirred for 5 min.","at RT.","tert-Butyl.","[2-oxo-1-(2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (37, 0.63 mmol, 0.20 g) was added, NaBH3CN (3 mmol, 188.5 mg) portionwise added after 10 min.","and the mixture stirred for 17 h at RT.","After evaporation, the residue was taken up in ethyl acetate and washed with NaHCO3— (pH 8-9), saturated NaCl— (1×) and a 10% FeSO4-solution (2×).","Chromatography (CHCl3/MeOH 0-5%) afforded 84 mg of the target product; ESI-MS [M+H+]=540.24, 270.75.Example 54 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}ethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Cleavage of the t-butylester and chromatography (CHCl3/MeOH 0-100%) afforded 4 mg of the target product; ESI-MS [M+H+]=484.1.Example 55 tert-Butyl [1-(2-{[(4-{[(benzylamino)carbonyl]amino}cyclohexyl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Analogously to example 49 under utilization of N-[4-(aminomethyl)cyclohexyl]-N′-benzyl urea (34) (0.50 mmol, 130 mg) afforded 320 mg; ESI-MS [M+H+]=577.11.Example 56 [1-(2-{[(4-{[(Benzylamino)carbonyl]amino}cyclohexyl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Analogous cleavage of the t-butylester afforded a raw product which after evaporation was distributed between ethyl acetate/water.","The watery phase was then adjusted to pH 10 with 0.1n NaOH and extracted with ethyl acetate.","It was adjusted then with 1nN HCl to pH4, extracted with CH2Cl2, washed and evaporated; 80 mg; ESI-MS [M+H+]=521.3.Example 57 tert-Butyl [1-(2-{[5-(1H-benzimidazole-2-ylamino)pentyl]amino}ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Preparation analogously to example 53 under utilization of N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8) (0.63 mmol, 183.47 mg) and tert-butyl [2-oxo-1-(2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (37, 0.63 mmol, 0.20 g) afforded 50.0 mg of the target product; ESI-MS [M+H+]=520.41, 260.79.Example 58 [1-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) tert-Butyl [1-(2-{[5-(1H-benzimidazole-2-ylamino)pentyl]amino}ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (example 57, 0.04 mmol, 20.00 mg) was dissolved in 5 ml CH2Cl2, TFA (65.34 mmol, 7.45 g) added at 0° C. and stirred overnight at room temperature.","Evaporation of the reaction mixture, chromatography (CHCl3/MeOH 0-100%) afforded 10 mg of the target product; ESI-MS [M+H+]=464.25.Example 59 tert-Butyl {2-oxo-1-[2-({[4-({4-[(1Z)-1-propenyl]-5-vinyl-1H-imidazole-2-yl}amino)cyclohexyl]methyl}amino)ethyl]-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Preparation analogously to example 53 under utilization of ethyldiisopropylamine and EDCI*HCl starting from trans-N-[[4-(aminomethyl)cyclohexyl]-1H-benzimidazole-2-amine (dihydrochloride) (11) (0.63 mmol, 0.209) afforded 84 mg; ESI-MS [M+H+]=546.32, 273.79.Example 60 {1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)ethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (trifluoro acetate) tert-Butyl {2-oxo-1-[2-({[4-({4-[(1Z)-1-propenyl]-5-vinyl-1H-imidazole-2-yl}amino)cyclohexyl]methyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (example 59, 0.01 mmol, 8 mg) was dissolved in 5 ml CH2Cl2, TFA (65.34 mmol, 7.45 g) added at 0° C. and stirred overnight at room temperature.","The reaction mixture was evaporated, the watery phase washed with a 3:1 mixture CHCl3/EtOH.","Evaporation of the watery phase afforded 6.0 mg of the target product; ESI-MS [M+H+]=490.25.Example 61 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) Coupling analogously to example 49 starting from N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) (1.70 mmol, 467.08 mg) and [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (1.63 mmol, 600 mg).","TFA (1.73 mmol, 197.72 mg) was added at 0° C. to the obtained raw product and it was stirred overnight at room temperature.","After evaporation, the residue was distributed between ethyl acetate and water, the watery phase adjusted to pH 10 with 2n NaOH and extracted with ethyl acetate; purification by means of MPLC afforded 90 mg of the target product as TFA-salt; ESI-MS [M+K+]=570.2, 534.2, 532.2, 266.5, 101.1.Example 62 [1-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) Coupling analogously to example 49 starting from N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8) (1.7 mmol, 433.10 mg) and [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (1.63 mmol, 600.00 mg).","Treatment of the raw product with TFA analogously to example 61 afforded 48 mg as a TFA-salt; ESI-MS: 514.2, 512.2, 101.2.Example 63 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)butyl]amino}-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Coupling analogously to example 49 starting from N1-(1H-benzimidazole-2-yl)butane-1,4-diamine (trifluoro acetate) (9) (1.7 mmol, 541.1 mg) and [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (1.63 mmol, 600 mg).","Treatment of the raw product with TFA analogously to example 61 afforded 15 mg as a TFA-salt; ESI-MS: 536.2, 500.1, 498.2, 105.1, 101.2.Example 64 [7-Chloro-1-(2-{[5-(4,5-dihydro-1H-imidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) Coupling analogously to example 49 starting from N1-(4,5-dihydro-1H-imidazole-2-yl)pentane-1,5-diamine (hydrochloride) (23) (1.70 mmol, 351.43 mg) and [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (1.63 mmol, 600 mg).","Treatment of the raw product with TFA analogously to example 61 afforded 85 mg as a TFA-salt; ESI-MS: 464.15.Example 65 tert-Butyl 7-[4-({[5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)butyl]-3,4-dihydro[1,8]naphthyridine-1(2H)-carboxylate Ethyldiisopropylamine (2.08 mmol, 268.41 mg) and EDCI*HCl (0.78 mmol, 150.44 mg) were added at 0° C. to a solution of [5-(2-t.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) (0.46 mmol, 0.15 g) in CH3CN (45 ml).","After 1 h at 0° C., 7-(4-aminobutyl)-1,2,3,4-tetrahydro[1,8]naphthyridine (bitrifluoro acetate) (35) (0.46 mmol, 0.2 g) was added, stirred for 1 h at 0° C. and overnight at RT.","Since by chromatography a purification could not be achieved, the obtained was reacted to the corresponding Boc-derivative according to standard methods.","Chromatography (heptane/CH2Cl2 0-100%, CH2Cl2/MeOH 0-100%) afforded 15 mg of the target product (about 95% purity); ESI-MS [M+Na+]: 643.5, 622.5, [M+H+]=621.5.Example 66 7-[4-({[5-(Carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)butyl]-1,2,3,4-tetrahydro[1,8]naphthyridine (trifluoro acetate) tert-Butyl 7-[4-({[5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)butyl]-3,4-dihydro[1,8]naphthyridine-1(2H)-carboxylate (example 65; 0.02 mmol, 15 mg) was dissolved in 2 ml CH2Cl2, TFA (0.53 mmol, 60.7 mg) added at 0° C. and stirred overnight at RT.","Usual workup afforded 9.3 mg of the target product as TFA-salt; ESI-MS: 466.2, [M+H+]=465.2, 233.3.Example 67 N-{4-[({[5-(Carboxymethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)methyl]cyclohexyl})-1H-benzimidazole (acetate) Coupling analogously to example 49 starting from trans-N-[4-(aminomethyl)cyclohexyl]-1H-benzimidazole-2-amine (dihydrochloride) (11) (2.99 mmol, 948.78 mg) and [5-(2-tert-butoxy-2-oxoethyl) 7 chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (2.72 mmol, 1.00 g) afforded 760 mg raw product.","Treatment of the raw product with TFA analogously to example 61 and purification of the raw product by means of MPLC afforded 400 mg; ESI-MS: [M+H+]=540.3, 538.25, 269.6, 101.1.Example 68 Ethyl-{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 15 ml HCl in diethyl ether (saturated at 0° C.) were added to 300 mg {1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2,3,4,5-tetrahydro-1H-1-1-benzazepine-5-yl}acetic acid in 30 ml ethyl alcohol and allowed to stand for 3 days at room temperature.","The mixture was evaporated, the remaining residue purified by chromatography on silica gel (CH2Cl2/CH3OH 5%+1% glacial acetic acid) and lyophilized.","230 mg; ESI-MS: [M+H+]=518.35.Example 69 {1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (acetate) Standard coupling of [5-(2-tert-butoxy-2-oxoethyl)-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetate (building block 49) (1 g; 2.54 mmol) with trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11); after chromatography on silica gel (CH2Cl2/CH3OH 5-7%), 1.03 g were isolated as a white glass; ESI-MS: [M+H+]=620.35.Cleavage of the ester under utilization of TFA and subsequent purification of the raw product by chromatography on silica gel (CH2Cl2/CH3OH 10%+2% glacial acetic acid) afforded 0.8 g of the target product; ESI-MS: [M+H+]=564.25.Example 70 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Standard coupling of [5-(2-tert-butoxy-2-oxoethyl)-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetate (building block 49) (0.5 g; 1.27 mmol) with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4); after chromatography on silica gel (CH2Cl2/CH3OH 3-5%) 0.67 g were isolated as a foam; ESI-MS: [M+H+]=614.35.Cleavage of the ester under utilization of TFA and lyophilization of the obtained product afforded 0.61 g; ESI-MS: [M+H+]=558.35.Example 80 {5-[2-({[4-(1H-Benzimidazole-2-yl)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3-dihydro-1H-1-benzazepine-1-yl}acetic acid 0.4 g (1.4 mmol) [1-(2-Methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) and 0.37 g (1.4 mmol) [4-(1H-benzimidazole-2-yl)cyclohexyl]methane amine (hydrochloride) (51) were reacted analogously to example I, the reaction product then purified by means of preparative thick-layer chromatography (eluent: CH2Cl2/CH3OH/conc.","NH3 45/5/0.2) and then the methyl ester cleaved with 0.8 ml 1n NaOH in 8 ml dioxane at room temperature.","After neutralization with 1n HCl, evaporation of the solvent, extraction with ethyl acetate and drying with Na2SO4, the raw product was purified by chromatography (CH2Cl2/CH3OH/50% glacial acetic acid 20/5/1).","After lyophilization, 0.22 g remained as a white amorphous residue; ESI-MS: [M+H+]=487.Example 81 [5-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-1-yl]acetic acid Analogously to example I 0.4 g (1.4 mmol) [1-(2-methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) and 0.36 g (1.4 mmol) N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8) were reacted.","Purification of the raw product, alkaline saponification of the methyl ester and purification of the end stage was conducted analogously to example 80.0.3 g of a white amorphous residue; ESI-MS: [M+H+]=476.Example 82 [5-(2-{4-[(1H-Benzimidazole-2-ylamino)methyl]piperidine-1-yl}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1H-benzazepine-1-yl]acetic acid Analogously to example I 0.49 (1.4 mmol) [1-(2-methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) was reacted with 0.63 g (1.4 mmol) N-(piperidine-4-ylmethyl)-1H-benzimidazole-2-amine (trifluoro acetate) (17).","After purification, alkaline ester hydrolysis and chromatographic purification of the end product (CH2Cl2/CH3OH/50% glacial acetic acid 20/5/1) 0.3 g of a white amorphous powder were obtained; ESI-MS: [M+H+]=488.Example 83 [5-(2-{4-[(1H-Benzimidazole-2-ylamino)methyl]piperidine-1-yl}-2-oxoethyl)-2-oxo 2,3-dihydro-1H-1-benzazepine-1-yl]acetic acid Analogously to example I 0.4 g (1.4 mmol) [1-(2-methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) were reacted with 0.43 g trans-N-J[4-(aminomethyl)cyclohexyl]1H-benzimidazole-2-amine (dihydrochloride) (11).","After purification of the ester (eluent: CH2Cl2/CH3OH/25% NH3 45/5/0.2), alkaline ester hydrolysis and chromatographic purification of the end product (CH2Cl2/CH3OH/50% glacial acetic acid 20/5/1) 0.18 g of a white amorphous powder were obtained; ESI-MS: [M+H+]=502.Example 84 [5-(2-{[5-H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (hydrochloride) Analogously to example I 0.65 g (2 mmol) [5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (54) were reacted with N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8), the reaction product purified by means of preparative thick-layer chromatography (eluent: CH2Cl2/CH3OH/conc.","NH3 45/5/0.2); ESI-MS: [M+H+]=535.Then the tert-butyl ester was cleaved with 4n HCl in dioxane, and after chromatographic purification 40 mg of a white amorphous powder were isolated; ESI-MS: [M+H+]=479.Example 85 {5-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl}acetic acid (hydrochloride) Preparation and purification was conducted analogously to example 84 by reaction with trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11); ester stage ESI-MS: [M+H+]=561.Purification after ester cleavage was conducted by means of preparative thick-layer chromatography (CH2Cl2/CH3OH/50% glacial acetic acid 12/3/1); 0.35 g of a white amorphous powder; ESI-MS: [M+H+]=505.Example 86 [5-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (hydrochloride) Preparation and purification was conducted analogously to example 84 by reaction with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4); ester stage ESI-MS: [M+H+]=555; target product: 0.4 g of a white amorphous powder; ESI-MS: [M+H+]=499.Example 87 [5-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid Analogously to example I 1.2 g (3.6 mmol) [5-(2-tert-butoxy-2-oxoethyl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (55) was reacted with 0.86 g (3.6 mmol) N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4), the reaction product purified by means of preparative thick-layer chromatography (eluent: CH2Cl2/CH3OH/conc.","NH3 45/5/0.1); ESI-MS: [M+H+]=: 555.Subsequent cleavage of the tert-butylester with 4n HCl in dioxane afforded 0.8 g of a white amorphous powder; ESI-MS [M+H+]=499.Example 88 {5-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl}acetic acid Preparation and purification analogously to example 87; ester stage ESI-MS: [M+H+]=561; 0.9 g of the target product were obtained as a white amorphous powder; ESI-MS [M+H+]=505.Example 89 (1-{2-[4-(1H-Benzimidazole-2-yl)piperidine-1-yl]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (acetate) Analogously to example I 0.5 g (1.5 mmol) [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) and 0.36 g (1.5 mmol) 2-(4-piperidinyl)-1H-benzimidazole (J. Heterocycl.","Chem.","1989, 26, 541) were reacted, purified by means of preparative thick-layer chromatography (eluent CH2Cl2/CH3OH/conc.","NH3 45/5/0.2); ESI-MS: [M+H+]=517.Subsequent cleavage of the tert-butyl ester with 4n HCl in a mixture of dioxane/glacial acetic acid and chromatographic purification afforded 0.259 of a white amorphous powder; ESI-MS [M+H+]=: 461.Example 90 (1-{2-[[3-(1H-Benzimidazole-2-yl)propyl](methyl)amino]-2-oxoethyl}-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (hydrochloride) Preparation analogously to example I by reaction with N-[3-(1H-benzimidazole-2-yl)propyl]-N-methylamine (WO 9849148); after chromatographic purification 0.69 were obtained as a white amorphous powder; ESI-MS [M+H+]=: 449.Example 91 (1-{2-[4-(1H-Benzimidazole-2-ylamino)piperidine-1-yl]-2-oxoethyl}-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Preparation analogously to example I by reaction with N-piperidine-4-yl-1H-benzimidazole-2-amine (J. Med.","Chem.","1985, 28, 1925); after chromatographic purification 0.45 g were obtained as a white amorphous powder; ESI-MS [M+H+]=: 476.Example 92 [5-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid Analogously to example I 0.4 g (1.4 mmol) [1-(2-methoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (56) and 0.33 g (1.4 mmol) N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) were reacted and purified by means of preparative thick-layer chromatography (eluent: CH2Cl2/CH3OH/conc.","NH3 45/5/0.2); ESI-MS: [M+H+]=512.Subsequent cleavage of the methyl ester with 1n NaOH in dioxane and chromatographic purification of the residue (CH2Cl2/CH3OH/50% glacial acetic acid 20/5/1) afforded 0.15 g, isolated as a white amorphous powder; ESI-MS [M+H+]=498.Example 93 {5-[2-({[4-(1H-Benzimidazole-2-yl)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl}acetic acid Preparation and purification analogously to example 92; ester stage ESI-MS [M+H+]=503; chromatographic purification after cleavage of the ester afforded 0.3 g of the target product as a white amorphous powder; ESI-MS [M+H+]=489.Example 94 [5-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-1-yl]acetic acid Preparation and purification analogously to example 92; ester stage ESI-MS [M+H+]=492.Chromatographic purification after cleavage of the ester afforded 20 mg as a white amorphous powder ESI-MS [M+H+]=478.Example 95 {5-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl}acetic acid Preparation and purification analogously to example 92; ester stage ESI-MS [M+H+]=518.Chromatographic purification after cleavage of the ester afforded 0.15 g as a white amorphous powder; ESI-MS [M+H+]=504.Example 96 Ethyl-{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 0.6 g (2.4 mmol) N,N-Bis(2-oxo-3-oxazolidinyl)phosphoryl chloride were added to a solution of 0.8 g (1.6 mmol) of the acid of example XI, 0.15 g (3.2 mmol) ethyl alcohol, 0.2 g (1.6 mmol) 4-dimethylaminopyridine and 0.4 g (4 mmol) triethylamine in 60 ml CH2Cl2 and stirred overnight.","After the reaction had completed 2 g glacial acetic acid and 3.7 g ethyl alcohol were added to the reaction solution and stirred for another 20 h at room temperature.","For workup, 50 ml H2O were added to the mixture, the organic phase washed with 10% K2CO3-solution and H2O, dried over MgSO4 and evaporated.","Chromatographic purification of the residue (eluent: CH2Cl2/ethyl alcohol/50% glacial acetic acid 15/5/1) afforded 0.35 g of a white amorphous powder; ESI-MS [M+H+]=532.Analogously to example 96 were prepared: Example 97 Cyclohexyl-{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 0.26 g; ESI-MS [M+H+]=586.Example 98 Neopentyl{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 0.21 g; ESI-MS [M+H+]=574.Example 99 tert-Butyl [1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate Preparation was carried out analogously to example I by reaction of [5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (3) with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4).","After chromatographic purification (eluent: CH2Cl2/ethyl alcohol/50% glacial acetic acid 45/5/0.3) the residue was dissolved in 70 ml CH2Cl2 and 5 ml CH3OH, washed with 5% K2CO3-solution and H2O, dried over Na2SO4 and evaporated to dryness.","The amorphous residue was mixed with 25 ml CH3OH in heat.","0.51 g of white crystals; Fp.",": 231° C. (decomposition); ESI-MS [M+H+]=554.Example 100 Cyclohexyl-[1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate 0.64 g (1.28 mmol) of [1-(2-{[4-(1H-benzimidazole-2ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (acid of example III) was suspended in 30 ml cyclohexanol, 1.0 g HCl-gas introduced with stirring and the resulting yellow solution allowed to stand for 4 days at room temperature.","Since an acid was still detectable by chromatography, it was heated for 7 h to 40-50° C. For workup, 100 ml diethylether were added, washed with K2CO3-solution and H2O, dried over Na2SO4 and the solvent—finally for removal of cyclohexanol under oil pump vacuum and at a bath temperature of 50° C.—distilled off.","The residue was purified chromatographically (eluent: CH2Cl2/acetone/methanol/50% acetic acid 45151410.3).","0.659 of a slightly beige coloured powder; ESI-MS [M+H+]=580.Example 101 Ethyl-[1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-6-yl]acetate 0.619 (1.23 mmol) of [1-(2-{[4-(1H-benzimidazole-2ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (acid of example III) was suspended in 30 ml ethyl alcohol, 0.4 g HCl-gas introduced and allowed to stand for 4 days at room temperature.","The ethyl alcohol was distilled off in vacuum, the residue taken up in ethyl acetate, washed with 5% NaHCO3- and NaCl-solution, dried over Na2SO4 and evaporated.","After thick-layer chromatographic purification (eluent: CH2Cl2/ethyl alcohol/50% acetic acid 43/7/0.5) the eluate was diluted with some CH2Cl2 and for removal of the acetic acid washed with 50% NaHCO3-solution.","After drying over Na2SO4 it was evaporated and the residue converted to an amorphous powder filterable with suction by means of diethylether/n-hexane; 0.55 g; ESI-MS [M+H+]=526.Example 102 1-{[(Cyclohexyloxy)carbonyl]oxy}ethyl [1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate 0.3 g K2CO3 were added at 3° C. to a solution of 0.6 g (1.2 mmol) of [1-(2-{[4-(1H-benzimidazole-2ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (add of example III) in 10 ml DMF with stirring, some crystals 18-crown-6, 0.4 g cyclohexyl-1-iodo ethylcarbonate (preparation from cyclohexyl-1-chloroethylcarbonate and NaI analogously to J. Antibiot.","1987, 40 (1), 81-90) dissolved in 5 ml CH3CN were added dropwise and stirred for 20 min.","After addition of 100 ml cold NaCl-solution it was extracted several times with ethyl acetate, the combined organic phases washed with NaCl-solution, dried over Na2SO4 and evaporated.","The residue was purified by column chromatography (eluent: CH2Cl2/acetone/methanol/50% acetic acid 45/5/5/0.3), after evaporation of the solvent taken up in 50 ml CH2Cl2, washed with 5% NaHCO3-solution, dried over Na2SO4 and again evaporated.","90 mg of a white amorphous powder; ESI-MS [M+H+]=668.Example 103 [(5R)-1-(2-{[4-(1H-Benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid 1.0 g (3.0 mmol) of the left-rotating acid (building block 57) and 0.72 g (3.0 mmol) N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) were reacted analogously to example I and the reaction product purified by column chromatography (eluent: CH2Cl2/acetone/methanol/50% acetic acid 45/5/4/0.3); ester stage ESI-MS [M+H+]=554.Cleavage of the tert-butyl ester with 4n HCl in dioxane afforded 0.82 g of a white amorphous powder; ESI-MS [M+H+]=498; [α]D20=−107.7° (K+-salt, c=1 in H2O).","Example 104 [(5S)-1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Preparation analogously to example 103 starting from the dextrorotatory acid building block 58.Ester stage: 1.5 g of a amorphous powder; ESI-MS [M+H+]=554.Target product: 0.79 g of a white amorphous powder; ESI-MS [M+H+]=498.Example 105 {(5R)-1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Preparation analogously to example I from the left-rotating acid building block 57 and trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11).","Ester stage: 0.9 g of a white amorphous powder; ESI-MS [M+H+]=560.Target product: 0.67 g of a white amorphous powder; ESI-MS [M+H+]=504; [α]D20=−104° (K+-salt, c=1 in H2O).","Example 106 {(SS)-1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Preparation analogously to example 103 starting from the dextrorotatory acid building block 58.Ester stage: 0.72 g of a amorphous powder; ESI-MS [M+H+]=560.Target product: 0.56 g of a white amorphous powder; ESI-MS [M+H+]=504; [α]D20=+101.60 (K+-salt, c=1 in H2O).","Example 107 [4-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-8-yl]acetic acid Analogously to example I 0.6 g (1.8 mmol) [8-(2-tert-butoxy-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-4-yl]acetic acid (61) were reacted with 0.42 g (1.8 mmol) N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) and the reaction product purified by thick-layer chromatography (eluent: CH2Cl2/methanol/conc.","NH3 451510.2); ESI-MS [M+H+]=560.Cleavage of the t-butyl group with 4n HCl in dioxane afforded 0.34 g of a slightly yellowish powder; ESI-MS [M+H+]=504.Example 108 {4-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-8-yl}acetic acid Analogously to example 107.Ester stage: 100 mg of a white amorphous powder, ESI-MS [M+H+]=566.Target product: 98 mg of a white amorphous powder; ESI-MS [M+H+]=510.II.","BIOLOGICAL EXAMPLES Example 1 Integrin αvβ3 Assay For the identification and assessment of integrin αvβ3 ligands, a test system was used which was based on competition between the natural integrin αvβ3 ligand vitronectin and the test substance for binding to solid phase-bound integrin αvβ3.Procedure Microtiter plates coated with 250 ng/ml of integrin αvβ3 in 0.05 M NaHCO3 pH 9.2; 0.1 ml/well; saturation with 1% powdered milk/assay buffer; 0.3 ml/well; 0.5 h/RT 3× washing with 0.05% Tween 20/assay buffer test substance in 0.1% powdered milk/assay buffer, 50 μl/well+0 μg/ml or 2 μg/ml of human vitronectin (Boehringer Ingelheim T007) in 0.1% powdered milk/assay buffer, 50 μl/well; 1 h/RT 3× washing with 0.05% Tween 20/assay buffer 1 μg/ml of anti human vitronectin antibody coupled to peroxidase (Kordia SAVN-APHRP) in 0.1% powdered milk/assay buffer; 0.1 ml/well; 1 h/RT 3× washing with 0.05% Tween 20/assay buffer 0.1 ml/well of peroxidase substrate stop reaction with 0.1 ml/well of 2 M H2SO4 measurement of the absorption at 450 nm Integrin αvβ3: Human placenta is solubilized with Nonidet and integrin αvβ3 affinity-purified on a GRGDSPK matrix (elution with EDTA).","Impurities due to integrin αIIbβ3 and human serum albumin, and the detergent and EDTA are removed by anion-exchange chromatography.","Assay buffer: 50 mM Tris pH 7.5; 100 mM NaCl; 1 mM CaCl2; 1 mM MgCl2; 10 μM MnCl2 Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M sodium acetate pH 4.9), then add 14.7 μl of 3% H2O2.Various dilutions of the test substances are employed in the assay and the IC50 values are determined (concentration of the ligand at which 50% of the ligand is displaced).","The compound from Example VII showed the best result here.","Example 2 Integrin αIIbβ3 Assay The assay is based on competition between the natural integrin αIIbβ3 ligand fibrinogen and the test substance for binding to integrin αIIbβ3.Procedure Coat microtiter plates with 10 μg/ml of fibrinogen (Calbiochem 341578) in 0.05 M NaHCO3 pH 9.2; 0.1 ml/well; saturate with 1% BSA/PBS; 0.3 ml/well; 30 min/RT 3× washing with 0.05% Tween 20/PBS test substance in 0.1% BSA/PBS; 50 μl/well+200 μg/ml of integrin αIIbβ3 (Kordia) in 0.1% BSA/PBS; 50 μl/well; 2 to 4 h/RT 3× washing as above biotinylated anti-integrin αIIbβ3 antibody (Dianova CBL 130 B); 1:1000 in 0.1% BSA/PBS; 0.1 ml/well; 2 to 4 h/RT.","3× washing as above streptavidin-peroxidase complex (B.M.","1089153) 1:10000 in 0.1% BSA/PBS; 0.1 ml/well; 30 min/RT 3× washing as above 0.1 ml/well of peroxidase substrate stop reaction using 0.1 ml/well of 2 M H2SO4 measurement of the absorption at 450 nm Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M Na acetate pH 4.9), then add 14.7 μl of 3% H2O2 Various dilutions of the test substances are employed in the assay and the IC50 values are determined (concentration of the antagonist at which 50% of the ligand is displaced).","By comparison of the IC50 values in the integrin αIIbβ3 and integrin αvb3 assay, the selectivity of the substances can be determined.","Example 3 CAM Assay The CAM (chorioallantoic membrane) assay serves as a generally recognized model for the assessment of the in vivo activity of integrin αvβ3 antagonists.","It is based on the inhibition of angiogenesis and neovascularization of tumor tissue (Am.","J. Pathol.","1975, 79, 597-618; Cancer Res.","1980, 40, 2300-2309; Nature 1987, 329, 630).","The procedure is carried out analogously to the prior art.","The growth of the chicken embryo blood vessels and of the transplanted tumor tissue can be readily monitored and assessed.","Example 4 Rabbit Eye Assay In this in vivo model, the inhibition of angiogenesis and neovascularization in the presence of integrin αvβ3 antagonists can be monitored and assessed analogously to Example 3.The model is generally recognized and is based on the growth of rabbit blood vessels starting from the edge in the corner of the eye (Proc.","Natl.","Acad.","Sci.","USA.","1994, 91, 4082-4085; Science 1976, 193, 70-72).","The procedure is carried out analogously to the prior art."]],"string":"[\n [\n \"Ligands of Integrin Receptors\",\n \"The invention relates to the use of cyclic compounds as ligands of integrin receptors, in particular as ligands of the αVβ3 integrin receptor, the novel compounds themselves, their use, and pharmaceutical preparations comprising these compounds.\"\n ],\n [\n \"1.The use of compounds of the formula I B-G-L I as ligand of integrin receptors, where B, G and L have the following meanings: L is a structural element of the formula IL —U-T IL where T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and —U— is —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1—, where a is 0 or 1, b is 0, 1 or 2 XL is CRL3RL4, NRL5, oxygen or sulfur, RL1, RL2, RL3, RL4 independently of one another are hydrogen, -T, —OH, —NRL6RL7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL1 and RL2 or RL3 and RL4, or optionally RL1 and RL3, together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three identical or different heteroatoms O, N, S, RL5, RL6, RL7 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, G is a structural element of the formula IG where the structural element B is bonded to the structural element G via the ring nitrogen and the structural element L is bonded via WG, YG is CO, CS, C═NRG2 or CRG3RG4, RG2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical, RG3, RG4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG3 and RG4 together a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG3 and RG4 together are an optionally substituted C3-C7-cycloalkyl radical, RG5 and RG6 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, an optionally substituted aryl or arylalkyl radical or both radicals RG5 and RG6 together are an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S, WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4 RG1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, RG7, RG8, RG9, RG10 independently of one another are hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —C1-NRG12RG13—NRG12RG13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical or in each case independently of one another two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 together are an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group O, N, S and up to two double bonds, RG11 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, RG12, RG13 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 and RG11* is a radical RG11 which is independent of RG11 B is a structural element containing at least one atom which, under physiological conditions, as a hydrogen acceptor can form hydrogen bridges, where at least one hydrogen acceptor atom has a distance of 5 to 14 atomic bonds from structural element G along the shortest possible route along the structural element skeleton, and the physiologically tolerable salts, prodrugs and the enantiomerically pure or diastereomerically pure and tautomeric forms.\",\n \"2.The use as claimed in claim 1, wherein the structural element B is a structural element of the formula IB A-E- IB where A and E have the following meanings: A is a structural element selected from the group: a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon which can contain up to 4 heteroatoms selected from the group O, N and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, or a 9- to 14-membered polycyclic, saturated, unsaturated or aromatic hydrocarbon which can contain up to 6 heteroatoms selected from the group N, O and S, where, in each case independently of one another, the ring nitrogen optionally contained or the carbon atoms can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, a radical where ZA1 is oxygen, sulfur or optionally substituted nitrogen and ZA2 is optionally substituted nitrogen, oxygen or sulfur, and a radical where RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11, and E is a spacer structural element which covalently bonds the structural element A to the structural element G, where the number of atomic bonds along the shortest possible route along the structural element skeleton E is 5 to 14.3.The use as claimed in one of claims 1 or 2, wherein the structural element A used is a structural element selected from the group of structural elements of the formulae IA1 to IA18, where m, p, q independently of one another are 1, 2 or 3, RA1, RA2 independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or SO2NRA15RA16 or both radicals RA1 and RA2 together are a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N, and S, RA13, RA13* independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, where RA14 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkylene-C3-C7-cycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RA15, RA16, independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, CO—Cl1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, arylalkyl, COO-alkylenearyl, SO2-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, CO-aryl, CO—NH-aryl, SO2-aryl, hetaryl, CO—NH-hetaryl or CO-hetaryl radical, RA3, RA4 independently of one another are hydrogen, —(CH2)n—(XA)j—RA12, or both radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle is optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, where n is 0, 1, 2 or 3, j is 0 or 1, XA is —CO—, —CO—N(RX1)—, —N(RX1)—CO—, —N(RX1)—CO—N(RX1*)—, —N(RX1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX1)—, —N(RX1)— or —N(RX1)—SO2—, RA12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally C1-C4-alkyl- or aryl-substituted C2-C6-alkynyl or C2-C6-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocycle, substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, a C3-C7-cycloalkyl, aryl or hetaryl radical, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RA12, together with RX1 or RX1* forms a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RX1, RX1* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, RA6, RA6* are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, —CO—O—C1-C4-alkyl, arylalkyl, —CO—O-alkylenearyl, —CO—O-allyl, —CO—C1-C4-alkyl, —CO-alkylenearyl, C3-C7-cycloalkyl or —CO-allyl radical or in the structural element IA7 both radicals RA6 and RA6* together are an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—CO—C1-C4-alkyl radical, or an optionally substituted arylalkyl, —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical, or both radicals RA6 and RA7 together are an optionally substituted, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms-O, N, S, RA8 is hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—C1-C4-alkyl, SO2—C1-C4-alkyl or CO—O—C1-C4-alkyl radical or an optionally substituted aryl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl, CO—O-alkylenearyl or alkylenearyl radical, RA9, RA10 independently of one another are hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, or both: radicals RA9 and RA10 together in the structural element IA14 are a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA11 is hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, RA17 is hydrogen or, in the structural element IA16, both radicals RA9 and RA17 together are a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA1, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- or bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 which is independent of RG11 Z1, Z2, Z3, Z4 independently of one another are nitrogen, C—H, C-halogen or a branched or unbranched, optionally substituted C—C1-C4-alkyl or C—C1-C4-alkoxy radical, Z5 is NRA8, oxygen or sulfur.\",\n \"4.The use as claimed in one of claims 1 to 3, wherein the spacer structural element E is composed of two to four substructural elements, selected from the group consisting of E1 and E2, where the sequence of linkage of the substructural elements is arbitrary and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE9RE10)g—(XE)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 1-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, or independently of one another in each case two radicals RE1 and RE2 or RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N and S x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms, together with RW2 or RW2*, a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NHC1-C6-alkoxyalkyl, CO—NHC1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an, optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical.\",\n \"5.The use as claimed in one of claims 1 to 4, wherein the spacer structural-element E used is a structural element of the formula IE1E2 -E2-E1- IE1E2 and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(XE)k5—(CRE9RE10)h—(NRE11*)k6—IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 11-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14 (ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical or independently of one another are in each case two radicals RE1 and RE2 or RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle, which can contain up to three heteroatoms selected from the group O, N and S, x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms together with RW2 or RW2* a saturated or unsaturated C3-C7-heterocycle, which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical.\",\n \"6.The use of the structural element of the formula IGL -G-L, IGL for the preparation of compounds which bind to integrin receptors, where G and L have the following meanings: L is a structural element of the formula IL —U-T IL where T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and —U— is —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1—, where a is 0 or 1, b is 0, 1 or 2 XL is CRL3RL4, NRL5, oxygen or sulfur, RL1, RL2, RL3, RL4 independently of one another are hydrogen, -T, —OH, —NRL6RL7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL1 and RL2 or RL3 and RL4, or optionally RL1 und RL3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, RL5, RL6, RL7 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, G is a structural element of the formula IG where the structural element B is bonded to the structural element G via the ring nitrogen and the structural element L is bonded via WG, YG is CO, CS, C═NRG2 or CRG3RG4, RG2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical, RG3, RG4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG3 and RG4 together are a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG3 and RG4 together are an optionally substituted, C3-C7-cycloalkyl radical, RG5 and RG6 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, an optionally substituted aryl or arylalkyl radical or both radicals RG5 and RG6 together are an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S, with the proviso that in the case of this fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle substituents are excluded which contain a structural element —V—CO—R8, where V is an optionally substituted C1-C2-alkylene radical R8 is a hydroxyl group, a C1-C8-alkoxy, aryl-C0-C6-alkoxy, C1-C8-alkylcarbonyloxy-C1-C4-alkoxy or aryl-C1-C8-alkylcarbonyloxy-C1-C4-alkoxy group or an L- or D-amino acid, which is bonded by an amide bond and in which the carboxylic acid component of said amino acid is present as a free acid or esterified with C1-C6-alkyl, WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4, RG1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, RG7, RG8, RG9, RG10 independently of one another are hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, —O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —CO—N12RG13, —NRG12RG13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical or in each case independently of one another two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 together are an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group O, N, S and which can contain up to two double bonds, RG11 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, RG12, RG13 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 and RG11* is a radical RG11 which is independent of RG11.7.The use of the compounds as claimed in one of claims 1 to 5 as ligands of the αVβ3 integrin receptor.\",\n \"8.The use of the compounds as claimed in one of claims 1 to 5 for the production of drugs for treating diseases in which the interaction between integrins and their natural ligands is excessive or decreased.\",\n \"9.The use of the compounds as claimed in one of claims 1 to 5 as claimed in claim 8 for the treatment of diseases in which the interaction between αVβ3 ingegrin and its natural ligands is excessive or decreased.\",\n \"10.The use of the compounds as claimed in one of claims 1 to 5 as claimed in claim 9 for the treatment of atherosclerosis, rheumatoid arthritis, restenosis after vascular injury or stent implantation, angioplasty, acute kidney failure, angiogenesis-associated microangiopathies, diabetic angiopathies, blood platelet-mediated vascular occlusion, arterial thrombosis, congestive heart failure, myocardial infarct, stroke, cancer, osteoporosis, high blood pressure, psoriasis or viral, parasitic or bacterial conditions, inflammation, wound healing, hyperparathyroidism, Paget's disease, malignant hypercalcemia or metastatic osteolytic lesions.\",\n \"11.A compound of the formula I′ A-E′-G′-L I′ where A, E′, G′ and L have the following meanings: L is a structural element of the formula IL —U-T IL where T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and —U— is —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1—, where a is 0 or 1, b is 0, 1 or 2 XL is CRL3RL4, NRL5, oxygen or sulfur, RL1, RL2, RL3, RL4 independently of one another are hydrogen, -T, —OH, —NRL6RL7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL1 and RL2 or RL3 and RL4, or optionally RL1 and RL3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three identical or different heteroatoms O, N, S, RL5, RL6, RL7 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, G′ is a structural element of the formula IG where the structural element A-E′ is bonded to the structural element G′ via the ring nitrogen and the structural element L is bonded via WG, YG is CO, CS, C═NRG2 or CRG3RG4, RG2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical, RG3, RG4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG3 and RG4 together are a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG3 and RG4 together are an optionally substituted C3-C7-cycloalkyl radical, RG5 and RG6 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, an optionally substituted aryl or arylalkyl radical or both radicals RG5 and RG6 together are an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S, WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4, RG1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, RG7, RG8, RG9, RG10 independently of one another are hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG′12RG′13, C1-C4-alkylene-CO—NRG′12RG′13, C1-C4-alkylene-O—CO—NRG′12RG′13, C1-C4-alkylene-NRG′12RG′13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, —O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG′12RG′13, —SO2—NRG′12RG′13, —CO—NRG′12RG′13, —NRG′12RG′13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical or in each case independently of one another two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 together are an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group O, N, S and up to two double bonds, RG11 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, RG′12, RG′13 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11, and RG11* is a radical RG11 which is independent of RG11, RG14 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-heterocycloalkyl, C1-C4-alkylene-heterocycloalkenyl or hetarylalkyl radical, E′ is a structural element, composed of two to four substructural elements, selected from the group E1 and E2, where the sequence of linkage of the substructural elements is arbitrary and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(XE)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 11-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO-o, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, or independently of one another in each case two radicals RE1 and RE2 or RE3 and RE4 or RE8 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N and S, x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—C—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW12)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms, together with RW2 or RW2*, a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical, with the proviso that in the case where YE or ZE=CO and a radical XE or QE or an aromatic or heteroaromatic radical from the structural element A is bonded directly to YE or ZE, a direct atomic bond from YE or ZE to the structural element G is excluded, A is a structural element selected from the group: a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon, which can contain up to 4 heteroatoms selected from the group O, N and S, where, in each case independently of one another, the ring nitrogen optionally present or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, or a 9- to 14-membered polycyclic saturated, unsaturated or aromatic hydrocarbon which can contain up to 6 heteroatoms selected from the group N, O and S, where, in each case independently of one another, the ring nitrogen optionally present or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, a radical where ZA1 is oxygen, sulfur or optionally substituted nitrogen and ZA2 is optionally substituted nitrogen, oxygen or sulfur, and a radical where RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11, and the physiologically tolerable salts, prodrugs and the enantiomerically pure or diastereomerically pure and tautomeric forms.\",\n \"12.A compound as claimed in claim 11, wherein the structural element A used is a structural element selected from the group of structural elements of the formulae IA1 to IA18 where m, p, q independently of one another are 1, 2 or 3, RA1, RA2 independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or SO2NRA15RA16 or both radicals RA1 and RA2 together are a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N, and S, RA13, RA13* independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, where RA14 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkylene-C3-C7-cycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RA15, RA16, independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, CO—C1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, arylalkyl, COO-alkylenearyl, SO2-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, CO-aryl, CO—NH-aryl, SO2-aryl, hetaryl, CO—NH-hetaryl or CO-hetaryl radical, RA3, RA4 independently of one another are hydrogen, —(CH2)n—(XA)j—RA12, or both radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N-heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle is optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, where n is 0, 1, 2 or 3, j is 0 or 1, XA —CO—, —CO—N(RX1)—, —N(RX1)—CO—, —N(RX1)—CO—N(RX1*)—, —N(RX1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX1)—, —N(RX1)— or —N(RX1)—SO2—, RA12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally C1-C4-alkyl or aryl-substituted C2-C6-alkynyl or C2-C6-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocycle, substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, a C3-C7-cycloalkyl, aryl or hetaryl radical, where both radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RA12, together with RX1 or RX1* is a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RX1, RX1* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, RA6, RA6 are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, —CO—O—C1-C4-alkyl, arylalkyl, —CO—O-alkylenearyl, —CO—O-allyl, —CO—C1-C4-alkyl, —CO-alkylenearyl, C3-C7-cycloalkyl or —CO-allyl radical or in the structural element IA7 both radicals RA6 and RA6* together are an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—CO—C1-C4-alkyl radical, or an optionally substituted arylalkyl, —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical, or both radicals RA6 and RA7 together are an optionally substituted, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA8 is hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—C1-C4-alkyl, SO2—C1-C4-alkyl or CO—O—C1-C4-alkyl radical or an optionally substituted aryl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl, CO—O-alkylenearyl or alkylenearyl radical, RA9, RA10 independently of one another are hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, or both radicals RA9 and RA10 together in the structural element IA14 are a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms Q, N, S and is optionally substituted by up to three identical or different radicals, RA11 is hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, RA17 is hydrogen or, in the structural element IA16, both radicals RA9 and RA17 together are a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 which is independent of RG11, Z1, Z2, Z3, Z4 independently of one another are nitrogen, C—H, C-halogen or a branched or unbranched, optionally substituted C—C1-C4-alkyl or C—C1-C4-alkoxy radical, Z5 is NRA8, oxygen or sulfur.\",\n \"13.A compound as claimed in claim 11 or 12, wherein the structural element E′ used is a structural element of the formula IE1E2 -E2-E1- IE1E2 and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 (NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(XE)k—(CRE9RE10)h—(NRE11*)k6— IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 11-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon, which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O, and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, or independently of one another in each case two radicals RE1 and RE2 or RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group-O, N and S, x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms, together with RW2 or RW2*, a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical, with the proviso that in the case where YE═CO, k1 and k5=1 and h and k6=0 the sum of the indices c, k2 and d must be other than 0 and in the case where an aromatic or heteroaromatic radical from the structural element A is bonded directly to YE or ZE, a direct atomic bond from YE or ZE to the structural element G is excluded.\",\n \"14.A compound as claimed in one of claims 11 to 13 for use as a drug.\",\n \"15.The use of the compounds as claimed in one of claims 11 to 13 for the production of drugs for treating diseases.\",\n \"16.A pharmaceutical preparation comprising, in addition to the customary pharmaceutical excipients, at least one compound as claimed in one of claims 11 to 13.17.A pharmaceutical preparation, comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group inhibitors of blood platelet adhesion, activation or aggregation, anticoagulants which prevent thrombin activity or formation, antagonists of blood platelet-activating compounds or selectin antagonists.\",\n \"18.The use of the pharmaceutical preparation as claimed in claim 17 for the production of a drug for treating blood platelet-mediated vascular occlusion or thrombosis.\",\n \"19.A pharmaceutical preparation, comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group inhibitors of blood platelet activation or aggregation, serine protease inhibitors, fibrinogen-lowering compounds, selectin antagonists, antagonists of ICAM-1 or VCAM-1 inhibitors of leukocyte adhesion inhibitors of vascular wall transmigration, fibrinolysis-modulating compounds, inhibitors of complement factors, endothelin receptor antagonists, tyrosine kinase inhibitors, antioxidants and interleukin 8 antagonists.\",\n \"20.The use of the pharmaceutical preparation as claimed in claim 19 for the production of a drug for treating myocardial infarct or stroke.\",\n \"21.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group endothelin antagonists, ACE inhibitors, angiotensin receptor antagonists, endopeptidase inhibitors, beta-blockers, calcium channel antagonists, phosphodiesterase inhibitors and caspase inhibitors.\",\n \"22.The use of the pharmaceutical preparation as claimed in claim 21 for the production of a drug for treating congestive heart failure.\",\n \"23.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group thrombin inhibitors, inhibitors of factor Xa, inhibitors of the coagulation pathway which leads to thrombin formation, inhibitors of blood platelet adhesion, activation or aggregation, endothelin receptor antagonists, nitrogen oxide synthase inhibitors, CD44 antagonists, selectin antagonists, MCP-1 antagonists, inhibitors of signal transduction in proliferating cells, antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF and antioxidants.\",\n \"24.The use of the pharmaceutical preparation as claimed in claim 23 for the production of a drug for treating restenosis after vascular injury or stent implantation.\",\n \"25.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF, heparin or low-molecular weight heparins or further GAGs, inhibitors of MMPs, selectin antagonists, endothelin antagonists, ACE inhibitors, angiotensin receptor antagonists, glycosylation inhibitors and AGE formation inhibitors or AGE breakers and antagonists of their receptors.\",\n \"26.The use of the pharmaceutical preparation as claimed in claim 25 for the production of a drug for treating diabetic angiopathies.\",\n \"27.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group lipid-lowering compounds, selectin antagonists, antagonists of ICAM-1 or VCAM-1 heparin or low-molecular weight heparins or further GAGs, inhibitors of MMPs, endothelin antagonists, apolipoprotein A1 antagonists, cholesterol antagonists, HMG CoA reductase inhibitors, ACAT inhibitors, ACE inhibitors, angiotensin receptor antagonists, tyrosine kinase inhibitors, protein kinase C inhibitors, calcium channel antagonists, LDL receptor function stimulants, antioxidants LCAT mimetics and free radical scavengers.\",\n \"28.The use of the pharmaceutical preparation as claimed in claim 27 for the production of a drug for treating atherosclerosis.\",\n \"29.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group cytostatic or antineoplastic compounds, compounds which inhibit proliferation and heparin or low-molecular weight heparins or further GAGs.\",\n \"30.The use of the pharmaceutical preparation as claimed in claim 29 for the production of a drug for the treatment of cancer.\",\n \"31.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group compounds for antiresorptive therapy, compounds for hormone exchange therapy, recombinant human growth hormone, bisphosphonates, compounds for calcitonin therapy, calcitonin stimulants, calcium channel antagonists, bone formation stimulants, interleukin-6 antagonists and Src tyrosine kinase inhibitors.\",\n \"32.The use of the pharmaceutical preparation as claimed in claim 31 for the production of a drug for the treatment of osteoporosis.\",\n \"33.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group TNF antagonists, antagonists of VLA-4 or VCAM-1, antagonists of LFA-1, Mac-1 or ICAMs, complement inhibitors, immunosuppressants, interleukin-1, -5 or -8 antagonists and dihydrofolate reductase inhibitors.\",\n \"34.The use of the pharmaceutical preparation as claimed in claim 33 for the production of a drug for treating rheumatoid arthritis.\",\n \"35.A pharmaceutical preparation comprising at least one compound as claimed in one of claims 1 to 5, if appropriate pharmaceutical excipients and at least one further compound selected from the group collagenase, PDGF antagonists and MMPs.\",\n \"36.The use of the pharmaceutical preparation as claimed in claim 35 for the production of a drug for improving wound healing.\"\n ],\n [\n \"The present invention relates to the use of cyclic compounds as ligands of integrin receptors, in particular as ligands of the αVβ3 integrin receptor, the novel compounds themselves, their use, and pharmaceutical preparations comprising these compounds.\",\n \"Integrins are cell surface glycoprotein receptors which mediate interactions between similar and different cells as well as between cells and extracellular matrix proteins.\",\n \"They are involved in physiological processes, such as embryogenesis, hemostasis, wound healing, immune response and formation/maintenance of the tissue architecture.\",\n \"Disturbances in the gene expression of cell adhesion molecules and functional disorders of the receptors can contribute to the pathogenesis of many disorders, such as tumors, thromboembolic events, cardiovascular disorders, lung diseases, disorders of the CNS, the kidney, the gastrointestinal tract or inflammation.\",\n \"Integrins are heterodimers of an α- and a β-transmembrane subunit in each case, which are noncovalently bonded.\",\n \"Up to now, 16 different α- and 8 different β-subunits and 22 different combinations have been identified.\",\n \"Integrin αvβ3, also called the vitronectin receptor, mediates adhesion to a multiplicity of ligands—plasma proteins, extracellular matrix proteins, cell surface proteins, of which the majority contain the amino acid sequence RGD (Cell, 1986, 44, 517-518; Science 1987, 238, 491-497), such as vitronectin, fibrinogen, fibronectin, von Willebrand factor, thrombospondin, osteopontin, laminin, collagen, thrombin, tenascin, MMP-2, bone sialoprotein II, various viral, fungal, parasitic and bacterial proteins, natural integrin antagonists such as disintegrins, neurotoxins—mambin—and blood fluke proteins—decorsin, ornatin—and also some non-RGD ligands, such as Cyr-61 and PECAM-1 (L. Piali, J.\",\n \"Cell Biol.\",\n \"1995, 130, 451-460; Buckley, J.\",\n \"Cell Science 1996, 109, 437-445, J. Biol.\",\n \"Chem.\",\n \"1998, 273, 3090-3096).\",\n \"A number of integrin receptors show cross-reactivity with ligands which contain the RGD motif.\",\n \"Thus integrin αIIbβ3, also called the platelet fibrinogen receptor, recognizes fibronectin, vitronectin, thrombospondin, von Willebrand factor and fibrinogen.\",\n \"Integrin αvβ3 is expressed, inter alia, on endothelial cells, blood platelets, monocytes/macrophages, smooth muscle cells, some B cells, fibroblasts, osteoclasts and various tumor cells, such as melanoma, glioblastoma, lung, breast, prostate and bladder carcinomas, osteosarcomas or neuroblastomas.\",\n \"Increased expression is observed under various pathological conditions, such as in the prothrombotic state, in vascular injury, tumor growth or metastasis or reperfusion and on activated cells, in particular on endothelial cells, smooth muscle cells or macrophages.\",\n \"An involvement of integrin αvβ3 has been demonstrated, inter alia, in the following syndromes: cardiovascular disorders such as atherosclerosis, restenosis after vascular injury, and angioplasty (neointima formation, smooth muscle cell migration and proliferation) (J. Vasc.\",\n \"Surg.\",\n \"1994, 19, 125-134; Circulation 1994, 90, 2203-2206), acute kidney failure (Kidney Int.\",\n \"1994, 46, 1050-1058; Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"1993, 90, 5700-5704; Kidney Int.\",\n \"1995, 48, 1375-1385), angiogenesis-associated microangiopathies such as diabetic retinopathy or rheumatoid arthritis (Ann.\",\n \"Rev.\",\n \"Physiol 1987, 49, 453-464; Int.\",\n \"Opthalmol.\",\n \"1987, 11, 41-50; Cell 1994, 79, 1157-1164; J. Biol.\",\n \"Chem.\",\n \"1992, 267, 1093.1-10934), arterial thrombosis, stroke (phase II studies with ReoPro, Centocor Inc., 8th annual European Stroke Meeting), carcinomatous disorders, such as in tumor metastasis or in tumor growth (tumor-induced angiogenesis) (Cell 1991, 64, 327-336; Nature 1989, 339, 58-61; Science 1995, 270, 1500-1502), osteoporosis (bone resorption after proliferation, chemotaxis and adhesion of osteoclasts to bone matrix) (FASEB J.\",\n \"1993, 7, 1475-1482; Exp.\",\n \"Cell Res.\",\n \"1991, 195, 368-375, Cell 1991, 64, 327-336), high blood pressure (Am.\",\n \"J. Physiol.\",\n \"1998, 275, H1449-H1454), psoriasis (Am.\",\n \"J. Pathol.\",\n \"1995, 147, 1661-1667), hyperparathyroidism, Paget's disease (J. Clin.\",\n \"Endocrinol.\",\n \"Metab.\",\n \"1996, 81, 1810-1820), malignant hypercalcemia (Cancer Res.\",\n \"1998, 58, 1930-1935), metastatic osteolytic lesions (Am.\",\n \"J. Pathol.\",\n \"1997, 150, 1383-1393), pathogenic protein (e.g.\",\n \"HIV-1 tat)-induced processes (e.g.\",\n \"angiogenesis, Kaposi's sarcoma) (Blood 1999, 94, 663-672) inflammation (J.\",\n \"Allergy Clin.\",\n \"Immunol.\",\n \"1998, 102, 376-381), cardiac insufficiency, CHF, and also in antiviral, antiparasitic, antifungal or antibacterial therapy and prophylaxis (adhesion and internalization) (J. Infect.\",\n \"Dis.\",\n \"1999, 180, 156-166; J. Virology 1995, 69, 2664-2666; Cell 1993, 73, 309-319).\",\n \"On account of its key role, pharmaceutical preparations which contain low-molecular weight integrin αvβ3 ligands are of high therapeutic or diagnostic benefit, inter alia, in the indications mentioned.\",\n \"Advantageous αvβ3 integrin receptor ligands bind to the integrin αvβ3 receptor with an increased affinity.\",\n \"In contrast to integrin αvβ3, particularly advantageous αvβ3 integrin receptor ligands additionally have an increased selectivity and are less active with respect to the integrin αIIbβ3 by at least a factor of 10, preferably at least a factor of 100.For a multiplicity of compounds, such as anti-αvβ3 monoclonal antibodies, peptides which contain the RGD binding sequence, natural, RGD-containing proteins (e.g.\",\n \"disintegrins) and low-molecular weight compounds, an integrin αvβ3 antagonistic action has been shown and a positive in vivo effect demonstrated (FEBS Letts 1991, 291, 50-54; J. Biol.\",\n \"Chem.\",\n \"1990, 265, 12267-12271; J. Biol.\",\n \"Chem.\",\n \"1994, 269, 20233-20238; J.\",\n \"Cell Biol 1993, 51, 206-218; J. Biol.\",\n \"Chem.\",\n \"1987, 262, 17703-17711; Bioorg.\",\n \"Med.\",\n \"Chem.\",\n \"1998, 6, 1185-1208).\",\n \"Antagonists of the αVβ3 integrin receptor based on a bicyclic structural element are described in WO 9906049, WO 9905107, WO 9814192, WO 9724124, WO 9724122 and WO 9626190.EP 540 334 and WO 9308174 describe bicyclic antagonists of the αIIbβ3 integrin receptor.\",\n \"WO 9407488 A1 describes compounds having a bicyclic molecular structure and which accelerate the release of growth hormone.\",\n \"Further, vasopressin antagonists having a bicyclic molecular structure are described in the specifications EP 620216, WO 9534540, WO 9408582, WO 9802432, WO 9420473, JP 09221476 A1, JP 11060488 A1, WO 9404525, JP 04321669 A1, WO 9722591, as well as in Matsuhisa et al., Chem.\",\n \"Pharm.\",\n \"Bull.\",\n \"1999, 47, 3, 329-339.It is an object of the present invention to make available novel integrin receptor ligands having advantageous properties.\",\n \"We have found that this object is achieved by the use of compounds of the formula I B-G-L I as ligands of integrin receptors, where B, G and L have the following meanings: L is a structural element of the formula IL —U-T IL where T is a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH and —U— is —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1—, where a is 0 or 1, b is 0, 1 or 2 XL is CRL3RL4, NRL5, oxygen or sulfur, RL1, RL2, RL3, RL4 independently of one another are hydrogen, -T, —OH, —NRL6RL7, —CO—NH2, a halogen radical, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 or C1-C4-alkoxy radical, an optionally substituted radical C1-C2-alkylene-T, C2-alkenylene-T or C2-alkynylene-T, an optionally substituted aryl or arylalkyl radical or in each case independently of one another are two radicals RL1 and RL2 or RL3 and RL4, or optionally RL1 and RL3 together are an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three identical or different heteroatoms O, N, S, RL5, RL6, RL7 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted CO—O-alkylenearyl, SO2-aryl, CO-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, G is a structural element of the formula IG where the structural element B is bonded to the structural element G via the ring nitrogen and the structural element L is bonded via WG, YG is CO, CS, C═NRG2 or CRG3RG4, RG2 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—C3-C7-cycloalkyl radical or an optionally substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical, RG3, RG4 independently of one another are hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radical or both radicals RG3 and RG4 together are a cyclic acetal —O—CH2—CH2—O— or —O—CH2—O— or both radicals RG3 and RG4 together are an optionally substituted C3-C7-cycloalkyl radical, RG5 and RG6 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, an optionally substituted aryl or arylalkyl radical or both radicals RG5 and RG6 together are an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S, WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4, RG1 is hydrogen, halogen, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radical, RG7, RG8, RG9, RG10 independently of one another are hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, —O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —CO—NRG12RG13, —NRG12RG13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical or in each case independently of one another two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 together are an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group O, N, S and up to two double bonds, RG11 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, RG12, RG13 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11, and RG11* is a radical RG11 which is independent of RG11, B is a structural element containing at least one atom which, under physiological conditions, as a hydrogen acceptor can form hydrogen bridges, where at least one hydrogen acceptor atom has a distance of 5 to 14 atomic bonds from structural element G along the shortest possible route along the structural element skeleton, and the physiologically tolerable salts, prodrugs and the enantiomerically pure or diastereomerically pure and tautomeric forms.\",\n \"In the structural element L, T is understood as meaning a group COOH, a radical hydrolyzable to COOH or a radical bioisosteric to COOH.\",\n \"A radical hydrolyzable to COOH is understood as meaning a radical which changes into a group COOH after hydrolysis.\",\n \"A group which may be mentioned by way of example as a radical T hydrolyzable to COOH is in which R1 has the following meanings: a) OM, where M can be a metal cation, such as an alkali metal cation, such as lithium, sodium, potassium, the equivalent of an alkaline earth metal cation, such as calcium, magnesium and barium, or an environmentally tolerable organic ammonium ion such as primary, secondary, tertiary or quaternary C1-C4-alkylammonium or ammonium ion, such as ONa, OK or OLi, b) a branched or unbranched, optionally halogen-substituted C1-C8-alkoxy radical, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particular methoxy, ethoxy, 1-methylethoxy, pentoxy, hexoxy, heptoxy, octoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy or pentafluoroethoxy c) a branched or unbranched, optionally halogen-substituted C1-C4-alkylthio radical such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio radical d) an optionally substituted —O-alkylenearyl radical, such as —O-benzyl e) R1 is further a radical —(O)m—N(R18)(R19), in which m is 0 or 1 and R18 and R19, which can be identical or different, have the following meanings: hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl or the corresponding substituted radicals, preferably methyl, ethyl, propyl, butyl or i-butyl, C2-C6-alkenyl radical, such as vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl or the corresponding substituted radicals, C2-C6-alkynyl radical, such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl or the corresponding substituted radicals, C3-C8-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl und cycloheptyl, cyclooctyl or the corresponding substituted radicals, or a phenyl radical, optionally mono- or polysubstituted, for example mono- to trisubstituted, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl, C1-C4-alkoxy, C1-C4-halogenoalkoxy or C1-C4-alkylthio such as 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methylphenyl, 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl, or R18 and R19 together form an optionally substituted, e.g.\",\n \"C1-C4-alkyl-substituted, C4-C7-alkylene chain closed to give a cycle, which can contain a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, such as —(CH2)4—, —(CH2)5—, —(CH2)6—, —(CH2)7—, —(CH2)2—O—(CH2)2—, —CH2—S—(CH2)3—, —(CH2)2—O—(CH2)3—, —NH—(CH2)3—, —CH2—NH—(CH2)2—, —CH2—CH═CH—CH2—, —CH═CH—(CH2)3—, —CO— (CH2)2—CO— or —CO— (CH2)3—CO—.\",\n \"A radical bioisosteric to COOH is understood as meaning radicals which can replace the function of a group COOH in active compounds by equivalent bond donor/acceptor capabilities or by equivalent charge distribution.\",\n \"Radicals which may be mentioned by way of example as radicals bioisosteric to —COOH are those such as described in “The Practice of Medicinal Chemistry, Editor: C. G. Wermuth, Academic Press 1996, pages 125 and 216, in particular the radicals —P═O(OH)2, —SO3H, tetrazole or acylsulfonamides.\",\n \"Preferred radicals T are —COOH, —CO—O—C1-C8-alkyl or —CO—O-benzyl.\",\n \"The radical —U— in the structural element L is a spacer selected from the group —(XL)a—(CRL1RL2)b—, —CRL1═CRL2—, ethynylene or ═CRL1-.\",\n \"In the case of the radical ═CRL1—, the structural element L is linked to the structural element G via a double bond.\",\n \"XL is a radical CRL3RL4, NRL5, oxygen or sulfur.\",\n \"Preferred radicals —U— are the radicals —CRL1═CRL2—, ethynylene or —(XL)a—(CRL1RL2)b—, where XL is preferably CRL3RL4 (a=0 or 1) or oxygen (a=1).\",\n \"Particularly preferred radicals —U— are the radicals —(XL)a—(CRL1RL2)b—, where XL is preferably CRL3RL4 (a=0 or 1) or oxygen (a 1).\",\n \"Under RL11, RL2, RL3 or RL4 in the structural element L, a halogen radical is understood as meaning, for example, F, Cl, Br or I, preferably F. Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C1-C6-alkyl radical is understood as meaning, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl, preferably branched or unbranched C1-C4-alkyl radicals such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, particularly preferably methyl.\",\n \"Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C2-C6-alkenyl radical is understood as meaning, for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl.\",\n \"Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C2-C6-alkynyl radical is understood as meaning, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably ethynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl.\",\n \"Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C3-C7-cycloalkyl radical is understood as meaning, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.\",\n \"Under RL1, RL2, RL3 or RL4 in structural element L, a branched or unbranched C1-C4-alkoxy radical is understood as meaning, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.\",\n \"The radicals —CO—NH(C1-C6-alkyl), —CO—N(C1-C6-alkyl)2 are secondary or tertiary amides and are composed of the amide bond and the corresponding C1-C6-alkyl radicals such as described above for RL1, RL2, RL3 or RL4.The radicals RL1, RL2, RL3 or RL4 can furthermore be a radical C1-C2-alkylene-T, such as methylene-T or ethylene-T, C2-alkenylene-T, such as ethenylene-T or C2-alkynylene-T, such as ethynylene-T, an aryl radical, such as phenyl, 1-naphthyl or 2-naphthyl or an arylalkyl radical, such as benzyl or ethylenephenyl (homobenzyl), where the radicals can optionally be substituted.\",\n \"Furthermore, two radicals RL1 and RL2 or RL3 and RL4 or optionally RL1 and RL3 can in each case independently of one another together be an optionally substituted 3- to 7-membered saturated or unsaturated carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S. All radicals for RL1, RL2, RL3 or RL4 can be optionally substituted.\",\n \"For the radicals RL1, RL2, RL3 oder RL4 and all further substituted radicals of the description below, suitable substituents, if the substituents are not specified in greater detail, are independently of one another up to 5 substituents, for example selected from the following group: —NO2, —NH2, —OH, —CN, —COOH, —O—CH2—COOH, halogen, a branched or unbranched, optionally substituted C1-C4-alkyl radical, such as methyl, CF3, C2F5 or CH2F, —CO—O—C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, C1-C4-thioalkyl, —NH—CO—O—C1-C4-alkyl, —O—CH2—COO—C1-C4-alkyl, —NH—CO—C1-C4-alkyl, —CO—NH—C1-C4-alkyl, —NH—SO2—C1-C4-alkyl, —SO2—NH—C1-C4-alkyl, —N(C1-C4-alkyl)2, —NH—C1-C4-alkyl, or —SO2—C1-C4-alkyl radical, such as —SO2—CF3, an optionally substituted —NH—CO-aryl, —CO—NH-aryl, —NH—CO—O-aryl, —NH—CO—O-alkylenearyl, —NH—SO2-aryl, —SO2—NH-aryl, —CO—NH-benzyl, —NH—SO2-benzyl or —SO2—NH-benzyl radical, an optionally substituted radical —SO2—NR2R3 or —CO—NR2R3 where the radicals R2 and R3 independently of one another can have the meaning RL5 as below or both radicals R2 and R3 together can be a 3- to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three further different or identical heteroatoms O, N, S, and optionally two radicals substituted on this heterocycle can together be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can be optionally substituted or a further, optionally substituted cycle can be fused to this cycle.\",\n \"If not specified in greater detail, in all terminally bonded, substituted-hetaryl radicals of the description, two substituents can form a fused 5- to 7-membered, unsaturated or aromatic carbocycle.\",\n \"Preferred radicals RL1, RL2, RL3 or RL4 are independently of one another hydrogen, halogen, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy or C3-C7-cycloalkyl radical or the radical —NRL6RL7.Particularly preferred radicals RL1, RL2, RL3 or RL4 are independently of one another hydrogen, fluorine or a branched or unbranched, optionally substituted C1-C4-alkyl radical, preferably methyl.\",\n \"The radicals RL5, RL6, RL7 in structural element L are independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, for example as described above for RL1, C3-C7-cycloalkyl radical, for example as described above for RL1, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl or CO—C1-C6-alkyl radical, which is composed of the group CO—O, SO2 and CO and, for example, of the C1-C6-alkyl radicals described above for RL1, or an optionally substituted CO—O-alkylenearyl, SO2-aryl, SO2-alkylenearyl or CO-alkylenearyl radical, which is composed of the group CO—O, SO2 and CO and, for example, of the aryl or arylalkyl radicals described above for RL1.Preferred radicals for RL6 in structural element L are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—O—C1-C4-alkyl, CO—C1-C4-alkyl or SO2—C1-C4-alkyl radical or an optionally substituted CO—O-benzyl, SO2-aryl, SO2-alkylenearyl or CO-aryl radical.\",\n \"Preferred radicals for RL7 in structural element L are hydrogen or a branched or unbranched, optionally substituted C1-C4-alkyl radical.\",\n \"Preferred structural elements L are composed of the preferred radicals of the structural element.\",\n \"Particularly preferred structural elements L are composed of the particularly preferred radicals of the structural element.\",\n \"G is a structural element of the formula IG where the structural element B is bonded via the ring nitrogen and the structural element L is bonded via WG to the structural element G, optionally via a double bond.\",\n \"YG in structural element G is CO, CS, C═NRG2 or CRG3RG4, preferably CO, C═NRG2 or CRG3RG4, particularly preferably CO or CRG3RG4.RG2 in structural element G is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy or C3-C7-cycloalkyl radical, for example as described above for RL1 in each case, an optionally substituted —O—C3-C7-cycloalkyl radical, which is composed of an ether group and, for example, of the C3-C7-cycloalkyl radical described above for RL1, an optionally substituted aryl or arylalkyl radical, for example as described above for RL1 in each case or an optionally substituted —O-aryl or —O-alkylenearyl radical, which is composed of a group —O— and, for example, of the aryl or arylalkyl radicals described above for RL1.Branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkoxy radicals for RG3 or RG4 in structural element G independently of one another are understood as meaning, for example, the corresponding radicals in each case described above for RL1.Further, both radicals RG3 and RG4 can together form a cyclic acetal, such as —O—CH2—CH2—O— or —O—CH2—O—.\",\n \"Furthermore, both radicals RG3 and RG4 can together form an optionally substituted C3-C7-cycloalkyl radical.\",\n \"Preferred radicals for RG3 or RG4 are independently of one another hydrogen, C1-C4-alkyl or C1-C4-alkoxy.\",\n \"Branched or unbranched, optionally substituted C1-C6-alkyl or C1-C4-alkoxy radicals and optionally substituted aryl or arylalkyl radicals for RG5 and RG6 in structural element G independently of one another are, for example, the corresponding radicals in each case described above for RL1.Further, both radicals RG5 and RG6 can together form an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S. Preferred radicals for RG5 and RG6 are independently of one another hydrogen or optionally substituted aryl radicals, preferably phenyl or arylalkyl radicals, preferably benzyl, and in each case both radicals RG5 and RG6 together can contain an optionally substituted, fused, unsaturated or aromatic 3- to 10-membered carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S. In particularly preferred radicals for RG5 and RG6, both radicals RG5 and RG6 together form an optionally substituted, fused, unsaturated or aromatic 3- to 6-membered carbocycle or heterocycle, for example selected from one of the following doubly bonded structural formulae: in particular selected from one of the following, doubly bonded structural formulae: Suitable substituents of these fused, unsaturated or aromatic 3- to 10-membered carbocycles or heterocycles which together can form RG5 and RG6 are in particular substituents such as generally described above.\",\n \"Particularly preferred substituents of these fused, unsaturated or aromatic 3- to 10-membered carbocycles or heterocycles which together can form RG5 and RG6 are independently of one another up to four substituents selected from the following group: hydroxyl, —CN, F or Cl or a branched or unbranched, optionally substituted C1-C4-alkoxy or C1-C4-alkyl radical, such as methoxy, methyl, CF3, C2F5 or CH2F.\",\n \"WG is a structural element selected from the group of structural elements of the formulae IWG1 to IWG4, where the dashed lines intersect the atomic bonds within the structural element G and the carbon atom substituted by RG7 and RG8 is bonded to YG.\",\n \"In a preferred embodiment, WG is a structural element selected from the group of structural elements of the formulae IWG2 and IWG3, in particular the structural element of the formula IWG2.RG1 in structural element WG is hydrogen, halogen, such as Cl, F, Br or I, a hydroxyl group or a branched or unbranched, optionally substituted C1-C6-alkyl radical, preferably C1-C4-alkyl or C1-C4-alkoxy radical such as in each case described above for RL1.Particularly preferred radicals for RG1 are hydrogen, methoxy or hydroxyl.\",\n \"RG7, RG8, RG9 and RG10 in structural element G are independently of one another hydrogen, a hydroxyl group, CN, halogen, such as F, Cl, Br, I, a branched or unbranched, optionally substituted C1-C6-alkyl radical, such as optionally substituted methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl, C2-C6-alkenyl radical, such as optionally substituted vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl or 1-ethyl-2-methyl-2-propenyl, C2-C6-alkynyl radical, such as optionally substituted ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl or 1-ethyl-1-methyl-2-propynyl, an optionally substituted C3-C7-cycloalkyl radical, such as optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, C3-C7-heterocycloalkyl radical, such as optionally substituted aziridinyl, diaziridinyl, oxiranyl, oxaziridinyl, oxetanyl, thiiranyl, thietanyl, pyrrolidinyl, piperazinyl, morpholinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, hexahydroazepinyl, oxepanyl, 1,2-oxathiolanyl or oxazolidinyl, C3-C7-heterocycloalkenyl radical, such as optionally substituted azirinyl, diazirinyl, thiirenyl, thietyl, pyrrolinyls, oxazolinyls, azepinyl, oxepinyl, α-pyranyl, β-pyranyl, γ-pyranyl, dihydropyranyls, 2,5-dihydropyrrolinyl or 4,5-dihydrooxazolyl, a branched or unbranched, optionally substituted C1-C4-alkylene-C3-C7-cycloalkyl radical, which is composed, for example, of branched or unbranched C1-C4-alkylene radicals such as methylene, ethylene, propylene, n-butylene, isobutylene or t-butylene and, for example, the abovementioned C3-C7-cycloalkyl radicals, a branched or unbranched optionally substituted C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, which is composed of optionally substituted C1-C4-alkylene radicals, such as methylene, ethylene, propylene, n-butylene, isobutylene or t-butylene and, for example, the abovementioned C3-C7-heterocycloalkyl or C3-C7-heterocycloalkenyl radicals, the radicals being preferred which in the cyclic moiety contain one or two heteroatoms selected from the group consisting of N, O and S and up to two double bonds, a branched or unbranched, optionally substituted radical C1-C4-alkylene-O—RG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13, C1-C4-alkylene-SRG11 or C1-C4-alkylene-SO—RG11, which is composed of branched or unbranched, optionally substituted C1-C4-alkylene radicals, such as methylene, ethylene, propylene, n-butylene, isobutylene or t-butylene, the corresponding groups —O—, —CO—, —S—, —N and the terminal radicals RG11, RG12 and RG13 described below, an optionally substituted aryl radical, preferably optionally substituted phenyl, 1-naphthyl or 2-naphthyl, arylalkyl radical, preferably optionally substituted benzyl or ethylenephenyl (homobenzyl), hetaryl radical, preferably optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, thiadiazolyl, oxadiazolyl or triazinyl or their fused derivatives such as indazolyl, indolyl, benzothiophenyl, benzofuranyl, indolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl or isoquinolinyl, hetarylalkyl radical, preferably optionally substituted —CH2-2-pyridyl, —CH2-3-pyridyl, —CH2-4-pyridyl, —CH2-2-thienyl, —CH2-3-thienyl, —CH2-2-thiazolyl, —CH2-4-thiazolyl, CH2-5-thiazolyl, —CH2—CH2-2-pyridyl, —CH2—CH2-3-pyridyl, —CH2—CH2-4-pyridyl, —CH2—CH2-2-thienyl, —CH2—CH2-3-thienyl, —CH2—CH2-2-thiazolyl, —CH2—CH2-4-thiazolyl or —CH2—CH2-5-thiazolyl or a radical —S—RG11, —O—RG11, —SO—RG11, —SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —CO—NRG12RG13, —NRG12RG13, CO—RG11.Further, two radicals RG7 and RG9 or RG8 and RG10 or RG7 and RG8 or RG9 and RG10 can in each case independently of one another together form an optionally substituted, saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle or heterocycle which can contain up to 3 heteroatoms selected from the group consisting of O, N, S and up to two double bonds.\",\n \"Preferred radicals for RG7, RG8, RG9 and RG10 in the structural element G are independently of one another hydrogen, a hydroxyl group, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkylene-C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radical, a branched or unbranched, optionally substituted radical C1-C4-alkylene-ORG11, C1-C4-alkylene-CO—ORG11, C1-C4-alkylene-O—CO—RG11, C1-C4-alkylene-CO—RG11, C1-C4-alkylene-SO2—NRG12RG13, C1-C4-alkylene-CO—NRG12RG13, C1-C4-alkylene-O—CO—NRG12RG13, C1-C4-alkylene-NRG12RG13 or C1-C4-alkylene-SRG11, C1-C4-alkylene-SO—RG11, a radical —S—RG11, —O—RG11, —SO—RG11, SO2—RG11, —CO—ORG11, —O—CO—RG11, —O—CO—NRG12RG13, —SO2—NRG12RG13, —CO—NRG12RG13, —NRG12RG13 or CO—RG11, an optionally substituted C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl radical, as described above in each case.\",\n \"Particularly preferred radicals for RG7, RG8, RG9 and RG10 in the structural element G are independently of one another hydrogen, F or a branched or unbranched, optionally substituted C1-C4-alkyl radical, as described above.\",\n \"A branched or unbranched, optionally substituted C1-C8-alkyl radical for RG11, RG12 and RG13 is understood as meaning independently of one another, for example, the C1-C6-alkyl radicals mentioned above for RG1, plus the radicals heptyl and octyl.\",\n \"Preferred substituents of the branched or unbranched, optionally substituted C1-C8-alkyl radicals for RG11, RG12 and RG13 independently of one another are the radicals halogen, hydroxyl, C1-C4-alkoxy, —CN, —COOH and —CO—O—C1-C4-alkyl.\",\n \"A branched or unbranched, optionally substituted C2-C6-alkenyl, C2-C6-alkynyl or C1-C4-alkylene-C3-C7-cycloalkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for RG11, RG12 and RG13 independently of one another is understood as meaning, for example, the corresponding radicals mentioned above for RG1.Preferred, branched or unbranched, optionally substituted —C1-C5-alkylene-C1-C4-alkoxy radicals for RG11, RG12 and RG13 are independently of one another methoxymethylene, ethoxymethylene, t-butoxymethylene, methoxyethylene or ethoxyethylene.\",\n \"Preferred, branched or unbranched, optionally substituted mono- and bis-alkylaminoalkylene or acylaminoalkylene radicals for RG11, RG12 and RG13 are independently of one another branched or unbranched, optionally substituted radicals —C1-C4-alkylene-NH(C1-C4-alkyl), —C1-C4-alkylene-N(C1-C4-alkyl)2 or —C1-C4-alkylene-NH—CO—C1-C4-alkyl.\",\n \"Preferred optionally substituted heterocycloalkyl, heterocycloalkenyl, C1-C4-alkyleneheterocycloalkyl or C1-C4-alkyleneheterocycloalkenyl radicals for RG11, RG12 and RG13 are independently of one another the C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radicals described above for RG1.Particularly preferred, optionally substituted heterocycloalkyl, heterocycloalkenyl, C1-C4-alkyleneheterocycloalkyl or C1-C4-alkyleneheterocycloalkenyl radicals for RG11, RG12 and RG13 are independently of one another the C3-C7-heterocycloalkyl, C3-C7-heterocycloalkenyl, C1-C4-alkylene-C3-C7-heterocycloalkyl or C1-C4-alkylene-C3-C7-heterocycloalkenyl radicals described above for RG1, one or two heteroatoms selected from the group consisting of N, O and S and up to two double bonds being contained in the cyclic moiety.\",\n \"Further, RG12 and RG13 can independently of one another be a radical —SO2—RG11, —CO—O—RG11, —CO—NRG11RG11* or —CO—RG11, RG11* being a radical RG11 which is independent of RG11.Preferred structural elements G are composed of at least one preferred radical of the structural element G, while the remaining radicals are widely variable.\",\n \"Particularly preferred structural elements G are composed of the preferred radicals of the structural element G. Very particularly preferred structural elements G are composed of the particularly preferred radicals of the structural element G. Structural element B is understood as meaning a structural element comprising at least one atom which under physiological conditions can form hydrogen bridges as a hydrogen acceptor, at least one hydrogen acceptor atom having a distance of 5 to 14 atomic bonds from structural element G along the shortest possible route along the structural element skeleton.\",\n \"The arrangement of the structural skeleton of structural element B is widely variable.\",\n \"Suitable atoms which under physiological conditions can form hydrogen bridges as hydrogen acceptors are, for example, atoms having Lewis base properties, such as the heteroatoms nitrogen, oxygen or sulfur.\",\n \"Physiological conditions is understood as meaning a pH which prevails at the site in a body at which the ligands interact with the receptors.\",\n \"In the present case, the physiological conditions have a pH of, for example, 5 to 9.In a preferred embodiment, structural element B is a structural element of the formula IB A-E- IB where A and E have the following meanings: A is a structural element selected from the group: a 4- to 8-membered monocyclic saturated, unsaturated or aromatic hydrocarbon which can contain up to 4 heteroatoms selected from the group O, N and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, or a 9- to 14-membered polycyclic, saturated, unsaturated or aromatic hydrocarbon which can contain up to 6 heteroatoms selected from the group N, O and S, where, in each case independently of one another, the optionally present ring nitrogen or the carbons can be substituted, with the proviso that at least one heteroatom selected from the group O, N and S is contained in the structural element A, a radical where ZA1 is oxygen, sulfur or optionally substituted nitrogen and ZA2 is optionally substituted nitrogen, oxygen or sulfur and a radical where RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—R11, and E is a spacer structural element which covalently bonds the structural element A to the structural element G, where the number of atomic bonds along the shortest possible route along the structural element skeleton E is 5 to 14.In a particularly preferred embodiment, the structural element A is a structural element selected from the group of structural elements of the formulae IA1 to IA18 where m, p, g independently of one another are 1, 2 or 3, RA1, RA2 independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl or CO—C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or SO2NRA15RA16 or both radicals RA1 and RA2 together are a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N, and S, RA13, RA13* independently of one another are hydrogen, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, where RA14 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkylene-C3-C7-cycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RA15, RA16, independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, CO—C1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, arylalkyl, COO-alkylenearyl, SO2-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, CO-aryl, CO—NH-aryl, SO2-aryl, hetaryl, CO—NH-hetaryl or CO-hetaryl radical, RA3, RA4 independently of one another are hydrogen, —(CH2)n—(XA)j—RA12, or both radicals together are a 3- to 8-membered, saturated, unsaturated or aromatic N-heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle is optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, where n is 0, 1, 2 or 3, j is 0 or 1, XA is —CO—, —CO—N(RX1)—, —N(RX1)—CO—, —N(RX1)—CO—N(RX1*)—, —N(RX1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX1), —N(RX1)— or —N(RX1)—SO2—, RA12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally C1-C4-alkyl- or aryl-substituted C2-C6-alkynyl or C2-C6-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocycle, substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, a C3-C7-cycloalkyl, aryl or hetaryl radical, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RA12, together with RX1 or RX1* forms a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RX1, RX1* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, RA6, RA6* are hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, —CO—O—C1-C4-alkyl, arylalkyl, —CO—O-alkylenearyl, —CO—O-allyl, —CO—C1-C4-alkyl, —CO-alkylenearyl, C3-C7-cycloalkyl or —CO-allyl radical or in the structural element IA7 both radicals RA6 and RA6* together are an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl or —O—CO—C1-C4-alkyl radical, or an optionally substituted arylalkyl, —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical, or both radicals RA6 and RA7 together are an optionally substituted, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S, RA8 is hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl, CO—C1-C4-alkyl, SO2—C1-C4-alkyl or CO—O—C1-C4-alkyl radical or an optionally substituted aryl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl, CO—O-alkylenearyl or alkylenearyl radical, RA9, RA10 independently of one another are hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, or both radicals RA9 and RA10 together in the structural element IA14 are a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA11 is hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16, RA17 is hydrogen or, in the structural element IA16, both radicals RA9 and RA17 together are a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, RA18, RA19 independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 which is independent of RG11, Z1, Z2, Z3, Z4 independently of one another are nitrogen, C—H, C-halogen or a branched or unbranched, optionally substituted C—C1-C4-alkyl or C—C1-C4-alkoxy radical, Z5 is NRA8, oxygen or sulfur.\",\n \"In a further very particularly preferred embodiment, the structural element A is a structural element of the formula IA1, IA4, IA7, IA8 or IA9.For RA1 or RA2 independently of one another a branched or unbranched, optionally substituted C1-C6-alkyl radical is understood as meaning, for example, the corresponding radicals described above for RG1, preferably methyl or trifluoromethyl.\",\n \"For RA1 or RA2 in the structural elements IA1, IA2, IA3 or IA17, the branched or unbranched, optionally substituted radical CO—C1-C6-alkyl is composed, for example, of the group CO and the branched or unbranched, optionally substituted C1-C6-alkyl radicals described above for RA1 or RA2.Optionally substituted hetaryl, hetarylalkyl, aryl, arylalkyl or C3-C7-cycloalkyl radicals for RA1 or RA2 independently of one another are understood as meaning, for example, the corresponding radicals described above for RG7.For RA1 or RA2, the optionally substituted radicals CO—O—RA14, O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or SO2NRA15RA16 are composed, for example, of the groups CO—O, O, S, N, CO—N or SO2—N and the radicals RA14, RA15 or RA16 described in greater detail below.\",\n \"Further, both radicals RA1 and RA2 can together form a fused, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocycle or heterocycle which can contain up to three heteroatoms selected from the group consisting of O, N and S. RA13 and RA13* are independently of one another hydrogen, CN, halogen, such as fluorine, chlorine, bromine or iodine, a branched or unbranched, optionally substituted C1-C6-alkyl radical, such as described above for RG1, preferably methyl or trifluoromethyl or an optionally substituted aryl, arylalkyl, hetaryl or C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2NRA15RA16 or CO—NRA15RA16 as in each case described above for RA1.Preferred radicals for RA13 and RA13* are the radicals hydrogen, F, Cl, a branched or unbranched, optionally substituted C1-C6-alkyl radical, optionally substituted aryl or arylalkyl or a radical CO—O—RA14, O—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16.A branched or unbranched, optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, alkylenecycloalkyl, alkylene-C1-C4-alkoxy, C2-C6-alkenyl or C2-C6-alkynyl radical for RA14 in structural element A is understood as meaning, for example, the corresponding radicals described above for RG7.Optionally substituted aryl, arylalkyl, hetaryl or alkylhetaryl radicals for RA14 in structural element A are understood as meaning, for example, the corresponding radicals described above for RG7.Preferred radicals for RA14 are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical and optionally substituted benzyl.\",\n \"A branched or unbranched, optionally substituted C1-C6-alkyl or arylalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or hetarylalkyl radical for RA15 or RA16 independently of one another is understood as meaning, for example, the corresponding radicals described above for RA14.The branched or unbranched, optionally substituted CO—C1-C6-alkyl, SO2—C1-C6-alkyl, COO—C1-C6-alkyl, CO—NH—C1-C6-alkyl, COO-alkylenearyl, CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or SO2-alkylenearyl radicals or the optionally substituted CO-aryl, SO2-aryl, CO—NH-aryl, CO—NH-hetaryl or CO-hetaryl radicals for RA15 or RA16 are composed, for example, of the corresponding groups —CO—, —SO2—, —CO—O—, —CO—NH— and the corresponding branched or unbranched, optionally substituted C1-C6-alkyl, hetarylalkyl or arylalkyl radicals or the corresponding optionally substituted aryl or hetaryl radicals described above.\",\n \"A radical —(CH2)n—(XA)j—RA12 for RA3 or RA4 independently of one another is understood as meaning a radical which is composed of the corresponding radicals —(CH2)n—, (XA)j and RA12.Here, n can be: 0, 1, 2 or 3 and j can be: 0 or 1.XA is a doubly bonded radical selected from the group —CO—, —CO—N(RX1)—, —N(RX1)—CO—, —N(RX1)—CO—N(RX1*)—, —N(RX1)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RX1)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RX1)—, —N(RX1)— and —N(RX1)—SO2—.\",\n \"RA12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, as described above for RG7.a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, or a 3- to 6-membered, saturated or unsaturated heterocycle which is substituted by up to three identical or different radicals and can contain up to three different or identical heteroatoms O, N, S, such as optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-(1,3,4-thiadiazolyl), 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, triazinyl.\",\n \"Further, RA12 and RX1 or RX1* can together form a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N. Preferably, the radical RA12 together with the radical RX1 or RX1* forms a cyclic amine as the C3-C7-heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl, where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amine protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO2—C1-C4-alkyl, —SO2-phenyl or —SO2-benzyl.\",\n \"A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C12-alkynyl, preferably C2-C6-alkynyl or C2-C6-alkenyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl or hetaryl radical for RX1 and RX1* independently of one another is understood as meaning, for example, the corresponding radicals described above for RG7.Preferred, branched or unbranched, optionally substituted C1-C6-alkoxyalkyl for RX1 and RX1* are independently of one another methoxymethylene, ethoxymethylene, t-butoxymethylene, methoxyethylene or ethoxyethylene.\",\n \"Preferred, branched or unbranched, optionally substituted radicals CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl are preferably composed of the C1-C6-alkyl, arylalkyl, aryl or hetaryl radicals and the radicals —CO—, —O—, —SO2— described above.\",\n \"Preferred radicals for RX1 and RX1* are independently of one another hydrogen, methyl, cyclopropyl, allyl and propargyl.\",\n \"RA3 and RA4 can further together form a 3- to 8-membered saturated, unsaturated or aromatic N heterocycle which can additionally contain two further, identical or different heteroatoms O, N or S, where the cycle can be optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, RA5 is a branched or unbranched, optionally substituted C1-C6-alkyl, arylalkyl, C1-C4-alkyl-C3-C7-cycloalkyl or C3-C7-cycloalkyl radical or an optionally substituted aryl, hetaryl, heterocycloalkyl or heterocycloalkenyl radical, such as described above for RG7.RA6 and RA6* are independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C4-alkyl radical, such as optionally substituted methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, —CO—O—C1-C4-alkyl or —CO—C1-C4-alkyl radical such as composed of the group —CO—O— or —CO— and the C1-C4-alkyl radicals described above, arylalkyl radical, as described above for RG7, —CO—O-alkylenearyl or —CO-alkylenearyl radical such as composed of the group —CO—O— or —CO— and the arylalkyl radicals described above, —CO—O-allyl or —CO-allyl radical, or C3-C7-cycloalkyl radical, such as described above for RG7.Further, both radicals RA6 and RA6* in structural element IA7 can together form an optionally substituted, saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S. RA7 is hydrogen, —OH, —CN, —CONH2, a branched or unbranched, optionally substituted C1-C4-alkyl radical, for example as described above for RA6, C1-C4-alkoxy, arylalkyl or C3-C7-cycloalkyl radical, for example as described above for RL14, a branched or unbranched, optionally substituted —O—CO—C1-C4-alkyl radical, which is composed of the group —O—CO— and, for example, of the C1-C4-alkyl radicals mentioned above or an optionally substituted —O-alkylenearyl, —O—CO-aryl, —O—CO-alkylenearyl or —O—CO-allyl radical which is composed of the groups —O— or —O—CO— and, for example, of the corresponding radicals described above for RG7.Further, both radicals RA6 and RA7 can together form an optionally substituted unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to two further different or identical heteroatoms O, N, S. For RAS in structural element A, the branched or unbranched, optionally substituted C1-C4-alkyl radical or an optionally substituted aryl or arylalkyl radical is understood as meaning, for example, the corresponding radicals described above for RA15, where the radicals CO—C1-C4-alkyl, SO2—C1-C4-alkyl, CO—O—C1-C4-alkyl, CO-aryl, SO2-aryl, CO—O-aryl, CO-alkylenearyl, SO2-alkylenearyl or CO—O-alkylenearyl are composed analogously to the other composed radicals of the group consisting of CO, SO2 and COO and, for example, of the corresponding C1-C4-alkyl, aryl or arylalkyl radicals described above for RA15 and these radicals can be optionally substituted.\",\n \"In each case, for RA9 or RA10 independently of one another, a branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl or C3-C7-cycloalkyl radical is understood as meaning, for example, the corresponding radicals described above for RA14, preferably methyl or trifluoromethyl.\",\n \"In each case, for RA9 or RA10 independently of one another, a radical CO—O—RA14, O—RA14, S—RA14, SO2—NRA15RA16, NRA15RA16 or CO—NRA15RA16 is understood as meaning, for example, the corresponding radicals described above for RA13.Further, both radicals RA9 and RA10 together in structural element IA14 can form a 5- to 7-membered saturated, unsaturated or aromatic carbocycle or heterocycle, which can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals.\",\n \"Substituents in this case are in particular understood as meaning halogen, CN, a branched or unbranched, optionally substituted C1-C4-alkyl radical, such as methyl or trifluoromethyl or the radicals O—RA14, S—RA14, NRA15RA16, CO—NRA15RA16 or —((RA8)HN)C═N—RA7.A branched or unbranched, optionally substituted C1-C6-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C3-C7-cycloalkyl radical or a radical CO—O—RA14, O—RA14, S—RA14, NRA15RA16, SO2—NRA15RA16 or CO—NRA15RA16 for RA11 is understood, for example, as meaning the corresponding radicals described above for RA9.Further, in structural element IA16, both radicals RA9 and RA17 together can form a 5- to 7-membered saturated, unsaturated or aromatic heterocycle which, in addition to the ring nitrogen, can contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals.\",\n \"A branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG11 for RA18 and RA19 independently of one another is understood as meaning, for example, the radicals described above for RG12, preferably hydrogen or a branched or unbranched, optionally substituted C1-C8-alkyl radical.\",\n \"Z1, Z2, Z3, Z4 are independently of one another nitrogen, C—H, C-halogen, such as C—F, C—Cl, C—Br or C—I or a branched or unbranched, optionally substituted C—C1-C4-alkyl radical which is composed of a carbon radical and, for example, a C1-C4-alkyl radical described above for RA6 or a branched or unbranched optionally substituted C—C1-C4-alkoxy radical which is composed of a carbon radical and, for example, a C1-C4-alkoxy radical described above for RA7.Z5 is oxygen, sulfur or a radical NRA8.Preferred structural elements A are composed of at least one preferred radical of the radicals belonging to the structural element A, while the remaining radicals are widely variable.\",\n \"Particularly preferred structural elements A are composed of the preferred radicals of the structural element A.\",\n \"In a preferred embodiment, the spacer structural element E is understood as meaning a structural element that consists of a branched or unbranched aliphatic C2-C30-hydrocarbon radical which is optionally substituted and contains heteroatoms and/or of a 4- to 20-membered aliphatic or aromatic mono- or polycyclic hydrocarbon radical which is optionally substituted and contains heteroatoms.\",\n \"In a further preferred embodiment, the spacer structural element E is composed of two to four substructural elements, selected from the group consisting of E1 and E2, where the sequence of linkage of the substructural elements is arbitrary and E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(XE)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where c, d, f, g, h independently of one another are 0, 1 or 2, k1, k2, k3, k4, k5, k6 independently of one another are 0 or 1, XE, QE independently of one another are an optionally substituted 4- to 11-membered mono- or polycyclic, aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O and S, where the ring carbons and/or the ring nitrogens can optionally be substituted, YE, ZE independently of one another are CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9, RE10 independently, of one another are hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical, a radical —(CH2)x—(WE)z—RE17, an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, or independently of one another in each case two radicals RE1 and RE2 or RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocycle or heterocycle which can contain up to three heteroatoms selected from the group O, N and S, x is 0, 1, 2, 3 or 4, z is 0 or 1, WE is —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, RW2, RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3- to 8-membered, saturated or unsaturated heterocycle substituted by up to three identical or different radicals, which can contain up to three different or identical heteroatoms O, N, S, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S and the cycle can optionally be substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, or the radical RE17 forms, together with RW2 or RW2*, a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group O, S and N, RE11, RE11* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl radical, RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl radical, an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical or a radical CO—RE16, COORE16 or SO2—RE16, RE13, RE14 independently of one another are hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE15 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, RE16 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical.\",\n \"The coefficient c is preferably 0 or 1, the coefficient d is preferably 1 or 2, and the coefficients f, g, h independently of one another are preferably 0 or 1.An optionally substituted 4- to 11-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which can contain up to 6 double bonds and up to 6 identical or different heteroatoms selected from the group N, O, S, where the ring carbons or ring nitrogens can optionally be substituted, for QE and XE independently of one another is preferably understood as meaning optionally substituted arylene, such as optionally substituted phenylene or naphthylene, or optionally substituted hetarylene such as the radicals and their substituted or fused derivatives, or radicals of the formulae IE1 to IE11, where the incorporation of the radicals can take place in both orientations.\",\n \"Aliphatic hydrocarbons are understood as meaning, for example, saturated and unsaturated hydrocarbons.\",\n \"Z6 and Z7 are independently of one another CH or nitrogen.\",\n \"Z8 is oxygen, sulfur or NH.\",\n \"Z9 is oxygen, sulfur or NRE20.r1, r2, r3 and t are independently of one another 0, 1, 2 or 3.s and u are independently of one another 0, 1 or 2.Particularly preferably, XE and QE independently of one another are optionally substituted phenylene, a radical and their substituted or fused derivatives, or radicals of the formulae IE1, IE2, IE3, IE4 and IE7, where the incorporation of the radicals can take place in both orientations.\",\n \"RE18 and RE19 are independently of one another hydrogen, —NO2, —NH2, —CN, —COOH, a hydroxyl group, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C4-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, as in each case described above.\",\n \"RE20 is independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C3-C12-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, hetaryl, CO-hetaryl or SO2-alkylenearyl radical, preferably hydrogen or a branched or unbranched, optionally substituted C1-C6-alkyl radical.\",\n \"YE and ZE are independently of one another CO, CO—NRE12, NRE12—CO, sulfur, SO, SO2, SO2—NRE12, NRE12—SO2, CS, CS—NRE12, NRE12—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CRE13—O—CRE14, C(═CRE13RE14), CRE13═CRE14, —CRE13(ORE15)—CHRE14— or —CHRE13—CRE14(ORE15)—, preferably CO, SO2 and oxygen.\",\n \"RE12 is hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl or C2-C8-alkynyl radical or an optionally substituted C3-C7-cycloalkyl, hetaryl, arylalkyl or hetarylalkyl radical, such as correspondingly described above for RG7 or a radical CO—RE16, COORE16 or SO2—RE16, preferably hydrogen, methyl, allyl, propargyl and cyclopropyl.\",\n \"A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for RE13, RE14 or RE15 independently of one another is understood as meaning, for example, the corresponding radicals described above for RG7.A branched or unbranched, optionally substituted C1-C4-alkoxy radical for RE13 or RE14 independently of one another is understood as meaning, for example, the C1-C4-alkoxy radicals described above for RA14.Preferred alkylenecycloalkyl radicals for RE13, RE14 or RE15 independently of one another are, for example, the C1-C4-alkylene-C3-C7-cycloalkyl radicals described above for RG7.A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical, or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkylene-C3-C7-heterocycloalkyl, C1-C4-alkylene-C3-C7-heterocycloalkenyl or hetarylalkyl radical for RE16 is understood as meaning, for example, the corresponding radicals described above for RG11.A branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or alkylenecycloalkyl radical or an optionally substituted C3-C7-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical for RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9 or RE10 independently of one another is understood as meaning, for example, the corresponding radicals mentioned above for RG1.Further, two radicals RE3 and RE4 or RE5 and RE6 or RE7 and RE8 or RE9 and RE10 can in each case independently of one another together form a 3- to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle which can contain up to three heteroatoms from the group O, N and S. The radical —(CH2)x—(WE)z—RE17 is composed of a C0-C4-alkylene radical, optionally a bonding element WE selected from the group —CO—, —CO—N(RW2)—, —N(RW2)—CO—, —N(RW2)—CO—N(RW2*)—, —N(RW2)—CO—O—, —O—, —S—, —SO2—, —SO2—N(RW2)—, —SO2—O—, —CO—O—, —O—CO—, —O—CO—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, preferably selected from the group —CO—N(RW2)—, —N(RW2)—CO—, —O—, —SO2—N(RW2)—, —N(RW2)— or —N(RW2)—SO2—, and the radical RE17, where RW2 and RW2* independently of one another are hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C8-alkynyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl or SO2—C1-C6-alkyl radical or an optionally substituted hetaryl, hetarylalkyl, arylalkyl, C3-C7-cycloalkyl, CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO2-aryl, CO-hetaryl or SO2-alkylenearyl radical, preferably independently of one another are hydrogen, methyl, cyclopropyl, allyl, propargyl, and RE17 is hydrogen, a hydroxyl group, CN, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, an optionally substituted C3-C7-cycloalkyl, aryl, hetaryl or arylalkyl radical, a C2-C6-alkynyl or C2-C6-alkenyl radical optionally substituted by C1-C4-alkyl or aryl, an optionally substituted C6-C12-bicycloalkyl, C1-C6-alkylene-C6-C12-bicycloalkyl, C7-C20-tricycloalkyl or C1-C6-alkylene-C7-C20-tricycloalkyl radical, or a 3 to 8-membered, saturated or unsaturated heterocycle which is substituted by up to three identical or different radicals and can contain up to three different or identical heteroatoms O, N, S, where two radicals together can be a fused, saturated, unsaturated or aromatic carbocycle or heterocycle which can contain up to three different or identical heteroatoms O, N, S, and the cycle can be optionally substituted or a further, optionally substituted, saturated, unsaturated or aromatic cycle can be fused to this cycle, such as optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-(1,3,4-thiadiazolyl), 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl or triazinyl.\",\n \"Further, RE17 and RW2 or RW2* can together form a saturated or unsaturated C3-C7-heterocycle which can optionally contain up to two further heteroatoms selected from the group consisting of O, S and N. Preferably, the radicals RE17 and RW2 or RW2* together form a cyclic amine as the C3-C7-heterocycle in the case where the radicals are bonded to the same nitrogen atom, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl where in heterocycles which carry free amine protons, such as N-piperazinyl, the free amine protons can be replaced by customary amine protective groups, such as methyl, benzyl, Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO2—C1-C4-alkyl, —SO2-phenyl or —SO2-benzyl.\",\n \"Preferred radicals for RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9 or RE10 are independently of one another hydrogen, halogen, a branched or unbranched, optionally substituted C1-C6-alkyl radical, optionally substituted aryl or the radical —(CH2)x—(WE)z—RE17.Particularly preferred radicals for RE1, RE2, RE3, RE4, RE5, RE6, RE7, RE8, RE9 or RE10 are independently of one another hydrogen, F, a branched or unbranched, optionally substituted C1-C4-alkyl radical, in particular methyl.\",\n \"A branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxyalkyl, C2-C6-alkenyl, C2-C12-alkynyl or arylalkyl radical or an optionally substituted aryl, hetaryl or C3-C7-cycloalkyl for RE11 and RE11* in structural element E independently of one another is understood as meaning, for example, the corresponding radicals described above for RG7.The branched or unbranched, optionally substituted radicals CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, CO—NH—C1-C6-alkoxyalkyl, CO—NH—C1-C6-alkyl or SO2—C1-C6-alkyl radical or the optionally substituted radicals CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO2-aryl, CO-hetaryl, SO2-alkylenearyl, SO2-hetaryl or SO2-alkylenehetaryl for RE11 and RE11* independently of one another are composed, for example, of the corresponding groups CO, COO, CONH or SO2 and the corresponding radicals mentioned above.\",\n \"Preferred radicals for RE11 or RE11* are independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C12-alkynyl or arylalkyl radical, or an optionally substituted hetaryl or C3-C7-cycloalkyl radical.\",\n \"Particularly preferred radicals for RE11 or RE11* are hydrogen, methyl, cyclopropyl, allyl or propargyl.\",\n \"In a particularly preferred embodiment of structural element E1, structural element E1 is a radical —CH2—CH2—CO—, —CH2—CH2—CH2—CO— or a C1-C5-alkylene radical.\",\n \"In a particularly preferred embodiment of structural element E, the spacer structural element E used is a structural element of the formula IE1E2 -E2-E1- IE1E2 where the structural elements E2 and E1 have the meanings described above.\",\n \"Preferred structural elements E are composed of at least one preferred radical of the radicals belonging to structural element E, while the remaining radicals are widely variable.\",\n \"Particularly preferred structural elements E are composed of the preferred radicals of structural element E. Preferred structural elements B are composed either of the preferred structural element A, while E is widely variable, or of the preferred structural element E, while A is widely variable.\",\n \"In a further preferred embodiment, the structural element E used is the structural element E′ described below for the novel compounds of the formula I′.\",\n \"In a further preferred embodiment, the structural element G used is the structural element G′ described below for the novel compounds of the formula I′.\",\n \"The compounds of the formula I, and also the intermediates for their preparation, can have one or more asymmetric substituted carbon atoms.\",\n \"The compounds can be present as pure enantiomers or pure diastereomers or as a mixture thereof.\",\n \"The use of an enantiomerically pure compound as the active compound is preferred.\",\n \"The compounds of the formula I can also be present in other tautomeric forms.\",\n \"The compounds of the formula I can also be present in the form of physiologically tolerable salts.\",\n \"The compounds of the formula I can also be present as prodrugs in a form in which the compounds of the formula I are liberated under physiological conditions.\",\n \"By way of example, reference may be made here to the group T in structural element L, which in some cases contains groups which are hydrolyzable to the free carboxylic acid group under physiological conditions.\",\n \"Derivatized structural elements B or A are also suitable which liberate the structural element B or A respectively under physiological conditions.\",\n \"In preferred compounds of the formula I, in each case one of the three structural elements B, G or L has the preferred range, while the remaining structural elements are widely variable.\",\n \"In particularly preferred compounds of the formula I, in each case two of the three structural elements B, G and L have the preferred range, while the remaining structural elements are widely variable.\",\n \"In very particularly preferred compounds of the formula I, in each case all three structural elements B, G and L have the preferred range, while the remaining structural element is widely variable.\",\n \"Preferred compounds of the formula I contain, for example, the preferred structural element G, while the structural elements B and L are widely variable.\",\n \"In particularly preferred compounds of the formula I, for example, B is replaced by the structural element A-E- and the compounds contain, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L are widely variable.\",\n \"Further particularly preferred compounds of the formula I contain, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L are widely variable.\",\n \"The invention further relates to the use of the structural element of the formula IGL -G-L IGL for the preparation of compounds which bind to integrin receptors.\",\n \"The compounds of the formula I bind to integrin receptors.\",\n \"The compounds of the formula I are therefore preferably suitable as integrin receptor ligands and for the production of drugs for treating diseases in which an integrin receptor is involved, in particular for treating diseases in which the interaction between integrins and their natural ligands is dysregulated, i.e.\",\n \"excessive or decreased.\",\n \"Integrin receptor ligands are understood as meaning agonists and antagonists.\",\n \"An excessive or decreased interaction is understood as meaning both an excessive or decreased expression of the natural ligand and/or of the integrin receptor and thus an excessive or decreased amount of natural ligand and/or integrin receptor or an increased or decreased affinity of the natural ligand for the integrin receptor.\",\n \"The interaction between integrins and their natural ligands is dysregulated compared with the normal state, i.e.\",\n \"excessive or decreased, if this dysregulation does not correspond to the physiological state.\",\n \"An increased or decreased interaction can lead to pathophysiological situations.\",\n \"The level of dysregulation which leads to a pathophysiological situation is dependent on the individual organism and on the site and nature of the disorder.\",\n \"Preferred integrin receptors for which the compounds of the formula I according to the invention can be used are the α5β1, α4β1, αVβ5 and αVβ3 integrin receptors.\",\n \"The compounds of the formula I particularly preferably bind to the αVβ3 integrin receptor and can thus be particularly preferably used as ligands of the αVβ3 integrin receptor and for the treatment of illnesses in which the interaction between αVβ3 integrin receptor and its natural ligand is excessive or reduced.\",\n \"The compounds of the formula I are preferably used for the treatment of the following illnesses: cardiovascular disorders such as atherosclerosis, restenosis after vascular injury or stent implantation, and angioplasty (neointima formation, smooth muscle cell migration and proliferation), acute kidney failure, angiogenesis-associated microangiopathies such as diabetic angiopathies or retinopathy or rheumatoid arthritis, blood platelet-mediated vascular occlusion, arterial thrombosis, stroke, reperfusion damage after myocardial infarct or stroke, carcinomatous disorders, such as in tumor metastasis or in tumor growth (tumor-induced angiogenesis), osteoporosis (bone resorption after chemotaxis and adhesion of osteoclasts to the bone matrix), high blood pressure, psoriasis, hyperparathyroidism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, inflammation, wound healing, cardiac insufficiency, congestive heart failure CHF, as well as in antiviral, antimycotic, antiparasitic or antibacterial therapy and prophylaxis (adhesion and internalization).\",\n \"Furthermore, the invention relates in particular to the use of the compounds of the formula I as ligands of the αVβ3 integrin receptor.\",\n \"The invention furthermore relates to the novel compounds of the formula I′ A-E′-G′-L I′ where the structural elements A and L have the meanings described above.\",\n \"Preferred structural elements A and L are described.\",\n \"Structural element E′ is composed of two to four substructural elements selected from the group consisting of E1 and E2, the linkage sequence of the substructural elements being arbitrary and E1 and E2 having the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)g—(X)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where all radicals and coefficients of structural element E′ have the meanings of structural element E described above, with the proviso that in the case in which YE or ZE=CO and a radical XE or QE or an aromatic or heteroaromatic radical of the structural element A is bonded directly to YE or ZE, a direct atomic bond from YE or ZE to the structural element G′ is excluded.\",\n \"In a further preferred embodiment of structural element E′, the structural element E′ used is a structural element of the formula IE1E2 -E2-E1- IE1E2 where E1 and E2 have the following meanings: E1 is a substructural element of the formula IE1 —(YE)k1—(CRE1RE2)c-(QE)k2-(CRE3RE4)d— IE1 and E2 is a substructural element of the formula IE2 —(NRE11)k3—(CRE5RE6)f-(ZE)k4-(CRE7RE8)—(XE)k5—(CRE9RE10)h—(NRE11*)k6— IE2, where all radicals and coefficients of structural element E′ have the meanings of structural element E described above, with the proviso that in the case where YE═CO, k1 and k5=1 and h and k6=0 the sum of the indices c, k2 and d must be other than 0 and in the case where an aromatic or heteroaromatic radical from the structural element A is bonded directly to YE or ZE, a direct atomic bond from YE or ZE to the structural element G′ is excluded.\",\n \"Further preferred embodiments of structural element E′ correspond to the preferred embodiments of structural element E with the proviso described above.\",\n \"Structural element G′ is identical to structural element G, as described above, except for the radicals RG12 and RG13.In structural element G′, the radicals RG12 and RG13 of structural element G are replaced by the radicals RG′12 and RG′13.The radicals RG12 and RG′13 in structural element G′ have the following meanings: independently of one another hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C5-alkylene-C1-C4-alkoxy, mono- and bis-alkylaminoalkylene or acylaminoalkylene radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical, or a radical —SO2—RG11, —CO—ORG11, —CO—NRG11RG11* or —CO—RG14, where RG14 is hydrogen, a branched or unbranched, optionally substituted C1-C8-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C1-C5-alkylene-C1-C4-alkoxy radical or an optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl, hetaryl, C3-C7-cycloalkyl, C1-C4-alkylene-C3-C7-cycloalkyl, arylalkyl, C1-C4-alkyleneheterocycloalkyl, C1-C4-alkyleneheterocycloalkenyl or hetarylalkyl radical.\",\n \"Preferred radicals of RG′12 and RG13 are the corresponding radicals described above for RG12 and RG13.Further preferred embodiments of the structural element G′ correspond to the preferred embodiments of structural element G. The compounds of the formula I′, and also the intermediates for their preparation, can have one or more asymmetric substituted carbon atoms.\",\n \"The compounds can be present as pure enantiomers or pure diastereomers or as a mixture thereof.\",\n \"The use of an enantiomerically pure compound as active compound is preferred.\",\n \"The compounds of the formula I′ can also be present in other tautomeric forms.\",\n \"The compounds of the formula I′ can also be present in the form of physiologically tolerable salts.\",\n \"The compounds of the formula I′ can also be present as prodrugs in a form in which the compounds of the formula I′ are liberated under physiological conditions.\",\n \"By way of example, reference may be made here to the group T in structural element L, which in some cases contains groups which are hydrolyzable to the free carboxylic acid group under physiological conditions.\",\n \"Derivatized structural elements A which liberate the structural element A under physiological conditions are also suitable.\",\n \"Analogously to the compounds of the formula I, the following applies for the compounds of the formula I′ as mentioned above: In preferred compounds of the formula I′, one of the four structural elements A, E′, G′ or L in each case have the preferred range, while the remaining structural elements are widely variable.\",\n \"In particularly preferred compounds of the formula I′, two of the four structural elements A, E′, G′ or L in each case have the preferred range, while the remaining structural elements are widely variable.\",\n \"In further particularly preferred compounds of the formula I′, three of the four structural elements A, E′, G′ or L in each case have the preferred range, while the remaining structural element is widely variable.\",\n \"In very particularly preferred compounds of the formula I′, all four structural elements A, E′, G′ or L have the preferred range.\",\n \"Preferred compounds of the formula I, have, for example, the preferred structural element G′, while the structural elements A, E′ and L are widely variable.\",\n \"Further particularly preferred compounds of the formula I′ have, for example, the preferred structural element G′ and the preferred structural element A, while the structural elements E′ and L are widely variable.\",\n \"Very particularly preferred compounds of the formula I′ are listed below, the number before the text block being the number of an individualized compound of the formula I′, and in the text block A-E′-G′-L the abbreviations separated by a bonding dash in each case being an individual structural element A, E′, G′ or L and the meaning of the abbreviations of the structural elements being explained after the table.\",\n \"No.\",\n \"A-E′-G′-L 1 bhs-edia3-phen-es 2 2py-inda2-phen-es 3 bhs-35thirna2-meph-es 4 bim-dibema2-dmeph-es 5 2py-bam2-4-clph-es 6 2py-dibema2-dmeph-es 7 bhs-a24thima2-dmeph-es 8 bhs-aaf-phen-es 9 bhs-a24thima2-4-clph-es 10 bim-me42thiaz2-phen-es 11 2py-edia2-phen-es 12 bim-a24thima2-hdb-es 13 2py-apma2-4-clph-es 14 gua-chex2-phen-es 15 bhs-dibema2-4-clph-es 16 bhs-bam2-phen-es 17 bim-a23thima2-4-clph-es 18 bim-dibema2-phen-es 19 bim-bam2-4-clph-es 20 2py-pipa2-4-clph-es 21 2py-me25thima2-phen-es 22 gua-a24thima2-ioph-es 23 imhs-apma2-phen-es 24 2py-apma2-ioph-es 25 gua-edia3-phen-es 26 bhs-a23thima2-4-clph-es 27 2py-a24thima2-2pyph-es 28 2py-bam2-thoph-es 29 gua-apma2-phen-es 30 2py-a24thima2-reph-es 31 gua-hexa-phen-es 32 dimethpym-apma2-phen-es 33 2py-dibema2-meph-es 34 bhs-apma2-phen-es 35 bim-edia3-phen-es 36 gua-apma2-meph-es 37 bim-apma2-reph-es 38 2py-a24thima2-dmeph-es 39 gua-aaf-phen-es 40 gua-apma2-yrph-es 41 gua-pipeme2-phen-es 42 2py-35thima2-phen-es 43 gua-a24thima2-reph-es 44 bim-bam2-phen-es 45 gua-a24thima2-phen-ms 46 gua-apma2-reph-es 47 mam2py-a24thima2-phen-es 48 2py-a24thima2-phen-gs 49 2py-apma2-phen-nes 50 2py-a24thima2-4-clph-es 51 bhs-penta-phen-es 52 gua-35thima2-dmeph-es 53 bim-dibema2-thoph-es 54 bim-a24thima2-reph-es 55 2py-a23thima2-4-clph-es 56 gua-a23thima2-phen-es 57 dhim-a24thima2-phen-es 58 gua-penta-phen-es 59 bhs-a24thima2-reph-es 60 2py-a23thima2-meph-es 61 gua-prodia2-phen-es 62 bhs-apma2-reph-es 63 2py-apma2-meph-es 64 gua-bam2-4-clph-es 65 2py-me35thima2-phen-es 66 gua-apma2-2pyph-es 67 2py-35thima2-thoph-es 68 clim-a24thima2-phen-es 69 2py-buta-phen-es 70 am2py-apma2-phen-es 71 gua-a24thima2-dmeph-es 72 bhs-apma2-hdb-es 73 bhs-dibema2-thoph-es 74 bim-dibema2-meph-es 75 bhs-bam2-meph-es 76 bhs-apma2-yrph-es 77 bhs-apma2-dmeph-es 78 gua-me25thima2-phen-es 79 2py-a24thima2-meph-es 80 gua-inda2-phen-es 81 bhs-mepipe2-phen-es 82 bhs-a24thima2-phen-as 83 bim-pipa2-thoph-es 84 bhs-bam2-4-clph-es 85 bhs-a24thima2-phen-es 86 bhs-35thima2-phen-es 87 bim-penta-phen-es 88 bhs-apma2-dbph-es 89 gua-42thiaz2-phen-es 90 bhs-a24thima2-24pym-es 91 2py-dibema2-phen-es 92 bim-a24thima2-dm-es 93 bhs-pipa2-4-clph-es 94 2py-apma2-phen-ps 95 2py-apma2-dmeph-es 96 2py-mepipe2-phen-es 97 bhs-35thima2-4-clph-es 98 gua-apma2-phen-mals 99 gua-35thima2-4-clph-es 100 mam2py-apma2-phen-es 101 gua-buta-phen-es 102 2py-a23thima2-thoph-es 103 2py-pyma2-phen-es 104 gua-apma2-phen-gs 105 bim-apma2-phen-as 106 bhs-apma2-4-clph-es 107 bhs-a24thima2-4-pyph-es 108 thpym-apma2-phen-es 109 gua-pipa2-dmeph-es 110 amim-a24thima2-phen-es 111 bim-aepi2-phen-es 112 bim-a23thima2-thoph-es 113 bhs-a23thima2-thoph-es 114 gua-pdagk-phen-es 115 2py-hexa-phen-es 116 bhs-a24thima2-meph-es 117 gua-bam2-meph-es 118 2py-35thima2-meph-es 119 2py-pipa2-meph-es 120 bhs-a23thima2-phen-es 121 bim-pipeme2-phen-es 122 bhs-buta-phen-es 123 bhs-pipa2-dmeph-es 124 bhs-pipa2-meph-es 125 2py-35thima2-dmeph-es 126 bim-bam2-thoph-es 127 gua-35thima2-thoph-es 128 bim-edia2-phen-es 129 bim-apma2-phen-nes 130 gua-bam2-thoph-es 131 gua-bam2-phen-es 132 pippy-a24thima2-phen-es 133 gua-35thima2-phen-es 134 bim-a23thima2-phen-es 135 gua-dibema2-dmeph-es 136 bhs-apma2-phen-gs 137 bhs-apma2-thoph-es 138 2py-apma2-phen-es 139 im-a24thima2-phen-es 140 gua-aepi2-phen-es 141 2py-mea2-phen-es 142 gua-a24thima2-phen-es 143 2py-a24thima2-thaph-es 144 gua-apma2-4-clph-es 145 bhs-apma2-phen-f2es 146 bhs-inda2-phen-es 147 bim-a24thima2-dbph-es 148 bim-apma2-phen-ms 149 gua-a23thima2-thoph-es 150 pippy-apma2-phen-es 151 bhs-apma2-meph-es 152 2py-apma2-phen-as 153 gua-mea2-phen-es 154 bhs-me35thima2-phen-es 155 bhs-pdagk-phen-es 156 bim-42thiaz2-phen-es 157 2py-pipeme2-phen-es 158 bim-me25thima2-phen-es 159 gua-dibema2-phen-es 160 2py-apma2-oxph-es 161 bhs-a24thima2-3clph-es 162 bim-pyma2-phen-es 163 bhs-edia2-phen-es 164 imhs-a24thima2-phen-es 165 gua-dibema2-thoph-es 166 bim-a24thima2-4-clph-es 167 bim-apma2-phen-ps 168 gua-apma2-dm-es 169 2py-a24thima2-phen-mals 170 2py-dibema2-4-clph-es 171 bhs-dibema2-meph-es 172 bim-aof-phen-es 173 bhs-pipeme2-phen-es 174 gua-35thima2-meph-es 175 bim-aaf-phen-es 176 bim-dibema2-4-clph-es 177 bim-a24thima2-2pyph-es 178 bim-a24thima2-yrph-es 179 bim-35thima2-4-clph-es 180 bhs-aepi2-phen-es 181 bim-pipa2-phen-es 182 gua-a23thima2-dmeph-es 183 2py-a24thima2-yrph-es 184 gua-a24thima2-dmeoph-es 185 bhs-42thiaz2-phen-es 186 bim-mepipe2-phen-es 187 2py-chex2-phen-es 188 bhs-prodia2-phen-es 189 gua-bam2-dmeph-es 190 bhs-me25thima2-phen-es 191 thpym-a2.4thima2-phen-es 192 bim-pipa2-dmeph-es 193 bhs-dibema2-phen-es 194 gua-a24thima2-thoph-es 195 2py-pipa2-thoph-es 196 clim-apma2-phen-es 197 bhs-chex2-phen-es 198 gua-a24thima2-phen-nes 199 gua-a24thima2-meph-es 200 bhs-a24thima2-dmeoph-es 201 2py-apma2-24pym-es 202 2py-a24thima2-phen-pms 203 gua-a24thima2-4-piph-es 204 bim-apma2-3clph-es 205 gua-apma2-hdb-es 206 2py-bam2-meph-es 207 bhs-a24thima2-phen-nes 208 gua-pyma2-phen-es 209 bim-a24thima2-thoph-es 210 gua-mepipe2-phen-es 211 bim-apma2-4-clph-es 212 2py-42thiaz2-phen-es 213 bim-apma2-24pym-es 214 bhs-a23thima2-dmeph-es 215 gua-apma2-dbph-es 216 gua-me35thima2-phen-es 217 bim-35thima2-phen-es 218 gua-apma2-thaph-es 219 bim-35thima2-thoph-es 220 gua-apma2-phen-f2es 221 2py-apma2-3clph-es 222 gua-apma2-thoph-es 223 bim-pipa2-meph-es 224 2py-aof-phen-es 225 bhs-35thima2-dmeph-es 226 bhs-hexa-phen-es 227 bim-pipa2-4-clph-es 228 bhs-apma2-phen-pms 229 bim-a23thima2-dmeph-es 230 2py-me42thiaz2-phen-es 231 bim-a24thima2-phen-gs 232 bim-apma2-dmeph-es 233 gua-a23thima2-4-clph-es 234 bim-a24thima2-phen-mals 235 2py-apma2-phen-ms 236 bhs-a24thima2-ioph-es 237 bim-a24thima2-phen-es 238 2py-pdagk-phen-es 239 gua-a24thima2-phen-ps 240 2py-pipa2-phen-es 241 2py-aepi2-phen-es 242 2py-a24thima2-thoph-es 243 bhs-bam2-dmeph-es 244 bim-hexa-phen-es 245 bim-a24thima2-meph-es 246 bhs-me42thiaz2-phen-es 247 am2py-a24thima2-phen-es 248 bim-apma2-meph-es 249 bim-me35thima2-phen-es 250 gua-pipa2-phen-es 251 bhs-a24thima2-oxph-es 252 2py-pipa2-dmeph-es 253 2py-apma2-4-pyph-es 254 bhs-35thima2-thoph-es 255 gua-me42thiaz2-phen-es 256 bim-a24thima2-thaph-es 257 gua-a24thima2-phen-as 258 2py-a24thima2-phen-f2es 259 2py-a24thima2-dbph-es 260 bim-35thima2-meph-es 261 bim-apma2-phen-es 262 bim-a24thima2-phen-pms 263 bim-chex2-phen-es 264 bim-a24thima2-dmeph-es 265 bim-mea2-phen-es 266 2py-apma2-thoph-es 267 dimethpym-a24thima2-phen-es 268 2py-dibema2-thoph-es 269 2py-apma2-dmeoph-es 270 gua-dibema2-4-clph-es 271 bhs-pipa2-phen-es 272 gua-edia2-phen-es 273 gua-apma2-dmeph-es 274 2py-edia3-phen-es 275 gua-a23thima2-meph-es 276 bim-pdagk-phen-es 277 gua-apma2-phen-pms 278 bhs-mea2-phen-es 279 bim-35thima2-dmeph-es 280 bhs-aof-phen-es 281 2py-prodia2-phen-es 282 bim-inda2-phen-es 283 bhs-bam2-thoph-es 284 bim-apma2-4-pyph-es 285 2py-aaf-phen-es 286 2py-bam2-phen-es 287 bhs-apma2-dm-es 288 2py-penta-phen-es 289 gua-aof-phen-es 290 im-apma2-phen-es 291 gua-pipa2-4-clph-es 292 bim-apma2-ioph-es 293 bim-bam2-meph-es 294 gua-pipa2-meph-es 295 bhs-apma2-thaph-es 296 bhs-apma2-2pyph-es 297 bim-apma2-dmeoph-es 298 amim-apma2-phen-es 299 dhim-apma2-phen-es 300 bhs-a24thima2-phen-ps 301 2py-a23thima2-dmeph-es 302 gua-pipa2-thoph-es 303 bim-a23thima2-meph-es 304 2py-bam2-dmeph-es 305 bhs-a24thima2-thoph-es 306 bhs-apma2-phen-mals 307 bhs-a23thima2-meph-es 308 bim-buta-phen-es 309 2py-apma2-reph-es 310 gua-dibema2-meph-es 311 2py-a24thima2-hdb-es 312 gua-a24thima2-4-clph-es 313 bhs-pipa2-thoph-es 314 gua-a24thima2-3clph-es 315 gua-a24thima2-oxph-es 316 bim-bam2-dmeph-es 317 bim-apma2-thoph-es 318 bim-apma2-oxph-es 319 2py-a24thima2-phen-es 320 bhs-a24thima2-phen-ms 321 bim-prodia2-phen-es 322 2py-a24thima2-dm-es 323 bhs-pyma2-phen-es 324 bim-a24thima2-phen-f2es 325 2py-a23thima2-phen-es 326 gua-a24thima2-24pym-es 327 2py-35thima2-4-clph-es 328 bhs-dibema2-dmeph-es In the above list, the following abbreviations are used for the structural units A, E′, G′ and L. A= Abbreviation 2py dhim bim imhs dimethpym mam2py am2py thpym bhs gua amim clim im pippy E′= Abbreviation edia2 pyma2 pipa2 aepi2 me35thima2 dibema2 edia3 buta aaf 42thiaz2 chex2 bam2 apma2 pdagk mepipe2 prodia2 inda2 35thima2 me25thima2 penta aof hexa mea2 pipeme2 me42thiaz2 a23thima2 a24thima2 The bond to the structural unit L should be understood as meaning a double bond in the compound where L=as.\",\n \"G′= Abbreviation 24pym dmeph dm thoph thaph 2pyph 4clph phen dbph hdb dmeoph meph 3clph oxph ioph yrph 4pyph reph L= Abbreviation es gs pms f2es mals ps ms nes as The compounds of the general formula I and thus also the compounds of the formula I′ as well as the starting substances used for their preparation can be prepared by methods of organic chemistry known to the person skilled in the art, such as are described in standard works such as Houben-Weyl, “Methoden der Organischen Chemie” [Methods of Organic Chemistry], Thieme-verlag, Stuttgart, or March “Advanced Organic Chemistry”, 4th Edition, Wiley & Sons.\",\n \"Further preparation methods are also described in R. Larock, “Comprehensive Organic Transformations”, Weinheim 1989, in particular the preparation of alkenes, alkynes, halides, amines, ethers, alcohols, phenols, aldehydes, ketones, nitrites, carboxylic acids, esters, amides and acid chlorides.\",\n \"The synthesis of compounds of the formula I can be carried out either according to the “classical” method in solution or on a polymeric support, in each case reaction conditions as are known and suitable for the respective reactions being used.\",\n \"Use can also be made in this case of variants which are known per se but not mentioned here.\",\n \"The general synthesis of compounds of the formula I is described in schemes 1-7.If not stated otherwise, all starting materials and reagents are commercially available, or can be prepared from commercially obtainable precursors by customary methods.\",\n \"Fused 2,3,4,5-tetrahydro-1H-azepinediones of type II are known and can be prepared by known methods, e.g.\",\n \"starting from anthranilic acid esters or the corresponding heterocyclic analogs via Dieckmann condensation and subsequent decarboxylation, as is described in the following publications: J.\",\n \"Am.\",\n \"Chem.\",\n \"Soc.\",\n \"80, 1958, 2172-2178; J. Chem.\",\n \"Soc.\",\n \"1959, 3111; J. Chem.\",\n \"Soc.\",\n \"1934, 1326; Arch.\",\n \"Pharm.\",\n \"324, 1991, 579-581.The preparation of 3,4-dihydro-1H-azepine-2,5-dione is described in Heterocycles 8, 1977, 345-350.The conversion into compounds of the type III is generally carried out by methods known to the person skilled in the art, such as are described, for example, in Larock, “Comprehensive Organic Transformations”, Weinheim 1989, pp.\",\n \"167ff, although methods which are not mentioned here can also be used.\",\n \"Preferably, compounds of the general formula III can be prepared by reaction of the ketones II with a phosphonic ester of the general formula (EtO)2P(═O)(XL)a(CRL1RL2)b—COOSG1 in the presence of a base.\",\n \"The reaction preferably takes place in a polar aprotic solvent, such as tetrahydrofuran, dioxane; dimethylformamide (DMF), dimethylacetamide or acetamide; dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone; in a temperature range depending on the nature of the solvent used from −40° C. up to the boiling point of the corresponding solvent.\",\n \"The base used can be an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g.\",\n \"sodium carbonate or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkoxide such as sodium methoxide, potassium tert-butoxide, an organometallic compound such as butyllithium or alkali metal amides such lithium diisopropylamide, or lithium, sodium or potassium bis(trimethylsilyl)amide.\",\n \"The reaction to give IV is carried out by hydrogenation of the double bond under standard conditions.\",\n \"Use can also be made here of variants which are known per se but not mentioned.\",\n \"Preferably, the hydrogenation is carried out in the presence of a noble metal catalyst, such as Pd on activated carbon, Pt, PtO2, Rh on Al2O3 in an inert solvent at a temperature of 0-150° C. and a pressure of 1-200 bar; the addition of an acid such as acetic acid or hydrochloric acid can be advantageous.\",\n \"Hydrogenation in the presence of 5-10% Pd on activated carbon is particularly preferred.\",\n \"Solvents which can be used are all customary inert solvents, such as hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; sulfoxides such as dimethyl sulfoxide, sulfolane; pyridine, N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, water or mixtures of the solvents mentioned.\",\n \"Compounds of type V are prepared by reaction with compounds of the general formula A-E-X1 (VI), the radical X1 being a customary leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl, trifluoromethanesulfonyl and methylsulfonyl or another equivalent leaving group.\",\n \"The reaction preferably takes place in an inert solvent (such as previously described) with addition of a suitable base, i.e.\",\n \"of a base which brings about deprotonation of the intermediate IV, in a temperature range from −40° C. up to the boiling point of the corresponding solvent.\",\n \"The base used can be an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g.\",\n \"sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkoxide such as sodium methoxide, potassium tert-butoxide, an organometallic compound such as butyllithium or alkali metal amides such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide.\",\n \"Removal of the protective group SG1 according to standard conditions (see below) leads to the compounds of the general formula I.\",\n \"If SG1 is C1-C4-alkyl or benzyl, the compounds of the general formula V correspond directly to the compounds of type I. Alternatively to this synthesis strategy, compounds of type I can also be prepared via VII as an intermediate, here too reaction conditions being used such as are known to the person skilled in the art and described in standard works.\",\n \"Compound VII is prepared by reaction of compounds of type IV having radio of the general formula DE-E-X2 (VIII) under reaction conditions such as have already been described for the preparation of V from IV and VI.\",\n \"X2 here is a suitable leaving group, as has already been described for X1, and DE is CN, N3 or a protected amino or acid function of the general formula NSG3 or COOSG2.The synthesis of the fragments DE-E or A-E is carried out—depending on the actual structure of E—by removal of the protective groups and coupling of the remaining fragments according to standard methods, e.g.\",\n \"amide couplings.\",\n \"The introduction of A is then carried out analogously to the reactions described in schemes 3-7.Compounds of the formula I in which WG in structural element G is a structural element of the formula IWG1 can be prepared according to scheme 2.The starting point of the synthesis is compounds of type IX, which are either known or are accessible by methods known to the person skilled in the art, such as are described, for example, in J.\",\n \"Am.\",\n \"Chem.\",\n \"Soc.\",\n \"71, 1949, 1985.Alkylation with a compound of the general formula XIII (X3, X4=a customary leaving group) under customary reaction conditions leads to X.\",\n \"The further reactions to give I then proceed analogously to scheme 1 via compounds of type XI.\",\n \"In the case in which WG in structural element G is a structural element of the formula IWG3, compounds of type III can be converted into compounds of type XII and then into I analogously to the preparation of V (scheme 2).\",\n \"The coupling of the individual fragments and the removal of the protective groups can be carried out according to known processes (see Larock, “Comprehensive Organic Transformations; protective groups: Greene, T., “Protective Groups in Organic Synthesis”, New York 1991), in the case of amide bonds also analogously to the methods of peptide synthesis, such as are described in standard works, e.g.\",\n \"in Bodanszky “The Practice of Peptide Synthesis”, 2nd Edition, Springer-Verlag 1994, and Bodanszky “Principles of Peptide Synthesis”, Springer-Verlag 1984.A general survey of the customary methods for peptide synthesis and a listing of suitable reagents can furthermore be found in NOVABIOCHEM 1999 “Catalog and Peptide Synthesis Handbook”.\",\n \"The amide couplings mentioned can be carried out with the aid of customary coupling reagents using suitably protected amino and carboxylic acid derivatives.\",\n \"Another method consists in the use of preactivated carboxylic acid derivatives, preferably of carboxylic acid halides, symmetrical or mixed anhydrides or so-called active esters, which are customarily used for the acylation of amines.\",\n \"These activated carboxylic acid derivatives can also be prepared in situ.\",\n \"As a rule, the couplings can be carried out in inert solvents in the presence of an acid-binding agent, preferably of an organic base such as triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, quinoline; the addition of an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogencarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or cesium, can also be favorable.\",\n \"Depending on the conditions used, the reaction time is between minutes and 14 days, the reaction temperature between −40° C. and 140° C., preferably between −20° C. and 100° C. Suitable inert solvents are, for example, hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; water; or mixtures of the solvents mentioned.\",\n \"Protective groups SG which can be used are all protective groups which are known from peptide synthesis and customary to the person skilled in the art, such as are also described in the abovementioned standard works.\",\n \"The protective groups in the compounds of the formulae V, VII, XI and XII are likewise removed according to conditions such as are known to the person skilled in the art and are described by Greene and Wuts in “Protective Groups in organic Synthesis”, 2nd Edition, Wiley & Sons, 1991.Protective groups such as SG3 are so-called N-terminal amino protective groups; Boc, Fmoc, benzyloxycarbonyl (Z), acetyl, Mtr are preferred here.\",\n \"SG1 and SG2 are acid protective groups; C1-C4-alkyl is preferred here, such as methyl, ethyl, tert-butyl, or alternatively benzyl or trityl, or alternatively polymer-bonded protective groups in the form of the commercially available polystyrene resins such as 2-chlorotrityl chloride resin or Wang resin (Bachem, Novabiochem).\",\n \"Acid-labile protective groups (e.g.\",\n \"Boc, tert-butyl, Mtr, trityl) can be removed—depending on the protective group used—using organic acids such as trifluoroacetic acid (TFA), trichloroacetic acid, perchloric acid, trifluoroethanol; but also inorganic acids such as hydrochloric acid or sulfuric acid, sulfonic acids such as benzene- or p-toluenesulfonic acid, the acids generally being employed in an excess.\",\n \"HCl or TFA is preferably used.\",\n \"In the case of trityl, the addition of thiols such as thioanisole or thiophenol can be advantageous.\",\n \"The presence of an additional inert solvent is possible, but not always necessary.\",\n \"Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid; ethers such as THF or dioxane; amides such as DMF or dimethylacetamide; halogenated hydrocarbons such as dichloromethane; alcohols such as methanol, isopropanol; or water.\",\n \"Suitable solvents are also mixtures of those mentioned.\",\n \"The reaction temperature for these reactions is between −10° C. and 50° C.; the reaction is preferably carried out in a range between 0° C. and 30° C. Base-labile protective groups such as Fmoc are cleaved by treatment with organic amines such as dimethylamine, diethylamine, morpholine or piperidine as 5-50% solutions in CH2Cl2 or DMF.\",\n \"The reaction temperature for these reactions is between −10° C. and 50° C.; the reaction is preferably carried out in a range between 0° C. and 30° C. Acid protective groups such as methyl or ethyl are preferably cleaved by basic hydrolysis in an inert solvent.\",\n \"The bases used are preferably alkali metal or alkaline earth metal hydroxides, preferably NaOH, KOH or LiOH; the solvents used are all customary inert solvents, such as hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyltert-butyl ether, diisopropyl-ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone; nitro compounds such as nitromethane or nitrobenzene; water or mixtures of the solvents mentioned.\",\n \"The addition of a phase-transfer catalyst—depending on the solvent or solvent mixture used—may be advantageous.\",\n \"The reaction temperature for these reactions is generally between −10° C. and 100° C. Hydrogenolytically removable protective groups such as benzyloxycarbonyl (Z) or benzyl can be removed, for example, by hydrogenolysis in the presence of a catalyst (e.g.\",\n \"of a noble metal catalyst on activated carbon as support).\",\n \"Suitable solvents are those mentioned above, in particular alcohols such as methanol, ethanol; amides such as DMF or dimethylacetamide; esters such as ethyl acetate.\",\n \"As a rule, the hydrogenolysis is carried out at a pressure of 1-200 bar and temperatures between 0° and 100° C.; the addition of an acid such as acetic acid or hydrochloric acid may be advantageous.\",\n \"The catalyst used is preferably 5-10% Pd on activated carbon.\",\n \"The synthesis of structural units of type E is generally carried out by methods known to the person skilled in the art; the structural units used are either commercially available or accessible by methods known from the literature.\",\n \"The synthesis of some of these structural units is described by way of example in the experimental section.\",\n \"In the case in which the fragments QE or XE contained in the compounds of type VI and VIII are a hetaryl radical, the structural units used are either commercially available or accessible by methods known to the person-skilled in the art.\",\n \"A multiplicity of preparation methods are described in detail in Houben-Weyl's “Methoden der organischen Chemie” (Vol.\",\n \"E6: furans, thiophenes, pyrroles, indoles, benzothiophenes, -furans, -pyrroles; Vol.\",\n \"E7: quinolines, pyridines, Vol.\",\n \"E8: isoxazoles, oxazoles, thiazoles, pyrazoles, imidazoles and their benzo-fused representatives, as well as oxadiazoles, thiadiazoles and triazoles; Vol.\",\n \"E9: pyridazines, pyrimidines, triazines, azepines and their benzo-fused representatives as well as purines).\",\n \"The linkage of these fragments to E, depending on the structure of E, can also take place via the amino or acid function according to methods which are known to the person skilled in the art.\",\n \"Structures of the general formula A-E-DE are synthesized according to methods known to the person skilled in the art, which are described, for example, in WO 97/08145.Examples of these are the conversion of compounds of the general formula: HNRE11EA1-DE (XIV) NC-EA2-DE (XV) into compounds of the general formula: A-HNRE11-EA1-DE (XVI) A-E-DE (XVII) The groups EA1 and EA in the formulae XIV-XVIII represent structural fragments which, after an appropriate modification (e.g.\",\n \"reaction with suitable reagents or coupling with appropriate structural units) as a whole form the structural fragment A-E.\",\n \"These structural units can then be reacted either directly—in the case of the corresponding free amines or carboxylic acids—or after removal of the protective groups—to give compounds of the general formula I (scheme 1 and 2).\",\n \"In principle, A, however, can also be introduced into compounds of the type IV, as described in scheme 1, where the reaction conditions mentioned can be used just as variants which are not described here.\",\n \"In schemes 3-7, a number of the methods for the introduction of A are described by way of example, in each case reaction conditions being used which are known and suitable for the respective reactions.\",\n \"Use can also be made in this case of variants which are known per se but not mentioned here.\",\n \"Ureas and thioureas (AE-1 to AE-3) can be prepared by customary methods of organic chemistry, e.g.\",\n \"by reaction of an isocyanate or of an isothiocyanate with an amine, if appropriate in an inert solvent with heating (Houben-Weyl Volume VIII, 157ff.)\",\n \"(scheme 3): Scheme 4 shows, by way of example, the preparation of compounds of the type AE-4, as is described, for example, by Blakemoore et al.\",\n \"in Eur.\",\n \"J. Med.\",\n \"Chem.\",\n \"1987 (22) 2, 91-100, or Misra et al.\",\n \"in Bioorg.\",\n \"Ned.\",\n \"Chem.\",\n \"Lett.\",\n \"1994 4 (18), 2165-2170.Unsubstituted or cyclic guanidine derivatives of the general formulae AE-5 and AE-6 can be prepared by means of commercially available or simply accessible reagents, such as are described, for example, in Synlett 1990, 745, J. Org.\",\n \"Chem.\",\n \"1992, 57, 2497, Bioorg.\",\n \"Ned.\",\n \"Chem.\",\n \"1996, 6, 1185-1208; Bioorg.\",\n \"Med.\",\n \"Chem.\",\n \"1998, 1185, or Synth.\",\n \"Comm.\",\n \"1998, 28, 741-746 (scheme 5).\",\n \"The preparation of compounds of the general formula AE-7 can be carried out analogously to U.S. Pat.\",\n \"No.\",\n \"3,202,660, compounds of the formulae AE-9, AE-10, AE-11 and AE-12 analogously to WO 97/08145.Compounds of the formula AE-8 can be prepared, as shown in scheme 6, e.g.\",\n \"according to the method described by Perkins et al., Tetrahedron Lett.\",\n \"1999, 40, 1103-1106.Scheme 5 gives a survey of the synthesis of the compounds mentioned, the circle in AE-8 representing a fused cycle, such as aryl or hetaryl.\",\n \"Compounds of the general formula AE-13 can be prepared analogously to Froeyen et al., Phosphorus Sulfur silicon Relat.\",\n \"Elem.\",\n \"1991, 63, 283-293; AE-14 analogously to Yoneda et al., Heterocycles 1998, 15 N′-1, Spec.\",\n \"Issue, 341-344 (scheme 6).\",\n \"The preparation of corresponding compounds can also be carried out analogously to WO 97/36859.Compounds of the general formula AE-15 can be prepared according to Synthesis 1981, 963-965 or Synth.\",\n \"Comm.\",\n \"1997, 27 (15), 2701-2707; AE-16 analogously to J. Org.\",\n \"Chem.\",\n \"1991, 56 (6), 2260-2262 (scheme 7), the circle being a fused cycle, such as aryl, hetaryl or cycloalkyl.\",\n \"The invention further relates to pharmaceutical preparations, comprising at least one compound of the formula I′ in addition to the customary pharmaceutical excipients.\",\n \"The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in the customary manner.\",\n \"Administration can also be carried out through the nasopharynx using vapors or sprays.\",\n \"Further, the compounds according to the invention can be introduced by direct contact with the affected tissue.\",\n \"The dose depends on the age, condition and weight of the patient and on the manner of administration.\",\n \"As a rule, the daily dose of active compound is between approximately 0.5 and 50 mg/kg of body weight in the case of oral administration and between approximately 0.1 and 10 mg/kg of body weight in the case of parenteral administration.\",\n \"The novel compounds can be administered in solid or liquid form in the customary pharmaceutical administration forms, e.g.\",\n \"as tablets, film-coated tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays.\",\n \"These are prepared in a customary manner.\",\n \"The active compounds can in this case be processed using the customary pharmaceutical excipients such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-delaying agents, antioxidants and/or propellants (cf.\",\n \"H. Sucker et al.\",\n \": Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991).\",\n \"The administration forms thus obtained normally contain the active compound in an amount from 0.1 to 90% by weight.\",\n \"The invention further relates to the use of compounds of the formula I′ for the production of drugs for treating illnesses.\",\n \"The compounds of the formula I′ can be used for treating human and animal illnesses.\",\n \"The compounds of the formula I′ which represent the novel compounds of the formula I bind, as mentioned above, to integrin receptors.\",\n \"They are therefore suitable, as mentioned above, preferably as integrin receptor ligands and for the production of drugs for treating illnesses in which an integrin receptor is involved, in particular for the treatment of illnesses in which the interaction between integrins and their natural ligands is dysregulated, i.e.\",\n \"excessive or reduced, as described above.\",\n \"Advantageously, the compounds of the formula I, preferably the compounds of the formula I′, can be administered in combination with at least one further compound in order to achieve an improved curative action in a number of indications.\",\n \"These further compounds can have the same or a different mechanism of action as/from the compounds of the formula I.\",\n \"In addition to the compounds of the formula I, preferably in addition to the compounds of the formula I′ and the customary pharmaceutical excipients, the pharmaceutical preparations can therefore contain at least one further compound, depending on the indication, in each case selected from one of the 10 groups below.\",\n \"Group 1: inhibitors of blood platelelet adhesion, activation or aggregation, such as acetylsalicylic acid, lysine acetylsalicylate, piracetam, dipyridamol, abciximab, thromboxane antagonists, fibrinogen antagonists, such as tirofiban, or inhibitors of ADP-induced aggregation such as ticlopidine or clopidogrel, anticoagulants which prevent thrombin activity or formation, such as inhibitors of IIa, Xa, XIa, IXa or VIIa, antagonists of blood platelet-activating compounds and selectin antagonists for the treatment of blood platelet-mediated vascular occlusion or thrombosis, or Group 2: inhibitors of blood platelet activation or aggregation, such as GPIIb/IIIa antagonists, thrombin or factor Xa inhibitors or ADP receptor antagonists, serine protease inhibitors, fibrinogen-lowering compounds, selectin antagonists, antagonists of ICAM-1 or VCAM-1 inhibitors of leukocyte adhesion inhibitors of vessel wall transmigration, fibrinolysis-modulating compounds, such as streptokinase, tPA, plasminogen-activating stimulants, TAFI inhibitors, XIa inhibitors or PAI-1 antagonists, inhibitors of complement factors, endothelin receptor antagonists, tyrosine kinase inhibitors, antioxidants and interleukin 8 antagonists for the treatment of myocardial infarct or stroke, or Group 3: endothelin antagonists, ACE inhibitors, angiotensin receptor antagonists, endopeptidase inhibitors, beta-blockers, calcium channel antagonists, phosphodiesterase inhibitors and caspase inhibitors for the treatment of congestive heart failure, or Group 4: thrombin inhibitors, inhibitors of factor Xa, inhibitors of the coagulation pathway which leads to thrombin formation, such as heparin or low-molecular weight heparins, inhibitors of blood platelet adhesion, activation or aggregation, such as GPIIb-IIIa antagonists or antagonists of the blood platelet adhesion and activation mediated by vWF or GPIb, endothelin receptor antagonists, nitrogen oxide synthase inhibitors, CD44 antagonists, selectin antagonists, MCP-1 antagonists, inhibitors of signal transduction in proliferating cells, antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF and antioxidants for the treatment of restenosis after vascular injury or stent implantation, or Group 5: antagonists of the cell response mediated by EGF, PDGF, VEGF or bFGF, heparin or low-molecular weight heparins or further GAGs, inhibitors of MMPs, selectin antagonists, endothelin antagonists, ACE inhibitors, angiotensin receptor antagonists and glycosylation inhibitors or AGE formation inhibitors or AGE breakers and antagonists of their receptors, such as RAGE, for the treatment of diabetic angiopathies, or Group 6: lipid-lowering compounds, selectin antagonists, antagonists of ICAM-1 or VCAM-1 heparin or low-molecular weight heparins or further GAGs, inhibitors of MMPs, endothelin antagonists, apolipoprotein A1 antagonists, cholesterol antagonists, HMG CoA reductase inhibitors, ACAT inhibitors, ACE inhibitors, angiotensin receptor antagonists, tyrosine kinase inhibitors, protein kinase C inhibitors, calcium channel antagonists, LDL receptor function stimulants, antioxidants LCAT mimetics and free radical scavengers for the treatment of atherosclerosis, or Group 7: cytostatic or antineoplastic compounds, compounds which inhibit proliferation, such as kinase inhibitors and heparin or low-molecular weight heparins or further GAGS for the treatment of cancer, preferably for the inhibition of tumor growth or metastasis, or Group 8: compounds for antiresorptive therapy, compounds for hormone exchange therapy, such as estrogen or progesterone antagonists, recombinant human growth hormone, bisphosphonates, such as alendronates compounds for calcitonin therapy, calcitonin stimulants, calcium channel antagonists, bone formation stimulants, such as growth factor antagonists, interleukin-6 antagonists and Src tyrosine kinase inhibitors for the treatment of osteoporosis, or Group 9: TNF antagonists, antagonists of VLA-4 or VCAM-1, antagonists of LFA-1, Mac-1 or ICAMs, complement inhibitors, immunosuppressants, interleukin-1, -5 or -8 antagonists and dihydrofolate reductase inhibitors for the treatment of rheumatoid arthritis, or Group 10: collagenase, PDGF antagonists and MMPs for improved wound healing.\",\n \"A pharmaceutical preparation comprising at least one compound of the formula I, preferably comprising at least one compound of the formula I′, if appropriate pharmaceutical excipients and at least one further compound, depending on the indication, in each case selected from one of the above groups, is understood as meaning a combined administration of at least one of the compounds of the formula I, preferably of one of the compounds of the formula I′, with at least one further compound in each case selected from one of the groups described above and, if appropriate, pharmaceutical excipients.\",\n \"Combined administration can be carried out by means of a substance mixture comprising at least one compound of the formula I, preferably of the formula I′, if appropriate pharmaceutical excipients and at least one further compound, depending on the indication, in each case selected from one of the above groups, but also spatially and/or chronologically separate.\",\n \"In the case of the spatially and/or chronologically separate administration, the administration of the components of the pharmaceutical preparation, the compounds of the formula I, preferably of the formula I′ and the compounds selected from one of the abovementioned groups, takes place spatially and/or chronologically separately.\",\n \"For the treatment of restenosis after vascular injury or stenting, the administrations of the compounds of the formula I, preferably of the formula I′, can be carried out locally at the affected sites, on their own or in combination with at least one compound selected from group 4.It may also be advantageous to coat the stents with these compounds.\",\n \"For the treatment of osteoporosis, it may be advantageous to carry out the administration of the compounds of the formula I, preferably of the formula I′, in combination with an antiresorptive or hormone exchange therapy.\",\n \"The invention accordingly relates to the use of the abovementioned pharmaceutical preparations for the production of drugs for treating illnesses.\",\n \"In a preferred embodiment, the invention relates to the use of the abovementioned combined pharmaceutical preparations for the production of drugs for treating blood platelet-mediated vascular occlusion or thrombosis when using compounds of group 1, myocardial infarct or stroke when using compounds of group 2, congestive heart failure when using compounds of group 3, restenosis after vascular injury or stent implantation when using compounds of group 4, diabetic angiopathies when using compounds of group 5, atherosclerosis when using compounds of group 6, cancer when using compounds of group 7, osteoporosis when using compounds of group 8, rheumatoid arthritis when using compounds of group 9, wound healing when using compounds of group 10.The following examples illustrate the invention, the selection of these examples being non-limiting.\",\n \"I. SYNTHESIS EXAMPLES I.A Precursors Example 1 t-Butyl (2-oxo-2,3-dihydro-1H-1-benzazepin-5-yl)acetate (1) 22.3 g (80 mmol) of t-butyl diethylphosphonate (95%) were added dropwise at 0° C. to a suspension of 3.27 g of NaH (60%; deoiled) in ml of DMF.\",\n \"The mixture was stirred until a clear solution was formed and then 12.4 g (70.9 mmol) of 3,4-dihydro-1H-1-benzazepine-2,5-dione (preparation according to Arch.\",\n \"Pharm.\",\n \"1991, 324, 579) in 90 ml of DMF were added dropwise at 0° C. The reaction mixture then remained standing at RT for about 3 days.\",\n \"For workup, the mixture was poured into 700 ml of cold 5% NaCl solution, and the resulting yellow precipitate was filtered off with suction and washed with H2O.\",\n \"The moist residue was taken up in CH2Cl2, washed with 5% NaHCO3 solution and dried over Na2SO4.The residue which remained after evaporation was treated with 150 ml of cyclohexane in the presence of heat, and after cooling, filtering off with suction and washing with n-hexane 17.5 g (90.5%) of white crystals remained; m.p.\",\n \": 136-138° C. Example 2 t-Butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)acetate (2) A suspension of 3 g of 10% Pd/C in 50 ml of ethanol was prehydrogenated, then a solution of compound 1 (14.7 g; 53.8 mmol) in 125 ml of ethanol and 75 ml of dioxane was added, and the mixture was hydrogenated under standard conditions until the absorption of hydrogen was complete.\",\n \"After filtering off the catalyst with suction and washing it with ethanol, the filtrate was concentrated in vacuo, the oily residue was dissolved in diethyl ether and the crystallization commencing was completed by addition of n-hexane.\",\n \"After filtering off the precipitate with suction and washing it with n-hexane, 14.2 g (96%) of white crystals remained; m.p.\",\n \": 101-103° C. Example 3 [5-(2-t-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-5-yl]acetic acid (3) a.)\",\n \"A solution of compound 2 (16.8 g; 61.1 mmol) in 60 ml of DMF was added dropwise at 10-20° C. to a suspension of 2.6 g of NaH (60%, deoiled) in 35 ml of DMF and the mixture was stirred until the appearance of an almost clear yellowish solution.\",\n \"t-Methyl bromoacetate (10 g; 63.4 mmol) was then added dropwise and the mixture was stirred overnight.\",\n \"For workup, the reaction mixture was poured into 400 ml of 5% cold NaCl solution and extracted 3× with 100 ml each of a diethyl ether/n-hexane mixture.\",\n \"The combined extracts were then washed with H2O, 10% NaHCO3 solution and NaCl solution, dried over Na2SO4, filtered and evaporated.\",\n \"The residual yellowish oil was reacted further without further purification; FAB-MS: 348 [M−H+].\",\n \"b.)\",\n \"Crude product 3a was dissolved in 100 ml of dioxane and 65 ml of 1N NaOH were added dropwise at RT with stirring.\",\n \"After about 45′, the reaction mixture was adjusted to pH 7 using 1N KHSO4 solution, the dioxane was largely distilled off in vacuo, and the residue was diluted with H2O, adjusted to pH 9 using 1N NaOH and extracted 3× with diethyl ether.\",\n \"The aqueous phase was then rendered acidic using 1N KHSO4 solution, the acid precipitating was extracted with a mixture of diethyl ether/n-hexane 4:1, and the organic phase was washed with H2O, 1N NaOH solution and NaCl solution and dried over Na2SO4.Filtration and evaporation afforded an oily residue, which could be crystallized by treatment with diethyl ether/n-hexane 1:4 (water-saturated).\",\n \"Filtering with suction, washing with n-hexane and drying afforded 17.8 g (87.5%) of white crystals: m.p.\",\n \": 117-119° C. Example 4 N-[4-(Aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) a.)\",\n \"20 g of tert-butyl-4-aminobenzyl carbamate (89.97 mmol)—dissolved in 100 ml of CH3CN—were added dropwise at 0° C. to a solution of 24.5 g of thiocarbonyldiimidazole and 1.56 g of imidazole in 600 ml of CH3CN and the mixture was stirred at RT overnight.\",\n \"19.5 g of 1,2-phenylenediamine were then added and the mixture was again stirred at RT for 2 h. For workup, the reaction mixture was evaporated in vacuo, the residue was taken up in CH2Cl2, and the solution was washed 7× with 10% citric acid solution and 2× with satd.\",\n \"NaCl solution, dried over Na2SO4, filtered and concentrated.\",\n \"The crude product thus obtained (31.78 g; brown foam) was reacted directly without further purification; ESI-MS [M+H+]=373.15.1H-NMR (360 MHz, DMSO) δ ppm: 9.5 and 9.05 (each s, 1H), 7.45 (d, 2H), 7.35 (m, 1H), 7.20 (d, 1H), 7.15, 6.95, 6.75, 6.60 (each m, 1H), 4.85 (s, 2H), 4.10 (d, 2H), 1.35 (s, 9H).\",\n \"b.)\",\n \"Crude product 4a was dissolved in 750 ml of ethanol together with 36.7 g of HgO (yellow) and 0.4 g of sulfur and heated to reflux for 2 h. The reaction mixture was then filtered twice through Celite and evaporated to dryness; 20.7 g, ESI-MS [M+H+]=339.15.c.)\",\n \"7 g of the crude product 4b were introduced into 70 ml of CH2Cl2, 35 ml of HCl in diethyl ether (satd.\",\n \"at 0° C.) were added and the mixture was stirred at RT for 2 h. The resulting precipitate was filtered off with suction, washed with CH2Cl2 and dried.\",\n \"6.7 g of brown amorphous solid; ESI-MS [M+H+]=239.15 1H-NMR (360 MHz, DMSO) δ ppm: 11.6 (s broad, 1H), 8.4 (s broad, 3H), 8.25 (s broad, 1H), 7.65 and 7.55 (each d, 2H), 7.45 and 7.3 (each m, 2H), 4.19 (m, 2H).\",\n \"Example 5 N-[5-(Aminomethyl)-1,3-thiazol-2-yl]guanidine (dihydrochloride) (5) a.)\",\n \"31 g (130 mmol) of 2-chloro-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanal (preparation according to THL 39 (1998), 8085-8088) and 15.4 g of amidinothiourea were heated at 110° C. for 75′ in 200 ml of n-butanol, then the mixture was evaporated and the residue was treated with CH2Cl2 and conc.\",\n \"NH3.Evaporation of the organic phase, purification of the residue by chromatography on silica gel (CH2Cl2/CH3OH 0-5%) and crystallization from acetone afforded 12.3 g of N-{5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazol-2-yl}guanidine.\",\n \"b.)\",\n \"1 g of 5a in 20 ml of CH3OH was treated with 0.81 ml of hydrazine hydrate and stirred at RT for 2 h. The mixture was then cooled to 0° C., filtered, and the filtrate was concentrated and stirred with dilute HCl.\",\n \"This process was repeated a number of times, and the crude product obtained in this way was then stirred with ethanol; 0.92 g of white solid, ESI-MS [M+H+]=172.05.Example 6 N-[4-(Aminomethyl)phenyl]-N′-benzylurea (6) a.)\",\n \"4-Aminobenzylamine (10.0 g, 81.85 mmol) in 150 ml CH2Cl2 was treated with triethylamine (6.8 g, 67.12 mmol) and then treated at 0° C. with di-t-butyl dicarbonate (18.6 g, 85.0 mmol).\",\n \"The mixture was stirred at 0° C. for 1 h and then at RT for 2 h. For workup, 150 ml of a 1%-aqueous citric acid solution were added, the phases were separated and the aqueous phase was reextracted 2 times with CH2Cl2 (150 ml).\",\n \"Fresh washing with H2O, drying of the combined organic phases using Na2SO4 and evaporation afforded a solid, which was washed with stirring with a little diisopropyl ether, filtered off with suction and dried.\",\n \"13.0 g; ESI-MS [M+H+-tBu]=167.05.1H-NMR (360 MHz, CDCl3) δ (ppm): 7.04 (2H, d), 6.61 (2H, d), 4.78 (1H, s br.\",\n \"), 4.17 (2H, d), 3.67 (2H, s br.\",\n \"), 1.46 (9H, s).\",\n \"b.)\",\n \"Benzyl isocyanate (2.40 g, 18.0 mmol) was added with ice-cooling to a solution of the protected amine 6a (4.0 g, 17.99 mmol) and triethylamine (1.82 g, 18.0 mmol) in 220 ml of toluene/DMF 10:1.The reaction mixture was stirred at RT overnight.\",\n \"It was possible to filter off some of the urea formed directly as a precipitate and dry it.\",\n \"The filtrate was washed 2× with H2O, with dilute tartaric acid to pH 3 and again 2 times with H2O to pH 5, and the organic phase was then dried and evaporated.\",\n \"Altogether, 6.0 g were thus obtained; ESI-MS [M+H+-tBu]=300.15.c.)\",\n \"The urea 6b thus obtained was introduced in 90 ml of CH2Cl2, and TFA (2.24 g, 196.25 mmol)—dissolved in 90 ml of CH2Cl2—was added dropwise at 0° C. After 3 h, 1 ml of TFA was added again, then the mixture was stirred at RT overnight.\",\n \"After fresh addition of 1 ml of TFA, the mixture was stirred for a further 5 h, then poured onto ice water and extracted with ethyl acetate (2×50 ml).\",\n \"The water phase was rendered basic with 2N NaOH solution and extracted with CH2Cl2 (2×50 ml).\",\n \"The insoluble portion between the phases was filtered off and dried.\",\n \"4 g; ESI-MS [2M+H+]=511.35 1H-NMR (200 MHz, DMSO) δ (ppm): 8.52 (1H, s), 7.39-7.07 (9H, m), 6.62 (1H, t), 4.27 (2H, d), 3.61 (2H, s).\",\n \"Example 7 [4-(1H-Benzimidazol-2-yl)phenyl]methaneamine (hydrochloride) (7) a.)\",\n \"Di(tert-butyl) 4-cyanobenzylimidodicarbonate (10 g, 30.08 mmol; preparation according to Synth.\",\n \"Comm.\",\n \"28, 23, 1998, 4419ff) in 200 ml of pyridine was treated with 45 ml of triethylamine and saturated at 0° C. with H2S for 1.5 h. The reaction mixture was allowed to stand at RT overnight and then evaporated.\",\n \"The residue thus obtained was then stirred with diethyl ether, filtered off with suction and dried (8.5 g).\",\n \"b.)\",\n \"6 g of the thioamide 7a (16.37 mmol) in 40 ml of dry CH2Cl2 were alkylated at RT overnight using 23.2 g of CH3I and the mixture was then evaporated.\",\n \"The residue thus obtained was taken up in 40 ml of CH3OH, 1.95 g of 1,2-phenylenediamine were added and it was again stirred overnight.\",\n \"Evaporating the reaction mixture and stirring the solid with n-pentane afforded 6.9 g of the desired benzimidazole.\",\n \"M.p.\",\n \": >170° C. (decomposition); ESI-MS: [M+H+]=424.25 c.) 1 g of the bis-Boc compound 7b was dissolved in 5 ml of CH2Cl2, 5 ml of TFA were added at 0° C. and the mixture was stirred at room temperature for 1 h. Evaporating the reaction mixture, treating with HCl in diethyl ether and stirring the isolated solid with diethyl ether afforded 0.6 g of the amine as the hydrochloride; ESI-MS: [M+H+]=224.05.Example 8 N1-(1H-Benzimidazol-2-yl)pentane-1,5-diamine (hydrochloride) (8) Preparation was carried out analogously to the preparation of compound 4 starting from 7 g of N-Boc-1,5-diaminopentane hydrochloride (29.3 mmol).\",\n \"After reaction analogously to 4a, 10.3 g of N-Boc 5-{[(2-aminoanilino)carbothioyl]amino}pentane-1-amine were obtained; ESI-MS [M+H+]=353.25.Cyclodesulfurization and subsequent removal of the Boc group with TFA afforded an oily crude product, which was taken up in CH3OH and converted into the corresponding hydrochloride using 250 ml of ethereal HCl (saturated at 0° C.).\",\n \"Stirring the solid obtained with a mixture of CH3OH/methyl t-butyl ether afforded 1.8 g of a reddish amorphous solid.\",\n \"1H-NMR (360 MHz, DMSO) δ ppm: 9.30 (t, 1H), 8.15 (s broad, 3H), 7.40 and 7.25 (each m, 2H), 3.35 (m, 2H superimposed with H2O peak), 2.80 (m, 2H), 1.65 (m, 4H), 1.45 (m, 2H).\",\n \"Example 9 N1-(1H-Benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (9) Preparation was carried out analogously to the preparation of compound 4 starting from 9.87 g of N-Boc-1,4-diaminobutane (52.3 mmol).\",\n \"After reaction analogously to 4a, 17.08 g of N-Boc 4-{[(2-aminoanilino)carbothioyl]amino}butane-1-amine were obtained; ESI-MS [M+H+]=338.99.Subsequent cyclodesulfurization and Boc removal using TFA afforded a brown solid, which was stirred a number of times with n-pentane and then recrystallized from a mixture of CH3OH/methyl t-butyl ether; 14.35 g, ESI-MS [M+H+]=205.15.1H-NMR (360 MHz, DMSO) δ ppm: 9.20 (t, 1H), 7.80 (s broad, 3H), 7.35 and 7.20 (each m, 2H), 3.40 (m, 2H partially superimposed with H2O peak), 2.80 (m, 2H), 1.65 (m, 4H).\",\n \"Example 10 trans-N-[(4-Aminocyclohexyl)methyl]-1H-benzimidazole-2-amine (dihydrochloride) (10) Preparation was carried out analogously to compound 4 starting from 5.4 g of tert-butyl-4-(aminomethyl)cyclohexylamine carbamate (WO 9603374; Bioorg.\",\n \"Med.\",\n \"Chem.\",\n \"Lett.\",\n \"1997, 7 (1), 67).\",\n \"After removal of the Boc group, 3.3 g of white dihydrochloride were obtained; FAB-MS [M+H+]: 245.Example 11 trans-N-{[4-(Aminomethyl)cyclohexyl]-1H-benzimidazole-2-amine (dihydrochloride) (11) Preparation was carried out analogously to compound 4 starting from 10 g of benzyl {4-[(tert-butoxycarbonyl)amino]cyclohexyl}-methylcarbamate (EP 669317) by removal of the Boc group using 4N HCl in dioxane, synthesis of the benzimidazole and subsequent hydrogenolysis.\",\n \"3.6 g of white dihydrochloride were isolated; FAB-MS [M+H+]: 245.Example 12 [6-(1H-Benzimidazol-2-yl)pyridin-3-yl]methaneamine (trifluoroacetate) (12) a.)\",\n \"Preparation was carried out analogously to 7 starting from tert-butyl (6-cyanopyridin-3-yl)methylcarbamate (6.0 g, 25.72 mmol); crystallization of the crude product from ethanol afforded 5.15 g; ESI-MS [M+H+]=325.b.)\",\n \"0.55 g of the Boc-protected amine 12a in 10 ml of CH2Cl2 was treated with 5 ml of TFA and stirred at RT for 2 h. Evaporation of the reaction mixture afforded 0.95 g of a white solid; ESI-MS [M+H+]: 225.25.Example 13 N-[4-(Aminomethyl)phenyl]-2-pyridineamine (13) tert-Butyl 4-aminobenzylcarbamate (2 g; 9 mmol) was heated to reflux for 32 h with 8.74 g of 2-fluoropyridine.\",\n \"The reaction mixture was evaporated in vacuo and the residue obtained was stirred with n-pentane (1.9 g).\",\n \"The Boc group was cleaved using TFA, and the crude product obtained was precipitated from diethyl ether as the hydrochloride and then converted into the free-base (0.8 g) using NH3; ESI-MS [M+H+]: 200.25.N-[4-(Aminomethyl)benzyl]-2-pyridineamine (14) a.)\",\n \"20 g 2-Aminopyridine were dissolved in 100 ml CH3OH, adjusted to pH 6 with isopropanolic HCl and 36 g p-cyanobenzaldehyde were added.\",\n \"9.35 g Sodium cyanoborohydride were added portionwise over one hour and stirred overnight.\",\n \"For workup, the suspension was evaporated, the residue taken up in 100 ml water and with KOH adjusted to pH>10.The watery phase was saturated with NaCl and extracted 3× with diethylether.\",\n \"The ether phase was washed after filtration of a precipitate 3× with a FeSO4 solution, dried and evaporated.\",\n \"Purification of the residue by chromatography on silica gel (heptane/ethyl acetate 1:1) afforded 28.15 g 4-[2-pyridinyl-amino)methyl]benzonitrile.\",\n \"b.)\",\n \"10 g 4-[2-Pyridinyl-amino)methyl]benzonitrile were dissolved in 280 ml ammonia-alkali CH3OH, 10 g Raney-nickel added and it was hydrogenated for 24 h. It was filtered, evaporated and the residue purified by chromatography on silica gel (ethyl acetate/ethyl alcohol 1:3).\",\n \"5.18 g, ESI-MS: [M+H+]=214.\",\n \"[5-(1H-Benzimidazole-2-yl(thiene-2-yl]methaneamine (15) Preparation was carried out starting from 5-(aminomethyl)thiophene-2-carbonitrile (preparation according to WO 95/23609), which was reacted to the respective Boc-derivative according to standard methods.\",\n \"1.1 eq.\",\n \"Sodium methanolate solution was added to t-butyl-5-cyanothiene-2-ylcarbamate (25 g; 104.9 mmol) in 330 ml CH3OH and stirred overnight at RT, then for 2 h at 40-50°.\",\n \"18.95 g Phenylenediaminebihydrochloride were then added and again stirred at RT.\",\n \"For workup, water was added, the resulting precipitate filtered off and carefully dried.\",\n \"19.6 yellow solid; ESI-MS: [M+H+]=330.The following cleavage of the Boc-group with TFA afforded a raw product, which was dissolved in water, 2× extracted with diethyl ether, the watery phase adjusted to pH 10-11 and then extracted 2× with ethyl acetate.\",\n \"The watery phase was saturated with NaCl and again extracted with ethyl acetate.\",\n \"The combined organic phases were dried and evaporated (6.3 g); ESI-MS [M+H+]=230.1.tert-Butyl-2-[4-(1H-benzimidazole-2-yl)phenyl]ethylcarbamate (16) Preparation was carried out analogously to the preparation of [4-(1H-benzimidazole-2-yl)phenyl]methaneamine (hydrochloride) (7) starting from tert-butyl-2-(4-cyanophenyl)ethylcarbamate.\",\n \"The raw product obtained after reaction with H2S, alkylation with CH3I and reaction with 1,2-phenylenediamine was purified by chromatography on silica gel (CH2Cl2/CH3OH 4-50%) (4.8 g); ESI-MS [M+H+]=338.15.The amine required for the further reaction was obtained by cleavage of the Boc-group with TFA (under standard conditions); the isolated TFA-salt was then directly utilized in the respective couplings.\",\n \"N-(Piperidine-4-ylmethyl)-1H-benzimidazole-2-amine (trifluoroacetate) (17) a) A solution of tert-butyloxycarbonyl-4-(aminomethyl)-1-piperidine (5.39 g; 25 mmol) in 25 ml CH3CN was added dropwise to 6.75 g thiocarbonyldiimidazole and 0.5 g imidazole in 100 ml CH3CN at 0° C. and then stirred for 3 h at RT.\",\n \"1,2-Phenylenediamine (5.5 g; 50.86 mmol) was then added and heated for about 1 h to 60° C. The solid obtained upon cooling was filtered off with suction and dried.\",\n \"6.79 g; ESI-MS [M+H+-tBu]=309.15 b) tert-Butyoxycarbonyl-4-({[(2-aminoanilino)carbothioyl]amino}methyl)1-piperidine (5 g; 13.72 mmol), 5.94 g HgO (yellow) and 0.6 g sulfur in 150 ml ethyl alcohol were heated under reflux for 1 h. The mixture was filtered 2× over Celite, evaporated and the obtained raw product purified by chromatography on silica gel (CH2Cl2/CH3OH 5-25%).\",\n \"2.65 g; ESI-MS [M+H+]=331.25 1H-NMR (360 MHz, DMSO) δ ppm: 7.15 and 6.9 (each m, 2H), 3.95 (d, 2H) 3.2 (m, 2H, 2.7 (br m; 2H), 1.8 (m, 1H), 1.7 (m, 2H), 1.35 (s, 9H), 1.05 (m, 2H).\",\n \"c) tert-Butyloxycarbonyl-4-[(1H-benzimidazole-2-ylamino)methyl]-1-piperidine (2.65 g; 8.02 mmol) was treated with 10 ml TFA according to standard conditions.\",\n \"Evaporation and mixing the raw product with n-pentane afforded 2.39; ESI-MS [M+H+]=231.15.1H-NMR (360 MHz, DMSO δ ppm: 13.25 (s, 1H), 9.35 (m, 1H), 8.8 and 8.5 (each br s, 1H), 7.4 and 7.20 (each m, 2H), 3.3 (m, 4H), 2.85 (m, 2H), 1.9 (m, 3H), 1.35 (m, 2H).\",\n \"N-{[5-(Aminomethyl)thiene-3-yl]methyl}pyridine-2-amine (trifluoroacetate) (18) a) A solution of tert-butyl-(4-cyanothiene-2-yl)methylcarbamate (7 g; 29.4 mmol) in 120 ml ethyl alcohol was saturated with NH3 and then hydrogenated under standard conditions in the presence of Ra—Ni (9 g watery suspension; decanted with ethyl alcohol).\",\n \"Filtration of the reaction mixture, evaporation and chromatography of the obtained residue on silica gel (CH2Cl2/CH3OH plus watery NH3) afforded 4.4 g of the amine as a yellow oil.\",\n \"b) 1.2.of the amine 18a (4.3 mmol), 06.g ethyldiisopropylamine and 15 g 2-fluoropyridine were heated for 20 h to reflux.\",\n \"The residue obtained after evaporation of the mixture was taken up in CH2Cl2, washed with 0.1n HCl and saturated NaCl solution, dried and again evaporated.\",\n \"1 g; ESI-MS [M+H+]=320.15 c) 0.9 of the Boc-protected amine 18b were dissolved in 10 ml CH2Cl2, 5 ml TFA was added at 0° C. and it was stirred at room temperature for 1 h. Evaporation of the reaction mixture afforded 1.65 g of a brownish oil which was reacted directly without further purification (ESI-MS [M+H+]=220.05).\",\n \"3-Amino-N-(1H-imidazole-2-yl)propaneamide (19) a) Z-β-Alanine (10 g; 44.8 mmol) was dissolved in 200 ml DMF and 15.86 g (3.5 eq) N-methylmorpholine and 5.9 g (0.5 eq) 2-aminoimidazolesulfate were added.\",\n \"7.87 g (1.3.eq) HOBt and 11.16 g (1.3 eq) N′-(dimethylaminopropyl)-N-ethylcarbodiimide were added at −10° C. and stirred for 1 h whilst to RT and then for 18 h. 150 ml diethyl ether were added whereupon a wide residue precipitated which was filtered with suction.\",\n \"The residue was washed with cold diethyl ether, suspended in ethyl acetate and 1n HCl was added up to an acid reaction.\",\n \"The watery solution was extracted 1× with ethyl acetate, the watery phase was then adjusted to a basic pH with 10% NaOH at 4° C. The resulting precipitate was filtered with suction and washed with water.\",\n \"5.4 g; ESI-MS [M+H+]=289.05.b) 5.3 g of the Z-compound 19a were suspended in 250 ml ethyl alcohol and 530 mg 10% Pd on activated carbon was added.\",\n \"It was hydrogenated with H2 for 18 h at RT, then diluted with CH3OH and the suspension was boiled up whereon the precipitate of the product disintegrated.\",\n \"Filtering and evaporation of the solution afforded 1.5 g; ESI-MS [M+H+]=155.05.N-[4-(Aminomethyl)phenyl]-4,5-dihydro-1H-imidazole-2-amine (hydrochloride) (20) tert-Butyl-4-aminobenzylcarbamate (2 g; 9 mmol), 2.2 g ethyldiisopropylamine and 4.4 g (2-(3,5-dimethylpyrazole)-4,5-dihydroimidazole×HBr in 15 ml DMF were stirred at 110° C. After the reaction had completed, the mixture was evaporated, the residue taken up in ethyl acetate, each 2× washed with saturated NaHCO3 and NaCl solution, dried and again evaporated.\",\n \"The basic watery phase was also evaporated, mixed with acetone, the precipitate filtered with suction and the mother liquor evaporated.\",\n \"The combined residues were purified by means of MPLC (silica gel: Fa.\",\n \"Bischoff Prontoprep 60-2540-C18E, 32 μm; solvent: CH3CN/H2O+0.1% acetic acid).\",\n \"0.22 g; ESI-MS [M+H+]=291.15.The product thus obtained was treated with 4n HCl in dioxane for 2 h at RT.\",\n \"The resulting precipitate was filtered with suction, washed with pentane and dried.\",\n \"110 mg; ESI-MS [M+H+]=191.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 11.85 (s, 1H), 8.45 (s broad, 3H), 8.40 (s, 1H), 7.60 and 7.30 (each d, 2H), 4.05 (m, 2H), 3.70 (s, 4H).\",\n \"N-{[5-Aminomethyl)thiene-3-yl]methyl}-1H-benzimidazole-2-amine (hydrochloride) (21) Amine 18a (6.5 g; 23.31 mmol) was reacted to the respective aminobenzimidazole by reaction with thiocarbonyldiimidazole, imidazole and then phenylenediamine analogously to the preparation of 17.1.6 g: ESI-MS [M+H+]=359.15.The subsequent cleavage of the Boc-group by means of 4n HCl in dioxane afforded 1.3 g of slightly yellow solids: ESI-MS [M+H+]=191.15.N1-Pyridine-2-ylpentane-1,5-diamine (hydrochloride) (22) Preparation analogously to 18b by reaction of N-1-Boc-1,5-diaminopentane×HCl (5 g; 20.94 mmol) and 20.3 g 2-fluoropyridine, 5.64 g clear oil; ESI-MS [M+H+]=280.15.Cleavage of the Boc-group with 4n HCl in dioxane afforded 3.46 g white solids; ESI-MS [M+H+]=180.20.1H-NMR (360 MHz, d6-DMSO) δ ppm: 9.10 (s broad, 1H), 8.05 (s broad, 3H), 7.85 (m, 2H), 7.20 (m, 2H), 6.80 (m, 1H), 3.45 (m, superimposed by H2O), 2.80 (m, 2H), 1.65 (m, 4H), 1.45 (m, 2H).\",\n \"N1-(4,5-Dihydro-1H-imidazole-2-yl)pentane-1,5-diamine (hydrochloride) (23) N-1-Boc-1,5-diaminopentane×HCl (5 g; 20.94 mmol), 5.4 g ethyldiisopropylamine and 5.11 g 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole×HI in 30 ml DMF were stirred overnight at RT.\",\n \"The reaction mixture was evaporated, taken up in CH2Cl2, washed with water and saturated NaCl solution, dried and again evaporated.\",\n \"5.05 g clear oil, ESI-MS [M+H+]: 271.18.Cleavage of the Boc-group with 4n HCl in dioxane and purification of the raw product by means of MPLC afforded 2.57 g; ESI-MS [M+H+]: 171.15.13C-NMR (90.55 MHz, d6-DMSO) δ ppm: 160.3, 43.3 (2 signals superimposed).\",\n \"42.85, 39.70, 28.90, 27.2, 23.60.N-[4-(Aminomethyl)phenyl]-1H-imidazole-2-amine (24) a) 5.24 g BrCN—dissolved in 50 ml CH3OH-were added dropwise to a mixture of tert-butyl-4-aminobenzylcarbamate (10 g; 44.99 mmol) and 11.07 g sodium acetate in 100 ml CH3OH at 0° C., and it was stirred for 3 hours at 0° C. and overnight at RT.\",\n \"The mixture was evaporated, the obtained residue taken up in water and 2× extracted with methyl-tert-butylether.\",\n \"Drying and evaporation of the organic phases afforded 12.99 of a yellow-orange oil.\",\n \"b) 28.6 g triethylamine were added to 7 g tert-butyl-4-[(iminomethylene)amino]benzyl carbamate in 50 ml pyridine, H2S was introduced for 1 hour at 0° C. and the mixture was allowed to stand for 48 hours.\",\n \"Evaporation afforded 9.79 g of a rosa foam; ESI-MS [M+H+]: 282.05.1H-NMR (360 MHz.\",\n \"D6DMSO) δ ppm: 9.70 (s, 1H), 7.35 (m, 4H), 7.20 (m, 2H), 4.15 (d, 2H), 1.45 (s, 9H).\",\n \"c) 5 g of the thioamide in 50 ml CH3OH where methylated with 5.05 g CH3I and the obtained raw product was directly reacted with 1.73 g aminoacetaldehyde-diethylacetal in 7.5 ml CH3CN for 3 hours at RT.\",\n \"Evaporation of the reaction mixture afforded 6.36 g of a reddish oil (ESI-MS [M+H+]: 381.25) which was dissolved in 50 ml 6n HCl and stirred for 3 hours at 0° C. A pH of 12 was then adjusted with a 25% NaOH solution and it was again stirred for 48 hours at RT.\",\n \"The mixture was extracted 4× with ethyl acetate, the combined organic phases dried and evaporated.\",\n \"The oil thus obtained was stirred 2× with methyl-tert-butylether, the obtained solids filtered with suction and dried.\",\n \"0.6 g red solid; ESI-MS [M+H+]: 189.15.13C-NMR (90.55 MHz, d6-DMSO) δ ppm: 145.5, 141.60, 130.75, 128.4, 119.8, 115.6, 44.85.N1-(1,4,5,6-Tetrahydropyrimidine-2-yl)pentane-1,5-diamine (hydrochloride) (25) Preparation was carried out analogously to 23 starting from N-1-Boc-1,5-diaminopentane×HCl (5 g; 20.94 mmol) and 5.4 g 2-(methylsulfanyl)-1,4,5,6-tetrahydropyrimidine×HI.\",\n \"After workup, 1.3 g of a yellowish oil was obtained; [M+H+]: 282.2.Cleavage of the Boc-group with 4n HCl in dioxane and purification by means of MPLC afforded 0.46 g; ESI-MS [M+H+]: 185.15.N-[4-(Aminomethyl)cyclohexyl]pyridine-2-amine (hydrochloride) (26) Benzyl (4-aminocyclohexyl)methylcarbamate (TFA-salt) (5 g; 13.28 mmol)-preparation by TFA cleavage starting from benzyl-{4-[(tert-butoxycarbonyl)amino]cyclohexyl}methylcarbamate (EP 669317)-was heated to reflux analogously to 18 with 1.71 g ethyldiisopropylamine in 50 ml 2-fluoropyridine.\",\n \"Usual workup and crystallization of the raw products from methyl-tert-butylether/methanol afforded 4.15 g; ESI-MS [M+H+]: 340.29.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.75 (d broad, 1H), 7.85 (m, 2H), 7.35 (m, 5H), 7.05 (d, 1H), 6.85 (m, 1H), 5.05 (s, 2H), 2.90 (m, 2H), 1.95 and 1.75 (each m, 2H), 1.45-0.90 (m, 6H).\",\n \"Cleavage of the Z group under standard conditions (H2; Pd-activated carbon), precipitation of the resulting amine as hydrochloride and drying of the obtained precipitates afforded 1.5 g; ESI-MS [M+H+]: 206.15.tert-Butyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-ylacetate (27) 75 ml of a 1.0 m BH3-THF solution were added to a solution of tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (2) (10 g; 36.32 mmol) in 100 ml THF and it was stirred at RT.\",\n \"For workup, water was carefully added, it was 2× extracted with diethyl ether and then the organic phases were washed 2× with water.\",\n \"Evaporation and drying afforded 9.3 g; ESI-MS [M+H+]: 262.04.\",\n \"[5-(2-tert-Butoxy-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (28) a) 3 g K2CO3, 0.05 g KI and 5 g methylbromoacetate were added to a solution of tert-butyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl acetate (27) in 50 ml DMF and it was stirred for 12 hours at 90° C. Thereafter, 4 g methylbromoacetate were added and it was stirred for further 5 hours at 120° C. For workup, the mixture was concentrated, diluted with CH2Cl2, washed with saturated NaCl solution, dried and again evaporated.\",\n \"Chromatography on silica gel (CH2Cl2/CH3OH 1-5%) afforded 4.6 g of a bright yellow oil; ESI-MS [M+H+]: 334.12.b) 4.19 of the methylester in 20 ml dioxane/15 ml H2O were saponified with 19 KOH at RT.\",\n \"For workup, the mixture was concentrated, adjusted to a pH of 2 with 2n HCl and extracted with CH2Cl2.The combined organic phases were dried, evaporated and the obtained raw product purified by chromatography on silica gel (CH2Cl2/CH3OH 2-7%).\",\n \"2.4 g oil, ESI-MS [M+H+]: 320.15.1H-NMR (360 MHz, CDCl3) δ ppm: 7.20-7.10 (m, 1H), 6.90 and 6.80 (each m, 1H), 4.0 (s, 2H), 3.55 (m, 1H), 3.10 (m, 2H), 2.85 and 2.70 (each m, 1H), 2.90-2.50 (m, 4H), 1.35 (s, 9H).\",\n \"N-[4-(Aminomethyl)cyclohexyl]-1H-imidazole-2-amine (hydrobromide) (29) Preparation analogously to the preparation of N-[4-(aminomethyl)phenyl]-1H-imidazole-2-amine (23) starting from benzyl-(4-aminocyclohexyl)methylcarbamate (TFA salt) (3 g; 7.97 mmol).\",\n \"a) Reaction with BrCN and subsequent purification (1.52 g; ESI-MS [M+H+]: 288.15).\",\n \"1H-NMR (360 MHz, d6-DMSO) δ ppm: 7.45-7.25 (m, 5H), 6.75 (d, 1H), 5.05 (d, 2H), 2.85 (m, 3H), 1.85 and 1.70 (each m, 2H), 1.35 (m, 1H), 1.20 and 0.95 (each m, 2H).\",\n \"b) Conversion to the corresponding thiourea and subsequent methylation (1.489; ESI-MS [M+H+]: 336.15.c) Reaction with aminoacetaldehyde-diethylacetal and subsequent cyclization afforded 0.79 g; ESI-MS [M+H+]: 329.15.1H-NMR (360 MHz, DMSO) δ ppm: 7.45-7.25 (m, 5H), 6.45 (s, 2H), 5.35 (d, 1H), 5.05 (s, 2H), 2.90 (m, 2H), 1.95 and 1.70 (each m, 2H), 1.35 (m, 1H), 1.15 and 0.95 (each m, 2H).\",\n \"d) For cleavage of the Z-group it was dissolved in 30 ml HBr/glacial acidic acid and stirred for 3 h at RT.\",\n \"For workup, the mixture was evaporated and several times co-evaporated with acetone.\",\n \"0.89 g; ESI-MS [M+H+]: 195.15.tert-Butyloxycarbonyl-4-[(2-pyridinylamino)methyl]-1-piperidine (30) tert-Butyloxycarbonyl-4-(aminomethyl)-1-piperidine (3 g; 14 mmol) and 10 ml 2-fluoropyridine were heated for 4 h to reflux.\",\n \"Evaporation and mixing the raw product in n-pentane afforded 3 g of a wide solid, mp: 126-130° C.; ESI-MS [M+H+]=292.15.The amine required for the further reaction was obtained by cleavage of the Boc-group with HCl in dioxane (under standard conditions); the isolated HCl-salt was then directly utilized.\",\n \"Ethyl-2-{[5-(2-tert-butoxy-2-oxoethyl)-oxo-2,3,4,6-tetrahydro H-1-benzazepine-1-yl]methyl}-1,3-thiazole-4-carboxylate (31) a) A solution of t-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (2) in 20 ml DMF was added dropwise to a suspension of 1.28 g NaH (60%; deoiled) in 10 ml DMF at 5° C. and it was stirred for 1 h. 3.49 g Bromoacetonitrile-dissolved in 20 ml DMF-were then added dropwise and it was stirred for 4 h at RT.\",\n \"For workup, water was added carefully, it was diluted with CH2Cl2, washed several times with H2O and saturated NaCl solution, dried and evaporated.\",\n \"Purification of the raw product by chromatography on silica gel (CH2Cl2/CH3OH 5%) afforded 7.61 g; ESI-MS [M+H+-tBu]: 259.05.b) 5 g tert-Butyl-[1-(cyanomethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate in 70 ml pyridine were saturated for 1 h with H2S and then allowed to stand overnight at RT.\",\n \"Evaporation of the mixture and mixing of the obtained residue with pentane afforded 5.5 g of a rosa solid which was directly reacted.\",\n \"c) A mixture of 2 g tert-butyl-[1-(2-amino-2-thioxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate, 1.62 g ethylpyruvate and 0.86 g KHCO3 in 30 ml dioxane was stirred for 2.5 h at RT.\",\n \"Dilution with CH2Cl2, washing with saturated NaCl solution, drying and evaporation afforded 2.65 g of a yellow oil; ESI-MS [M+H+]: 445.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.50 (s, 1H), 7.50 and 7.35 (each m, 1H), 7.30-7.20 (m, 2H), 7.35 (d, 1H), 5.20 (broad, 1H), 4.30 (q, 2H), 4.20 (m, 1H), 3.65-3.50 (m, 2H), 2.70 (m, 2H), 2.35-2.10 (m, 3H), 1.70-1.50 (m, 2H), 1.30 (s, 9H; superimposed by t, 3H).\",\n \"2-{[5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]methyl}-1,3-thiazole-4-carbonic acid (32) 2.6 g Ethyl-2-{[5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]methyl}-1,3-thiazole-4-carboxylate (31) was provided in a mixture of 31 ml dioxane and 4 ml H2O, 1.5 eq.\",\n \"KOH was added and it was heated to reflux.\",\n \"After 5 h, again 1 eq.\",\n \"KOH was added and it was further stirred for 12 h at RT.\",\n \"For workup, it was concentrated, the residue was taken up in water, a pH of 4-5 was adjusted with 2n HCl and it was extracted several times with CH2Cl2.The combined org.\",\n \"phases were washed with saturated NaCl solution, dried and evaporated.\",\n \"Mixing with n-pentane afforded 2.1 g of a white solid; ESI-MS [M+H+]: 417.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.40 (broad, 1H), 7.5 (m, 1H), 7.35 (m, 1H), 7.30-7.20 (m, 3H), 5.25 (m, 2H), 2.70 (m, 2H), 2.35-2.10 (m, 6H), 1.70 (m, 1H), 1.30 (s, 9H).\",\n \"2-Ammonio-6-(ammoniomethyl)pyridinium trichloride (33) a) 2-Amino-6-methylpyridine (0.14 mol, 15.0 g) and phthalanhydride (0.14 mol, 20.55 g) were heated to 190° C. at the water separator.\",\n \"Distributing between H2O and CH2Cl2, evaporation of the org.\",\n \"phase and recrystallisation of the residue (diethyl ether) afforded 28.25 g of a slightly yellowish solid; ESI-MS [M+H+]=239.15.1H-NMR (270 MHz, CDCl3) δ (ppm): 7.95 (2H, m), 7.78 (3H, m), 7.23 (2H, m), 2.64 (3H, s).\",\n \"b.)\",\n \"N-bromosuccimide (25.18 mmol, 4.48 g) was added portionwise to a boiling suspension of 2-(6-methyl-2-pyridinyl)-1H-isoindole-1,3(2H)-dione (33a, 20.99 mmol, 5.0 g), AIBN (2.10 mmol, 0.35 g) and dibenzoylperoxide (2.10 mmol, 0.51 g) in CCl4.The reaction mixture was boiled for 20 h, filtered and the filtrate evaporated.\",\n \"Chromatography (CH2Cl2) afforded 3.12 g of the target product and 1.20 g of the dibromo compound; ESI-MS 318.95, 316.95.1H-NMR (270 MHz, CDCl3) δ (ppm): 7.98 (2H, m), 7.95 (1H, t), 7.81 (2H, m), 7.58 (1H, d), 7.35 (1H, d), 4.60 (2H, s).\",\n \"c) Potassium phthalimide (9.46 mmol, 1.75 g) was added to a solution of 2-[6-(bromomethyl)-2-pyridinyl]-1H-isoindole-1,3(2H)-dione (33b, 6.31 mmol, 2.0 g) in DMF (30 ml), the reaction mixture was heated for 15 h to 60° C., stirred for 24 h at RT, water (60 ml) was added and it was stirred for 2 h at 0° C. The residue was filtrated and washed with a mixture of H2O-DMF and then with diethyl ether; 2.12 g; ESI-MS [M+H+]=384.05.1H-NMR (270 MHz, CDCl3) δ (ppm): 7.98-7.91 (4H, m), 7.88 (1H, t), 7.85-7.75 (4H, m), 7.38-7.32 (2H, m), 5.10 (2H, s).\",\n \"d) 2-{6-[(1,3-Dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]-2-pyridinyl}-1H-isoindole-1,3(2H)-dione (33c, 5.22 mmol, 2.09) was heated to reflux for 3 h with hydrazinium hydroxide (13.04 mmol, 0.65 g) in methanol (50 ml).\",\n \"For workup, water was added, it was evaporated and the watery phase acidified with conc.\",\n \"HCl.\",\n \"Anew evaporation and recrystallising (ethyl alcohol) afforded 1.20 g of a white solid; ESI-MS [M+H+]=124.05.1H-NMR (270 MHz, D2O) δ (ppm): 7.94 (1H, t), 7.08 (1H, d), 6.99 (1H, d), 4.33 (2H, s).\",\n \"trans-N-[4-(Aminomethyl)cyclohexyl]-N′-benzylurea (34) Preparation was carried out analogously to compound 6 starting from benzyl-{4-[(tert-butoxycarbonyl)amino]cyclohexyl}methylcarbamate (EP 669317) by cleavage of the boc-group with 4n HCl in dioxane.\",\n \"Build-up of the benzyl urea by reaction with benzyl isocyanate and triethylamine in DMF and subsequent hydrogenolysis afforded 0.55 g of the target product; ESI-MS [M+H+]=262.20.7-(4-Aminobutyl)-1,2,3,4-tetrahydro[1,8]naphthyridine (bitrifluoroacetate) (35) a.)\",\n \"A solution of 5-tert-butoxycarbonylaminovaleric acid (50.0 mmol, 10.86 g), O,N-dimethylhydroxylamine hydrochloride (50 mmol, 4.88 g), N-Methylmorpholine (0.30 mol, 30.35 g), HOBT (53.90 mmol, 8.42 g) and EDCI*HCl (55.0 mmol, 10.54 g) in CH3CN (200 ml) were stirred for 2 days at RT.\",\n \"After evaporation the residue was taken up in ethyl acetate, and then washed with water, a 10% KHSO4-solution, a saturated watery NaHCO3 solution and a saturated watery NaCl-solution, subsequently.\",\n \"Drying and evaporation of the organic phase afforded 6.96 g of a yellowish oil; ESI-MS: [2M+Na+]=543.3, [M+Na+]=283.1, 205.1, 161.1.1H-NMR (270 MHz, CDCl3) δ (ppm): 4.63 (1H, s.\",\n \"br.\",\n \"), 3.68 (3H, s), 3.21-3.05 (3+2H, m), 2.44 (2H, t), 1.76-1.48 (2+2H, m), 1.43 (9H, s).\",\n \"b.)\",\n \"Methyl magnesia bromide (60.0 mmol, 17.30 ml of a 3M solution in Et2O) at 0° C. was added dropwise to a solution of tert-butyl 5-[methoxy(methyl)amino]-5-oxopentylcarbamate (35a, 30.0 mmol, 6.9 g) in THF (120 ml) and stirred for 5 h at 0° C. The reaction mixture was then carefully acidified with a 10% KHSO4-solution, extracted with ethyl acetate and the organic phase then washed with saturated watery NaHCO3— and saturated watery NaCl-solution, dried and evaporated: 5.5 g yellowish oil; ESI-MS: [M-BOC+H+]=116.15.c.)\",\n \"A mixture of tert-butyl 5-oxohexylcarbamate (35b, 9.29 mmol, 2.0 g), 2-aminonicotinaldehyde (Heterocycl.\",\n \"1993, 36, 2518; 11.20 mmol, 1.379) and KOH (0.37 ml of a 20% watery solution) was heated to reflux for 8 h. Evaporation and column chromatography afforded 1.60 g of the target product; ESI-MS: [M+H+]=302.15.d.)\",\n \"A suspension of tert-butyl 4-[1,8]naphthyridine-2-ylbutylcarbamate (35c, 5.31 mmol, 1.60 g) and Pd/C (10%, 1.59) in ethyl alcohol (40 ml) were stirred overnight under H2 atmosphere, then filtered over celite and washed with ethyl alcohol.\",\n \"Column chromatography afforded 290 mg; ESI-MS: [M+H+]=306.25.1H-NMR (360 MHz, CDCl3) δ (ppm): 7.04 (1H, d), 6.29 (1H, d), 4.97 (1H, s.br.\",\n \"), 4.81 (1H, s.br.\",\n \"), 3.37 (2H, m sym.\",\n \"), 3.12 (2H, q br.\",\n \"), 2.65 (2H, t), 2.53 (2H, t), 1.89 (2H, quint.\",\n \"), 1.67 (2H, quint.\",\n \"), 1.51 (2H, quint.\",\n \"), 1.43 (9H, s).\",\n \"e.) TFA (18.30 mmol, 2.099) was added to a solution of tert-butyl 4-(5,6,7,8-tetrahydro[1,8]naphthyridine-2-yl)butylcarbamate (35d, 0.92 mmol, 0.289) in CH2Cl2 (8 ml), the solution was stirred for 20 h and evaporated: 380 mg; ESI-MS: 206.1, 130.7.1H-NMR (400 MHz, CDCl3) δ (ppm): 7.07 (1H, d), 6.31 (1H, d), 5.58 (1H, s.br.\",\n \"), 3.39 (2H, m sym.\",\n \"), 2.96 (2H, s br.\",\n \"), 2.76 (2H, t), 2.68 (2H, t), 2.56 (2H, t), 1.88 (2H, quint.\",\n \"), 1.69 (2H, quint.\",\n \"), 1.51 (2H, quint.).\",\n \"tert-Butyl [1-(2-hydroxyethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (36) Tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (2) (10.9 mmol, 3.0 g)—dissolved in THF—was added at 0° C. to a solution of diisopropylamine (11.0 mmol, 1.119) and butyl lithium (11.0 mmol, 6.91 ml of a 15% solution in hexane) in THF (100 ml) and the solution further stirred for 1 h. About 100 ml ethylene oxide were then added and the mixture was stirred overnight at RT.\",\n \"The solution was distributed between saturated NH4Cl and ethyl acetate, the organic phase was washed with water and evaporated; 2.7 g; ESI-MS: [2M+Na+]=661.3, [M+K+]=358.1, 321.1, [M+H+]=320.1, 264.0.tert-Butyl [2-oxo-1-(2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (37) tert-Butyl [1-(2-hydroxyethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (36, 6.26 mmol, 2.00 g) dissolved in CH2Cl2 was added dropwise within 10 minutes to a solution of oxalyl chloride (7.93 mmol, 1.0 g) and DMSO (16.59 mmol, 1.26 g) in little CH2Cl2.After 30 min.\",\n \"triethyl amine (38.22 mmol, 3.87 g) was added, stirred for 5 min., left to reach RT and stirred overnight at RT.\",\n \"For workup, water was added, the mixture extracted with CH2Cl2 and the organic phase washed with saturated NaCl—, 1%-H2SO4— and with 5%-NaHCO3-solution.\",\n \"Evaporation afforded 1.8 g of the target product; ESI-MS: 693.2, [M+K+]=358.1, 319.1, [M+H+]=318.1, 262.0.Methyl-2-amino-5-chlorobenzoic acid (38) Thionyl chloride (0.47 mmol, 55.46 g) was added dropwise at 0° C. to a solution of 2-chloro-5-aminobenzoic acid (0.23 mmol, 40.09) in methanol (400 ml) and the mixture heated to 50-60° C. After the reaction had finished, water was added and it was extracted with ethyl acetate.\",\n \"Then the organic phase was washed with 1n NaOH and diluted HCl solution (pH 1-2), subsequently, and evaporated; 23.0 g; ESI-MS: [M+H+]=186.05.Methyl 4-chloro-2-[(4-ethoxy-4-oxobutanoyl)amino]benzoic acid (39) Ethyl succinic acid-chloride (0.14 mol, 22.44 g) in toluen (15 ml) was added dropwise at 0° C. to a solution of methyl 2-amino-5-chloro-benzoic acid (38, 123.9 mmol, 23.0 g) and pyridine (0.26 mol, 20.58 g) in toluen (40 ml).\",\n \"The solution was stirred overnight at RT, water was added and it was extracted with ethyl acetate.\",\n \"The organic phase was washed with 1N HCl-solution, with water, with a saturated NaHCO3-solution and with a saturated NaCl-solution.\",\n \"Evaporation, recrystallisation (methanol) afforded 34.1 g of the target product; ESI-MS: [2M+Na+]=649.0, [M+K+]=352.0, [M+H+]=314.05; 1H-NMR (270.MHz, CDCl3) δ (ppm): 11.06 (1H, s br.\",\n \"), 8.68 (1H, d), 7.99 (1H, m), 7.47 (1H, dd), 4.16 (2H, q), 3.92 (3H, s), 2.74 (4H, m), 1.24 (3H, t).\",\n \"Ethyl-7-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (40) Methyl 4-chloro-2-[(4-ethoxy-4-oxobutanoyl)amino]benzoic acid (39, 0.16 mol, 50.20 g) in DMSO (250 ml) was added dropwise at 15° C. to a suspension of deoiled NaH (0.27 mol) in THF (50 ml) and DMSO (80 ml) and the mixture was stirred for 2 h at RT.\",\n \"At 0° C. glacial acetic acid (24 ml) was added and stirred for 20 min.\",\n \"Water (25 ml) was added, the resulting precipitate filtered off, washed with water, taken up in CH2Cl2, extracted with water and the organic phase evaporated.\",\n \"The residue was then stirred with diethyl ether (50 ml), filtered and dried; 32 g of a 6:4-mixture methyl/ethyl ester, which was not separated; ESI-MS (Me-ester): [M+K+]=307.9, [M+Na+]=290.0, [M+H+]=268.0; ESI-MS (Et-ester): [M+K+]=321.9, [M+Na+]=304.0, [M+H+]=282.0.7-Chloro-3,4-dihydro-1H-1-benzazepine-2,5-dione (41) Ethyl-7-chloro-5-hydroxy-2-oxo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (40, 0.11 mol, 32.0 g) was heated to 150° C. in DMSO (500 ml) and water (0.23 mol, 4.09 g) and stirred for 2 h. Water was added at 100° C., the mixture cooled to 0° C. and the resulting precipitate filtered off.\",\n \"Drying afforded 19.09; ESI-MS: [M+Na+]=251.1, [M+H+]=211.9, 209.95, 130.1.tert-Butyl (2E,Z)-(7-Chloro-2-oxo-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene) ethane acid (42) t-Butyl diethylphosphono acetic acid (0.10 mol, 25.849) was added dropwise at 0° C. to a solution of deoiled NaH (0.10 mol) in DMF (40 ml) and stirred until a clear solution develops.\",\n \"7-Chloro-3,4-dihydro-1H-1-benzazepine-2,5-dione (41, 90.63 mmol, 19.09) in DMF (185 ml) was added dropwise at 0° C. and stirred at RT.\",\n \"Water was added to the reaction mixture, it was stirred for 1 h and the resulting yellow residue filtered off with suction, washed with water and taken up in CH2Cl2.The organic phase was washed with a 5%-NaHCO3-solution and evaporated.\",\n \"Recrystallisation afforded 23.5 g of the target product; ESI-MS: [2M+H+]=615.2, [M+Na+]=330.0, 293.0, 254.1, 252.1.1H-NMR (400 MHz, CDCl3) δ (ppm): 9.59 (1H, s br.\",\n \"), 7.45 (1H, m), 7.25 (1H, m), 7.06 (1H, m), 5.99 (1H, t), 3.43 (2H, s), 2.84 (2H, d), 1.32 (9H, s).\",\n \"t-Butyl (7-chloro-2-oxo-2,3,4,4-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (43) tert-Butyl (2E,Z)-(7-chloro-2-oxo-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)ethane acid (42, 75.0 mmol, 23.089) in ethyl alcohol/dioxane (250 ml/100 ml) was hydrogenated for 4 days with Pt/carbon (5%, 4.1 g) under standard conditions.\",\n \"Water was added to the reaction mixture, stirred for 1 h, the yellow residue filtered off with suction, washed with water and taken up in CH2Cl2.The organic phase was washed with a 5%-NaHCO3-solution and evaporated.\",\n \"Recrystallisation afforded 23.5 g of a solid (mixture of target product and the corresponding dechlorinated compound; the mixture was reacted directly); ESI-MS: [2M+H+]=618.94, [M+K+]=350.66, 309.75, 254.11.Methyl [5-(2-tert-butoxy-2-oxo ethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (44) tert-Butyl (7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (43, 60.00 mmol, 18.59 g) in DMF (10 ml) was added dropwise at 15° C. to deoiled NaH (69.00 mmol) in DMF (5 ml) and the mixture was stirred overnight at RT.\",\n \"Ice water was added to the reaction mixture, extracted (2×) with ethyl acetate and the organic phase washed with a 10% CH3COOH-solution, with water and then with 1n NaOH.\",\n \"Evaporation afforded 20.4 g of a raw product, which was reacted without further purification.\",\n \"[5-(2-tert-Butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) KOH (80.45 mmol, 4.51 g) in water (150 ml) was added to methyl [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (44, 50.28 mmol, 19.29) dissolved in dioxane (250 ml) and stirred for 1 h at RT.\",\n \"The reaction mixture was evaporated, water (100 ml) was added and it was extracted with ethyl acetate (2×).\",\n \"After the evaporation, the residue was taken up in diethyl ether and precipitated by addition of n-pentane.\",\n \"Recrystallisation (diisopropyl ether, 2×) afforded 4.8 g (comprises about 15% of the corresponding dechloro compound); ESI-MS: [M+Na+]=390.0, 314.0, 312.0.\",\n \"[4-(Aminomethyl)phenyl]guanidine (Bihydrochloride) (46) p-Aminobenzylamine (6.7 g; 54.84 mmol) was suspended in 20 ml 6n HCl and 5.3 g cyanamide—dissolved in 5 ml H20—added slowly under reflux.\",\n \"After the reaction had completed, 50% NaOH-solution was added at 0° C. to the solution, the resulting precipitate filtered with suction, boiled up in 50 ml ethyl alcohol and filtered off.\",\n \"Evaporation of the mother liquor and mixing of the obtained residue with diethyl ether afforded 1.4 g of yellow solids; Fp.\",\n \": 255° C. 7,8-Dimethoxy-3,4-dihydro-1H-1-benzazepine-2,5-dione (47) Analogously to the preparation of the corresponding building blocks 39, 40 and 41 first ethyl-2-amino-4,5-dimethoxybenzoate (20 g; 88.8 mmol) was reacted with ethyl succinic acid-chloride to the respective amide.\",\n \"After mixing with n-pentane 30.4 g of a solid was obtained; ESI-MS [M+H+]: 354.15.1H-NMR (400 MHz, DMSO) δ (ppm): 10.65 (s, 1H), 8.10 and 7.40 (each s, 1H), 4.30 and 4.10 (each q, 2H), 3.85 and 3.80 (each s, 3H), 2.70 (m, 4H), 1.30 and 1.20 (each t, 3H).\",\n \"Subsequent cyclization with 25 g of the obtained amide under utilization of NaH analogously to 40 and usual workup afforded 19.5 g of a white solid; ESI-MS [M+H+]: 308.05.1H-NMR (400 MHz, DMSO) δ (ppm): 13.3 (s, 1H), 10.10 (s, 1H), 7.25 and 6.75 (each s, 1H), 4.30 (q, 2H), 3.80 (s, 6H), 2.95 (s, 2H), 1.35 (t, 3H).\",\n \"Decarboxylation analogously to 41 starting from 17 g afforded 10.5 g of the target product as a solid; ESI-MS [M+H+]: 236.15.1H-NMR (400 MHz, DMSO) δ (ppm): 9.90 (s, 1H), 7.35 and 6.80 (each s, 1H), 3.80 and 3.75 (each s, 3H), 2.85 and 2.65 (each m, 2H).\",\n \"tert-Butyl (7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate (48) Preparation analogously to building blocks 42 and 43 by Wittig-Homer-reaction and subsequent hydrogenation; after mixing with n-pentane 8.16 g of solids were obtained; ESI-MS [M+H+-tBu]: 280.15.\",\n \"[5-(2-tert-Butoxy-2-oxoethyl)-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetate (49) Analogously to 44 and 45, starting from 4 g tert-butyl-(7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate 2.6 g of the target product were isolated as a bright foam; [M+H+-tBu]: 338.15.1H-NMR (400 MHz, DMSO) δ (ppm): 6.85 and 6.75 (each s, 1H), 4.35 (s broad, 2H), 3.80 and 3.75 (each s, 3H), 3.60 (s, 2H), 2.70 (m, 2H), 2.25 (m, 1H), 2.15 (m, 2H), 1.60 (m, 1H), 1.35 (s, 9H).\",\n \"[1-(2-Methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) a.)\",\n \"56.1 g (406 mmol) powdered K2CO3 were added at room temperature to a solution of 37 g (135.3 mmol) t-butyl (2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl)acetic acid (1) and 3.7 g tetrabutylammoniumbromide in 370 ml DMF, 22.7 g (148.9 mmol) methylbromoacetic acid was added dropwise, then it was stirred for 3 h at 40° C. and overnight at room temperature.\",\n \"The reaction mixture was poured into 1000 ml of a water-ice-mixture, and 2× extracted with each 200 ml methyl-tert.butyl ether.\",\n \"The combined extracts were washed with H2O, 5% NaHCO3— and NaCl-solution, dried over Na2SO4, filtered off and evaporated.\",\n \"The remaining yellow oil (about 52 g, purity about 90%) was reacted without further purification; ESI-MS [M+H+]: 346.b.)\",\n \"9.2 g (26.6 mmol) of the raw product 50a were dissolved in 66.6 ml 4n HCl in dioxane and stirred for 24 h at 50° C., then the dioxane was extensively distilled off, 5% NaHCO3-solution and diethyl ether added to the residue, the watery phase again washed with diethyl ether and acidified with 1n KHSO4-solution.\",\n \"The precipitating acid was extracted with diethyl ether, the ether phase washed with a NaCl-solution, dried over Na2SO4, filtered off with suction and evaporated.\",\n \"It remained 3.2 g of a slightly yellow oil; ESI-MS [M+H+]: 290.trans-[4-(1H-Benzimidazole-2-yl)cyclohexyl]methaneamine (hydrochloride) (51) 39.3 g (0.25 mol) trans-4-(Aminomethyl)cyclohexanecarbonic acid and 27.0 g (0.25 mol) 1,2-phenylene diamine were heated to reflux for 18 h in a mixture of 167 ml conc.\",\n \"hydrochloric acid and 333 ml H2O analogously to J. Heterocycl.\",\n \"Chem.\",\n \"26, 541 (1989).\",\n \"The green reaction solution was concentrated until the occurrence of a yellow crystalline pulp and stirred with 400 ml isopropanol, filtered off, washed with 90% isopropanol and finally with diethyl ether.\",\n \"After 2 times recrystallisation from a isopropanol-water mixture (70/30), 30 g of a white monohydrochloride remained; ESI-MS [M+H+]: 230.Methyl (2-oxo-2,3,4,5-tetrahydro-1H-1,5benzodiazepine-1-yl)acetic acid (52) 1.99 (79.8 mmol) NaH (60% dispersion in mineral oil) were added to an ice cooled solution of 12.2 g (75.3 mmol) 1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-2-One (preparation: J.\",\n \"Am.\",\n \"Chem.\",\n \"Soc.\",\n \"1949, 71, 1985) in 350 ml DMF, stirred for 30 min.\",\n \"at 0-5° C. and for 10 min.\",\n \"at room temperature.\",\n \"Then 11.5 g (75.3 mmol) methyl bromo acetic acid were added dropwise at 0° C. and it was then stirred for 30 min.\",\n \"at the same temperature.\",\n \"The reaction solution was poured onto 600 ml ice water and 3× extracted with each 150 ml ethyl acetate.\",\n \"The organic phase was washed with a NaCl-solution, dried over MgSO4 and ethyl acetate was distilled off.\",\n \"The residue was purified by column chromatography (eluent: CH2Cl2/CH3OH 9/1).\",\n \"9.6 g of a yellowish oil were isolated; ESI-MS [M+H+]: 235.tert-butyl (2-oxo-2,3,4,6-tetrahydro-1H-1,5-benzodiazepine-1-yl)acetic acid (53) Preparation was carried out analogously to building block 52 by reaction of 11.99 (73 mmol) 1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-2-one with 14.3 g (73 mmol) tert-butyl bromo acetic acid.\",\n \"17 g of a slightly yellowish oil were isolated; ESI-MS [M+H+]: 277.\",\n \"[5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (54) a.)\",\n \"14.2 g (102 mmol) powdered K2CO3 were added at 0° C. to a solution of 9.6 g (41 mmol) compound 52 and 8.09 (41 mmol) tert-butyl bromo acetic acid in 90 ml DMF, and stirred for 1 h at 0° C. and then for 14 h at room temperature.\",\n \"The reaction mixture was poured onto 300 ml ice water and 3× extracted with each 100 ml methyl-tert.butyl ether.\",\n \"The combined organic phases were washed several times with a NaCl-solution, dried over MgSO4 and evaporated to dryness.\",\n \"The residue was purified by column chromatography (eluent: ethyl acetate/cyclohexane 7/3).\",\n \"7.0 g of a slightly yellowish oil were isolated; ESI-MS [M+H+]: 349.b.)\",\n \"The alkaline saponification of the methyl ester was carried out analogously to 3b.\",\n \"3.8 g white crystals were obtained; Fp.\",\n \": 140-142° C.; ESI-MS [M+H+]: 335.\",\n \"[5-(2-tert-Butoxy-2 oxoethyl)-4-oxo-2,3,4,6-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (55) Analogously to building block 54a tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl)acetic acid (53) was reacted with methyl bromoacetic acid and then alkaline saponified analogously to 3b.\",\n \"After purification by column chromatography 2.9 g white crystals were obtained; Fp.\",\n \": 82-84° C.; ESI-MS [M+H+]: 335.\",\n \"[1-(2-Methoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (56) 14.5 g (42 mmol) building block 3a were dissolved in 105 ml 4n HCl in dioxane and stirred for 2 days at 50° C. After evaporation of the solvent, the residue was dissolved in 5% NaHCO3-solution, 2× extracted with methyl-tert.butyl ether, then the watery phase was acidified with a 1n KHSO4-solution and the precipitating acid extracted with methyl-tert.butyl ether.\",\n \"After drying over MgSO4, evaporation of the solvent and purification by column chromatography (eluent: CH2Cl2/CH3OH/glacial acetic acid 451511) 1.6 g of a viscous, slightly yellowish oil remained; ESI-MS [M+H+]: 292.\",\n \"[(5R)-5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (57) 14.2 g (42.6 mmol) [5-(2-t.Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) were suspended in 170 ml diethylether and dissolved by addition of 7.3 g (42.64 mmol) (1S)-(−)-1-napthyl)ethylamine.\",\n \"The yellow solution was inoculated with (1S)-1-napthyl)ethaneaminium[(5R)-5-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetate—prepared by preparative HPLC-separation of compound 3 by means of a chiral column (Chiralpak AD 500×; 50 mm; 20 μm) and subsequent salification-, the deposited precipitate filtered off with suction after 3.5 h and 3× recrystallized from a ethyl acetate/isopropanol mixture.\",\n \"The purity of enantiomers was checked by means of a chiral HPLC.\",\n \"3.5 g. of the salt were suspended in 30 ml of a diethylether/hexane-mixture 10/3 and after addition of 50 ml of a 5% watery amidosulfonic acid solution stirred until occurrence of a clear phase.\",\n \"After separation of the watery phase, the organic phase was washed 3× with 5 ml amidosulfonic acid- and then with a NaCl-solution, dried over Na2SO4 and evaporated.\",\n \"2.25 g amorphous residue; ESI-MS [M+H+]: 505.\",\n \"[(5S)-5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (58) From the combined mother liquors of building block 57, 8 g of the acid were isolated as a yellowish amorphous residue as described with a amidosulfonic acid solution, said acid was reacted with (1R)-(+)-1-napthyl)ethyl amine into the diastereomeric salt and recrystallized until the achievement of enantiomeric purity.\",\n \"Analogously to example 57, 2.5 g of the dextrorotatory acid were isolated as an amorphous solid, ESI-MS [M+H+]: 505.A sample of the acid was reacted with 4-bromobenzylamine into the good crystallizing amide and the absolute configuration figured out by means of a x-ray structure analysis.\",\n \"tert-Butyl-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]azepine-8-yl)acetate (59) A solution of 5.3 g (29.2 mmol) 6,7-dihydro-4H-thieno[3,2-b]azepine-5,8-dione (Arch.\",\n \"Pharm.\",\n \"1991 324, 579) and 12 g (32.2 mmol) (tert-butoxycarbonylmethylene)-triphenyl phosphorane in 15 ml toluen was heated to reflux for 10 h, then toluen was distilled off and the black residue purified by chromatography (eluent: ethyl acetate/cyclohexane 7/3).\",\n \"The consistent fraction was again digested with 40 ml boiling cyclohexane, cooled and filtered with suction.\",\n \"3 g yellowish crystals; ESI-MS [M+H+]: 280.tert-Butyl-(5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-8-yl)acetate (60) 39 (11 mol) tert-Butyl-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]azepine-8-yl)acetate were hydrogenated analogously to building block 2 in the presence of 10% Pd/C.\",\n \"Since educt was still present after 6 h according to HPLC, the catalyst was filtered with suction and after addition of new catalyst it was again hydrogenated for 6 h. After workup and chromatographic purification (eluent: ethyl acetate/cyclohexane 7/3), 1.4 g yellowish crystals were isolated, which comprised according to HPLC still about 2.5% educt; ESI-MS [M+H+]: 282.\",\n \"[8-(2-tert-Butoxy-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-4-yl]acetic acid (61) Preparation was carried out analogously to building block 50.Ester stage: 1.5 g yellowish crystals; ESI-MS [M+H+]: 354.Target product: 1.2 g yellowish crystals; ESI-MS [M+H+]: 340.I.B Compounds of the Formula I or I′ Example I t-Butyl [1-(2-{[(2-{[amino(imino)methyl]amino}-1,3-thiazol-5-yl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetate 1.1 g of N-methylmorpholine were added dropwise at 0° C. to 1.5 g (4.65 mmol) of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) and 1.22 g (4.8 mmol) of N-[5-(aminomethyl)-1,3-thiazol-2-yl]guanidine dihydrochloride (5) in 20 ml of DMF, and 1.55 g (4.7 mmol) of TOTU (O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetrafluoroborate) were then introduced in portions over the course of 35′.\",\n \"The yellow reaction solution was stirred at 0° C. for 1 h and then largely evaporated in vacuo.\",\n \"The residue was then digested a number of times with H2O, taken up in a mixture of 120 ml of ethyl acetate and 40 ml of diethyl ether, washed with 10% K2CO3 and NaCl solution, dried over Na2SO4 and concentrated, the crude product thoroughly crystallizing.\",\n \"Purification by chromatography on silica gel (CH2Cl2/CH3OH/NH3 42:8:0.1) and crystallization from ethyl acetate/n-hexane afforded 1.45 g (65%) of white crystals.\",\n \"M.p.\",\n \": 190-193° C. (dec.); FAB-MS [M+H+]: 487.Example II [1-(2-{[(2-{[Amino(imino)methyl]amino}-1,3-thiazol-5-yl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid 1.2 g of the t-butyl ester from Example I were suspended in 70 ml of CH2Cl2, treated with 45 ml of 4N HCl in dioxane and stirred overnight at RT.\",\n \"The solution was evaporated, and the residue was digested a number of times with CH2Cl2 and then dried.\",\n \"In this way, 1.07 g of a slightly yellowish amorphous powder were isolated; FAB-MS [M−H+]: 432.Example III [1-(2-{[4-(1H-Benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine hydrochloride (4) and subsequent removal of the t-butyl group analogously to Example II.\",\n \"A slightly yellowish amorphous residue was obtained, FAB-MS [M−H+]: 554.Example IV t-Butyl [1-(2-{[(2-{[amino(imino)methyl]amino}-1,3-thiazol-5-yl)methyl]amino}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepin-5-yl]acetate Analogously to the preparation of compound 3a, 0.9 g (3.3 mmol) of t-butyl (2-oxo-2,3-dihydro-1H-1-benzazepin-5-yl)acetate (1) was alkylated with methyl bromoacetate (FAB-MS [M−H+]: 346) and then hydrolyzed analogously to 3b (0.44 g; FAB-MS [M−H+]: 332).\",\n \"Coupling of 0.57 g (1.72 mmol) of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepin-1-yl]acetic acid with N-[5-(aminomethyl)-1,3-thiazol-2-yl]guanidine dihydrochloride (5) analogously to Example I afforded the title compound as a slightly yellowish powder; FAB-MS [M−H+]: 485.Example V [1-(2-{[(2-{[Amino(imino)methyl]amino}-1,3-thiazol-5-yl)methyl]amino}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepin-5-yl]acetic acid The t-butyl ester was removed analogously to Example II and afforded 0.42 g of the title compound as a slightly yellowish powder; FAB-MS [M−H+]: 429.Example VI (1-{2-[(4-{[(Benzylamino)carbonyl]amino}benzyl)amino]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-5-yl]acetic acid (3) with N-[4-(aminomethyl)phenyl]-N′-benzylurea (6) and subsequent removal of the t-butyl group analogously to Example II.\",\n \"Purification of the crude product by elution through a silica gel cartridge (Chromasorb; CH2Cl2/CH3OH 0-20%) afforded 27 mg as an amorphous solid; ESI-MS [M+H+]: 515.2; [M+K+]: 553.2.Example VII [1-(2-{[4-(1H-Benzimidazol-2-yl)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with [4-(1H-benzimidazol-2-yl)phenyl]methaneamine (7) and subsequent cleavage of the t-butyl group analogously to Example II.\",\n \"Purification of the crude product by elution through a silica gel cartridge (Chromasorb; CH2Cl2/CH3OH 0-20%) afforded 9 mg as an amorphous solid; ESI-MS [M+H+]: 485.2.Example VIII [1-(2-{[4-(1H-Benzimidazol-2-ylamino)butyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-5-yl]acetic acid (3) with N1-(1H-benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (9) and subsequent cleavage of the t-butyl group analogously to Example II.\",\n \"After chromatographic purification on silica gel (eluent: CH2Cl2/CH3OH/50% acetic acid 42:8:0.7), 0.5 g was isolated as a slightly yellowish amorphous powder; FAB-MS [M−H+]: 464.Example IX [1-(2-{[5-(1H-Benzimidazol-2-ylamino)pentyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with N1-(1H-benzimidazol-2-yl)pentane-1,5-diamine (hydrochloride) (8) and subsequent cleavage of the t-butyl group analogously to Example II.\",\n \"After chromatographic purification on silica gel (eluent: CH2Cl2/CH3OH/50% acetic acid 42:8:0.7), 0.48 g was isolated as a slightly yellowish amorphous powder; FAB-MS [M−H+]: 478.Example X {1-[2-({4-[(1H-Benzimidazol-2-ylamino)methyl]cyclohexyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl}acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with trans-N-[(4-aminocyclohexyl)methyl]-1H-benzimidazole-2-amine (dihydrochloride) (10) and subsequent cleavage of the t-butyl group analogously to Example II.\",\n \"After chromatographic purification on silica gel, 0.7 g of slightly yellowish amorphous powder was isolated; FAB-MS [M+H+]: 504.Example XI {1-[2-({[4-(1H-Benzimidazol-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl}acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-5-yl]acetic acid (3) with trans-N-{[4-(aminomethyl)cyclohexyl]-1H-benzimidazole-2-amine (dihydrochloride) (11) and subsequent cleavage of the t-butyl group analogously to Example II.\",\n \"After chromatographic purification on silica gel, 0.5 g of slightly yellowish amorphous powder was isolated; FAB-MS [M+H+]: 504.Example XII [2-Oxo-1-(2-oxo-2-{[4-(pyridin-2-ylamino)benzyl]amino}ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with N-[4-(aminomethyl)phenyl]-2-pyridineamine (13) and subsequent cleavage of the t-butyl group analogously to Example II (14 mg); ESI-MS [M+H+]: 459.15.Example XIII {1-[2-({[6-(1H-Benzimidazol-2-yl)pyridin-3-yl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl}acetic acid (bishydrochloride) Preparation was carried out analogously to Example I by reaction of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl]acetic acid (3) with [6-(1H-benzimidazol-2-yl)pyridin-3-yl]methaneamine (trifluoroacetate) (12) and subsequent cleavage of the t-butyl group analogously to Example II.\",\n \"(13 mg); ESI-MS [M+H+]: 484.15.Compounds of the general formula I analogously to example II were prepared: Example 14 {2-Oxo-1-[2-oxo-2-({4-[(pyridine-2-ylamino)methyl]benzyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Under utilization of N-[4-(aminomethyl)benzyl]-2-pyridine amine (14) as educt, 207 mg as an amorphous solid were obtained according to MPLC 207 mg; ESI-MS [M+H+]: 473.28.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.5 (m, 1H), 7.95 (d, 1H), 7.45 (m, 1H), 7.35-72.0 (m, 9H), 6.60 (m, 2H), 4.45 (m, 3H), 4.25 (m, 3H), 3.55 (m, 1H), 2.70 (m, 2H), 2.35 (m, 1H), 2.20 (m, 2H), 1.65 (m 1H).\",\n \"Example 15 {1-[2-({[5-(1H-Benzimidazole-2-yl)thiene-2-yl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Under utilization of [5-(1H-benzimidazole-2-yl)thiene-2-yl]methaneamine (15) as educt, 210 mg as amorphous white solids were obtained according to MPLC; ESI-MS [M+H+]: 489.27.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.80 (m, 1H), 7.70 (m, 1H), 7.65 (m, 2H), 7.35-7.15 (m, 6H), 7.05 (m, 1H), 4.55 (m, 3H), 4.20 (m, 1H), 3.55 (m, 1H), 2.75 (m, 2H), 2.35 (m, 1H), 2.15 (m, 2H), 1.65 (m, 1H).\",\n \"Example 16 {1-[2-({2-[4-(1H-Benzimidazole-2-yl)phenyl]ethyl}amino)-2-oxoethyl]-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Under utilization of tert-butyl-2-[4-(1H-benzimidazole-2-yl)phenyl]ethylcarbamate (16) as educt, 190 mg as amorphous white solids were obtained according to MPLC; ESI-MS [M+H+]: 497.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.15 (d, 2H), 7.65 (d, 2H), 7.45 (m, 2H), 7.30-7.15 (m, 6H), 4.45 and 4.15 (each m, 1H), 3.6-3.25 (m, superimposed by H2O), 2.80 (m, 2H), 2.70 (m, 2H), 2.35 (m, 1H), 2.20 (m, 2H), 1.70 (m, 1H).\",\n \"Example 17 [1-(2-{4-[(1H-Benzimidazole-2-ylamino)methyl]piperidine-1-yl}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Under utilization of (3 N-(piperidine-4-ylmethyl)-1H-benzimidazole-2-amine (trifluoro acetate) (17) as educt, 134 mg as amorphous white solids were obtained according to MPLC; ESI-MS [M+H+]: 490.29.Example 18 [2-Oxo-1-(2-oxo-2-{[2-(pyridine-2-ylamino)ethyl]amino}ethyl)-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Under utilization of N1-pyridine-2-ylethane-1,2-diamine, the subsequent MPLC afforded 278 mg as amorphous white solids; ESI-MS [M+H+]: 397.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.20 (m, 1H), 7.95 (m, 1H), 7.70 (m, 2H), 7.35-7.20 (m, 4H) 6.80 and 6.70 (each m, 1H), 4.45 and 4.15 (each m, 1H), 3.70-3.0 (m, superimposed by H2O), 2.70 (m, 2H), 2.30 (m, 1H), 2.15 (m, 2H), 1.60 (m, 1H).\",\n \"Example 19 (2-Oxo-1-{2-oxo-2-[({4-[(pyridine-2-ylamino)methyl]thiene-2-yl}methyl)amino]ethyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Under utilization of N-{[5-(aminomethyl)thiene-3-yl]methyl}pyridine-2-amine (trifluoro acetate) (18), the subsequent MPLC afforded 135 mg as amorphous white solids; ESI-MS [M+H+]: 479.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.65 (m, 1H), 8.0 (m, 1H), 7.45 (m, 1H), 7.35-7.15 (m, 6H), 6.95 (s, 1H), 6.60 and 6.55 (each m, 1H), 4.60-4.30 (m, 5H), 4.15 (m 1H), 3.50 (m, 1H), 2.80-2.60 (m, 2H), 2.35 (m, 1H), 2.15 (m, 2H), 1.70 (m, 1H).\",\n \"Example 20 [1-(2-{[3-(1H-imidazole-2-ylamino)-3-oxopropyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Under utilization of 3-amino-N-(1H-imidazole-2-yl)propane amide (19) and following purification of the raw product by MPLC 50 mg were obtained as amorphous white solids; ESI-MS [M+H+]: 414.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.20 (m, 1H), 7.30-7.20 (m, 7H), 4.45 and 4.15 (each m, 1H), 3.75-3.25 (m, superimposed by H2O), 2.80-2.65 (m, 4H), 2.35 (m, 1H), 2.15 (m, 2H), 1.60 (m, 1H).\",\n \"Example 21 [1-(2-{[4-(4,5-Dihydro-1H-imidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Under utilization of N-[4-(aminomethyl)-phenyl]-4,5-dihydro-1H-imidazole-2-amine (hydrochloride) (20) as educt, 12 mg were obtained as amorphous white solids after MPLC; ESI-MS [M+H+]: 450.3.Example 22 (1-{2-[({4-[(1H-Benzimidazole-2-ylamino)methyl]thiene-2-yl}methyl)amino]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-6-yl)acetic acid Utilization of N-{[5-(aminomethyl)thiene-3-yl]methyl}-1H-benzimidazole-2-amine (hydrochloride) (21) as educt; purification by MPLC afforded 90 mg; ESI-MS [M+H+]: 518.29.Example 23 [2-Oxo-1-(2-oxo-2-{[5-(pyridine-2-ylamino)pentyl]amino}ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Utilization of N1-pyridine-2-ylpentane-1,5-diamine (hydrochloride) (22) as educt; after MPLC, 210 mg white solids were obtained; ESI-MS [M+H+]: 439.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.05 (m, 1H), 7.95 (m, 1H), 7.75 (m broad, 1H), 7.65 (m, 1H), 7.30-7.15 (m, 4H), 6.75 and 6.60 (each m, 1H), 4.45 and 4.15 (each m, 1H), 3.70-3.20 (m, superimposed by H2O), 2.70 (m, 2H), 2.35 (m, 1H), 2.15 (m, 2H), 1.60, 1.45 and 1.30 (each m, 2H).\",\n \"Example 24 N-[5-({[5-(Carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)pentyl]-4,5-dihydro-1H-imidazole-2-amine (acetate) Utilization of N1-(4,5-Dihydro-1H-imidazole-2-yl)pentane-1,5-diamine (hydrochloride) (23) as educt; 22 mg were obtained after MPLC; ESI-MS [M+H+]: 430.15.Example 25 [1-(2-{[4-(1H-imidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Utilization of N-[4-(aminomethyl)phenyl]-1H-imidazole-2-amine (24) as educt; purification by means of MPLC afforded 40 mg; ESI-MS [M+H+]: 448.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.95 (s, 1H), 8.45 (m, 1H), 7.35-7.10 (m, 8H), 6.75 (s, 2H), 4.50 (m, 1H), 4.20 (m, 3H), 3.5-3.1 (m, superimposed by H2O).\",\n \"2.70 (m, 1H), 2.35 (m 1H), 2.20 (m, 2H), 1.65 (m, 1H).\",\n \"Example 26 [2-Oxo-1-(2-oxo-2-{[1-(1,4,6,6-tetrahydropyrimidine-2-ylamino)pentyl]amino}ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Utilization of N1-(1,4,5,6-tetrahydropyrimidine-2-yl)pentane-1,5-diamine (hydrochloride) (26) as educt; 40 mg were obtained after MPLC; ESI-MS [M+H+]: 444.9.Example 27 {2-Oxo-1-[2-oxo-2-({[4-(pyridine-2-ylamino)cyclohexyl]methyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Utilization of N-[4-(aminomethyl)cyclohexyl]pyridine-2-amine (hydrochloride) (26), purification by means of an elution over a Chromabond-C18-cartridge afforded 85 mg; ESI-MS [M+H+]: 465.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.55 (s broad, 1H), 8.05 (m, 1H), 7.90 (d, 1H), 7.85 (m, 1H), 7.35 (m, 2H), 7.25 (m, 2H), 6.95 (d, 1H), 6.80 (m, 1H), 4.40 and 4.20 (each m 1H), 3.55 (m, superimposed by H2O), 2.95 (m, 2H), 2.70 (m, 2H), 2.35 (m, 1H), 2.15, 1.95 and 1.75 (each m, 2H), 1.60 and 1.40 (each m, 1H), 1.25 (m, 2H), 1.05 (m, 2H).\",\n \"Example 28 Ethyl-{2-oxo-1-[2-oxo-2-({[4-(pyridine-2-ylamino)cyclohexyl]methyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 30 ml 4n HCl in dioxane were added to 100 mg {2-oxo-1-[2-oxo-2-({[4-(pyridine-2-ylamino)cyclohexyl]methyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid in 10 ml EtOH and it was stirred for 48 h at RT.\",\n \"Evaporation and elution over a Chromabond-C8-cartridge afforded 26 mg; ESI-MS [M+H+]: 493.25.Example 29 (1-{4-[4-(1H-Benzimidazole-2-ylamino)phenyl]butyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid a.)\",\n \"A solution of t-butyl (2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (2) (0.8 g; 2.91 mmol) in 20 ml DMF was added dropwise at 0° C. to a suspension of 0.169 NaH (60%; deoiled) in 10 ml DMF and stirred for 1 h. A spatula tip full of KI was then added likewise at 0° C., 1 g 1-(4-bromo butyl)-4-nitrobenzene (preparation according to J. Med.\",\n \"Chem.\",\n \"38, 13 (1995), 2418-2420)—dissolved in 10 ml DMF—was slowly added dropwise and stirred for 2 h at RT.\",\n \"For workup, water was carefully added to the reaction mixture, it was diluted with CH2Cl2 and several times extracted with a saturated NaCl-solution.\",\n \"After drying and evaporation, the obtained raw product was purified by chromatography on silica gel (CH2Cl2/CH3OH 2-10%); 0.429 yellow oil, ESI-MS [M+H+-Boc]: 397.15.b.)\",\n \"Hydrogenation of the nitro group in 75 ml CH3OH with 100 mg 10% Pd on activated carbon under standard conditions afforded 0.36 mg of a bright oil; ESI-MS [M+H+]: 423.25.c.)\",\n \"The build-up of the corresponding aminobenzimidazole was carried out analogously to the preparation of 17 by reaction with thiocarbonyldiimidazole, imidazole and then phenylene diamine.\",\n \"Chromatography on silica gel (CH2Cl2/CH3OH 2-4%) afforded 220 mg of a bright foam; ESI-MS [M+H+]: 539.25.d.)\",\n \"200 mg tert-Butyl-(1-(4-[4-(1H-benzimidazole-2-ylamino)phenyl]butyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate was treated at RT with 10 ml TFA.\",\n \"Evaporation and lyophilizing the obtained oil afforded 213 mg of a solid; ESI-MS [M+H+]: 483.25.Example 30 2-(4-{[{[5-(Carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}(methyl)amino]methyl}anilino)-1H-benzimidazole (trifluoro acetate) a.)\",\n \"Standard coupling of [5-(2-t.Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) (2.2 g; 6.6 mmol) with 1.32 g N-methyl(4-nitrophenyl)methane amine (J.\",\n \"Am.\",\n \"Chem.\",\n \"Soc.\",\n \"65 (1943), 1984-1990) in 40 ml CH2Cl2 under utilization of HATU as a coupling reagent and ethyldiisopropylamine as a base.\",\n \"Subsequent chromatography of the raw product on silica gel (CH2Cl2/CH3OH 2-4%) afforded 2.269 of a slightly yellow oil; ESI-MS [M+H+]: 482.03.1H-NMR (360 MHz, d6-DMSO) δ ppm (Rotamers): 8.25/8.20 (d, 2H), 7.60/7.50 (d, 2H), 7.35-7.20 (m, 4H), 4.85-4.5 (m, 4H), 3.05/2.85 (s, 3H), 2.70 (m, 1H), 2.30 (m, 1H), 2.15 (m, 2H), 1.65 (m, 1H), 1.30 (s, 9H).\",\n \"b.)\",\n \"5 ml Hydrazine hydrate were added at 60° C. to 1.26 g nitro compound a and 15 mg FeCl3×6H2O in 20 ml CH3OH and for 1 h stirred at 60° C. The mixture was filtered over Celite and the filtrate evaporated.\",\n \"1.17 g; ESI-MS [M+H+]: 452.17.c.)\",\n \"The build-up of the respective aminobenzimidazole was carried out analogously to the preparation of 17 by reaction with thiocarbonyldiimidazole, imidazole and phenylene diamine, subsequently.\",\n \"Chromatography on silica gel (CH2Cl2/CH3OH 4-7.5%) afforded 0.9 g of a slightly beige foam; ESI-MS [M+H+]: 568.25.d.)\",\n \"Cleavage of the t-butylester with 50 ml TFA and subsequent purification by chromatography on silica gel (CH2Cl2/CH3OH 8-10%) afforded 0.88 g; ESI-MS [M+H+]: 512.25.1H-NMR (360 MHz, d6-DMSO) δ ppm (Rotamers): 11.05 (broad, 1H), 7.60-7.20 (m, 1.2H), 4.85 (m, 1H), 4.75-4.45 (m, 3H), 3.65 (m, 1H), 3.20 (s, 3H), 2.70 (m, 2H), 2.35 (m, 1H), 2.20 (m, 2H), 1.65 (m, 1H).\",\n \"Example 31 tert-Butyl-[1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate Coupling of [5-(2-tert-butoxy-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (28) with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) analogously to I and purification by chromatography on silica gel (CH2Cl2/CH3OH 2-3%) afforded 200 mg of a beige foam; ESI-MS [M+H+]: 540.25.Example 32 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) TFA-cleavage of tert-butyl-[1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate afforded 240 mg; ESI-MS [M+H+]: 484.36.1H-NMR (360 MHz, d6-DMSO) δ ppm (Rotamers): 11.10 (s, 1H), 8.30 (t, 1H), 7.5-7.25 (m, 8H), 7.15 (m, 2H), 6.85 (m, 2H), 4.40 (m, 2H), 3.75-3.55 (m, superimposed by H2O), 3.5 (m, 1H), 3.0 (m, 1H), 2.70 (m, 2H), 1.70 (m, 2H), 1.45 (m, 1H).\",\n \"Example 33 tert-Butyl-{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate Preparation analogously to example 31 starting from [5-(2-tert-butoxy-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (28) and trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11).\",\n \"410 mg of a white foam; ESI-MS [M+H+]: 546.35.Example 34 {1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (trifluoro acetate) Analogously to example 32; 420 mg of white solids; ESI-MS [M+H+]: 490.47.1H-NMR (360 MHz, d6-DMSO) δ ppm: 9.0 (d, 1H), 7.65 (m, 1H), 7.40 and 7.30 (each m, 2H), 7.15 and 6.85 (each m, 2H), 3.80 (m, 2H), 3.50 (m, 1H), 3.0 (m, 4H), 2.75 (m, 2H), 2.0 (m, 2H), 1.75-1.50 (m, 5H), 1.50-1.20 (m, 5H), 0.95 (m, 2H).\",\n \"Example 35 tert-Butyl-[1-(2-{[5-(1H-benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetate Preparation analogously to example 31 starting from [5-(2-tert-butoxy-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (28) and N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8).\",\n \"300 mg of a foam; ESI-MS [M+H+]: 520.39.Example 36 [1-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Cleavage of the t-butyl ester from example 35 with 15 ml 4nHCl in dioxane afforded 300 mg solid; ESI-MS [M+H+]: 464.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 9.10 (m, 1H), 7.70 (m, 1H), 7.35, 7.25, 7.10 and 6.85 (each m, 2H), 4.75 (m 2H), 3.30, 3.15, 2.95, 2.70 (each m, 2H), 1.65 (m, 5H), 1.45 and 1.30 (each m, 2H).\",\n \"Example 37 tert-Butyl-{1-[2-({[4-(1H-imidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate Preparation analogously to example I under utilization of N-[4-(aminomethyl)cyclohexyl]-1H-imidazole-2-amine (hydrobromide) (29) as educt; chromatography on silica gel (CH2Cl2/CH3OH 4-15%) afforded 530 mg of a solid foam; ESI-MS [M+H+]: 510.35.Example 38 {1-[2-({[4-(1H-Imidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (acetate) Cleavage of the t-butyl ester from example 37 mit TFA and subsequent purification by means of chromatography on silica gel (CH2Cl2/CH3OH 10-15%+2% glacial acetic acid) afforded 570 mg; ESI-MS [M+H+]: 454.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.0 (broad, 1H), 7.30 and 7.25 (each m, 2H), 6.80 (broad, 1H), 6.70 (s, 2H), 4.40 and 4.20 (each broad, 1H), 4.75-4.25 (superimposed by H2O), 3.0 (m, 2H), 2.65 (m, 2H), 2.35 (m, 1H), 2.15 (m, 2H), 1.95 (m, 1H), 1.75 (m, 2H), 1.60 and 1.35 (each m, 1H), 1.20 (m, 4H), 0.95 (m, 2H).\",\n \"Example 39 tert-Butyl-(2-oxo-1-{[4-({4-[(pyridine-2-ylamino)methyl]piperidine-1-yl}carbonyl)-1,3-thiazole-2-yl]methyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate Standard coupling of 2-{[5-(2-tert-Butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]methyl}-1,3-thiazole-4-carbonic acid (32) (0.5 g; 1.2 mmol) with N-(piperidine-4-ylmethyl)pyridine-2-amine (hydrochloride; accessibly from 29) in 15 ml CH2Cl2 under utilization of HATU as a coupling reagent and ethyldiisopropylamine as a base.\",\n \"Subsequent chromatography of the raw product on silica gel (CH2Cl2/CH3OH 3-20%) afforded 0.44 g of a slightly yellow oil; ESI-MS [M+H+]: 590.35.Example 40 (2-Oxo-1-{[4-({4-[(pyridine-2-ylamino)methyl]piperidine-1-yl}carbonyl)-1,3-thiazole-2-yl]methyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Cleavage of the t-butylester of example 31 with TFA afforded 385 mg; ESI-MS [M+H+]: 534.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.05 (s, 1H), 7.90 (m, 2H), 7.55 (m, 1H), 7.35 (m, 1H), 7.25 (m, 2H), 7.05 and 6.80 (each m, 1H), 5.40-5.20 (m, 2H), 4.20 and 4.0 (each m, 1H), 3.25 (m, 2H), 2.95 (m, 1H), 2.80-2.60 (m, 3H), 2.30 (m, 1H), 2.25-2.05 (m, 2H), 1.80 and 1.65 (each m, 2H), 1.20-1.10 (m, 3H).\",\n \"Example 41 tert-Butyl-[1-({4-[({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino) carbonyl]-1,3-thiazole-2-yl}methyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetate Analogously to example 29 under utilization of trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11) as educt; chromatography of the raw product on silica gel (CH2Cl2/CH3OH 5-8%) afforded 350 mg of a bright yellow oil; ESI-MS [M+H+]: 643.45.Example 42 [1-({4-[({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)carbonyl]-1,3-thiazole-2-yl}methyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Cleavage of the t-butylester of example 31 and purification by elution over Chromabond-C18 (acetonitrile/H2O 10-80%+0.1% glacial acetic acid) afforded 300 mg; ESI-MS [M+H+]: 587.35.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.40 (broad, 1H), 8.20 (m, 1H), 8.20 (s, 1H), 7.35-7.20 (m, 5H), 7.15 (m, 2H), 5.40 and 5.25 (each d, 1H), 3.15 (m, superimposed by H2O), 2.80-2.60 (m, 2H), 2.35 (m, 1H), 2.20 (m, 2H), 2.05 and 1.80 (each m, 2H), 1.65, 1.30 and 1.15 (each m, 2H).\",\n \"Example 43 tert-Butyl-(1-{[4 ({4-[(1H-benzimidazole-2-ylamino)methyl]piperidine-1-yl}carbonyl)-1,3-thiazole-2-yl]methyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetate 430 mg were obtained analogously to example 29 under utilization of N-(piperidine-4-ylmethyl)-1H-benzimidazole-2-amine (trifluoro acetate) (17) and subsequent purification; ESI-MS [M+H+]: 629.45.Example 44 (1-{[4-({4-[(1H-Benzimidazole-2-ylamino)methyl]piperidine-1-yl}carbonyl)-1,3-thiazole-2-yl]methyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Cleavage of the t-butylester of example 43 and purification by elution over Chromabond-C18 (acetonitrile/H2O 10-80%+0.1% glacial acetic acid) afforded 340 mg; ESI-MS [M+H+]: 573.35.1H-NMR (360 MHz, d-DMSO) δ ppm: 9.20 (m, 1H), 7.95 (s, 1H), 7.45 (m, 1H), 7.40 (m, 2H), 7.30-7.15 (m, 5H), 5.35-5.10 (m, 2H), 4.45 (m, 1H), 4.0-3.25 (m, superimposed by H2O), 2.95 (m, 1H), 2.8-2.60 (m, 2H), 2.30 and 2.20 (each m, 1H), 2.0-1.75 (m, 3H), 1.70-1.50 (m, 2H), 1.20 (m, 3H).\",\n \"Example 45 tert-Butyl-{2-oxo-1-[(4-{[({4-[(pyridine-2-ylamino)methyl]thiene-2-yl}methyl)amino]carbonyl}-1,3-thiazole-2-yl)methyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 330 mg were obtained analogously to example 39 under utilization of N-{[5-(aminomethyl)thiene-3-yl]methyl}pyridine-2-amine (trifluoro acetate) (18) and purification; ESI-MS [M+H+]: 618.25.Example 46 {2-Oxo-1-[(4-{([{4-[(pyridine-2-ylamino)methyl]thiene-2-yl}methyl)amino]carbonyl}-1,3-thiazole-2-yl)methyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Cleavage of the t-butylesters of example 45 and purification by means of MPLC afforded 150 mg; ESI-MS [M+H+]: 562.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.80 (m, 1H), 8.20 (m, 1H), 8.0 (d, 1H), 7.50 (d, 1H), 7.30-7.20 (m, 4H), 7.10 and 6.95 (each s, 1H), 6.85 (m, 1H), 6.50 (m, 2H), 5.40 and 5.20 (each d, 1H), 4.55 and 4.35 (each m, 2H), 2.80-2.55 (m, 2H), 2.30 (m, 1H), 2.20 (m, 2H), 1.65 (m, 1H).\",\n \"Example 47 tert-Butyl-[1-({4-[4-(1H-benzimidazole-2-ylamino)phenyl]-1,3-thiazole-2-yl}methyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate a.)\",\n \"A mixture of 1.5 g tert-butyl-[1-(2-amino-2-thioxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate, 1.36 g 2-bromo-4-nitroacetophenone and 0.65 g KHCO3 in 30 ml dioxane were stirred for 12 h at RT.\",\n \"Workup analogously to building block 30c and mixing of the raw product with n-pentane afforded 2.1 g of a brown solid; ESI-MS [M+H+]: 494.15.1H-NMR (360 MHz, d6-DMSO) δ ppm: 8.40 (s, 1H), 8.30 and 8.20 (each m, 2H), 7.60 and 7.35 (each m, 1H), 7.25 (m, 2H), 5.50 and 5.30 (each d, 1H), 2.70 (m, 2H), 2.30 (m, 1H), 2.20 (m, 3H), 1.65 (m, 1H), 1.25 (s, 9H).\",\n \"b.)\",\n \"Reduction of the nitro group analogously to example 30b (1.6 g; ESI-MS [M+H+]: 464.15) and build-up of the aminobenzimidazole as already described afforded after chromatography on silica gel (CH2Cl2/CH3OH 24%) 0.58 g of a slightly yellow foam; ESI-MS [M+H+]: 614.35.Example 48 [1-({4-[4-(1H-Benzimidazole-2-ylamino)phenyl]-1,3-thiazole-2-yl}methyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Cleavage of the t-butylester of example XXXXVII and purification by means of MPLC afforded 40 mg; ESI-MS [M+H+]: 524.25.1H-NMR (360 MHz, d6-DMSO) δ ppm: 11.95 and 9.60 (each broad, 1H), 7.85-7.75 (m, 4H), 7.65 (m, 1H), 7.40-7.25 (m, 5H), 7.0 (m, 2H), 5.40 and 5.30 (each d, 1H), 3.50 (m, 1H), 2.75 (m, 1H), 2.45 (m, 2H), 2.20 (m, 2H), 1.70 (m, 1H).\",\n \"Example 49 tert-Butyl (1-{2-[(4{[amino(imino)methyl]amino}benzyl)amino]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Ethyldiisopropylamine (0.42 mmol, 54.50 mg) and HATU (0.50 mmol, 190.11 mg) were added at 0° C. to a solution of [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) (0.42 mmol, 140.59 mg) in CH2Cl2 (10 ml), the mixture was stirred for 1 h at 0° C. and [4-(aminomethyl)phenyl]guanidine (bihydrochloride) (46) (0.42 mmol, 100 mg), ethyldiisopropylamine (0.63 mmol, 81.76 mg) added.\",\n \"The mixture was stirred for 1 h at 0° C. and overnight at RT.\",\n \"After evaporation, the residue was taken up in CH2Cl2/water, washed with watery NaHCO3—, 5%-citric acid- and finally with watery saturated NaCl-solution.\",\n \"Evaporation and chromatography on silica gel (CH2Cl2/CH3OH 0-100%) afforded 6.0 mg target product; ESI-MS [M+H+]: 426.1, 425.1.Example 50 {4-[({[5-(Carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)methyl]anilino}(imino)methaneamine (trifluoro acetate) tert-Butyl-({2-[(4{[amino(imino)methyl]amino}benzyl)amino]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (example 49, 0.01 mmol, 6 mg) was dissolved in 5 ml CH2Cl2, TFA (1.25 mmol, 142.53 mg) added at 0° C. and stirred overnight at room temperature.\",\n \"After evaporation, the residue was taken up in CHCl3/water and the watery phase washed with CHCl3; evaporation of the watery phase affords 4.8 mg target product; ESI-MS [M+H+]=425.1.Example 51 tert-Butyl [1-(2-{[(6-amino-2-pyridinyl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Analogously to example 49, under utilization of 2-ammonio-6-(ammonio methyl)pyridinium trichloride (33) (0.30 mmol, 69.76 mg) and following purification and subsequent purification (chromatography; CH2Cl2/MeOH 0-100%) afforded 120 mg of the target product; ESI-MS: [M+H+]=439.28, 383.36.Example 52 [1-(2-{([(6-Amino-2-pyridinyl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (hydrochloride) Cleavage of the t-butylester, chromatography of the raw product (CHCl3/MeOH 0-5%) and ester interchange with HCl in diethyl ether afforded 15.0 mg; the target product as hydrochloride; ESI-MS [M+H+]=383.1.Example 53 tert-Butyl [1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid 2 Drops of a solution of HCl in diethylether were added to N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) (0.63 mmol, 196.10 mg) in methanol (40 mL) and stirred for 5 min.\",\n \"at RT.\",\n \"tert-Butyl.\",\n \"[2-oxo-1-(2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (37, 0.63 mmol, 0.20 g) was added, NaBH3CN (3 mmol, 188.5 mg) portionwise added after 10 min.\",\n \"and the mixture stirred for 17 h at RT.\",\n \"After evaporation, the residue was taken up in ethyl acetate and washed with NaHCO3— (pH 8-9), saturated NaCl— (1×) and a 10% FeSO4-solution (2×).\",\n \"Chromatography (CHCl3/MeOH 0-5%) afforded 84 mg of the target product; ESI-MS [M+H+]=540.24, 270.75.Example 54 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}ethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Cleavage of the t-butylester and chromatography (CHCl3/MeOH 0-100%) afforded 4 mg of the target product; ESI-MS [M+H+]=484.1.Example 55 tert-Butyl [1-(2-{[(4-{[(benzylamino)carbonyl]amino}cyclohexyl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Analogously to example 49 under utilization of N-[4-(aminomethyl)cyclohexyl]-N′-benzyl urea (34) (0.50 mmol, 130 mg) afforded 320 mg; ESI-MS [M+H+]=577.11.Example 56 [1-(2-{[(4-{[(Benzylamino)carbonyl]amino}cyclohexyl)methyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Analogous cleavage of the t-butylester afforded a raw product which after evaporation was distributed between ethyl acetate/water.\",\n \"The watery phase was then adjusted to pH 10 with 0.1n NaOH and extracted with ethyl acetate.\",\n \"It was adjusted then with 1nN HCl to pH4, extracted with CH2Cl2, washed and evaporated; 80 mg; ESI-MS [M+H+]=521.3.Example 57 tert-Butyl [1-(2-{[5-(1H-benzimidazole-2-ylamino)pentyl]amino}ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Preparation analogously to example 53 under utilization of N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8) (0.63 mmol, 183.47 mg) and tert-butyl [2-oxo-1-(2-oxoethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (37, 0.63 mmol, 0.20 g) afforded 50.0 mg of the target product; ESI-MS [M+H+]=520.41, 260.79.Example 58 [1-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) tert-Butyl [1-(2-{[5-(1H-benzimidazole-2-ylamino)pentyl]amino}ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (example 57, 0.04 mmol, 20.00 mg) was dissolved in 5 ml CH2Cl2, TFA (65.34 mmol, 7.45 g) added at 0° C. and stirred overnight at room temperature.\",\n \"Evaporation of the reaction mixture, chromatography (CHCl3/MeOH 0-100%) afforded 10 mg of the target product; ESI-MS [M+H+]=464.25.Example 59 tert-Butyl {2-oxo-1-[2-({[4-({4-[(1Z)-1-propenyl]-5-vinyl-1H-imidazole-2-yl}amino)cyclohexyl]methyl}amino)ethyl]-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Preparation analogously to example 53 under utilization of ethyldiisopropylamine and EDCI*HCl starting from trans-N-[[4-(aminomethyl)cyclohexyl]-1H-benzimidazole-2-amine (dihydrochloride) (11) (0.63 mmol, 0.209) afforded 84 mg; ESI-MS [M+H+]=546.32, 273.79.Example 60 {1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)ethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (trifluoro acetate) tert-Butyl {2-oxo-1-[2-({[4-({4-[(1Z)-1-propenyl]-5-vinyl-1H-imidazole-2-yl}amino)cyclohexyl]methyl}amino)ethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (example 59, 0.01 mmol, 8 mg) was dissolved in 5 ml CH2Cl2, TFA (65.34 mmol, 7.45 g) added at 0° C. and stirred overnight at room temperature.\",\n \"The reaction mixture was evaporated, the watery phase washed with a 3:1 mixture CHCl3/EtOH.\",\n \"Evaporation of the watery phase afforded 6.0 mg of the target product; ESI-MS [M+H+]=490.25.Example 61 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) Coupling analogously to example 49 starting from N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) (1.70 mmol, 467.08 mg) and [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (1.63 mmol, 600 mg).\",\n \"TFA (1.73 mmol, 197.72 mg) was added at 0° C. to the obtained raw product and it was stirred overnight at room temperature.\",\n \"After evaporation, the residue was distributed between ethyl acetate and water, the watery phase adjusted to pH 10 with 2n NaOH and extracted with ethyl acetate; purification by means of MPLC afforded 90 mg of the target product as TFA-salt; ESI-MS [M+K+]=570.2, 534.2, 532.2, 266.5, 101.1.Example 62 [1-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) Coupling analogously to example 49 starting from N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8) (1.7 mmol, 433.10 mg) and [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (1.63 mmol, 600.00 mg).\",\n \"Treatment of the raw product with TFA analogously to example 61 afforded 48 mg as a TFA-salt; ESI-MS: 514.2, 512.2, 101.2.Example 63 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)butyl]amino}-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Coupling analogously to example 49 starting from N1-(1H-benzimidazole-2-yl)butane-1,4-diamine (trifluoro acetate) (9) (1.7 mmol, 541.1 mg) and [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (1.63 mmol, 600 mg).\",\n \"Treatment of the raw product with TFA analogously to example 61 afforded 15 mg as a TFA-salt; ESI-MS: 536.2, 500.1, 498.2, 105.1, 101.2.Example 64 [7-Chloro-1-(2-{[5-(4,5-dihydro-1H-imidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (trifluoro acetate) Coupling analogously to example 49 starting from N1-(4,5-dihydro-1H-imidazole-2-yl)pentane-1,5-diamine (hydrochloride) (23) (1.70 mmol, 351.43 mg) and [5-(2-tert-butoxy-2-oxoethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (1.63 mmol, 600 mg).\",\n \"Treatment of the raw product with TFA analogously to example 61 afforded 85 mg as a TFA-salt; ESI-MS: 464.15.Example 65 tert-Butyl 7-[4-({[5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)butyl]-3,4-dihydro[1,8]naphthyridine-1(2H)-carboxylate Ethyldiisopropylamine (2.08 mmol, 268.41 mg) and EDCI*HCl (0.78 mmol, 150.44 mg) were added at 0° C. to a solution of [5-(2-t.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) (0.46 mmol, 0.15 g) in CH3CN (45 ml).\",\n \"After 1 h at 0° C., 7-(4-aminobutyl)-1,2,3,4-tetrahydro[1,8]naphthyridine (bitrifluoro acetate) (35) (0.46 mmol, 0.2 g) was added, stirred for 1 h at 0° C. and overnight at RT.\",\n \"Since by chromatography a purification could not be achieved, the obtained was reacted to the corresponding Boc-derivative according to standard methods.\",\n \"Chromatography (heptane/CH2Cl2 0-100%, CH2Cl2/MeOH 0-100%) afforded 15 mg of the target product (about 95% purity); ESI-MS [M+Na+]: 643.5, 622.5, [M+H+]=621.5.Example 66 7-[4-({[5-(Carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)butyl]-1,2,3,4-tetrahydro[1,8]naphthyridine (trifluoro acetate) tert-Butyl 7-[4-({[5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)butyl]-3,4-dihydro[1,8]naphthyridine-1(2H)-carboxylate (example 65; 0.02 mmol, 15 mg) was dissolved in 2 ml CH2Cl2, TFA (0.53 mmol, 60.7 mg) added at 0° C. and stirred overnight at RT.\",\n \"Usual workup afforded 9.3 mg of the target product as TFA-salt; ESI-MS: 466.2, [M+H+]=465.2, 233.3.Example 67 N-{4-[({[5-(Carboxymethyl)-7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetyl}amino)methyl]cyclohexyl})-1H-benzimidazole (acetate) Coupling analogously to example 49 starting from trans-N-[4-(aminomethyl)cyclohexyl]-1H-benzimidazole-2-amine (dihydrochloride) (11) (2.99 mmol, 948.78 mg) and [5-(2-tert-butoxy-2-oxoethyl) 7 chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (45) (2.72 mmol, 1.00 g) afforded 760 mg raw product.\",\n \"Treatment of the raw product with TFA analogously to example 61 and purification of the raw product by means of MPLC afforded 400 mg; ESI-MS: [M+H+]=540.3, 538.25, 269.6, 101.1.Example 68 Ethyl-{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 15 ml HCl in diethyl ether (saturated at 0° C.) were added to 300 mg {1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2,3,4,5-tetrahydro-1H-1-1-benzazepine-5-yl}acetic acid in 30 ml ethyl alcohol and allowed to stand for 3 days at room temperature.\",\n \"The mixture was evaporated, the remaining residue purified by chromatography on silica gel (CH2Cl2/CH3OH 5%+1% glacial acetic acid) and lyophilized.\",\n \"230 mg; ESI-MS: [M+H+]=518.35.Example 69 {1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid (acetate) Standard coupling of [5-(2-tert-butoxy-2-oxoethyl)-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetate (building block 49) (1 g; 2.54 mmol) with trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11); after chromatography on silica gel (CH2Cl2/CH3OH 5-7%), 1.03 g were isolated as a white glass; ESI-MS: [M+H+]=620.35.Cleavage of the ester under utilization of TFA and subsequent purification of the raw product by chromatography on silica gel (CH2Cl2/CH3OH 10%+2% glacial acetic acid) afforded 0.8 g of the target product; ESI-MS: [M+H+]=564.25.Example 70 [1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Standard coupling of [5-(2-tert-butoxy-2-oxoethyl)-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetate (building block 49) (0.5 g; 1.27 mmol) with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4); after chromatography on silica gel (CH2Cl2/CH3OH 3-5%) 0.67 g were isolated as a foam; ESI-MS: [M+H+]=614.35.Cleavage of the ester under utilization of TFA and lyophilization of the obtained product afforded 0.61 g; ESI-MS: [M+H+]=558.35.Example 80 {5-[2-({[4-(1H-Benzimidazole-2-yl)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3-dihydro-1H-1-benzazepine-1-yl}acetic acid 0.4 g (1.4 mmol) [1-(2-Methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) and 0.37 g (1.4 mmol) [4-(1H-benzimidazole-2-yl)cyclohexyl]methane amine (hydrochloride) (51) were reacted analogously to example I, the reaction product then purified by means of preparative thick-layer chromatography (eluent: CH2Cl2/CH3OH/conc.\",\n \"NH3 45/5/0.2) and then the methyl ester cleaved with 0.8 ml 1n NaOH in 8 ml dioxane at room temperature.\",\n \"After neutralization with 1n HCl, evaporation of the solvent, extraction with ethyl acetate and drying with Na2SO4, the raw product was purified by chromatography (CH2Cl2/CH3OH/50% glacial acetic acid 20/5/1).\",\n \"After lyophilization, 0.22 g remained as a white amorphous residue; ESI-MS: [M+H+]=487.Example 81 [5-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-1-yl]acetic acid Analogously to example I 0.4 g (1.4 mmol) [1-(2-methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) and 0.36 g (1.4 mmol) N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8) were reacted.\",\n \"Purification of the raw product, alkaline saponification of the methyl ester and purification of the end stage was conducted analogously to example 80.0.3 g of a white amorphous residue; ESI-MS: [M+H+]=476.Example 82 [5-(2-{4-[(1H-Benzimidazole-2-ylamino)methyl]piperidine-1-yl}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1H-benzazepine-1-yl]acetic acid Analogously to example I 0.49 (1.4 mmol) [1-(2-methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) was reacted with 0.63 g (1.4 mmol) N-(piperidine-4-ylmethyl)-1H-benzimidazole-2-amine (trifluoro acetate) (17).\",\n \"After purification, alkaline ester hydrolysis and chromatographic purification of the end product (CH2Cl2/CH3OH/50% glacial acetic acid 20/5/1) 0.3 g of a white amorphous powder were obtained; ESI-MS: [M+H+]=488.Example 83 [5-(2-{4-[(1H-Benzimidazole-2-ylamino)methyl]piperidine-1-yl}-2-oxoethyl)-2-oxo 2,3-dihydro-1H-1-benzazepine-1-yl]acetic acid Analogously to example I 0.4 g (1.4 mmol) [1-(2-methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-1-benzazepine-5-yl]acetic acid (50) were reacted with 0.43 g trans-N-J[4-(aminomethyl)cyclohexyl]1H-benzimidazole-2-amine (dihydrochloride) (11).\",\n \"After purification of the ester (eluent: CH2Cl2/CH3OH/25% NH3 45/5/0.2), alkaline ester hydrolysis and chromatographic purification of the end product (CH2Cl2/CH3OH/50% glacial acetic acid 20/5/1) 0.18 g of a white amorphous powder were obtained; ESI-MS: [M+H+]=502.Example 84 [5-(2-{[5-H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (hydrochloride) Analogously to example I 0.65 g (2 mmol) [5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (54) were reacted with N1-(1H-benzimidazole-2-yl)pentane-1,5-diamine (hydrochloride) (8), the reaction product purified by means of preparative thick-layer chromatography (eluent: CH2Cl2/CH3OH/conc.\",\n \"NH3 45/5/0.2); ESI-MS: [M+H+]=535.Then the tert-butyl ester was cleaved with 4n HCl in dioxane, and after chromatographic purification 40 mg of a white amorphous powder were isolated; ESI-MS: [M+H+]=479.Example 85 {5-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl}acetic acid (hydrochloride) Preparation and purification was conducted analogously to example 84 by reaction with trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11); ester stage ESI-MS: [M+H+]=561.Purification after ester cleavage was conducted by means of preparative thick-layer chromatography (CH2Cl2/CH3OH/50% glacial acetic acid 12/3/1); 0.35 g of a white amorphous powder; ESI-MS: [M+H+]=505.Example 86 [5-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (hydrochloride) Preparation and purification was conducted analogously to example 84 by reaction with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4); ester stage ESI-MS: [M+H+]=555; target product: 0.4 g of a white amorphous powder; ESI-MS: [M+H+]=499.Example 87 [5-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid Analogously to example I 1.2 g (3.6 mmol) [5-(2-tert-butoxy-2-oxoethyl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl]acetic acid (55) was reacted with 0.86 g (3.6 mmol) N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4), the reaction product purified by means of preparative thick-layer chromatography (eluent: CH2Cl2/CH3OH/conc.\",\n \"NH3 45/5/0.1); ESI-MS: [M+H+]=: 555.Subsequent cleavage of the tert-butylester with 4n HCl in dioxane afforded 0.8 g of a white amorphous powder; ESI-MS [M+H+]=499.Example 88 {5-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-yl}acetic acid Preparation and purification analogously to example 87; ester stage ESI-MS: [M+H+]=561; 0.9 g of the target product were obtained as a white amorphous powder; ESI-MS [M+H+]=505.Example 89 (1-{2-[4-(1H-Benzimidazole-2-yl)piperidine-1-yl]-2-oxoethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (acetate) Analogously to example I 0.5 g (1.5 mmol) [5-(2-t-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-yl]acetic acid (3) and 0.36 g (1.5 mmol) 2-(4-piperidinyl)-1H-benzimidazole (J. Heterocycl.\",\n \"Chem.\",\n \"1989, 26, 541) were reacted, purified by means of preparative thick-layer chromatography (eluent CH2Cl2/CH3OH/conc.\",\n \"NH3 45/5/0.2); ESI-MS: [M+H+]=517.Subsequent cleavage of the tert-butyl ester with 4n HCl in a mixture of dioxane/glacial acetic acid and chromatographic purification afforded 0.259 of a white amorphous powder; ESI-MS [M+H+]=: 461.Example 90 (1-{2-[[3-(1H-Benzimidazole-2-yl)propyl](methyl)amino]-2-oxoethyl}-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl)acetic acid (hydrochloride) Preparation analogously to example I by reaction with N-[3-(1H-benzimidazole-2-yl)propyl]-N-methylamine (WO 9849148); after chromatographic purification 0.69 were obtained as a white amorphous powder; ESI-MS [M+H+]=: 449.Example 91 (1-{2-[4-(1H-Benzimidazole-2-ylamino)piperidine-1-yl]-2-oxoethyl}-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-5-yl)acetic acid Preparation analogously to example I by reaction with N-piperidine-4-yl-1H-benzimidazole-2-amine (J. Med.\",\n \"Chem.\",\n \"1985, 28, 1925); after chromatographic purification 0.45 g were obtained as a white amorphous powder; ESI-MS [M+H+]=: 476.Example 92 [5-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid Analogously to example I 0.4 g (1.4 mmol) [1-(2-methoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (56) and 0.33 g (1.4 mmol) N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) were reacted and purified by means of preparative thick-layer chromatography (eluent: CH2Cl2/CH3OH/conc.\",\n \"NH3 45/5/0.2); ESI-MS: [M+H+]=512.Subsequent cleavage of the methyl ester with 1n NaOH in dioxane and chromatographic purification of the residue (CH2Cl2/CH3OH/50% glacial acetic acid 20/5/1) afforded 0.15 g, isolated as a white amorphous powder; ESI-MS [M+H+]=498.Example 93 {5-[2-({[4-(1H-Benzimidazole-2-yl)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl}acetic acid Preparation and purification analogously to example 92; ester stage ESI-MS [M+H+]=503; chromatographic purification after cleavage of the ester afforded 0.3 g of the target product as a white amorphous powder; ESI-MS [M+H+]=489.Example 94 [5-(2-{[5-(1H-Benzimidazole-2-ylamino)pentyl]amino}-2-oxoethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-1-yl]acetic acid Preparation and purification analogously to example 92; ester stage ESI-MS [M+H+]=492.Chromatographic purification after cleavage of the ester afforded 20 mg as a white amorphous powder ESI-MS [M+H+]=478.Example 95 {5-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl}acetic acid Preparation and purification analogously to example 92; ester stage ESI-MS [M+H+]=518.Chromatographic purification after cleavage of the ester afforded 0.15 g as a white amorphous powder; ESI-MS [M+H+]=504.Example 96 Ethyl-{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 0.6 g (2.4 mmol) N,N-Bis(2-oxo-3-oxazolidinyl)phosphoryl chloride were added to a solution of 0.8 g (1.6 mmol) of the acid of example XI, 0.15 g (3.2 mmol) ethyl alcohol, 0.2 g (1.6 mmol) 4-dimethylaminopyridine and 0.4 g (4 mmol) triethylamine in 60 ml CH2Cl2 and stirred overnight.\",\n \"After the reaction had completed 2 g glacial acetic acid and 3.7 g ethyl alcohol were added to the reaction solution and stirred for another 20 h at room temperature.\",\n \"For workup, 50 ml H2O were added to the mixture, the organic phase washed with 10% K2CO3-solution and H2O, dried over MgSO4 and evaporated.\",\n \"Chromatographic purification of the residue (eluent: CH2Cl2/ethyl alcohol/50% glacial acetic acid 15/5/1) afforded 0.35 g of a white amorphous powder; ESI-MS [M+H+]=532.Analogously to example 96 were prepared: Example 97 Cyclohexyl-{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 0.26 g; ESI-MS [M+H+]=586.Example 98 Neopentyl{1-[2-({[4-(1H-benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetate 0.21 g; ESI-MS [M+H+]=574.Example 99 tert-Butyl [1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate Preparation was carried out analogously to example I by reaction of [5-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl]acetic acid (3) with N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4).\",\n \"After chromatographic purification (eluent: CH2Cl2/ethyl alcohol/50% glacial acetic acid 45/5/0.3) the residue was dissolved in 70 ml CH2Cl2 and 5 ml CH3OH, washed with 5% K2CO3-solution and H2O, dried over Na2SO4 and evaporated to dryness.\",\n \"The amorphous residue was mixed with 25 ml CH3OH in heat.\",\n \"0.51 g of white crystals; Fp.\",\n \": 231° C. (decomposition); ESI-MS [M+H+]=554.Example 100 Cyclohexyl-[1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate 0.64 g (1.28 mmol) of [1-(2-{[4-(1H-benzimidazole-2ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (acid of example III) was suspended in 30 ml cyclohexanol, 1.0 g HCl-gas introduced with stirring and the resulting yellow solution allowed to stand for 4 days at room temperature.\",\n \"Since an acid was still detectable by chromatography, it was heated for 7 h to 40-50° C. For workup, 100 ml diethylether were added, washed with K2CO3-solution and H2O, dried over Na2SO4 and the solvent—finally for removal of cyclohexanol under oil pump vacuum and at a bath temperature of 50° C.—distilled off.\",\n \"The residue was purified chromatographically (eluent: CH2Cl2/acetone/methanol/50% acetic acid 45151410.3).\",\n \"0.659 of a slightly beige coloured powder; ESI-MS [M+H+]=580.Example 101 Ethyl-[1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,6-tetrahydro-1H-1-benzazepine-6-yl]acetate 0.619 (1.23 mmol) of [1-(2-{[4-(1H-benzimidazole-2ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (acid of example III) was suspended in 30 ml ethyl alcohol, 0.4 g HCl-gas introduced and allowed to stand for 4 days at room temperature.\",\n \"The ethyl alcohol was distilled off in vacuum, the residue taken up in ethyl acetate, washed with 5% NaHCO3- and NaCl-solution, dried over Na2SO4 and evaporated.\",\n \"After thick-layer chromatographic purification (eluent: CH2Cl2/ethyl alcohol/50% acetic acid 43/7/0.5) the eluate was diluted with some CH2Cl2 and for removal of the acetic acid washed with 50% NaHCO3-solution.\",\n \"After drying over Na2SO4 it was evaporated and the residue converted to an amorphous powder filterable with suction by means of diethylether/n-hexane; 0.55 g; ESI-MS [M+H+]=526.Example 102 1-{[(Cyclohexyloxy)carbonyl]oxy}ethyl [1-(2-{[4-(1H-benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetate 0.3 g K2CO3 were added at 3° C. to a solution of 0.6 g (1.2 mmol) of [1-(2-{[4-(1H-benzimidazole-2ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid (add of example III) in 10 ml DMF with stirring, some crystals 18-crown-6, 0.4 g cyclohexyl-1-iodo ethylcarbonate (preparation from cyclohexyl-1-chloroethylcarbonate and NaI analogously to J. Antibiot.\",\n \"1987, 40 (1), 81-90) dissolved in 5 ml CH3CN were added dropwise and stirred for 20 min.\",\n \"After addition of 100 ml cold NaCl-solution it was extracted several times with ethyl acetate, the combined organic phases washed with NaCl-solution, dried over Na2SO4 and evaporated.\",\n \"The residue was purified by column chromatography (eluent: CH2Cl2/acetone/methanol/50% acetic acid 45/5/5/0.3), after evaporation of the solvent taken up in 50 ml CH2Cl2, washed with 5% NaHCO3-solution, dried over Na2SO4 and again evaporated.\",\n \"90 mg of a white amorphous powder; ESI-MS [M+H+]=668.Example 103 [(5R)-1-(2-{[4-(1H-Benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid 1.0 g (3.0 mmol) of the left-rotating acid (building block 57) and 0.72 g (3.0 mmol) N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) were reacted analogously to example I and the reaction product purified by column chromatography (eluent: CH2Cl2/acetone/methanol/50% acetic acid 45/5/4/0.3); ester stage ESI-MS [M+H+]=554.Cleavage of the tert-butyl ester with 4n HCl in dioxane afforded 0.82 g of a white amorphous powder; ESI-MS [M+H+]=498; [α]D20=−107.7° (K+-salt, c=1 in H2O).\",\n \"Example 104 [(5S)-1-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]acetic acid Preparation analogously to example 103 starting from the dextrorotatory acid building block 58.Ester stage: 1.5 g of a amorphous powder; ESI-MS [M+H+]=554.Target product: 0.79 g of a white amorphous powder; ESI-MS [M+H+]=498.Example 105 {(5R)-1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Preparation analogously to example I from the left-rotating acid building block 57 and trans-N-{[4-(aminomethyl)cyclohexyl]}-1H-benzimidazole-2-amine (dihydrochloride) (11).\",\n \"Ester stage: 0.9 g of a white amorphous powder; ESI-MS [M+H+]=560.Target product: 0.67 g of a white amorphous powder; ESI-MS [M+H+]=504; [α]D20=−104° (K+-salt, c=1 in H2O).\",\n \"Example 106 {(SS)-1-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl}acetic acid Preparation analogously to example 103 starting from the dextrorotatory acid building block 58.Ester stage: 0.72 g of a amorphous powder; ESI-MS [M+H+]=560.Target product: 0.56 g of a white amorphous powder; ESI-MS [M+H+]=504; [α]D20=+101.60 (K+-salt, c=1 in H2O).\",\n \"Example 107 [4-(2-{[4-(1H-Benzimidazole-2-ylamino)benzyl]amino}-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-8-yl]acetic acid Analogously to example I 0.6 g (1.8 mmol) [8-(2-tert-butoxy-2-oxoethyl)-5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-4-yl]acetic acid (61) were reacted with 0.42 g (1.8 mmol) N-[4-(aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (4) and the reaction product purified by thick-layer chromatography (eluent: CH2Cl2/methanol/conc.\",\n \"NH3 451510.2); ESI-MS [M+H+]=560.Cleavage of the t-butyl group with 4n HCl in dioxane afforded 0.34 g of a slightly yellowish powder; ESI-MS [M+H+]=504.Example 108 {4-[2-({[4-(1H-Benzimidazole-2-ylamino)cyclohexyl]methyl}amino)-2-oxoethyl]-5-oxo-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-8-yl}acetic acid Analogously to example 107.Ester stage: 100 mg of a white amorphous powder, ESI-MS [M+H+]=566.Target product: 98 mg of a white amorphous powder; ESI-MS [M+H+]=510.II.\",\n \"BIOLOGICAL EXAMPLES Example 1 Integrin αvβ3 Assay For the identification and assessment of integrin αvβ3 ligands, a test system was used which was based on competition between the natural integrin αvβ3 ligand vitronectin and the test substance for binding to solid phase-bound integrin αvβ3.Procedure Microtiter plates coated with 250 ng/ml of integrin αvβ3 in 0.05 M NaHCO3 pH 9.2; 0.1 ml/well; saturation with 1% powdered milk/assay buffer; 0.3 ml/well; 0.5 h/RT 3× washing with 0.05% Tween 20/assay buffer test substance in 0.1% powdered milk/assay buffer, 50 μl/well+0 μg/ml or 2 μg/ml of human vitronectin (Boehringer Ingelheim T007) in 0.1% powdered milk/assay buffer, 50 μl/well; 1 h/RT 3× washing with 0.05% Tween 20/assay buffer 1 μg/ml of anti human vitronectin antibody coupled to peroxidase (Kordia SAVN-APHRP) in 0.1% powdered milk/assay buffer; 0.1 ml/well; 1 h/RT 3× washing with 0.05% Tween 20/assay buffer 0.1 ml/well of peroxidase substrate stop reaction with 0.1 ml/well of 2 M H2SO4 measurement of the absorption at 450 nm Integrin αvβ3: Human placenta is solubilized with Nonidet and integrin αvβ3 affinity-purified on a GRGDSPK matrix (elution with EDTA).\",\n \"Impurities due to integrin αIIbβ3 and human serum albumin, and the detergent and EDTA are removed by anion-exchange chromatography.\",\n \"Assay buffer: 50 mM Tris pH 7.5; 100 mM NaCl; 1 mM CaCl2; 1 mM MgCl2; 10 μM MnCl2 Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M sodium acetate pH 4.9), then add 14.7 μl of 3% H2O2.Various dilutions of the test substances are employed in the assay and the IC50 values are determined (concentration of the ligand at which 50% of the ligand is displaced).\",\n \"The compound from Example VII showed the best result here.\",\n \"Example 2 Integrin αIIbβ3 Assay The assay is based on competition between the natural integrin αIIbβ3 ligand fibrinogen and the test substance for binding to integrin αIIbβ3.Procedure Coat microtiter plates with 10 μg/ml of fibrinogen (Calbiochem 341578) in 0.05 M NaHCO3 pH 9.2; 0.1 ml/well; saturate with 1% BSA/PBS; 0.3 ml/well; 30 min/RT 3× washing with 0.05% Tween 20/PBS test substance in 0.1% BSA/PBS; 50 μl/well+200 μg/ml of integrin αIIbβ3 (Kordia) in 0.1% BSA/PBS; 50 μl/well; 2 to 4 h/RT 3× washing as above biotinylated anti-integrin αIIbβ3 antibody (Dianova CBL 130 B); 1:1000 in 0.1% BSA/PBS; 0.1 ml/well; 2 to 4 h/RT.\",\n \"3× washing as above streptavidin-peroxidase complex (B.M.\",\n \"1089153) 1:10000 in 0.1% BSA/PBS; 0.1 ml/well; 30 min/RT 3× washing as above 0.1 ml/well of peroxidase substrate stop reaction using 0.1 ml/well of 2 M H2SO4 measurement of the absorption at 450 nm Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M Na acetate pH 4.9), then add 14.7 μl of 3% H2O2 Various dilutions of the test substances are employed in the assay and the IC50 values are determined (concentration of the antagonist at which 50% of the ligand is displaced).\",\n \"By comparison of the IC50 values in the integrin αIIbβ3 and integrin αvb3 assay, the selectivity of the substances can be determined.\",\n \"Example 3 CAM Assay The CAM (chorioallantoic membrane) assay serves as a generally recognized model for the assessment of the in vivo activity of integrin αvβ3 antagonists.\",\n \"It is based on the inhibition of angiogenesis and neovascularization of tumor tissue (Am.\",\n \"J. Pathol.\",\n \"1975, 79, 597-618; Cancer Res.\",\n \"1980, 40, 2300-2309; Nature 1987, 329, 630).\",\n \"The procedure is carried out analogously to the prior art.\",\n \"The growth of the chicken embryo blood vessels and of the transplanted tumor tissue can be readily monitored and assessed.\",\n \"Example 4 Rabbit Eye Assay In this in vivo model, the inhibition of angiogenesis and neovascularization in the presence of integrin αvβ3 antagonists can be monitored and assessed analogously to Example 3.The model is generally recognized and is based on the growth of rabbit blood vessels starting from the edge in the corner of the eye (Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA.\",\n \"1994, 91, 4082-4085; Science 1976, 193, 70-72).\",\n \"The procedure is carried out analogously to the prior art.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10297202"}}},{"rowIdx":96,"cells":{"text":{"kind":"list like","value":[["Method, apparatus and system for building a compact language model for large vocabulary continous speech recognition (lvcsr) system","According to one aspect of the invention, a method is provided in which a set of probabilistic attributes in an N-gram language model is classified into a plurality of classes.","Each resultant class is clustered into a plurality of segments to build a code-book for the respective class using a modified K-means clustering process which dynamically adjusts the size and centroid of each segment during each iteration in the modified K-means clustering process.","A probabilistic attribute in each class is then represented by the centroid of the corresponding segment to which the respective probabilistic attribute belongs."],["1.A method comprising: classifying a set of probabilistic attributes in an N-gram language model into a plurality of classes; clustering each resultant class into a plurality of segments to build a codebook for the respective class using a modified K-means clustering process which dynamically adjusts the size and centroid of each segment during each iteration in the modified K-means clustering process; and representing a probabilistic attribute in each class by the centroid of the corresponding segment to which the respective probabilistic attribute belongs.","2.The method of claim 1 wherein a probabilistic attribute is represented by a first number of data bits before clustering.","3.The method of claim 2 wherein the respective probabilistic attribute is represented by an index value having a second number of data bits after clustering, the second number being smaller than the first number, the respective index value being used to reference a corresponding codeword in the respective codebook.","4.The method of claim 1 wherein a probabilistic attribute is a probability value associated with an n-gram node in the N-gram language model.","5.The method of claim 1 wherein a probabilistic attribute is a back-off weight associated with an n-gram node in the N-gram language model.","6.The method of claim 1 wherein the N-gram language model is a tri-gram language model and wherein the plurality of classes includes a first class corresponding to a set of unigram probability values, a second class corresponding to a set of unigram back-off weights, a third class corresponding to a set of bigram probability values, a fourth class corresponding to a set of bigram back-off weights, and a fifth class corresponding to a set of trigram probability values.","7.The method of claim 1 wherein clustering each resultant class includes: initializing the plurality of segments such that all segments have equivalent areas; setting the centroid of each segment such that the area of the respective segment is approximately equally split based on the corresponding centroid; and performing a set of operations iteratively until one or more optimization criteria are met, including: computing a total deviation of the plurality of segments; replacing the edge of each segment by an arithmetic average of the nearest two centroids; and setting a new centroid for each resultant segment.","8.The method of claim 7 wherein computing the total deviation includes: computing a deviation of each segment based upon the corresponding centroid of the respective segment; and summing the deviations of all segments to generate the total deviation.","9.The method of claim 7 wherein performing the set of operations includes: determining, for each segment in the plurality of segments, whether the new edge value equals the previous edge value; and indicating that the one or more optimization criteria are met if the new edge value equals the previous edge value.","10.The method of claim 7 wherein performing the set of operations includes: determining whether a predetermined number of iterations is reached; and indicating that the one or more optimization criteria are met if the predetermined number of iterations is reached.","11.The method of claim 7 wherein performing the set of operations includes: determining whether a changing rate in the total deviation is less than a predetermined threshold; and indicating that the one or more optimization criteria are met if the changing rate in the total deviation is less than the predetermined threshold.","12.A method comprising: clustering a set of probabilistic values associated with each data class of a plurality of data classes of an N-gram language model into a plurality of clusters using a modified K-means clustering process which dynamically adjusts the size and centroid of each respective cluster during each iteration in the modified K-means clustering process until one or more predetermined conditions are satisfied, the clustering including: initializing the plurality of clusters such that all clusters have equivalent areas; setting the centroid of each resultant cluster such that the area of each respective cluster is approximately equally split based on the corresponding centroid; and performing a set of operations iteratively until one or more predetermined conditions are satisfied, including: computing a total deviation of the clusters; replacing the edge of each cluster by an arithmetic average of the nearest two centroids; and setting a new centroid for each resultant segment.","13.The method of claim 12 wherein performing the set of operations includes: determining, for each cluster in the plurality of clusters, whether the new edge value equals the previous edge value; and indicating that the one or more predetermined conditions are satisfied if the new edge value equals the previous edge value.","14.The method of claim 12 wherein performing the set of operations includes: determining whether a predetermined number of iterations is reached; and indicating that the one or more predetermined conditions are satisfied if the predetermined number of iterations is reached.","15.The method of claim 12 wherein performing the set of operations includes: determining whether a changing rate in the total deviation is less than a predetermined threshold; and indicating that the one or more predetermined conditions are satisfied if the changing rate in the total deviation is less than the predetermined threshold.","16.An apparatus comprising: a plurality of codebooks each being built based upon a corresponding class of probabilistic values that represent conditional probabilities of a set of words in a language model, each codebook including a plurality of codewords each representing one or more corresponding probabilistic values, wherein each codebook of the plurality of codebooks is built using a modified K-means clustering process which dynamically adjusts the size and the centroid of each cluster during each iteration in the modified K-means clustering process until a total deviation of the clusters is optimized based upon one or more optimization criteria.","17.The apparatus of claim 16 wherein the language model is a tri-gram language model and wherein the plurality of classes includes a first class corresponding to a set of unigram probability values, a second class corresponding to a set of unigram back-off weights, a third class corresponding to a set of bigram probability values, a fourth class corresponding tp a set of bigram back-off weights, and a fifth class corresponding to a set of trigram probability values.","18.The apparatus of claim 16 wherein each codebook for the corresponding class of probabilistic values is built by the modified K-means clustering process which includes: logic to initialize a plurality of clusters such that all clusters have equivalent areas; logic to set the centroid of each cluster such that the area of the respective cluster is approximately equally split based on the corresponding centroid; and logic to perform a set of operations iteratively until one or more optimization criteria are met, including: logic to compute a total deviation of the plurality of clusters; logic to replace the edge of each cluster by an arithmetic average of the nearest two centroids; and logic to set a new centroid for each resultant cluster.","19.The apparatus of claim 18 wherein logic to compute the total deviation includes: logic to compute a deviation of each cluster based upon the corresponding centroid of the respective cluster; and logic to sum the deviations of all clusters to generate the total deviation.","20.The apparatus of claim 18 wherein logic to perform the set of operations includes: logic to determine, for each cluster, whether the new edge value equals the previous edge value.","21.The apparatus of claim 18 wherein logic to perform the set of operations includes: logic to determine whether a predetermined number of iterations is reached.","22.The apparatus of claim 18 wherein logic to perform the set of operations includes: logic to determine whether a changing rate in the total deviation is less than a predetermined threshold.","23.A system comprising: a feature extraction unit to convert an input signal representing an input speech into a set of feature vectors each representing a corresponding frame of the input signal; an acoustic model comprising a set of phonetic statistical models each representing a distinct phonetic unit; a language model including: a plurality of codebooks each being built based upon a corresponding class of probabilistic values that represent conditional probabilities of a set of words in the language model, each codebook including a plurality of codewords each representing one or more corresponding probabilistic values, wherein each codebook of the plurality of codebooks is built using a modified K-means clustering process which dynamically adjusts the size and the centroid of each cluster during each iteration in the modified K-means clustering process until a total deviation of the clusters is optimized based upon one or more optimization criteria; and a decoder coupled to the feature extraction unit, the acoustic model, and the language model, the decoder to recognize the input speech based, at least in part, upon the feature vectors, the acoustic model, and the language model.","24.The system of claim 23 wherein the language model is an tri-gram language model and wherein the plurality of classes includes a first class corresponding to a set of unigram probability values, a second class corresponding to a set of unigram back-off weights, a third class corresponding to a set of bigram probability values, a fourth class corresponding to a set of bigram back-off weights, and a fifth class corresponding to a set of trigram probability values.","25.The system of claim 23 wherein each codebook for the corresponding class of probabilistic values is built by the modified K-means clustering process which includes: logic to initialize a plurality of clusters such that all clusters have equivalent areas; logic to set the centroid of each cluster such that the area of the respective cluster is approximately equally split based on the corresponding centroid; and logic to perform a set of operations iteratively until one or more optimization criteria are met, including: logic to compute a total deviation of the plurality of clusters; logic to replace the edge of each cluster by an arithmetic average of the nearest two centroids; and logic to set a new centroid for each resultant cluster.","26.The system of claim 25 wherein logic to perform the set of operations includes: logic to determine, for each cluster, whether the new edge value equals the previous edge value; logic to determine whether a predetermined number of iterations is reached; and logic to determine whether a changing rate in the total deviation is less than a predetermined threshold.","27.A machine-readable medium comprising instructions which, when executed by a machine, cause the machine to perform operations including: classifying a set of probabilistic attributes in an N-gram language model into a plurality of classes; clustering each resultant class into a plurality of segments to build a codebook for the respective class using a modified K-means clustering process which dynamically adjusts the size and centroid of each segment during each iteration in the modified K-means clustering process; and representing a probabilistic attribute in each class by the centroid of the corresponding segment to which the respective probabilistic attribute belongs.","28.The machine-readable medium of claim 27 wherein the N-gram language model is a tri-gram language model and wherein thy plurality of classes includes a first class corresponding to a set of unigram probability values, a second class corresponding to a set of unigram back-off weights, a third class corresponding to a set of bigram probability values, a fourth class corresponding to a set of bigrarn back-off weights, and a fifth class corresponding to a set of trigram probability values.","29.The machine-readable medium of claim 27 wherein clustering each resultant class includes: initializing the plurality of segments such that all segments have equivalent areas; setting the centroid of each segment such that the area of the respective segment is approximately equally split based on the corresponding centroid; and performing a set of operations iteratively until one or more optimization criteria are met, including: computing a total deviation of the plurality of segments; replacing the edge of each segment by an arithmetic average of the nearest two centroids; and setting a new centroid for each resultant segment.","30.The machine-readable medium of claim 29 wherein performing the set of operations includes: determining, for each cluster, whether the new edge value equals the previous edge value; determining whether a predetermined number of iterations is reached; and determining whether a changing rate in the total deviation is less than a predetermined threshold."],["<SOH> BACKGROUND OF THE INVENTION <EOH>Modern speech recognition systems are based on principles of statistical pattern recognition and typically employ an acoustic model and a language model to decode an input sequence of observations (also referred to as acoustic events or acoustic signals) representing an input speech (e.g., a sentence or string of words) to determine the most probable sentence or word sequence given the input sequence of observations.","In other words, the function of a modern speech recognizer is to search through a vast space of potential or candidate sentences and to choose the sentence or word sequence that has the highest probability of generating the input sequence of observations or acoustic events.","In general, most modern speech recognition systems employ acoustic models that are based on continuous density hidden Markov models (CDHMMs).","In particular, CDHMMs have been widely used in speaker-independent LVCSR because they outperform discrete HMMs and semi-continuous HMBs.","In CDHMMs, the probability function of observations or state observation distribution is modeled by multivariate mixture Gaussians (also referred to herein as Gaussian mixtures) which can approximate the speech feature distribution more accurately.","The purpose of a language model is to provide a mechanism for estimating the probability of a word in an utterance given the preceding words.","Most modern LVCSR systems typically employ some forms of N-gram language model which assumes that the probability of a word depends only on the preceding (N-1) words.","N is usually limited to 2 (for a bi-gram model) or 3 for a tri-gram model).","In a typical LVCSR system, the size of the language model is usually very large.","For example, for a Chinese dictation system having a vocabulary size of about 50,000 words, the size of a typical tri-gram language model file is about 130 Mbytes and the size of a typical bi-gram look-ahead language model file is about 109 Mbytes.","Since the language models files are usually very large, it is difficult to load such files directly into memory because of insufficient physical memory in most of the desktop machines.","One solution is to use a memory-map file format to access language model files in LVCSR system.","Accessing the language model files using memory-map file format is slower than loading the language model files directly into memory.","In addition, because a LVCSR system accesses language model files randomly, searching such a big space randomly also costs much time.","In short, the large size of language model files in a LVCSR system can negatively impact the system performance in terms of memory requirement and run-time speed."],["<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The present invention will be more fully understood by reference to the accompanying drawings, in which: FIG.","1 is a block diagram of one embodiment of a speech recognition system according to the teachings of the present invention; FIG.","2 is a diagram illustrating an HMM-based phone model; FIG.","3 is a diagram illustrating an N-gram language model; FIG.","4 shows a flow diagram of one embodiment of a method according to the teachings of the present invention; FIG.","5 shows a block diagram of one embodiment of a method according to the teachings of the present invention; FIG.","6 illustrates a flow diagram of one embodiment of a modified K-means clustering process according to the teachings of the present invention; FIG.","7 provides a graphical illustration of the segment/cluster initialization according to the teachings of the present invention; FIG.","8 provides a graphical illustration of a centroid (central point) of a segment; and FIG.","9 provides a graphical illustration of a segment refinement according to the teachings of the present invention.","detailed-description description=\"Detailed Description\" end=\"lead\"?"],["FIELD OF THE INVENTION The present invention relates to the field of speech recognition.","More specifically, the present invention relates to a method, apparatus, and system for building a compact language model for a large vocabulary continuous speech recognition (LVCSR) system.","BACKGROUND OF THE INVENTION Modern speech recognition systems are based on principles of statistical pattern recognition and typically employ an acoustic model and a language model to decode an input sequence of observations (also referred to as acoustic events or acoustic signals) representing an input speech (e.g., a sentence or string of words) to determine the most probable sentence or word sequence given the input sequence of observations.","In other words, the function of a modern speech recognizer is to search through a vast space of potential or candidate sentences and to choose the sentence or word sequence that has the highest probability of generating the input sequence of observations or acoustic events.","In general, most modern speech recognition systems employ acoustic models that are based on continuous density hidden Markov models (CDHMMs).","In particular, CDHMMs have been widely used in speaker-independent LVCSR because they outperform discrete HMMs and semi-continuous HMBs.","In CDHMMs, the probability function of observations or state observation distribution is modeled by multivariate mixture Gaussians (also referred to herein as Gaussian mixtures) which can approximate the speech feature distribution more accurately.","The purpose of a language model is to provide a mechanism for estimating the probability of a word in an utterance given the preceding words.","Most modern LVCSR systems typically employ some forms of N-gram language model which assumes that the probability of a word depends only on the preceding (N-1) words.","N is usually limited to 2 (for a bi-gram model) or 3 for a tri-gram model).","In a typical LVCSR system, the size of the language model is usually very large.","For example, for a Chinese dictation system having a vocabulary size of about 50,000 words, the size of a typical tri-gram language model file is about 130 Mbytes and the size of a typical bi-gram look-ahead language model file is about 109 Mbytes.","Since the language models files are usually very large, it is difficult to load such files directly into memory because of insufficient physical memory in most of the desktop machines.","One solution is to use a memory-map file format to access language model files in LVCSR system.","Accessing the language model files using memory-map file format is slower than loading the language model files directly into memory.","In addition, because a LVCSR system accesses language model files randomly, searching such a big space randomly also costs much time.","In short, the large size of language model files in a LVCSR system can negatively impact the system performance in terms of memory requirement and run-time speed.","BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be more fully understood by reference to the accompanying drawings, in which: FIG.","1 is a block diagram of one embodiment of a speech recognition system according to the teachings of the present invention; FIG.","2 is a diagram illustrating an HMM-based phone model; FIG.","3 is a diagram illustrating an N-gram language model; FIG.","4 shows a flow diagram of one embodiment of a method according to the teachings of the present invention; FIG.","5 shows a block diagram of one embodiment of a method according to the teachings of the present invention; FIG.","6 illustrates a flow diagram of one embodiment of a modified K-means clustering process according to the teachings of the present invention; FIG.","7 provides a graphical illustration of the segment/cluster initialization according to the teachings of the present invention; FIG.","8 provides a graphical illustration of a centroid (central point) of a segment; and FIG.","9 provides a graphical illustration of a segment refinement according to the teachings of the present invention.","DETAILED DESCRIPTION In the following detailed description numerous specific details are set forth in order to provide a thorough understanding of the present invention.","However, it will be appreciated by one skilled in the art that the present invention may be understood and practiced without these specific details.","In the discussion below, the teachings of the present invention are utilized to implement a method, apparatus, system, and machine-readable medium for building a compact language model for a speech recognition system.","In one embodiment, a set of N-gram probabilistic attributes that represent conditional probabilities of a set of words in an N-gram language model is classified into a plurality of classes based upon a relative order of the respective N-gram probabilistic attributes.","Each resultant class is then clustered into a plurality of segments or clusters to build a corresponding codebook for the respective class using a modified K-means clustering process which dynamically adjusts the size and the centroid of each segment during each iteration in the modified K-means clustering process.","In one embodiment, the modified K-means clustering process is performed until one or more optimization criteria are met.","In one embodiment, after the codebook for the respective class has been built, each N-gram probabilistic attribute in the respective class can be represented by the centroid of the corresponding segment to which the respective N-gram probabilistic attribute belongs.","For example, after a corresponding codebook has been built for a class of uni-gram probability values, a probability value associated with a given uni-gram node can be represented by a corresponding codeword in the respective codebook which can be referenced by a corresponding index value.","In one embodiment, an N-gram probabilistic attribute is represented by a first number of data bits prior to the construction of the corresponding codebook.","After the construction of the corresponding codebook, the respective N-gram probabilistic attribute can be represented by a corresponding index value having a second number of data bits which is smaller than the first number of data bits.","In one embodiment, an N-gram probabilistic attribute corresponds to an N-gram probability value or an N-gram back-off weight.","In one embodiment, the N-gram language model can be a tri-gram language model and the plurality of class can include a first class corresponding to a set of uni-gram probability values, a second class corresponding to a set of uni-gram back-off weights, a third class corresponding to a set of bi-gram probability values, a fourth class corresponding to a set of bi-gram back-off weights, and a fifth class corresponding to a set of tri-gram probability values.","In one embodiment, the clustering of each class of probabilistic attributes is performed as follows.","First, the plurality of segments are initialized such that all segments have equivalent areas.","The centroid for each segment is set such that the area of the respective segment is approximately equally split based on the corresponding centroid.","A set of clustering operations is then performed iteratively until one or more optimization criteria are met to create a corresponding codebook for the respective class of probabilistic attributes.","During each iteration, a total deviation of the plurality of segments is computed.","The edge of each segment is then replaced by the arithmetic average of the nearest two centroids.","A new centroid is then set for each resultant segment such that each resultant segment is approximately equally split by the corresponding centroid.","A new total deviation of the resultant segments is then computed.","In one embodiment, the one or more optimization criteria are met (e.g., the total deviation becomes steady) if one of the following conditions is satisfied: a) For each segment, the new edge value equals the previous edge value.","In other words, if the arithmetic average of the nearest two centroids equals the previous edge value then the total deviation is considered steady; b) A predetermined number of iterations is reached; or c) A change of total deviation is less than a predetermined threshold.","The teachings of the present invention are applicable to any method, apparatus, and system for speech recognition that employs N-gram language models.","However, the present invention is not limited to N-gram language models in speech recognition systems and can be applied to the other types of language modeling in speech recognition.","In addition, the present invention can also be applied to data modeling in other fields or disciplines including, but not limited to, image processing, signal processing, geometric modeling, computer-aided-design (CAD), computer-aided-manufacturing (CAM), etc.","FIG.","1 illustrates a block diagram of one embodiment of a speech recognition system 100 according to the teachings of the present invention.","The system 100, as shown in FIG.","1, includes an analog to digital converter (A/D) 110, a feature extractor or spectral analysis unit 120, a decoder 130, an acoustic model 140, and a language model 150.An input signal 105 representing the input speech is first digitized using the A/D 110.In one embodiment, the digital signal is then sliced up into frames typically of 10, 15, or 20 ms. Each frame of the signal is then converted into a corresponding feature vector which is used to characterize the spectral properties of the input signal.","In one embodiment, the feature vector is multi-dimensional and has a plurality of feature components.","The feature vectors generated by the feature extractor unit 120 are then inputted into the decoder 130 which determines the sentence or sequence of words that has the highest probability given the acoustic events characterized by the feature vectors, based upon the acoustic model 140 and the language model 150.The language model 150, in one embodiment, is an N-gram language model which includes a plurality of codebooks.","Each codebook corresponds to a class of probabilistic attributes (e.g., uni-gram probability values, uni-gram back-off weights, bi-gram probability values, etc.)","that are used to represent various conditional probabilities of a set of words.","For example, one of the codebook may correspond to the uni-gram probability class, another codebook may correspond to the uni-gram back-off weight class, and so on.","The language model 150 and the construction of the corresponding codebooks are described in greater detail below.","FIG.","2 illustrates a diagram of one embodiment of an HMM-based phone model structure used in the acoustic model 140 to model a phonetic unit (e.g., a phoneme or a subword unit, etc.).","Each individual phonetic unit is represented or modeled by a corresponding HM.","As shown in FIG.","2, an “MM has a set of sequence of states (1-5) that are connected by a set of transition probabilities (a12, a23, a34, a45), and a set of observation probabilities or likelihoods (b2 (o1),b2(o2),b3(o3),b4(o4),b4(o5),b4(o6)).","Each transition probability aij represents the probability of transitioning from a state i to a state j.","Each observation probability or distribution bi(oj) represents the probability of an observation vector oj being generated from a state i.","Thus, the transition probabilities model the durational variability in speech and the output probabilities model the spectral variability.","Accordingly, the set of states, the set of transition probabilities and the set of output probabilities are the parameters that are used to define an HMM.","The HMM shown in FIG.","2 has a left-right topology.","In many modern speech recognition systems, each state output distribution or observation probability function is modeled by a multivariate mixture Gaussian as follows: b j ( o t ) = ∑ k = 1 M c jk N ( o t , m jk , V jk ) where cjk is the weight of mixture component k in state j and N(oi, mjk, Vjk) denotes a multivariate Gaussian of mean mjk and covanance Vjk for the kth mixture component in state j.","FIG.","3 shows a structure diagram of one embodiment of an N-gram language model.","As described above, the purpose of a language model is to provide a mechanism for estimating the probability of some word, wk, in an utterance given the preceding words, W1k-1=w1 .",".",".","wk1.An N-gram language model assumes that wk depends only on the preceding N-1 words, that is P ( w k ❘ W 1 k - 1 ) = P ( w k ❘ W k - n + 1 k - 1 ) .","Because of the very large amount of models and associated data that need to be stored and processed, N is usually limited to two (for a bi-gram or 2-gram language model) or three (for a tri-gram or 3-gram language model).","A back-off mechanism can be used to compute a conditional probability of a given word when some N-gram context (e.g., a tri-gram or a bi-gram) does not exist or cannot be found for the given word.","For example, for given words “a” “b” “c”, there may be no bi-gram probability for “b→a” or tri-gram probability for “c→b→a” in certain contexts.","In this case, a back-off mechanism is used to compute the bi-gram or tri-gram probability for the given word “a”.","For example, for a tri-gram of words “c→b→a” (meaning word “a” preceded by word “b” preceded by word “c”), the corresponding tri-gram and bi-gram probabilities of this word sequence can be computed as follows using a back-off mechanism: P ( a / b , c ) = { P ( a / b , c ) , if P ( a / b , c ) exists , P ( a / b ) × w ( b , c ) , if w ( b , c ) exists , P ( a / b ) otherwise } P ( a / b ) = { P ( a / b ) , if P ( a / b ) exists , P ( a ) × w ( b ) otherwise } where: P(a/b,c) represents the tri-gram probability of the tri-gram c→b→a; P(a/b) represents the bi-gram probability of the bi-gram b→a; P(a) represents the uni-gram probability of word a; w(b,c) represents the back-off weight for the bi-gram c→b; and w(b) represents the back-off weight for the word b.","In various LVCSR systems, language model look-head techniques can be used to speed up the search in the corresponding N-gram language model.","The look-head techniques are used to incorporate the language model probabilities as early as possible in the pruning process of the beam search.","In general, look-head probabilities are pre-computed and stored in certain file formats or data structures.","Referring to FIG.","3, an N-gram language model in a typical LVSR system can be logically represented as a set of nodes 300 which includes a set of uni-gram nodes 310, a set of bi-gram nodes 320, and so on.","The uni-gram nodes are used to represent single words and their associated probability data (e.g., probability value and back-off weight).","The bi-gram nodes are used to represent word pairs and their associated probability data, etc.","In one embodiment, the second words in the bi-gram nodes that follow the same first word in a uni-gram node can be grouped together and point them to the corresponding first word in the uni-gram node.","Thus, only the second words and the corresponding bi-gram probability data need to be stored in the bi-gram nodes.","Tri-gram nodes can be structured similarly.","For example, all the third words in the tri-gram nodes that follow the same bi-gram node can be grouped together and point to the corresponding bi-gram node.","Thus, only the third words and their associated probability data need to be stored in the tri-gram nodes.","As shown in FIG.","3, each uni-gram node can be linked to its corresponding bi-gram nodes via a pointer.","Similarly, each bi-gram node can be linked to its corresponding tri-gram nodes via a pointer, and so on.","In other words, each uni-gram node points to the head of a set of bi-gram nodes whose words follow the word stored in the respective uni-gram node, each bi-gram node points to the head of a set of tri-gram nodes, and so on.","Each n-gram node (e.g., uni-gram node, bi-gram node, tri-gram node, etc.)","typically has the following components: the word identity of the word that the respective node represents (which can be the word itself or a word index corresponding to the word), an n-gram probability value, a back-off weight, and a pointer to the head of the corresponding (n+1)-gram nodes.","For example, a uni-gram node typically contains an index value of a particular word that is represented by the respective uni-gram node, a uni-gram probability value, a uni-gram back-off weight, and a pointer to a corresponding set of bi-gram nodes that are linked with the respective uni-gram node.","In one embodiment, as described above, each n-gram node only needs to store the last word of the corresponding n-gram.","For example, a bi-gram node only needs to store the second word of the corresponding bi-gram that the respective bi-gram node represents, a tri-gram node only needs to store the third word of the corresponding tri-gram that the respective tri-gram node represents, and so on.","In general, for computational efficiency and to avoid numerical underflow, probability values and back-off weights associated with the n-gram nodes can be represented in logarithmic space.","A n-gram node may be represented by various data structures depending upon the particular implementations and applications of the language model.","For example, an n-gram node may be represented by a corresponding data structure as shown below: typedef struct _asNGram{ unsigned short WID; float P; int PTR; float W; } asNGram; where: WID is an index of the word W that this node represents; P and W are the corresponding probability value and back-off weight, respectively; PTR is a pointer that points to the (n+1)-gram area linked by this node.","If there is no (n+1)-gram linked with this node, PTR can be set to a pre-defined value.","In this example, the word index WID is an unsigned 16-bit value (e.g., unsigned short data type); the probability value P and the back-off weight are 32-bit float values (e.g., 32-bit float data type); and the PTR is a 32-bit integer value.","The whole size of the data structure in this example is therefore 112 bits or 14 bytes.","An example of a data structure that can be used to represent a look-head node is shown below: typedef struct _asTreeBi-gramt{ int NODENO; float P; } asTreeBi-gram; In this example, the NODENO is a 32-bit index of the corresponding node and P is a 32-bit probability value.","It can be understood from the above description that a typical language model for a LVCSR system can contain a very large number of nodes each of which may contain corresponding probability value and/or backup weight that are represented by very large number of data bits (e.g., probability value and back-off weight are 32-bit float values in the above examples).","Thus, a language model for a typical LVCSR requires a very large amount of memory space.","As discussed above and described in more details below, the present invention provides a method and mechanism for reducing the size of the language model and the access time while maintaining a high level of recognition accuracy.","According to the teachings of the present invention, a method is introduced and described in detail herein to reduce the size of a language model in a LVCSR system.","In one embodiment, the probability values and back-off weights (also referred to as probabilistic attributes herein) associated with the respective n-gram nodes in the respective language model are quantized or clustered by a modified K-means clustering algorithm to compress the size of the respective language model.","In one embodiment, the probability values or back-off weights are divided or grouped into separate classes or groups based on the relative n-th order of the corresponding n-gram nodes and a modified K-means clustering algorithm is applied to each class to cluster the probability values or back-off weights in each class to build a corresponding codebook for the respective class.","For example, uni-gram probability values associated with uni-gram nodes are grouped into one class, uni-gram back-off weights are grouped into another class, bi-gram probability values are grouped into yet another class, and so on.","Thus, for a tri-gram language model (which includes uni-gram nodes, bi-gram nodes, and tri-gram nodes), there can be five separate classes (also referred to as data classes herein) that can be quantized or clustered to reduce the size of the language model.","These classes include a uni-gram probability class, a uni-gram back-off weight class, a bi-gram probability class, a bi-gram back-off weight class, and a tri-gram probability class.","For each class, the field of probability values (also referred to as the range of probability values) is quantized or clustered into a plurality of clusters or segments using a modified K-means clustering algorithm described in more detail below.","A centroid is defined for each cluster or segment.","Thus, a separate codebook can be constructed for each class of probability values or each class of back-off weights.","After quantization or clustering, a given probability value or back-off weight can be represented by the centroid (also called codeword) of the corresponding segment or cluster to which the respective probability value or back-off weight belongs.","By quantizing or clustering the field of probability values in each class, the probability values or back-off weights (which originally were represented by large-size data types such as 32-bit float type) can now be represented by smaller-size index values such as 8-bit char type that points to the corresponding codeword (centroid) in the corresponding codebook.","In one embodiment, the field of probability value for each class is divided into 256 segments or clusters using the modified K-means clustering process described in greater details below.","As such, the corresponding codebook will have 256 codewords.","Each codeword can be referenced by an 8-bit index value.","Thus, assuming that the original probability values or back-off weights use 32-bit float type, these probability values or back-off weights can now be replaced by 8-bit index values which are used to reference the corresponding codewords in the codebook.","It should be appreciated and understood by one skilled in the art that the teachings of the present invention are not limited to any particular number of segments or clusters.","Similarly, the teachings of the present invention are not limited to any particular data types that are used to represent the probability values and back-off weights before and after the quantization.","The number of segments or clusters for each class (hence the size of the corresponding codebook) and the data types that are used to represent the probability values, the back-off weights, or the indices to the codebook can vary depending upon the particular applications and implementations of the present invention.","FIG.","4 illustrates a flow diagram of one embodiment of a method 400 according to the teachings of the present invention.","At block 410, the probabilistic attributes (e.g., the probability values and back-off weights) in a N-gram language model are classified or grouped into a plurality of separate classes.","For example, in a tri-gram language model that includes uni-gram nodes, bi-gram nodes, and tri-gram nodes, the probabilistic attributes can be classified into five separate classes as follows: uni-gram probability, uni-gram back-off weight, bi-gram probability, bi-gram back-off weight, and tri-gram probability.","At block 420, the field of value for each class is clustered or quantized using a modified K-means clustering process to build a corresponding codebook for the respective class.","The modified K-means clustering process is described in more details below.","At block 430, each probabilistic attribute (e.g., a probability value or a back-off weight) can be represented by the corresponding codeword in the respective codebook.","In one embodiment, as described herein, after quantization or clustering, the probability value or back-off weight for any given node in the language model can then be replaced by a corresponding index value that is used to reference the corresponding codeword.","For example, assuming that the original probability value or back-off weight for a given node was 32-bit data type (e.g., 32-bit float value) and that there are 256 codewords in the corresponding codebook, then after quantization or clustering, the respective probability value or back-off weight for the given node can be represented by an 8-bit index value which is used to reference or point to the corresponding codeword in the codebook.","FIG.","5 shows a block diagram of one embodiment of a method according to teachings of the present invention.","As shown in FIG.","5, the probabilistic attributes (e.g., probability values and back-off weights) 510 in an N-gram language model are classified or grouped into separate classes based on the n-gram order of the respective nodes.","In this example, the classes include: uni-gram probability 520A, uni-gram back-off weight 520B, bi-gram probability 520C, bi-gram back-off weight 520D, tri-gram probability 520E, etc.","Each class is then clustered or quantized using a modified K-means clustering process to create a corresponding codebook (e.g., 530A-E) for each respective class.","As described herein, the size of the codebook for each class may or may not be the same, depending on the particular applications and implementations of the present invention.","Each probabilistic attribute (e.g., a uni-gram probability value associated with a uni-gram node) can then be represented by a corresponding codeword in the respective codebook (e.g., the codebook for the uni-gram probability class).","FIG.","6 illustrates a flow diagram of one embodiment of a modified K-means clustering process 600 to create a corresponding codebook for a probabilistic class (e.g., uni-gram probability class or bi-gram probability class, etc.","), according to the teachings of the present invention.","The process starts at block 601 and proceeds to block 605 to initialize the codebook as follows: At block 605: initialization of the process is performed by clustering the field of values for the respective class into a plurality of segments (e.g., n segments in this example) and initialize the segments such that all the segments have equivalent areas.","The segments are also called clusters herein.","The centroid of each segment is then set such that the respective segment is about equally split (i.e., the segment can be split into two equivalent sub-areas by the corresponding centroid).","As shown in FIGS.","7 and 8, the segment initialization is performed according to the following conditions: E 1 = min ( x ) , E 2 … E n , E n + 1 = max ( x ) , C 1 , C 2 … C n - 1 , C n ∫ E 1 E 2 P ( x ) ⅆ x = ∫ E 2 E 3 P ( x ) ⅆ x = … = ∫ E n - 1 E n P ( x ) ⅆ x = ∫ E n E n + 1 P ( x ) ⅆ x ∫ E i C i P ( x ) ⅆ x = ∫ C i E i + 1 P ( x ) ⅆ x i = 1 , 2 … n Where: x is a possible probability value in the respective class; P(x) is the probability that x occurs; the i segment is defined as [Ei, Ei+1; and Ci is defined as the centroid of the i segment.","At this point, there are n segments or clusters which have equivalent areas and each i segment has a corresponding centroid Ci which can split the respective segment into two equivalent sub-areas.","Set the number of iterations R=0 At block 610: compute the total deviation Dev as sum of the deviation of each segment Devi as follows: Dev=ΣDevi.","for the i segment, Devi is defined as ∫ E i E i + 1 P ( x ) * abs ( x - C i ) ⅆ x , (illustrated in FIG.","8) At block 615: replace the edge Ei of each segment by the arithmetic average of the nearest two centroids as shown below: Ei=(Ci-1+Ci)/2 (illustrated in FIG.","9) set the new centroid Ci for each resultant segment compute the new total deviation Dev increment the number of iterations R=R+1 At block 625: if the total deviation is not steady, then the process 600 loops back to block 615.Otherwise, the corresponding codebook is obtained at block 635 and the process 600 proceeds to ends at block 691.In one embodiment, the total deviation is considered steady if one of the following conditions (also called optimization criteria) is met: a.","For each i, Ei=Ei (the new edge value is the same as the previous edge value); b.","The number of iterations performed reaches a predetermined number (R=Rmax); or c. The change of total deviation is less than a pre-determined threshold value Δth, |Dev−Dev|/Dev<Δth Significant reduction in memory requirement and access time for a language model can be attained according to the teachings of the present invention.","For example, assuming that before compression or quantization, the following data structures were used for n-gram nodes and look-head nodes, respectively: n-gram node data structure (before compression): typedef struct _asNGram{ unsigned short WID; float P; int PTR; float W; } asNGram; where: WID (16-bit unsigned value) is an index of the word W that this node represents; P (32-bit float value) and W (32-bit float value) are the corresponding probability value and back-off weight, respectively, PTR (32-bit integer value) is a pointer that points to the (n+1)-gram area linked by this node.","If there is no (n+1)-gram linked with this node, PTK is a pre-defined value.","Thus the whole size of an-gram data structure in this example is 112 bits or 14 bytes.","look-head node data structure (before compression): typedef struct _asTreeBi-gramt{ int NODENO; float P; } asTreeBi-gram; where: NODENO is a 32-bit index of the corresponding node and P is a 32-bit probability value.","Thus the whole size of a look-head data structure is 64 bits.","After compression, an n-gram node and a look-head node can be represented by the following data structures, respectively.","It is assumed in this example that 8-bit codebooks are used (e.g., each codebook has 256 codewords): n-gram node data structure (after compression): typedef struct _asNGram{ unsigned short WID; unsigned char P; int PTR; unsigned char W; } asNGram; where: WID (16-bit unsigned value) is an index of the word W that this node represents; P (8-bit unsigned char type) is the index value used to reference the corresponding quantized probability value (codeword) in the corresponding codebook; W (8-bit unsigned char type) is the index value used to reference the corresponding quantized back-off weight (codeword) in the corresponding codebook; PTR (32-bit integer value) is a pointer that points to the (n+1)-gram area linked by this node.","If there is no (n+1)-gram linked with this node, PTR is a pre-defined value.","Thus the whole size of an n-gram data structure after compression in this example is 64 bits or 8 bytes.","look-head node data structure (after compression): typedef struct _asTreeBi-gramt{ int NODENO; unsigned P; } asTreeBi-gram; where: NODENO is now an 8-bit index value that is used to reference the corresponding quantized probability value in the corresponding codebook.","Thus the size of the look-head data structure after compression is 40 bits.","From the above example, it can be seen that the size of the language model can be significantly reduced according to the teachings of the present invention.","In this example, the size of each n-gram node is reduced from 112 bits to 64 bits and the size of each look-head node is reduced from 64 bits to 40 bits.","For a language model in a typical LVCSR system which usually has a very large number of nodes, the reduction in memory requirement can be very substantial.","The additional memory requirement for the codebooks is minimal or insignificant compared to the reduction in the memory requirement for the whole language model.","For example, the memory requirement for an 8-bit codebook which has 256 codewords and each codeword is a 32-bit float value is only: 256(codewords)*32(bits/codeword)=8192 bits Tables 1 and 2 below show some experimental results based upon various experiments conducted according to the teachings of the present invention.","These experiments were conducted on a 51K Mandarin LVCSR system and using a testing machine such as a double-PIII866 with 512M memory and 256K L2 Cache.","Table 1 illustrates the improvements with respect to memory requirement and decoding speed using 8-bit codebooks (e.g., each codebook has 256 codewords).","It can be seen from table 1 that the memory requirement and decoding speed have been reduced after compression while the increase in the word error rate (WER) of the system after compression is minimal or insignificant.","The XRT notation in table 1 is used to mean times of real time.","TABLE 1 System using BaseLine modified K-Means System (before clustering (after compression) compression) WER 10.0% 10.1% Tri-gram file size 130M 75M Treebi-gram file size 109M 68M MapMode XRT 1.18XRT 1.08XRT Loading directly mode 1.11XRT 1.02XRT XRT As shown in table 1, the experiments and comparisons were done to show the improvements with respect to two different embodiments: one embodiment using memory-map file format for the language model files and the other embodiment loading the language model files directly into memory.","After quantization the size of the language model file is reduced by 40% from 239M(130M+109M) to 143M (75M+68M).","In addition, the decoding speed has been improved by 8% from 1.18×RT to 1.08×RT using memory-map file format while WER only increases from 10.0% to 10.1%.","Furthermore, if language model files are loaded directly to memory, the decoding speed can be improved by another 6%.","Table 2 shows the experimental results using smaller-size codebooks.","In this example, 6-bit codebooks and 4bit codebooks were used.","TABLE 2 System using modified K-means clustering (after compression) 6-bit 4-bit codebooks codebooks WER 10.1% 12.8% MapMode XRT 1.07XRT 1.03XRT Loading directly 1.01XRT 0.98XRT mode XRT The invention has been described in conjunction with the preferred embodiment.","It is evident that numerous alternatives, modifications, variations and uses will be apparent to those skilled in the art in light of the foregoing description."]],"string":"[\n [\n \"Method, apparatus and system for building a compact language model for large vocabulary continous speech recognition (lvcsr) system\",\n \"According to one aspect of the invention, a method is provided in which a set of probabilistic attributes in an N-gram language model is classified into a plurality of classes.\",\n \"Each resultant class is clustered into a plurality of segments to build a code-book for the respective class using a modified K-means clustering process which dynamically adjusts the size and centroid of each segment during each iteration in the modified K-means clustering process.\",\n \"A probabilistic attribute in each class is then represented by the centroid of the corresponding segment to which the respective probabilistic attribute belongs.\"\n ],\n [\n \"1.A method comprising: classifying a set of probabilistic attributes in an N-gram language model into a plurality of classes; clustering each resultant class into a plurality of segments to build a codebook for the respective class using a modified K-means clustering process which dynamically adjusts the size and centroid of each segment during each iteration in the modified K-means clustering process; and representing a probabilistic attribute in each class by the centroid of the corresponding segment to which the respective probabilistic attribute belongs.\",\n \"2.The method of claim 1 wherein a probabilistic attribute is represented by a first number of data bits before clustering.\",\n \"3.The method of claim 2 wherein the respective probabilistic attribute is represented by an index value having a second number of data bits after clustering, the second number being smaller than the first number, the respective index value being used to reference a corresponding codeword in the respective codebook.\",\n \"4.The method of claim 1 wherein a probabilistic attribute is a probability value associated with an n-gram node in the N-gram language model.\",\n \"5.The method of claim 1 wherein a probabilistic attribute is a back-off weight associated with an n-gram node in the N-gram language model.\",\n \"6.The method of claim 1 wherein the N-gram language model is a tri-gram language model and wherein the plurality of classes includes a first class corresponding to a set of unigram probability values, a second class corresponding to a set of unigram back-off weights, a third class corresponding to a set of bigram probability values, a fourth class corresponding to a set of bigram back-off weights, and a fifth class corresponding to a set of trigram probability values.\",\n \"7.The method of claim 1 wherein clustering each resultant class includes: initializing the plurality of segments such that all segments have equivalent areas; setting the centroid of each segment such that the area of the respective segment is approximately equally split based on the corresponding centroid; and performing a set of operations iteratively until one or more optimization criteria are met, including: computing a total deviation of the plurality of segments; replacing the edge of each segment by an arithmetic average of the nearest two centroids; and setting a new centroid for each resultant segment.\",\n \"8.The method of claim 7 wherein computing the total deviation includes: computing a deviation of each segment based upon the corresponding centroid of the respective segment; and summing the deviations of all segments to generate the total deviation.\",\n \"9.The method of claim 7 wherein performing the set of operations includes: determining, for each segment in the plurality of segments, whether the new edge value equals the previous edge value; and indicating that the one or more optimization criteria are met if the new edge value equals the previous edge value.\",\n \"10.The method of claim 7 wherein performing the set of operations includes: determining whether a predetermined number of iterations is reached; and indicating that the one or more optimization criteria are met if the predetermined number of iterations is reached.\",\n \"11.The method of claim 7 wherein performing the set of operations includes: determining whether a changing rate in the total deviation is less than a predetermined threshold; and indicating that the one or more optimization criteria are met if the changing rate in the total deviation is less than the predetermined threshold.\",\n \"12.A method comprising: clustering a set of probabilistic values associated with each data class of a plurality of data classes of an N-gram language model into a plurality of clusters using a modified K-means clustering process which dynamically adjusts the size and centroid of each respective cluster during each iteration in the modified K-means clustering process until one or more predetermined conditions are satisfied, the clustering including: initializing the plurality of clusters such that all clusters have equivalent areas; setting the centroid of each resultant cluster such that the area of each respective cluster is approximately equally split based on the corresponding centroid; and performing a set of operations iteratively until one or more predetermined conditions are satisfied, including: computing a total deviation of the clusters; replacing the edge of each cluster by an arithmetic average of the nearest two centroids; and setting a new centroid for each resultant segment.\",\n \"13.The method of claim 12 wherein performing the set of operations includes: determining, for each cluster in the plurality of clusters, whether the new edge value equals the previous edge value; and indicating that the one or more predetermined conditions are satisfied if the new edge value equals the previous edge value.\",\n \"14.The method of claim 12 wherein performing the set of operations includes: determining whether a predetermined number of iterations is reached; and indicating that the one or more predetermined conditions are satisfied if the predetermined number of iterations is reached.\",\n \"15.The method of claim 12 wherein performing the set of operations includes: determining whether a changing rate in the total deviation is less than a predetermined threshold; and indicating that the one or more predetermined conditions are satisfied if the changing rate in the total deviation is less than the predetermined threshold.\",\n \"16.An apparatus comprising: a plurality of codebooks each being built based upon a corresponding class of probabilistic values that represent conditional probabilities of a set of words in a language model, each codebook including a plurality of codewords each representing one or more corresponding probabilistic values, wherein each codebook of the plurality of codebooks is built using a modified K-means clustering process which dynamically adjusts the size and the centroid of each cluster during each iteration in the modified K-means clustering process until a total deviation of the clusters is optimized based upon one or more optimization criteria.\",\n \"17.The apparatus of claim 16 wherein the language model is a tri-gram language model and wherein the plurality of classes includes a first class corresponding to a set of unigram probability values, a second class corresponding to a set of unigram back-off weights, a third class corresponding to a set of bigram probability values, a fourth class corresponding tp a set of bigram back-off weights, and a fifth class corresponding to a set of trigram probability values.\",\n \"18.The apparatus of claim 16 wherein each codebook for the corresponding class of probabilistic values is built by the modified K-means clustering process which includes: logic to initialize a plurality of clusters such that all clusters have equivalent areas; logic to set the centroid of each cluster such that the area of the respective cluster is approximately equally split based on the corresponding centroid; and logic to perform a set of operations iteratively until one or more optimization criteria are met, including: logic to compute a total deviation of the plurality of clusters; logic to replace the edge of each cluster by an arithmetic average of the nearest two centroids; and logic to set a new centroid for each resultant cluster.\",\n \"19.The apparatus of claim 18 wherein logic to compute the total deviation includes: logic to compute a deviation of each cluster based upon the corresponding centroid of the respective cluster; and logic to sum the deviations of all clusters to generate the total deviation.\",\n \"20.The apparatus of claim 18 wherein logic to perform the set of operations includes: logic to determine, for each cluster, whether the new edge value equals the previous edge value.\",\n \"21.The apparatus of claim 18 wherein logic to perform the set of operations includes: logic to determine whether a predetermined number of iterations is reached.\",\n \"22.The apparatus of claim 18 wherein logic to perform the set of operations includes: logic to determine whether a changing rate in the total deviation is less than a predetermined threshold.\",\n \"23.A system comprising: a feature extraction unit to convert an input signal representing an input speech into a set of feature vectors each representing a corresponding frame of the input signal; an acoustic model comprising a set of phonetic statistical models each representing a distinct phonetic unit; a language model including: a plurality of codebooks each being built based upon a corresponding class of probabilistic values that represent conditional probabilities of a set of words in the language model, each codebook including a plurality of codewords each representing one or more corresponding probabilistic values, wherein each codebook of the plurality of codebooks is built using a modified K-means clustering process which dynamically adjusts the size and the centroid of each cluster during each iteration in the modified K-means clustering process until a total deviation of the clusters is optimized based upon one or more optimization criteria; and a decoder coupled to the feature extraction unit, the acoustic model, and the language model, the decoder to recognize the input speech based, at least in part, upon the feature vectors, the acoustic model, and the language model.\",\n \"24.The system of claim 23 wherein the language model is an tri-gram language model and wherein the plurality of classes includes a first class corresponding to a set of unigram probability values, a second class corresponding to a set of unigram back-off weights, a third class corresponding to a set of bigram probability values, a fourth class corresponding to a set of bigram back-off weights, and a fifth class corresponding to a set of trigram probability values.\",\n \"25.The system of claim 23 wherein each codebook for the corresponding class of probabilistic values is built by the modified K-means clustering process which includes: logic to initialize a plurality of clusters such that all clusters have equivalent areas; logic to set the centroid of each cluster such that the area of the respective cluster is approximately equally split based on the corresponding centroid; and logic to perform a set of operations iteratively until one or more optimization criteria are met, including: logic to compute a total deviation of the plurality of clusters; logic to replace the edge of each cluster by an arithmetic average of the nearest two centroids; and logic to set a new centroid for each resultant cluster.\",\n \"26.The system of claim 25 wherein logic to perform the set of operations includes: logic to determine, for each cluster, whether the new edge value equals the previous edge value; logic to determine whether a predetermined number of iterations is reached; and logic to determine whether a changing rate in the total deviation is less than a predetermined threshold.\",\n \"27.A machine-readable medium comprising instructions which, when executed by a machine, cause the machine to perform operations including: classifying a set of probabilistic attributes in an N-gram language model into a plurality of classes; clustering each resultant class into a plurality of segments to build a codebook for the respective class using a modified K-means clustering process which dynamically adjusts the size and centroid of each segment during each iteration in the modified K-means clustering process; and representing a probabilistic attribute in each class by the centroid of the corresponding segment to which the respective probabilistic attribute belongs.\",\n \"28.The machine-readable medium of claim 27 wherein the N-gram language model is a tri-gram language model and wherein thy plurality of classes includes a first class corresponding to a set of unigram probability values, a second class corresponding to a set of unigram back-off weights, a third class corresponding to a set of bigram probability values, a fourth class corresponding to a set of bigrarn back-off weights, and a fifth class corresponding to a set of trigram probability values.\",\n \"29.The machine-readable medium of claim 27 wherein clustering each resultant class includes: initializing the plurality of segments such that all segments have equivalent areas; setting the centroid of each segment such that the area of the respective segment is approximately equally split based on the corresponding centroid; and performing a set of operations iteratively until one or more optimization criteria are met, including: computing a total deviation of the plurality of segments; replacing the edge of each segment by an arithmetic average of the nearest two centroids; and setting a new centroid for each resultant segment.\",\n \"30.The machine-readable medium of claim 29 wherein performing the set of operations includes: determining, for each cluster, whether the new edge value equals the previous edge value; determining whether a predetermined number of iterations is reached; and determining whether a changing rate in the total deviation is less than a predetermined threshold.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>Modern speech recognition systems are based on principles of statistical pattern recognition and typically employ an acoustic model and a language model to decode an input sequence of observations (also referred to as acoustic events or acoustic signals) representing an input speech (e.g., a sentence or string of words) to determine the most probable sentence or word sequence given the input sequence of observations.\",\n \"In other words, the function of a modern speech recognizer is to search through a vast space of potential or candidate sentences and to choose the sentence or word sequence that has the highest probability of generating the input sequence of observations or acoustic events.\",\n \"In general, most modern speech recognition systems employ acoustic models that are based on continuous density hidden Markov models (CDHMMs).\",\n \"In particular, CDHMMs have been widely used in speaker-independent LVCSR because they outperform discrete HMMs and semi-continuous HMBs.\",\n \"In CDHMMs, the probability function of observations or state observation distribution is modeled by multivariate mixture Gaussians (also referred to herein as Gaussian mixtures) which can approximate the speech feature distribution more accurately.\",\n \"The purpose of a language model is to provide a mechanism for estimating the probability of a word in an utterance given the preceding words.\",\n \"Most modern LVCSR systems typically employ some forms of N-gram language model which assumes that the probability of a word depends only on the preceding (N-1) words.\",\n \"N is usually limited to 2 (for a bi-gram model) or 3 for a tri-gram model).\",\n \"In a typical LVCSR system, the size of the language model is usually very large.\",\n \"For example, for a Chinese dictation system having a vocabulary size of about 50,000 words, the size of a typical tri-gram language model file is about 130 Mbytes and the size of a typical bi-gram look-ahead language model file is about 109 Mbytes.\",\n \"Since the language models files are usually very large, it is difficult to load such files directly into memory because of insufficient physical memory in most of the desktop machines.\",\n \"One solution is to use a memory-map file format to access language model files in LVCSR system.\",\n \"Accessing the language model files using memory-map file format is slower than loading the language model files directly into memory.\",\n \"In addition, because a LVCSR system accesses language model files randomly, searching such a big space randomly also costs much time.\",\n \"In short, the large size of language model files in a LVCSR system can negatively impact the system performance in terms of memory requirement and run-time speed.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The present invention will be more fully understood by reference to the accompanying drawings, in which: FIG.\",\n \"1 is a block diagram of one embodiment of a speech recognition system according to the teachings of the present invention; FIG.\",\n \"2 is a diagram illustrating an HMM-based phone model; FIG.\",\n \"3 is a diagram illustrating an N-gram language model; FIG.\",\n \"4 shows a flow diagram of one embodiment of a method according to the teachings of the present invention; FIG.\",\n \"5 shows a block diagram of one embodiment of a method according to the teachings of the present invention; FIG.\",\n \"6 illustrates a flow diagram of one embodiment of a modified K-means clustering process according to the teachings of the present invention; FIG.\",\n \"7 provides a graphical illustration of the segment/cluster initialization according to the teachings of the present invention; FIG.\",\n \"8 provides a graphical illustration of a centroid (central point) of a segment; and FIG.\",\n \"9 provides a graphical illustration of a segment refinement according to the teachings of the present invention.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\"\n ],\n [\n \"FIELD OF THE INVENTION The present invention relates to the field of speech recognition.\",\n \"More specifically, the present invention relates to a method, apparatus, and system for building a compact language model for a large vocabulary continuous speech recognition (LVCSR) system.\",\n \"BACKGROUND OF THE INVENTION Modern speech recognition systems are based on principles of statistical pattern recognition and typically employ an acoustic model and a language model to decode an input sequence of observations (also referred to as acoustic events or acoustic signals) representing an input speech (e.g., a sentence or string of words) to determine the most probable sentence or word sequence given the input sequence of observations.\",\n \"In other words, the function of a modern speech recognizer is to search through a vast space of potential or candidate sentences and to choose the sentence or word sequence that has the highest probability of generating the input sequence of observations or acoustic events.\",\n \"In general, most modern speech recognition systems employ acoustic models that are based on continuous density hidden Markov models (CDHMMs).\",\n \"In particular, CDHMMs have been widely used in speaker-independent LVCSR because they outperform discrete HMMs and semi-continuous HMBs.\",\n \"In CDHMMs, the probability function of observations or state observation distribution is modeled by multivariate mixture Gaussians (also referred to herein as Gaussian mixtures) which can approximate the speech feature distribution more accurately.\",\n \"The purpose of a language model is to provide a mechanism for estimating the probability of a word in an utterance given the preceding words.\",\n \"Most modern LVCSR systems typically employ some forms of N-gram language model which assumes that the probability of a word depends only on the preceding (N-1) words.\",\n \"N is usually limited to 2 (for a bi-gram model) or 3 for a tri-gram model).\",\n \"In a typical LVCSR system, the size of the language model is usually very large.\",\n \"For example, for a Chinese dictation system having a vocabulary size of about 50,000 words, the size of a typical tri-gram language model file is about 130 Mbytes and the size of a typical bi-gram look-ahead language model file is about 109 Mbytes.\",\n \"Since the language models files are usually very large, it is difficult to load such files directly into memory because of insufficient physical memory in most of the desktop machines.\",\n \"One solution is to use a memory-map file format to access language model files in LVCSR system.\",\n \"Accessing the language model files using memory-map file format is slower than loading the language model files directly into memory.\",\n \"In addition, because a LVCSR system accesses language model files randomly, searching such a big space randomly also costs much time.\",\n \"In short, the large size of language model files in a LVCSR system can negatively impact the system performance in terms of memory requirement and run-time speed.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be more fully understood by reference to the accompanying drawings, in which: FIG.\",\n \"1 is a block diagram of one embodiment of a speech recognition system according to the teachings of the present invention; FIG.\",\n \"2 is a diagram illustrating an HMM-based phone model; FIG.\",\n \"3 is a diagram illustrating an N-gram language model; FIG.\",\n \"4 shows a flow diagram of one embodiment of a method according to the teachings of the present invention; FIG.\",\n \"5 shows a block diagram of one embodiment of a method according to the teachings of the present invention; FIG.\",\n \"6 illustrates a flow diagram of one embodiment of a modified K-means clustering process according to the teachings of the present invention; FIG.\",\n \"7 provides a graphical illustration of the segment/cluster initialization according to the teachings of the present invention; FIG.\",\n \"8 provides a graphical illustration of a centroid (central point) of a segment; and FIG.\",\n \"9 provides a graphical illustration of a segment refinement according to the teachings of the present invention.\",\n \"DETAILED DESCRIPTION In the following detailed description numerous specific details are set forth in order to provide a thorough understanding of the present invention.\",\n \"However, it will be appreciated by one skilled in the art that the present invention may be understood and practiced without these specific details.\",\n \"In the discussion below, the teachings of the present invention are utilized to implement a method, apparatus, system, and machine-readable medium for building a compact language model for a speech recognition system.\",\n \"In one embodiment, a set of N-gram probabilistic attributes that represent conditional probabilities of a set of words in an N-gram language model is classified into a plurality of classes based upon a relative order of the respective N-gram probabilistic attributes.\",\n \"Each resultant class is then clustered into a plurality of segments or clusters to build a corresponding codebook for the respective class using a modified K-means clustering process which dynamically adjusts the size and the centroid of each segment during each iteration in the modified K-means clustering process.\",\n \"In one embodiment, the modified K-means clustering process is performed until one or more optimization criteria are met.\",\n \"In one embodiment, after the codebook for the respective class has been built, each N-gram probabilistic attribute in the respective class can be represented by the centroid of the corresponding segment to which the respective N-gram probabilistic attribute belongs.\",\n \"For example, after a corresponding codebook has been built for a class of uni-gram probability values, a probability value associated with a given uni-gram node can be represented by a corresponding codeword in the respective codebook which can be referenced by a corresponding index value.\",\n \"In one embodiment, an N-gram probabilistic attribute is represented by a first number of data bits prior to the construction of the corresponding codebook.\",\n \"After the construction of the corresponding codebook, the respective N-gram probabilistic attribute can be represented by a corresponding index value having a second number of data bits which is smaller than the first number of data bits.\",\n \"In one embodiment, an N-gram probabilistic attribute corresponds to an N-gram probability value or an N-gram back-off weight.\",\n \"In one embodiment, the N-gram language model can be a tri-gram language model and the plurality of class can include a first class corresponding to a set of uni-gram probability values, a second class corresponding to a set of uni-gram back-off weights, a third class corresponding to a set of bi-gram probability values, a fourth class corresponding to a set of bi-gram back-off weights, and a fifth class corresponding to a set of tri-gram probability values.\",\n \"In one embodiment, the clustering of each class of probabilistic attributes is performed as follows.\",\n \"First, the plurality of segments are initialized such that all segments have equivalent areas.\",\n \"The centroid for each segment is set such that the area of the respective segment is approximately equally split based on the corresponding centroid.\",\n \"A set of clustering operations is then performed iteratively until one or more optimization criteria are met to create a corresponding codebook for the respective class of probabilistic attributes.\",\n \"During each iteration, a total deviation of the plurality of segments is computed.\",\n \"The edge of each segment is then replaced by the arithmetic average of the nearest two centroids.\",\n \"A new centroid is then set for each resultant segment such that each resultant segment is approximately equally split by the corresponding centroid.\",\n \"A new total deviation of the resultant segments is then computed.\",\n \"In one embodiment, the one or more optimization criteria are met (e.g., the total deviation becomes steady) if one of the following conditions is satisfied: a) For each segment, the new edge value equals the previous edge value.\",\n \"In other words, if the arithmetic average of the nearest two centroids equals the previous edge value then the total deviation is considered steady; b) A predetermined number of iterations is reached; or c) A change of total deviation is less than a predetermined threshold.\",\n \"The teachings of the present invention are applicable to any method, apparatus, and system for speech recognition that employs N-gram language models.\",\n \"However, the present invention is not limited to N-gram language models in speech recognition systems and can be applied to the other types of language modeling in speech recognition.\",\n \"In addition, the present invention can also be applied to data modeling in other fields or disciplines including, but not limited to, image processing, signal processing, geometric modeling, computer-aided-design (CAD), computer-aided-manufacturing (CAM), etc.\",\n \"FIG.\",\n \"1 illustrates a block diagram of one embodiment of a speech recognition system 100 according to the teachings of the present invention.\",\n \"The system 100, as shown in FIG.\",\n \"1, includes an analog to digital converter (A/D) 110, a feature extractor or spectral analysis unit 120, a decoder 130, an acoustic model 140, and a language model 150.An input signal 105 representing the input speech is first digitized using the A/D 110.In one embodiment, the digital signal is then sliced up into frames typically of 10, 15, or 20 ms. Each frame of the signal is then converted into a corresponding feature vector which is used to characterize the spectral properties of the input signal.\",\n \"In one embodiment, the feature vector is multi-dimensional and has a plurality of feature components.\",\n \"The feature vectors generated by the feature extractor unit 120 are then inputted into the decoder 130 which determines the sentence or sequence of words that has the highest probability given the acoustic events characterized by the feature vectors, based upon the acoustic model 140 and the language model 150.The language model 150, in one embodiment, is an N-gram language model which includes a plurality of codebooks.\",\n \"Each codebook corresponds to a class of probabilistic attributes (e.g., uni-gram probability values, uni-gram back-off weights, bi-gram probability values, etc.)\",\n \"that are used to represent various conditional probabilities of a set of words.\",\n \"For example, one of the codebook may correspond to the uni-gram probability class, another codebook may correspond to the uni-gram back-off weight class, and so on.\",\n \"The language model 150 and the construction of the corresponding codebooks are described in greater detail below.\",\n \"FIG.\",\n \"2 illustrates a diagram of one embodiment of an HMM-based phone model structure used in the acoustic model 140 to model a phonetic unit (e.g., a phoneme or a subword unit, etc.).\",\n \"Each individual phonetic unit is represented or modeled by a corresponding HM.\",\n \"As shown in FIG.\",\n \"2, an “MM has a set of sequence of states (1-5) that are connected by a set of transition probabilities (a12, a23, a34, a45), and a set of observation probabilities or likelihoods (b2 (o1),b2(o2),b3(o3),b4(o4),b4(o5),b4(o6)).\",\n \"Each transition probability aij represents the probability of transitioning from a state i to a state j.\",\n \"Each observation probability or distribution bi(oj) represents the probability of an observation vector oj being generated from a state i.\",\n \"Thus, the transition probabilities model the durational variability in speech and the output probabilities model the spectral variability.\",\n \"Accordingly, the set of states, the set of transition probabilities and the set of output probabilities are the parameters that are used to define an HMM.\",\n \"The HMM shown in FIG.\",\n \"2 has a left-right topology.\",\n \"In many modern speech recognition systems, each state output distribution or observation probability function is modeled by a multivariate mixture Gaussian as follows: b j ( o t ) = ∑ k = 1 M c jk N ( o t , m jk , V jk ) where cjk is the weight of mixture component k in state j and N(oi, mjk, Vjk) denotes a multivariate Gaussian of mean mjk and covanance Vjk for the kth mixture component in state j.\",\n \"FIG.\",\n \"3 shows a structure diagram of one embodiment of an N-gram language model.\",\n \"As described above, the purpose of a language model is to provide a mechanism for estimating the probability of some word, wk, in an utterance given the preceding words, W1k-1=w1 .\",\n \".\",\n \".\",\n \"wk1.An N-gram language model assumes that wk depends only on the preceding N-1 words, that is P ( w k ❘ W 1 k - 1 ) = P ( w k ❘ W k - n + 1 k - 1 ) .\",\n \"Because of the very large amount of models and associated data that need to be stored and processed, N is usually limited to two (for a bi-gram or 2-gram language model) or three (for a tri-gram or 3-gram language model).\",\n \"A back-off mechanism can be used to compute a conditional probability of a given word when some N-gram context (e.g., a tri-gram or a bi-gram) does not exist or cannot be found for the given word.\",\n \"For example, for given words “a” “b” “c”, there may be no bi-gram probability for “b→a” or tri-gram probability for “c→b→a” in certain contexts.\",\n \"In this case, a back-off mechanism is used to compute the bi-gram or tri-gram probability for the given word “a”.\",\n \"For example, for a tri-gram of words “c→b→a” (meaning word “a” preceded by word “b” preceded by word “c”), the corresponding tri-gram and bi-gram probabilities of this word sequence can be computed as follows using a back-off mechanism: P ( a / b , c ) = { P ( a / b , c ) , if P ( a / b , c ) exists , P ( a / b ) × w ( b , c ) , if w ( b , c ) exists , P ( a / b ) otherwise } P ( a / b ) = { P ( a / b ) , if P ( a / b ) exists , P ( a ) × w ( b ) otherwise } where: P(a/b,c) represents the tri-gram probability of the tri-gram c→b→a; P(a/b) represents the bi-gram probability of the bi-gram b→a; P(a) represents the uni-gram probability of word a; w(b,c) represents the back-off weight for the bi-gram c→b; and w(b) represents the back-off weight for the word b.\",\n \"In various LVCSR systems, language model look-head techniques can be used to speed up the search in the corresponding N-gram language model.\",\n \"The look-head techniques are used to incorporate the language model probabilities as early as possible in the pruning process of the beam search.\",\n \"In general, look-head probabilities are pre-computed and stored in certain file formats or data structures.\",\n \"Referring to FIG.\",\n \"3, an N-gram language model in a typical LVSR system can be logically represented as a set of nodes 300 which includes a set of uni-gram nodes 310, a set of bi-gram nodes 320, and so on.\",\n \"The uni-gram nodes are used to represent single words and their associated probability data (e.g., probability value and back-off weight).\",\n \"The bi-gram nodes are used to represent word pairs and their associated probability data, etc.\",\n \"In one embodiment, the second words in the bi-gram nodes that follow the same first word in a uni-gram node can be grouped together and point them to the corresponding first word in the uni-gram node.\",\n \"Thus, only the second words and the corresponding bi-gram probability data need to be stored in the bi-gram nodes.\",\n \"Tri-gram nodes can be structured similarly.\",\n \"For example, all the third words in the tri-gram nodes that follow the same bi-gram node can be grouped together and point to the corresponding bi-gram node.\",\n \"Thus, only the third words and their associated probability data need to be stored in the tri-gram nodes.\",\n \"As shown in FIG.\",\n \"3, each uni-gram node can be linked to its corresponding bi-gram nodes via a pointer.\",\n \"Similarly, each bi-gram node can be linked to its corresponding tri-gram nodes via a pointer, and so on.\",\n \"In other words, each uni-gram node points to the head of a set of bi-gram nodes whose words follow the word stored in the respective uni-gram node, each bi-gram node points to the head of a set of tri-gram nodes, and so on.\",\n \"Each n-gram node (e.g., uni-gram node, bi-gram node, tri-gram node, etc.)\",\n \"typically has the following components: the word identity of the word that the respective node represents (which can be the word itself or a word index corresponding to the word), an n-gram probability value, a back-off weight, and a pointer to the head of the corresponding (n+1)-gram nodes.\",\n \"For example, a uni-gram node typically contains an index value of a particular word that is represented by the respective uni-gram node, a uni-gram probability value, a uni-gram back-off weight, and a pointer to a corresponding set of bi-gram nodes that are linked with the respective uni-gram node.\",\n \"In one embodiment, as described above, each n-gram node only needs to store the last word of the corresponding n-gram.\",\n \"For example, a bi-gram node only needs to store the second word of the corresponding bi-gram that the respective bi-gram node represents, a tri-gram node only needs to store the third word of the corresponding tri-gram that the respective tri-gram node represents, and so on.\",\n \"In general, for computational efficiency and to avoid numerical underflow, probability values and back-off weights associated with the n-gram nodes can be represented in logarithmic space.\",\n \"A n-gram node may be represented by various data structures depending upon the particular implementations and applications of the language model.\",\n \"For example, an n-gram node may be represented by a corresponding data structure as shown below: typedef struct _asNGram{ unsigned short WID; float P; int PTR; float W; } asNGram; where: WID is an index of the word W that this node represents; P and W are the corresponding probability value and back-off weight, respectively; PTR is a pointer that points to the (n+1)-gram area linked by this node.\",\n \"If there is no (n+1)-gram linked with this node, PTR can be set to a pre-defined value.\",\n \"In this example, the word index WID is an unsigned 16-bit value (e.g., unsigned short data type); the probability value P and the back-off weight are 32-bit float values (e.g., 32-bit float data type); and the PTR is a 32-bit integer value.\",\n \"The whole size of the data structure in this example is therefore 112 bits or 14 bytes.\",\n \"An example of a data structure that can be used to represent a look-head node is shown below: typedef struct _asTreeBi-gramt{ int NODENO; float P; } asTreeBi-gram; In this example, the NODENO is a 32-bit index of the corresponding node and P is a 32-bit probability value.\",\n \"It can be understood from the above description that a typical language model for a LVCSR system can contain a very large number of nodes each of which may contain corresponding probability value and/or backup weight that are represented by very large number of data bits (e.g., probability value and back-off weight are 32-bit float values in the above examples).\",\n \"Thus, a language model for a typical LVCSR requires a very large amount of memory space.\",\n \"As discussed above and described in more details below, the present invention provides a method and mechanism for reducing the size of the language model and the access time while maintaining a high level of recognition accuracy.\",\n \"According to the teachings of the present invention, a method is introduced and described in detail herein to reduce the size of a language model in a LVCSR system.\",\n \"In one embodiment, the probability values and back-off weights (also referred to as probabilistic attributes herein) associated with the respective n-gram nodes in the respective language model are quantized or clustered by a modified K-means clustering algorithm to compress the size of the respective language model.\",\n \"In one embodiment, the probability values or back-off weights are divided or grouped into separate classes or groups based on the relative n-th order of the corresponding n-gram nodes and a modified K-means clustering algorithm is applied to each class to cluster the probability values or back-off weights in each class to build a corresponding codebook for the respective class.\",\n \"For example, uni-gram probability values associated with uni-gram nodes are grouped into one class, uni-gram back-off weights are grouped into another class, bi-gram probability values are grouped into yet another class, and so on.\",\n \"Thus, for a tri-gram language model (which includes uni-gram nodes, bi-gram nodes, and tri-gram nodes), there can be five separate classes (also referred to as data classes herein) that can be quantized or clustered to reduce the size of the language model.\",\n \"These classes include a uni-gram probability class, a uni-gram back-off weight class, a bi-gram probability class, a bi-gram back-off weight class, and a tri-gram probability class.\",\n \"For each class, the field of probability values (also referred to as the range of probability values) is quantized or clustered into a plurality of clusters or segments using a modified K-means clustering algorithm described in more detail below.\",\n \"A centroid is defined for each cluster or segment.\",\n \"Thus, a separate codebook can be constructed for each class of probability values or each class of back-off weights.\",\n \"After quantization or clustering, a given probability value or back-off weight can be represented by the centroid (also called codeword) of the corresponding segment or cluster to which the respective probability value or back-off weight belongs.\",\n \"By quantizing or clustering the field of probability values in each class, the probability values or back-off weights (which originally were represented by large-size data types such as 32-bit float type) can now be represented by smaller-size index values such as 8-bit char type that points to the corresponding codeword (centroid) in the corresponding codebook.\",\n \"In one embodiment, the field of probability value for each class is divided into 256 segments or clusters using the modified K-means clustering process described in greater details below.\",\n \"As such, the corresponding codebook will have 256 codewords.\",\n \"Each codeword can be referenced by an 8-bit index value.\",\n \"Thus, assuming that the original probability values or back-off weights use 32-bit float type, these probability values or back-off weights can now be replaced by 8-bit index values which are used to reference the corresponding codewords in the codebook.\",\n \"It should be appreciated and understood by one skilled in the art that the teachings of the present invention are not limited to any particular number of segments or clusters.\",\n \"Similarly, the teachings of the present invention are not limited to any particular data types that are used to represent the probability values and back-off weights before and after the quantization.\",\n \"The number of segments or clusters for each class (hence the size of the corresponding codebook) and the data types that are used to represent the probability values, the back-off weights, or the indices to the codebook can vary depending upon the particular applications and implementations of the present invention.\",\n \"FIG.\",\n \"4 illustrates a flow diagram of one embodiment of a method 400 according to the teachings of the present invention.\",\n \"At block 410, the probabilistic attributes (e.g., the probability values and back-off weights) in a N-gram language model are classified or grouped into a plurality of separate classes.\",\n \"For example, in a tri-gram language model that includes uni-gram nodes, bi-gram nodes, and tri-gram nodes, the probabilistic attributes can be classified into five separate classes as follows: uni-gram probability, uni-gram back-off weight, bi-gram probability, bi-gram back-off weight, and tri-gram probability.\",\n \"At block 420, the field of value for each class is clustered or quantized using a modified K-means clustering process to build a corresponding codebook for the respective class.\",\n \"The modified K-means clustering process is described in more details below.\",\n \"At block 430, each probabilistic attribute (e.g., a probability value or a back-off weight) can be represented by the corresponding codeword in the respective codebook.\",\n \"In one embodiment, as described herein, after quantization or clustering, the probability value or back-off weight for any given node in the language model can then be replaced by a corresponding index value that is used to reference the corresponding codeword.\",\n \"For example, assuming that the original probability value or back-off weight for a given node was 32-bit data type (e.g., 32-bit float value) and that there are 256 codewords in the corresponding codebook, then after quantization or clustering, the respective probability value or back-off weight for the given node can be represented by an 8-bit index value which is used to reference or point to the corresponding codeword in the codebook.\",\n \"FIG.\",\n \"5 shows a block diagram of one embodiment of a method according to teachings of the present invention.\",\n \"As shown in FIG.\",\n \"5, the probabilistic attributes (e.g., probability values and back-off weights) 510 in an N-gram language model are classified or grouped into separate classes based on the n-gram order of the respective nodes.\",\n \"In this example, the classes include: uni-gram probability 520A, uni-gram back-off weight 520B, bi-gram probability 520C, bi-gram back-off weight 520D, tri-gram probability 520E, etc.\",\n \"Each class is then clustered or quantized using a modified K-means clustering process to create a corresponding codebook (e.g., 530A-E) for each respective class.\",\n \"As described herein, the size of the codebook for each class may or may not be the same, depending on the particular applications and implementations of the present invention.\",\n \"Each probabilistic attribute (e.g., a uni-gram probability value associated with a uni-gram node) can then be represented by a corresponding codeword in the respective codebook (e.g., the codebook for the uni-gram probability class).\",\n \"FIG.\",\n \"6 illustrates a flow diagram of one embodiment of a modified K-means clustering process 600 to create a corresponding codebook for a probabilistic class (e.g., uni-gram probability class or bi-gram probability class, etc.\",\n \"), according to the teachings of the present invention.\",\n \"The process starts at block 601 and proceeds to block 605 to initialize the codebook as follows: At block 605: initialization of the process is performed by clustering the field of values for the respective class into a plurality of segments (e.g., n segments in this example) and initialize the segments such that all the segments have equivalent areas.\",\n \"The segments are also called clusters herein.\",\n \"The centroid of each segment is then set such that the respective segment is about equally split (i.e., the segment can be split into two equivalent sub-areas by the corresponding centroid).\",\n \"As shown in FIGS.\",\n \"7 and 8, the segment initialization is performed according to the following conditions: E 1 = min ( x ) , E 2 … E n , E n + 1 = max ( x ) , C 1 , C 2 … C n - 1 , C n ∫ E 1 E 2 P ( x ) ⅆ x = ∫ E 2 E 3 P ( x ) ⅆ x = … = ∫ E n - 1 E n P ( x ) ⅆ x = ∫ E n E n + 1 P ( x ) ⅆ x ∫ E i C i P ( x ) ⅆ x = ∫ C i E i + 1 P ( x ) ⅆ x i = 1 , 2 … n Where: x is a possible probability value in the respective class; P(x) is the probability that x occurs; the i segment is defined as [Ei, Ei+1; and Ci is defined as the centroid of the i segment.\",\n \"At this point, there are n segments or clusters which have equivalent areas and each i segment has a corresponding centroid Ci which can split the respective segment into two equivalent sub-areas.\",\n \"Set the number of iterations R=0 At block 610: compute the total deviation Dev as sum of the deviation of each segment Devi as follows: Dev=ΣDevi.\",\n \"for the i segment, Devi is defined as ∫ E i E i + 1 P ( x ) * abs ( x - C i ) ⅆ x , (illustrated in FIG.\",\n \"8) At block 615: replace the edge Ei of each segment by the arithmetic average of the nearest two centroids as shown below: Ei=(Ci-1+Ci)/2 (illustrated in FIG.\",\n \"9) set the new centroid Ci for each resultant segment compute the new total deviation Dev increment the number of iterations R=R+1 At block 625: if the total deviation is not steady, then the process 600 loops back to block 615.Otherwise, the corresponding codebook is obtained at block 635 and the process 600 proceeds to ends at block 691.In one embodiment, the total deviation is considered steady if one of the following conditions (also called optimization criteria) is met: a.\",\n \"For each i, Ei=Ei (the new edge value is the same as the previous edge value); b.\",\n \"The number of iterations performed reaches a predetermined number (R=Rmax); or c. The change of total deviation is less than a pre-determined threshold value Δth, |Dev−Dev|/Dev<Δth Significant reduction in memory requirement and access time for a language model can be attained according to the teachings of the present invention.\",\n \"For example, assuming that before compression or quantization, the following data structures were used for n-gram nodes and look-head nodes, respectively: n-gram node data structure (before compression): typedef struct _asNGram{ unsigned short WID; float P; int PTR; float W; } asNGram; where: WID (16-bit unsigned value) is an index of the word W that this node represents; P (32-bit float value) and W (32-bit float value) are the corresponding probability value and back-off weight, respectively, PTR (32-bit integer value) is a pointer that points to the (n+1)-gram area linked by this node.\",\n \"If there is no (n+1)-gram linked with this node, PTK is a pre-defined value.\",\n \"Thus the whole size of an-gram data structure in this example is 112 bits or 14 bytes.\",\n \"look-head node data structure (before compression): typedef struct _asTreeBi-gramt{ int NODENO; float P; } asTreeBi-gram; where: NODENO is a 32-bit index of the corresponding node and P is a 32-bit probability value.\",\n \"Thus the whole size of a look-head data structure is 64 bits.\",\n \"After compression, an n-gram node and a look-head node can be represented by the following data structures, respectively.\",\n \"It is assumed in this example that 8-bit codebooks are used (e.g., each codebook has 256 codewords): n-gram node data structure (after compression): typedef struct _asNGram{ unsigned short WID; unsigned char P; int PTR; unsigned char W; } asNGram; where: WID (16-bit unsigned value) is an index of the word W that this node represents; P (8-bit unsigned char type) is the index value used to reference the corresponding quantized probability value (codeword) in the corresponding codebook; W (8-bit unsigned char type) is the index value used to reference the corresponding quantized back-off weight (codeword) in the corresponding codebook; PTR (32-bit integer value) is a pointer that points to the (n+1)-gram area linked by this node.\",\n \"If there is no (n+1)-gram linked with this node, PTR is a pre-defined value.\",\n \"Thus the whole size of an n-gram data structure after compression in this example is 64 bits or 8 bytes.\",\n \"look-head node data structure (after compression): typedef struct _asTreeBi-gramt{ int NODENO; unsigned P; } asTreeBi-gram; where: NODENO is now an 8-bit index value that is used to reference the corresponding quantized probability value in the corresponding codebook.\",\n \"Thus the size of the look-head data structure after compression is 40 bits.\",\n \"From the above example, it can be seen that the size of the language model can be significantly reduced according to the teachings of the present invention.\",\n \"In this example, the size of each n-gram node is reduced from 112 bits to 64 bits and the size of each look-head node is reduced from 64 bits to 40 bits.\",\n \"For a language model in a typical LVCSR system which usually has a very large number of nodes, the reduction in memory requirement can be very substantial.\",\n \"The additional memory requirement for the codebooks is minimal or insignificant compared to the reduction in the memory requirement for the whole language model.\",\n \"For example, the memory requirement for an 8-bit codebook which has 256 codewords and each codeword is a 32-bit float value is only: 256(codewords)*32(bits/codeword)=8192 bits Tables 1 and 2 below show some experimental results based upon various experiments conducted according to the teachings of the present invention.\",\n \"These experiments were conducted on a 51K Mandarin LVCSR system and using a testing machine such as a double-PIII866 with 512M memory and 256K L2 Cache.\",\n \"Table 1 illustrates the improvements with respect to memory requirement and decoding speed using 8-bit codebooks (e.g., each codebook has 256 codewords).\",\n \"It can be seen from table 1 that the memory requirement and decoding speed have been reduced after compression while the increase in the word error rate (WER) of the system after compression is minimal or insignificant.\",\n \"The XRT notation in table 1 is used to mean times of real time.\",\n \"TABLE 1 System using BaseLine modified K-Means System (before clustering (after compression) compression) WER 10.0% 10.1% Tri-gram file size 130M 75M Treebi-gram file size 109M 68M MapMode XRT 1.18XRT 1.08XRT Loading directly mode 1.11XRT 1.02XRT XRT As shown in table 1, the experiments and comparisons were done to show the improvements with respect to two different embodiments: one embodiment using memory-map file format for the language model files and the other embodiment loading the language model files directly into memory.\",\n \"After quantization the size of the language model file is reduced by 40% from 239M(130M+109M) to 143M (75M+68M).\",\n \"In addition, the decoding speed has been improved by 8% from 1.18×RT to 1.08×RT using memory-map file format while WER only increases from 10.0% to 10.1%.\",\n \"Furthermore, if language model files are loaded directly to memory, the decoding speed can be improved by another 6%.\",\n \"Table 2 shows the experimental results using smaller-size codebooks.\",\n \"In this example, 6-bit codebooks and 4bit codebooks were used.\",\n \"TABLE 2 System using modified K-means clustering (after compression) 6-bit 4-bit codebooks codebooks WER 10.1% 12.8% MapMode XRT 1.07XRT 1.03XRT Loading directly 1.01XRT 0.98XRT mode XRT The invention has been described in conjunction with the preferred embodiment.\",\n \"It is evident that numerous alternatives, modifications, variations and uses will be apparent to those skilled in the art in light of the foregoing description.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10297354"}}},{"rowIdx":97,"cells":{"text":{"kind":"list like","value":[["Refrigeration unit","The refrigerating unit can be operated by means of a thermal solar system as energy source.","Therein it is provided that the refrigerating unit is formed as a diffusion-absorption refrigerating unit.","The refrigerating unit has an expeller, a triple heat exchanger, a condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir which are actively connected to form a closed fuel circuit with one another."],["1-12.Cancelled.","12.A refrigerating unit, which is formed as a diffusion-absorption refrigerating unit, comprising: a closed fuel circuit having a triple heat exchanger for preheating a solution which is high in fuel and precooling a solution which is low in fuel, and for rectification of a mixture of fuel and water vapor.","13.The refrigerating unit according to claim 12, further comprising a thermal solar system actively connected to an expeller formed as a gas bubble pump for the desorption and vaporization of a fuel contained in a solution.","14.The refrigerating unit according to claim 13, wherein the the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.","15.The refrigerating unit according to claim 13, wherein the the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.","16.The refrigerating unit according to claim 13, wherein the expeller has a plurality of parallel rising tubes spaced at a distance from one another for the conveyance of a solution which is high in fuel, where a parallel recycling line for the conveyance of the solution which is low in fuel is disposed between at least two rising tubes.","17.The refrigerating unit according to claim 13, further comprising a rising tube and wherein the expeller is actively connected, on an inlet side with respect to the rising tube, to a supply line, coming from the triple heat exchanger, for the conveyance of the solution which is high in fuel, on the outlet side with respect to the rising tube, to a fuel vapor supply line leading to the triple heat exchanger, and, on the outlet side with respect to the recycling line, to a supply line, leading to the triple heat exchanger, for the conveyance of the solution which is low in fuel.","18.The refrigerating unit according to claim 17, wherein the fuel vapor supply line leads essentially coaxially through the recycling line.","19.The refrigerating unit according to claim 13, further comprising a rising tube having an inner structure promoting the formation of bubbles.","20.The refrigerating unit according to claim 12, wherein the fuel is ammonia (NH3) and the solution a mixture of ammonia and water (NH3/H2O).","21.The refrigerating unit according to claim 13, wherein the thermal solar system is actively connected over an entire longitudinal extension of the rising tube of the expeller.","22.The refrigerating unit according to claim 13, further comprising at least one of an absorber and an evaportator having conveyance lines, wherein the conveyance lines have upper free ends with a corresponding capillary sleeve 23.The refrigeration unit of claim 12, where the closed fuel circuit comprises an expeller condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir which are actively connected to one another to form a closed fuel circuit.","24.The refrigerating unit according to claim 23, further comprising a thermal solar system actively connected to an expeller formed as a gas bubble pump for the desorption and vaporization of a fuel contained in a solution.","25.The refrigerating unit according to claim 23, wherein the the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.","26.The refrigerating unit according to claim 23, wherein the the expeller has at leapt one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.","27.The refrigerating unit according to claim 12, wherein the expeller has a plurality of parallel rising tubes spaced at a distance from one another for the conveyance of a solution which is high in fuel, where a parallel recycling line for the conveyance of the solution which is low in fuel is disposed between at least two rising tubes.","28.The refrigerating unit according to claim 23, further comprising a rising tube and wherein the expeller is actively connected, on an inlet side with respect to the rising tube, to a supply line, coming from the triple heat exchanger, for the conveyance of the solution which is high in fuel, on the outlet side with respect to the rising tube, to a fuel vapor supply line leading to the triple heat exchanger, and, on the outlet side with respect to the recycling line, to a supply line, leading to the triple heat exchanger, for the conveyance of the solution which is low in fuel.","29.The refrigerating unit according to claim 28, wherein the fuel vapor supply line leads essentially coaxially through the recycling line.","30.The refrigerating unit according to claim 23, further comprising a rising tube having an inner structure promoting the formation of bubbles.","31.The refrigerating unit according to claim 23, wherein the fuel is ammonia (NH3) and the solution a mixture of ammonia and water (NH3/H2O).","32.The refrigerating unit according to claim 23, wherein the thermal solar system is actively connected over an entire longitudinal extension of the rising tube of the expeller.","33.The refrigerating unit according to claim 23, further comprising at least one of an absorber and an evaportator having conveyance lines, wherein the conveyance lines have upper free ends with a corresponding capillary sleeve 34.A refrigerating unit, which is formed as a diffusion-absorption refrigerating unit and can be operated by means of a thermal solar system as energy source, with an expeller, a triple heat exchanger, a condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir which are actively connected to one another to form a closed fuel circuit, wherein the refrigerating unit has, in the fuel circuit, a triple heat exchanger for preheating a solution which is high in fuel and precooling a solution which is low in fuel, and for the rectification of a mixture of fuel and water vapor.","35.A method for refrigerating a unit, the method comprising: forming a fuel circuit having a triple head exchanger; and preheating a solution which is high in fuel, precooling a solution which is low in fuel, and rectifying a mixture of fuel and water vapor."],["<SOH> BACKGROUND <EOH>The invention relates to a refrigerating unit, which can be operated by means of a thermal solar system as energy source, according to the preamble of claim 1 .","Refrigerating units of the type addressed here, such as, for example, absorption refrigerating units or compression refrigerating units, are known.","For solar operation, these absorption refrigerating units disadvantageously require a high outlay with regard to control technology and investment, in particular with regard to a continuous reheating or heat storage.","In view of this, absorption refrigerating units are limited to a relatively narrow temperature and flow range.","Also the known, photovoltaically operated compression refrigerating units are characterized by a high outlay with regard to investment and have relatively low efficiency.","These known refrigerating units are not suited to problem-free and economical operation with thermal solar systems, in particular in the average capacity range."],["<SOH> SUMMARY OF THE INVENTION <EOH>It is the objective of the invention to provide a refrigerating unit of the type stated initially which can be operated in a reliable, effective, and operation-friendly manner by means of a thermal solar system, in particular in the lower to average refrigerating capacity range.","For the realization of this objective, a refrigerating unit with the features of claim 1 is proposed which is distinguished by the fact that the refrigerating unit is formed as a diffusion-absorption refrigerating unit.","A diffusion-absorption refrigerating unit can be operated in a particularly reliable and efficient manner by means of a thermal solar system as an energy source.","This behavior, which is favorable to operation, can also be achieved in a smaller to average refrigerating capacity range.","A diffusion-absorption refrigerating unit is advantageously suitable to be operated by means of various energy sources.","Among these, a thermal solar system as well as another heat transfer medium circuit, e.g.","from a heat recovery process, can be used for the alternative or enhancing energizing of the refrigerating unit.","A diffusion-absorption refrigerating unit is thus advantageously suitable, in a manner which is flexible and favorable for operation, to be energized with thermal energy by means of a thermal solar system as well as, if needed or desired, additional, different energy sources.","The refrigerating unit advantageously has an expeller, a triple heat exchanger, a condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir, which are actively connected to one another to form a closed fuel circuit.","The refrigerating unit characterized by a closed fuel circuit can be formed as a hermetically closed, compact unit which is distinguished by an advantageous independence of site.","It is operated merely by means of thermal energy and thus advantageously needs no electrical power supply.","Since no components working mechanically within the refrigerating unit, such as, for example, pumps, are required to operate the refrigerating unit, the unit is maintenance-friendly, relatively favorable from the standpoint of cost, and can be operated, at least nearly, without noise.","Furthermore, it is possible to develop the refrigerating unit so that the mounting of several refrigerating units in parallel can be realized in a relatively simple manner.","Preferably, the thermal solar system can be actively connected to an expeller formed as a gas bubble pump for the desorption and vaporization of a fuel contained in a solution.","A gas bubble pump is particularly suitable for desorbing and vaporizing, in a manner which is effective and favorable for operation, a fuel contained in a solution such as, for example, ammonia (NH3) in an ammonia-rich solution.","Furthermore, a gas bubble pump permits an efficient heat transfer accomplished by means of a thermal energy source, which is a prerequisite for reliable and effective desorption and vaporization of the fuel (ammonia).","According to a preferred form of embodiment, the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.","The rising tube of the expeller formed as a gas bubble pump contains a solution which is high in fuel and which, due to the vaporization of the fuel in the rising tube, experiences an increase in volume so that it assumes an operating volume which is a multiple of the original volume value, i.e.","of the still not vaporized fuel.","Due to this increase in volume, the level of the vaporous fuel, or of the fuel mixture in the rising tube, rises to a corresponding operational conveyance height.","If this operational conveyance height exceeds the length of the rising tube due to a corresponding increase in volume of the fuel mixture or a vaporization of the fuel, the conveyance of the vaporous fuel, or a remaining solution which is low in fuel, to additional functional units of the refrigerating unit is started, said functional units being actively connected to one another in the form of a closed fuel circuit so that the refrigerating unit is activated at this moment in its operation.","In so doing, an effective heat transfer from a thermal energy source (solar system) into the expeller or into the rising tube serves for a reliable and rapid activation of the refrigerating unit.","This is guaranteed by means of a suitable ribbing of the rising tube whereby an enlargement of the heat transfer surface to improve the heat transfer into the rising tube is obtained.","Instead of ribbing, deflecting plates can also be provided.","Advantageously, the expeller has a plurality of parallel rising tubes spaced at a distance from one another for the conveyance of a solution which is high in fuel, where a parallel recycling line for the conveyance of the solution which is low in fuel is disposed between at least two rising tubes.","This makes possible an expeller formation which is compact and has the form of a bundle of tubes, where advantageously the rising tubes disposed externally can be energized with thermal energy, in a manner favorable to efficiency and operation, by means of a thermal energy source (solar system) while the interposed, parallel recycling line, through which a heated solution which is low in fuel is conveyed, makes possible an additional heating of the outer rising tubes, or counteracts a cooling of the same.","The amount of heat radiating, and thus not actively utilized, is reduced in an effective manner due to a compact arrangement of the outer rising tubes as a bundle of tubes and a centrally disposed recycling line.","Preferably, the expeller is actively connected, on the inlet side with respect to the rising tube, to a supply line coming from the triple heat exchanger for the conveyance of the solution which is high in fuel, on the outlet side with respect to the rising tube, to a fuel vapor supply line leading to the triple heat exchanger, and, on the outlet side with respect to the recycling line, to a supply line leading to the triple heat exchanger for the conveyance of the solution which is low in fuel.","The expeller preferably having a compact bundle of tubes is thus actively connected, on the inlet side as well as on the outlet side, to the triple heat exchanger which in turn is actively connected to additional functional units of the refrigerating unit to form a closed fuel circuit.","In so doing, a solution which is high in fuel, a solution which is low in fuel, and fuel vapor are conveyed in the expeller after activation of the refrigerating unit.","Advantageously, the fuel vapor supply line leads essentially coaxially through the recycling line.","An expeller of this type is formed particularly compactly and is distinguished by a particularly effective and reliable desorption and vaporization of a fuel in a solution which is high in fuel, said solution being contained in the respective rising tube, since an undesirable radiation of heat from the expeller into the environment can be reduced to a significant extent due to its compact arrangement as a bundle of tubes.","Advantageously, the rising tube has an inner structure promoting the formation of bubbles.","An inner structure of this type in the rising tube can, for example, be achieved by means of a coating and/or a roughening of the inner surface and serves for the desired bubble formation in a solution which is high in fuel in a definite area in the rising tube due desired turbulence of the same solution, said turbulence being caused by the inner structure.","The expeller formed as a gas bubble pump is suitable, with the use of rising tubes of this type, for a particularly effective desorption, vaporization, and conveyance of fuel contained in a solution which is high in fuel and for the conveyance of a solution which is low in fuel.","Advantageously, the fuel is ammonia (NH3) and the solution a mixture of ammonia and water (NH3/H 2 O).","NH3 as fuel and a mixture of NH3 and H 2 O as solution are particularly suited to an effective operation of the refrigerating unit according to the invention.","Along with this, an auxiliary gas, used, if needed or desired, for the operation of the refrigerating unit, can be helium (He).","According to a preferred form of embodiment, the thermal solar system is actively connected over the entire longitudinal extension of the rising tube of the expeller to the same.","By means of heating of the rising tube over its entire longitudinal extension, it is avoided in a reliable manner that, due to an undesired cooling in an unheated area of the rising tube, vaporous NH3, already expelled, condenses and thus cancels an intended increase in volume of the fuel contained in the rising tube, where the increase in volume would lead to the starting of the conveyance of the fuel, or the solution which is low in fuel.","In this, the rising tubes are preferably each provided on the inlet side with a ribbing for the heating of the triple heat exchanger, of a fuel reservoir, and of a supply line leading to the condenser (vapor line).","Additional advantageous developments of the invention follow from the description."],["RELATED APPLICATIONS The present application is the U.S. National Phase of PCT Application PCT/EP01/06412, filed Jun.","6, 2001, which claims priority to German Patent Application No.","10028543.0, filed Jun.","8, 2000.BACKGROUND The invention relates to a refrigerating unit, which can be operated by means of a thermal solar system as energy source, according to the preamble of claim 1.Refrigerating units of the type addressed here, such as, for example, absorption refrigerating units or compression refrigerating units, are known.","For solar operation, these absorption refrigerating units disadvantageously require a high outlay with regard to control technology and investment, in particular with regard to a continuous reheating or heat storage.","In view of this, absorption refrigerating units are limited to a relatively narrow temperature and flow range.","Also the known, photovoltaically operated compression refrigerating units are characterized by a high outlay with regard to investment and have relatively low efficiency.","These known refrigerating units are not suited to problem-free and economical operation with thermal solar systems, in particular in the average capacity range.","SUMMARY OF THE INVENTION It is the objective of the invention to provide a refrigerating unit of the type stated initially which can be operated in a reliable, effective, and operation-friendly manner by means of a thermal solar system, in particular in the lower to average refrigerating capacity range.","For the realization of this objective, a refrigerating unit with the features of claim 1 is proposed which is distinguished by the fact that the refrigerating unit is formed as a diffusion-absorption refrigerating unit.","A diffusion-absorption refrigerating unit can be operated in a particularly reliable and efficient manner by means of a thermal solar system as an energy source.","This behavior, which is favorable to operation, can also be achieved in a smaller to average refrigerating capacity range.","A diffusion-absorption refrigerating unit is advantageously suitable to be operated by means of various energy sources.","Among these, a thermal solar system as well as another heat transfer medium circuit, e.g.","from a heat recovery process, can be used for the alternative or enhancing energizing of the refrigerating unit.","A diffusion-absorption refrigerating unit is thus advantageously suitable, in a manner which is flexible and favorable for operation, to be energized with thermal energy by means of a thermal solar system as well as, if needed or desired, additional, different energy sources.","The refrigerating unit advantageously has an expeller, a triple heat exchanger, a condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir, which are actively connected to one another to form a closed fuel circuit.","The refrigerating unit characterized by a closed fuel circuit can be formed as a hermetically closed, compact unit which is distinguished by an advantageous independence of site.","It is operated merely by means of thermal energy and thus advantageously needs no electrical power supply.","Since no components working mechanically within the refrigerating unit, such as, for example, pumps, are required to operate the refrigerating unit, the unit is maintenance-friendly, relatively favorable from the standpoint of cost, and can be operated, at least nearly, without noise.","Furthermore, it is possible to develop the refrigerating unit so that the mounting of several refrigerating units in parallel can be realized in a relatively simple manner.","Preferably, the thermal solar system can be actively connected to an expeller formed as a gas bubble pump for the desorption and vaporization of a fuel contained in a solution.","A gas bubble pump is particularly suitable for desorbing and vaporizing, in a manner which is effective and favorable for operation, a fuel contained in a solution such as, for example, ammonia (NH3) in an ammonia-rich solution.","Furthermore, a gas bubble pump permits an efficient heat transfer accomplished by means of a thermal energy source, which is a prerequisite for reliable and effective desorption and vaporization of the fuel (ammonia).","According to a preferred form of embodiment, the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.","The rising tube of the expeller formed as a gas bubble pump contains a solution which is high in fuel and which, due to the vaporization of the fuel in the rising tube, experiences an increase in volume so that it assumes an operating volume which is a multiple of the original volume value, i.e.","of the still not vaporized fuel.","Due to this increase in volume, the level of the vaporous fuel, or of the fuel mixture in the rising tube, rises to a corresponding operational conveyance height.","If this operational conveyance height exceeds the length of the rising tube due to a corresponding increase in volume of the fuel mixture or a vaporization of the fuel, the conveyance of the vaporous fuel, or a remaining solution which is low in fuel, to additional functional units of the refrigerating unit is started, said functional units being actively connected to one another in the form of a closed fuel circuit so that the refrigerating unit is activated at this moment in its operation.","In so doing, an effective heat transfer from a thermal energy source (solar system) into the expeller or into the rising tube serves for a reliable and rapid activation of the refrigerating unit.","This is guaranteed by means of a suitable ribbing of the rising tube whereby an enlargement of the heat transfer surface to improve the heat transfer into the rising tube is obtained.","Instead of ribbing, deflecting plates can also be provided.","Advantageously, the expeller has a plurality of parallel rising tubes spaced at a distance from one another for the conveyance of a solution which is high in fuel, where a parallel recycling line for the conveyance of the solution which is low in fuel is disposed between at least two rising tubes.","This makes possible an expeller formation which is compact and has the form of a bundle of tubes, where advantageously the rising tubes disposed externally can be energized with thermal energy, in a manner favorable to efficiency and operation, by means of a thermal energy source (solar system) while the interposed, parallel recycling line, through which a heated solution which is low in fuel is conveyed, makes possible an additional heating of the outer rising tubes, or counteracts a cooling of the same.","The amount of heat radiating, and thus not actively utilized, is reduced in an effective manner due to a compact arrangement of the outer rising tubes as a bundle of tubes and a centrally disposed recycling line.","Preferably, the expeller is actively connected, on the inlet side with respect to the rising tube, to a supply line coming from the triple heat exchanger for the conveyance of the solution which is high in fuel, on the outlet side with respect to the rising tube, to a fuel vapor supply line leading to the triple heat exchanger, and, on the outlet side with respect to the recycling line, to a supply line leading to the triple heat exchanger for the conveyance of the solution which is low in fuel.","The expeller preferably having a compact bundle of tubes is thus actively connected, on the inlet side as well as on the outlet side, to the triple heat exchanger which in turn is actively connected to additional functional units of the refrigerating unit to form a closed fuel circuit.","In so doing, a solution which is high in fuel, a solution which is low in fuel, and fuel vapor are conveyed in the expeller after activation of the refrigerating unit.","Advantageously, the fuel vapor supply line leads essentially coaxially through the recycling line.","An expeller of this type is formed particularly compactly and is distinguished by a particularly effective and reliable desorption and vaporization of a fuel in a solution which is high in fuel, said solution being contained in the respective rising tube, since an undesirable radiation of heat from the expeller into the environment can be reduced to a significant extent due to its compact arrangement as a bundle of tubes.","Advantageously, the rising tube has an inner structure promoting the formation of bubbles.","An inner structure of this type in the rising tube can, for example, be achieved by means of a coating and/or a roughening of the inner surface and serves for the desired bubble formation in a solution which is high in fuel in a definite area in the rising tube due desired turbulence of the same solution, said turbulence being caused by the inner structure.","The expeller formed as a gas bubble pump is suitable, with the use of rising tubes of this type, for a particularly effective desorption, vaporization, and conveyance of fuel contained in a solution which is high in fuel and for the conveyance of a solution which is low in fuel.","Advantageously, the fuel is ammonia (NH3) and the solution a mixture of ammonia and water (NH3/H2O).","NH3 as fuel and a mixture of NH3 and H2O as solution are particularly suited to an effective operation of the refrigerating unit according to the invention.","Along with this, an auxiliary gas, used, if needed or desired, for the operation of the refrigerating unit, can be helium (He).","According to a preferred form of embodiment, the thermal solar system is actively connected over the entire longitudinal extension of the rising tube of the expeller to the same.","By means of heating of the rising tube over its entire longitudinal extension, it is avoided in a reliable manner that, due to an undesired cooling in an unheated area of the rising tube, vaporous NH3, already expelled, condenses and thus cancels an intended increase in volume of the fuel contained in the rising tube, where the increase in volume would lead to the starting of the conveyance of the fuel, or the solution which is low in fuel.","In this, the rising tubes are preferably each provided on the inlet side with a ribbing for the heating of the triple heat exchanger, of a fuel reservoir, and of a supply line leading to the condenser (vapor line).","Additional advantageous developments of the invention follow from the description.","BRIEF DESCRIPTION OF THE DRAWINGS The invention is explained below in several embodiment examples with the aid of the accompanying drawings.","Shown are: FIG.","1 shows a block diagram of a refrigerating unit according to the invention; FIG.","2a shows a schematic representation of a first part of the refrigerating unit according to FIG.","1; FIG.","2b shows a schematic representation of a second part of the refrigerating unit according to FIG.","1; FIG.","3 shows an alternative form of embodiment of an expeller for the refrigerating unit according to FIG.","2; FIG.","4 shows a schematic representation of a conveyance line having a capillary sleeve on an enlarged scale.","DETAILED DESCRIPTION FIG.","1 shows a block diagram of a refrigerating unit 10.Furthermore, FIGS.","2a and 2b, which complement one another as partial figures, show the refrigerating unit 10 according to FIG.","1 in schematic representation.","The refrigerating unit 10 has an expeller 12 which is actively connected to a thermal solar system 11 by means of heat transfer medium lines represented as arrows 13 and 14 (FIG.","2a: 43, 43a, 43b, 44).","A fuel vapor supply line represented as an arrow 16 (FIG.","2a: 51) and a supply line, represented as an arrow 17 (FIG.","2a: 47) and serving to convey a solution which is low in fuel, leads from the expeller 12 to a triple heat exchanger 15, from which a supply line, represented as an arrow 18 (FIG.","2a: 48) and serving to convey a solution which is high in fuel, leads to the expeller 12.The triple heat exchanger 15 is actively connected to a condenser 19 by means of a supply line, represented as an arrow 20 (FIGS.","2a/2b: 55), for fuel vapor and, if needed or desired, with low percentages of water (H2O).","The condenser 19 is actively connected to a refrigerating medium circuit 21 by means of cold transfer medium lines, represented as arrows 22, 23 (FIG.","2b: 56, 57).","A supply line, represented as an arrow 25 (FIG.","2b: 58) for liquid fuel leads from the condenser 19 to an evaporator 24 which is actively connected to a refrigerating medium circuit 26 by means of cold transfer medium lines, represented as arrows 27, 28 (FIG.","2b: 60).","A supply line, represented as an arrow 30 (FIG.","2b: 59) for a gaseous mixture of vaporized fuel and an auxiliary gas leads from the evaporator 24 to a gas heat exchanger 29 which, in operation, is actively connected to the evaporator 24 by means of a supply line, represented as an arrow 31 (FIG.","2b: 76), for the precooled auxiliary gas.","By means of a supply line, for the heated gas mixture consisting of fuel and auxiliary gas and represented as an arrow 33 (FIG.","2b: 77), the gas heat exchanger 29 is actively connected to an absorber 32, from which a supply line, for warm auxiliary gas and represented as an arrow 34 (FIG.","2b: 61), leads to the gas heat exchanger 29.The absorber 32 is actively connected to a refrigerating medium circuit 35 by means of cold transfer medium lines represented as arrows 36, 37 (FIG.","2b: 63, 64).","A supply line, for a solution which is high in fuel and represented as an arrow 38 (FIGS.","2a/2b: 68), leads from the absorber 32 to a triple gas heat exchanger 15 and from the latter a supply line, for a solution which is low in fuel and represented as an arrow 39 (FIGS.","2a/2b: 69), leads to the absorber 32.The refrigerating unit 10 is divided, by means of a dotted line 40 according to arrow 42, into an upper area in which the total operational pressure is equal to the fuel pressure and, according to arrow 41, into a lower area in which the total operational pressure is equal to the sum of the fuel pressure and the auxiliary gas pressure.","Preferably the fuel is ammonia (NH3), the auxiliary gas is helium (He), and each of the solution which is high in fuel and the solution which is low in fuel is a mixture of ammonia and water (NH3/H2O).","NH3 vapor with low percentages of H2O is thus conveyed from the expeller 12 to the triple heat exchanger 15 (arrow 16), from which NH3 vapor flows into the condenser 19 (arrow 20) and is cooled to liquid NH3 where the liquid NH3 subsequently flows into the evaporator 24 (arrow 25) in which NH3 diffuses into a precooled He atmosphere forming a “heavy” cold He-NH3 gas mixture.","This cold gas mixture flows into the gas heat exchanger 29 (arrow 30) in which the same is heated due to a heat transfer from a warm He stream (arrow 34) flowing in the opposite direction through the gas heat exchanger 29 and subsequently flows from the absorber 32 to the absorber 32 (arrow 33).","The solution which is high in NH3/H2O flows on the contrary from the absorber 32 to the triple heat exchanger 15 (arrow 38) and from there to the expeller 12 (arrow 18).","The solution which is low in NH3/H2O flows on the contrary to the triple heat exchanger 15 (arrow 17) and from there to the absorber 32 (arrow 39).","Furthermore, the withdrawal of cooling capacity of the refrigerating unit 10 is done by means of the refrigerating medium circuit 26, which is actively connected to the evaporator 24.FIG.","2a shows in addition the expeller 12 preferably formed as a gas bubble pump, said expeller being actively connected to the thermal solar system 11 and to the triple heat exchanger 15.The thermal solar system 11 has a solar cell unit 72 in the form of a solar collector cell unit which is actively connected, by means of the heat transfer medium lines 43, 43a, 43b, and 44, to a plurality of rising tubes 45 (in FIG.","2a two rising tubes 45 are represented) of the expeller 12.The heat transfer medium lines 43, 43a, and 43b are connected to one another in operation by means of a change-over valve 78 in such a manner that a heat transfer medium is conveyed according to arrow 13 from the solar cell unit through the heat transfer medium line 43 to the change-over valve 78, which conducts the heat transfer medium through the heat transfer medium line 43a and/or 43b according to arrow 13a or 13b to the expeller 12.The rising tubes 45 have on one side a ribbing 50 (or deflecting plate not represented) in order to insure a rapid, spatially defined, and reliable heat transfer from the heat carrier of the solar cell unit 11 to the solution which is high in fuel, said solution being located in the rising tubes 45.Between the rising tubes 45 disposed in parallel at a distance from one another, a parallel recycling line 49 is disposed to convey a solution which is low in fuel.","The expeller 12 is thus formed as a compact bundle of tubes (rising tubes 45 for solution which is high in fuel, recycling line 49 for solution which is low in fuel).","The solution which is low in fuel is conducted, by means of a supply line 47, from the expeller 12 to the triple heat exchanger 15 and conducted from there to the absorber 32 by means of the supply line 69 (see also FIG.","2b).","The fuel vapor is conducted, by means of a conducting line 51, from the expeller 12 to the triple heat exchanger 15 in which water is condensed out from the mixture of fuel and water vapor and conducted, by means of the line 52, according to the arrow 53 to the supply line 48 which serves to convey the solution which is high in fuel into the expeller 12.Pure, or nearly pure, fuel is conducted, by means of the supply line 55, from the triple heat exchanger 15 to the condenser 19 (see also FIG.","2b).","The supply line 48 for conveying the solution which is high in fuel is actively connected to a fuel reservoir 54.A dotted line 70 denotes the level of liquid in the fuel reservoir 54 while a dotted line 71 represents the level of liquid in the inlet of the absorber 32 (see also FIG.","2b).","The expeller 12 is formed as a compact bundle of tubes with a plurality of cold transfer medium lines 65 and a plurality of auxiliary gas conveyance lines 62.Likewise, the gas heat exchanger 29, the evaporator 24, and the condenser 19 are each formed as a compact bundle of tubes.","The absorber 32 can however also be formed in such a manner that the cold transfer medium lines 65 are provided with intermediate spaces for the auxiliary gas conveyance lines 62 and preferably with deflecting plates.","To expel the fuel from the solution which is high in fuel as well as to convey the same, the expeller 12 needs a certain minimum supply of energy from the solar cell unit 72.A supply of energy into the expeller 12 below this limit would lead, when conveying the heat transfer medium into the expeller 12 through the heat transfer medium line 43a below the liquid level denoted as the dotted line 70, to undesirable reduction of the solution which is high in fuel without the same being conveyed.","With longer operation of the refrigerating unit in a state of this type, the solution which is high in fuel, said solution being located in the expeller 12, would be reduced still further in fuel so that higher and higher operating temperatures would be required in order to expel additional fuel from the solution which is high in fuel.","This has as a consequence that the refrigerating unit could no longer be put in operation without additional effort.","Providing a second heat transfer medium line 43b, which is actively connected to the expeller 12 above the liquid level denoted as the dotted line 70, advantageously makes it possible that, on starting the refrigerating unit, that energy which is not sufficient to expel the fuel from the solution which is high in fuel can still be used to preheat the expeller 12.Thereby it is avoided that a “high-value” energy has to be used to heat the expeller 12 (material of the tubes) so that this energy can be used exclusively for the conveyance of the solution which is high in fuel, said solution being located in the expeller 12, and to expel the fuel from the same.","Furthermore, the solution which is high in fuel can be preheated in the triple heat exchanger 15, the fuel reservoir 54, and in the supply line 55 (vapor line) which leads to the condenser 19 by means of “low-value” solar energy.","FIG.","3 shows an expeller 12 according to an alternative development.","This expeller 12 corresponds essentially to that of FIG.","2 and is different in that according to FIG.","3 the fuel vapor supply line 51 leads coaxially through the recycling line 49.In order to guarantee reliable separation in the expeller 12 of the fuel vapor (supply line 51) and the solution which is low in fuel (recycling line 49), an encircling, conically tapering baffle plate 73 is provided, disposed on the outlet side with respect to the rising tubes 45.The baffle plate 73 serves to conduct the solution which is high in fuel according to the arrows 75 into the recycling line 49 while the fuel vapor is conducted through a gap formed between the baffle plate 73 and the supply line 51 according to the arrow 74 into the supply line 51.The expeller 12 according to FIG.","3 is thus formed as a compact bundle of tubes with a plurality of rising tubes 45, a central recycling line 49, and a supply line 51 guided coaxially through the recycling line 49.The additional active connections of the expeller 12, or of the corresponding supply lines, to the corresponding functional units of the refrigerating unit 10 correspond to the above-described form of embodiment according to FIGS.","1 and 2.The individual functional units of the refrigerating unit 10 are actively connected to one another and disposed spatially so as to form three gravity-based gas or liquid circuits.","In so doing, only the external circuits for cooling (cooling circuits 21, 26, and 35) and for the thermal solar system 11 are maintained by means of conventional pumps.","Within the refrigerating unit, each of the solution circuit, refrigerating medium circuit, and auxiliary gas circuit is closed.","The solution circuit begins in the expeller 12 formed as a gas bubble pump, where, by means of the solar system 11, thermal energy is supplied to convert a solution which is high in fuel into a mixture of vaporous fuel and water and into a solution which is low in fuel.","The solution which is low in fuel is conveyed from the expeller 12 to the absorber 32 in which the solution which is low in fuel backs up in the supply line 69 up to a certain level of liquid.","The solution which is low in fuel is thus raised from the level of liquid in the fuel reservoir 54 (dotted line 70) to the level of the inlet of the absorber 32 (dotted line 71).","In the process, the conveyance height and the mass flow of the solution which is low in fuel depend on the geometric configuration of the expeller 12, the level of liquid in the fuel reservoir 54 (dotted line 70), and thus the immersion depth of the rising tubes 45, and the recycling line 49 of the expeller 12 as well as on the number of conveyance tubes (rising tubes 45, recycling line 49) of the expeller 12.The solution which is low in fuel conveyed to the absorber 32 absorbs the fuel supplied by the evaporator 24 to form a solution which is high in fuel, said solution being conducted for preheating through the triple heat exchanger 15 and flowing back into the expeller 12.The solution which is high in fuel flowing back into the expeller 12 is thus available once again to expel the fuel in the same.","In the refrigerating medium circuit, the mixture of hot fuel and water vapor, said mixture having been vaporized in the expeller 12, flows into the triple heat exchanger 15 and is precooled and rectified there by the cold solution which is high in fuel coming from the absorber 32 and flowing in the opposite direction.","The pure fuel vapor, near to the condensation temperature, rises from the triple heat exchanger 15 into condenser 19 in which, through additional withdrawal of heat by means of the refrigerating medium circuit 21, the pure fuel is cooled to under its condensation temperature so that the fuel vapor condenses.","The liquid fuel subsequently flows from the condenser 19 into the evaporator 24 in which the liquid fuel diffuses into an atmosphere of auxiliary gas and draws heat from the refrigerating medium of the refrigerating medium circuit 26.Subsequently the relatively heavy mixture of auxiliary gas and fuel sinks into the absorber 32.In the auxiliary gas circuit, the atmosphere of auxiliary gas in the evaporator 24 is constantly pressurized with pure auxiliary gas in order to avoid the atmosphere of auxiliary gas reaching its saturation limit through the diffusing fuel and thus sufficient diffusion of liquid fuel into the atmosphere of auxiliary gas not taking place.","The relatively heavy mixture of auxiliary gas and fuel sinks through the lines 59 from the evaporator 24 into the gas heat exchanger 29 and flows from it through the supply line 77 into the absorber 32.In the absorber 32 the fuel contained in the mixture is absorbed by the solution which is low in fuel, where the then lighter, pure auxiliary gas rises through the lines 62 from the absorber 32, flowing in the opposite direction, and with precooling by means of the refrigerating medium circuit 35 in the gas heat exchanger 29.From there, the pure auxiliary gas flows through the supply lines 61 and 76 into the upper area of the evaporator 24 in which it is enriched with diffusing fuel and subsequently sinks back into the absorber 32 once again as a mixture of fuel and auxiliary gas.","Advantageously, the triple heat exchanger 15 simultaneously fulfills three different functions, namely preheating of the solution which is high in fuel coming from the expeller 12, precooling of the low solution flowing to the absorber 32, and rectification of the NH3-H2O vapor coming from the expeller 12.By conducting the hot vapor mixture along the solution which is high in fuel cooled in the absorber 32, the water vapor contained condenses and falls back as condensate into the solution which is high in fuel.","The heat of condensation or rectification being released is thus also used to preheat the rich solution.","The triple heat exchanger 15 thus provides for a nearly complete recovery of the heat of rectification which advantageously no longer has to be supplied to the expeller 12 from outside.","FIG.","4 shows a detail of the absorber 32 on an enlarged scale.","According to this preferred form of embodiment, the given auxiliary gas conveyance line 62 of the absorber 32 is provided with a capillary sleeve 79 which is actively connected to the line 62, on the outlet side with respect to the auxiliary gas conveyance line (arrow 82).","The capillary sleeve 79 forms, together with the line 62, a capillary gap 81, extending circumferentially, through which the solution which is low in fuel (liquid) can flow according to the arrows 83 and 84.The solution which is low in fuel is thus conducted by means of the supply line 69 into the absorber 32 and, due to the capillary action present, conveyed according to the arrows 83 and 84 into the given auxiliary gas conveyance line 62 of the absorber 32 in which the same slides downwards along its walls (arrow 84).","The auxiliary gas is conducted according to the arrows 82 through the auxiliary gas conveyance line 62 and through a central longitudinal hole 80 of the capillary sleeve 79 and flows according to the arrows 34 to the supply line 61 which actively connects the absorber 32 to the gas heat exchanger 29.A separating plate 85 connected to a jacket tube 86 of the absorber 32 makes it possible that the solution which is low in fuel, said solution being located in the absorber 32, can be backed up to a certain level of liquid (FIG.","2b: dotted line 71).","A given auxiliary gas conveyance line 62 equipped with a capillary sleeve 79 is advantageous since, due to the capillary action present at the time in the corresponding capillary gap 81, a uniform distribution of the solution which is low in fuel to the individual auxiliary gas conveyance line 62 in the absorber 32 is guaranteed independently of the level, present at the time, of the solution which is low in fuel in the absorber 32 or on the amount of the solution which is low in fuel flowing through the supply line 69 into the absorber 32 according to the arrows 39.In particular in the case of an oblique position (not represented) of the absorber 32, it is avoided by means of the capillary sleeves 79, due to capillary action setting in, that several auxiliary gas conveyance lines 62 are completely filled with solution which is low in fuel and the remaining auxiliary gas conveyance lines 62 are not pressurized with solution which is low in fuel so that the absorber 32 would not be functional, at least not completely.","According to a preferred form of embodiment not represented, each of the auxiliary gas conveyance line 62 can be provided with a plurality of projections acting as space holders at its free end projecting into the interior of the auxiliary gas conveyance line 62, by means of which projections a coaxial, with respect to the corresponding auxiliary gas conveyance lines 62, positioning of the respective capillary sleeve 79 is possible in a relatively simple manner.","Projections of this type at the free end of the respective capillary sleeve 79 are preferably distributed uniformly over its circumference and spaced sufficiently far from one another that a free flow of the solution which is low in fuel through the capillary gap according to arrows 83 and 84 is guaranteed.","Corresponding to another additional form of embodiment not represented, the lines 59 of the evaporator 24 are provided at their upper free end with a corresponding capillary sleeve 79 according to FIG.","4."]],"string":"[\n [\n \"Refrigeration unit\",\n \"The refrigerating unit can be operated by means of a thermal solar system as energy source.\",\n \"Therein it is provided that the refrigerating unit is formed as a diffusion-absorption refrigerating unit.\",\n \"The refrigerating unit has an expeller, a triple heat exchanger, a condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir which are actively connected to form a closed fuel circuit with one another.\"\n ],\n [\n \"1-12.Cancelled.\",\n \"12.A refrigerating unit, which is formed as a diffusion-absorption refrigerating unit, comprising: a closed fuel circuit having a triple heat exchanger for preheating a solution which is high in fuel and precooling a solution which is low in fuel, and for rectification of a mixture of fuel and water vapor.\",\n \"13.The refrigerating unit according to claim 12, further comprising a thermal solar system actively connected to an expeller formed as a gas bubble pump for the desorption and vaporization of a fuel contained in a solution.\",\n \"14.The refrigerating unit according to claim 13, wherein the the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.\",\n \"15.The refrigerating unit according to claim 13, wherein the the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.\",\n \"16.The refrigerating unit according to claim 13, wherein the expeller has a plurality of parallel rising tubes spaced at a distance from one another for the conveyance of a solution which is high in fuel, where a parallel recycling line for the conveyance of the solution which is low in fuel is disposed between at least two rising tubes.\",\n \"17.The refrigerating unit according to claim 13, further comprising a rising tube and wherein the expeller is actively connected, on an inlet side with respect to the rising tube, to a supply line, coming from the triple heat exchanger, for the conveyance of the solution which is high in fuel, on the outlet side with respect to the rising tube, to a fuel vapor supply line leading to the triple heat exchanger, and, on the outlet side with respect to the recycling line, to a supply line, leading to the triple heat exchanger, for the conveyance of the solution which is low in fuel.\",\n \"18.The refrigerating unit according to claim 17, wherein the fuel vapor supply line leads essentially coaxially through the recycling line.\",\n \"19.The refrigerating unit according to claim 13, further comprising a rising tube having an inner structure promoting the formation of bubbles.\",\n \"20.The refrigerating unit according to claim 12, wherein the fuel is ammonia (NH3) and the solution a mixture of ammonia and water (NH3/H2O).\",\n \"21.The refrigerating unit according to claim 13, wherein the thermal solar system is actively connected over an entire longitudinal extension of the rising tube of the expeller.\",\n \"22.The refrigerating unit according to claim 13, further comprising at least one of an absorber and an evaportator having conveyance lines, wherein the conveyance lines have upper free ends with a corresponding capillary sleeve 23.The refrigeration unit of claim 12, where the closed fuel circuit comprises an expeller condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir which are actively connected to one another to form a closed fuel circuit.\",\n \"24.The refrigerating unit according to claim 23, further comprising a thermal solar system actively connected to an expeller formed as a gas bubble pump for the desorption and vaporization of a fuel contained in a solution.\",\n \"25.The refrigerating unit according to claim 23, wherein the the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.\",\n \"26.The refrigerating unit according to claim 23, wherein the the expeller has at leapt one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.\",\n \"27.The refrigerating unit according to claim 12, wherein the expeller has a plurality of parallel rising tubes spaced at a distance from one another for the conveyance of a solution which is high in fuel, where a parallel recycling line for the conveyance of the solution which is low in fuel is disposed between at least two rising tubes.\",\n \"28.The refrigerating unit according to claim 23, further comprising a rising tube and wherein the expeller is actively connected, on an inlet side with respect to the rising tube, to a supply line, coming from the triple heat exchanger, for the conveyance of the solution which is high in fuel, on the outlet side with respect to the rising tube, to a fuel vapor supply line leading to the triple heat exchanger, and, on the outlet side with respect to the recycling line, to a supply line, leading to the triple heat exchanger, for the conveyance of the solution which is low in fuel.\",\n \"29.The refrigerating unit according to claim 28, wherein the fuel vapor supply line leads essentially coaxially through the recycling line.\",\n \"30.The refrigerating unit according to claim 23, further comprising a rising tube having an inner structure promoting the formation of bubbles.\",\n \"31.The refrigerating unit according to claim 23, wherein the fuel is ammonia (NH3) and the solution a mixture of ammonia and water (NH3/H2O).\",\n \"32.The refrigerating unit according to claim 23, wherein the thermal solar system is actively connected over an entire longitudinal extension of the rising tube of the expeller.\",\n \"33.The refrigerating unit according to claim 23, further comprising at least one of an absorber and an evaportator having conveyance lines, wherein the conveyance lines have upper free ends with a corresponding capillary sleeve 34.A refrigerating unit, which is formed as a diffusion-absorption refrigerating unit and can be operated by means of a thermal solar system as energy source, with an expeller, a triple heat exchanger, a condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir which are actively connected to one another to form a closed fuel circuit, wherein the refrigerating unit has, in the fuel circuit, a triple heat exchanger for preheating a solution which is high in fuel and precooling a solution which is low in fuel, and for the rectification of a mixture of fuel and water vapor.\",\n \"35.A method for refrigerating a unit, the method comprising: forming a fuel circuit having a triple head exchanger; and preheating a solution which is high in fuel, precooling a solution which is low in fuel, and rectifying a mixture of fuel and water vapor.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>The invention relates to a refrigerating unit, which can be operated by means of a thermal solar system as energy source, according to the preamble of claim 1 .\",\n \"Refrigerating units of the type addressed here, such as, for example, absorption refrigerating units or compression refrigerating units, are known.\",\n \"For solar operation, these absorption refrigerating units disadvantageously require a high outlay with regard to control technology and investment, in particular with regard to a continuous reheating or heat storage.\",\n \"In view of this, absorption refrigerating units are limited to a relatively narrow temperature and flow range.\",\n \"Also the known, photovoltaically operated compression refrigerating units are characterized by a high outlay with regard to investment and have relatively low efficiency.\",\n \"These known refrigerating units are not suited to problem-free and economical operation with thermal solar systems, in particular in the average capacity range.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>It is the objective of the invention to provide a refrigerating unit of the type stated initially which can be operated in a reliable, effective, and operation-friendly manner by means of a thermal solar system, in particular in the lower to average refrigerating capacity range.\",\n \"For the realization of this objective, a refrigerating unit with the features of claim 1 is proposed which is distinguished by the fact that the refrigerating unit is formed as a diffusion-absorption refrigerating unit.\",\n \"A diffusion-absorption refrigerating unit can be operated in a particularly reliable and efficient manner by means of a thermal solar system as an energy source.\",\n \"This behavior, which is favorable to operation, can also be achieved in a smaller to average refrigerating capacity range.\",\n \"A diffusion-absorption refrigerating unit is advantageously suitable to be operated by means of various energy sources.\",\n \"Among these, a thermal solar system as well as another heat transfer medium circuit, e.g.\",\n \"from a heat recovery process, can be used for the alternative or enhancing energizing of the refrigerating unit.\",\n \"A diffusion-absorption refrigerating unit is thus advantageously suitable, in a manner which is flexible and favorable for operation, to be energized with thermal energy by means of a thermal solar system as well as, if needed or desired, additional, different energy sources.\",\n \"The refrigerating unit advantageously has an expeller, a triple heat exchanger, a condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir, which are actively connected to one another to form a closed fuel circuit.\",\n \"The refrigerating unit characterized by a closed fuel circuit can be formed as a hermetically closed, compact unit which is distinguished by an advantageous independence of site.\",\n \"It is operated merely by means of thermal energy and thus advantageously needs no electrical power supply.\",\n \"Since no components working mechanically within the refrigerating unit, such as, for example, pumps, are required to operate the refrigerating unit, the unit is maintenance-friendly, relatively favorable from the standpoint of cost, and can be operated, at least nearly, without noise.\",\n \"Furthermore, it is possible to develop the refrigerating unit so that the mounting of several refrigerating units in parallel can be realized in a relatively simple manner.\",\n \"Preferably, the thermal solar system can be actively connected to an expeller formed as a gas bubble pump for the desorption and vaporization of a fuel contained in a solution.\",\n \"A gas bubble pump is particularly suitable for desorbing and vaporizing, in a manner which is effective and favorable for operation, a fuel contained in a solution such as, for example, ammonia (NH3) in an ammonia-rich solution.\",\n \"Furthermore, a gas bubble pump permits an efficient heat transfer accomplished by means of a thermal energy source, which is a prerequisite for reliable and effective desorption and vaporization of the fuel (ammonia).\",\n \"According to a preferred form of embodiment, the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.\",\n \"The rising tube of the expeller formed as a gas bubble pump contains a solution which is high in fuel and which, due to the vaporization of the fuel in the rising tube, experiences an increase in volume so that it assumes an operating volume which is a multiple of the original volume value, i.e.\",\n \"of the still not vaporized fuel.\",\n \"Due to this increase in volume, the level of the vaporous fuel, or of the fuel mixture in the rising tube, rises to a corresponding operational conveyance height.\",\n \"If this operational conveyance height exceeds the length of the rising tube due to a corresponding increase in volume of the fuel mixture or a vaporization of the fuel, the conveyance of the vaporous fuel, or a remaining solution which is low in fuel, to additional functional units of the refrigerating unit is started, said functional units being actively connected to one another in the form of a closed fuel circuit so that the refrigerating unit is activated at this moment in its operation.\",\n \"In so doing, an effective heat transfer from a thermal energy source (solar system) into the expeller or into the rising tube serves for a reliable and rapid activation of the refrigerating unit.\",\n \"This is guaranteed by means of a suitable ribbing of the rising tube whereby an enlargement of the heat transfer surface to improve the heat transfer into the rising tube is obtained.\",\n \"Instead of ribbing, deflecting plates can also be provided.\",\n \"Advantageously, the expeller has a plurality of parallel rising tubes spaced at a distance from one another for the conveyance of a solution which is high in fuel, where a parallel recycling line for the conveyance of the solution which is low in fuel is disposed between at least two rising tubes.\",\n \"This makes possible an expeller formation which is compact and has the form of a bundle of tubes, where advantageously the rising tubes disposed externally can be energized with thermal energy, in a manner favorable to efficiency and operation, by means of a thermal energy source (solar system) while the interposed, parallel recycling line, through which a heated solution which is low in fuel is conveyed, makes possible an additional heating of the outer rising tubes, or counteracts a cooling of the same.\",\n \"The amount of heat radiating, and thus not actively utilized, is reduced in an effective manner due to a compact arrangement of the outer rising tubes as a bundle of tubes and a centrally disposed recycling line.\",\n \"Preferably, the expeller is actively connected, on the inlet side with respect to the rising tube, to a supply line coming from the triple heat exchanger for the conveyance of the solution which is high in fuel, on the outlet side with respect to the rising tube, to a fuel vapor supply line leading to the triple heat exchanger, and, on the outlet side with respect to the recycling line, to a supply line leading to the triple heat exchanger for the conveyance of the solution which is low in fuel.\",\n \"The expeller preferably having a compact bundle of tubes is thus actively connected, on the inlet side as well as on the outlet side, to the triple heat exchanger which in turn is actively connected to additional functional units of the refrigerating unit to form a closed fuel circuit.\",\n \"In so doing, a solution which is high in fuel, a solution which is low in fuel, and fuel vapor are conveyed in the expeller after activation of the refrigerating unit.\",\n \"Advantageously, the fuel vapor supply line leads essentially coaxially through the recycling line.\",\n \"An expeller of this type is formed particularly compactly and is distinguished by a particularly effective and reliable desorption and vaporization of a fuel in a solution which is high in fuel, said solution being contained in the respective rising tube, since an undesirable radiation of heat from the expeller into the environment can be reduced to a significant extent due to its compact arrangement as a bundle of tubes.\",\n \"Advantageously, the rising tube has an inner structure promoting the formation of bubbles.\",\n \"An inner structure of this type in the rising tube can, for example, be achieved by means of a coating and/or a roughening of the inner surface and serves for the desired bubble formation in a solution which is high in fuel in a definite area in the rising tube due desired turbulence of the same solution, said turbulence being caused by the inner structure.\",\n \"The expeller formed as a gas bubble pump is suitable, with the use of rising tubes of this type, for a particularly effective desorption, vaporization, and conveyance of fuel contained in a solution which is high in fuel and for the conveyance of a solution which is low in fuel.\",\n \"Advantageously, the fuel is ammonia (NH3) and the solution a mixture of ammonia and water (NH3/H 2 O).\",\n \"NH3 as fuel and a mixture of NH3 and H 2 O as solution are particularly suited to an effective operation of the refrigerating unit according to the invention.\",\n \"Along with this, an auxiliary gas, used, if needed or desired, for the operation of the refrigerating unit, can be helium (He).\",\n \"According to a preferred form of embodiment, the thermal solar system is actively connected over the entire longitudinal extension of the rising tube of the expeller to the same.\",\n \"By means of heating of the rising tube over its entire longitudinal extension, it is avoided in a reliable manner that, due to an undesired cooling in an unheated area of the rising tube, vaporous NH3, already expelled, condenses and thus cancels an intended increase in volume of the fuel contained in the rising tube, where the increase in volume would lead to the starting of the conveyance of the fuel, or the solution which is low in fuel.\",\n \"In this, the rising tubes are preferably each provided on the inlet side with a ribbing for the heating of the triple heat exchanger, of a fuel reservoir, and of a supply line leading to the condenser (vapor line).\",\n \"Additional advantageous developments of the invention follow from the description.\"\n ],\n [\n \"RELATED APPLICATIONS The present application is the U.S. National Phase of PCT Application PCT/EP01/06412, filed Jun.\",\n \"6, 2001, which claims priority to German Patent Application No.\",\n \"10028543.0, filed Jun.\",\n \"8, 2000.BACKGROUND The invention relates to a refrigerating unit, which can be operated by means of a thermal solar system as energy source, according to the preamble of claim 1.Refrigerating units of the type addressed here, such as, for example, absorption refrigerating units or compression refrigerating units, are known.\",\n \"For solar operation, these absorption refrigerating units disadvantageously require a high outlay with regard to control technology and investment, in particular with regard to a continuous reheating or heat storage.\",\n \"In view of this, absorption refrigerating units are limited to a relatively narrow temperature and flow range.\",\n \"Also the known, photovoltaically operated compression refrigerating units are characterized by a high outlay with regard to investment and have relatively low efficiency.\",\n \"These known refrigerating units are not suited to problem-free and economical operation with thermal solar systems, in particular in the average capacity range.\",\n \"SUMMARY OF THE INVENTION It is the objective of the invention to provide a refrigerating unit of the type stated initially which can be operated in a reliable, effective, and operation-friendly manner by means of a thermal solar system, in particular in the lower to average refrigerating capacity range.\",\n \"For the realization of this objective, a refrigerating unit with the features of claim 1 is proposed which is distinguished by the fact that the refrigerating unit is formed as a diffusion-absorption refrigerating unit.\",\n \"A diffusion-absorption refrigerating unit can be operated in a particularly reliable and efficient manner by means of a thermal solar system as an energy source.\",\n \"This behavior, which is favorable to operation, can also be achieved in a smaller to average refrigerating capacity range.\",\n \"A diffusion-absorption refrigerating unit is advantageously suitable to be operated by means of various energy sources.\",\n \"Among these, a thermal solar system as well as another heat transfer medium circuit, e.g.\",\n \"from a heat recovery process, can be used for the alternative or enhancing energizing of the refrigerating unit.\",\n \"A diffusion-absorption refrigerating unit is thus advantageously suitable, in a manner which is flexible and favorable for operation, to be energized with thermal energy by means of a thermal solar system as well as, if needed or desired, additional, different energy sources.\",\n \"The refrigerating unit advantageously has an expeller, a triple heat exchanger, a condenser, an evaporator, a gas heat exchanger, an absorber, and a fuel reservoir, which are actively connected to one another to form a closed fuel circuit.\",\n \"The refrigerating unit characterized by a closed fuel circuit can be formed as a hermetically closed, compact unit which is distinguished by an advantageous independence of site.\",\n \"It is operated merely by means of thermal energy and thus advantageously needs no electrical power supply.\",\n \"Since no components working mechanically within the refrigerating unit, such as, for example, pumps, are required to operate the refrigerating unit, the unit is maintenance-friendly, relatively favorable from the standpoint of cost, and can be operated, at least nearly, without noise.\",\n \"Furthermore, it is possible to develop the refrigerating unit so that the mounting of several refrigerating units in parallel can be realized in a relatively simple manner.\",\n \"Preferably, the thermal solar system can be actively connected to an expeller formed as a gas bubble pump for the desorption and vaporization of a fuel contained in a solution.\",\n \"A gas bubble pump is particularly suitable for desorbing and vaporizing, in a manner which is effective and favorable for operation, a fuel contained in a solution such as, for example, ammonia (NH3) in an ammonia-rich solution.\",\n \"Furthermore, a gas bubble pump permits an efficient heat transfer accomplished by means of a thermal energy source, which is a prerequisite for reliable and effective desorption and vaporization of the fuel (ammonia).\",\n \"According to a preferred form of embodiment, the expeller has at least one rising tube which on the inlet side is provided with a ribbing promoting the vaporization of the fuel contained in the rising tube.\",\n \"The rising tube of the expeller formed as a gas bubble pump contains a solution which is high in fuel and which, due to the vaporization of the fuel in the rising tube, experiences an increase in volume so that it assumes an operating volume which is a multiple of the original volume value, i.e.\",\n \"of the still not vaporized fuel.\",\n \"Due to this increase in volume, the level of the vaporous fuel, or of the fuel mixture in the rising tube, rises to a corresponding operational conveyance height.\",\n \"If this operational conveyance height exceeds the length of the rising tube due to a corresponding increase in volume of the fuel mixture or a vaporization of the fuel, the conveyance of the vaporous fuel, or a remaining solution which is low in fuel, to additional functional units of the refrigerating unit is started, said functional units being actively connected to one another in the form of a closed fuel circuit so that the refrigerating unit is activated at this moment in its operation.\",\n \"In so doing, an effective heat transfer from a thermal energy source (solar system) into the expeller or into the rising tube serves for a reliable and rapid activation of the refrigerating unit.\",\n \"This is guaranteed by means of a suitable ribbing of the rising tube whereby an enlargement of the heat transfer surface to improve the heat transfer into the rising tube is obtained.\",\n \"Instead of ribbing, deflecting plates can also be provided.\",\n \"Advantageously, the expeller has a plurality of parallel rising tubes spaced at a distance from one another for the conveyance of a solution which is high in fuel, where a parallel recycling line for the conveyance of the solution which is low in fuel is disposed between at least two rising tubes.\",\n \"This makes possible an expeller formation which is compact and has the form of a bundle of tubes, where advantageously the rising tubes disposed externally can be energized with thermal energy, in a manner favorable to efficiency and operation, by means of a thermal energy source (solar system) while the interposed, parallel recycling line, through which a heated solution which is low in fuel is conveyed, makes possible an additional heating of the outer rising tubes, or counteracts a cooling of the same.\",\n \"The amount of heat radiating, and thus not actively utilized, is reduced in an effective manner due to a compact arrangement of the outer rising tubes as a bundle of tubes and a centrally disposed recycling line.\",\n \"Preferably, the expeller is actively connected, on the inlet side with respect to the rising tube, to a supply line coming from the triple heat exchanger for the conveyance of the solution which is high in fuel, on the outlet side with respect to the rising tube, to a fuel vapor supply line leading to the triple heat exchanger, and, on the outlet side with respect to the recycling line, to a supply line leading to the triple heat exchanger for the conveyance of the solution which is low in fuel.\",\n \"The expeller preferably having a compact bundle of tubes is thus actively connected, on the inlet side as well as on the outlet side, to the triple heat exchanger which in turn is actively connected to additional functional units of the refrigerating unit to form a closed fuel circuit.\",\n \"In so doing, a solution which is high in fuel, a solution which is low in fuel, and fuel vapor are conveyed in the expeller after activation of the refrigerating unit.\",\n \"Advantageously, the fuel vapor supply line leads essentially coaxially through the recycling line.\",\n \"An expeller of this type is formed particularly compactly and is distinguished by a particularly effective and reliable desorption and vaporization of a fuel in a solution which is high in fuel, said solution being contained in the respective rising tube, since an undesirable radiation of heat from the expeller into the environment can be reduced to a significant extent due to its compact arrangement as a bundle of tubes.\",\n \"Advantageously, the rising tube has an inner structure promoting the formation of bubbles.\",\n \"An inner structure of this type in the rising tube can, for example, be achieved by means of a coating and/or a roughening of the inner surface and serves for the desired bubble formation in a solution which is high in fuel in a definite area in the rising tube due desired turbulence of the same solution, said turbulence being caused by the inner structure.\",\n \"The expeller formed as a gas bubble pump is suitable, with the use of rising tubes of this type, for a particularly effective desorption, vaporization, and conveyance of fuel contained in a solution which is high in fuel and for the conveyance of a solution which is low in fuel.\",\n \"Advantageously, the fuel is ammonia (NH3) and the solution a mixture of ammonia and water (NH3/H2O).\",\n \"NH3 as fuel and a mixture of NH3 and H2O as solution are particularly suited to an effective operation of the refrigerating unit according to the invention.\",\n \"Along with this, an auxiliary gas, used, if needed or desired, for the operation of the refrigerating unit, can be helium (He).\",\n \"According to a preferred form of embodiment, the thermal solar system is actively connected over the entire longitudinal extension of the rising tube of the expeller to the same.\",\n \"By means of heating of the rising tube over its entire longitudinal extension, it is avoided in a reliable manner that, due to an undesired cooling in an unheated area of the rising tube, vaporous NH3, already expelled, condenses and thus cancels an intended increase in volume of the fuel contained in the rising tube, where the increase in volume would lead to the starting of the conveyance of the fuel, or the solution which is low in fuel.\",\n \"In this, the rising tubes are preferably each provided on the inlet side with a ribbing for the heating of the triple heat exchanger, of a fuel reservoir, and of a supply line leading to the condenser (vapor line).\",\n \"Additional advantageous developments of the invention follow from the description.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The invention is explained below in several embodiment examples with the aid of the accompanying drawings.\",\n \"Shown are: FIG.\",\n \"1 shows a block diagram of a refrigerating unit according to the invention; FIG.\",\n \"2a shows a schematic representation of a first part of the refrigerating unit according to FIG.\",\n \"1; FIG.\",\n \"2b shows a schematic representation of a second part of the refrigerating unit according to FIG.\",\n \"1; FIG.\",\n \"3 shows an alternative form of embodiment of an expeller for the refrigerating unit according to FIG.\",\n \"2; FIG.\",\n \"4 shows a schematic representation of a conveyance line having a capillary sleeve on an enlarged scale.\",\n \"DETAILED DESCRIPTION FIG.\",\n \"1 shows a block diagram of a refrigerating unit 10.Furthermore, FIGS.\",\n \"2a and 2b, which complement one another as partial figures, show the refrigerating unit 10 according to FIG.\",\n \"1 in schematic representation.\",\n \"The refrigerating unit 10 has an expeller 12 which is actively connected to a thermal solar system 11 by means of heat transfer medium lines represented as arrows 13 and 14 (FIG.\",\n \"2a: 43, 43a, 43b, 44).\",\n \"A fuel vapor supply line represented as an arrow 16 (FIG.\",\n \"2a: 51) and a supply line, represented as an arrow 17 (FIG.\",\n \"2a: 47) and serving to convey a solution which is low in fuel, leads from the expeller 12 to a triple heat exchanger 15, from which a supply line, represented as an arrow 18 (FIG.\",\n \"2a: 48) and serving to convey a solution which is high in fuel, leads to the expeller 12.The triple heat exchanger 15 is actively connected to a condenser 19 by means of a supply line, represented as an arrow 20 (FIGS.\",\n \"2a/2b: 55), for fuel vapor and, if needed or desired, with low percentages of water (H2O).\",\n \"The condenser 19 is actively connected to a refrigerating medium circuit 21 by means of cold transfer medium lines, represented as arrows 22, 23 (FIG.\",\n \"2b: 56, 57).\",\n \"A supply line, represented as an arrow 25 (FIG.\",\n \"2b: 58) for liquid fuel leads from the condenser 19 to an evaporator 24 which is actively connected to a refrigerating medium circuit 26 by means of cold transfer medium lines, represented as arrows 27, 28 (FIG.\",\n \"2b: 60).\",\n \"A supply line, represented as an arrow 30 (FIG.\",\n \"2b: 59) for a gaseous mixture of vaporized fuel and an auxiliary gas leads from the evaporator 24 to a gas heat exchanger 29 which, in operation, is actively connected to the evaporator 24 by means of a supply line, represented as an arrow 31 (FIG.\",\n \"2b: 76), for the precooled auxiliary gas.\",\n \"By means of a supply line, for the heated gas mixture consisting of fuel and auxiliary gas and represented as an arrow 33 (FIG.\",\n \"2b: 77), the gas heat exchanger 29 is actively connected to an absorber 32, from which a supply line, for warm auxiliary gas and represented as an arrow 34 (FIG.\",\n \"2b: 61), leads to the gas heat exchanger 29.The absorber 32 is actively connected to a refrigerating medium circuit 35 by means of cold transfer medium lines represented as arrows 36, 37 (FIG.\",\n \"2b: 63, 64).\",\n \"A supply line, for a solution which is high in fuel and represented as an arrow 38 (FIGS.\",\n \"2a/2b: 68), leads from the absorber 32 to a triple gas heat exchanger 15 and from the latter a supply line, for a solution which is low in fuel and represented as an arrow 39 (FIGS.\",\n \"2a/2b: 69), leads to the absorber 32.The refrigerating unit 10 is divided, by means of a dotted line 40 according to arrow 42, into an upper area in which the total operational pressure is equal to the fuel pressure and, according to arrow 41, into a lower area in which the total operational pressure is equal to the sum of the fuel pressure and the auxiliary gas pressure.\",\n \"Preferably the fuel is ammonia (NH3), the auxiliary gas is helium (He), and each of the solution which is high in fuel and the solution which is low in fuel is a mixture of ammonia and water (NH3/H2O).\",\n \"NH3 vapor with low percentages of H2O is thus conveyed from the expeller 12 to the triple heat exchanger 15 (arrow 16), from which NH3 vapor flows into the condenser 19 (arrow 20) and is cooled to liquid NH3 where the liquid NH3 subsequently flows into the evaporator 24 (arrow 25) in which NH3 diffuses into a precooled He atmosphere forming a “heavy” cold He-NH3 gas mixture.\",\n \"This cold gas mixture flows into the gas heat exchanger 29 (arrow 30) in which the same is heated due to a heat transfer from a warm He stream (arrow 34) flowing in the opposite direction through the gas heat exchanger 29 and subsequently flows from the absorber 32 to the absorber 32 (arrow 33).\",\n \"The solution which is high in NH3/H2O flows on the contrary from the absorber 32 to the triple heat exchanger 15 (arrow 38) and from there to the expeller 12 (arrow 18).\",\n \"The solution which is low in NH3/H2O flows on the contrary to the triple heat exchanger 15 (arrow 17) and from there to the absorber 32 (arrow 39).\",\n \"Furthermore, the withdrawal of cooling capacity of the refrigerating unit 10 is done by means of the refrigerating medium circuit 26, which is actively connected to the evaporator 24.FIG.\",\n \"2a shows in addition the expeller 12 preferably formed as a gas bubble pump, said expeller being actively connected to the thermal solar system 11 and to the triple heat exchanger 15.The thermal solar system 11 has a solar cell unit 72 in the form of a solar collector cell unit which is actively connected, by means of the heat transfer medium lines 43, 43a, 43b, and 44, to a plurality of rising tubes 45 (in FIG.\",\n \"2a two rising tubes 45 are represented) of the expeller 12.The heat transfer medium lines 43, 43a, and 43b are connected to one another in operation by means of a change-over valve 78 in such a manner that a heat transfer medium is conveyed according to arrow 13 from the solar cell unit through the heat transfer medium line 43 to the change-over valve 78, which conducts the heat transfer medium through the heat transfer medium line 43a and/or 43b according to arrow 13a or 13b to the expeller 12.The rising tubes 45 have on one side a ribbing 50 (or deflecting plate not represented) in order to insure a rapid, spatially defined, and reliable heat transfer from the heat carrier of the solar cell unit 11 to the solution which is high in fuel, said solution being located in the rising tubes 45.Between the rising tubes 45 disposed in parallel at a distance from one another, a parallel recycling line 49 is disposed to convey a solution which is low in fuel.\",\n \"The expeller 12 is thus formed as a compact bundle of tubes (rising tubes 45 for solution which is high in fuel, recycling line 49 for solution which is low in fuel).\",\n \"The solution which is low in fuel is conducted, by means of a supply line 47, from the expeller 12 to the triple heat exchanger 15 and conducted from there to the absorber 32 by means of the supply line 69 (see also FIG.\",\n \"2b).\",\n \"The fuel vapor is conducted, by means of a conducting line 51, from the expeller 12 to the triple heat exchanger 15 in which water is condensed out from the mixture of fuel and water vapor and conducted, by means of the line 52, according to the arrow 53 to the supply line 48 which serves to convey the solution which is high in fuel into the expeller 12.Pure, or nearly pure, fuel is conducted, by means of the supply line 55, from the triple heat exchanger 15 to the condenser 19 (see also FIG.\",\n \"2b).\",\n \"The supply line 48 for conveying the solution which is high in fuel is actively connected to a fuel reservoir 54.A dotted line 70 denotes the level of liquid in the fuel reservoir 54 while a dotted line 71 represents the level of liquid in the inlet of the absorber 32 (see also FIG.\",\n \"2b).\",\n \"The expeller 12 is formed as a compact bundle of tubes with a plurality of cold transfer medium lines 65 and a plurality of auxiliary gas conveyance lines 62.Likewise, the gas heat exchanger 29, the evaporator 24, and the condenser 19 are each formed as a compact bundle of tubes.\",\n \"The absorber 32 can however also be formed in such a manner that the cold transfer medium lines 65 are provided with intermediate spaces for the auxiliary gas conveyance lines 62 and preferably with deflecting plates.\",\n \"To expel the fuel from the solution which is high in fuel as well as to convey the same, the expeller 12 needs a certain minimum supply of energy from the solar cell unit 72.A supply of energy into the expeller 12 below this limit would lead, when conveying the heat transfer medium into the expeller 12 through the heat transfer medium line 43a below the liquid level denoted as the dotted line 70, to undesirable reduction of the solution which is high in fuel without the same being conveyed.\",\n \"With longer operation of the refrigerating unit in a state of this type, the solution which is high in fuel, said solution being located in the expeller 12, would be reduced still further in fuel so that higher and higher operating temperatures would be required in order to expel additional fuel from the solution which is high in fuel.\",\n \"This has as a consequence that the refrigerating unit could no longer be put in operation without additional effort.\",\n \"Providing a second heat transfer medium line 43b, which is actively connected to the expeller 12 above the liquid level denoted as the dotted line 70, advantageously makes it possible that, on starting the refrigerating unit, that energy which is not sufficient to expel the fuel from the solution which is high in fuel can still be used to preheat the expeller 12.Thereby it is avoided that a “high-value” energy has to be used to heat the expeller 12 (material of the tubes) so that this energy can be used exclusively for the conveyance of the solution which is high in fuel, said solution being located in the expeller 12, and to expel the fuel from the same.\",\n \"Furthermore, the solution which is high in fuel can be preheated in the triple heat exchanger 15, the fuel reservoir 54, and in the supply line 55 (vapor line) which leads to the condenser 19 by means of “low-value” solar energy.\",\n \"FIG.\",\n \"3 shows an expeller 12 according to an alternative development.\",\n \"This expeller 12 corresponds essentially to that of FIG.\",\n \"2 and is different in that according to FIG.\",\n \"3 the fuel vapor supply line 51 leads coaxially through the recycling line 49.In order to guarantee reliable separation in the expeller 12 of the fuel vapor (supply line 51) and the solution which is low in fuel (recycling line 49), an encircling, conically tapering baffle plate 73 is provided, disposed on the outlet side with respect to the rising tubes 45.The baffle plate 73 serves to conduct the solution which is high in fuel according to the arrows 75 into the recycling line 49 while the fuel vapor is conducted through a gap formed between the baffle plate 73 and the supply line 51 according to the arrow 74 into the supply line 51.The expeller 12 according to FIG.\",\n \"3 is thus formed as a compact bundle of tubes with a plurality of rising tubes 45, a central recycling line 49, and a supply line 51 guided coaxially through the recycling line 49.The additional active connections of the expeller 12, or of the corresponding supply lines, to the corresponding functional units of the refrigerating unit 10 correspond to the above-described form of embodiment according to FIGS.\",\n \"1 and 2.The individual functional units of the refrigerating unit 10 are actively connected to one another and disposed spatially so as to form three gravity-based gas or liquid circuits.\",\n \"In so doing, only the external circuits for cooling (cooling circuits 21, 26, and 35) and for the thermal solar system 11 are maintained by means of conventional pumps.\",\n \"Within the refrigerating unit, each of the solution circuit, refrigerating medium circuit, and auxiliary gas circuit is closed.\",\n \"The solution circuit begins in the expeller 12 formed as a gas bubble pump, where, by means of the solar system 11, thermal energy is supplied to convert a solution which is high in fuel into a mixture of vaporous fuel and water and into a solution which is low in fuel.\",\n \"The solution which is low in fuel is conveyed from the expeller 12 to the absorber 32 in which the solution which is low in fuel backs up in the supply line 69 up to a certain level of liquid.\",\n \"The solution which is low in fuel is thus raised from the level of liquid in the fuel reservoir 54 (dotted line 70) to the level of the inlet of the absorber 32 (dotted line 71).\",\n \"In the process, the conveyance height and the mass flow of the solution which is low in fuel depend on the geometric configuration of the expeller 12, the level of liquid in the fuel reservoir 54 (dotted line 70), and thus the immersion depth of the rising tubes 45, and the recycling line 49 of the expeller 12 as well as on the number of conveyance tubes (rising tubes 45, recycling line 49) of the expeller 12.The solution which is low in fuel conveyed to the absorber 32 absorbs the fuel supplied by the evaporator 24 to form a solution which is high in fuel, said solution being conducted for preheating through the triple heat exchanger 15 and flowing back into the expeller 12.The solution which is high in fuel flowing back into the expeller 12 is thus available once again to expel the fuel in the same.\",\n \"In the refrigerating medium circuit, the mixture of hot fuel and water vapor, said mixture having been vaporized in the expeller 12, flows into the triple heat exchanger 15 and is precooled and rectified there by the cold solution which is high in fuel coming from the absorber 32 and flowing in the opposite direction.\",\n \"The pure fuel vapor, near to the condensation temperature, rises from the triple heat exchanger 15 into condenser 19 in which, through additional withdrawal of heat by means of the refrigerating medium circuit 21, the pure fuel is cooled to under its condensation temperature so that the fuel vapor condenses.\",\n \"The liquid fuel subsequently flows from the condenser 19 into the evaporator 24 in which the liquid fuel diffuses into an atmosphere of auxiliary gas and draws heat from the refrigerating medium of the refrigerating medium circuit 26.Subsequently the relatively heavy mixture of auxiliary gas and fuel sinks into the absorber 32.In the auxiliary gas circuit, the atmosphere of auxiliary gas in the evaporator 24 is constantly pressurized with pure auxiliary gas in order to avoid the atmosphere of auxiliary gas reaching its saturation limit through the diffusing fuel and thus sufficient diffusion of liquid fuel into the atmosphere of auxiliary gas not taking place.\",\n \"The relatively heavy mixture of auxiliary gas and fuel sinks through the lines 59 from the evaporator 24 into the gas heat exchanger 29 and flows from it through the supply line 77 into the absorber 32.In the absorber 32 the fuel contained in the mixture is absorbed by the solution which is low in fuel, where the then lighter, pure auxiliary gas rises through the lines 62 from the absorber 32, flowing in the opposite direction, and with precooling by means of the refrigerating medium circuit 35 in the gas heat exchanger 29.From there, the pure auxiliary gas flows through the supply lines 61 and 76 into the upper area of the evaporator 24 in which it is enriched with diffusing fuel and subsequently sinks back into the absorber 32 once again as a mixture of fuel and auxiliary gas.\",\n \"Advantageously, the triple heat exchanger 15 simultaneously fulfills three different functions, namely preheating of the solution which is high in fuel coming from the expeller 12, precooling of the low solution flowing to the absorber 32, and rectification of the NH3-H2O vapor coming from the expeller 12.By conducting the hot vapor mixture along the solution which is high in fuel cooled in the absorber 32, the water vapor contained condenses and falls back as condensate into the solution which is high in fuel.\",\n \"The heat of condensation or rectification being released is thus also used to preheat the rich solution.\",\n \"The triple heat exchanger 15 thus provides for a nearly complete recovery of the heat of rectification which advantageously no longer has to be supplied to the expeller 12 from outside.\",\n \"FIG.\",\n \"4 shows a detail of the absorber 32 on an enlarged scale.\",\n \"According to this preferred form of embodiment, the given auxiliary gas conveyance line 62 of the absorber 32 is provided with a capillary sleeve 79 which is actively connected to the line 62, on the outlet side with respect to the auxiliary gas conveyance line (arrow 82).\",\n \"The capillary sleeve 79 forms, together with the line 62, a capillary gap 81, extending circumferentially, through which the solution which is low in fuel (liquid) can flow according to the arrows 83 and 84.The solution which is low in fuel is thus conducted by means of the supply line 69 into the absorber 32 and, due to the capillary action present, conveyed according to the arrows 83 and 84 into the given auxiliary gas conveyance line 62 of the absorber 32 in which the same slides downwards along its walls (arrow 84).\",\n \"The auxiliary gas is conducted according to the arrows 82 through the auxiliary gas conveyance line 62 and through a central longitudinal hole 80 of the capillary sleeve 79 and flows according to the arrows 34 to the supply line 61 which actively connects the absorber 32 to the gas heat exchanger 29.A separating plate 85 connected to a jacket tube 86 of the absorber 32 makes it possible that the solution which is low in fuel, said solution being located in the absorber 32, can be backed up to a certain level of liquid (FIG.\",\n \"2b: dotted line 71).\",\n \"A given auxiliary gas conveyance line 62 equipped with a capillary sleeve 79 is advantageous since, due to the capillary action present at the time in the corresponding capillary gap 81, a uniform distribution of the solution which is low in fuel to the individual auxiliary gas conveyance line 62 in the absorber 32 is guaranteed independently of the level, present at the time, of the solution which is low in fuel in the absorber 32 or on the amount of the solution which is low in fuel flowing through the supply line 69 into the absorber 32 according to the arrows 39.In particular in the case of an oblique position (not represented) of the absorber 32, it is avoided by means of the capillary sleeves 79, due to capillary action setting in, that several auxiliary gas conveyance lines 62 are completely filled with solution which is low in fuel and the remaining auxiliary gas conveyance lines 62 are not pressurized with solution which is low in fuel so that the absorber 32 would not be functional, at least not completely.\",\n \"According to a preferred form of embodiment not represented, each of the auxiliary gas conveyance line 62 can be provided with a plurality of projections acting as space holders at its free end projecting into the interior of the auxiliary gas conveyance line 62, by means of which projections a coaxial, with respect to the corresponding auxiliary gas conveyance lines 62, positioning of the respective capillary sleeve 79 is possible in a relatively simple manner.\",\n \"Projections of this type at the free end of the respective capillary sleeve 79 are preferably distributed uniformly over its circumference and spaced sufficiently far from one another that a free flow of the solution which is low in fuel through the capillary gap according to arrows 83 and 84 is guaranteed.\",\n \"Corresponding to another additional form of embodiment not represented, the lines 59 of the evaporator 24 are provided at their upper free end with a corresponding capillary sleeve 79 according to FIG.\",\n \"4.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10297462"}}},{"rowIdx":98,"cells":{"text":{"kind":"list like","value":[["Acetyl glucosaminyl inositol deacetylase, a mycothiol biosynthetic enzyme, and methods of use","The present invention provides a family of bacterial acetyl glucosaminyl inositol deacetylases (MshB) with deacetylase activity against acyl glucosaminyl inositol and which play a key role in mycothiol biosynthesis.","The invention deacetylases are characterized by a conserved 100 amino acid N-terminal region and three highly conserved histidine-containing regions and by having deacetylase activity as well as amide hydrolase activity.","The invention further provides methods for using the invention deacetylases in drug screening assays to determine compounds that inhibit activity.","The invention provides for treatment of actino-mycete infections in mammals using antibiotics that inhibit production or activity of MshB and thereby reduce the production of mycothiol and the virulence of the infecting bacteria."],["1.A purified acetyl glucosaminyl inositol deacetylase, characterized as having: a) an N-terminal region with an amino acid sequence with 40% or more sequence identity to SEQ ID NO:2 and conservative variations thereof, b) three domains of conservation, wherein two of the domains contain conserved histidine residues, and c) deacetylase activity against acetyl glucosaminyl inositol.","2.The purified deacetylase of claim 1, wherein the deacetylase hydrolyzes a C2-amide bond of the glucosaminyl inositol moiety.","3.The purified deacetylase of claim 1, wherein the acetyl glucosaminyl inositol is a precursor of mycothiol.","4.The purified deacetylase of claim 1, wherein the acetyl glucoasaminyl inositol is N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcNAc-Ins).","5.The purified deacetylase of claim 1, wherein the three domains have amino acid sequences selected from the group consisting of SEQ ID NOS: 3, 4, 5, 6, conservative variations thereof, and any combination of two or more thereof.","6.The purified deacetylase of claim 1, wherein the deacetylase is derived from an actinomycetes.","7.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. smegmatis.","8.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. tuberculosis.","9.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. leprae.","10.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. bovis.","11.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. smegmatis, M. tuberculosis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum.","M. chelonai, Corynebacterium diphtheriae, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, or M. scrofulaceum.","12.The purified deacetylase of claim 6, wherein the bacterium is selected from the group consisting of Streptomyces lincolnensis, Amycolatopsis mediterranei, Amycolatopsis orientalis, Streptomyces lavendulae, Streptomyces coelicolor, Streptomyces rochei and Saccharopolyspora erythraea.","13.The purified deacetylase of claim 1, wherein the deacetylase has amidase activity against acyl glucosaminyl inositols.","14.The purified deacetylase of claim 1, wherein the deacetylase has an amino acid sequence as set forth in SEQ ID NO:1 15.The purified deacetylase of claim 1, wherein the deacetylase is encoded by a polynucleotide comprising a nucleic acid sequence as set forth in SEQ ID NO:7.16.A purified acetyl glucosaminyl inositol deacetylase, characterized as having: a) an N-terminal region with an amino acid sequence with at least 40% sequence identity to SEQ ID NO:2, b) one or more domains of conservation containing conserved metal chelating residues, and c) deacetylase activity against acetyl glucosaminyl inositol in the presence of metal ion.","17.The purified deacetylase of claim 16, wherein the metal ion is selected from the group consisting of Mn2+ and Ni2, Cd2+, Co2+, and Zn2+.","18.The purified deacetylase of claim 17 wherein the metal ion is Zn2+.","19.The purified deacetylase of claim 16, wherein the metal chelating residues are selected from the group consisting of histidine, aspartic acid and glutamic acid, and combinations thereof.","20.An antibody, or functional fragment thereof, that binds specifically to an deacetylase of claim 1.21.An isolated polynucleotide that encodes a deacetylase of claim 1.22.A vector containing a polynucleotide that encodes an deacetylase of claim 1.23.A cell transformed with a vector of claim 22.24.A method for identifying an inhibitor of acetyl glucosaminyl inositol deacetylase, said method comprising: a) contacting a candidate compound with a deacetylase of claim 1 in the presence of an acyl glucosaminyl inositol under suitable conditions and b) determining the presence or absence of breakdown products of the acyl glucosaminyl inositol indicative of deacetylase activity or amidase activity, wherein the substantial absence of the deacetylase activity or the amidase activity is indicative of a candidate compound that inhibits activity of the deacetylase.","25.The method of claim 24, wherein the deacetylase is an acetyl glucosaminyl inositol deacetylase.","26.The method of claim 24, wherein a breakdown product is a free amine.","27.The method of claim 26, wherein the free amine is GlcN-Ins.","28.The method of claim 24, wherein a breakdown product is acetate 29.The method of claim 24, wherein a breakdown product is a derivative of cysteine.","30.The method of claim 24, wherein the acyl glucosaminyl inositol is N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside.","31.The method of claim 24, wherein the acyl glucosaminyl inositol is an S-conjugate of mycothiol.","32.The method of claim 31, wherein the S-conjugate of mycothiol is the monobromobimane derivative of mycothiol (MSmB).","33.The method of claim 24, wherein the three domains in the deacetylase that contain conserved histidine residues have amino acid sequences selected from SEQ ID NOs: 3, 5, 6 and any combination of two or more thereof.","34.The method of claim 24, wherein the deacetylase is produced in an actinomycete.","35.The method of claim 34, wherein the actinomycete is M. smegmatis.","36.The method of claim 34, wherein the actinomycete is M. tuberculosis.","37.The method of claim 34, wherein the actinomycete is M. leprae.","38.The method of claim 34, wherein the actinomycete is M. bovis.","39.The method of claim 34, wherein the actinomycete is M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheriae, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, or M. scrofulaceum.","40.The method of claim 24, wherein candidate compound is a polypeptide, polynucleotide or small molecule.","41.A high throughput screening method for identifying inhibitors of the deacetylase of claim 1, said method comprising: a) contacting each of a plurality of candidate compounds with a deacetylase of claim 1 in the presence of acyl glucosaminyl inositol under suitable conditions to form a plurality of reaction mixtures and b) determining the presence or absence of binding to the reaction mixtures of a detectable marker that binds to free amine, wherein the substantial absence of binding of the marker to a reaction mixture is indicative of a candidate compound that inhibits activity of the deacetylase.","42.The method of claim 41, wherein the plurality of reaction mixtures are formed in the wells of a microtiter plate.","43.The method of claim 41, wherein the detectable marker is colorometric or fluorometric.","44.The method of claim 43 wherein the fluorometric marker is fluorescamine or 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate.","45.An inhibitor of the deacetylase of claim 1 wherein the inhibitor is derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates Zn2+, or otherwise binds the enzyme active site of the deacetylase.","46.The inhibitor of claim 45 wherein the inhibitor additionally chelates one or more metal ions metal ions selected from the group consisting of Mn2+ and Ni2, Cd2+, and Co2+.","47.A derivative of GlcN-Ins, wherein the derivative contains a reactive residue attached to the amino group that promotes oxidative stress so as to be selectively toxic to a mycothiol-producing actinomycete by being concentrated in the actinomycete.","48.The derivative of claim 47, wherein the reactive residue is a nitroso residue.","49.The derivative of claim 47, wherein the reactive residue is a nitroalkyl residue comprising 1 to 3 carbon atoms.","50.The derivative of claim 47, wherein the reactive residue is a S-nitrosomercaptoalkyl residue comprising 2 to 4 carbon atoms.","51.The derivative of claim 47, wherein the reactive residue is a peroxyalkyl residue comprising 2 to 4 carbon atoms.","52.A live mutant actinomycete, whose genome comprises a disruption in an endogenous acetyl glucosaminyl inositol deacetylase gene, wherein said disruption prevents function of an endogenous acetyl glucosaminyl inositol deacetylase while cell surface proteins and lipids are substantially unaffected, and wherein said disruption results in said mutant actinomycetes exhibiting transient survival in mammalian white blood cells for an immune response-raising period of time.","53.The live mutant actinomycete of claim 52, wherein the period of time is from 1 to 30 days.","54.The live mutant actinomycete of claim 52, wherein the survival of the mutant actinomycetes in mammalian white blood cells does not exceed 30 days.","55.The live mutant actinomycete of claim 52, wherein the mutant actinomycete is derived from a pathogen selected from the group consisting of M. smegmatis, M. tuberculosis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheria, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, and M. scrofulaceum.","56.The live mutant actinomycete of claim 52, wherein the mutant actinomycetes.","is derived from M. smegmatis.","57.The live mutant actinomycete of claim 52, wherein the mutant actinomycetes is derived from M. tuberculosis.","58.The live mutant actinomycete of claim 52, wherein the mutant actinomycetes is derived from M. leprae.","59.The live mutant actinomycete of claim 52, wherein the mutant actinomycetes is derived from M. bovis and said mammal is bovine.","60.A method for decreasing the virulence of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium in mammalian cells, said method comprising: introducing into the bacterium an inhibitor of acetyl glucosaminyl inositol deacetylase activity, wherein the intracellular presence of the inhibitor decreases activity of the deacetylase, thereby decreasing mycothiol biosynthesis by the bacterium as compared with untreated control bacterium.","61.The method of claim 60, wherein the inhibitor inhibits intracellular production of the deacetylase.","62.The method of claim 60, wherein the inhibitor inhibits intracellular deacetylase activity of the deacetylase.","63.The method of claim 60, wherein the introducing comprises culturing the bacterium in the presence of the inhibitor.","64.The method of claim 60, wherein the inhibitor is an anti-sense oligonucleotide complementary to a target region in a messenger RNA that encodes a polypeptide having an amino acid sequence segment with 40% or more sequence identity to the amino acid sequence of SEQ ID NO:2 or at least one amino acid sequence selected from the group consisting of SEQ ID NOS: 3, 4, 5, 6 and conservative variations thereof.","65.The method of claim 60, wherein the inhibitor is an anti-sense oligonucleotide that hybridizes under intracellular conditions with a messenger RNA that encodes a polypeptide having an N-terminal amino acid sequence as set forth in SEQ ID NO:2.66.The method of claim 60, wherein the bacterium is an actinomycete and the inhibitor inhibits intracellular production of mycothiol.","67.The method of claim 60, wherein the bacterium is selected from the group consisting of the pathogenic bacteria M. smegmatis, M. tuberculosis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheria, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M abscessus, and M. scrofulaceum.","68.The method of claim 60, wherein the bacterium is an actinomycete.","69.A method for inhibiting growth of an acetyl glucosaminyl inositol-producing bacterium in a mammal, said method comprising administering to the mammal an effective amount of an inhibitor of intracellular acetyl glucosaminyl inositol deacetylase, thereby inhibiting growth of the bacterium in the mammal.","70.The method of claim 69, wherein the inhibitor is derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates a metal ion selected from the group consisting of Mn2+ and Ni2, Cd2+, Co2+, and Zn2+, or otherwise binds the enzyme active site in the deacetylase.","71.The method of claim 70, wherein the moiety is ClCH2CONH—.","72.The method of claim 70 wherein the moiety is HONHCONH—.","73.The method of claim 70, wherein the moiety is HONHCOCH2—.","74.The method of claim 70, wherein the moiety is HOPO(CH3)NH—.","75.The method of claim 70, wherein the moiety is HOPO(CH3)nCH2—; wherein n=1-5.76.The method of claim 70 wherein the moiety is HSCH2(CH2)nNH—; wherein n=2-5.77.The method of claim 70 wherein the moiety is HS(CH2)nCONH—; wherein n=1-3.78.The method of claim 69 wherein the acetyl glucosaminyl inositol-producing bacterium is a mycothiol-producing bacterium.","79.A process for preparation of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins), said method comprising: contacting an acyl glucosaminyl inositol with an deacetylase of claim 1 under suitable conditions so as to hydrolyze the amide bond therein, and obtaining the GlcN-Ins.","80.A method for determination of acetyl glucosaminyl inositol (GlcNAc-Ins) in a sample, said method comprising: a) contacting a sample containing GlcNAc-Ins with a deacetylase of claim 1 under suitable conditions and b) determining the amount of GlcN-Ins produced, wherein the amount of GlcN-Ins produced is a measure of the GlcNAc-Ins in the sample.","81.The method of claim 80, wherein the amount of GlcN-Ins is determined by HPLC after labeling thereof with a fluorometric or calorimetric reagent.","82.The method of claim 81, wherein the fluorometric reagent is fluorescamine.","83.The method of claim 81, wherein the fluorometric reagent is 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate."],["<SOH> BACKGROUND INFORMATION <EOH>Glutathione (GSH) is the dominant low molecular weight thiol in most eukaryotes and Gram-negative bacteria, and it plays a key role in protection of the cell against oxygen toxicity and electrophilic toxins.","However, most gram positive bacteria, including many strict aerobes, do not produce glutathione.","Yet aerobic organisms are subjected to oxidative stress from many sources, including atmospheric oxygen, basal metabolic activities, and, in the case of pathogenic microorganisms, toxic oxidants from the host phagocytic response intended to destroy the bacterial invader.","Actinomycetes, including Streptomyces and Mycobacteria , do not make GSH but produce instead millimolar levels of mycothiol (MSH, AcCys-GlcN-Ins), an unusual conjugate of N-acetylcysteine (AcCys) with 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins).","The biochemistry of mycothiol appears to have evolved completely independently of that of glutathione.","However, it has already been established that the metabolism of mycothiol parallels that of glutathione metabolism in two enzymatic processes.","First, formaldehyde is detoxified in glutathione-producing organisms by NAD/glutathione-dependent formaldehyde dehydrogenase (L. Uotila, et al.","(1989) in Glutathione: Chemical, Biochemical, and Medical Aspects—Part A (D. Dolphin, et al., Eds.)","pp 517-551, John Wiley & Sons, et al.).","An analogous process involving NAD/mycothiol-dependent formaldehyde dehydrogenase has been identified in the actinomycete Amycolatopsis methanolica (M. Misset-Smits, et al.","(1997) FEBS Lett.","409:221-222).","This enzyme has been sequenced (A. Norin, et al.","(1997) Eur.","J. Biochem.","248:282-289).","The second enzymatic process involves a mycothiol homolog of glutahione reductase recently cloned from M. tuberculosis and expressed in M. smegmatis (M. P. Patel, et al.","(1999) J. Amer.","Chem.","Soc.","120:11538-11539; M. P. Patel et al.","(1999) Biochemistry 38:11827-11833; M. P. Patel et al (2001) Biochemistry 40:3119-3126).","The reductase is reasonably specific for the disulfide of mycothiol, but is also active with the disulfide of AcCys-GlcN, the desmyo-inositol derivative of mycothiol.","Therefore, there is a need in the art for methods and compounds useful for investigation of the details of the metabolism of mycothiol and comparison with the established roles for the metabolism of glutathione.","Antibiotic resistance of pathogenic bacteria, including pathogenic actinomycetes, such as M. tuberculosis , is a well-known problem faced by medical practitioners in treatment of bacterial diseases.","Therefore, there is a need in the art for new antibiotics, drugs and vaccines and for screening techniques to discover antibiotics, drugs and vaccines effective to treat or prevent bacterial infections in humans and in other mammals, such as domestic and farm animals."],["<SOH> SUMMARY OF THE INVENTION <EOH>The present invention solves these and other problems in the art by providing, in one embodiment, purified acetyl glucosaminyl inositol deacetylases, characterized as having an N-terminal region with an amino acid sequence with 40% or more sequence identity to SEQ ID NO:2 and conservative variations thereof, four domains of conservation, wherein three of the domains contain conserved histidine residues, and deacetylase activity against acetyl glucosaminyl inositol.","In another embodiment, the invention provides purified acetyl glucosaminyl inositol deacetylases characterized as having an N-terminal region with an amino acid sequence with at least 40% sequence identity to SEQ ID NO:2, one or more domains of conservation containing conserved metal chelating residues, and deacetylase activity against acetyl glucosaminyl inositol in the presence of metal ion.","Antibodies and functional fragment thereof, that bind specifically to invention deacetylases, isolated polynucleotide that encode the invention deacetylases, vectors containing a polynucleotide that encodes an invention deacetylase and cells containing such vectors are also provided.","In another embodiment, the invention provides methods for identifying an inhibitor of acetyl glucosaminyl inositol deacetylase by contacting a candidate compound with an invention deacetylase in the presence of an acyl glucosaminyl inositol under suitable conditions and determining the presence or absence of breakdown products of the acyl glucosaminyl inositol indicative of deacetylase activity.","Substantial absence of the breakdown product of deacetylase activity is indicative of a candidate compound that inhibits activity of the deacetylase.","In yet another embodiment, the present invention provides high throughput screening methods for identifying inhibitors of the invention deacetylases.","The screening methods involve contacting each of a plurality of candidate compounds with an invention deacetylase in the presence of acyl glucosaminyl inositol under suitable conditions to form a plurality of reaction mixtures and determining the presence or absence of binding to the reaction mixtures of a detectable marker that binds to free amine.","Substantial absence of binding of the marker to a reaction mixture in the invention screening methods is indicative of a candidate compound that inhibits activity of the deacetylase.","In yet another embodiment, the present invention provides derivatives of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins), wherein the derivative contains a reactive residue attached to the amino group that promotes oxidative stress and wherein the derivative is selectively toxic to a mycothiol-producing actinomycete by being concentrated in the actinomycete.","In still another embodiment, the present invention provides live mutant actinomycetes.","The invention mutant actinomycetes have a genome with a disruption in an endogenous acetyl glucosaminyl inositol deacetylase gene, wherein said disruption prevents function of an endogenous acetyl glucosaminyl inositol deacetylase while cell surface proteins and lipids are substantially unaffected, and wherein the disruption results in the mutant actinomycetes exhibiting survival in mammalian white blood cells for an immune response raising period of time.","In yet another embodiment, the present invention provides methods for decreasing the virulence of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium in mammalian cells by introducing into the bacterium an inhibitor of acetyl glucosaminyl inositol deacetylase activity.","The intracellular presence of the inhibitor in the bacterium decreases activity of the deacetylase, thereby decreasing mycothiol biosynthesis by the bacterium as compared with untreated control bacterium.","By virulence is meant the relative power and degree of pathogenicity possessed by organisms to produce disease as measured by clinical symptoms particular to the disease under consideration.","For example, the virulence of a M. tuberculosis is measured with reference to the manifestation in an infected individual of the clinical symptoms recognized by a medical practitioner as indicative of tuberculosis.","In another embodiment, the present invention provides inhibitors of the invention acetyl glucosaminyl inositol deacetylases wherein the inhibitor is derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates Zn 2+ , or otherwise binds the enzyme active site of the deacetylase.","In still another embodiment, the present invention provides methods for inhibiting growth of an acetyl glucosaminyl inositol-producing bacterium in a mammal, by administering to the mammal an effective amount of an inhibitor of intracellular acetyl glucosaminyl inositol deacetylase, thereby inhibiting growth of the bacterium in the mammal.","In yet another embodiment, the present invention provides processes for preparation of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins) by contacting an acyl glucosaminyl inositol with an invention deacetylase under suitable conditions so as to hydrolyze the amide bond therein, and obtaining the GlcN-Ins."],["FIELD OF THE INVENTION The present invention generally relates to a family of enzymatic compounds produced by bacteria and methods of their use in drug discovery and disease control, and more specifically to acetyl glucosaminyl inositol deacetylases and methods of their use.","BACKGROUND INFORMATION Glutathione (GSH) is the dominant low molecular weight thiol in most eukaryotes and Gram-negative bacteria, and it plays a key role in protection of the cell against oxygen toxicity and electrophilic toxins.","However, most gram positive bacteria, including many strict aerobes, do not produce glutathione.","Yet aerobic organisms are subjected to oxidative stress from many sources, including atmospheric oxygen, basal metabolic activities, and, in the case of pathogenic microorganisms, toxic oxidants from the host phagocytic response intended to destroy the bacterial invader.","Actinomycetes, including Streptomyces and Mycobacteria, do not make GSH but produce instead millimolar levels of mycothiol (MSH, AcCys-GlcN-Ins), an unusual conjugate of N-acetylcysteine (AcCys) with 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins).","The biochemistry of mycothiol appears to have evolved completely independently of that of glutathione.","However, it has already been established that the metabolism of mycothiol parallels that of glutathione metabolism in two enzymatic processes.","First, formaldehyde is detoxified in glutathione-producing organisms by NAD/glutathione-dependent formaldehyde dehydrogenase (L. Uotila, et al.","(1989) in Glutathione: Chemical, Biochemical, and Medical Aspects—Part A (D. Dolphin, et al., Eds.)","pp 517-551, John Wiley & Sons, et al.).","An analogous process involving NAD/mycothiol-dependent formaldehyde dehydrogenase has been identified in the actinomycete Amycolatopsis methanolica (M. Misset-Smits, et al.","(1997) FEBS Lett.","409:221-222).","This enzyme has been sequenced (A. Norin, et al.","(1997) Eur.","J. Biochem.","248:282-289).","The second enzymatic process involves a mycothiol homolog of glutahione reductase recently cloned from M. tuberculosis and expressed in M. smegmatis (M. P. Patel, et al.","(1999) J. Amer.","Chem.","Soc.","120:11538-11539; M. P. Patel et al.","(1999) Biochemistry 38:11827-11833; M. P. Patel et al (2001) Biochemistry 40:3119-3126).","The reductase is reasonably specific for the disulfide of mycothiol, but is also active with the disulfide of AcCys-GlcN, the desmyo-inositol derivative of mycothiol.","Therefore, there is a need in the art for methods and compounds useful for investigation of the details of the metabolism of mycothiol and comparison with the established roles for the metabolism of glutathione.","Antibiotic resistance of pathogenic bacteria, including pathogenic actinomycetes, such as M. tuberculosis, is a well-known problem faced by medical practitioners in treatment of bacterial diseases.","Therefore, there is a need in the art for new antibiotics, drugs and vaccines and for screening techniques to discover antibiotics, drugs and vaccines effective to treat or prevent bacterial infections in humans and in other mammals, such as domestic and farm animals.","SUMMARY OF THE INVENTION The present invention solves these and other problems in the art by providing, in one embodiment, purified acetyl glucosaminyl inositol deacetylases, characterized as having an N-terminal region with an amino acid sequence with 40% or more sequence identity to SEQ ID NO:2 and conservative variations thereof, four domains of conservation, wherein three of the domains contain conserved histidine residues, and deacetylase activity against acetyl glucosaminyl inositol.","In another embodiment, the invention provides purified acetyl glucosaminyl inositol deacetylases characterized as having an N-terminal region with an amino acid sequence with at least 40% sequence identity to SEQ ID NO:2, one or more domains of conservation containing conserved metal chelating residues, and deacetylase activity against acetyl glucosaminyl inositol in the presence of metal ion.","Antibodies and functional fragment thereof, that bind specifically to invention deacetylases, isolated polynucleotide that encode the invention deacetylases, vectors containing a polynucleotide that encodes an invention deacetylase and cells containing such vectors are also provided.","In another embodiment, the invention provides methods for identifying an inhibitor of acetyl glucosaminyl inositol deacetylase by contacting a candidate compound with an invention deacetylase in the presence of an acyl glucosaminyl inositol under suitable conditions and determining the presence or absence of breakdown products of the acyl glucosaminyl inositol indicative of deacetylase activity.","Substantial absence of the breakdown product of deacetylase activity is indicative of a candidate compound that inhibits activity of the deacetylase.","In yet another embodiment, the present invention provides high throughput screening methods for identifying inhibitors of the invention deacetylases.","The screening methods involve contacting each of a plurality of candidate compounds with an invention deacetylase in the presence of acyl glucosaminyl inositol under suitable conditions to form a plurality of reaction mixtures and determining the presence or absence of binding to the reaction mixtures of a detectable marker that binds to free amine.","Substantial absence of binding of the marker to a reaction mixture in the invention screening methods is indicative of a candidate compound that inhibits activity of the deacetylase.","In yet another embodiment, the present invention provides derivatives of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins), wherein the derivative contains a reactive residue attached to the amino group that promotes oxidative stress and wherein the derivative is selectively toxic to a mycothiol-producing actinomycete by being concentrated in the actinomycete.","In still another embodiment, the present invention provides live mutant actinomycetes.","The invention mutant actinomycetes have a genome with a disruption in an endogenous acetyl glucosaminyl inositol deacetylase gene, wherein said disruption prevents function of an endogenous acetyl glucosaminyl inositol deacetylase while cell surface proteins and lipids are substantially unaffected, and wherein the disruption results in the mutant actinomycetes exhibiting survival in mammalian white blood cells for an immune response raising period of time.","In yet another embodiment, the present invention provides methods for decreasing the virulence of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium in mammalian cells by introducing into the bacterium an inhibitor of acetyl glucosaminyl inositol deacetylase activity.","The intracellular presence of the inhibitor in the bacterium decreases activity of the deacetylase, thereby decreasing mycothiol biosynthesis by the bacterium as compared with untreated control bacterium.","By virulence is meant the relative power and degree of pathogenicity possessed by organisms to produce disease as measured by clinical symptoms particular to the disease under consideration.","For example, the virulence of a M. tuberculosis is measured with reference to the manifestation in an infected individual of the clinical symptoms recognized by a medical practitioner as indicative of tuberculosis.","In another embodiment, the present invention provides inhibitors of the invention acetyl glucosaminyl inositol deacetylases wherein the inhibitor is derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates Zn2+, or otherwise binds the enzyme active site of the deacetylase.","In still another embodiment, the present invention provides methods for inhibiting growth of an acetyl glucosaminyl inositol-producing bacterium in a mammal, by administering to the mammal an effective amount of an inhibitor of intracellular acetyl glucosaminyl inositol deacetylase, thereby inhibiting growth of the bacterium in the mammal.","In yet another embodiment, the present invention provides processes for preparation of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins) by contacting an acyl glucosaminyl inositol with an invention deacetylase under suitable conditions so as to hydrolyze the amide bond therein, and obtaining the GlcN-Ins.","BRIEF DESCRIPTION OF THE DRAWINGS FIGS.","1A and B show the nucleotide sequence of M. tuberculosis deacetylase gene mshB (Rv1170) (SEQ ID NO:7).","FIG.","1C shows the deduced amino acid sequence of M. tuberculosis GlcNAc-Ins deacetylase (SEQ ID NO:1) encoded by mshB.","FIG.","2 is a schematic drawing showing a map of plasmid pYA1170b employed to express Rv1170 in E. coli.","FIG.","3 is a chart showing the chemical structures of the substrates for assaying deacetylase and amidase activities of the invention acetyl glucosaminyl inositol deacetylases (MshB), such as MshB Rv1170 and homologs.","FIG.","4 is a graph showing growth of a mutant M. smegmatis (mutant 49) in 7H9 Middlebrook medium containing 17 μM GlcNAc-Ins.","Mycothiol (MSH) and MSH precursor contents in cells are expressed in micromoles per gram of residual dry weight (RDW).","FIG.","5 is a schematic representation of the proposed MSH biosynthesis pathway.","FIG.","6 is a chart showing alignment of the amino acid sequences of four homologs of MshB of M. tuberculosis H37Rv (Rv1170) GenBank accession number B70875 and M. leprae GenBank accession number CAC30445.Sequences for M. avium (The Institute for Genomic Research (TIGR)), and M. smegmatis (Sanger Center) are from unfinished genomes.","FIG.","7 is a graph showing MshB deacetylase activity with 0.1 mM GlcNAc-Ins in the presence of 1,10-phenanthroline.","FIG.","8A is a graph showing MshB deacetylase reaction specific activity with 0.8 mM GlcNAc-Ins as substrate in the presence of increasing concentrations of thiol inhibitors.","FIG.","8B is a graph showing MshB amidase reaction specific activity with 0.55 mM MSmB as substrate in the presence of increasing concentrations of inhibitors.","FIG.","9 is a map of the plasmid pYA1170C used to express the recombinant His-tagged acetyl glucosaminyl inositol deacetylase encoded by M. tuberculosis Rv1170.FIG.","10 is a graph showing percent survival of strains of M. smegmatis versus hydrogen peroxide concentration after treatment as described in Example 11 herein.","Open triangles=mutant TN3, which produces no MSH; open circles=chemical mutant 164, which produces a low residual MSH content; and darkened squares=high MSH content mc2 155.FIG.","11 is a graph showing percent survival over time of strains of M. smegmatis in murine macrophages as described in Example 11 herein.","Open circles=chemical mutant TN3 (0% MSH content), Experiment 1; open triangles=mutant TN3 (0% MSH content), Experiment 2; and darkened squares=mc2155 (100% MSH content).","DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there are provided a family of purified acetyl glucosaminyl inositol deacetylase polypeptides with enzymatic deacetylase activity for acetyl glucosaminyl inositol.","The invention acetyl glucosaminyl inositol deacetylases are characterized by having an N-terminal region with an amino acid sequence with 40% or greater sequence identity to an amino acid sequence as set forth in SEQ ID NO:2 and conservative variation thereof, four domains of conservation, wherein three of the domains contain conserved histidine residues, and deacetylase activity against acetyl glucosaminyl inositol.","SEQ ID NO:2 corresponds to amino acid residues 1-100 of amino acids of SEQ ID NO:1 (FIG.","1C).","The members of the family of invention deacetylases hydrolyze a C2-amide bond of acetyl glucosaminyl inositol moiety, such as N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcNAc-Ins).","Preferably the acetyl glucosaminyl inositol is a precursor of mycothiol (e.g., in a mycothiol producing bacterium).","In preferred embodiments the three histidine-containing conserved domains in the invention deacetylases are selected from VHAHPDDE (SEQ ID NO:3), which corresponds to amino acids 10 through 17 of SEQ ID NO:1; VTCTLGEXGEV (SEQ ID NO:4), which corresponds to amino acids 38 through 49 of amino acid SEQ ID NO:1; YDPXGGYGHPDH (SEQ ID NO:5), which corresponds to amino acids 136 through 147 of SEQ ID NO:1; and AXXAHATQ (SEQ ID NO:6), which corresponds to amino acids 240 through 247 of amino acid SEQ ID NO:1 (FIG.","1C) wherein X is any amino acid; and conservative variations thereof, or any combination of any two or more thereof (See FIG.","6).","Members of the invention family of acetyl glucosaminyl inositol deacetylase polypeptides are metalloproteases.","Accordingly, the invention further provides purified acetyl glucosaminyl inositol deacetylases that are characterized as having an N-terminal region with an amino acid sequence with at least 40% sequence identity to SEQ ID NO:2, one or more domains of conservation containing conserved metal chelating residues, and deacetylase activity against acetyl glucosaminyl inositol in the presence of metal ion.","The invention deacetylases have been shown to contain an active site that contains a metal ion selected from the group consisting of Mn2+, Ni2, Cd2+, Co2+, and Zn2+, with the preferred metal ion being Zn2+.","The metal chelating residues in the invention deacetylases are preferably selected from the group consisting of histidine, aspartic acid and glutamic acid, and combinations thereof.","In preferred embodiments, the invention deacetylases have additional activity as amidases, catalyzing the hydrolysis of acyl glucosaminyl inositols.","As used herein, the term “acyl glucosaminyl inositol” means substrate compounds for the invention family of deacetylases having the chemical formula R—CONH-GlcN-Ins wherein R═CH3(CH2)n— where n=0-6.Included in the group of substrate compounds is the natural substrate, acetyl-GlcN-Ins, where n=0.Members of this group of substrate compounds are derived from an alkanoic acid.","In addition, compounds having the chemical structure R—CONH-GlcN-Ins wherein R=aryl-(CH2)n, where n=0-6 are encompassed by the term.","Members of this group of substrate compounds are derived from an aryl alkanoic acid such as phenyl-(CH2)nCOOH.","The acyl glucosaminyl inositols of the above chemical formula can also be derived from the reaction of GlcN-Ins with any commercial acid chloride in the form RCOCl, wherein R is: o-tolyl-, 4-ethylphenyl-, 4-propylphenyl-, 4-biphenyl-, 3,4-dimethoxyphenyl-, 3,4,5-trimethoxyphenyl-, 2-furyl-, and the like.","The acyl glucosaminyl inositols of the above chemical formula can also be derived from an amino acid or an N-acetyl amino acid.","Preferred amino acids include N-acetylcysteinyl-S—R′ or cysteinyl-S—R′, wherein R′ is an organic group attached to the cysteine sulfur, such as may be derived from commercial thiol labeling reagents like 2-bromoacetophenone, monobromobinane, N-ethylmaleimide, cerulenin, 7-diethylamino-3-(4′-maleimidyl phenyl)-4-methyl coumarin, 3(N-maleimidopropionyl)biocytin, and the like.","The studies described herein further elaborate the pathway involved in MSH biosynthesis.","The present studies demonstrate that GlcNAc-Ins is a major intracellular MSH component in M. smegmatis and is converted to GlcN-Ins by GlcNAc-Ins deacetylase.","This conversion defines the second step in MSH biosynthesis.","The discovery described herein that Rv1170 is the gene encoding the deacetylase in the M. tuberculosis genome represents the first gene of the MSH biosynthesis pathway to be identified.","Assuming that a single enzyme produces GlcNAc-Ins, it is proposed that the genes for the MSH biosynthesis pathway be designated mshA, mshB, mshC, and mshD, with the corresponding enzymes labeled as shown in FIG.","5.Identification of mshA, mshC, and mshD would be greatly simplified if they were clustered with mshB in a single operon, but inspection of the gene assignments and open reading frames surrounding mshB (Rv1170) in the M. tuberculosis genome indicates that this is not the case.","All mycobacteria thus far examined have high MSH content (G. L. Newton et al.","(1996) J. Bacteriol.","178:1990-1995) and, based on the studies described herein, are expected to have an ortholog of the MSH biosynthesis enzyme MshB (Rv1170).","The available unfinished mycobacterial genome databases yield homologs close to Rv1170 for Mycobacterium leprae (Sanger Centre), Mycobacterium bovis (Sanger Centre), M tuberculosis CDC1551 (The Institute for Genomic Research [TIGR]), M. smegmatis (TIGR), and Mycobacterium avium (TIGR).","This sequence homology (FIG.","6) indicates that MSH biosynthesis in these organisms utilizes a GlcNAc-Ins deacetylase (MshB) in the same manner as that described here for M. smegmatis.","Other actinomycetes that produce MSH are also expected to have a GlcNAc-Ins deacetylase (MshB) gene homologous to Rv1170.Sequence BLAST searches to determine molecules with amino acid homology to the Rv1170 sequence of SEQ ID NO:1 (FIG.","1C) also show M. tuberculosis homolog Rv1082 (mycothiol S-conjugate deacetylase) and the Rv1082 orthologs from M. leprae, M. bovis (Sanger Centre), M. tuberculosis CDC1551 (TIGR), M. smegmatis (TIGR), and M. avium (TIGR) to be close homologs.","Sequences with partial homology to Rv1170 were also found in the yeast, rat, and human genome databases.","These genes code for PIG-L, the second enzyme in glycosylphosphatidylinositol (GPI) anchor biosynthesis (Nakamura et al., (1997) J. Biol.","Chem.","272:15834-15840), and catalyze the deacetylation of N-acetylglucosaminyl-phosphatidylinositol (GlcNAc-PI).","The studies described in the Examples herein indicate that the invention deacetylase is rather specific for GlcNAc-Ins and is not a broad spectrum deacetylase.","For example, removal of the inositol residue from the substrate GlcNAc-Ins resulted in a more than 300-fold decrease in reactivity (i.e., GlcNAc-Ins versus GlcNAc) (Table 1).","Also, the studies described herein (Table 1) show that neither MSH nor MSmB is deacetylated by the invention deacetylases.","Therefore, the AcCys moiety of MSH is inert to the deacetylase.","This finding shows that the invention deacetylase has no significant activity for the degradation of MSH.","The invention deacetylase appears to be the control point for MSH biosynthesis.","In cells tested, a very large endogenous pool of its substrate GlcNAc-Ins (12 to 15 μmol per g of residual dry weight (RDW)) was found (Table 2), but quite low levels were found of its product GlcN-Ins (˜0.2 μmol per g of RDW) (Table 2) and of the final intermediate Cys-GlcN-Ins (<0.006 μmol per g of RDW) leading to MSH.","This finding shows that substantial quantities of MSH can be produced upon demand from the endogenous pool of GlcNAc-Ins under control of the invention family of acetyl glucosaminyl inositol deacetylases.","If a particular member of the invention family of polypeptide deacetylases hydrolyzes its substrate (GlcNAc-Ins), cleavage of the substrate molecule will form breakdown products wherein one product is a free amine (e.g., 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins)) and the other product is acetate.","If a particular member of the invention family of polypeptide deacetylases has activity as an amide hydrolase (amidase), cleavage of the substrate acyl glucosaminyl inositol will form breakdown products wherein one product is a carboxylic acid, and the other product is a free amine (e.g., GlcN-Ins).","If the substrate amide is a mycothiol-derived amide, one of the breakdown products will be GlcN-Ins and the other breakdown product will be a sulfur-containing carboxylic acid, such as an AcCys S-conjugate.","AcCys S-conjugates are termed mercapturic acids, the final excreted product in the mercapturic acid pathway of glutathione-dependent detoxification in mammals.","Mycothiol (1-D-myo-inosityl-2-(N-acetylcysteinyl)amido-2-deoxy-α-D-glucopyranoside) (MSH) is present in a variety of actinomycetes and plays an essential role in a pathway of detoxification in such bacteria.","Mycothiol is comprised of N-acetylcysteine (AcCys) amide linked to 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins) and is the major thiol produced by most actinomycetes.","In the mycothiol-dependent detoxification process in actinomycetes, an alkylating agent is converted to a S-conjugate of mycothiol, the latter is cleaved to release a mercapturic acid, and the mercapturic acid is excreted from the cell (Newton et al.","(2000) Biochemistry 39:10739-10746).","It has been discovered that invention acetyl glucosaminyl inositol deacetylases participate in the pathway of mycothiol biosynthesis in which substrate GlcNAc-Ins is an intermediate.","In the mycothiol pathway as shown schematically in FIG.","5, GlcNAc-Ins is converted to GlcN-Ins by the invention deacetylase.","In fact, the studies disclosed herein have shown that the invention deacetylases are the critical step in the production of mycothiol in actinomycetes.","For example, it has been shown by the studies described herein (Example 10) that MshB is inhibited by mycothiol in a manner consistent with a negative feedback loop dependent upon the level of mycothiol for control of mycothiol biosynthesis in the cell.","Thus, a falling level of mycothiol in the cell available for detoxification of intracellular toxins increases activity of the deacetylase so that substrate GlcNAc-Ins will be cleaved by the expressed deacetylase, in turn, providing the GlcN-Ins moiety necessary for mycothiol production.","A member of the invention family of polypeptide deacetylases shown to be responsible for cleavage of GlcNAc-Ins has been cloned from M. tuberculosis gene Rv1170 and has an amino acid sequence as set for in SEQ ID NO:1 (shown in FIG.","1C; see also GenBank Accession No.","B70875) and a nucleotide sequence as set forth in SEQ ID NO:7 (shown in FIG.","1; see also nucleic acid residues 4222-5133 of GenBank Accession No.","AL010186).","The N-terminal region 100 residues of this newly discovered GlcNAc-Ins deacetylase has the amino acid sequence as shown in SEQ ID NO:2.Members of invention family of acetyl glucosaminyl inositol deacetylases are formed in vivo by bacteria as part of a mycothiol biosynthesis pathway, most usually in bacteria characterized by intracellular production of mycothiol.","Additional bacteria from which the invention deacetylase polypeptides can be derived include actinomycetes, such as M. smegmatis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheria, Actinomycetes israelii, M. avium complex (MAC) (Holzman, in Tuberculosis ed.","by Rom and Gary (Little, Brown, and Company, 1996) Chapter 56), M. ulcerans, M. abscessus, or M. scrofulaceum, and the like.","Homologous non-mycobacterial deacetylase proteins can also be derived from the antibiotic producers Streptomyces lincolnensis, Amycolatopsis mediterranei, Amycolatopsis orientalis, Streptomyces lavendulae, Streptomyces coelicolor, Streptomyces rochei, and the polyketide erythromycin antibiotic producer Saccharopolyspora erythraea.","Inhibitors of the invention acetyl glucosaminyl inositol deacetylases are particularly well suited as antibiotics since mycothiol production will cease in the absence of the product GlcN-Ins produced by activity of the invention deacetylases.","Accordingly, in another embodiment according to the present invention, there are provided methods for identifying an inhibitor of an invention acetyl glucosaminyl inositol deacetylase, MshB.","The invention methods comprise contacting a candidate compound with a member of the invention family of deacetylases in the presence of a substrate for the enzyme under suitable conditions and determining the presence or absence of breakdown products of the substrate indicative of deacetylase (or optionally S-conjugate amidase) activity.","For example, if the test compound is a putative inhibitor of amide hydrolase activity of the invention polypeptide deacetylase, the absence of acetate or other carboxylic acid and/or free amine, such as GlcN-Ins, as breakdown products indicates the candidate compound is an inhibitor of the activity of the invention polypeptide as a deacetylase.","The preferred substrate for testing for deacetylase activity of the invention polypeptides is the acetyl glucosaminyl inositol (GlcNAc-Ins).","On the other hand, if the test compound is a putative inhibitor of MshB, the appearance of free amine, such as GlcN-Ins, and/or acetate or carboxylate indicates that the candidate compound is not an inhibitor of the activity of the invention deacetylase as a deacetylase or as an amidase of an acyl glucosaminyl inositol.","A preferred substrate for use in screening for inhibitors of deacetylase activity is N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcNAc-Ins).","Substantial absence of the breakdown products of enzymatic activity is indicative of a candidate compound that inhibits enzymatic activity of the deacetylase.","In a preferred embodiment, the deacetylase used in the invention method is an acetyl glucosaminyl inositol deacetylase and the method is designed to assay for production of free amine.","Such assays can be conducted en masse using a high throughput screening method for identifying inhibitors of the invention deacetylase.","For example, a plurality of candidate compounds can be contacted with an invention deacetylase in the presence of a substrate for the enzyme (e.g.","an acyl glucosaminyl inositol) under suitable conditions (e.g., as shown in the Examples herein) for activity of the deacetylase.","Binding of a marker selected to bind to a breakdown product can then be assayed using any technique known in the art for high throughput screening.","For example, a colorometric or fluorometric marker that binds to free amine can be used to screen a plurality of reaction mixtures formed in the wells of a microtitre plate (Wong, et al.","(2001) Anal.","Biochem.","290:338-346).","A preferred fluorometric marker for use in the invention high throughput screening methods is fluorescamine, which binds to free amine.","In another embodiment of the invention, methods are provided for determination of acetyl glucosaminyl inositol (GlcNAc-Ins) in a sample by contacting a sample containing GlcNAc-Ins with an invention deacetylase under suitable conditions and determining the amount of GlcN-Ins produced, wherein the amount of GlcN-Ins produced is a measure of the GlcNAc-Ins in the sample.","The amount of GlcN-Ins in the sample can be determined by HPLC after labeling thereof with a fluorometric or colorimetric reagent, such as 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (sold as AccQFluor® reagent by Waters), and the like.","In an alternative embodiment of the invention, methods are provided for decreasing the virulence in mammalian cells of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium, such as an actinomycete.","In the invention method for decreasing the virulence of pathogenic acetyl glucosaminyl inositol deacetylase-producing bacteria, an inhibitor of acetyl glucosaminyl inositol deacetylase (for example, one identified by the above-described screening method) is introduced into the bacterium.","Intracellular uptake by the treated bacterium of the inhibitor results in decreased activity of the deacetylase, thereby decreasing mycothiol biosynthesis by the bacterium as compared with untreated control bacterium.","For example, for treatment of isolated mammalian cells, the introducing can comprise culturing the bacterium in the presence of the inhibitor.","Alternatively, for treatment of mammalian cells contained in a living organism, the inhibitor may be administered systemically to the living organism.","Pathogenic acetyl glucosaminyl inositol deacetylase-producing bacteria whose virulence can be reduced according to the invention methods include such actinomycetes as M. smegmatis, M. tuberculosis, M. leprae, M. bovis particularly in bovine subjects), M. intracellulare, M. africanum, and M. marinarum.","M. chelonai, Corynebacterium diphtheriae, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, M. scrofulaceum, and the like.","The inhibitors used in the invention methods for decreasing the virulence of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium may either inhibit intracellular production of the deacetylase or inhibit intracellular deacetylase activity of the deacetylase.","In one embodiment according to the present invention, there are provided inhibitors of the members of the invention family of deacetylase polypeptides.","The invention inhibitors are characterized by being derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates Zn2+ or otherwise binds the enzyme active site.","The invention inhibitors may also chelate one or more metal ions selected from the group consisting of Mn2+ and Ni2, Cd2+, and Co2+.","The following are examples of moieties that can substitute for the amino group in GlcN-Ins in the invention inhibitors: ClCH2CONH— HONHCONH— HONHCOCH2— HOPO(CH3)NH— HOPO(CH3)nCH2—; wherein n=1-5 HSCH2(CH2)nNH—; wherein n=2-5 HS(CH2)nCONH—; wherein n=1-3.In another embodiment according to the present invention, there are provided derivatives of GlcN-Ins, wherein the derivative contains a reactive residue attached to the amino group that promotes oxidative stress (e.g., including nitrosative stress) so as to be selectively toxic to a mycothiol-producing actinomycete by being concentrated in the actinomycete.","Examples of reactive residues that can be attached to the amino group of GlcN-Ins to cause the compound to be selectively toxic to mycothiol-producing actinomycetes by intracellular concentration include, but are not limited to a nitroso residue, a nitroalkyl residue comprising 1 to 3 carbon atoms, a S-nitrosomercaptoalkyl residue comprising 2 to 4 carbon atoms, or a peroxyalkyl residue comprising 2 to 4 carbon atoms.","In another embodiment according to the present invention, the invention inhibitor is an anti-sense oligonucleotide complementary to a target region in a messenger RNA that encodes a polypeptide having an amino acid sequence segment with 40% or more sequence identity to the amino acid sequence of SEQ ID NO:2 or 80% or more sequence identity to at least one amino acid sequence selected from the group consisting of SEQ ID NOS: 3, 4, 5, 6 and conservative variations thereof.","In another embodiment the anti-sense oligonucleotide hybridizes under intracellular conditions with a messenger RNA that encodes a polypeptide having an N-terminal amino acid sequence as set forth in SEQ ID NO:2.For example, in one embodiment, the candidate compound inhibits intracellular production or activity of the acetyl glucosaminyl inositol deacetylase.","A presently preferred drug candidate for screening in live bacteria for activity that inhibits intracellular production or activity of acetyl glucosaminyl inositol deacetylase is an anti-sense oligonucleotide complementary to a target region in a messenger RNA that encodes a polypeptide having an N-terminal amino acid sequence with 40% or more sequence identity to the amino acid sequence set forth in SEQ ID NO:2, or a conservative variation thereof, for example, 50%, 55%, 60% or 65% sequence identity.","Suitable conditions for conducting invention drug screening methods are well known in the art and are described, for example, in the Examples hereinbelow.","Alternatively, an anti-sense oligonucleotide can be designed to hybridize under in vivo conditions with a messenger RNA that encodes a polypeptide having an N-terminal amino acid sequence as set forth in SEQ ID NO:2, or contains an amino acid segment as set forth in SEQ ID NOs:3, 4, 5, and 6, or a conservative variation thereof.","The anti-sense oligonucleotide can comprise from about 10 to about 60 nucleic acid residues, for example from 10 to about 50, or from 10 to about 40, 30 or 20 nucleic acid residues.","“Hybridization” refers to the process by which a nucleic acid strand joins with a complementary strand through base pairing.","Hybridization reactions can be sensitive and selective so that a particular sequence of interest will join with a complementary strand even in samples in which it is present at low concentrations.","Suitable intracellular conditions for hybridization of an anti-sense oligonucleotide to messenger RNA will be determined by the particular bacterium used in the invention method.","In general, the pH, temperature and salt concentration must be comparable to intracellular conditions in the test bacterium.","In yet another embodiment according to the present invention, there are provided live mutant actinomycetes, whose genomes comprise a disruption in an endogenous acetyl glucosaminyl inositol deacetylase gene and thereby prevents mycothiol synthesis.","Disruption of genes for mycothiol biosynthesis in mycobacteria reduces their survival in mammalian macrophages (FIG.","11).","Disruption of the endogenous acetyl glucosaminyl inositol deacetylase gene will prevent function of an endogenous acetyl glucosaminyl inositol deacetylase while cell surface proteins and lipids should be substantially unaffected.","As a result, invention live mutant actinomycetes exhibit the phenotype of transient survival in mammalian white blood cells, such as murine or human white blood cells, for an immune response raising period of time.","Such genetically engineered live mutant actinomycetes will survive in mammalian white blood cells for a period of time from 1 to 30 days, for example from 4 to 25 days or from 5 to 20 days, but in no event for more than 30 days.","Due to lack of intracellular acetyl glucosaminyl inositol deacetylase the invention live mutant bacterium will fail to produce mycothiol.","Hence, the mutant live bacterium is unable to survive the oxidative stress inherent in the intracellular environment of mammalian white blood cells long enough to establish infection in the cells or to establish infection in an immunocompetent mammal containing such white blood cells.","Thus, invention live mutant actinomycetes possess a combination of features desired for a vaccine effective in mammals against infection by such pathogenic actinomycetes as M. smegmatis, M. tuberculosis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheria, Actinomycetes israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, M. scrofulaceum, and the like.","An individual (e.g., an animal, such as a mouse, a farm animal or a human) to which the live mutant is administered according to a protocol appropriate for inducing a protective immune response and who has not previously been infected by the counterpart wild type will mount an immune response to the vaccine, for example an immune response sufficient to protect the individual against future infection by the corresponding wild-type live pathogen.","Alternatively, the invention live mutant actinomycetes are useful as a research tool to investigate the properties desirable in a live mutant vaccine.","In still another embodiment according to the present invention, there are provided processes for preparation of GlcN-Ins by contacting an N-acyl glucosaminyl inositol under suitable conditions with an acetyl glucosaminyl inositol deacetylase so as to hydrolyze the amide bond therein to obtain stereochemically pure α(1-1) GlcN-Ins (1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside).","For example, the N-acyl glucosaminyl inositol can be a mycothiol S-conjugate, such as the bimane derivative of mycothiol.","The deacetylase cleaves the N-acyl glucosaminyl inositol, freeing GlcN-Ins as one of the cleavage breakdown products.","GlcN-Ins has utility in conducting research regarding deacetylase activity and mycothiol biochemistry in bacteria, development of products and procedures for overcoming the antibiotic resistance of pathogenic bacteria, such as actinomycetes, and as a precursor for formation of acyl glucosaminyl inositol derivatives and inhibitors of deacetylases thereof as disclosed herein.","A “conservative variation” in an amino acid sequence is a sequence that differs from a reference sequence by one or more conservative or non-conservative amino acid substitutions, deletions, or insertions, particularly when such a substitution occurs at a site that is not the active site of the molecule, and provided that the polypeptide essentially retains its functional properties.","A conservative amino acid substitution, for example, substitutes one amino acid for another of the same class (e.g., substitution of one hydrophobic amino acid, such as isoleucine, valine, leucine, or methionine, for another, or substitution of one polar amino acid for another, such as substitution of arginine for lysine, glutamic acid for aspartic acid or glutamine for asparagine).","One or more amino acids can be deleted, for example, from an deacetylase polypeptide, resulting in modification of the structure of the polypeptide, without significantly altering its biological activity.","For example, carboxyl-terminal amino acids that are not required for deacetylase or deacetylase activity of the invention polypeptides can be removed.","Biologically functional viral and plasmid DNA vectors capable of expression and replication in a host are known in the art.","Such vectors are used to incorporate DNA sequences of the invention.","In general, expression vectors containing promoter sequences which facilitate the efficient transcription of the inserted eukaryotic genetic sequence are used in connection with the host.","The expression vector typically contains an origin of replication, a promoter, and a terminator, as well as specific genes that are capable of providing phenotypic selection of the transformed cells.","In addition to expression vectors known in the art such as bacterial, yeast and mammalian expression systems, baculovirus vectors may also be used.","One advantage to expression of foreign genes in this invertebrate virus expression vector is that it is capable of expression of high levels of recombinant proteins, which are antigenically and functionally similar to their natural counterparts.","Baculovirus vectors and the appropriate insect host cells used in conjunction with the vectors will be known to those skilled in the art.","The term “recombinant expression vector” refers to a plasmid, virus or other vehicle known in the art that has been manipulated by insertion or incorporation of the invention acetyl glucosaminyl inositol deacetylase genetic sequences.","Such expression vectors contain a promoter sequence that facilitates the efficient transcription of the inserted genetic sequence of the host.","The expression vector typically contains an origin of replication, a promoter, as well as specific genes which allow phenotypic selection of the transformed cells.","Vectors suitable for use in the present invention include, but are not limited to the T7-based expression vector for expression in bacteria (Rosenberg, et al., Gene, 56:125, 1987), the pMSXND expression vector for expression in mammalian cells (Lee and Nathans, J. Biol.","Chem., 263:3521, 1988) and baculovirus-derived vectors for expression in insect cells.","The DNA segment can be present in the vector operably linked to regulatory elements, for example, a promoter (e.g., T7, metallothionein I, or polyhedrin promoters).","The vector may include a phenotypically selectable marker to identify host cells which contain the expression vector.","Examples of markers typically used in prokaryotic expression vectors include antibiotic resistance genes for ampicillin (β-lactamases), tetracycline and chloramphenicol (chloramphenicol acetyltransferase).","Examples of such markers typically used in mammalian expression vectors include the gene for adenosine deaminase (ADA), aminoglycoside phosphotransferase (neo, G418), dihydrofolate reductase (DHFR), hygromycin-B-phosphotransferase (HPH), thymidine kinase (TK), and xanthine guanine phosphoribosyltransferse (XGPRT, gpt).","The isolation and purification of host cell expressed polypeptides of the invention may be by any conventional means such as, for example, preparative chromatographic separations and immunological separations such as those involving the use of monoclonal or polyclonal antibody.","Transformation of the host cell with the recombinant DNA may be carried out by conventional techniques well known to those skilled in the art.","Where the host is prokaryotic, such as E. coli, competent cells which are capable of DNA uptake can be prepared from cells harvested after exponential growth and subsequently treated by electroporation or the CaCl2 method using procedures well known in the art.","Alternatively, MgCl2 or RbCl could be used.","Where the host used is a eukaryote, various methods of DNA transfer can be used.","These include transfection of DNA by calcium phosphate-precipitates, conventional mechanical procedures such as microinjection, insertion of a plasmid encased in liposomes, or the use of virus vectors.","Eukaryotic cells can also be cotransformed with DNA sequences encoding the polypeptides of the invention, and a second foreign DNA molecule encoding a selectable phenotype, such as the herpes simplex thymidine kinase gene.","Another method is to use a eukaryotic viral vector, such as simian virus 40 (SV40) or bovine papilloma virus, to transiently infect or transform eukaryotic cells and express the protein.","(Eukaryotic Viral Vectors, Cold Spring Harbor Laboratory, Gluzman ed., 1982).","Examples of mammalian host cells include COS, BHK, 293, and CHO cells.","Eukaryotic host cells may also include yeast.","For example, DNA can be expressed in yeast by inserting the DNA into appropriate expression vectors and introducing the product into the host cells.","Various shuttle vectors for the expression of foreign genes in yeast have been reported (Heinemann, J. et al., Nature, 340:205, 1989; Rose, M. et al., Gene, 60:237, 1987).","The invention provides antibodies that are specifically reactive with invention deacetylase polypeptides or fragments thereof.","Antibody that consists essentially of pooled monoclonal antibodies with different epitopic specificities, as well as distinct monoclonal antibody preparations are provided.","Monoclonal antibodies are made from antigen containing fragments of the protein by methods well known in the art (Kohler, et al., Nature, 256:495, 1975; Current Protocols in Molecular Biology, Ausubel, et al., ed., 1989).","Monoclonal antibodies specific for acetyl glucosaminyl inositol deacetylase polypeptide can be selected, for example, by screening for hybridoma culture supernatants that react with acetyl glucosaminyl inositol deacetylase polypeptides, but do not react with other bacterial deacetylases.","Antibody that consists essentially of pooled monoclonal antibodies with different epitopic specificities, as well as distinct monoclonal antibody preparations are provided.","Monoclonal antibodies are made from antigen containing fragments of the protein by methods well known in the art (Kohler, et al., Nature, 256:495, 1975; Current Protocols in Molecular Biology, Ausubel, et al., ed., 1989).","The term “antibody” as used in this invention includes intact molecules as well as fragments thereof, such as Fab, F(ab′)2 and Fv, which are capable of binding the epitopic determinant.","These antibody fragments retain some ability to selectively bind with its antigen or receptor and are defined as follows: (1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule can be produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain; (2) Fab′, the fragment of an antibody molecule can be obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab′ fragments are obtained per antibody molecule; (3) (Fab′)2, the fragment of the antibody that can be obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; F(ab′)2 is a dimer of two Fab′ fragments held together by two disulfide bonds; (4) Fv, defined as a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains; and (5) Single chain antibody (“SCA”), defined as a genetically engineered molecule containing the variable region of the light chain, the variable region of the heavy chain, linked by a suitable polypeptide linker as a genetically fused single chain molecule.","Methods of making these fragments are known in the art.","(See for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1988), incorporated herein by reference).","As used in this invention, the term “epitope” means any antigenic determinant on an antigen to which the paratope of an antibody binds.","Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics.","Antibodies that bind to acetyl glucosaminyl inositol deacetylase polypeptide of the invention can be prepared using an intact polypeptide or fragments containing small peptides of interest as the immunizing antigen.","The polypeptide or a peptide used to immunize an animal can be derived from translated cDNA or chemical synthesis and can be conjugated to a carrier protein, if desired.","Such commonly used carriers, which are chemically coupled to the peptide, include keyhole limpet hemocyanin (KLH), thyroglobulin, bovine serum albumin (BSA), and tetanus toxoid.","The coupled peptide is then used to immunize the animal (e.g., a mouse, a rat, or a rabbit).","If desired, polyclonal or monoclonal antibodies can be further purified, for example, by binding to and elution from a matrix to which the polypeptide or a peptide to which the antibodies were raised is bound.","Those of skill in the art will know of various techniques common in the immunology arts for purification and/or concentration of polyclonal antibodies, as well as monoclonal antibodies (See for example, Coligan, et al., Unit 9, Current Protocols in Immunology, Wiley Interscience, 1994, incorporated herein by reference).","It is also possible to use the anti-idiotype technology to produce monoclonal antibodies that mimic an epitope.","For example, an anti-idiotypic monoclonal antibody made to a first monoclonal antibody will have a binding domain in the hypervariable region that is the “image” of the epitope bound by the first monoclonal antibody.","In yet other preferred embodiments, the recombinant acetyl glucosaminyl inositol deacetylase polypeptide is a fusion protein further-comprising a second polypeptide portion having an amino acid sequence from a protein unrelated to the acetyl glucosaminyl inositol deacetylase.","Such fusion proteins can be functional in a two-hybrid assay.","Another aspect of the present invention provides a substantially pure nucleic acid having a nucleotide sequence which encodes an acetyl glucosaminyl inositol deacetylase polypeptide, or a fragment thereof, having an amino acid sequence at least 60% homologous to one of SEQ ID NOs:2, 3, 4 or 5.In a more preferred embodiment, the nucleic acid encodes a protein having an amino acid sequence 40% or more homologous to SEQ ID NO:2, more preferably at least 50% homologous to SEQ ID NO:2, and most preferably at least 65% homologous to SEQ ID NO:2.In another embodiment, the nucleic acid hybridizes under stringent conditions to a nucleic acid probe corresponding to at least 12 consecutive nucleotides encoding SEQ ID NO:3; more preferably to at least 20 consecutive nucleotides encoding SEQ ID NO:3; more preferably to at least 24 consecutive nucleotides encoding SEQ ID NO:3.In a further embodiment, the nucleic acid hybridizes under stringent conditions to a nucleic acid probe corresponding to at least 12 consecutive nucleotides encoding SEQ ID NO:4; more preferably to at least 20 consecutive nucleotides encoding SEQ ID NO:4; more preferably to at least 30 consecutive nucleotides encoding SEQ ID NO:4.In yet a further embodiment, the nucleic acid hybridizes under stringent conditions to a nucleic acid probe corresponding to at least 12 consecutive nucleotides encoding SEQ ID NO:5; more preferably to at least 20 consecutive nucleotides encoding SEQ ID NO:5; more preferably to at least 30 consecutive nucleotides encoding SEQ ID NO:5.In yet a further embodiment, the nucleic acid hybridizes under stringent conditions to a nucleic acid probe corresponding to at least 12 consecutive nucleotides encoding SEQ ID NO:6; more preferably to at least 20 consecutive nucleotides encoding SEQ ID NO:6.Furthermore, in certain embodiments, the acetyl glucosaminyl inositol deacetylase nucleic acid will comprise a transcriptional regulatory sequence, e.g.","at least one of a transcriptional promoter or transcriptional enhancer sequence, operably linked to the acetyl glucosaminyl inositol deacetylase-gene sequence so as to render the recombinant acetyl glucosaminyl inositol deacetylase gene sequence suitable for use as an expression vector.","The present invention also features transgenic non-human organisms, e.g.","live mutant actinomycetes, which either express a heterologous acetyl glucosaminyl inositol deacetylase gene, or in which expression of their own acetyl glucosaminyl inositol deacetylase gene is disrupted.","In addition to the other utilities of such organisms disclosed herein, such a transgenic organism has utility for overproduction of acetyl glucosaminyl inositol needed for screening (particularly high throughput screening) for compounds that inhibit acetyl glucosaminyl inositol deacetylase activity in mycothiol-producing bacteria.","The present invention also provides a probe/primer comprising a substantially purified oligonucleotide, wherein the oligonucleotide comprises a region of nucleotide sequence which hybridizes under stringent conditions to at least 10 consecutive nucleotides of sense or anti-sense sequence encoding one of the amino acid sequences encompassed by SEQ ID NOs:2, 3, 4 5, or 6, or naturally occurring mutants thereof.","Yet another aspect of the invention pertains to a peptidomimetic that binds to or interferes with an acetyl glucosaminyl inositol deacetylase polypeptide and inhibits its binding to or cleavage of substrate acyl glucosaminyl inositols.","For example, a preferred peptidomimetic is an analog of a peptide having the sequence of one of the SEQ ID NOs.","1, 2, 3, 4, 5, or 6.Non-hydrolyzable peptide analogs of such residues can be generated using, for example, benzodiazepine, azepine, substituted gama-lactam rings, keto-methylene pseudopeptides, beta-turn dipeptide cores, or beta-aminoalcohols.","Other features and advantages of the invention will be apparent from the detailed description herein, and from the claims.","The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology, recombinant DNA, and immunology, which are within the skill of the art.","Such techniques are explained fully in the literature.","See, for example, Molecular Cloning A Laboratory Manual, 2nd Ed., ed.","by Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press: 1989); DNA Cloning, Volumes I and II (D. N. Glover ed., 1985); Oligonucleotide Synthesis (M. J. Gait ed., 1984); Mullis et al.","U.S. Pat.","No.","4,683,195; Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds.","1984); Transcription And Translation (B. D. Hames & S. J. Higgins eds.","1984); Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols.","154 and 155 (Wu et al.","eds.","), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds., 1986); Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).","As used herein, the term “actinomycetes” and “an actinomycete” encompasses any bacterium of the order Actinomycetales.","As used herein, the term “nucleic acid” refers to polynucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA).","The term should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and, as applicable to the embodiment being described, single (sense or anti-sense) and double-stranded polynucleotides.","As used herein, the terms “gene”, “recombinant gene” and “gene construct” refer to a nucleic acid comprising an open reading frame encoding an invention acetyl glucosaminyl inositol deacetylase, including both exon and (optionally) intron sequences.","The term “intron” refers to a DNA sequence present in a given acetyl glucosaminyl inositol deacetylase gene which is not translated into protein and is generally found between exons.","“Homology” refers to sequence similarity between two peptides or between two nucleic acid molecules.","Homology can be determined by comparing a position in each sequence which may be aligned for purposes of comparison.","When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position.","Percent homology between sequences is a function of the number of matching or homologous positions shared by the sequences.","The sequence data of a test clone is aligned to the sequences in the database or databases using algorithms designed to measure homology between two or more sequences.","Sequence alignment methods include, for example, BLAST (Altschul et al., 1990), BLITZ (MPsrch) (Sturrock & Collins, 1993), and FASTA (Person & Lipman, 1988).","For example, optimal alignment of sequences for aligning a comparison window may be conducted by the local homology algorithm of Smith (Smith and Waterman, Adv Appl Math, 1981; Smith and Waterman, J Teor Biol, 1981; Smith and Waterman, J Mol Biol, 1981; Smith et al, J Mol Evol, 1981), by the homology alignment algorithm of Needleman (Needleman and Wuncsch, 1970), by the search of similarity method of Pearson (Pearson and Lipman, 1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Dr., Madison, Wis., or the Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin, Madison, Wis.), or by inspection, and the best alignment (i.e., resulting in the highest percentage of homology over the comparison window) generated by the various methods is selected.","The term “transfection” or “transforming” and grammatical equivalents thereof, refers to the introduction of a nucleic acid, e.g., an expression vector, into a recipient cell by nucleic acid-mediated gene transfer.","“Transformation”, as used herein, refers to a process in which a cell's genotype is changed as a result of the cellular uptake of exogenous DNA or RNA, and, for example, the transformed cell expresses a recombinant form of one of the invention family of acetyl glucosaminyl inositol deacetylases.","“Cells” or “cell cultures” or “recombinant host cells” or “host cells” are often used interchangeably as will be clear from the context.","These terms include the immediate subject cells that express the acetyl glucosaminyl inositol deacetylases of the present invention, and, of course, the progeny thereof.","It is understood that not all progeny are exactly identical to the parental cell, due to chance mutations or difference in environment.","However, such altered progeny are included in these terms, so long as the progeny retain the characteristics relevant to those conferred on the originally transformed cell.","In the present case, such a characteristic might be the ability to produce a recombinant acetyl glucosaminyl inositol deacetylase polypeptide.","As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.","The term “expression vector” includes plasmids, cosmids or phages capable of synthesizing the subject acetyl glucosaminyl inositol deacetylase polypeptide encoded by the respective recombinant gene carried by the vector.","Preferred vectors are those capable of autonomous replication and/expression of nucleic acids to which they are linked.","In the present specification, “plasmid” and “vector” are used interchangeably as the plasmid is the most commonly used form of vector.","Moreover, the invention is intended to include such other forms of expression vectors which serve equivalent functions and which become known in the art subsequently hereto.","“Transcriptional regulatory sequence” is a generic term used throughout the specification to refer to DNA sequences, such as initiation signals, enhancers, and promoters, as well as polyadenylation sites, which induce or control transcription of protein coding sequences with which they are operably linked.","In preferred embodiments, transcription of a recombinant acetyl glucosaminyl inositol deacetylase gene is under the control of a promoter sequence (or other transcriptional regulatory sequence) that controls the expression of the recombinant gene in a cell-type in which expression is intended.","It will also be understood that the recombinant gene can be under the control of transcriptional regulatory sequences which are the same or which are different from those sequences that control transcription of the naturally occurring form of the regulatory protein.","As used herein, a “transgenic organism” is any organism, preferably a bacteria in which one or more of the cells of the organism contain heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art.","The nucleic acid is introduced into the cell by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus or a vector.","The term genetic manipulation does not include classical crossbreeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule.","This molecule may be integrated within a chromosome, or it may be extrachromosomally replicating DNA.","In the typical transgenic organisms described herein, the transgene causes cells to express a recombinant form of the subject acetyl glucosaminyl inositol deacetylase polypeptides.","As used herein, the term “transgene” means a nucleic acid sequence (encoding, e.g., an acetyl glucosaminyl inositol deacetylase polypeptide), which is partly or entirely heterologous, i.e., foreign, to the transgenic organism or cell into which it is introduced, or, is homologous to an endogenous gene of the transgenic organism or cell into which it is introduced, but which is designed to be inserted, or is inserted, into the organism's genome in such a way as to alter the genome of the cell into which it is inserted (e.g., it is inserted at a location which differs from that of the natural gene or its insertion results in a knockout).","A transgene can include one or more transcriptional regulatory sequences and any other nucleic acid, such as introns, that may be necessary for optimal expression of a selected nucleic acid.","The term “evolutionarily related to”, with respect to nucleic acid sequences encoding acetyl glucosaminyl inositol deacetylase polypeptides, refers to nucleic acid sequences that have arisen naturally in an organism, including naturally occurring mutants.","The term also refers to nucleic acid sequences which, while derived from a naturally occurring acetyl glucosaminyl inositol deacetylase polypeptide, have been altered by mutagenesis, as for example, combinatorial mutagenesis, yet still encode polypeptides which have the deacetylase activity of an acetyl glucosaminyl inositol deacetylase polypeptide.","One aspect of the present invention pertains to an isolated nucleic acid comprising the nucleotide sequence encoding an acetyl glucosaminyl inositol deacetylase polypeptide, fragments thereof encoding polypeptides having acetyl glucosaminyl inositol deacetylase activity, and/or equivalents of such nucleic acids.","The term-nucleic acid as used herein is intended to include such fragments and equivalents.","The term equivalent is understood to include nucleotide sequences encoding functionally equivalent acetyl glucosaminyl inositol deacetylase polypeptides or functionally equivalent peptides having an activity of an acetyl glucosaminyl inositol deacetylase polypeptide such as described herein.","Equivalent nucleotide sequences will include sequences that differ by one or more nucleotide substitutions, additions or deletions, such as allelic variants; and will also include sequences that differ from the nucleotide sequence encoding native acetyl glucosaminyl inositol deacetylases due to the degeneracy of the genetic code.","Equivalents will also include nucleotide sequences that hybridize under stringent conditions (i.e., equivalent to about 20-27° C. below the melting temperature of the DNA duplex formed in about 1 M salt) to the nucleotide sequence of an acetyl glucosaminyl inositol deacetylase gene, such as that as set forth in SEQ ID NO:7, particularly those segments encoding the polypeptides shown in one of SEQ ID NOs.","2, 3, 4, 5 or 6, and conservative variations thereof.","In one embodiment, equivalents will further include nucleic acid sequences derived from and evolutionarily related to such nucleotide sequences.","The term “isolated” or “purified” as also used herein with respect to nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs, or RNAs, respectively, that are present in the natural source of the macromolecule.","For example, an isolated nucleic acid encoding one of the subject acetyl glucosaminyl inositol deacetylase polypeptides preferably includes no more than 10 kilobases (kb) of nucleic acid sequence which naturally immediately flanks the acetyl glucosaminyl inositol deacetylase gene in genomic DNA, more preferably no more than 5 kb of such naturally occurring flanking sequences, and most preferably less than 1.5 kb of such naturally occurring flanking sequence.","The term isolated or purified as used herein also refers to a nucleic acid or peptide that is substantially free of cellular material or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.","Moreover, an “isolated nucleic acid” is meant to include nucleic acid fragments that are not naturally occurring as fragments and would not be found in the natural state.","In yet another embodiment, the nucleic acid of the invention encodes a peptide having an amino acid sequence as shown SEQ ID NO:1.Preferred nucleic acids encode a peptide having acetyl glucosaminyl inositol deacetylase polypeptide activity and being 40% or more homologous, more preferably 50% homologous and most preferably 65% homologous with an amino acid sequence as set forth in SEQ ID NO:2 (encoded by a nucleic acid sequence as set forth in SEQ ID NO:7).","Nucleic acids that encode peptides having an activity of an invention acetyl glucosaminyl inositol deacetylase polypeptide are also within the scope of the invention.","Another aspect of the invention provides a nucleic acid which hybridizes under high or low stringency conditions to a nucleic acid which encodes an acetyl glucosaminyl inositol deacetylase polypeptide having all or a portion of an amino acid sequence shown in one of SEQ ID NOs.","2, 3, 4, 5 or 6.Appropriate stringency conditions which promote DNA hybridization, for example, 6.0× sodium chloride/sodium citrate (SSC) at about 45° C., followed by a wash of 2.0×SSC at 50° C., are known to those skilled in the art or can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6.For example, the salt concentration in the wash step can be selected from a low stringency of about 2.0×SSC at 50° C. to a high stringency of about 0.2×SSC at 50° C. In addition, the temperature in the wash step can be increased from low stringency conditions at room temperature, about 22° C., to high stringency conditions at about 65° C. Isolated nucleic acids that differ from the nucleotide sequences disclosed herein due to degeneracy in the genetic code are also within the scope of the invention.","For example, more than one triplet designates a number of amino acids.","Codons that specify the same amino acid, or synonyms (for example, CAU and CAC are synonyms for histidine) may result in “silent” mutations that do not affect the amino acid sequence of the protein.","However, it is expected that DNA sequence polymorphisms that do lead to changes in the amino acid sequences of the subject acetyl glucosaminyl inositol deacetylase polypeptides will exist among prokaryotic cells.","One skilled in the art will appreciate that these variations in one or more nucleotides (up to about 3-4% of the nucleotides) of the nucleic acids encoding a particular member of the acetyl glucosaminyl inositol deacetylase polypeptide family may exist among individuals of a given species due to natural allelic variation.","Any and all such nucleotide variations and resulting amino acid polymorphisms are within the scope of this invention.","Fragments of the nucleic acid encoding a biologically active portion of the subject acetyl glucosaminyl inositol deacetylase polypeptides are also within the scope of the invention.","As used herein, a fragment of the nucleic acid encoding an active portion of an acetyl glucosaminyl inositol deacetylase polypeptide refers to a nucleotide sequence having fewer nucleotides than the nucleotide sequence encoding the full length amino acid sequence of, for example, the deacetylase polypeptides represented in nucleic acid SEQ ID NO:1, and which encodes a peptide which retains at least a portion of the biological activity of the full-length protein (i.e., a peptide capable of acetyl glucosaminyl inositol deacetylase activity) as defined herein, or alternatively, which is functional as an antagonist of the deacetylase activity of the full-length protein.","Nucleic acid fragments within the scope of the invention include those capable of hybridizing under high or low stringency conditions with nucleic acids from other species, e.g.","for use in screening protocols to detect homologs of the subject acetyl glucosaminyl inositol deacetylase polypeptides.","Nucleic acids within the scope of the invention may also contain linker sequences, modified restriction endonuclease sites and other sequences useful for molecular cloning, expression or purification of such recombinant peptides.","As indicated by the examples set out below, a nucleic acid encoding a peptide having an activity of an invention deacetylase polypeptide may be obtained from mRNA or genomic DNA present in any of a number of antibiotic-producing or pathogenic bacteria, particularly actinomycetes, in accordance with protocols described herein, as well as those generally known to those skilled in the art.","A cDNA encoding an acetyl glucosaminyl inositol deacetylase polypeptide, for example, can be obtained by isolating total mRNA from a bacterial cell.","Double stranded cDNAs can then be prepared from the total mRNA, and subsequently inserted into a suitable plasmid or bacteriophage vector using any one of a number of known techniques.","A gene encoding an acetyl glucosaminyl inositol deacetylase polypeptide can also be cloned using established polymerase chain reaction techniques in accordance with the nucleotide sequence information provided by the invention.","Another aspect of the invention relates to the use of an “anti-sense” isolated nucleic acid.","As used herein, an “anti-sense” inhibition of endogenous production of an acetyl glucosaminyl inositol deacetylase molecule is carried out by administration or in situ generation of oligonucleotide probes or their derivatives which specifically hybridize (e.g.","bind) under intracellular conditions, with the cellular mRNA and/or genomic DNA encoding an acetyl glucosaminyl inositol deacetylase polypeptide so as to inhibit expression of that protein or a constituent thereof, e.g.","by inhibiting transcription and/or translation.","The binding may be by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix.","In general, “anti-sense” therapy refers to the range of techniques generally employed in the art, and includes any therapy that relies on specific binding to oligonucleotide sequences.","An anti-sense construct of the present invention can be delivered, for example, as an expression plasmid which, when transcribed in the transformed cell, produces RNA which is complementary to at least a unique portion of the cellular mRNA which encodes an acetyl glucosaminyl inositol deacetylase polypeptide.","Alternatively, the anti-sense construct is an oligonucleotide probe which is generated ex vivo and which, when introduced into the cell causes inhibition of expression by hybridizing with the mRNA and/or genomic sequences encoding one of the subject acetyl glucosaminyl inositol deacetylase proteins.","Such oligonucleotide probes are preferably modified oligonucleotides that are resistant to endogenous nucleases, e.g.","exonucleases and/or endonucleases, and is therefore stable in vivo.","Exemplary nucleic acid molecules for use as anti-sense oligonucleotides are phosphoramidate, phosphothioate and methylphosphonate analogs of DNA (see also U.S. Pat.","Nos.","5,176,996; 5,264,564; and 5,256,775).","Additionally, general approaches to constructing oligomers useful in anti-sense techniques have been reviewed, for example, by van der Krol et al.","(1988) Biotechniques 6:958-976; and Stein et al.","(1988) Cancer Res 48:2659-2668.In addition, the oligomers of the invention may be used as reagents to detect the presence or absence of the target DNA or RNA sequences to which they specifically bind.","Such diagnostic tests are described in further detail below.","This invention also provides expression vectors comprising a nucleotide sequence encoding a member of the invention family of acetyl glucosaminyl inositol deacetylase polypeptides and operably linked to at least one regulatory sequence.","Operably linked is intended to mean that the nucleotide sequence is linked to a regulatory sequence in a manner that allows expression of the nucleotide sequence.","Regulatory sequences are art-recognized and are selected to direct expression of the peptide having an activity of an acetyl glucosaminyl inositol deacetylase polypeptide.","Accordingly, the term regulatory sequence includes promoters, enhancers and other expression control elements.","Exemplary regulatory sequences are described in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990).","For instance, any of a wide variety of expression control sequences-sequences that control the expression of a DNA sequence when operatively linked to it may be used in these vectors to express DNA sequences encoding the acetyl glucosaminyl inositol deacetylase polypeptides of this invention.","Such useful expression control sequences, include, for example, the early and late promoters of SV40, adenovirus or cytomegalovirus immediate early promoter, the lac system, the trp system, the TAC or TRC system, T7 promoter whose expression is directed by T7 RNA polymerase, the major operator and promoter regions of phage lambda, the control regions for fd coat protein, the promoter for 3-phosphoglycerate kinase or other glycolytic enzymes, the promoters of acid phosphatase, e.g., Pho5, the promoters of the yeast α-mating factors, the polyhedron promoter of the baculovirus system and other sequences known to control the expression of genes of prokaryotic or eukaryotic cells or their viruses, and various combinations thereof.","It should be understood that the design of the expression vector may depend on such factors as the choice of the host cell to be transformed and/or the type of protein desired to be expressed.","Moreover, the vector's copy number, the ability to control that copy number and the expression of any other proteins encoded by the vector, such as antibiotic markers, should also be considered.","As will be apparent, the subject gene constructs can be used to cause expression of the subject acetyl glucosaminyl inositol deacetylase polypeptides in cells propagated in culture, e.g.","to produce proteins or peptides, including fusion proteins or peptides, for purification.","This invention also pertains to a host cell transfected with a recombinant acetyl glucosaminyl inositol deacetylase gene in order to express a polypeptide having an activity of an acetyl glucosaminyl inositol deacetylase polypeptide.","The host cell may be any prokaryotic or eukaryotic cell.","For example, an acetyl glucosaminyl inositol deacetylase polypeptide of the present invention may be expressed in bacterial cells such as E. coli, insect cells (baculovirus), yeast, or mammalian cells.","Other suitable host cells are known to those skilled in the art.","Another aspect of the present invention concerns recombinant acetyl glucosaminyl inositol deacetylase polypeptides that have the deacetylase activity of an acetyl glucosaminyl inositol deacetylase polypeptide, or which are naturally occurring mutants thereof.","The term “recombinant protein” refers to a protein of the present invention which is produced by recombinant DNA techniques, wherein generally DNA encoding the acetyl glucosaminyl inositol deacetylase polypeptide is inserted into a suitable expression vector which is in turn used to transform a host cell to produce the heterologous protein.","Moreover, the phrase “derived from”, with respect to a recombinant gene encoding the recombinant acetyl glucosaminyl inositol deacetylase polypeptide, is meant to include within the meaning of “recombinant protein” those proteins having an amino acid sequence of a native acetyl glucosaminyl inositol deacetylase polypeptide, or an amino acid sequence similar thereto which is generated by mutations including substitutions and deletions of a naturally occurring acetyl glucosaminyl inositol deacetylase polypeptide of a organism.","The present invention further pertains to methods of producing the subject acetyl glucosaminyl inositol deacetylase polypeptides.","For example, a host cell transfected with expression vector encoding one of the subject acetyl glucosaminyl inositol deacetylase polypeptide can be cultured under appropriate conditions to allow expression of the peptide to occur.","The peptide may be secreted and isolated from a mixture of cells and medium containing the peptide.","Alternatively, the peptide may be retained cytoplasmically and the cells harvested, lysed and the protein isolated.","A cell culture includes host cells, media and other byproducts.","Suitable media for cell culture are well known in the art.","The peptide can be isolated from cell culture medium, host cells, or both using techniques known in the art for purifying proteins including ion-exchange chromatography, gel filtration chromatography, ultrafiltration, electrophoresis, and immunoaffinity purification with antibodies specific for particular epitopes of the subject acetyl glucosaminyl inositol deacetylase polypeptides.","Thus, a nucleotide sequence derived from the cloning of an acetyl glucosaminyl inositol deacetylase polypeptide of the present invention, encoding all or a selected portion of the protein, can be used to produce a recombinant form of the protein via microbial cellular processes.","The recombinant acetyl glucosaminyl inositol deacetylase polypeptide can be produced by ligating the cloned gene, or a portion thereof, into a vector suitable for expression in bacterial cells.","Expression vehicles for production of a recombinant acetyl glucosaminyl inositol deacetylase polypeptide include plasmids and other vectors.","For instance, suitable vectors include plasmids of the types: pBR322-derived plasmids, pEMBL-derived plasmids, pEX-derived plasmids, pBTac-derived plasmids and pUC-derived plasmids for expression in prokaryotic cells, such as E. coli.","A number of vectors exist for the expression of recombinant proteins in yeast.","For instance, YEP24, YIP5, YEP51, YEP52, pYES2, and YRP17 are cloning and expression vehicles useful in the introduction of genetic constructs into S. cerevisiae (see, for example, Broach et al.","(1983) in Experimental Manipulation of Gene Expression, ed.","M. Inouye Academic Press, p. 83, incorporated by reference herein).","These vectors can replicate in E. coli due the presence of the pBR322 ori, and in S. cerevisiae due to the replication determinant of the yeast 2 micron plasmid.","In addition, drug resistance markers such as ampicillin can be used.","The various methods employed in the preparation of the plasmids and transformation of host organisms are well known in the art.","For other suitable expression systems for both prokaryotic and eukaryotic cells, as well as general recombinant procedures, see Molecular Cloning A Laboratory Manual, 2nd Ed., ed.","by Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press: 1989) Chapters 16 and 17.In some instances, it may be desirable to express the recombinant acetyl glucosaminyl inositol deacetylase polypeptide by the use of a baculovirus expression system.","Examples of such baculovirus expression systems include pVL-derived vectors (such as pVL1392, pVL1393 and pVL941), pAcUW-derived vectors (such as pAcUW1), and pBlueBac-derived vectors (such as the β-gal containing pBlueBac III).","This invention further contemplates a method of generating sets of combinatorial mutants of the present acetyl glucosaminyl inositol deacetylase polypeptides, as well as truncation mutants, and is especially useful for identifying potential variant sequences (e.g.","homologs) that are functional in cleaving acetyl glucosaminyl inositol or other acyl glucosaminyl inositol amide molecules.","In a representative embodiment of this method, the amino acid sequences for a population of acetyl glucosaminyl inositol deacetylase polypeptide homologs are aligned, preferably to promote the highest homology possible.","Such a population of variants can include, for example, homologs from one or more species, or homologs from the same species but which differ due to mutation.","Amino acids that appear at each position of the aligned sequences are selected to create a degenerate set of combinatorial sequences.","The presence or absence of amino acids from an aligned sequence of a particular variant is relative to a chosen consensus length of a reference sequence, which can be real or artificial.","In order to maintain the highest homology in alignment of sequences, deletions in the sequence of a variant relative to the reference sequence can be represented by an amino acid space (*), while insertional mutations in the variant relative to the reference sequence can be disregarded and left out of the sequence of the variant when aligned.","Further expansion of the combinatorial library can be made by, for example, by including amino acids that would represent conservative mutations at one or more of the degenerate positions.","Inclusion of such conservative mutations can give rise to a library of potential acetyl glucosaminyl inositol deacetylase sequences.","Alternatively, amino acid replacement at degenerate positions can be based on steric criteria, e.g.","isosteric replacement, without regard for polarity or charge of amino acid sidechains.","Similarly, completely random mutagenesis of one or more of the variant positions can be carried out.","In a preferred embodiment, the combinatorial acetyl glucosaminyl inositol deacetylase library is produced by way of a degenerate library of genes encoding a library of polypeptides which each include at least a portion of potential acetyl glucosaminyl inositol deacetylase polypeptide sequences.","For instance, a mixture of synthetic oligonucleotides can be enzymatically ligated into gene sequences such that the degenerate set of potential acetyl glucosaminyl inositol deacetylase nucleotide sequences are expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g.","for phage display) containing the set of acetyl glucosaminyl inositol deacetylase polypeptide sequences therein.","There are many ways by which the library of potential acetyl glucosaminyl inositol deacetylase homologs can be generated from a degenerate oligonucleotide sequence.","Chemical synthesis of a degenerate gene sequence can be carried out in an automatic DNA synthesizer, and the synthetic genes then be ligated into an appropriate gene for expression.","The purpose of a degenerate set of genes is to provide, in one mixture, all of the sequences encoding the desired set of potential acetyl glucosaminyl inositol deacetylase sequences.","The synthesis of degenerate oligonucleotides is well known in the art (see for example, Narang, SA (1983) Tetrahedron 39:3; Itakura et al.","(1981) Recombinant DNA, Proc 3rd Cleveland Sympos.","Macromolecules, ed.","A G Walton, Amsterdam: Elsevier pp.","273-289; Itakura et al.","(1984) Annu.","Rev.","Biochem.","53:323; Itakura et al.","(1984) Science 198:1056; Ike et al.","(1983) Nucleic Acid Res.","11:477.A wide range of techniques are known in the art for screening gene products of combinatorial libraries made by point mutations, and, for that matter, for screening cDNA libraries for gene products having a certain property.","Such techniques will be generally adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of acetyl glucosaminyl inositol deacetylase homologs.","The most widely used techniques for screening large gene libraries typically comprises cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates relatively easy isolation of the vector encoding the gene product was detected.","Each of the illustrative assays described below are amenable to high throughput analysis as necessary to screen large numbers of degenerate sequences created by combinatorial mutagenesis techniques.","The invention also provides for reduction of the subject acetyl glucosaminyl inositol deacetylase polypeptides to generate mimetics, e.g.","peptide or non-peptide agents, which are able to mimic binding of the authentic acetyl glucosaminyl inositol deacetylase polypeptide to a substrate molecule.","Such mutagenic techniques as described above, as well as the thioredoxin system, are also particularly useful for mapping the determinants of an acetyl glucosaminyl inositol deacetylase polypeptide which participate in protein-protein interactions involved in, for example, binding of the subject acetyl glucosaminyl inositol deacetylase polypeptide to a substrate.","To illustrate, the critical residues of a subject acetyl glucosaminyl inositol deacetylase polypeptide which are involved in molecular recognition of substrate can be determined and used to generate acetyl glucosaminyl inositol deacetylase-derived peptidomimetics which cleave acetyl glucosaminyl inositol or other acyl glucosaminyl inositol amide substrates and, like the authentic acetyl glucosaminyl inositol deacetylase polypeptide, cleave the substrate molecule, for example by amide hydrolase activity.","By employing, for example, scanning mutagenesis to map the amino acid residues of a particular acetyl glucosaminyl inositol deacetylase polypeptide involved in binding to a substrate, peptidomimetic compounds (e.g.","diazepine or isoquinoline derivatives) can be generated which mimic those residues cleaving substrate.","For instance, non-hydrolyzable peptide analogs of such residues can be generated using benzodiazepine (e.g., see Freidinger et al; in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), azepine (e.g., see Huffman et al.","in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), substituted gama lactam rings (Garvey et al.","in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), keto-methylene pseudopeptides (Ewenson et al.","(1986) J Med Chem 29:295; and Ewenson et al.","in Peptides: Structure and Function (Proceedings of the 9th American Peptide Symposium) Pierce Chemical Co. Rockland, Ill., 1985), beta-turn dipeptide cores (Nagai et al.","(1985) Tetrahedron Lett 26:647; and Sato et al.","(1986) J Chem Soc Perkin Trans 1:1231), and β-aminoalcohols (Gordon et al.","(1985) Biochem Biophys Res Commun 126:419; and Dann et al.","(1986) Biochem Biophys Res Commun 134:71).","The invention will be further described with reference to the following examples; however, it is to be understood that the invention is not limited to such examples.","EXAMPLE 1 Preparation of Reagents and Assay Methods Used.","Mycothiol (MSH) was isolated from M. smegmatis and derivatized with monobromobimane to form the MSH-bimane derivative (MSmB).","Mycothiol can be purified from Streptomyces clavuligerus, M. smegmatis, or from cells of any other mycothiol containing bacterium.","Early stationary phase cells (25 gm wet weight) were extracted with 250 ml of 50% acetonitirile containing 25 mM methanesulfonic acid and 1 mM DTT at 60° C. for 15 min.","The cell debris was removed by centrifugation for 30 min (4° C.) at 20,000×g.","The excess acetonitrile was removed using a rotary evaporator.","The aqueous extract was neutralized with Tris base to pH 8.0 and clarified by centrifugation for 30 min (4° C.) at 20,000×g The extract was loaded on a 25×70 mm propyl thiol Sepharose 6B resin activated with 2-mercaptopyridine with 1 mmole total thiol binding capacity.","The column was washed with 10 column volumes of 20 mM Tris-HCl pH 8.0 to remove unbound extract components.","The bound thiols were eluted with 200 ml of 20 mM Tris-HCl pH 8.0 containing 3 mM DTT.","The eluate was extracted 5 times with an equal volume of ethyl acetate to remove excess DTT.","The ethyl acetate washed aqueous extract was reduced to dryness by lyophilization.","The extract was suspended in 5 ml of aqueous 0.1% trifluoroacetic acid (TFA).","The mycothiol was purified by preparative HPLC using a 10×250 mm Vydac C-18 (Cat.","# 218TP152022) reverse phase column (or equivalent).","Mycothiol eluted at 26 min using an isocratic elution in aqueous 0.1% TFA at 5 ml per min.","The volatile solvent was removed by lyophilization to yield pure mycothiol.","Mycothiol is stable for years when stored as a mildly acidic aqueous solution of 30-100 mM at −70° C. The bimane derivative of mycothiol is readily made using monobromobimane (Molecular Probes) at 2 mM excess over the thiol concentration.","The derivatization is carried out in aqueous 20 mM Tris-HCl pH 8.0 for 15 min in the dark at room temperature.","The derivatization mixture was acidified to pH<3 with TFA and extracted 2 times with equal volumes of dichloromethane to remove excess monobromobimane.","The derivatization mixture was purified on the preparative reverse phase column described above using a gradient elution.","The A-buffer was 0.1% aqueous TFA and the B buffer was methanol.","The linear gradient was 15-30% methanol over 30 min with a flow rate of 5 ml per min.","The MSmB was detected at 385 nm and eluted as a symmetrical peak at 33 min.","The volatile solvent was removed by lyophilization to yield>98% pure MSmB.","This derivative was stored as a 10-30 mM solution in water at −70° C. The purified M. smegmatis mycothiol S-conjugate amidase was used to quantitatively hydrolyze MSMB to stereochemically pure GlcN-Ins, and the latter was purified from the other hydrolysis product, AcCySmB, using a Sep-Pak® C18 (Waters) cartridge.","A 10 mM stock solution of GlcNAc-Ins was prepared by addition of a tenfold excess of acetic anhydride (Fisher) to 10 mM GlcN-Ins in 10 mM NaHCO3 over 20 min while adjusting the pH to 8.5 with NaOH.","The reaction was monitored for GlcN-Ins loss as described below to insure that the reaction was complete and that no residual GlcN-Ins was present.","This stock solution of GlcNAc-Ins was assayed as described below and used without further purification.","Preparation of Mycothiol S-conjugates.","Mycothiol S-conjugates were prepared by reaction of excess electrophile with mycothiol followed by removal of excess electrophile.","Stock solutions (100 mM) of iodoacetamide (Sigma) or bromoacetophenone (Sigma) were prepared in acetonitrile.","Reaction of these electrophiles at 2 mM in 25 mM HEPES chloride pH 7.5 was initiated by addition of mycothiol to 1 mM from a 32 mM stock solution in H2O (pH˜3) and was allowed to proceed 15 min at 22° C. Excess reagent was removed by extracting 3 times with an equal volume of H2O-saturated dichloromethane.","Prior to extraction a 1 μl aliquot was withdrawn for reaction with mBBr and analysis of residual mycothiol by HPLC (see above) to verify complete reaction.","This showed that>99% of the mycothiol had reacted.","The MS-acetophenone was purified to homogeneity by reverse phase preparative HPLC as described above for MSmB, except that MS-acetophenone was detected at 260 nm.","Assay of MSH and MSH precursors.","Mycothiol and its precursors cysteine, and Cys-GlcN-Ins were assayed as the bimane derivative by high performance liquid chromatography (HPLC) on a Ultrasphere® ODS IP (Beckman) reversed phase column.","The bimane derivatives were detected by fluorescence using a Fluoromonitor III® monitor (Thermo Separation products) with excitation filters 340-380 nm and emission filters 418-700 nm.","The A buffer was 0.1% TFA and the B buffer was 7.5% methanol in acetonitrile.","The separation was achieved at 22° C. and a flow rate of 1 ml/min with linear gradients as follows: time 0 min 0% B, 10 min 0% B, 30 min 20% B, 33 min 100% B, 36 min 100% B, 38 min 0% B, 50 min reinject.","CySmB-GlcN-Ins, CySmB and mycothiol-mB (MSmB) eluted at 28, 31 and 33 min, respectively.","GlcN-Ins was assayed by precolumn derivatization using AccQFluor® (Waters) reagent followed by HPLC analysis.","A sample, 7.5 μl of 50% acetonitrile sample containing 5 mM NEM or 5 mM NEM and 1 mM 1,10 phenanthroline was mixed with 39.4 μl of buffer stock.","The buffer stock was composed of 30% acetonitrile in aqueous 160 mM HEPES pH 7.5.This was mixed with 15.6 μl of AccQ-Fluor® reagent (Waters) and incubated for 1 min at 22° C. followed by 10 min at 60° C. The sample was diluted with 188 μl of water and the sample was analyzed by HPLC.","The sample was centrifuged for 3 min 14,000×g in a microcentrifuge.","The HPLC separation conditions were the same as described above for bimane derivatives, except the B buffer was 0.1% TFA in methanol.","The product was detected by fluorescence using 254 nm excitation and 370-700 nm emission filters.","AccQ-GlcN and AccQ-GlcN-Ins eluted at 12 and 24 min respectively.","Mycothiol S-conjugate amidase assay.","The enzymatic activity was routinely assayed by quantitation of the bimane derivative of N-acetylcysteine (AcCySmB) produced from the bimane derivative of mycothiol (MSmB), prepared from purified mycothiol (see above).","To conduct an amidase assay a sample (2-10 μL) of extract was mixed with 40 μL of 30 μM MSmB in 3 mM 2-mercaptoethanol, 25 mM HEPES chloride pH 7.5 and reacted 10-30 min at 30° C. before quenching the reaction with 50 μL of 40 mM methanesulfonic acid on ice.","The mixture was centrifuged for 3 min at 14,000×g in a microcentrifuge at room temperature and the supernatant analyzed by HPLC without dilution.","Separation of MSmB and AcCySmB was achieved by HPLC on a 0.46×250 mM Ultrasphere®ODS column (Beckman) using a linear gradients: time 0 min 10% B, 15 min 18% B, 30 min 27% B, 32 min 100% B, 34 min 10% B, 45 min reinject.","Buffer A (aqueous 0.25% acetic acid titrated to pH 3.6 with NaOH) and buffer B (methanol) were pumped at 1.2 ml/min at ambient temperature (22° C.).","The bimane derivative of mycothiol (MSmB) eluted at 23.5 min and AcCySmB eluted at 27 min.","EXAMPLE 2 Cloning and Expression of the Rv1170 gene from M. tuberculosis and demonstration of its GlcNAc-Ins deacetylase activity.","Since the invention deacetylases and the mycothiol S-conjugate amidase both cleave an amide bond involving glucosamine, further studies were conducted to determine whether these proteins might be structurally related.","A search was conducted of the Sanger Centre database for homologs of the 288 amino acid M. tuberculosis deacetylase, Rv1082.The closest homolog found was Rv1170, with a length of 304 residues and 36% identity to Rv1082 with homology throughout the sequence.","To isolate the Rv1170 gene from M. tuberculosis H37Rv genomic DNA was prepared using known methods.","The open reading frame Rv1170 was amplified from this DNA with the following primers: 5′-TAGCCATGGTGTCTGAGACGCCGCG-3′ (SEQ ID NO:8) and 5′-GGATCCCGGGGTGAAGCCCAGAC-3′ (SEQ ID NO:9) These primers contain NcoI and BamHI restriction sites, respectively.","PCR was performed with Taq polymerase (Gibco BRL), using 1.5 mM MgCl2 and 5% dimethyl sulfoxide.","The 30 cycles of PCR included denaturation at 94° C. for 40 s, annealing at 55° C. for 1 min, and amplification at 72° C. The PCR products were separated on a 1% agarose gel.","The appropriate PCR product was ligated into vector pCR2.1 of the TA cloning kit (Invitrogen) and transformed into Escherichia coli DH5α by standard chemical transformation procedures.","Clones containing the vector were selected on plates of Luria-Bertani (LB) agar plus ampicillin (100 μg/ml), and plasmid DNA was digested with the restriction endonucleases NcoI and BamHI (Fermentas).","Restriction enzyme-digested plasmids were isolated with a QIAquick® gel extraction kit (Qiagen Ltd.).","A corresponding digestion was applied to the plasmid pET-22b, and the two products were ligated together with T4 DNA ligase to obtain the plasmid pYA1170.In order to express Rv1170 in E. coli without the pelB leader sequence, the gene from pYA1170 was excised using NcoI and Bpu1102I (Fermentas) and ligated to an aliquot of pET16b cut with NcoI and Bpu1102I to generate the plasmid pYA1170b (FIG.","2).","This plasmid was transformed by the heat shock method to competent E. coli BL21(DE3) prepared according to the CaCl2 method and plated on LB agar containing 100 μg ampicillin/ml.","Single colonies were inoculated into 5 ml of LB broth also containing ampicillin (100 μg/ml).","After overnight incubation at 37° C. with shaking, the individual cultures were diluted 1:100 in the same medium and incubation was continued at 37° C. with shaking.","Isopropyl-β-D-thiogalactopyranoside was added to a final concentration of 0.4 mM when the A600 reached 0.6, and incubation was continued overnight at 25° C. before harvesting by centrifugation at 5000×g for 15 min at room temperature.","The pellets were lysed by sonication.","Proteins were separated by centrifugation (15,000×g, 4° C., 30 min) into soluble and insoluble fractions.","Total proteins were separated by sodium dodecyl sulfate 7.5% polyacrylamide gel electrophoresis (SDS-PAGE) and stained with Coomassie blue or transferred to polyvinylidene difluoride membranes (Bio-Rad).","The N-terminal amino acid sequence was verified using Edman degradation after separation of samples by SDS-PAGE and electroblotting to a polyvinylidene difluoride membrane.","E. coli BL21 (DE3) was transformed with the blank cloning vector (pET16b) or with vector containing Rv1170 (pYA1170b).","SDS-PAGE was used to separate desalted 20% to 50% saturated ammonium sulfate extracts of these isopropyl-β-D-thiogalactopyranoside induced E. coli.","Bio-Rad Broad Range molecular mass standards and purified M. smegmatis mycothiol S-conjugate deacetylase were also assayed for controls.","The results of the SDS-PAGE showed that the 20% to 50% saturated ammonium sulfate fraction from E. coli carrying the Rv 1170 gene contained elevated levels of a protein of the expected size (36 kDa) as compared to those from E. coli prepared with a blank cloning vector.","Another, smaller protein (˜26 kDa) was also present at elevated levels and is believed to be a degradation product of the deacetylase.","The identity of the 36-kDa protein was confirmed by determining the N-terminal amino acid sequence and finding it identical to that predicted for the protein encoded by open reading frame Rv1170.The amidase and deacetylase activity of the 20 to 50% saturated ammonium sulfate extracts of E. coli transformed with pYA1170b or with the blank cloning vector pET16b after desalting and concentrating was assayed as described above.","The results of these assays are shown in Table 1 below.","TABLE 1 Substrate specificity of crude deacetylase from E. coli transformed with pYA1170b Activity (nmol min−1 mg of protein−1)(n = 3) Substrate Rv1170 Blank vector MsmBa 1.2 ± 0.1 <0.002 MSmBb <10−4 NDf GlcNAc-Insc 27 ± 2 <0.002 GlcNAcc 0.087 ± 0.005 <0.005 MSHd 0.002 ± 0.001 ND MSHe <10−4 ND aAnalysis for AcCySmB produced by amidase cleavage.","bAnalysis for production of the deacetylase product CySmB-GlcN-Ins.","cAnalysis for corresponding amine resulting from deacetylase reaction.","dAnalysis for AcCys produced by amidase cleavage.","eAnalysis for production of the deacetylase product Cys-GlcN-Ins.","fNot determined.","As shown by the results summarized in Table 1, extract from cells expressing Rv1170 exhibited substantial deacetylase activity with GlcNAc-Ins as the substrate, over 300-fold greater than the deacetylase activity determined with GlcNAc and 23-fold greater than the amidase activity measured with MSMB (FIG.","2).","Thus, Rv1170 was putatively identified as the GlcNAc-Ins deacetylase gene in the MSH biosynthesis pathway of M. tuberculosis.","M. smegmatis mycothiol S-conjugate amidase lacks deacetylase activity.","Mycothiol S-conjugate amidase from M. smegmatis, a homolog of the protein encoded by M. tuberculosis Rv1082, cleaves the amide bond linking Cys to GlcN in MSH derivatives having an alkylated sulfur residue (G. L. Newton et al., Biochemistry 39:10739-10746, 2000).","Tests were conducted to determine whether the mycothiol S-conjugate amidase also cleaves the corresponding bond in GlcNAc-Ins, functioning as a deacetylase (FIG.","3).","GlcNAc-Ins was prepared from GlcN-Ins and the ability of the amidase purified from M. smegmatis to hydrolyze GlcNAc-Ins (i.e., to function as a deacetylase) was compared with its ability to function as an amidase by cleaving the amide bond in the monobromobimane conjugate of MSH (MSmB).","The assays utilized are described above.","For a test with 100 μM substrate, the activity measured with deacetylase substrate MSmB was 4.5±1.0 μmol min−1 mg of protein−1, whereas that measured with the invention deacetylase substrate GlcNAc-Ins was <1 nmol min−1 mg of protein−1 (n=4).","The comparative assays showed that the mycothiol S-conjugate deacetylase does not exhibit measurable deacetylase activity and cannot serve this function in the MSH biosynthesis pathway of M. smegmatis.","EXAMPLE 3 Extracts of M. smegmatis and mutant 49 have deacetylase activity.","If the deacetylase is involved in MSH biosynthesis and if mutant 49 is blocked at an earlier step in the MSH-production pathway, then strains mc2155 and 49 should both produce deacetylase activity.","To test this hypothesis, centrifuged extracts of exponentially growing cells were assayed in duplicate for GlcN-Ins production with and without the addition of 100 μM GlcNAc-Ins.","The background rate for production of GlcN-Ins measured without added GlcNAc-Ins was high for strain mc2155 (6.1±0.1 pmol min−1 mg of protein−1) presumably reflecting the substantial endogenous level of GlcNAc-Ins present in the undialyzed extract.","Addition of 100 μM GlcNAc-Ins increased the rate to 19.7±0.4 pmol min−1 mg of protein−1, giving a net rate increase of 13.6±0.5 pmol min−1 mg of protein−1.For mutant 49, which does not contain GlcNAc-Ins, the background rate was <0.06 pmol min−1 mg of protein−1 and the rate with 100 μM GlcNAc-Ins was 16.4±1.4 pmol min−1 mg of protein−1.Thus, the deacetylase activity of strain 49 is essentially the same as that of the parent strain.","EXAMPLE 4 Assay for GlcNAc-Ins.","To confirm that GlcNAc-Ins is present in mycobacteria, an assay for this component was needed.","The availability of cloned Rv1170 allowed the development of such an assay.","Cell extracts were prepared in warm 50% acetonitrile containing NEM, as employed previously for an assay of GlcN-Ins (Anderberg et al.","(1998) J. Biol.","Chem.","273:30391-30397).","One portion of the extract was assayed directly for GlcN-Ins content while a second portion was assayed after treatment with a preparation of expressed Rv1170 under conditions sufficient to convert all GlcNAc-Ins to GlcN-Ins.","The difference in these two assay results yields the GlcNAc-Ins content for the sample.","In most cases, GlcN-Ins levels were at least an order of magnitude lower than those of GlcNAc-Ins, so this method gives reliable results.","Recovery experiments for GlcNAc-Ins were conducted using a M. smegmatis MSH-deficient mutant (“mutant 49”), derived from mc2155 by chemical mutagenesis.","Mutant 49 was cultured in Middlebrook 7H9 medium at 37° C. as previously described (Newton, et al.","(1999) Biochem.","Biophys.","Res.","Comm.","255:239-244).","In the uptake and metabolism assay, 50% acetonitrile-NEM extracts were analyzed after the addition of 0.7 and 7.0 μM GlcNAc-Ins.","Extracts of mutant 49 contained no detectable GlcN-Ins or MSH, so that any GlcN-Ins found in the extracts after treatment with the deacetylase preparation was derived solely from the deacetylation of GlcNAc-Ins.","The relationship between A600 and RDW was determined for aliquots of mc2155 cells producing ˜30 mg of RDW and found to be 0.42±0.02 mg of RDW per ml of cells with A600 at 1.00.No variation of >15% in this value was seen between log- and stationary-phase cells.","The method was tested with extracts prepared from log-phase cells of mutant 49 by spiking the extract with GlcNAc-Ins at levels equivalent to 0.13 and 0.013 μmol per g of RDW.","The recoveries from triplicate determinations were 97%±5% and 132%±3%, respectively.","At the lowest level of added GlcNAc-Ins, a significant correction had to be applied for background peaks present in unspiked controls that overlapped the GlcN-Ins peak.","The greater than 100% recovery found for the samples spiked at lowest level indicates that this correction produces a systematic error and thus defines the lower limit of useful sensitivity for this assay.","EXAMPLE 5 M. smegmatis mc2155 produces GlcNAc-Ins but MSH-deficient mutant 49 does not.","M. smegmatis mc2155 cells were examined in exponential and stationary phases for their content of MSH and its precursors using the methods described above.","The results of these studies are summarized in Table 2 below: TABLE 2 Levels of MSH and precursors in M. smegmatis mc2155 Content (μmol [g of RDW]−1) ( n = 3) Growth phase A600 MSH GlcNAc-Ins GlcN-Ins Log 0.54 7.8 ± 0.6 14.5 ± 1.2 0.2 ± 0.1a Stationary 3.3 6.6 ± 0.6 12.6 ± 0.6 <0.03 aBest estimate after correction for overlapping peak in HPLC analysis.","These results show that M. smegmatis accumulates GlcNAc-Ins to a substantial level, almost twice the level of MSH content.","The GlcN-Ins content was very much lower in log phase and declined further in stationary phase, as had been observed previously (Anderberg et al; (1998) Supra.","EXAMPLE 6 MSH-deficient mutant 49 can import GlcNAc-Ins and utilize it to sythesize MSH.","The foregoing results imply that mutant 49 should be able to synthesize MSH if supplied with GlcNAc-Ins.","The concentration dependence of the uptake of GlcNAc-Ins was examined with cultures of M. smegmatis mutant 49.For this study mutant 49 was cultured at 37° C. for 23 hr in 5 ml of 7H9 Middlebrook medium as described below, supplemented with 0, 4, 8, 21 μM GlcNAc-Ins.","The cells were collected by centrifugation and extracted for amine and thiol analysis as described above.","The absence of GlcNAc-Ins in mutant 49 shows that it is defective in an initial step of MSH biosynthesis.","When mutant 49 was grown in media supplemented with GlcNAc-Ins, the cells did show the presence of MSH and mycothiol precursors in increasing concentrations with the media content of GlcNAc-Ins.","These results established that GlcNAc-Ins is indeed imported intact, deacetylated and utilized for the production of MSH in a concentration dependent manner (Table 3).","TABLE 3 Levels of MSH and precursors in MSH-deficient strain 49 (M. smegmatis) Content (μmol [g of RDW]−1) [GlcNAc-Ins]a (μM) MSH GlcNAc-Ins GlcN-Ins 0 <0.04 <0.01 <0.02 4 0.47 0.39 <0.02 8 0.91 0.80 0.026 21 2.1 1.4 0.047 aIn Middlebrook 7H9 medium.","; [GlcNAc-Ins] = 0).","In another experiment mutant 49 was cultured in 7H9 Middlebrook medium with 0.4% glucose and 0.5% TWEEN 80 detergent to log phase (A600=0.6) and 10-ml aliquots transferred to sterile 25 ml erlenmeyer flasks.","Duplicate flasks contained cells only (control), 20 μM inositol, 20 μM glucosamine, 20 μM N-acetylglucosamine, or 17 μM GlcNAc-Ins and were cultured at 37° C., shaking at 225 rpm.","Samples (2.3×108 cells) were taken at 2, 6, 19 and 46 hr of culture.","the cells were pelleted by centrifugation for 2 min at 14,000×g and were extracted in 50% acetonitrile containing 20 mM HEPES (pH 8.0) and either 2 mM monobromobimane for thiol analysis or 5 mM NEM for amine analysis and thiol control samples.","Cells from duplicate cultures were analyzed for GlcN-Ins, GlcNAc-Ins, Cys-GlcN-Ins, cysteine, and MSH.","No significant MSH was found in any sample except for the cultures supplemented with GlcNAc-Ins (FIG.","4).","Strain 49 cultured in 17 μM GlcNAc-Ins showed a cysteine level that remained unchanged at 0.36±0.08 μmol per gm of residual dry weight over the experiment.","Cells contained 2.9 μmole per gm of residual dry weight of GlcNAc-Ins at the first measurement (2 hr), which corresponds to a level of GlcN-Ins approaching millimolar.","This occurred prior to the appearance of significant GlcN-Ins in the cell, showing that strain 49 is able to import and concentrate GlcNAc-Ins intact prior to its deacetylation.","The level of GlcNAc-Ins appeared to fall at 6 hr before rising to an even higher level in stationary phase.","The MSH content was measurable as early as 2 hr, but was about 10-fold less than the GlcNAc-Ins content at that time.","The MSH content increased thereafter, and the level at 48 hr was about 60% of that measured for the parent strain (Table 2).","The level of GlcN-Ins ranged from 0.025 (2 hr) to 0.1 (48 hr) μmole per gm of residual dry weight, values in the range of those measured for mc2155 (Table 2).","These results show that exogenous GlcNAc-Ins is efficiently imported by strain 49 and substantially restores its defective biosynthesis of MSH.","The intracellular level of GlcN-Ins found in mutant 49 at 48 hours indicates that GlcNAc-Ins has been concentrated more than 100 fold from the supplemented medium.","This implies that toxic analogs of GlcNAc-Ins, such as those with oxidizing or nitrosating moieties, will be concentrated inside pathogenic mycobacteria or other actinomycetes and function as antimicrobial agents.","EXAMPLE 7 Cloning, expression and purification of M. tuberculosis His-tagged MshB.","To facilitate the purification of the M. tuberculosis deacetylase, Rv1170 was cloned to contain a C-terminal HisTag permitting its easy isolation by affinity chromatography on a Ni2+ chelate resin.","Genomic DNA of M. tuberculosis H37Rv was prepared as described previously (Av-Gay et al., Infect.","Immun.","67:5676-5682, 1999).","The open reading frame Rv1170 was amplified from this DNA with the primers 5′-TTCATATGGTGTCTGAGACGCCG-3′; (SEQ ID NO:10 and 5′-ATAAGCTTGTAGCCGGACGCGGTG-3′ (SEQ ID NO:11) containing NdeI and HindIII restriction sites, respectively.","PCR was performed with Taq polymerase obtained from Gibco BRL, using 1.5 mM MgCl2 and 5% dimethyl sulfoxide.","The 30 cycles of PCR included denaturation at 94° C. for 40 seconds, annealing at 55° C. for 1 min and amplification at 72° C. The PCR products were separated on a 1% agarose gel.","The appropriate PCR product was ligated into the vector pCR2.1 of the TA cloning kit (Invitrogen) and transformed into E. coli DH5a by standard chemical transformation procedure.","Clones containing the vector were selected on plates of Luria-Bertani (LB) agar plus ampicillin (100 μg/ml) and plasmid DNA was digested with restriction endonucleases NdeI and HindIII (Fermentas).","Restriction enzyme-digested plasmids were isolated with a QIAquick gel extraction kit (Qiagen Ltd.).","A corresponding digestion was applied to the plasmid pET-22b and the two products were ligated together with T4 DNA ligase to obtain the plasmid pYA1170c (shown in FIG.","9).","This provides a recombinant protein without a pelB leader sequence, but with a c-terminal His tag.","This plasmid was transformed by the heat shock method to competent E. coli BL21(DE3) prepared according to the CaCl2 method and plated on LB agar containing 100 μg/ml ampicillin.","Single colonies were inoculated into 5 ml of LB broth also containing ampicillin (100 μg/ml).","After over-night incubation at 37° C. with shaking, 5 1-liter cultures were inoculated to 1% with the starter culture and incubated at 37° C. with shaking.","Isopropyl-β-D-thiogalactopyranoside was added to a final concentration of 0.5 mM when the A600 reached 0.6 and incubation was continued overnight at 22° C. before harvesting by centrifugation at 5000×g for 20 minutes at 4° C. The pellets were lysed by sonication in 3 mM 2-mercaptoethanol with 50 mM HEPES pH 7.4 (lysis buffer) containing 35 μM each protease inhibitors (N-α-p-tosyl-L-lysinechloromethyl ketone and N-α-p-tosyl-L-phenylalaninechloromethyl ketone).","Proteins were separated by centrifugation (1-5,000×g, 4° C., 30 min) into-soluble and insoluble-fractions.","The soluble proteins were applied to a 2.5×11 cm Fast Flow® chelating resin (Pharmacia) in the Ni2+ form in lysis buffer containing 10 mM imidazole.","The column was washed with 10 volumes of the loading buffer and then step eluted with lysis buffer containing 150 mM imidazole followed by lysis buffer containing 500 mM imidazole.","Fractions were collected and the purity of the eluted protein was assayed by SDS PAGE gel electrophoresis.","The early 150 mM imidazole fractions were contaminated with E. coli proteins, but the later fractions of the 150 mM and the early 500 mM imidazole fractions were judged>95% pure and pooled.","The yield of pure recombinant MshB (Rv1170) was estimated to be ˜125 mg of protein.","The protein was concentrated and the buffer exchanged repeatedly with 50 mM HEPES containing 50 mM NaCl (assay buffer) in a Centricon® 10 spin ultra filter, adjusted to 10% glycerol and frozen at −70° C. The enzyme as purified was assayed for deacetylase activity with 0.1 mM GlcNAc-Ins as substrate and was found to be sensitive to chelating agents such as 1,10-phenanthroline.","The deacetylase reaction was substantially inhibited by the presence of 0.1 mM 1,10-phenanthroline in the reaction mixture (FIG.","7).","1 mM 1,10-phenanthroline completely inhibited the deacetylase reaction, indicating a dependence of the reaction on divalent metal ions.","The apoenzyme was generated by treatment of the concentrated enzyme with 5 mM 1,10-phenanthroline in assay buffer for 30 min on ice.","The chelator was removed by repeated dilution with assay buffer and concentration until the 1,10-phenanthroline concentration was estimated to be below 1 μM.","All solutions were treated with Chelex-100® chelator to remove extraneous divalent cations.","The apoenzyme was stored at 10 mg/ml in 50 mM NaCl+50 mM HEPES pH 7.5 with 10% glycerol at −70° C. The zinc form (Zn2+) of the deacetylase was prepared by treating the apoenzyme with 0.1 mM ZnCl2 in the assay buffer for 30 min on ice.","The excess Zn2+ was removed by repeated dilution and concentration with assay buffer until the Zn2+ was estimated to be below 1 μM.","The Zn2+ form of the enzyme was stored as described above for the apoenzyme and is herein referred to as “His-tagged MshB”.","EXAMPLE 8 Metal ion dependence of the deacetylase.","The metal ion dependence of the deacetylase activity of MshB was assayed using GlcNAc-Ins in the presence of 0.1 mM divalent metal ion.","Previous studies with ZnCl2 have shown that excess Zn2+ is not inhibitory at 0.1 mM and only slightly inhibitory at 1 mM (see above).","The metal salts tested, ZnCl2, CuSO4, MgCl2, MnCl2, CaCl2, COCl2, CdCl2 and NiCl2, were of reagent grade or higher purity and solutions of the metals were prepared as 10 mM stock solutions in water treated with Chelex-100 chelator.","Enzymatic activity was assayed in Chelex-100® treated 50 mM NaCl with 50 mM HEPES pH 7.4 (assay buffer) containing 0.1 mM of the desired metal salt and 0.1 mM GlcNAc-Ins as substrate.","Buffer and 10 μg of purified apoenzyme were preincubated the divalent metal ion in an 80 μl total reaction volume for 10 min at 37° C. and the assay initiated by the addition of the substrate.","Duplicate reactions were sampled at 3, 10, and 30 min by removing a 20 μl sample of the reaction mixture and adding it to 20 μl of acetonitrile containing 10 mM NEM and 2 mM 1,10-phenanthroline.","The samples were incubated for 10 min at 60° C., placed on ice, and subsequently reacted with AccQ Fluor® (Waters) reagent as described above assayed for AccQ-GlcN-Ins by HPLC as described above.","The MshB apoenzyme was able to catalyze both the deacetylase (GlcNAc-Ins as substrate) and the amidase (MSmB as substrate) reactions at substantially reduced rates, as shown in Table 4 below.","TABLE 4 M. tuberculosis MshB (Rv1170) metal ion dependencea Amidase Specific Deacetylase Activityb Amidase Specific Deacetylase Metalloenzyme nmole/ Activity Activityc Activity Form min/mg relative rate nmole/min/mg Relative rate Apoenzyme 3.4 ± 0.5 1.0 35 ± 6 1.0 Untreated 15 ± 0.2 4.4 70 ± 19 2.0 Zn2+ 17 ± 0.7 5.0 81 ± 16 2.3 Ni2+ 13 ± 0.7 3.8 62 ± 23 1.8 Mn2+ 22 ± 0.7 6.5 69 ± 5 2.0 Ca2+ 3.3 ± 0.1 0.97 34 ± 5 0.97 Mg2+ 3.5 ± 0.2 1.0 41 ± 4 1.2 Cu2+ 3.2 ± 0.1 0.94 32 ± 10 0.9 Cd2+ 21 ± 1.5 6.2 34 ± 2 0.97 Co2+ 29 ± 0.3 8.5 236 ± 23 6.7 Zn2+ + Mg2+ ND — 75 ± 14 2.1 Ni2+ + Mg2+ ND — 64 ± 15 1.8 aRecombinant Rv1170 purified to homogeneity over Ni2+ Sepharose.","b0.1 mM MSmB as substrate with 0.1 mM metal ion.","c0.1 mM GlcNAc-Ins as substrate with 0.1 mM metal ion.","The low metal ion content of the apoenzyme reduced the amidase activity to a greater extent than the deacetylase activity relative to the untreated purified protein.","The activity of the Ni2+ Sepharose purified (untreated) form of the MshB appears to be consistent with the Ni2+ form of the enzyme.","The Zn2+, Mn2+ and Ni2+ forms appear to have about the same activity for both the amidase and deacetylase reactions.","The MshB apoenzyme was not activated by the presence of Ca2+, Mg2+ or Cu2+ for either the amidase or deacetylase reactions.","The MshB deacetylase and amidase reactions were differently affected by the presence of the Cd2+ ion.","The amidase reaction was enhanced to the level of Zn2+ while the deacetylase reaction remained at the apoenzyme activity level.","Similarly anomalous activity with Cd2+ was observed for the peptidase and esterase activity of carboxypeptidase, a zinc metalloprotease (R. C. Davis et al Biochemistry 7, 1090-1099 (1968)).","The highest level of activation for both the amidase and deacetylase reactions was observed with Co2+, as has been reported for numerous zinc metalloproteases (D. S. Auld, Chapter 14, Methods in Enzymology, 248:229-243, 1995).","Some zinc metalloproteases have been reported to require the presence of Mg2+ for optimal activity (Vallee and Auld (1993) Biochemistry 32:6493-6500) so activity assays were conducted with 0.1 mM each Zn2+ and Mg2+.","No additional activation over that of Zn2+ alone for either the amidase or deacetylase reactions was observed.","Thus, the metal ion dependence of MshB is similar to that found for members of the metalloprotease superfamily and is therefore likely that MshB is a zinc metalloenzyme in its native state.","EXAMPLE 9 Kinetics and substrate specificity of His-tagged MshB.","The kinetic constants were determined for GlcNAc-Ins, the deacetylase substrate for MshB, and for MSmB, an amidase substrate.","The rates were determined with His-tagged MshB in 50 mM NaCl containing 50 mM HEPES pH 7.5 (assay buffer).","The enzyme (10 μg) was preincubated with 80 μl of assay buffer for 10 min at 37° C. and the reaction was initiated with the addition of the substrate.","The deacetylase substrate was assayed at 9 different concentrations between 10 μM and 2 mM.","Duplicate reactions were sampled at 3, 10, and 30 min by removing 20 μl of the sample, and mixing with 20 μl of acetonitrile containing 10 mM NEM and 2 mM 1,10-phenanthroline.","The samples were quenched by incubation for 10 min at 60° C. The quenched sample was reacted with AccQ Fluor® reagent (Waters) and analyzed for GlcN-Ins by HPLC as described above.","The amidase reaction was assayed similarly using 10 concentrations of MSmB between 10 μM and 10 mM.","The amidase reaction was sampled at 3, 10, and 30 min by removing 20 μl of sample and mixing it with 60 μl of 40 mM methanesulfonic acid.","The mercapturate product, AcCySmB was analyzed by HPLC as described above.","Initial rates were obtained by extrapolation of the rates calculated at 3, 10, and 30 min to zero time.","The kinetic constants were obtained from an Eadie-Hofstee plot.","The amidase and deacetylase substrates have Km values near of 0.5 mM as shown below in Table 5 below.","TABLE 5 Kinetic characterization of M. tuberculosis MshB (Rv1170) Km Vmax kcat Substrate Activity μM nmol min−1mg−1 s−1 GlcNAc-Ins deacetylase 400 470 0.25 MSmB amidase 560 220 0.12 The intracellular concentration of GlcN-Ins is roughly twice the mycothiol level, or about 2-6 mM (Newton et al, J.","Bacteriol., 182: 6958-6963, 2000) and is sufficient to saturate the enzyme at physiological concentrations.","The substrate specificity of MshB was examined with various amidase and deacetylase substrates at a concentration of 0.1 mM.","The product analyzed will vary with the substrate used.","The deacetylase substrates tested were GlcNAc, GlcNAc-Ins, MSH, and MSmB, and the products assayed were GlcN, GlcN-Ins, Cys-GlcN-Ins, and CySmB-GlcN-Ins, respectively.","The amidase substrates tested were MSH, MSmB, AcCySmB-GlcN, CySmB-GlcN-Ins, MS-acetamide, and MS-acetophenone and the product assayed was GlcN-Ins, except for AcCySmB-GlcN were GlcN was assayed.","The amines were analyzed as the AccQ-derivative and thiols as the bimane derivative as described above.","The results of these substrate specificity studies are summarized in Table 6 below.","TABLE 6 Substrate specificity of M. tuberculosis MshB (Rv1170)a Amidase Specific Deacetylase Activityb Specific Activityb Relative Substratea nmol min−1mg−1 nmol min−1mg−1 Rate GlcNAc-Insc 70 ± 3 1.0 GlcNAcd 1.6 ± 1 0.023 MSHe <0.025 ± 0.012 <0.00036 MSHc 0.3 ± 0.1 0.0043 MSmBf <0.006 <0.00009 MSmBc 20 ± 2 0.29 AcCySmB-GlcNd <0.1 <0.001 CySmB-GlcN-Insc 265 ± 10 3.8 MS-acetamidec 0.14 ± 0.013 0.002 MS-acetophenonec 88 ± 8 1.3 aHis tagged MshB (Rv1170) in the Zn2+ form.","b0.1 mM substrate assayed in 50 mM NaCl + 50 mM HEPES pH 7.4 at 37° C. cReaction assayed for GlcN-Ins.","dReaction assayed for GlcN.","eReaction assayed for CyS-GlcN-Ins.","fReaction assayed for CySmB-GlcN-Ins.","As shown by the results in Table 6, the deacetylase activity of MshB is dependent on the presence of the inositol moiety as the GlcNAc substrate is 44 fold less active than GlcNAc-Ins.","Interestingly MSH and MSmB are not substrates for the deacetylase activity of MshB.","However, mycothiol S-conjugates with reasonably large groups on the cysteine sulfur, such as acetophenone and bimane S-conjugates, are good substrates for the amidase activity of the MshB.","The smaller mycothiol S-conjugate acetamide is a poor substrate for the MshB amidase activity, as was observed previously for mycothiol S-conjugate amidase from M. smegmatis (Newton et al Biochemistry, 39, 10739-10746, 2000).","The importance of the inositol moiety for the amidase activity of MshB is also apparent by the lack of activity with AcCySmB-GlcN.","One difference between the amidase activity of M. tuberculosis His-tagged MshB and the amidase from M. smegmatis is the ability to use CySmB-GlcN-Ins as substrate.","The M. smegmatis amidase required the acetylated amine on the cysteine moiety (or MSmB) for activity.","Another difference between MshB and the M. smegmatis amidase is that the amidase will not deacetylate GlcNAc-Ins (Newton et al J.","Bacteriol., 182, 6958-6963, 2000).","EXAMPLE 10 Inhibition of His-tagged MshB.","Naturally occurring inhibitors of the His-tagged MshB deacetylase and amidase activities have been examined.","The inhibition assays are similar to those described above in Example 9.For the amidase reaction of His-tagged MshB 10 μg enzyme was preincubated for 10 min at 37° C. in 80 μl of buffer containing 50 mM NaCl, 50 mM HEPES pH 7.5, 0.1 mM ZnCl2, 0.2 mM DTT and 0.1-1.0 mM inhibitor.","The inhibitors examined were mycothiol, glutathione and GlcN-Ins.","The purpose of the excess Zn+2 is to prevent depletion of the protein bound Zn2+ by thiols.","The DTT is added to limit the oxidation of the thiol inhibitors, which can be significant at the lower concentrations.","The uninhibited enzyme activity was determined using the same buffer and preincubation conditions without inhibitor.","The assays were initiated with the addition of MSmB to 0.55 mM and sampled at 3, 10, and 30 min by removing a 20 μl sample and quenching the reaction by mixing with 60 μl of 40 mM aqueous methanesulfonic acid.","This sample was assayed directly by HPLC for AcCySmB as described above.","The deacetylase reaction was assayed with GlcNAc-Ins using 0.1-1.0 mM glutathione and mycothiol as inhibitors.","The reaction was initiated by the addition of GlcNAc-Ins to 0.8 mM and was sampled at 3, 10, and 30 min.","The reaction was quenched and analyzed for GlcN-Ins as described in Example 9.Mycothiol appears to be an effective inhibitor of both the amidase (FIG.","8A) and the deacetylase (FIG.","8B) activities of His-Tagged MshB in the range of 0.1 to 1 mM.","This is not simply due to disruption of the enzyme metal binding site by a thiol as shown by the lack of inhibition by glutathione in this concentration range.","The lack of inhibition of the amidase reaction by GlcN-Ins (FIG.","8A) also shows that the immediate product of the reaction is not inhibitory.","Mycothiol is the terminal product in the biosynthesis scheme shown in FIG.","5 and it appears to completely inhibit the deacetylase (MshB) at mycothiol concentrations above 1 mM.","The estimated intracellular concentration of mycothiol in mycobacteria is about 1-3 mM and thus the deacetylase is in a substantially inhibited state until the mycothiol level falls below 1 mM, as may happen during cell division or cell stress.","Inhibition of the deacetylase reaction was analyzed at 0.8 mM GlcNAc-Ins, a concentration nearing saturation, but still below the estimated cellular concentration of 2-6 mM for M. smegmatis.","Thus, in M. smegmatis the deacetylase is exposed to saturating GlcNAc-Ins concentrations but is inhibited when the cellular mycothiol level is above 1 mM.","If mycothiol level falls substantially below 1 mM, the enzyme will catalyze the deacetylation of GlcNAc-Ins from a large cellular pool at near maximal rates to GlcN-Ins and ultimately to mycothiol.","It has previously been shown that mycothiol levels are quite constant from logarithmic through stationary phase growth of M. smegmatis (Newton et al, J.","Bacteriol., 178: 1990-1995, 1996).","It appears that the intracellular mycothiol level is regulated by feedback inhibition of the GlcNAc-Ins deacetylase by mycothiol itself.","The amidase substrate, MSmB, served as a useful model substrate for finding inhibitors of the GlcNAc-Ins deacetylase.","The amidase and deacetylase activities are both completely inhibited by mycothiol at concentrations over 1 mM.","These results identify mycothiol as an inhibitor for the deacetylase and amidase reactions with similar inhibitory concentrations.","Thus, the substrates for either the amidase or deacetylase activity of GlcNAc-Ins deacetylase can be used to screen for inhibitors of the enzyme.","EXAMPLE 11 Oxidant sensitivity of M. smegmatis MSH-deficient mutants.","The importance of mycothiol biosynthesis for the survival of mycobacteria under oxidative stress is illustrated by results obtained with chemical and transposon mutants deficient in mycothiol biosynthesis.","Chemical mutants were produced by mutagenesis of M. smegmatis mc2155 (˜2.5×109 colony forming units per ml Middlebrook 7H9 liquid medium) with N-methyl-N-nitro-N-nitrosoguanidine (4 μg per ml) for 30 min at 37° C. Cells were washed three times with 9 ml of fresh medium, resuspended in 10 ml of fresh medium, and incubated 8.5 h at 37° C. with shaking.","After dilution in fresh medium and passage through a 22-guage needle, the cells were plated on Middlebrook 7H9 agar containing 0.05% Tween 80 and 0.4% glucose.","After 9 days in a humidified incubator, the plates were scored and individual colonies replated in duplicate using a grid layout in 100 mm culture dishes.","After colony development, one plate was used to screen for MSH-deficient mutants using a membrane-based immunoassay specific for MSH (Unson, et al.","(1998) J. Immunol.","Methods 214:29-39).","MSH-deficient candidates were grown in bulk in liquid medium and analyzed for MSH content as described in Example 1.Two MSH-deficient mutants (strains 49 and 164) were identified and strain 49 was complemented using a M. tuberculosis library (pYUB412::H37Rv) of ˜18 kb DNA fragments cloned in the integrative shuttle plasmid pYUB412 to produce the strain 49::H37Rv A18 with partially restored MSH biosynthesis.","Transposon mutants of M. smegmatis mc2155 were prepared using the pCG79 plasmid carrying transposon Tn611 following the methods of Perez, et al.","(1998) Meth.","Molecular Biol.","101:187-198).","Plasmid pCG79 was introduced into M. smegmatis mc2155 by electroporation after which the cells were incubated 2 h at 32° C. in 7H9 medium without antibiotic.","They were then plated on Middlebrook 7H10 agar plates with ADC enrichment and 20 μg/mL of kanamycin and incubated 6 days at 32° C. Single colonies were restreaked on 7H10km plates and incubated 4 days at 32° C. A loopful of each streaked transformant was resuspended, serially diluted, and plated in duplicate on 7H10 Km plates.","One set of plates was incubated 36 h at 32° C. and then shifted to 42° C. for 5 days to select transposon mutants.","The other set of plates was incubated at 32° C. for 7 days and served as positive controls.","The transposon mutants were replated on 7H10Km plates at 1000-2000 colonies per plate and incubated 5d at 42° C. The cells were scraped into 10 ml of 7H9 medium, mixed with 1 mL of glycerol, and stored at −70° C. This library contained ˜10,000 mutants.","Screening of the library for MSH-deficient mutants was accomplished using as ELISA assay method to detect MSH production in cultures grown in microtiter plates (Unson, et al.","(1999) J. Clin.","Microbiol 37:2153-2157).","The first 1000 mutants screened produced three nearly identical MSH-deficient mutants (TN1, TN2 and TN3) that accumulated GlcN-Ins to high levels but failed to produce detectable levels of Cys-GlcN-Ins or MSH.","Since these clones seemed likely to be daughter cells, TN3 was selected for more detailed studies.","Results obtained with the parent and mutant strains of M. smegmatis are summarized in Table 7 below.","TABLE 7 Characterization of M. smegmatis mutant strains MSH Content H2O2 IC50a Strain μmol per g RDW Enzyme Deficiency mM mc2155 10 None 12 49b <0.004 no MshAc 1 49::H37Rv A18b 3.3 partial MshAd 1.8 I64 0.1 low MshCe 3.5 TN3 <0.004 no MshCe 0.5 aConcentration producing 50% loss of viability following 2 h incubation in Middlebrook 7H9 liquid medium containing H2O2 at 37° C., dilution and plating on 7H10 agar, incubation for 10 d, and counting of colony formation.","bData from Newton, et al.","(1999) Biochem.","Biophys.","Res.","Commun.","255: 239-244.cBased upon failure to produce GlcNAc-Ins or GlcN-Ins.","dBased upon restoration of ability to produce GlcN-Ins to ˜15% that of the parent strain.","eBased upon absence of MshC activity in cell extracts and accumulation of GlcN-Ins to 2-3 μmol per g RDW (˜25-fold above the level of the parent strain).","The results of these experiments show that the parent strain (mc2 155) has a high MSH content and exhibits a marked resistance to killing by hydrogen peroxide.","By contrast, strain 49, which is blocked in the first step of MSH biosynthesis and produces no detectable MSH, is 12-fold more sensitive to H2O2.Partial restoration of MSH biosynthesis in strain 49 through complementation (strain 49::H37Rv A18) reduced the peroxide sensitivity of mutant 49 by a factor of two.","Chemical mutant 164, blocked at the ligase biosynthetic enzyme MshC, has a low residual MSH content and is three-fold more sensitive to peroxide than the parent strain.","However, transposon mutant TN3, also blocked at MshC but producing no detectable MSH, was >20-fold more sensitive to H2O2 than the parent strain (FIG.","10).","These results show that blocking MSH biosynthesis before or after the deacetylase step (MshB) produces a dramatic increase in peroxide sensitivity.","It logically follows that blocking-MSH biosynthesis at MshB would produce a comparable increase in peroxide sensitivity in mycothiol-producing bacteria.","The sensitivity of strains mc2155, 164, and TN3 to superoxide was also examined (courtesy of Drs.","H. Buchmeier and D. Piddington).","Superoxide sensitivity was determined according to the method of De Groote, et al.","(1997) Proc.","Natl.","Acad.","Sci.","94: 13997-14001 using timed exposure of cells to 250 μM hypoxanthine in the presence of 0.1 unit/ml of xanthine oxidase followed by dilution and plating to determine survival.","Under these conditions, strain mc2155 exhibits no significant killing whereas mutant TN3 is >90% killed in 1 hour.","By contrast, chemical mutant 164, with a low residual MSH content, exhibited an intermediate level of killing.","Survival of mycothiol-deficient mutant in macrophage.","Transposon mutant TN3 was compared with the parent strain for survival in murine macrophages (data courtesy of Drs.","N. Buchmeier and D. Piddington).","Following the method of De Groote, et al.","(1997) Supra, periodate activated, γ-interferon treated murine peritoneal exudate cells were infected with TN3 and mc2155, and extracellular bacteria were washed free of the macrophages with medium.","At timed intervals the macrophages were resuspended in PBS and lysed with 0.5% deoxycholate; serial dilutions of the lysate were plated on Middlebrook 7H9 agar for determination of colony forming units.","The results of two independent experiments performed on different days (FIG.","11, experiments 1 and 2) show no loss of viability of the parent strain mc2155 in the macrophages over the period of 24 hours; whereas over 60% of the MSH-deficient mutant TN3 was killed by the macrophages within 6 hours.","These results suggest that mycobacteria deficient in MSH biosynthesis will exhibit significantly enhanced killing by mammalian macrophages.","While the invention has been described in detail with reference to certain preferred embodiments thereof, it will be understood that modifications and variations are within the spirit and scope of that which is described and claimed."]],"string":"[\n [\n \"Acetyl glucosaminyl inositol deacetylase, a mycothiol biosynthetic enzyme, and methods of use\",\n \"The present invention provides a family of bacterial acetyl glucosaminyl inositol deacetylases (MshB) with deacetylase activity against acyl glucosaminyl inositol and which play a key role in mycothiol biosynthesis.\",\n \"The invention deacetylases are characterized by a conserved 100 amino acid N-terminal region and three highly conserved histidine-containing regions and by having deacetylase activity as well as amide hydrolase activity.\",\n \"The invention further provides methods for using the invention deacetylases in drug screening assays to determine compounds that inhibit activity.\",\n \"The invention provides for treatment of actino-mycete infections in mammals using antibiotics that inhibit production or activity of MshB and thereby reduce the production of mycothiol and the virulence of the infecting bacteria.\"\n ],\n [\n \"1.A purified acetyl glucosaminyl inositol deacetylase, characterized as having: a) an N-terminal region with an amino acid sequence with 40% or more sequence identity to SEQ ID NO:2 and conservative variations thereof, b) three domains of conservation, wherein two of the domains contain conserved histidine residues, and c) deacetylase activity against acetyl glucosaminyl inositol.\",\n \"2.The purified deacetylase of claim 1, wherein the deacetylase hydrolyzes a C2-amide bond of the glucosaminyl inositol moiety.\",\n \"3.The purified deacetylase of claim 1, wherein the acetyl glucosaminyl inositol is a precursor of mycothiol.\",\n \"4.The purified deacetylase of claim 1, wherein the acetyl glucoasaminyl inositol is N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcNAc-Ins).\",\n \"5.The purified deacetylase of claim 1, wherein the three domains have amino acid sequences selected from the group consisting of SEQ ID NOS: 3, 4, 5, 6, conservative variations thereof, and any combination of two or more thereof.\",\n \"6.The purified deacetylase of claim 1, wherein the deacetylase is derived from an actinomycetes.\",\n \"7.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. smegmatis.\",\n \"8.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. tuberculosis.\",\n \"9.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. leprae.\",\n \"10.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. bovis.\",\n \"11.The purified deacetylase of claim 6, wherein the deacetylase is derived from M. smegmatis, M. tuberculosis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum.\",\n \"M. chelonai, Corynebacterium diphtheriae, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, or M. scrofulaceum.\",\n \"12.The purified deacetylase of claim 6, wherein the bacterium is selected from the group consisting of Streptomyces lincolnensis, Amycolatopsis mediterranei, Amycolatopsis orientalis, Streptomyces lavendulae, Streptomyces coelicolor, Streptomyces rochei and Saccharopolyspora erythraea.\",\n \"13.The purified deacetylase of claim 1, wherein the deacetylase has amidase activity against acyl glucosaminyl inositols.\",\n \"14.The purified deacetylase of claim 1, wherein the deacetylase has an amino acid sequence as set forth in SEQ ID NO:1 15.The purified deacetylase of claim 1, wherein the deacetylase is encoded by a polynucleotide comprising a nucleic acid sequence as set forth in SEQ ID NO:7.16.A purified acetyl glucosaminyl inositol deacetylase, characterized as having: a) an N-terminal region with an amino acid sequence with at least 40% sequence identity to SEQ ID NO:2, b) one or more domains of conservation containing conserved metal chelating residues, and c) deacetylase activity against acetyl glucosaminyl inositol in the presence of metal ion.\",\n \"17.The purified deacetylase of claim 16, wherein the metal ion is selected from the group consisting of Mn2+ and Ni2, Cd2+, Co2+, and Zn2+.\",\n \"18.The purified deacetylase of claim 17 wherein the metal ion is Zn2+.\",\n \"19.The purified deacetylase of claim 16, wherein the metal chelating residues are selected from the group consisting of histidine, aspartic acid and glutamic acid, and combinations thereof.\",\n \"20.An antibody, or functional fragment thereof, that binds specifically to an deacetylase of claim 1.21.An isolated polynucleotide that encodes a deacetylase of claim 1.22.A vector containing a polynucleotide that encodes an deacetylase of claim 1.23.A cell transformed with a vector of claim 22.24.A method for identifying an inhibitor of acetyl glucosaminyl inositol deacetylase, said method comprising: a) contacting a candidate compound with a deacetylase of claim 1 in the presence of an acyl glucosaminyl inositol under suitable conditions and b) determining the presence or absence of breakdown products of the acyl glucosaminyl inositol indicative of deacetylase activity or amidase activity, wherein the substantial absence of the deacetylase activity or the amidase activity is indicative of a candidate compound that inhibits activity of the deacetylase.\",\n \"25.The method of claim 24, wherein the deacetylase is an acetyl glucosaminyl inositol deacetylase.\",\n \"26.The method of claim 24, wherein a breakdown product is a free amine.\",\n \"27.The method of claim 26, wherein the free amine is GlcN-Ins.\",\n \"28.The method of claim 24, wherein a breakdown product is acetate 29.The method of claim 24, wherein a breakdown product is a derivative of cysteine.\",\n \"30.The method of claim 24, wherein the acyl glucosaminyl inositol is N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside.\",\n \"31.The method of claim 24, wherein the acyl glucosaminyl inositol is an S-conjugate of mycothiol.\",\n \"32.The method of claim 31, wherein the S-conjugate of mycothiol is the monobromobimane derivative of mycothiol (MSmB).\",\n \"33.The method of claim 24, wherein the three domains in the deacetylase that contain conserved histidine residues have amino acid sequences selected from SEQ ID NOs: 3, 5, 6 and any combination of two or more thereof.\",\n \"34.The method of claim 24, wherein the deacetylase is produced in an actinomycete.\",\n \"35.The method of claim 34, wherein the actinomycete is M. smegmatis.\",\n \"36.The method of claim 34, wherein the actinomycete is M. tuberculosis.\",\n \"37.The method of claim 34, wherein the actinomycete is M. leprae.\",\n \"38.The method of claim 34, wherein the actinomycete is M. bovis.\",\n \"39.The method of claim 34, wherein the actinomycete is M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheriae, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, or M. scrofulaceum.\",\n \"40.The method of claim 24, wherein candidate compound is a polypeptide, polynucleotide or small molecule.\",\n \"41.A high throughput screening method for identifying inhibitors of the deacetylase of claim 1, said method comprising: a) contacting each of a plurality of candidate compounds with a deacetylase of claim 1 in the presence of acyl glucosaminyl inositol under suitable conditions to form a plurality of reaction mixtures and b) determining the presence or absence of binding to the reaction mixtures of a detectable marker that binds to free amine, wherein the substantial absence of binding of the marker to a reaction mixture is indicative of a candidate compound that inhibits activity of the deacetylase.\",\n \"42.The method of claim 41, wherein the plurality of reaction mixtures are formed in the wells of a microtiter plate.\",\n \"43.The method of claim 41, wherein the detectable marker is colorometric or fluorometric.\",\n \"44.The method of claim 43 wherein the fluorometric marker is fluorescamine or 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate.\",\n \"45.An inhibitor of the deacetylase of claim 1 wherein the inhibitor is derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates Zn2+, or otherwise binds the enzyme active site of the deacetylase.\",\n \"46.The inhibitor of claim 45 wherein the inhibitor additionally chelates one or more metal ions metal ions selected from the group consisting of Mn2+ and Ni2, Cd2+, and Co2+.\",\n \"47.A derivative of GlcN-Ins, wherein the derivative contains a reactive residue attached to the amino group that promotes oxidative stress so as to be selectively toxic to a mycothiol-producing actinomycete by being concentrated in the actinomycete.\",\n \"48.The derivative of claim 47, wherein the reactive residue is a nitroso residue.\",\n \"49.The derivative of claim 47, wherein the reactive residue is a nitroalkyl residue comprising 1 to 3 carbon atoms.\",\n \"50.The derivative of claim 47, wherein the reactive residue is a S-nitrosomercaptoalkyl residue comprising 2 to 4 carbon atoms.\",\n \"51.The derivative of claim 47, wherein the reactive residue is a peroxyalkyl residue comprising 2 to 4 carbon atoms.\",\n \"52.A live mutant actinomycete, whose genome comprises a disruption in an endogenous acetyl glucosaminyl inositol deacetylase gene, wherein said disruption prevents function of an endogenous acetyl glucosaminyl inositol deacetylase while cell surface proteins and lipids are substantially unaffected, and wherein said disruption results in said mutant actinomycetes exhibiting transient survival in mammalian white blood cells for an immune response-raising period of time.\",\n \"53.The live mutant actinomycete of claim 52, wherein the period of time is from 1 to 30 days.\",\n \"54.The live mutant actinomycete of claim 52, wherein the survival of the mutant actinomycetes in mammalian white blood cells does not exceed 30 days.\",\n \"55.The live mutant actinomycete of claim 52, wherein the mutant actinomycete is derived from a pathogen selected from the group consisting of M. smegmatis, M. tuberculosis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheria, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, and M. scrofulaceum.\",\n \"56.The live mutant actinomycete of claim 52, wherein the mutant actinomycetes.\",\n \"is derived from M. smegmatis.\",\n \"57.The live mutant actinomycete of claim 52, wherein the mutant actinomycetes is derived from M. tuberculosis.\",\n \"58.The live mutant actinomycete of claim 52, wherein the mutant actinomycetes is derived from M. leprae.\",\n \"59.The live mutant actinomycete of claim 52, wherein the mutant actinomycetes is derived from M. bovis and said mammal is bovine.\",\n \"60.A method for decreasing the virulence of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium in mammalian cells, said method comprising: introducing into the bacterium an inhibitor of acetyl glucosaminyl inositol deacetylase activity, wherein the intracellular presence of the inhibitor decreases activity of the deacetylase, thereby decreasing mycothiol biosynthesis by the bacterium as compared with untreated control bacterium.\",\n \"61.The method of claim 60, wherein the inhibitor inhibits intracellular production of the deacetylase.\",\n \"62.The method of claim 60, wherein the inhibitor inhibits intracellular deacetylase activity of the deacetylase.\",\n \"63.The method of claim 60, wherein the introducing comprises culturing the bacterium in the presence of the inhibitor.\",\n \"64.The method of claim 60, wherein the inhibitor is an anti-sense oligonucleotide complementary to a target region in a messenger RNA that encodes a polypeptide having an amino acid sequence segment with 40% or more sequence identity to the amino acid sequence of SEQ ID NO:2 or at least one amino acid sequence selected from the group consisting of SEQ ID NOS: 3, 4, 5, 6 and conservative variations thereof.\",\n \"65.The method of claim 60, wherein the inhibitor is an anti-sense oligonucleotide that hybridizes under intracellular conditions with a messenger RNA that encodes a polypeptide having an N-terminal amino acid sequence as set forth in SEQ ID NO:2.66.The method of claim 60, wherein the bacterium is an actinomycete and the inhibitor inhibits intracellular production of mycothiol.\",\n \"67.The method of claim 60, wherein the bacterium is selected from the group consisting of the pathogenic bacteria M. smegmatis, M. tuberculosis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheria, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M abscessus, and M. scrofulaceum.\",\n \"68.The method of claim 60, wherein the bacterium is an actinomycete.\",\n \"69.A method for inhibiting growth of an acetyl glucosaminyl inositol-producing bacterium in a mammal, said method comprising administering to the mammal an effective amount of an inhibitor of intracellular acetyl glucosaminyl inositol deacetylase, thereby inhibiting growth of the bacterium in the mammal.\",\n \"70.The method of claim 69, wherein the inhibitor is derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates a metal ion selected from the group consisting of Mn2+ and Ni2, Cd2+, Co2+, and Zn2+, or otherwise binds the enzyme active site in the deacetylase.\",\n \"71.The method of claim 70, wherein the moiety is ClCH2CONH—.\",\n \"72.The method of claim 70 wherein the moiety is HONHCONH—.\",\n \"73.The method of claim 70, wherein the moiety is HONHCOCH2—.\",\n \"74.The method of claim 70, wherein the moiety is HOPO(CH3)NH—.\",\n \"75.The method of claim 70, wherein the moiety is HOPO(CH3)nCH2—; wherein n=1-5.76.The method of claim 70 wherein the moiety is HSCH2(CH2)nNH—; wherein n=2-5.77.The method of claim 70 wherein the moiety is HS(CH2)nCONH—; wherein n=1-3.78.The method of claim 69 wherein the acetyl glucosaminyl inositol-producing bacterium is a mycothiol-producing bacterium.\",\n \"79.A process for preparation of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins), said method comprising: contacting an acyl glucosaminyl inositol with an deacetylase of claim 1 under suitable conditions so as to hydrolyze the amide bond therein, and obtaining the GlcN-Ins.\",\n \"80.A method for determination of acetyl glucosaminyl inositol (GlcNAc-Ins) in a sample, said method comprising: a) contacting a sample containing GlcNAc-Ins with a deacetylase of claim 1 under suitable conditions and b) determining the amount of GlcN-Ins produced, wherein the amount of GlcN-Ins produced is a measure of the GlcNAc-Ins in the sample.\",\n \"81.The method of claim 80, wherein the amount of GlcN-Ins is determined by HPLC after labeling thereof with a fluorometric or calorimetric reagent.\",\n \"82.The method of claim 81, wherein the fluorometric reagent is fluorescamine.\",\n \"83.The method of claim 81, wherein the fluorometric reagent is 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate.\"\n ],\n [\n \"<SOH> BACKGROUND INFORMATION <EOH>Glutathione (GSH) is the dominant low molecular weight thiol in most eukaryotes and Gram-negative bacteria, and it plays a key role in protection of the cell against oxygen toxicity and electrophilic toxins.\",\n \"However, most gram positive bacteria, including many strict aerobes, do not produce glutathione.\",\n \"Yet aerobic organisms are subjected to oxidative stress from many sources, including atmospheric oxygen, basal metabolic activities, and, in the case of pathogenic microorganisms, toxic oxidants from the host phagocytic response intended to destroy the bacterial invader.\",\n \"Actinomycetes, including Streptomyces and Mycobacteria , do not make GSH but produce instead millimolar levels of mycothiol (MSH, AcCys-GlcN-Ins), an unusual conjugate of N-acetylcysteine (AcCys) with 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins).\",\n \"The biochemistry of mycothiol appears to have evolved completely independently of that of glutathione.\",\n \"However, it has already been established that the metabolism of mycothiol parallels that of glutathione metabolism in two enzymatic processes.\",\n \"First, formaldehyde is detoxified in glutathione-producing organisms by NAD/glutathione-dependent formaldehyde dehydrogenase (L. Uotila, et al.\",\n \"(1989) in Glutathione: Chemical, Biochemical, and Medical Aspects—Part A (D. Dolphin, et al., Eds.)\",\n \"pp 517-551, John Wiley & Sons, et al.).\",\n \"An analogous process involving NAD/mycothiol-dependent formaldehyde dehydrogenase has been identified in the actinomycete Amycolatopsis methanolica (M. Misset-Smits, et al.\",\n \"(1997) FEBS Lett.\",\n \"409:221-222).\",\n \"This enzyme has been sequenced (A. Norin, et al.\",\n \"(1997) Eur.\",\n \"J. Biochem.\",\n \"248:282-289).\",\n \"The second enzymatic process involves a mycothiol homolog of glutahione reductase recently cloned from M. tuberculosis and expressed in M. smegmatis (M. P. Patel, et al.\",\n \"(1999) J. Amer.\",\n \"Chem.\",\n \"Soc.\",\n \"120:11538-11539; M. P. Patel et al.\",\n \"(1999) Biochemistry 38:11827-11833; M. P. Patel et al (2001) Biochemistry 40:3119-3126).\",\n \"The reductase is reasonably specific for the disulfide of mycothiol, but is also active with the disulfide of AcCys-GlcN, the desmyo-inositol derivative of mycothiol.\",\n \"Therefore, there is a need in the art for methods and compounds useful for investigation of the details of the metabolism of mycothiol and comparison with the established roles for the metabolism of glutathione.\",\n \"Antibiotic resistance of pathogenic bacteria, including pathogenic actinomycetes, such as M. tuberculosis , is a well-known problem faced by medical practitioners in treatment of bacterial diseases.\",\n \"Therefore, there is a need in the art for new antibiotics, drugs and vaccines and for screening techniques to discover antibiotics, drugs and vaccines effective to treat or prevent bacterial infections in humans and in other mammals, such as domestic and farm animals.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>The present invention solves these and other problems in the art by providing, in one embodiment, purified acetyl glucosaminyl inositol deacetylases, characterized as having an N-terminal region with an amino acid sequence with 40% or more sequence identity to SEQ ID NO:2 and conservative variations thereof, four domains of conservation, wherein three of the domains contain conserved histidine residues, and deacetylase activity against acetyl glucosaminyl inositol.\",\n \"In another embodiment, the invention provides purified acetyl glucosaminyl inositol deacetylases characterized as having an N-terminal region with an amino acid sequence with at least 40% sequence identity to SEQ ID NO:2, one or more domains of conservation containing conserved metal chelating residues, and deacetylase activity against acetyl glucosaminyl inositol in the presence of metal ion.\",\n \"Antibodies and functional fragment thereof, that bind specifically to invention deacetylases, isolated polynucleotide that encode the invention deacetylases, vectors containing a polynucleotide that encodes an invention deacetylase and cells containing such vectors are also provided.\",\n \"In another embodiment, the invention provides methods for identifying an inhibitor of acetyl glucosaminyl inositol deacetylase by contacting a candidate compound with an invention deacetylase in the presence of an acyl glucosaminyl inositol under suitable conditions and determining the presence or absence of breakdown products of the acyl glucosaminyl inositol indicative of deacetylase activity.\",\n \"Substantial absence of the breakdown product of deacetylase activity is indicative of a candidate compound that inhibits activity of the deacetylase.\",\n \"In yet another embodiment, the present invention provides high throughput screening methods for identifying inhibitors of the invention deacetylases.\",\n \"The screening methods involve contacting each of a plurality of candidate compounds with an invention deacetylase in the presence of acyl glucosaminyl inositol under suitable conditions to form a plurality of reaction mixtures and determining the presence or absence of binding to the reaction mixtures of a detectable marker that binds to free amine.\",\n \"Substantial absence of binding of the marker to a reaction mixture in the invention screening methods is indicative of a candidate compound that inhibits activity of the deacetylase.\",\n \"In yet another embodiment, the present invention provides derivatives of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins), wherein the derivative contains a reactive residue attached to the amino group that promotes oxidative stress and wherein the derivative is selectively toxic to a mycothiol-producing actinomycete by being concentrated in the actinomycete.\",\n \"In still another embodiment, the present invention provides live mutant actinomycetes.\",\n \"The invention mutant actinomycetes have a genome with a disruption in an endogenous acetyl glucosaminyl inositol deacetylase gene, wherein said disruption prevents function of an endogenous acetyl glucosaminyl inositol deacetylase while cell surface proteins and lipids are substantially unaffected, and wherein the disruption results in the mutant actinomycetes exhibiting survival in mammalian white blood cells for an immune response raising period of time.\",\n \"In yet another embodiment, the present invention provides methods for decreasing the virulence of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium in mammalian cells by introducing into the bacterium an inhibitor of acetyl glucosaminyl inositol deacetylase activity.\",\n \"The intracellular presence of the inhibitor in the bacterium decreases activity of the deacetylase, thereby decreasing mycothiol biosynthesis by the bacterium as compared with untreated control bacterium.\",\n \"By virulence is meant the relative power and degree of pathogenicity possessed by organisms to produce disease as measured by clinical symptoms particular to the disease under consideration.\",\n \"For example, the virulence of a M. tuberculosis is measured with reference to the manifestation in an infected individual of the clinical symptoms recognized by a medical practitioner as indicative of tuberculosis.\",\n \"In another embodiment, the present invention provides inhibitors of the invention acetyl glucosaminyl inositol deacetylases wherein the inhibitor is derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates Zn 2+ , or otherwise binds the enzyme active site of the deacetylase.\",\n \"In still another embodiment, the present invention provides methods for inhibiting growth of an acetyl glucosaminyl inositol-producing bacterium in a mammal, by administering to the mammal an effective amount of an inhibitor of intracellular acetyl glucosaminyl inositol deacetylase, thereby inhibiting growth of the bacterium in the mammal.\",\n \"In yet another embodiment, the present invention provides processes for preparation of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins) by contacting an acyl glucosaminyl inositol with an invention deacetylase under suitable conditions so as to hydrolyze the amide bond therein, and obtaining the GlcN-Ins.\"\n ],\n [\n \"FIELD OF THE INVENTION The present invention generally relates to a family of enzymatic compounds produced by bacteria and methods of their use in drug discovery and disease control, and more specifically to acetyl glucosaminyl inositol deacetylases and methods of their use.\",\n \"BACKGROUND INFORMATION Glutathione (GSH) is the dominant low molecular weight thiol in most eukaryotes and Gram-negative bacteria, and it plays a key role in protection of the cell against oxygen toxicity and electrophilic toxins.\",\n \"However, most gram positive bacteria, including many strict aerobes, do not produce glutathione.\",\n \"Yet aerobic organisms are subjected to oxidative stress from many sources, including atmospheric oxygen, basal metabolic activities, and, in the case of pathogenic microorganisms, toxic oxidants from the host phagocytic response intended to destroy the bacterial invader.\",\n \"Actinomycetes, including Streptomyces and Mycobacteria, do not make GSH but produce instead millimolar levels of mycothiol (MSH, AcCys-GlcN-Ins), an unusual conjugate of N-acetylcysteine (AcCys) with 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins).\",\n \"The biochemistry of mycothiol appears to have evolved completely independently of that of glutathione.\",\n \"However, it has already been established that the metabolism of mycothiol parallels that of glutathione metabolism in two enzymatic processes.\",\n \"First, formaldehyde is detoxified in glutathione-producing organisms by NAD/glutathione-dependent formaldehyde dehydrogenase (L. Uotila, et al.\",\n \"(1989) in Glutathione: Chemical, Biochemical, and Medical Aspects—Part A (D. Dolphin, et al., Eds.)\",\n \"pp 517-551, John Wiley & Sons, et al.).\",\n \"An analogous process involving NAD/mycothiol-dependent formaldehyde dehydrogenase has been identified in the actinomycete Amycolatopsis methanolica (M. Misset-Smits, et al.\",\n \"(1997) FEBS Lett.\",\n \"409:221-222).\",\n \"This enzyme has been sequenced (A. Norin, et al.\",\n \"(1997) Eur.\",\n \"J. Biochem.\",\n \"248:282-289).\",\n \"The second enzymatic process involves a mycothiol homolog of glutahione reductase recently cloned from M. tuberculosis and expressed in M. smegmatis (M. P. Patel, et al.\",\n \"(1999) J. Amer.\",\n \"Chem.\",\n \"Soc.\",\n \"120:11538-11539; M. P. Patel et al.\",\n \"(1999) Biochemistry 38:11827-11833; M. P. Patel et al (2001) Biochemistry 40:3119-3126).\",\n \"The reductase is reasonably specific for the disulfide of mycothiol, but is also active with the disulfide of AcCys-GlcN, the desmyo-inositol derivative of mycothiol.\",\n \"Therefore, there is a need in the art for methods and compounds useful for investigation of the details of the metabolism of mycothiol and comparison with the established roles for the metabolism of glutathione.\",\n \"Antibiotic resistance of pathogenic bacteria, including pathogenic actinomycetes, such as M. tuberculosis, is a well-known problem faced by medical practitioners in treatment of bacterial diseases.\",\n \"Therefore, there is a need in the art for new antibiotics, drugs and vaccines and for screening techniques to discover antibiotics, drugs and vaccines effective to treat or prevent bacterial infections in humans and in other mammals, such as domestic and farm animals.\",\n \"SUMMARY OF THE INVENTION The present invention solves these and other problems in the art by providing, in one embodiment, purified acetyl glucosaminyl inositol deacetylases, characterized as having an N-terminal region with an amino acid sequence with 40% or more sequence identity to SEQ ID NO:2 and conservative variations thereof, four domains of conservation, wherein three of the domains contain conserved histidine residues, and deacetylase activity against acetyl glucosaminyl inositol.\",\n \"In another embodiment, the invention provides purified acetyl glucosaminyl inositol deacetylases characterized as having an N-terminal region with an amino acid sequence with at least 40% sequence identity to SEQ ID NO:2, one or more domains of conservation containing conserved metal chelating residues, and deacetylase activity against acetyl glucosaminyl inositol in the presence of metal ion.\",\n \"Antibodies and functional fragment thereof, that bind specifically to invention deacetylases, isolated polynucleotide that encode the invention deacetylases, vectors containing a polynucleotide that encodes an invention deacetylase and cells containing such vectors are also provided.\",\n \"In another embodiment, the invention provides methods for identifying an inhibitor of acetyl glucosaminyl inositol deacetylase by contacting a candidate compound with an invention deacetylase in the presence of an acyl glucosaminyl inositol under suitable conditions and determining the presence or absence of breakdown products of the acyl glucosaminyl inositol indicative of deacetylase activity.\",\n \"Substantial absence of the breakdown product of deacetylase activity is indicative of a candidate compound that inhibits activity of the deacetylase.\",\n \"In yet another embodiment, the present invention provides high throughput screening methods for identifying inhibitors of the invention deacetylases.\",\n \"The screening methods involve contacting each of a plurality of candidate compounds with an invention deacetylase in the presence of acyl glucosaminyl inositol under suitable conditions to form a plurality of reaction mixtures and determining the presence or absence of binding to the reaction mixtures of a detectable marker that binds to free amine.\",\n \"Substantial absence of binding of the marker to a reaction mixture in the invention screening methods is indicative of a candidate compound that inhibits activity of the deacetylase.\",\n \"In yet another embodiment, the present invention provides derivatives of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins), wherein the derivative contains a reactive residue attached to the amino group that promotes oxidative stress and wherein the derivative is selectively toxic to a mycothiol-producing actinomycete by being concentrated in the actinomycete.\",\n \"In still another embodiment, the present invention provides live mutant actinomycetes.\",\n \"The invention mutant actinomycetes have a genome with a disruption in an endogenous acetyl glucosaminyl inositol deacetylase gene, wherein said disruption prevents function of an endogenous acetyl glucosaminyl inositol deacetylase while cell surface proteins and lipids are substantially unaffected, and wherein the disruption results in the mutant actinomycetes exhibiting survival in mammalian white blood cells for an immune response raising period of time.\",\n \"In yet another embodiment, the present invention provides methods for decreasing the virulence of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium in mammalian cells by introducing into the bacterium an inhibitor of acetyl glucosaminyl inositol deacetylase activity.\",\n \"The intracellular presence of the inhibitor in the bacterium decreases activity of the deacetylase, thereby decreasing mycothiol biosynthesis by the bacterium as compared with untreated control bacterium.\",\n \"By virulence is meant the relative power and degree of pathogenicity possessed by organisms to produce disease as measured by clinical symptoms particular to the disease under consideration.\",\n \"For example, the virulence of a M. tuberculosis is measured with reference to the manifestation in an infected individual of the clinical symptoms recognized by a medical practitioner as indicative of tuberculosis.\",\n \"In another embodiment, the present invention provides inhibitors of the invention acetyl glucosaminyl inositol deacetylases wherein the inhibitor is derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates Zn2+, or otherwise binds the enzyme active site of the deacetylase.\",\n \"In still another embodiment, the present invention provides methods for inhibiting growth of an acetyl glucosaminyl inositol-producing bacterium in a mammal, by administering to the mammal an effective amount of an inhibitor of intracellular acetyl glucosaminyl inositol deacetylase, thereby inhibiting growth of the bacterium in the mammal.\",\n \"In yet another embodiment, the present invention provides processes for preparation of 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins) by contacting an acyl glucosaminyl inositol with an invention deacetylase under suitable conditions so as to hydrolyze the amide bond therein, and obtaining the GlcN-Ins.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIGS.\",\n \"1A and B show the nucleotide sequence of M. tuberculosis deacetylase gene mshB (Rv1170) (SEQ ID NO:7).\",\n \"FIG.\",\n \"1C shows the deduced amino acid sequence of M. tuberculosis GlcNAc-Ins deacetylase (SEQ ID NO:1) encoded by mshB.\",\n \"FIG.\",\n \"2 is a schematic drawing showing a map of plasmid pYA1170b employed to express Rv1170 in E. coli.\",\n \"FIG.\",\n \"3 is a chart showing the chemical structures of the substrates for assaying deacetylase and amidase activities of the invention acetyl glucosaminyl inositol deacetylases (MshB), such as MshB Rv1170 and homologs.\",\n \"FIG.\",\n \"4 is a graph showing growth of a mutant M. smegmatis (mutant 49) in 7H9 Middlebrook medium containing 17 μM GlcNAc-Ins.\",\n \"Mycothiol (MSH) and MSH precursor contents in cells are expressed in micromoles per gram of residual dry weight (RDW).\",\n \"FIG.\",\n \"5 is a schematic representation of the proposed MSH biosynthesis pathway.\",\n \"FIG.\",\n \"6 is a chart showing alignment of the amino acid sequences of four homologs of MshB of M. tuberculosis H37Rv (Rv1170) GenBank accession number B70875 and M. leprae GenBank accession number CAC30445.Sequences for M. avium (The Institute for Genomic Research (TIGR)), and M. smegmatis (Sanger Center) are from unfinished genomes.\",\n \"FIG.\",\n \"7 is a graph showing MshB deacetylase activity with 0.1 mM GlcNAc-Ins in the presence of 1,10-phenanthroline.\",\n \"FIG.\",\n \"8A is a graph showing MshB deacetylase reaction specific activity with 0.8 mM GlcNAc-Ins as substrate in the presence of increasing concentrations of thiol inhibitors.\",\n \"FIG.\",\n \"8B is a graph showing MshB amidase reaction specific activity with 0.55 mM MSmB as substrate in the presence of increasing concentrations of inhibitors.\",\n \"FIG.\",\n \"9 is a map of the plasmid pYA1170C used to express the recombinant His-tagged acetyl glucosaminyl inositol deacetylase encoded by M. tuberculosis Rv1170.FIG.\",\n \"10 is a graph showing percent survival of strains of M. smegmatis versus hydrogen peroxide concentration after treatment as described in Example 11 herein.\",\n \"Open triangles=mutant TN3, which produces no MSH; open circles=chemical mutant 164, which produces a low residual MSH content; and darkened squares=high MSH content mc2 155.FIG.\",\n \"11 is a graph showing percent survival over time of strains of M. smegmatis in murine macrophages as described in Example 11 herein.\",\n \"Open circles=chemical mutant TN3 (0% MSH content), Experiment 1; open triangles=mutant TN3 (0% MSH content), Experiment 2; and darkened squares=mc2155 (100% MSH content).\",\n \"DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there are provided a family of purified acetyl glucosaminyl inositol deacetylase polypeptides with enzymatic deacetylase activity for acetyl glucosaminyl inositol.\",\n \"The invention acetyl glucosaminyl inositol deacetylases are characterized by having an N-terminal region with an amino acid sequence with 40% or greater sequence identity to an amino acid sequence as set forth in SEQ ID NO:2 and conservative variation thereof, four domains of conservation, wherein three of the domains contain conserved histidine residues, and deacetylase activity against acetyl glucosaminyl inositol.\",\n \"SEQ ID NO:2 corresponds to amino acid residues 1-100 of amino acids of SEQ ID NO:1 (FIG.\",\n \"1C).\",\n \"The members of the family of invention deacetylases hydrolyze a C2-amide bond of acetyl glucosaminyl inositol moiety, such as N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcNAc-Ins).\",\n \"Preferably the acetyl glucosaminyl inositol is a precursor of mycothiol (e.g., in a mycothiol producing bacterium).\",\n \"In preferred embodiments the three histidine-containing conserved domains in the invention deacetylases are selected from VHAHPDDE (SEQ ID NO:3), which corresponds to amino acids 10 through 17 of SEQ ID NO:1; VTCTLGEXGEV (SEQ ID NO:4), which corresponds to amino acids 38 through 49 of amino acid SEQ ID NO:1; YDPXGGYGHPDH (SEQ ID NO:5), which corresponds to amino acids 136 through 147 of SEQ ID NO:1; and AXXAHATQ (SEQ ID NO:6), which corresponds to amino acids 240 through 247 of amino acid SEQ ID NO:1 (FIG.\",\n \"1C) wherein X is any amino acid; and conservative variations thereof, or any combination of any two or more thereof (See FIG.\",\n \"6).\",\n \"Members of the invention family of acetyl glucosaminyl inositol deacetylase polypeptides are metalloproteases.\",\n \"Accordingly, the invention further provides purified acetyl glucosaminyl inositol deacetylases that are characterized as having an N-terminal region with an amino acid sequence with at least 40% sequence identity to SEQ ID NO:2, one or more domains of conservation containing conserved metal chelating residues, and deacetylase activity against acetyl glucosaminyl inositol in the presence of metal ion.\",\n \"The invention deacetylases have been shown to contain an active site that contains a metal ion selected from the group consisting of Mn2+, Ni2, Cd2+, Co2+, and Zn2+, with the preferred metal ion being Zn2+.\",\n \"The metal chelating residues in the invention deacetylases are preferably selected from the group consisting of histidine, aspartic acid and glutamic acid, and combinations thereof.\",\n \"In preferred embodiments, the invention deacetylases have additional activity as amidases, catalyzing the hydrolysis of acyl glucosaminyl inositols.\",\n \"As used herein, the term “acyl glucosaminyl inositol” means substrate compounds for the invention family of deacetylases having the chemical formula R—CONH-GlcN-Ins wherein R═CH3(CH2)n— where n=0-6.Included in the group of substrate compounds is the natural substrate, acetyl-GlcN-Ins, where n=0.Members of this group of substrate compounds are derived from an alkanoic acid.\",\n \"In addition, compounds having the chemical structure R—CONH-GlcN-Ins wherein R=aryl-(CH2)n, where n=0-6 are encompassed by the term.\",\n \"Members of this group of substrate compounds are derived from an aryl alkanoic acid such as phenyl-(CH2)nCOOH.\",\n \"The acyl glucosaminyl inositols of the above chemical formula can also be derived from the reaction of GlcN-Ins with any commercial acid chloride in the form RCOCl, wherein R is: o-tolyl-, 4-ethylphenyl-, 4-propylphenyl-, 4-biphenyl-, 3,4-dimethoxyphenyl-, 3,4,5-trimethoxyphenyl-, 2-furyl-, and the like.\",\n \"The acyl glucosaminyl inositols of the above chemical formula can also be derived from an amino acid or an N-acetyl amino acid.\",\n \"Preferred amino acids include N-acetylcysteinyl-S—R′ or cysteinyl-S—R′, wherein R′ is an organic group attached to the cysteine sulfur, such as may be derived from commercial thiol labeling reagents like 2-bromoacetophenone, monobromobinane, N-ethylmaleimide, cerulenin, 7-diethylamino-3-(4′-maleimidyl phenyl)-4-methyl coumarin, 3(N-maleimidopropionyl)biocytin, and the like.\",\n \"The studies described herein further elaborate the pathway involved in MSH biosynthesis.\",\n \"The present studies demonstrate that GlcNAc-Ins is a major intracellular MSH component in M. smegmatis and is converted to GlcN-Ins by GlcNAc-Ins deacetylase.\",\n \"This conversion defines the second step in MSH biosynthesis.\",\n \"The discovery described herein that Rv1170 is the gene encoding the deacetylase in the M. tuberculosis genome represents the first gene of the MSH biosynthesis pathway to be identified.\",\n \"Assuming that a single enzyme produces GlcNAc-Ins, it is proposed that the genes for the MSH biosynthesis pathway be designated mshA, mshB, mshC, and mshD, with the corresponding enzymes labeled as shown in FIG.\",\n \"5.Identification of mshA, mshC, and mshD would be greatly simplified if they were clustered with mshB in a single operon, but inspection of the gene assignments and open reading frames surrounding mshB (Rv1170) in the M. tuberculosis genome indicates that this is not the case.\",\n \"All mycobacteria thus far examined have high MSH content (G. L. Newton et al.\",\n \"(1996) J. Bacteriol.\",\n \"178:1990-1995) and, based on the studies described herein, are expected to have an ortholog of the MSH biosynthesis enzyme MshB (Rv1170).\",\n \"The available unfinished mycobacterial genome databases yield homologs close to Rv1170 for Mycobacterium leprae (Sanger Centre), Mycobacterium bovis (Sanger Centre), M tuberculosis CDC1551 (The Institute for Genomic Research [TIGR]), M. smegmatis (TIGR), and Mycobacterium avium (TIGR).\",\n \"This sequence homology (FIG.\",\n \"6) indicates that MSH biosynthesis in these organisms utilizes a GlcNAc-Ins deacetylase (MshB) in the same manner as that described here for M. smegmatis.\",\n \"Other actinomycetes that produce MSH are also expected to have a GlcNAc-Ins deacetylase (MshB) gene homologous to Rv1170.Sequence BLAST searches to determine molecules with amino acid homology to the Rv1170 sequence of SEQ ID NO:1 (FIG.\",\n \"1C) also show M. tuberculosis homolog Rv1082 (mycothiol S-conjugate deacetylase) and the Rv1082 orthologs from M. leprae, M. bovis (Sanger Centre), M. tuberculosis CDC1551 (TIGR), M. smegmatis (TIGR), and M. avium (TIGR) to be close homologs.\",\n \"Sequences with partial homology to Rv1170 were also found in the yeast, rat, and human genome databases.\",\n \"These genes code for PIG-L, the second enzyme in glycosylphosphatidylinositol (GPI) anchor biosynthesis (Nakamura et al., (1997) J. Biol.\",\n \"Chem.\",\n \"272:15834-15840), and catalyze the deacetylation of N-acetylglucosaminyl-phosphatidylinositol (GlcNAc-PI).\",\n \"The studies described in the Examples herein indicate that the invention deacetylase is rather specific for GlcNAc-Ins and is not a broad spectrum deacetylase.\",\n \"For example, removal of the inositol residue from the substrate GlcNAc-Ins resulted in a more than 300-fold decrease in reactivity (i.e., GlcNAc-Ins versus GlcNAc) (Table 1).\",\n \"Also, the studies described herein (Table 1) show that neither MSH nor MSmB is deacetylated by the invention deacetylases.\",\n \"Therefore, the AcCys moiety of MSH is inert to the deacetylase.\",\n \"This finding shows that the invention deacetylase has no significant activity for the degradation of MSH.\",\n \"The invention deacetylase appears to be the control point for MSH biosynthesis.\",\n \"In cells tested, a very large endogenous pool of its substrate GlcNAc-Ins (12 to 15 μmol per g of residual dry weight (RDW)) was found (Table 2), but quite low levels were found of its product GlcN-Ins (˜0.2 μmol per g of RDW) (Table 2) and of the final intermediate Cys-GlcN-Ins (<0.006 μmol per g of RDW) leading to MSH.\",\n \"This finding shows that substantial quantities of MSH can be produced upon demand from the endogenous pool of GlcNAc-Ins under control of the invention family of acetyl glucosaminyl inositol deacetylases.\",\n \"If a particular member of the invention family of polypeptide deacetylases hydrolyzes its substrate (GlcNAc-Ins), cleavage of the substrate molecule will form breakdown products wherein one product is a free amine (e.g., 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins)) and the other product is acetate.\",\n \"If a particular member of the invention family of polypeptide deacetylases has activity as an amide hydrolase (amidase), cleavage of the substrate acyl glucosaminyl inositol will form breakdown products wherein one product is a carboxylic acid, and the other product is a free amine (e.g., GlcN-Ins).\",\n \"If the substrate amide is a mycothiol-derived amide, one of the breakdown products will be GlcN-Ins and the other breakdown product will be a sulfur-containing carboxylic acid, such as an AcCys S-conjugate.\",\n \"AcCys S-conjugates are termed mercapturic acids, the final excreted product in the mercapturic acid pathway of glutathione-dependent detoxification in mammals.\",\n \"Mycothiol (1-D-myo-inosityl-2-(N-acetylcysteinyl)amido-2-deoxy-α-D-glucopyranoside) (MSH) is present in a variety of actinomycetes and plays an essential role in a pathway of detoxification in such bacteria.\",\n \"Mycothiol is comprised of N-acetylcysteine (AcCys) amide linked to 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins) and is the major thiol produced by most actinomycetes.\",\n \"In the mycothiol-dependent detoxification process in actinomycetes, an alkylating agent is converted to a S-conjugate of mycothiol, the latter is cleaved to release a mercapturic acid, and the mercapturic acid is excreted from the cell (Newton et al.\",\n \"(2000) Biochemistry 39:10739-10746).\",\n \"It has been discovered that invention acetyl glucosaminyl inositol deacetylases participate in the pathway of mycothiol biosynthesis in which substrate GlcNAc-Ins is an intermediate.\",\n \"In the mycothiol pathway as shown schematically in FIG.\",\n \"5, GlcNAc-Ins is converted to GlcN-Ins by the invention deacetylase.\",\n \"In fact, the studies disclosed herein have shown that the invention deacetylases are the critical step in the production of mycothiol in actinomycetes.\",\n \"For example, it has been shown by the studies described herein (Example 10) that MshB is inhibited by mycothiol in a manner consistent with a negative feedback loop dependent upon the level of mycothiol for control of mycothiol biosynthesis in the cell.\",\n \"Thus, a falling level of mycothiol in the cell available for detoxification of intracellular toxins increases activity of the deacetylase so that substrate GlcNAc-Ins will be cleaved by the expressed deacetylase, in turn, providing the GlcN-Ins moiety necessary for mycothiol production.\",\n \"A member of the invention family of polypeptide deacetylases shown to be responsible for cleavage of GlcNAc-Ins has been cloned from M. tuberculosis gene Rv1170 and has an amino acid sequence as set for in SEQ ID NO:1 (shown in FIG.\",\n \"1C; see also GenBank Accession No.\",\n \"B70875) and a nucleotide sequence as set forth in SEQ ID NO:7 (shown in FIG.\",\n \"1; see also nucleic acid residues 4222-5133 of GenBank Accession No.\",\n \"AL010186).\",\n \"The N-terminal region 100 residues of this newly discovered GlcNAc-Ins deacetylase has the amino acid sequence as shown in SEQ ID NO:2.Members of invention family of acetyl glucosaminyl inositol deacetylases are formed in vivo by bacteria as part of a mycothiol biosynthesis pathway, most usually in bacteria characterized by intracellular production of mycothiol.\",\n \"Additional bacteria from which the invention deacetylase polypeptides can be derived include actinomycetes, such as M. smegmatis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheria, Actinomycetes israelii, M. avium complex (MAC) (Holzman, in Tuberculosis ed.\",\n \"by Rom and Gary (Little, Brown, and Company, 1996) Chapter 56), M. ulcerans, M. abscessus, or M. scrofulaceum, and the like.\",\n \"Homologous non-mycobacterial deacetylase proteins can also be derived from the antibiotic producers Streptomyces lincolnensis, Amycolatopsis mediterranei, Amycolatopsis orientalis, Streptomyces lavendulae, Streptomyces coelicolor, Streptomyces rochei, and the polyketide erythromycin antibiotic producer Saccharopolyspora erythraea.\",\n \"Inhibitors of the invention acetyl glucosaminyl inositol deacetylases are particularly well suited as antibiotics since mycothiol production will cease in the absence of the product GlcN-Ins produced by activity of the invention deacetylases.\",\n \"Accordingly, in another embodiment according to the present invention, there are provided methods for identifying an inhibitor of an invention acetyl glucosaminyl inositol deacetylase, MshB.\",\n \"The invention methods comprise contacting a candidate compound with a member of the invention family of deacetylases in the presence of a substrate for the enzyme under suitable conditions and determining the presence or absence of breakdown products of the substrate indicative of deacetylase (or optionally S-conjugate amidase) activity.\",\n \"For example, if the test compound is a putative inhibitor of amide hydrolase activity of the invention polypeptide deacetylase, the absence of acetate or other carboxylic acid and/or free amine, such as GlcN-Ins, as breakdown products indicates the candidate compound is an inhibitor of the activity of the invention polypeptide as a deacetylase.\",\n \"The preferred substrate for testing for deacetylase activity of the invention polypeptides is the acetyl glucosaminyl inositol (GlcNAc-Ins).\",\n \"On the other hand, if the test compound is a putative inhibitor of MshB, the appearance of free amine, such as GlcN-Ins, and/or acetate or carboxylate indicates that the candidate compound is not an inhibitor of the activity of the invention deacetylase as a deacetylase or as an amidase of an acyl glucosaminyl inositol.\",\n \"A preferred substrate for use in screening for inhibitors of deacetylase activity is N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcNAc-Ins).\",\n \"Substantial absence of the breakdown products of enzymatic activity is indicative of a candidate compound that inhibits enzymatic activity of the deacetylase.\",\n \"In a preferred embodiment, the deacetylase used in the invention method is an acetyl glucosaminyl inositol deacetylase and the method is designed to assay for production of free amine.\",\n \"Such assays can be conducted en masse using a high throughput screening method for identifying inhibitors of the invention deacetylase.\",\n \"For example, a plurality of candidate compounds can be contacted with an invention deacetylase in the presence of a substrate for the enzyme (e.g.\",\n \"an acyl glucosaminyl inositol) under suitable conditions (e.g., as shown in the Examples herein) for activity of the deacetylase.\",\n \"Binding of a marker selected to bind to a breakdown product can then be assayed using any technique known in the art for high throughput screening.\",\n \"For example, a colorometric or fluorometric marker that binds to free amine can be used to screen a plurality of reaction mixtures formed in the wells of a microtitre plate (Wong, et al.\",\n \"(2001) Anal.\",\n \"Biochem.\",\n \"290:338-346).\",\n \"A preferred fluorometric marker for use in the invention high throughput screening methods is fluorescamine, which binds to free amine.\",\n \"In another embodiment of the invention, methods are provided for determination of acetyl glucosaminyl inositol (GlcNAc-Ins) in a sample by contacting a sample containing GlcNAc-Ins with an invention deacetylase under suitable conditions and determining the amount of GlcN-Ins produced, wherein the amount of GlcN-Ins produced is a measure of the GlcNAc-Ins in the sample.\",\n \"The amount of GlcN-Ins in the sample can be determined by HPLC after labeling thereof with a fluorometric or colorimetric reagent, such as 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (sold as AccQFluor® reagent by Waters), and the like.\",\n \"In an alternative embodiment of the invention, methods are provided for decreasing the virulence in mammalian cells of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium, such as an actinomycete.\",\n \"In the invention method for decreasing the virulence of pathogenic acetyl glucosaminyl inositol deacetylase-producing bacteria, an inhibitor of acetyl glucosaminyl inositol deacetylase (for example, one identified by the above-described screening method) is introduced into the bacterium.\",\n \"Intracellular uptake by the treated bacterium of the inhibitor results in decreased activity of the deacetylase, thereby decreasing mycothiol biosynthesis by the bacterium as compared with untreated control bacterium.\",\n \"For example, for treatment of isolated mammalian cells, the introducing can comprise culturing the bacterium in the presence of the inhibitor.\",\n \"Alternatively, for treatment of mammalian cells contained in a living organism, the inhibitor may be administered systemically to the living organism.\",\n \"Pathogenic acetyl glucosaminyl inositol deacetylase-producing bacteria whose virulence can be reduced according to the invention methods include such actinomycetes as M. smegmatis, M. tuberculosis, M. leprae, M. bovis particularly in bovine subjects), M. intracellulare, M. africanum, and M. marinarum.\",\n \"M. chelonai, Corynebacterium diphtheriae, Actinomyces israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, M. scrofulaceum, and the like.\",\n \"The inhibitors used in the invention methods for decreasing the virulence of a pathogenic acetyl glucosaminyl inositol deacetylase-producing bacterium may either inhibit intracellular production of the deacetylase or inhibit intracellular deacetylase activity of the deacetylase.\",\n \"In one embodiment according to the present invention, there are provided inhibitors of the members of the invention family of deacetylase polypeptides.\",\n \"The invention inhibitors are characterized by being derived from GlcN-Ins by replacing the amino group therein with a moiety that chelates Zn2+ or otherwise binds the enzyme active site.\",\n \"The invention inhibitors may also chelate one or more metal ions selected from the group consisting of Mn2+ and Ni2, Cd2+, and Co2+.\",\n \"The following are examples of moieties that can substitute for the amino group in GlcN-Ins in the invention inhibitors: ClCH2CONH— HONHCONH— HONHCOCH2— HOPO(CH3)NH— HOPO(CH3)nCH2—; wherein n=1-5 HSCH2(CH2)nNH—; wherein n=2-5 HS(CH2)nCONH—; wherein n=1-3.In another embodiment according to the present invention, there are provided derivatives of GlcN-Ins, wherein the derivative contains a reactive residue attached to the amino group that promotes oxidative stress (e.g., including nitrosative stress) so as to be selectively toxic to a mycothiol-producing actinomycete by being concentrated in the actinomycete.\",\n \"Examples of reactive residues that can be attached to the amino group of GlcN-Ins to cause the compound to be selectively toxic to mycothiol-producing actinomycetes by intracellular concentration include, but are not limited to a nitroso residue, a nitroalkyl residue comprising 1 to 3 carbon atoms, a S-nitrosomercaptoalkyl residue comprising 2 to 4 carbon atoms, or a peroxyalkyl residue comprising 2 to 4 carbon atoms.\",\n \"In another embodiment according to the present invention, the invention inhibitor is an anti-sense oligonucleotide complementary to a target region in a messenger RNA that encodes a polypeptide having an amino acid sequence segment with 40% or more sequence identity to the amino acid sequence of SEQ ID NO:2 or 80% or more sequence identity to at least one amino acid sequence selected from the group consisting of SEQ ID NOS: 3, 4, 5, 6 and conservative variations thereof.\",\n \"In another embodiment the anti-sense oligonucleotide hybridizes under intracellular conditions with a messenger RNA that encodes a polypeptide having an N-terminal amino acid sequence as set forth in SEQ ID NO:2.For example, in one embodiment, the candidate compound inhibits intracellular production or activity of the acetyl glucosaminyl inositol deacetylase.\",\n \"A presently preferred drug candidate for screening in live bacteria for activity that inhibits intracellular production or activity of acetyl glucosaminyl inositol deacetylase is an anti-sense oligonucleotide complementary to a target region in a messenger RNA that encodes a polypeptide having an N-terminal amino acid sequence with 40% or more sequence identity to the amino acid sequence set forth in SEQ ID NO:2, or a conservative variation thereof, for example, 50%, 55%, 60% or 65% sequence identity.\",\n \"Suitable conditions for conducting invention drug screening methods are well known in the art and are described, for example, in the Examples hereinbelow.\",\n \"Alternatively, an anti-sense oligonucleotide can be designed to hybridize under in vivo conditions with a messenger RNA that encodes a polypeptide having an N-terminal amino acid sequence as set forth in SEQ ID NO:2, or contains an amino acid segment as set forth in SEQ ID NOs:3, 4, 5, and 6, or a conservative variation thereof.\",\n \"The anti-sense oligonucleotide can comprise from about 10 to about 60 nucleic acid residues, for example from 10 to about 50, or from 10 to about 40, 30 or 20 nucleic acid residues.\",\n \"“Hybridization” refers to the process by which a nucleic acid strand joins with a complementary strand through base pairing.\",\n \"Hybridization reactions can be sensitive and selective so that a particular sequence of interest will join with a complementary strand even in samples in which it is present at low concentrations.\",\n \"Suitable intracellular conditions for hybridization of an anti-sense oligonucleotide to messenger RNA will be determined by the particular bacterium used in the invention method.\",\n \"In general, the pH, temperature and salt concentration must be comparable to intracellular conditions in the test bacterium.\",\n \"In yet another embodiment according to the present invention, there are provided live mutant actinomycetes, whose genomes comprise a disruption in an endogenous acetyl glucosaminyl inositol deacetylase gene and thereby prevents mycothiol synthesis.\",\n \"Disruption of genes for mycothiol biosynthesis in mycobacteria reduces their survival in mammalian macrophages (FIG.\",\n \"11).\",\n \"Disruption of the endogenous acetyl glucosaminyl inositol deacetylase gene will prevent function of an endogenous acetyl glucosaminyl inositol deacetylase while cell surface proteins and lipids should be substantially unaffected.\",\n \"As a result, invention live mutant actinomycetes exhibit the phenotype of transient survival in mammalian white blood cells, such as murine or human white blood cells, for an immune response raising period of time.\",\n \"Such genetically engineered live mutant actinomycetes will survive in mammalian white blood cells for a period of time from 1 to 30 days, for example from 4 to 25 days or from 5 to 20 days, but in no event for more than 30 days.\",\n \"Due to lack of intracellular acetyl glucosaminyl inositol deacetylase the invention live mutant bacterium will fail to produce mycothiol.\",\n \"Hence, the mutant live bacterium is unable to survive the oxidative stress inherent in the intracellular environment of mammalian white blood cells long enough to establish infection in the cells or to establish infection in an immunocompetent mammal containing such white blood cells.\",\n \"Thus, invention live mutant actinomycetes possess a combination of features desired for a vaccine effective in mammals against infection by such pathogenic actinomycetes as M. smegmatis, M. tuberculosis, M. leprae, M. bovis, M. intracellulare, M. africanum, M. marinarum, M. chelonai, Corynebacterium diphtheria, Actinomycetes israelii, M. avium complex (MAC), M. ulcerans, M. abscessus, M. scrofulaceum, and the like.\",\n \"An individual (e.g., an animal, such as a mouse, a farm animal or a human) to which the live mutant is administered according to a protocol appropriate for inducing a protective immune response and who has not previously been infected by the counterpart wild type will mount an immune response to the vaccine, for example an immune response sufficient to protect the individual against future infection by the corresponding wild-type live pathogen.\",\n \"Alternatively, the invention live mutant actinomycetes are useful as a research tool to investigate the properties desirable in a live mutant vaccine.\",\n \"In still another embodiment according to the present invention, there are provided processes for preparation of GlcN-Ins by contacting an N-acyl glucosaminyl inositol under suitable conditions with an acetyl glucosaminyl inositol deacetylase so as to hydrolyze the amide bond therein to obtain stereochemically pure α(1-1) GlcN-Ins (1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside).\",\n \"For example, the N-acyl glucosaminyl inositol can be a mycothiol S-conjugate, such as the bimane derivative of mycothiol.\",\n \"The deacetylase cleaves the N-acyl glucosaminyl inositol, freeing GlcN-Ins as one of the cleavage breakdown products.\",\n \"GlcN-Ins has utility in conducting research regarding deacetylase activity and mycothiol biochemistry in bacteria, development of products and procedures for overcoming the antibiotic resistance of pathogenic bacteria, such as actinomycetes, and as a precursor for formation of acyl glucosaminyl inositol derivatives and inhibitors of deacetylases thereof as disclosed herein.\",\n \"A “conservative variation” in an amino acid sequence is a sequence that differs from a reference sequence by one or more conservative or non-conservative amino acid substitutions, deletions, or insertions, particularly when such a substitution occurs at a site that is not the active site of the molecule, and provided that the polypeptide essentially retains its functional properties.\",\n \"A conservative amino acid substitution, for example, substitutes one amino acid for another of the same class (e.g., substitution of one hydrophobic amino acid, such as isoleucine, valine, leucine, or methionine, for another, or substitution of one polar amino acid for another, such as substitution of arginine for lysine, glutamic acid for aspartic acid or glutamine for asparagine).\",\n \"One or more amino acids can be deleted, for example, from an deacetylase polypeptide, resulting in modification of the structure of the polypeptide, without significantly altering its biological activity.\",\n \"For example, carboxyl-terminal amino acids that are not required for deacetylase or deacetylase activity of the invention polypeptides can be removed.\",\n \"Biologically functional viral and plasmid DNA vectors capable of expression and replication in a host are known in the art.\",\n \"Such vectors are used to incorporate DNA sequences of the invention.\",\n \"In general, expression vectors containing promoter sequences which facilitate the efficient transcription of the inserted eukaryotic genetic sequence are used in connection with the host.\",\n \"The expression vector typically contains an origin of replication, a promoter, and a terminator, as well as specific genes that are capable of providing phenotypic selection of the transformed cells.\",\n \"In addition to expression vectors known in the art such as bacterial, yeast and mammalian expression systems, baculovirus vectors may also be used.\",\n \"One advantage to expression of foreign genes in this invertebrate virus expression vector is that it is capable of expression of high levels of recombinant proteins, which are antigenically and functionally similar to their natural counterparts.\",\n \"Baculovirus vectors and the appropriate insect host cells used in conjunction with the vectors will be known to those skilled in the art.\",\n \"The term “recombinant expression vector” refers to a plasmid, virus or other vehicle known in the art that has been manipulated by insertion or incorporation of the invention acetyl glucosaminyl inositol deacetylase genetic sequences.\",\n \"Such expression vectors contain a promoter sequence that facilitates the efficient transcription of the inserted genetic sequence of the host.\",\n \"The expression vector typically contains an origin of replication, a promoter, as well as specific genes which allow phenotypic selection of the transformed cells.\",\n \"Vectors suitable for use in the present invention include, but are not limited to the T7-based expression vector for expression in bacteria (Rosenberg, et al., Gene, 56:125, 1987), the pMSXND expression vector for expression in mammalian cells (Lee and Nathans, J. Biol.\",\n \"Chem., 263:3521, 1988) and baculovirus-derived vectors for expression in insect cells.\",\n \"The DNA segment can be present in the vector operably linked to regulatory elements, for example, a promoter (e.g., T7, metallothionein I, or polyhedrin promoters).\",\n \"The vector may include a phenotypically selectable marker to identify host cells which contain the expression vector.\",\n \"Examples of markers typically used in prokaryotic expression vectors include antibiotic resistance genes for ampicillin (β-lactamases), tetracycline and chloramphenicol (chloramphenicol acetyltransferase).\",\n \"Examples of such markers typically used in mammalian expression vectors include the gene for adenosine deaminase (ADA), aminoglycoside phosphotransferase (neo, G418), dihydrofolate reductase (DHFR), hygromycin-B-phosphotransferase (HPH), thymidine kinase (TK), and xanthine guanine phosphoribosyltransferse (XGPRT, gpt).\",\n \"The isolation and purification of host cell expressed polypeptides of the invention may be by any conventional means such as, for example, preparative chromatographic separations and immunological separations such as those involving the use of monoclonal or polyclonal antibody.\",\n \"Transformation of the host cell with the recombinant DNA may be carried out by conventional techniques well known to those skilled in the art.\",\n \"Where the host is prokaryotic, such as E. coli, competent cells which are capable of DNA uptake can be prepared from cells harvested after exponential growth and subsequently treated by electroporation or the CaCl2 method using procedures well known in the art.\",\n \"Alternatively, MgCl2 or RbCl could be used.\",\n \"Where the host used is a eukaryote, various methods of DNA transfer can be used.\",\n \"These include transfection of DNA by calcium phosphate-precipitates, conventional mechanical procedures such as microinjection, insertion of a plasmid encased in liposomes, or the use of virus vectors.\",\n \"Eukaryotic cells can also be cotransformed with DNA sequences encoding the polypeptides of the invention, and a second foreign DNA molecule encoding a selectable phenotype, such as the herpes simplex thymidine kinase gene.\",\n \"Another method is to use a eukaryotic viral vector, such as simian virus 40 (SV40) or bovine papilloma virus, to transiently infect or transform eukaryotic cells and express the protein.\",\n \"(Eukaryotic Viral Vectors, Cold Spring Harbor Laboratory, Gluzman ed., 1982).\",\n \"Examples of mammalian host cells include COS, BHK, 293, and CHO cells.\",\n \"Eukaryotic host cells may also include yeast.\",\n \"For example, DNA can be expressed in yeast by inserting the DNA into appropriate expression vectors and introducing the product into the host cells.\",\n \"Various shuttle vectors for the expression of foreign genes in yeast have been reported (Heinemann, J. et al., Nature, 340:205, 1989; Rose, M. et al., Gene, 60:237, 1987).\",\n \"The invention provides antibodies that are specifically reactive with invention deacetylase polypeptides or fragments thereof.\",\n \"Antibody that consists essentially of pooled monoclonal antibodies with different epitopic specificities, as well as distinct monoclonal antibody preparations are provided.\",\n \"Monoclonal antibodies are made from antigen containing fragments of the protein by methods well known in the art (Kohler, et al., Nature, 256:495, 1975; Current Protocols in Molecular Biology, Ausubel, et al., ed., 1989).\",\n \"Monoclonal antibodies specific for acetyl glucosaminyl inositol deacetylase polypeptide can be selected, for example, by screening for hybridoma culture supernatants that react with acetyl glucosaminyl inositol deacetylase polypeptides, but do not react with other bacterial deacetylases.\",\n \"Antibody that consists essentially of pooled monoclonal antibodies with different epitopic specificities, as well as distinct monoclonal antibody preparations are provided.\",\n \"Monoclonal antibodies are made from antigen containing fragments of the protein by methods well known in the art (Kohler, et al., Nature, 256:495, 1975; Current Protocols in Molecular Biology, Ausubel, et al., ed., 1989).\",\n \"The term “antibody” as used in this invention includes intact molecules as well as fragments thereof, such as Fab, F(ab′)2 and Fv, which are capable of binding the epitopic determinant.\",\n \"These antibody fragments retain some ability to selectively bind with its antigen or receptor and are defined as follows: (1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule can be produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain; (2) Fab′, the fragment of an antibody molecule can be obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab′ fragments are obtained per antibody molecule; (3) (Fab′)2, the fragment of the antibody that can be obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; F(ab′)2 is a dimer of two Fab′ fragments held together by two disulfide bonds; (4) Fv, defined as a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains; and (5) Single chain antibody (“SCA”), defined as a genetically engineered molecule containing the variable region of the light chain, the variable region of the heavy chain, linked by a suitable polypeptide linker as a genetically fused single chain molecule.\",\n \"Methods of making these fragments are known in the art.\",\n \"(See for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1988), incorporated herein by reference).\",\n \"As used in this invention, the term “epitope” means any antigenic determinant on an antigen to which the paratope of an antibody binds.\",\n \"Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics.\",\n \"Antibodies that bind to acetyl glucosaminyl inositol deacetylase polypeptide of the invention can be prepared using an intact polypeptide or fragments containing small peptides of interest as the immunizing antigen.\",\n \"The polypeptide or a peptide used to immunize an animal can be derived from translated cDNA or chemical synthesis and can be conjugated to a carrier protein, if desired.\",\n \"Such commonly used carriers, which are chemically coupled to the peptide, include keyhole limpet hemocyanin (KLH), thyroglobulin, bovine serum albumin (BSA), and tetanus toxoid.\",\n \"The coupled peptide is then used to immunize the animal (e.g., a mouse, a rat, or a rabbit).\",\n \"If desired, polyclonal or monoclonal antibodies can be further purified, for example, by binding to and elution from a matrix to which the polypeptide or a peptide to which the antibodies were raised is bound.\",\n \"Those of skill in the art will know of various techniques common in the immunology arts for purification and/or concentration of polyclonal antibodies, as well as monoclonal antibodies (See for example, Coligan, et al., Unit 9, Current Protocols in Immunology, Wiley Interscience, 1994, incorporated herein by reference).\",\n \"It is also possible to use the anti-idiotype technology to produce monoclonal antibodies that mimic an epitope.\",\n \"For example, an anti-idiotypic monoclonal antibody made to a first monoclonal antibody will have a binding domain in the hypervariable region that is the “image” of the epitope bound by the first monoclonal antibody.\",\n \"In yet other preferred embodiments, the recombinant acetyl glucosaminyl inositol deacetylase polypeptide is a fusion protein further-comprising a second polypeptide portion having an amino acid sequence from a protein unrelated to the acetyl glucosaminyl inositol deacetylase.\",\n \"Such fusion proteins can be functional in a two-hybrid assay.\",\n \"Another aspect of the present invention provides a substantially pure nucleic acid having a nucleotide sequence which encodes an acetyl glucosaminyl inositol deacetylase polypeptide, or a fragment thereof, having an amino acid sequence at least 60% homologous to one of SEQ ID NOs:2, 3, 4 or 5.In a more preferred embodiment, the nucleic acid encodes a protein having an amino acid sequence 40% or more homologous to SEQ ID NO:2, more preferably at least 50% homologous to SEQ ID NO:2, and most preferably at least 65% homologous to SEQ ID NO:2.In another embodiment, the nucleic acid hybridizes under stringent conditions to a nucleic acid probe corresponding to at least 12 consecutive nucleotides encoding SEQ ID NO:3; more preferably to at least 20 consecutive nucleotides encoding SEQ ID NO:3; more preferably to at least 24 consecutive nucleotides encoding SEQ ID NO:3.In a further embodiment, the nucleic acid hybridizes under stringent conditions to a nucleic acid probe corresponding to at least 12 consecutive nucleotides encoding SEQ ID NO:4; more preferably to at least 20 consecutive nucleotides encoding SEQ ID NO:4; more preferably to at least 30 consecutive nucleotides encoding SEQ ID NO:4.In yet a further embodiment, the nucleic acid hybridizes under stringent conditions to a nucleic acid probe corresponding to at least 12 consecutive nucleotides encoding SEQ ID NO:5; more preferably to at least 20 consecutive nucleotides encoding SEQ ID NO:5; more preferably to at least 30 consecutive nucleotides encoding SEQ ID NO:5.In yet a further embodiment, the nucleic acid hybridizes under stringent conditions to a nucleic acid probe corresponding to at least 12 consecutive nucleotides encoding SEQ ID NO:6; more preferably to at least 20 consecutive nucleotides encoding SEQ ID NO:6.Furthermore, in certain embodiments, the acetyl glucosaminyl inositol deacetylase nucleic acid will comprise a transcriptional regulatory sequence, e.g.\",\n \"at least one of a transcriptional promoter or transcriptional enhancer sequence, operably linked to the acetyl glucosaminyl inositol deacetylase-gene sequence so as to render the recombinant acetyl glucosaminyl inositol deacetylase gene sequence suitable for use as an expression vector.\",\n \"The present invention also features transgenic non-human organisms, e.g.\",\n \"live mutant actinomycetes, which either express a heterologous acetyl glucosaminyl inositol deacetylase gene, or in which expression of their own acetyl glucosaminyl inositol deacetylase gene is disrupted.\",\n \"In addition to the other utilities of such organisms disclosed herein, such a transgenic organism has utility for overproduction of acetyl glucosaminyl inositol needed for screening (particularly high throughput screening) for compounds that inhibit acetyl glucosaminyl inositol deacetylase activity in mycothiol-producing bacteria.\",\n \"The present invention also provides a probe/primer comprising a substantially purified oligonucleotide, wherein the oligonucleotide comprises a region of nucleotide sequence which hybridizes under stringent conditions to at least 10 consecutive nucleotides of sense or anti-sense sequence encoding one of the amino acid sequences encompassed by SEQ ID NOs:2, 3, 4 5, or 6, or naturally occurring mutants thereof.\",\n \"Yet another aspect of the invention pertains to a peptidomimetic that binds to or interferes with an acetyl glucosaminyl inositol deacetylase polypeptide and inhibits its binding to or cleavage of substrate acyl glucosaminyl inositols.\",\n \"For example, a preferred peptidomimetic is an analog of a peptide having the sequence of one of the SEQ ID NOs.\",\n \"1, 2, 3, 4, 5, or 6.Non-hydrolyzable peptide analogs of such residues can be generated using, for example, benzodiazepine, azepine, substituted gama-lactam rings, keto-methylene pseudopeptides, beta-turn dipeptide cores, or beta-aminoalcohols.\",\n \"Other features and advantages of the invention will be apparent from the detailed description herein, and from the claims.\",\n \"The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology, recombinant DNA, and immunology, which are within the skill of the art.\",\n \"Such techniques are explained fully in the literature.\",\n \"See, for example, Molecular Cloning A Laboratory Manual, 2nd Ed., ed.\",\n \"by Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press: 1989); DNA Cloning, Volumes I and II (D. N. Glover ed., 1985); Oligonucleotide Synthesis (M. J. Gait ed., 1984); Mullis et al.\",\n \"U.S. Pat.\",\n \"No.\",\n \"4,683,195; Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds.\",\n \"1984); Transcription And Translation (B. D. Hames & S. J. Higgins eds.\",\n \"1984); Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols.\",\n \"154 and 155 (Wu et al.\",\n \"eds.\",\n \"), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds., 1986); Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).\",\n \"As used herein, the term “actinomycetes” and “an actinomycete” encompasses any bacterium of the order Actinomycetales.\",\n \"As used herein, the term “nucleic acid” refers to polynucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA).\",\n \"The term should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and, as applicable to the embodiment being described, single (sense or anti-sense) and double-stranded polynucleotides.\",\n \"As used herein, the terms “gene”, “recombinant gene” and “gene construct” refer to a nucleic acid comprising an open reading frame encoding an invention acetyl glucosaminyl inositol deacetylase, including both exon and (optionally) intron sequences.\",\n \"The term “intron” refers to a DNA sequence present in a given acetyl glucosaminyl inositol deacetylase gene which is not translated into protein and is generally found between exons.\",\n \"“Homology” refers to sequence similarity between two peptides or between two nucleic acid molecules.\",\n \"Homology can be determined by comparing a position in each sequence which may be aligned for purposes of comparison.\",\n \"When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position.\",\n \"Percent homology between sequences is a function of the number of matching or homologous positions shared by the sequences.\",\n \"The sequence data of a test clone is aligned to the sequences in the database or databases using algorithms designed to measure homology between two or more sequences.\",\n \"Sequence alignment methods include, for example, BLAST (Altschul et al., 1990), BLITZ (MPsrch) (Sturrock & Collins, 1993), and FASTA (Person & Lipman, 1988).\",\n \"For example, optimal alignment of sequences for aligning a comparison window may be conducted by the local homology algorithm of Smith (Smith and Waterman, Adv Appl Math, 1981; Smith and Waterman, J Teor Biol, 1981; Smith and Waterman, J Mol Biol, 1981; Smith et al, J Mol Evol, 1981), by the homology alignment algorithm of Needleman (Needleman and Wuncsch, 1970), by the search of similarity method of Pearson (Pearson and Lipman, 1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Dr., Madison, Wis., or the Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin, Madison, Wis.), or by inspection, and the best alignment (i.e., resulting in the highest percentage of homology over the comparison window) generated by the various methods is selected.\",\n \"The term “transfection” or “transforming” and grammatical equivalents thereof, refers to the introduction of a nucleic acid, e.g., an expression vector, into a recipient cell by nucleic acid-mediated gene transfer.\",\n \"“Transformation”, as used herein, refers to a process in which a cell's genotype is changed as a result of the cellular uptake of exogenous DNA or RNA, and, for example, the transformed cell expresses a recombinant form of one of the invention family of acetyl glucosaminyl inositol deacetylases.\",\n \"“Cells” or “cell cultures” or “recombinant host cells” or “host cells” are often used interchangeably as will be clear from the context.\",\n \"These terms include the immediate subject cells that express the acetyl glucosaminyl inositol deacetylases of the present invention, and, of course, the progeny thereof.\",\n \"It is understood that not all progeny are exactly identical to the parental cell, due to chance mutations or difference in environment.\",\n \"However, such altered progeny are included in these terms, so long as the progeny retain the characteristics relevant to those conferred on the originally transformed cell.\",\n \"In the present case, such a characteristic might be the ability to produce a recombinant acetyl glucosaminyl inositol deacetylase polypeptide.\",\n \"As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.\",\n \"The term “expression vector” includes plasmids, cosmids or phages capable of synthesizing the subject acetyl glucosaminyl inositol deacetylase polypeptide encoded by the respective recombinant gene carried by the vector.\",\n \"Preferred vectors are those capable of autonomous replication and/expression of nucleic acids to which they are linked.\",\n \"In the present specification, “plasmid” and “vector” are used interchangeably as the plasmid is the most commonly used form of vector.\",\n \"Moreover, the invention is intended to include such other forms of expression vectors which serve equivalent functions and which become known in the art subsequently hereto.\",\n \"“Transcriptional regulatory sequence” is a generic term used throughout the specification to refer to DNA sequences, such as initiation signals, enhancers, and promoters, as well as polyadenylation sites, which induce or control transcription of protein coding sequences with which they are operably linked.\",\n \"In preferred embodiments, transcription of a recombinant acetyl glucosaminyl inositol deacetylase gene is under the control of a promoter sequence (or other transcriptional regulatory sequence) that controls the expression of the recombinant gene in a cell-type in which expression is intended.\",\n \"It will also be understood that the recombinant gene can be under the control of transcriptional regulatory sequences which are the same or which are different from those sequences that control transcription of the naturally occurring form of the regulatory protein.\",\n \"As used herein, a “transgenic organism” is any organism, preferably a bacteria in which one or more of the cells of the organism contain heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art.\",\n \"The nucleic acid is introduced into the cell by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus or a vector.\",\n \"The term genetic manipulation does not include classical crossbreeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule.\",\n \"This molecule may be integrated within a chromosome, or it may be extrachromosomally replicating DNA.\",\n \"In the typical transgenic organisms described herein, the transgene causes cells to express a recombinant form of the subject acetyl glucosaminyl inositol deacetylase polypeptides.\",\n \"As used herein, the term “transgene” means a nucleic acid sequence (encoding, e.g., an acetyl glucosaminyl inositol deacetylase polypeptide), which is partly or entirely heterologous, i.e., foreign, to the transgenic organism or cell into which it is introduced, or, is homologous to an endogenous gene of the transgenic organism or cell into which it is introduced, but which is designed to be inserted, or is inserted, into the organism's genome in such a way as to alter the genome of the cell into which it is inserted (e.g., it is inserted at a location which differs from that of the natural gene or its insertion results in a knockout).\",\n \"A transgene can include one or more transcriptional regulatory sequences and any other nucleic acid, such as introns, that may be necessary for optimal expression of a selected nucleic acid.\",\n \"The term “evolutionarily related to”, with respect to nucleic acid sequences encoding acetyl glucosaminyl inositol deacetylase polypeptides, refers to nucleic acid sequences that have arisen naturally in an organism, including naturally occurring mutants.\",\n \"The term also refers to nucleic acid sequences which, while derived from a naturally occurring acetyl glucosaminyl inositol deacetylase polypeptide, have been altered by mutagenesis, as for example, combinatorial mutagenesis, yet still encode polypeptides which have the deacetylase activity of an acetyl glucosaminyl inositol deacetylase polypeptide.\",\n \"One aspect of the present invention pertains to an isolated nucleic acid comprising the nucleotide sequence encoding an acetyl glucosaminyl inositol deacetylase polypeptide, fragments thereof encoding polypeptides having acetyl glucosaminyl inositol deacetylase activity, and/or equivalents of such nucleic acids.\",\n \"The term-nucleic acid as used herein is intended to include such fragments and equivalents.\",\n \"The term equivalent is understood to include nucleotide sequences encoding functionally equivalent acetyl glucosaminyl inositol deacetylase polypeptides or functionally equivalent peptides having an activity of an acetyl glucosaminyl inositol deacetylase polypeptide such as described herein.\",\n \"Equivalent nucleotide sequences will include sequences that differ by one or more nucleotide substitutions, additions or deletions, such as allelic variants; and will also include sequences that differ from the nucleotide sequence encoding native acetyl glucosaminyl inositol deacetylases due to the degeneracy of the genetic code.\",\n \"Equivalents will also include nucleotide sequences that hybridize under stringent conditions (i.e., equivalent to about 20-27° C. below the melting temperature of the DNA duplex formed in about 1 M salt) to the nucleotide sequence of an acetyl glucosaminyl inositol deacetylase gene, such as that as set forth in SEQ ID NO:7, particularly those segments encoding the polypeptides shown in one of SEQ ID NOs.\",\n \"2, 3, 4, 5 or 6, and conservative variations thereof.\",\n \"In one embodiment, equivalents will further include nucleic acid sequences derived from and evolutionarily related to such nucleotide sequences.\",\n \"The term “isolated” or “purified” as also used herein with respect to nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs, or RNAs, respectively, that are present in the natural source of the macromolecule.\",\n \"For example, an isolated nucleic acid encoding one of the subject acetyl glucosaminyl inositol deacetylase polypeptides preferably includes no more than 10 kilobases (kb) of nucleic acid sequence which naturally immediately flanks the acetyl glucosaminyl inositol deacetylase gene in genomic DNA, more preferably no more than 5 kb of such naturally occurring flanking sequences, and most preferably less than 1.5 kb of such naturally occurring flanking sequence.\",\n \"The term isolated or purified as used herein also refers to a nucleic acid or peptide that is substantially free of cellular material or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.\",\n \"Moreover, an “isolated nucleic acid” is meant to include nucleic acid fragments that are not naturally occurring as fragments and would not be found in the natural state.\",\n \"In yet another embodiment, the nucleic acid of the invention encodes a peptide having an amino acid sequence as shown SEQ ID NO:1.Preferred nucleic acids encode a peptide having acetyl glucosaminyl inositol deacetylase polypeptide activity and being 40% or more homologous, more preferably 50% homologous and most preferably 65% homologous with an amino acid sequence as set forth in SEQ ID NO:2 (encoded by a nucleic acid sequence as set forth in SEQ ID NO:7).\",\n \"Nucleic acids that encode peptides having an activity of an invention acetyl glucosaminyl inositol deacetylase polypeptide are also within the scope of the invention.\",\n \"Another aspect of the invention provides a nucleic acid which hybridizes under high or low stringency conditions to a nucleic acid which encodes an acetyl glucosaminyl inositol deacetylase polypeptide having all or a portion of an amino acid sequence shown in one of SEQ ID NOs.\",\n \"2, 3, 4, 5 or 6.Appropriate stringency conditions which promote DNA hybridization, for example, 6.0× sodium chloride/sodium citrate (SSC) at about 45° C., followed by a wash of 2.0×SSC at 50° C., are known to those skilled in the art or can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6.For example, the salt concentration in the wash step can be selected from a low stringency of about 2.0×SSC at 50° C. to a high stringency of about 0.2×SSC at 50° C. In addition, the temperature in the wash step can be increased from low stringency conditions at room temperature, about 22° C., to high stringency conditions at about 65° C. Isolated nucleic acids that differ from the nucleotide sequences disclosed herein due to degeneracy in the genetic code are also within the scope of the invention.\",\n \"For example, more than one triplet designates a number of amino acids.\",\n \"Codons that specify the same amino acid, or synonyms (for example, CAU and CAC are synonyms for histidine) may result in “silent” mutations that do not affect the amino acid sequence of the protein.\",\n \"However, it is expected that DNA sequence polymorphisms that do lead to changes in the amino acid sequences of the subject acetyl glucosaminyl inositol deacetylase polypeptides will exist among prokaryotic cells.\",\n \"One skilled in the art will appreciate that these variations in one or more nucleotides (up to about 3-4% of the nucleotides) of the nucleic acids encoding a particular member of the acetyl glucosaminyl inositol deacetylase polypeptide family may exist among individuals of a given species due to natural allelic variation.\",\n \"Any and all such nucleotide variations and resulting amino acid polymorphisms are within the scope of this invention.\",\n \"Fragments of the nucleic acid encoding a biologically active portion of the subject acetyl glucosaminyl inositol deacetylase polypeptides are also within the scope of the invention.\",\n \"As used herein, a fragment of the nucleic acid encoding an active portion of an acetyl glucosaminyl inositol deacetylase polypeptide refers to a nucleotide sequence having fewer nucleotides than the nucleotide sequence encoding the full length amino acid sequence of, for example, the deacetylase polypeptides represented in nucleic acid SEQ ID NO:1, and which encodes a peptide which retains at least a portion of the biological activity of the full-length protein (i.e., a peptide capable of acetyl glucosaminyl inositol deacetylase activity) as defined herein, or alternatively, which is functional as an antagonist of the deacetylase activity of the full-length protein.\",\n \"Nucleic acid fragments within the scope of the invention include those capable of hybridizing under high or low stringency conditions with nucleic acids from other species, e.g.\",\n \"for use in screening protocols to detect homologs of the subject acetyl glucosaminyl inositol deacetylase polypeptides.\",\n \"Nucleic acids within the scope of the invention may also contain linker sequences, modified restriction endonuclease sites and other sequences useful for molecular cloning, expression or purification of such recombinant peptides.\",\n \"As indicated by the examples set out below, a nucleic acid encoding a peptide having an activity of an invention deacetylase polypeptide may be obtained from mRNA or genomic DNA present in any of a number of antibiotic-producing or pathogenic bacteria, particularly actinomycetes, in accordance with protocols described herein, as well as those generally known to those skilled in the art.\",\n \"A cDNA encoding an acetyl glucosaminyl inositol deacetylase polypeptide, for example, can be obtained by isolating total mRNA from a bacterial cell.\",\n \"Double stranded cDNAs can then be prepared from the total mRNA, and subsequently inserted into a suitable plasmid or bacteriophage vector using any one of a number of known techniques.\",\n \"A gene encoding an acetyl glucosaminyl inositol deacetylase polypeptide can also be cloned using established polymerase chain reaction techniques in accordance with the nucleotide sequence information provided by the invention.\",\n \"Another aspect of the invention relates to the use of an “anti-sense” isolated nucleic acid.\",\n \"As used herein, an “anti-sense” inhibition of endogenous production of an acetyl glucosaminyl inositol deacetylase molecule is carried out by administration or in situ generation of oligonucleotide probes or their derivatives which specifically hybridize (e.g.\",\n \"bind) under intracellular conditions, with the cellular mRNA and/or genomic DNA encoding an acetyl glucosaminyl inositol deacetylase polypeptide so as to inhibit expression of that protein or a constituent thereof, e.g.\",\n \"by inhibiting transcription and/or translation.\",\n \"The binding may be by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix.\",\n \"In general, “anti-sense” therapy refers to the range of techniques generally employed in the art, and includes any therapy that relies on specific binding to oligonucleotide sequences.\",\n \"An anti-sense construct of the present invention can be delivered, for example, as an expression plasmid which, when transcribed in the transformed cell, produces RNA which is complementary to at least a unique portion of the cellular mRNA which encodes an acetyl glucosaminyl inositol deacetylase polypeptide.\",\n \"Alternatively, the anti-sense construct is an oligonucleotide probe which is generated ex vivo and which, when introduced into the cell causes inhibition of expression by hybridizing with the mRNA and/or genomic sequences encoding one of the subject acetyl glucosaminyl inositol deacetylase proteins.\",\n \"Such oligonucleotide probes are preferably modified oligonucleotides that are resistant to endogenous nucleases, e.g.\",\n \"exonucleases and/or endonucleases, and is therefore stable in vivo.\",\n \"Exemplary nucleic acid molecules for use as anti-sense oligonucleotides are phosphoramidate, phosphothioate and methylphosphonate analogs of DNA (see also U.S. Pat.\",\n \"Nos.\",\n \"5,176,996; 5,264,564; and 5,256,775).\",\n \"Additionally, general approaches to constructing oligomers useful in anti-sense techniques have been reviewed, for example, by van der Krol et al.\",\n \"(1988) Biotechniques 6:958-976; and Stein et al.\",\n \"(1988) Cancer Res 48:2659-2668.In addition, the oligomers of the invention may be used as reagents to detect the presence or absence of the target DNA or RNA sequences to which they specifically bind.\",\n \"Such diagnostic tests are described in further detail below.\",\n \"This invention also provides expression vectors comprising a nucleotide sequence encoding a member of the invention family of acetyl glucosaminyl inositol deacetylase polypeptides and operably linked to at least one regulatory sequence.\",\n \"Operably linked is intended to mean that the nucleotide sequence is linked to a regulatory sequence in a manner that allows expression of the nucleotide sequence.\",\n \"Regulatory sequences are art-recognized and are selected to direct expression of the peptide having an activity of an acetyl glucosaminyl inositol deacetylase polypeptide.\",\n \"Accordingly, the term regulatory sequence includes promoters, enhancers and other expression control elements.\",\n \"Exemplary regulatory sequences are described in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990).\",\n \"For instance, any of a wide variety of expression control sequences-sequences that control the expression of a DNA sequence when operatively linked to it may be used in these vectors to express DNA sequences encoding the acetyl glucosaminyl inositol deacetylase polypeptides of this invention.\",\n \"Such useful expression control sequences, include, for example, the early and late promoters of SV40, adenovirus or cytomegalovirus immediate early promoter, the lac system, the trp system, the TAC or TRC system, T7 promoter whose expression is directed by T7 RNA polymerase, the major operator and promoter regions of phage lambda, the control regions for fd coat protein, the promoter for 3-phosphoglycerate kinase or other glycolytic enzymes, the promoters of acid phosphatase, e.g., Pho5, the promoters of the yeast α-mating factors, the polyhedron promoter of the baculovirus system and other sequences known to control the expression of genes of prokaryotic or eukaryotic cells or their viruses, and various combinations thereof.\",\n \"It should be understood that the design of the expression vector may depend on such factors as the choice of the host cell to be transformed and/or the type of protein desired to be expressed.\",\n \"Moreover, the vector's copy number, the ability to control that copy number and the expression of any other proteins encoded by the vector, such as antibiotic markers, should also be considered.\",\n \"As will be apparent, the subject gene constructs can be used to cause expression of the subject acetyl glucosaminyl inositol deacetylase polypeptides in cells propagated in culture, e.g.\",\n \"to produce proteins or peptides, including fusion proteins or peptides, for purification.\",\n \"This invention also pertains to a host cell transfected with a recombinant acetyl glucosaminyl inositol deacetylase gene in order to express a polypeptide having an activity of an acetyl glucosaminyl inositol deacetylase polypeptide.\",\n \"The host cell may be any prokaryotic or eukaryotic cell.\",\n \"For example, an acetyl glucosaminyl inositol deacetylase polypeptide of the present invention may be expressed in bacterial cells such as E. coli, insect cells (baculovirus), yeast, or mammalian cells.\",\n \"Other suitable host cells are known to those skilled in the art.\",\n \"Another aspect of the present invention concerns recombinant acetyl glucosaminyl inositol deacetylase polypeptides that have the deacetylase activity of an acetyl glucosaminyl inositol deacetylase polypeptide, or which are naturally occurring mutants thereof.\",\n \"The term “recombinant protein” refers to a protein of the present invention which is produced by recombinant DNA techniques, wherein generally DNA encoding the acetyl glucosaminyl inositol deacetylase polypeptide is inserted into a suitable expression vector which is in turn used to transform a host cell to produce the heterologous protein.\",\n \"Moreover, the phrase “derived from”, with respect to a recombinant gene encoding the recombinant acetyl glucosaminyl inositol deacetylase polypeptide, is meant to include within the meaning of “recombinant protein” those proteins having an amino acid sequence of a native acetyl glucosaminyl inositol deacetylase polypeptide, or an amino acid sequence similar thereto which is generated by mutations including substitutions and deletions of a naturally occurring acetyl glucosaminyl inositol deacetylase polypeptide of a organism.\",\n \"The present invention further pertains to methods of producing the subject acetyl glucosaminyl inositol deacetylase polypeptides.\",\n \"For example, a host cell transfected with expression vector encoding one of the subject acetyl glucosaminyl inositol deacetylase polypeptide can be cultured under appropriate conditions to allow expression of the peptide to occur.\",\n \"The peptide may be secreted and isolated from a mixture of cells and medium containing the peptide.\",\n \"Alternatively, the peptide may be retained cytoplasmically and the cells harvested, lysed and the protein isolated.\",\n \"A cell culture includes host cells, media and other byproducts.\",\n \"Suitable media for cell culture are well known in the art.\",\n \"The peptide can be isolated from cell culture medium, host cells, or both using techniques known in the art for purifying proteins including ion-exchange chromatography, gel filtration chromatography, ultrafiltration, electrophoresis, and immunoaffinity purification with antibodies specific for particular epitopes of the subject acetyl glucosaminyl inositol deacetylase polypeptides.\",\n \"Thus, a nucleotide sequence derived from the cloning of an acetyl glucosaminyl inositol deacetylase polypeptide of the present invention, encoding all or a selected portion of the protein, can be used to produce a recombinant form of the protein via microbial cellular processes.\",\n \"The recombinant acetyl glucosaminyl inositol deacetylase polypeptide can be produced by ligating the cloned gene, or a portion thereof, into a vector suitable for expression in bacterial cells.\",\n \"Expression vehicles for production of a recombinant acetyl glucosaminyl inositol deacetylase polypeptide include plasmids and other vectors.\",\n \"For instance, suitable vectors include plasmids of the types: pBR322-derived plasmids, pEMBL-derived plasmids, pEX-derived plasmids, pBTac-derived plasmids and pUC-derived plasmids for expression in prokaryotic cells, such as E. coli.\",\n \"A number of vectors exist for the expression of recombinant proteins in yeast.\",\n \"For instance, YEP24, YIP5, YEP51, YEP52, pYES2, and YRP17 are cloning and expression vehicles useful in the introduction of genetic constructs into S. cerevisiae (see, for example, Broach et al.\",\n \"(1983) in Experimental Manipulation of Gene Expression, ed.\",\n \"M. Inouye Academic Press, p. 83, incorporated by reference herein).\",\n \"These vectors can replicate in E. coli due the presence of the pBR322 ori, and in S. cerevisiae due to the replication determinant of the yeast 2 micron plasmid.\",\n \"In addition, drug resistance markers such as ampicillin can be used.\",\n \"The various methods employed in the preparation of the plasmids and transformation of host organisms are well known in the art.\",\n \"For other suitable expression systems for both prokaryotic and eukaryotic cells, as well as general recombinant procedures, see Molecular Cloning A Laboratory Manual, 2nd Ed., ed.\",\n \"by Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press: 1989) Chapters 16 and 17.In some instances, it may be desirable to express the recombinant acetyl glucosaminyl inositol deacetylase polypeptide by the use of a baculovirus expression system.\",\n \"Examples of such baculovirus expression systems include pVL-derived vectors (such as pVL1392, pVL1393 and pVL941), pAcUW-derived vectors (such as pAcUW1), and pBlueBac-derived vectors (such as the β-gal containing pBlueBac III).\",\n \"This invention further contemplates a method of generating sets of combinatorial mutants of the present acetyl glucosaminyl inositol deacetylase polypeptides, as well as truncation mutants, and is especially useful for identifying potential variant sequences (e.g.\",\n \"homologs) that are functional in cleaving acetyl glucosaminyl inositol or other acyl glucosaminyl inositol amide molecules.\",\n \"In a representative embodiment of this method, the amino acid sequences for a population of acetyl glucosaminyl inositol deacetylase polypeptide homologs are aligned, preferably to promote the highest homology possible.\",\n \"Such a population of variants can include, for example, homologs from one or more species, or homologs from the same species but which differ due to mutation.\",\n \"Amino acids that appear at each position of the aligned sequences are selected to create a degenerate set of combinatorial sequences.\",\n \"The presence or absence of amino acids from an aligned sequence of a particular variant is relative to a chosen consensus length of a reference sequence, which can be real or artificial.\",\n \"In order to maintain the highest homology in alignment of sequences, deletions in the sequence of a variant relative to the reference sequence can be represented by an amino acid space (*), while insertional mutations in the variant relative to the reference sequence can be disregarded and left out of the sequence of the variant when aligned.\",\n \"Further expansion of the combinatorial library can be made by, for example, by including amino acids that would represent conservative mutations at one or more of the degenerate positions.\",\n \"Inclusion of such conservative mutations can give rise to a library of potential acetyl glucosaminyl inositol deacetylase sequences.\",\n \"Alternatively, amino acid replacement at degenerate positions can be based on steric criteria, e.g.\",\n \"isosteric replacement, without regard for polarity or charge of amino acid sidechains.\",\n \"Similarly, completely random mutagenesis of one or more of the variant positions can be carried out.\",\n \"In a preferred embodiment, the combinatorial acetyl glucosaminyl inositol deacetylase library is produced by way of a degenerate library of genes encoding a library of polypeptides which each include at least a portion of potential acetyl glucosaminyl inositol deacetylase polypeptide sequences.\",\n \"For instance, a mixture of synthetic oligonucleotides can be enzymatically ligated into gene sequences such that the degenerate set of potential acetyl glucosaminyl inositol deacetylase nucleotide sequences are expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g.\",\n \"for phage display) containing the set of acetyl glucosaminyl inositol deacetylase polypeptide sequences therein.\",\n \"There are many ways by which the library of potential acetyl glucosaminyl inositol deacetylase homologs can be generated from a degenerate oligonucleotide sequence.\",\n \"Chemical synthesis of a degenerate gene sequence can be carried out in an automatic DNA synthesizer, and the synthetic genes then be ligated into an appropriate gene for expression.\",\n \"The purpose of a degenerate set of genes is to provide, in one mixture, all of the sequences encoding the desired set of potential acetyl glucosaminyl inositol deacetylase sequences.\",\n \"The synthesis of degenerate oligonucleotides is well known in the art (see for example, Narang, SA (1983) Tetrahedron 39:3; Itakura et al.\",\n \"(1981) Recombinant DNA, Proc 3rd Cleveland Sympos.\",\n \"Macromolecules, ed.\",\n \"A G Walton, Amsterdam: Elsevier pp.\",\n \"273-289; Itakura et al.\",\n \"(1984) Annu.\",\n \"Rev.\",\n \"Biochem.\",\n \"53:323; Itakura et al.\",\n \"(1984) Science 198:1056; Ike et al.\",\n \"(1983) Nucleic Acid Res.\",\n \"11:477.A wide range of techniques are known in the art for screening gene products of combinatorial libraries made by point mutations, and, for that matter, for screening cDNA libraries for gene products having a certain property.\",\n \"Such techniques will be generally adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of acetyl glucosaminyl inositol deacetylase homologs.\",\n \"The most widely used techniques for screening large gene libraries typically comprises cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates relatively easy isolation of the vector encoding the gene product was detected.\",\n \"Each of the illustrative assays described below are amenable to high throughput analysis as necessary to screen large numbers of degenerate sequences created by combinatorial mutagenesis techniques.\",\n \"The invention also provides for reduction of the subject acetyl glucosaminyl inositol deacetylase polypeptides to generate mimetics, e.g.\",\n \"peptide or non-peptide agents, which are able to mimic binding of the authentic acetyl glucosaminyl inositol deacetylase polypeptide to a substrate molecule.\",\n \"Such mutagenic techniques as described above, as well as the thioredoxin system, are also particularly useful for mapping the determinants of an acetyl glucosaminyl inositol deacetylase polypeptide which participate in protein-protein interactions involved in, for example, binding of the subject acetyl glucosaminyl inositol deacetylase polypeptide to a substrate.\",\n \"To illustrate, the critical residues of a subject acetyl glucosaminyl inositol deacetylase polypeptide which are involved in molecular recognition of substrate can be determined and used to generate acetyl glucosaminyl inositol deacetylase-derived peptidomimetics which cleave acetyl glucosaminyl inositol or other acyl glucosaminyl inositol amide substrates and, like the authentic acetyl glucosaminyl inositol deacetylase polypeptide, cleave the substrate molecule, for example by amide hydrolase activity.\",\n \"By employing, for example, scanning mutagenesis to map the amino acid residues of a particular acetyl glucosaminyl inositol deacetylase polypeptide involved in binding to a substrate, peptidomimetic compounds (e.g.\",\n \"diazepine or isoquinoline derivatives) can be generated which mimic those residues cleaving substrate.\",\n \"For instance, non-hydrolyzable peptide analogs of such residues can be generated using benzodiazepine (e.g., see Freidinger et al; in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), azepine (e.g., see Huffman et al.\",\n \"in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), substituted gama lactam rings (Garvey et al.\",\n \"in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), keto-methylene pseudopeptides (Ewenson et al.\",\n \"(1986) J Med Chem 29:295; and Ewenson et al.\",\n \"in Peptides: Structure and Function (Proceedings of the 9th American Peptide Symposium) Pierce Chemical Co. Rockland, Ill., 1985), beta-turn dipeptide cores (Nagai et al.\",\n \"(1985) Tetrahedron Lett 26:647; and Sato et al.\",\n \"(1986) J Chem Soc Perkin Trans 1:1231), and β-aminoalcohols (Gordon et al.\",\n \"(1985) Biochem Biophys Res Commun 126:419; and Dann et al.\",\n \"(1986) Biochem Biophys Res Commun 134:71).\",\n \"The invention will be further described with reference to the following examples; however, it is to be understood that the invention is not limited to such examples.\",\n \"EXAMPLE 1 Preparation of Reagents and Assay Methods Used.\",\n \"Mycothiol (MSH) was isolated from M. smegmatis and derivatized with monobromobimane to form the MSH-bimane derivative (MSmB).\",\n \"Mycothiol can be purified from Streptomyces clavuligerus, M. smegmatis, or from cells of any other mycothiol containing bacterium.\",\n \"Early stationary phase cells (25 gm wet weight) were extracted with 250 ml of 50% acetonitirile containing 25 mM methanesulfonic acid and 1 mM DTT at 60° C. for 15 min.\",\n \"The cell debris was removed by centrifugation for 30 min (4° C.) at 20,000×g.\",\n \"The excess acetonitrile was removed using a rotary evaporator.\",\n \"The aqueous extract was neutralized with Tris base to pH 8.0 and clarified by centrifugation for 30 min (4° C.) at 20,000×g The extract was loaded on a 25×70 mm propyl thiol Sepharose 6B resin activated with 2-mercaptopyridine with 1 mmole total thiol binding capacity.\",\n \"The column was washed with 10 column volumes of 20 mM Tris-HCl pH 8.0 to remove unbound extract components.\",\n \"The bound thiols were eluted with 200 ml of 20 mM Tris-HCl pH 8.0 containing 3 mM DTT.\",\n \"The eluate was extracted 5 times with an equal volume of ethyl acetate to remove excess DTT.\",\n \"The ethyl acetate washed aqueous extract was reduced to dryness by lyophilization.\",\n \"The extract was suspended in 5 ml of aqueous 0.1% trifluoroacetic acid (TFA).\",\n \"The mycothiol was purified by preparative HPLC using a 10×250 mm Vydac C-18 (Cat.\",\n \"# 218TP152022) reverse phase column (or equivalent).\",\n \"Mycothiol eluted at 26 min using an isocratic elution in aqueous 0.1% TFA at 5 ml per min.\",\n \"The volatile solvent was removed by lyophilization to yield pure mycothiol.\",\n \"Mycothiol is stable for years when stored as a mildly acidic aqueous solution of 30-100 mM at −70° C. The bimane derivative of mycothiol is readily made using monobromobimane (Molecular Probes) at 2 mM excess over the thiol concentration.\",\n \"The derivatization is carried out in aqueous 20 mM Tris-HCl pH 8.0 for 15 min in the dark at room temperature.\",\n \"The derivatization mixture was acidified to pH<3 with TFA and extracted 2 times with equal volumes of dichloromethane to remove excess monobromobimane.\",\n \"The derivatization mixture was purified on the preparative reverse phase column described above using a gradient elution.\",\n \"The A-buffer was 0.1% aqueous TFA and the B buffer was methanol.\",\n \"The linear gradient was 15-30% methanol over 30 min with a flow rate of 5 ml per min.\",\n \"The MSmB was detected at 385 nm and eluted as a symmetrical peak at 33 min.\",\n \"The volatile solvent was removed by lyophilization to yield>98% pure MSmB.\",\n \"This derivative was stored as a 10-30 mM solution in water at −70° C. The purified M. smegmatis mycothiol S-conjugate amidase was used to quantitatively hydrolyze MSMB to stereochemically pure GlcN-Ins, and the latter was purified from the other hydrolysis product, AcCySmB, using a Sep-Pak® C18 (Waters) cartridge.\",\n \"A 10 mM stock solution of GlcNAc-Ins was prepared by addition of a tenfold excess of acetic anhydride (Fisher) to 10 mM GlcN-Ins in 10 mM NaHCO3 over 20 min while adjusting the pH to 8.5 with NaOH.\",\n \"The reaction was monitored for GlcN-Ins loss as described below to insure that the reaction was complete and that no residual GlcN-Ins was present.\",\n \"This stock solution of GlcNAc-Ins was assayed as described below and used without further purification.\",\n \"Preparation of Mycothiol S-conjugates.\",\n \"Mycothiol S-conjugates were prepared by reaction of excess electrophile with mycothiol followed by removal of excess electrophile.\",\n \"Stock solutions (100 mM) of iodoacetamide (Sigma) or bromoacetophenone (Sigma) were prepared in acetonitrile.\",\n \"Reaction of these electrophiles at 2 mM in 25 mM HEPES chloride pH 7.5 was initiated by addition of mycothiol to 1 mM from a 32 mM stock solution in H2O (pH˜3) and was allowed to proceed 15 min at 22° C. Excess reagent was removed by extracting 3 times with an equal volume of H2O-saturated dichloromethane.\",\n \"Prior to extraction a 1 μl aliquot was withdrawn for reaction with mBBr and analysis of residual mycothiol by HPLC (see above) to verify complete reaction.\",\n \"This showed that>99% of the mycothiol had reacted.\",\n \"The MS-acetophenone was purified to homogeneity by reverse phase preparative HPLC as described above for MSmB, except that MS-acetophenone was detected at 260 nm.\",\n \"Assay of MSH and MSH precursors.\",\n \"Mycothiol and its precursors cysteine, and Cys-GlcN-Ins were assayed as the bimane derivative by high performance liquid chromatography (HPLC) on a Ultrasphere® ODS IP (Beckman) reversed phase column.\",\n \"The bimane derivatives were detected by fluorescence using a Fluoromonitor III® monitor (Thermo Separation products) with excitation filters 340-380 nm and emission filters 418-700 nm.\",\n \"The A buffer was 0.1% TFA and the B buffer was 7.5% methanol in acetonitrile.\",\n \"The separation was achieved at 22° C. and a flow rate of 1 ml/min with linear gradients as follows: time 0 min 0% B, 10 min 0% B, 30 min 20% B, 33 min 100% B, 36 min 100% B, 38 min 0% B, 50 min reinject.\",\n \"CySmB-GlcN-Ins, CySmB and mycothiol-mB (MSmB) eluted at 28, 31 and 33 min, respectively.\",\n \"GlcN-Ins was assayed by precolumn derivatization using AccQFluor® (Waters) reagent followed by HPLC analysis.\",\n \"A sample, 7.5 μl of 50% acetonitrile sample containing 5 mM NEM or 5 mM NEM and 1 mM 1,10 phenanthroline was mixed with 39.4 μl of buffer stock.\",\n \"The buffer stock was composed of 30% acetonitrile in aqueous 160 mM HEPES pH 7.5.This was mixed with 15.6 μl of AccQ-Fluor® reagent (Waters) and incubated for 1 min at 22° C. followed by 10 min at 60° C. The sample was diluted with 188 μl of water and the sample was analyzed by HPLC.\",\n \"The sample was centrifuged for 3 min 14,000×g in a microcentrifuge.\",\n \"The HPLC separation conditions were the same as described above for bimane derivatives, except the B buffer was 0.1% TFA in methanol.\",\n \"The product was detected by fluorescence using 254 nm excitation and 370-700 nm emission filters.\",\n \"AccQ-GlcN and AccQ-GlcN-Ins eluted at 12 and 24 min respectively.\",\n \"Mycothiol S-conjugate amidase assay.\",\n \"The enzymatic activity was routinely assayed by quantitation of the bimane derivative of N-acetylcysteine (AcCySmB) produced from the bimane derivative of mycothiol (MSmB), prepared from purified mycothiol (see above).\",\n \"To conduct an amidase assay a sample (2-10 μL) of extract was mixed with 40 μL of 30 μM MSmB in 3 mM 2-mercaptoethanol, 25 mM HEPES chloride pH 7.5 and reacted 10-30 min at 30° C. before quenching the reaction with 50 μL of 40 mM methanesulfonic acid on ice.\",\n \"The mixture was centrifuged for 3 min at 14,000×g in a microcentrifuge at room temperature and the supernatant analyzed by HPLC without dilution.\",\n \"Separation of MSmB and AcCySmB was achieved by HPLC on a 0.46×250 mM Ultrasphere®ODS column (Beckman) using a linear gradients: time 0 min 10% B, 15 min 18% B, 30 min 27% B, 32 min 100% B, 34 min 10% B, 45 min reinject.\",\n \"Buffer A (aqueous 0.25% acetic acid titrated to pH 3.6 with NaOH) and buffer B (methanol) were pumped at 1.2 ml/min at ambient temperature (22° C.).\",\n \"The bimane derivative of mycothiol (MSmB) eluted at 23.5 min and AcCySmB eluted at 27 min.\",\n \"EXAMPLE 2 Cloning and Expression of the Rv1170 gene from M. tuberculosis and demonstration of its GlcNAc-Ins deacetylase activity.\",\n \"Since the invention deacetylases and the mycothiol S-conjugate amidase both cleave an amide bond involving glucosamine, further studies were conducted to determine whether these proteins might be structurally related.\",\n \"A search was conducted of the Sanger Centre database for homologs of the 288 amino acid M. tuberculosis deacetylase, Rv1082.The closest homolog found was Rv1170, with a length of 304 residues and 36% identity to Rv1082 with homology throughout the sequence.\",\n \"To isolate the Rv1170 gene from M. tuberculosis H37Rv genomic DNA was prepared using known methods.\",\n \"The open reading frame Rv1170 was amplified from this DNA with the following primers: 5′-TAGCCATGGTGTCTGAGACGCCGCG-3′ (SEQ ID NO:8) and 5′-GGATCCCGGGGTGAAGCCCAGAC-3′ (SEQ ID NO:9) These primers contain NcoI and BamHI restriction sites, respectively.\",\n \"PCR was performed with Taq polymerase (Gibco BRL), using 1.5 mM MgCl2 and 5% dimethyl sulfoxide.\",\n \"The 30 cycles of PCR included denaturation at 94° C. for 40 s, annealing at 55° C. for 1 min, and amplification at 72° C. The PCR products were separated on a 1% agarose gel.\",\n \"The appropriate PCR product was ligated into vector pCR2.1 of the TA cloning kit (Invitrogen) and transformed into Escherichia coli DH5α by standard chemical transformation procedures.\",\n \"Clones containing the vector were selected on plates of Luria-Bertani (LB) agar plus ampicillin (100 μg/ml), and plasmid DNA was digested with the restriction endonucleases NcoI and BamHI (Fermentas).\",\n \"Restriction enzyme-digested plasmids were isolated with a QIAquick® gel extraction kit (Qiagen Ltd.).\",\n \"A corresponding digestion was applied to the plasmid pET-22b, and the two products were ligated together with T4 DNA ligase to obtain the plasmid pYA1170.In order to express Rv1170 in E. coli without the pelB leader sequence, the gene from pYA1170 was excised using NcoI and Bpu1102I (Fermentas) and ligated to an aliquot of pET16b cut with NcoI and Bpu1102I to generate the plasmid pYA1170b (FIG.\",\n \"2).\",\n \"This plasmid was transformed by the heat shock method to competent E. coli BL21(DE3) prepared according to the CaCl2 method and plated on LB agar containing 100 μg ampicillin/ml.\",\n \"Single colonies were inoculated into 5 ml of LB broth also containing ampicillin (100 μg/ml).\",\n \"After overnight incubation at 37° C. with shaking, the individual cultures were diluted 1:100 in the same medium and incubation was continued at 37° C. with shaking.\",\n \"Isopropyl-β-D-thiogalactopyranoside was added to a final concentration of 0.4 mM when the A600 reached 0.6, and incubation was continued overnight at 25° C. before harvesting by centrifugation at 5000×g for 15 min at room temperature.\",\n \"The pellets were lysed by sonication.\",\n \"Proteins were separated by centrifugation (15,000×g, 4° C., 30 min) into soluble and insoluble fractions.\",\n \"Total proteins were separated by sodium dodecyl sulfate 7.5% polyacrylamide gel electrophoresis (SDS-PAGE) and stained with Coomassie blue or transferred to polyvinylidene difluoride membranes (Bio-Rad).\",\n \"The N-terminal amino acid sequence was verified using Edman degradation after separation of samples by SDS-PAGE and electroblotting to a polyvinylidene difluoride membrane.\",\n \"E. coli BL21 (DE3) was transformed with the blank cloning vector (pET16b) or with vector containing Rv1170 (pYA1170b).\",\n \"SDS-PAGE was used to separate desalted 20% to 50% saturated ammonium sulfate extracts of these isopropyl-β-D-thiogalactopyranoside induced E. coli.\",\n \"Bio-Rad Broad Range molecular mass standards and purified M. smegmatis mycothiol S-conjugate deacetylase were also assayed for controls.\",\n \"The results of the SDS-PAGE showed that the 20% to 50% saturated ammonium sulfate fraction from E. coli carrying the Rv 1170 gene contained elevated levels of a protein of the expected size (36 kDa) as compared to those from E. coli prepared with a blank cloning vector.\",\n \"Another, smaller protein (˜26 kDa) was also present at elevated levels and is believed to be a degradation product of the deacetylase.\",\n \"The identity of the 36-kDa protein was confirmed by determining the N-terminal amino acid sequence and finding it identical to that predicted for the protein encoded by open reading frame Rv1170.The amidase and deacetylase activity of the 20 to 50% saturated ammonium sulfate extracts of E. coli transformed with pYA1170b or with the blank cloning vector pET16b after desalting and concentrating was assayed as described above.\",\n \"The results of these assays are shown in Table 1 below.\",\n \"TABLE 1 Substrate specificity of crude deacetylase from E. coli transformed with pYA1170b Activity (nmol min−1 mg of protein−1)(n = 3) Substrate Rv1170 Blank vector MsmBa 1.2 ± 0.1 <0.002 MSmBb <10−4 NDf GlcNAc-Insc 27 ± 2 <0.002 GlcNAcc 0.087 ± 0.005 <0.005 MSHd 0.002 ± 0.001 ND MSHe <10−4 ND aAnalysis for AcCySmB produced by amidase cleavage.\",\n \"bAnalysis for production of the deacetylase product CySmB-GlcN-Ins.\",\n \"cAnalysis for corresponding amine resulting from deacetylase reaction.\",\n \"dAnalysis for AcCys produced by amidase cleavage.\",\n \"eAnalysis for production of the deacetylase product Cys-GlcN-Ins.\",\n \"fNot determined.\",\n \"As shown by the results summarized in Table 1, extract from cells expressing Rv1170 exhibited substantial deacetylase activity with GlcNAc-Ins as the substrate, over 300-fold greater than the deacetylase activity determined with GlcNAc and 23-fold greater than the amidase activity measured with MSMB (FIG.\",\n \"2).\",\n \"Thus, Rv1170 was putatively identified as the GlcNAc-Ins deacetylase gene in the MSH biosynthesis pathway of M. tuberculosis.\",\n \"M. smegmatis mycothiol S-conjugate amidase lacks deacetylase activity.\",\n \"Mycothiol S-conjugate amidase from M. smegmatis, a homolog of the protein encoded by M. tuberculosis Rv1082, cleaves the amide bond linking Cys to GlcN in MSH derivatives having an alkylated sulfur residue (G. L. Newton et al., Biochemistry 39:10739-10746, 2000).\",\n \"Tests were conducted to determine whether the mycothiol S-conjugate amidase also cleaves the corresponding bond in GlcNAc-Ins, functioning as a deacetylase (FIG.\",\n \"3).\",\n \"GlcNAc-Ins was prepared from GlcN-Ins and the ability of the amidase purified from M. smegmatis to hydrolyze GlcNAc-Ins (i.e., to function as a deacetylase) was compared with its ability to function as an amidase by cleaving the amide bond in the monobromobimane conjugate of MSH (MSmB).\",\n \"The assays utilized are described above.\",\n \"For a test with 100 μM substrate, the activity measured with deacetylase substrate MSmB was 4.5±1.0 μmol min−1 mg of protein−1, whereas that measured with the invention deacetylase substrate GlcNAc-Ins was <1 nmol min−1 mg of protein−1 (n=4).\",\n \"The comparative assays showed that the mycothiol S-conjugate deacetylase does not exhibit measurable deacetylase activity and cannot serve this function in the MSH biosynthesis pathway of M. smegmatis.\",\n \"EXAMPLE 3 Extracts of M. smegmatis and mutant 49 have deacetylase activity.\",\n \"If the deacetylase is involved in MSH biosynthesis and if mutant 49 is blocked at an earlier step in the MSH-production pathway, then strains mc2155 and 49 should both produce deacetylase activity.\",\n \"To test this hypothesis, centrifuged extracts of exponentially growing cells were assayed in duplicate for GlcN-Ins production with and without the addition of 100 μM GlcNAc-Ins.\",\n \"The background rate for production of GlcN-Ins measured without added GlcNAc-Ins was high for strain mc2155 (6.1±0.1 pmol min−1 mg of protein−1) presumably reflecting the substantial endogenous level of GlcNAc-Ins present in the undialyzed extract.\",\n \"Addition of 100 μM GlcNAc-Ins increased the rate to 19.7±0.4 pmol min−1 mg of protein−1, giving a net rate increase of 13.6±0.5 pmol min−1 mg of protein−1.For mutant 49, which does not contain GlcNAc-Ins, the background rate was <0.06 pmol min−1 mg of protein−1 and the rate with 100 μM GlcNAc-Ins was 16.4±1.4 pmol min−1 mg of protein−1.Thus, the deacetylase activity of strain 49 is essentially the same as that of the parent strain.\",\n \"EXAMPLE 4 Assay for GlcNAc-Ins.\",\n \"To confirm that GlcNAc-Ins is present in mycobacteria, an assay for this component was needed.\",\n \"The availability of cloned Rv1170 allowed the development of such an assay.\",\n \"Cell extracts were prepared in warm 50% acetonitrile containing NEM, as employed previously for an assay of GlcN-Ins (Anderberg et al.\",\n \"(1998) J. Biol.\",\n \"Chem.\",\n \"273:30391-30397).\",\n \"One portion of the extract was assayed directly for GlcN-Ins content while a second portion was assayed after treatment with a preparation of expressed Rv1170 under conditions sufficient to convert all GlcNAc-Ins to GlcN-Ins.\",\n \"The difference in these two assay results yields the GlcNAc-Ins content for the sample.\",\n \"In most cases, GlcN-Ins levels were at least an order of magnitude lower than those of GlcNAc-Ins, so this method gives reliable results.\",\n \"Recovery experiments for GlcNAc-Ins were conducted using a M. smegmatis MSH-deficient mutant (“mutant 49”), derived from mc2155 by chemical mutagenesis.\",\n \"Mutant 49 was cultured in Middlebrook 7H9 medium at 37° C. as previously described (Newton, et al.\",\n \"(1999) Biochem.\",\n \"Biophys.\",\n \"Res.\",\n \"Comm.\",\n \"255:239-244).\",\n \"In the uptake and metabolism assay, 50% acetonitrile-NEM extracts were analyzed after the addition of 0.7 and 7.0 μM GlcNAc-Ins.\",\n \"Extracts of mutant 49 contained no detectable GlcN-Ins or MSH, so that any GlcN-Ins found in the extracts after treatment with the deacetylase preparation was derived solely from the deacetylation of GlcNAc-Ins.\",\n \"The relationship between A600 and RDW was determined for aliquots of mc2155 cells producing ˜30 mg of RDW and found to be 0.42±0.02 mg of RDW per ml of cells with A600 at 1.00.No variation of >15% in this value was seen between log- and stationary-phase cells.\",\n \"The method was tested with extracts prepared from log-phase cells of mutant 49 by spiking the extract with GlcNAc-Ins at levels equivalent to 0.13 and 0.013 μmol per g of RDW.\",\n \"The recoveries from triplicate determinations were 97%±5% and 132%±3%, respectively.\",\n \"At the lowest level of added GlcNAc-Ins, a significant correction had to be applied for background peaks present in unspiked controls that overlapped the GlcN-Ins peak.\",\n \"The greater than 100% recovery found for the samples spiked at lowest level indicates that this correction produces a systematic error and thus defines the lower limit of useful sensitivity for this assay.\",\n \"EXAMPLE 5 M. smegmatis mc2155 produces GlcNAc-Ins but MSH-deficient mutant 49 does not.\",\n \"M. smegmatis mc2155 cells were examined in exponential and stationary phases for their content of MSH and its precursors using the methods described above.\",\n \"The results of these studies are summarized in Table 2 below: TABLE 2 Levels of MSH and precursors in M. smegmatis mc2155 Content (μmol [g of RDW]−1) ( n = 3) Growth phase A600 MSH GlcNAc-Ins GlcN-Ins Log 0.54 7.8 ± 0.6 14.5 ± 1.2 0.2 ± 0.1a Stationary 3.3 6.6 ± 0.6 12.6 ± 0.6 <0.03 aBest estimate after correction for overlapping peak in HPLC analysis.\",\n \"These results show that M. smegmatis accumulates GlcNAc-Ins to a substantial level, almost twice the level of MSH content.\",\n \"The GlcN-Ins content was very much lower in log phase and declined further in stationary phase, as had been observed previously (Anderberg et al; (1998) Supra.\",\n \"EXAMPLE 6 MSH-deficient mutant 49 can import GlcNAc-Ins and utilize it to sythesize MSH.\",\n \"The foregoing results imply that mutant 49 should be able to synthesize MSH if supplied with GlcNAc-Ins.\",\n \"The concentration dependence of the uptake of GlcNAc-Ins was examined with cultures of M. smegmatis mutant 49.For this study mutant 49 was cultured at 37° C. for 23 hr in 5 ml of 7H9 Middlebrook medium as described below, supplemented with 0, 4, 8, 21 μM GlcNAc-Ins.\",\n \"The cells were collected by centrifugation and extracted for amine and thiol analysis as described above.\",\n \"The absence of GlcNAc-Ins in mutant 49 shows that it is defective in an initial step of MSH biosynthesis.\",\n \"When mutant 49 was grown in media supplemented with GlcNAc-Ins, the cells did show the presence of MSH and mycothiol precursors in increasing concentrations with the media content of GlcNAc-Ins.\",\n \"These results established that GlcNAc-Ins is indeed imported intact, deacetylated and utilized for the production of MSH in a concentration dependent manner (Table 3).\",\n \"TABLE 3 Levels of MSH and precursors in MSH-deficient strain 49 (M. smegmatis) Content (μmol [g of RDW]−1) [GlcNAc-Ins]a (μM) MSH GlcNAc-Ins GlcN-Ins 0 <0.04 <0.01 <0.02 4 0.47 0.39 <0.02 8 0.91 0.80 0.026 21 2.1 1.4 0.047 aIn Middlebrook 7H9 medium.\",\n \"; [GlcNAc-Ins] = 0).\",\n \"In another experiment mutant 49 was cultured in 7H9 Middlebrook medium with 0.4% glucose and 0.5% TWEEN 80 detergent to log phase (A600=0.6) and 10-ml aliquots transferred to sterile 25 ml erlenmeyer flasks.\",\n \"Duplicate flasks contained cells only (control), 20 μM inositol, 20 μM glucosamine, 20 μM N-acetylglucosamine, or 17 μM GlcNAc-Ins and were cultured at 37° C., shaking at 225 rpm.\",\n \"Samples (2.3×108 cells) were taken at 2, 6, 19 and 46 hr of culture.\",\n \"the cells were pelleted by centrifugation for 2 min at 14,000×g and were extracted in 50% acetonitrile containing 20 mM HEPES (pH 8.0) and either 2 mM monobromobimane for thiol analysis or 5 mM NEM for amine analysis and thiol control samples.\",\n \"Cells from duplicate cultures were analyzed for GlcN-Ins, GlcNAc-Ins, Cys-GlcN-Ins, cysteine, and MSH.\",\n \"No significant MSH was found in any sample except for the cultures supplemented with GlcNAc-Ins (FIG.\",\n \"4).\",\n \"Strain 49 cultured in 17 μM GlcNAc-Ins showed a cysteine level that remained unchanged at 0.36±0.08 μmol per gm of residual dry weight over the experiment.\",\n \"Cells contained 2.9 μmole per gm of residual dry weight of GlcNAc-Ins at the first measurement (2 hr), which corresponds to a level of GlcN-Ins approaching millimolar.\",\n \"This occurred prior to the appearance of significant GlcN-Ins in the cell, showing that strain 49 is able to import and concentrate GlcNAc-Ins intact prior to its deacetylation.\",\n \"The level of GlcNAc-Ins appeared to fall at 6 hr before rising to an even higher level in stationary phase.\",\n \"The MSH content was measurable as early as 2 hr, but was about 10-fold less than the GlcNAc-Ins content at that time.\",\n \"The MSH content increased thereafter, and the level at 48 hr was about 60% of that measured for the parent strain (Table 2).\",\n \"The level of GlcN-Ins ranged from 0.025 (2 hr) to 0.1 (48 hr) μmole per gm of residual dry weight, values in the range of those measured for mc2155 (Table 2).\",\n \"These results show that exogenous GlcNAc-Ins is efficiently imported by strain 49 and substantially restores its defective biosynthesis of MSH.\",\n \"The intracellular level of GlcN-Ins found in mutant 49 at 48 hours indicates that GlcNAc-Ins has been concentrated more than 100 fold from the supplemented medium.\",\n \"This implies that toxic analogs of GlcNAc-Ins, such as those with oxidizing or nitrosating moieties, will be concentrated inside pathogenic mycobacteria or other actinomycetes and function as antimicrobial agents.\",\n \"EXAMPLE 7 Cloning, expression and purification of M. tuberculosis His-tagged MshB.\",\n \"To facilitate the purification of the M. tuberculosis deacetylase, Rv1170 was cloned to contain a C-terminal HisTag permitting its easy isolation by affinity chromatography on a Ni2+ chelate resin.\",\n \"Genomic DNA of M. tuberculosis H37Rv was prepared as described previously (Av-Gay et al., Infect.\",\n \"Immun.\",\n \"67:5676-5682, 1999).\",\n \"The open reading frame Rv1170 was amplified from this DNA with the primers 5′-TTCATATGGTGTCTGAGACGCCG-3′; (SEQ ID NO:10 and 5′-ATAAGCTTGTAGCCGGACGCGGTG-3′ (SEQ ID NO:11) containing NdeI and HindIII restriction sites, respectively.\",\n \"PCR was performed with Taq polymerase obtained from Gibco BRL, using 1.5 mM MgCl2 and 5% dimethyl sulfoxide.\",\n \"The 30 cycles of PCR included denaturation at 94° C. for 40 seconds, annealing at 55° C. for 1 min and amplification at 72° C. The PCR products were separated on a 1% agarose gel.\",\n \"The appropriate PCR product was ligated into the vector pCR2.1 of the TA cloning kit (Invitrogen) and transformed into E. coli DH5a by standard chemical transformation procedure.\",\n \"Clones containing the vector were selected on plates of Luria-Bertani (LB) agar plus ampicillin (100 μg/ml) and plasmid DNA was digested with restriction endonucleases NdeI and HindIII (Fermentas).\",\n \"Restriction enzyme-digested plasmids were isolated with a QIAquick gel extraction kit (Qiagen Ltd.).\",\n \"A corresponding digestion was applied to the plasmid pET-22b and the two products were ligated together with T4 DNA ligase to obtain the plasmid pYA1170c (shown in FIG.\",\n \"9).\",\n \"This provides a recombinant protein without a pelB leader sequence, but with a c-terminal His tag.\",\n \"This plasmid was transformed by the heat shock method to competent E. coli BL21(DE3) prepared according to the CaCl2 method and plated on LB agar containing 100 μg/ml ampicillin.\",\n \"Single colonies were inoculated into 5 ml of LB broth also containing ampicillin (100 μg/ml).\",\n \"After over-night incubation at 37° C. with shaking, 5 1-liter cultures were inoculated to 1% with the starter culture and incubated at 37° C. with shaking.\",\n \"Isopropyl-β-D-thiogalactopyranoside was added to a final concentration of 0.5 mM when the A600 reached 0.6 and incubation was continued overnight at 22° C. before harvesting by centrifugation at 5000×g for 20 minutes at 4° C. The pellets were lysed by sonication in 3 mM 2-mercaptoethanol with 50 mM HEPES pH 7.4 (lysis buffer) containing 35 μM each protease inhibitors (N-α-p-tosyl-L-lysinechloromethyl ketone and N-α-p-tosyl-L-phenylalaninechloromethyl ketone).\",\n \"Proteins were separated by centrifugation (1-5,000×g, 4° C., 30 min) into-soluble and insoluble-fractions.\",\n \"The soluble proteins were applied to a 2.5×11 cm Fast Flow® chelating resin (Pharmacia) in the Ni2+ form in lysis buffer containing 10 mM imidazole.\",\n \"The column was washed with 10 volumes of the loading buffer and then step eluted with lysis buffer containing 150 mM imidazole followed by lysis buffer containing 500 mM imidazole.\",\n \"Fractions were collected and the purity of the eluted protein was assayed by SDS PAGE gel electrophoresis.\",\n \"The early 150 mM imidazole fractions were contaminated with E. coli proteins, but the later fractions of the 150 mM and the early 500 mM imidazole fractions were judged>95% pure and pooled.\",\n \"The yield of pure recombinant MshB (Rv1170) was estimated to be ˜125 mg of protein.\",\n \"The protein was concentrated and the buffer exchanged repeatedly with 50 mM HEPES containing 50 mM NaCl (assay buffer) in a Centricon® 10 spin ultra filter, adjusted to 10% glycerol and frozen at −70° C. The enzyme as purified was assayed for deacetylase activity with 0.1 mM GlcNAc-Ins as substrate and was found to be sensitive to chelating agents such as 1,10-phenanthroline.\",\n \"The deacetylase reaction was substantially inhibited by the presence of 0.1 mM 1,10-phenanthroline in the reaction mixture (FIG.\",\n \"7).\",\n \"1 mM 1,10-phenanthroline completely inhibited the deacetylase reaction, indicating a dependence of the reaction on divalent metal ions.\",\n \"The apoenzyme was generated by treatment of the concentrated enzyme with 5 mM 1,10-phenanthroline in assay buffer for 30 min on ice.\",\n \"The chelator was removed by repeated dilution with assay buffer and concentration until the 1,10-phenanthroline concentration was estimated to be below 1 μM.\",\n \"All solutions were treated with Chelex-100® chelator to remove extraneous divalent cations.\",\n \"The apoenzyme was stored at 10 mg/ml in 50 mM NaCl+50 mM HEPES pH 7.5 with 10% glycerol at −70° C. The zinc form (Zn2+) of the deacetylase was prepared by treating the apoenzyme with 0.1 mM ZnCl2 in the assay buffer for 30 min on ice.\",\n \"The excess Zn2+ was removed by repeated dilution and concentration with assay buffer until the Zn2+ was estimated to be below 1 μM.\",\n \"The Zn2+ form of the enzyme was stored as described above for the apoenzyme and is herein referred to as “His-tagged MshB”.\",\n \"EXAMPLE 8 Metal ion dependence of the deacetylase.\",\n \"The metal ion dependence of the deacetylase activity of MshB was assayed using GlcNAc-Ins in the presence of 0.1 mM divalent metal ion.\",\n \"Previous studies with ZnCl2 have shown that excess Zn2+ is not inhibitory at 0.1 mM and only slightly inhibitory at 1 mM (see above).\",\n \"The metal salts tested, ZnCl2, CuSO4, MgCl2, MnCl2, CaCl2, COCl2, CdCl2 and NiCl2, were of reagent grade or higher purity and solutions of the metals were prepared as 10 mM stock solutions in water treated with Chelex-100 chelator.\",\n \"Enzymatic activity was assayed in Chelex-100® treated 50 mM NaCl with 50 mM HEPES pH 7.4 (assay buffer) containing 0.1 mM of the desired metal salt and 0.1 mM GlcNAc-Ins as substrate.\",\n \"Buffer and 10 μg of purified apoenzyme were preincubated the divalent metal ion in an 80 μl total reaction volume for 10 min at 37° C. and the assay initiated by the addition of the substrate.\",\n \"Duplicate reactions were sampled at 3, 10, and 30 min by removing a 20 μl sample of the reaction mixture and adding it to 20 μl of acetonitrile containing 10 mM NEM and 2 mM 1,10-phenanthroline.\",\n \"The samples were incubated for 10 min at 60° C., placed on ice, and subsequently reacted with AccQ Fluor® (Waters) reagent as described above assayed for AccQ-GlcN-Ins by HPLC as described above.\",\n \"The MshB apoenzyme was able to catalyze both the deacetylase (GlcNAc-Ins as substrate) and the amidase (MSmB as substrate) reactions at substantially reduced rates, as shown in Table 4 below.\",\n \"TABLE 4 M. tuberculosis MshB (Rv1170) metal ion dependencea Amidase Specific Deacetylase Activityb Amidase Specific Deacetylase Metalloenzyme nmole/ Activity Activityc Activity Form min/mg relative rate nmole/min/mg Relative rate Apoenzyme 3.4 ± 0.5 1.0 35 ± 6 1.0 Untreated 15 ± 0.2 4.4 70 ± 19 2.0 Zn2+ 17 ± 0.7 5.0 81 ± 16 2.3 Ni2+ 13 ± 0.7 3.8 62 ± 23 1.8 Mn2+ 22 ± 0.7 6.5 69 ± 5 2.0 Ca2+ 3.3 ± 0.1 0.97 34 ± 5 0.97 Mg2+ 3.5 ± 0.2 1.0 41 ± 4 1.2 Cu2+ 3.2 ± 0.1 0.94 32 ± 10 0.9 Cd2+ 21 ± 1.5 6.2 34 ± 2 0.97 Co2+ 29 ± 0.3 8.5 236 ± 23 6.7 Zn2+ + Mg2+ ND — 75 ± 14 2.1 Ni2+ + Mg2+ ND — 64 ± 15 1.8 aRecombinant Rv1170 purified to homogeneity over Ni2+ Sepharose.\",\n \"b0.1 mM MSmB as substrate with 0.1 mM metal ion.\",\n \"c0.1 mM GlcNAc-Ins as substrate with 0.1 mM metal ion.\",\n \"The low metal ion content of the apoenzyme reduced the amidase activity to a greater extent than the deacetylase activity relative to the untreated purified protein.\",\n \"The activity of the Ni2+ Sepharose purified (untreated) form of the MshB appears to be consistent with the Ni2+ form of the enzyme.\",\n \"The Zn2+, Mn2+ and Ni2+ forms appear to have about the same activity for both the amidase and deacetylase reactions.\",\n \"The MshB apoenzyme was not activated by the presence of Ca2+, Mg2+ or Cu2+ for either the amidase or deacetylase reactions.\",\n \"The MshB deacetylase and amidase reactions were differently affected by the presence of the Cd2+ ion.\",\n \"The amidase reaction was enhanced to the level of Zn2+ while the deacetylase reaction remained at the apoenzyme activity level.\",\n \"Similarly anomalous activity with Cd2+ was observed for the peptidase and esterase activity of carboxypeptidase, a zinc metalloprotease (R. C. Davis et al Biochemistry 7, 1090-1099 (1968)).\",\n \"The highest level of activation for both the amidase and deacetylase reactions was observed with Co2+, as has been reported for numerous zinc metalloproteases (D. S. Auld, Chapter 14, Methods in Enzymology, 248:229-243, 1995).\",\n \"Some zinc metalloproteases have been reported to require the presence of Mg2+ for optimal activity (Vallee and Auld (1993) Biochemistry 32:6493-6500) so activity assays were conducted with 0.1 mM each Zn2+ and Mg2+.\",\n \"No additional activation over that of Zn2+ alone for either the amidase or deacetylase reactions was observed.\",\n \"Thus, the metal ion dependence of MshB is similar to that found for members of the metalloprotease superfamily and is therefore likely that MshB is a zinc metalloenzyme in its native state.\",\n \"EXAMPLE 9 Kinetics and substrate specificity of His-tagged MshB.\",\n \"The kinetic constants were determined for GlcNAc-Ins, the deacetylase substrate for MshB, and for MSmB, an amidase substrate.\",\n \"The rates were determined with His-tagged MshB in 50 mM NaCl containing 50 mM HEPES pH 7.5 (assay buffer).\",\n \"The enzyme (10 μg) was preincubated with 80 μl of assay buffer for 10 min at 37° C. and the reaction was initiated with the addition of the substrate.\",\n \"The deacetylase substrate was assayed at 9 different concentrations between 10 μM and 2 mM.\",\n \"Duplicate reactions were sampled at 3, 10, and 30 min by removing 20 μl of the sample, and mixing with 20 μl of acetonitrile containing 10 mM NEM and 2 mM 1,10-phenanthroline.\",\n \"The samples were quenched by incubation for 10 min at 60° C. The quenched sample was reacted with AccQ Fluor® reagent (Waters) and analyzed for GlcN-Ins by HPLC as described above.\",\n \"The amidase reaction was assayed similarly using 10 concentrations of MSmB between 10 μM and 10 mM.\",\n \"The amidase reaction was sampled at 3, 10, and 30 min by removing 20 μl of sample and mixing it with 60 μl of 40 mM methanesulfonic acid.\",\n \"The mercapturate product, AcCySmB was analyzed by HPLC as described above.\",\n \"Initial rates were obtained by extrapolation of the rates calculated at 3, 10, and 30 min to zero time.\",\n \"The kinetic constants were obtained from an Eadie-Hofstee plot.\",\n \"The amidase and deacetylase substrates have Km values near of 0.5 mM as shown below in Table 5 below.\",\n \"TABLE 5 Kinetic characterization of M. tuberculosis MshB (Rv1170) Km Vmax kcat Substrate Activity μM nmol min−1mg−1 s−1 GlcNAc-Ins deacetylase 400 470 0.25 MSmB amidase 560 220 0.12 The intracellular concentration of GlcN-Ins is roughly twice the mycothiol level, or about 2-6 mM (Newton et al, J.\",\n \"Bacteriol., 182: 6958-6963, 2000) and is sufficient to saturate the enzyme at physiological concentrations.\",\n \"The substrate specificity of MshB was examined with various amidase and deacetylase substrates at a concentration of 0.1 mM.\",\n \"The product analyzed will vary with the substrate used.\",\n \"The deacetylase substrates tested were GlcNAc, GlcNAc-Ins, MSH, and MSmB, and the products assayed were GlcN, GlcN-Ins, Cys-GlcN-Ins, and CySmB-GlcN-Ins, respectively.\",\n \"The amidase substrates tested were MSH, MSmB, AcCySmB-GlcN, CySmB-GlcN-Ins, MS-acetamide, and MS-acetophenone and the product assayed was GlcN-Ins, except for AcCySmB-GlcN were GlcN was assayed.\",\n \"The amines were analyzed as the AccQ-derivative and thiols as the bimane derivative as described above.\",\n \"The results of these substrate specificity studies are summarized in Table 6 below.\",\n \"TABLE 6 Substrate specificity of M. tuberculosis MshB (Rv1170)a Amidase Specific Deacetylase Activityb Specific Activityb Relative Substratea nmol min−1mg−1 nmol min−1mg−1 Rate GlcNAc-Insc 70 ± 3 1.0 GlcNAcd 1.6 ± 1 0.023 MSHe <0.025 ± 0.012 <0.00036 MSHc 0.3 ± 0.1 0.0043 MSmBf <0.006 <0.00009 MSmBc 20 ± 2 0.29 AcCySmB-GlcNd <0.1 <0.001 CySmB-GlcN-Insc 265 ± 10 3.8 MS-acetamidec 0.14 ± 0.013 0.002 MS-acetophenonec 88 ± 8 1.3 aHis tagged MshB (Rv1170) in the Zn2+ form.\",\n \"b0.1 mM substrate assayed in 50 mM NaCl + 50 mM HEPES pH 7.4 at 37° C. cReaction assayed for GlcN-Ins.\",\n \"dReaction assayed for GlcN.\",\n \"eReaction assayed for CyS-GlcN-Ins.\",\n \"fReaction assayed for CySmB-GlcN-Ins.\",\n \"As shown by the results in Table 6, the deacetylase activity of MshB is dependent on the presence of the inositol moiety as the GlcNAc substrate is 44 fold less active than GlcNAc-Ins.\",\n \"Interestingly MSH and MSmB are not substrates for the deacetylase activity of MshB.\",\n \"However, mycothiol S-conjugates with reasonably large groups on the cysteine sulfur, such as acetophenone and bimane S-conjugates, are good substrates for the amidase activity of the MshB.\",\n \"The smaller mycothiol S-conjugate acetamide is a poor substrate for the MshB amidase activity, as was observed previously for mycothiol S-conjugate amidase from M. smegmatis (Newton et al Biochemistry, 39, 10739-10746, 2000).\",\n \"The importance of the inositol moiety for the amidase activity of MshB is also apparent by the lack of activity with AcCySmB-GlcN.\",\n \"One difference between the amidase activity of M. tuberculosis His-tagged MshB and the amidase from M. smegmatis is the ability to use CySmB-GlcN-Ins as substrate.\",\n \"The M. smegmatis amidase required the acetylated amine on the cysteine moiety (or MSmB) for activity.\",\n \"Another difference between MshB and the M. smegmatis amidase is that the amidase will not deacetylate GlcNAc-Ins (Newton et al J.\",\n \"Bacteriol., 182, 6958-6963, 2000).\",\n \"EXAMPLE 10 Inhibition of His-tagged MshB.\",\n \"Naturally occurring inhibitors of the His-tagged MshB deacetylase and amidase activities have been examined.\",\n \"The inhibition assays are similar to those described above in Example 9.For the amidase reaction of His-tagged MshB 10 μg enzyme was preincubated for 10 min at 37° C. in 80 μl of buffer containing 50 mM NaCl, 50 mM HEPES pH 7.5, 0.1 mM ZnCl2, 0.2 mM DTT and 0.1-1.0 mM inhibitor.\",\n \"The inhibitors examined were mycothiol, glutathione and GlcN-Ins.\",\n \"The purpose of the excess Zn+2 is to prevent depletion of the protein bound Zn2+ by thiols.\",\n \"The DTT is added to limit the oxidation of the thiol inhibitors, which can be significant at the lower concentrations.\",\n \"The uninhibited enzyme activity was determined using the same buffer and preincubation conditions without inhibitor.\",\n \"The assays were initiated with the addition of MSmB to 0.55 mM and sampled at 3, 10, and 30 min by removing a 20 μl sample and quenching the reaction by mixing with 60 μl of 40 mM aqueous methanesulfonic acid.\",\n \"This sample was assayed directly by HPLC for AcCySmB as described above.\",\n \"The deacetylase reaction was assayed with GlcNAc-Ins using 0.1-1.0 mM glutathione and mycothiol as inhibitors.\",\n \"The reaction was initiated by the addition of GlcNAc-Ins to 0.8 mM and was sampled at 3, 10, and 30 min.\",\n \"The reaction was quenched and analyzed for GlcN-Ins as described in Example 9.Mycothiol appears to be an effective inhibitor of both the amidase (FIG.\",\n \"8A) and the deacetylase (FIG.\",\n \"8B) activities of His-Tagged MshB in the range of 0.1 to 1 mM.\",\n \"This is not simply due to disruption of the enzyme metal binding site by a thiol as shown by the lack of inhibition by glutathione in this concentration range.\",\n \"The lack of inhibition of the amidase reaction by GlcN-Ins (FIG.\",\n \"8A) also shows that the immediate product of the reaction is not inhibitory.\",\n \"Mycothiol is the terminal product in the biosynthesis scheme shown in FIG.\",\n \"5 and it appears to completely inhibit the deacetylase (MshB) at mycothiol concentrations above 1 mM.\",\n \"The estimated intracellular concentration of mycothiol in mycobacteria is about 1-3 mM and thus the deacetylase is in a substantially inhibited state until the mycothiol level falls below 1 mM, as may happen during cell division or cell stress.\",\n \"Inhibition of the deacetylase reaction was analyzed at 0.8 mM GlcNAc-Ins, a concentration nearing saturation, but still below the estimated cellular concentration of 2-6 mM for M. smegmatis.\",\n \"Thus, in M. smegmatis the deacetylase is exposed to saturating GlcNAc-Ins concentrations but is inhibited when the cellular mycothiol level is above 1 mM.\",\n \"If mycothiol level falls substantially below 1 mM, the enzyme will catalyze the deacetylation of GlcNAc-Ins from a large cellular pool at near maximal rates to GlcN-Ins and ultimately to mycothiol.\",\n \"It has previously been shown that mycothiol levels are quite constant from logarithmic through stationary phase growth of M. smegmatis (Newton et al, J.\",\n \"Bacteriol., 178: 1990-1995, 1996).\",\n \"It appears that the intracellular mycothiol level is regulated by feedback inhibition of the GlcNAc-Ins deacetylase by mycothiol itself.\",\n \"The amidase substrate, MSmB, served as a useful model substrate for finding inhibitors of the GlcNAc-Ins deacetylase.\",\n \"The amidase and deacetylase activities are both completely inhibited by mycothiol at concentrations over 1 mM.\",\n \"These results identify mycothiol as an inhibitor for the deacetylase and amidase reactions with similar inhibitory concentrations.\",\n \"Thus, the substrates for either the amidase or deacetylase activity of GlcNAc-Ins deacetylase can be used to screen for inhibitors of the enzyme.\",\n \"EXAMPLE 11 Oxidant sensitivity of M. smegmatis MSH-deficient mutants.\",\n \"The importance of mycothiol biosynthesis for the survival of mycobacteria under oxidative stress is illustrated by results obtained with chemical and transposon mutants deficient in mycothiol biosynthesis.\",\n \"Chemical mutants were produced by mutagenesis of M. smegmatis mc2155 (˜2.5×109 colony forming units per ml Middlebrook 7H9 liquid medium) with N-methyl-N-nitro-N-nitrosoguanidine (4 μg per ml) for 30 min at 37° C. Cells were washed three times with 9 ml of fresh medium, resuspended in 10 ml of fresh medium, and incubated 8.5 h at 37° C. with shaking.\",\n \"After dilution in fresh medium and passage through a 22-guage needle, the cells were plated on Middlebrook 7H9 agar containing 0.05% Tween 80 and 0.4% glucose.\",\n \"After 9 days in a humidified incubator, the plates were scored and individual colonies replated in duplicate using a grid layout in 100 mm culture dishes.\",\n \"After colony development, one plate was used to screen for MSH-deficient mutants using a membrane-based immunoassay specific for MSH (Unson, et al.\",\n \"(1998) J. Immunol.\",\n \"Methods 214:29-39).\",\n \"MSH-deficient candidates were grown in bulk in liquid medium and analyzed for MSH content as described in Example 1.Two MSH-deficient mutants (strains 49 and 164) were identified and strain 49 was complemented using a M. tuberculosis library (pYUB412::H37Rv) of ˜18 kb DNA fragments cloned in the integrative shuttle plasmid pYUB412 to produce the strain 49::H37Rv A18 with partially restored MSH biosynthesis.\",\n \"Transposon mutants of M. smegmatis mc2155 were prepared using the pCG79 plasmid carrying transposon Tn611 following the methods of Perez, et al.\",\n \"(1998) Meth.\",\n \"Molecular Biol.\",\n \"101:187-198).\",\n \"Plasmid pCG79 was introduced into M. smegmatis mc2155 by electroporation after which the cells were incubated 2 h at 32° C. in 7H9 medium without antibiotic.\",\n \"They were then plated on Middlebrook 7H10 agar plates with ADC enrichment and 20 μg/mL of kanamycin and incubated 6 days at 32° C. Single colonies were restreaked on 7H10km plates and incubated 4 days at 32° C. A loopful of each streaked transformant was resuspended, serially diluted, and plated in duplicate on 7H10 Km plates.\",\n \"One set of plates was incubated 36 h at 32° C. and then shifted to 42° C. for 5 days to select transposon mutants.\",\n \"The other set of plates was incubated at 32° C. for 7 days and served as positive controls.\",\n \"The transposon mutants were replated on 7H10Km plates at 1000-2000 colonies per plate and incubated 5d at 42° C. The cells were scraped into 10 ml of 7H9 medium, mixed with 1 mL of glycerol, and stored at −70° C. This library contained ˜10,000 mutants.\",\n \"Screening of the library for MSH-deficient mutants was accomplished using as ELISA assay method to detect MSH production in cultures grown in microtiter plates (Unson, et al.\",\n \"(1999) J. Clin.\",\n \"Microbiol 37:2153-2157).\",\n \"The first 1000 mutants screened produced three nearly identical MSH-deficient mutants (TN1, TN2 and TN3) that accumulated GlcN-Ins to high levels but failed to produce detectable levels of Cys-GlcN-Ins or MSH.\",\n \"Since these clones seemed likely to be daughter cells, TN3 was selected for more detailed studies.\",\n \"Results obtained with the parent and mutant strains of M. smegmatis are summarized in Table 7 below.\",\n \"TABLE 7 Characterization of M. smegmatis mutant strains MSH Content H2O2 IC50a Strain μmol per g RDW Enzyme Deficiency mM mc2155 10 None 12 49b <0.004 no MshAc 1 49::H37Rv A18b 3.3 partial MshAd 1.8 I64 0.1 low MshCe 3.5 TN3 <0.004 no MshCe 0.5 aConcentration producing 50% loss of viability following 2 h incubation in Middlebrook 7H9 liquid medium containing H2O2 at 37° C., dilution and plating on 7H10 agar, incubation for 10 d, and counting of colony formation.\",\n \"bData from Newton, et al.\",\n \"(1999) Biochem.\",\n \"Biophys.\",\n \"Res.\",\n \"Commun.\",\n \"255: 239-244.cBased upon failure to produce GlcNAc-Ins or GlcN-Ins.\",\n \"dBased upon restoration of ability to produce GlcN-Ins to ˜15% that of the parent strain.\",\n \"eBased upon absence of MshC activity in cell extracts and accumulation of GlcN-Ins to 2-3 μmol per g RDW (˜25-fold above the level of the parent strain).\",\n \"The results of these experiments show that the parent strain (mc2 155) has a high MSH content and exhibits a marked resistance to killing by hydrogen peroxide.\",\n \"By contrast, strain 49, which is blocked in the first step of MSH biosynthesis and produces no detectable MSH, is 12-fold more sensitive to H2O2.Partial restoration of MSH biosynthesis in strain 49 through complementation (strain 49::H37Rv A18) reduced the peroxide sensitivity of mutant 49 by a factor of two.\",\n \"Chemical mutant 164, blocked at the ligase biosynthetic enzyme MshC, has a low residual MSH content and is three-fold more sensitive to peroxide than the parent strain.\",\n \"However, transposon mutant TN3, also blocked at MshC but producing no detectable MSH, was >20-fold more sensitive to H2O2 than the parent strain (FIG.\",\n \"10).\",\n \"These results show that blocking MSH biosynthesis before or after the deacetylase step (MshB) produces a dramatic increase in peroxide sensitivity.\",\n \"It logically follows that blocking-MSH biosynthesis at MshB would produce a comparable increase in peroxide sensitivity in mycothiol-producing bacteria.\",\n \"The sensitivity of strains mc2155, 164, and TN3 to superoxide was also examined (courtesy of Drs.\",\n \"H. Buchmeier and D. Piddington).\",\n \"Superoxide sensitivity was determined according to the method of De Groote, et al.\",\n \"(1997) Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"94: 13997-14001 using timed exposure of cells to 250 μM hypoxanthine in the presence of 0.1 unit/ml of xanthine oxidase followed by dilution and plating to determine survival.\",\n \"Under these conditions, strain mc2155 exhibits no significant killing whereas mutant TN3 is >90% killed in 1 hour.\",\n \"By contrast, chemical mutant 164, with a low residual MSH content, exhibited an intermediate level of killing.\",\n \"Survival of mycothiol-deficient mutant in macrophage.\",\n \"Transposon mutant TN3 was compared with the parent strain for survival in murine macrophages (data courtesy of Drs.\",\n \"N. Buchmeier and D. Piddington).\",\n \"Following the method of De Groote, et al.\",\n \"(1997) Supra, periodate activated, γ-interferon treated murine peritoneal exudate cells were infected with TN3 and mc2155, and extracellular bacteria were washed free of the macrophages with medium.\",\n \"At timed intervals the macrophages were resuspended in PBS and lysed with 0.5% deoxycholate; serial dilutions of the lysate were plated on Middlebrook 7H9 agar for determination of colony forming units.\",\n \"The results of two independent experiments performed on different days (FIG.\",\n \"11, experiments 1 and 2) show no loss of viability of the parent strain mc2155 in the macrophages over the period of 24 hours; whereas over 60% of the MSH-deficient mutant TN3 was killed by the macrophages within 6 hours.\",\n \"These results suggest that mycobacteria deficient in MSH biosynthesis will exhibit significantly enhanced killing by mammalian macrophages.\",\n \"While the invention has been described in detail with reference to certain preferred embodiments thereof, it will be understood that modifications and variations are within the spirit and scope of that which is described and claimed.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10297512"}}},{"rowIdx":99,"cells":{"text":{"kind":"list like","value":[["Process for the electromagnetic modelling of electronic components and systems","Process for the electromagnetic modelling of electronic components and systems, for the extraction of certain electrical parameters, such as the static V-I characteristics and the input and output impedance, the output switching times in particular conditions of load and the transition times of the protection diodes.","A test machine of the commercial type is used for these measurements, by generating stimulus signals and measuring the correlated signals, the test machine being suitable for parametric direct current measurements, functional tests and digital integrated circuit timing and also being used as a time domain reflectometer.","The measurement phase is followed by a simulation phase during which the electric parameters used for modelling electronic components and systems are extracted."],["1.Process for the electromagnetic modelling of electronic components and systems, in particular for the extraction of certain electrical parameters, such as the static V-I characteristics and the input and output impedance, the output switching times in particular conditions of load and the transition times of the protection diodes of said electronic components and systems, to ports of these components and systems suitable stimulus signals are sent and the correlated signals are measured, reconstructing the respective time patterns, characterised in that a test machine of the commercial type is used for generating the stimulus signals and measuring the correlated signals, the test machine being suitable for parametric direct current measurements, functional tests and digital integrated circuit timing and also being used as a time domain reflectometer, in which case the test machine sends said stimulus signals to the component or system inputs or outputs, fitted on a suitable support and connected by means of suitable interconnection channels, and detects the reflection due to impedance offset, providing the respective time patterns, which are then compared with those provided by a simulated measurement system model, comprising the test machine signal generation and measurement part, the interconnection channels and the support, to verify the coincidence between the measure time pattern and that provided by the simulated model obtained by setting different values with respect to the electric parameters to be determined.","2.Process according to claim 1, characterised in that the model simulated by the measurement system is obtained by the reflectometer response of each channel of the test machine in the situation in which the support of the component or system is not connected to the machine.","3.Process according to claim 1, characterised in that the reflected signals are reconstructed by means of the periodical sampling method, by fine tuning the sampling pulse phase and operating on the comparison threshold of the measurement part of the test machine to identify the succession of values assumed in time by the reflected signal, so as to obtain the time pattern.","4.Process according to claim 1, characterised in that for measuring the electronic component and system input and output impedance, a variable load impedance is introduced in the simulated model, so as to obtain various patterns of the reflected signal, following the same stimulus signal, to find the pattern which best reproduces the measured pattern by subsequent approximation, the simulated impedance value corresponding to the impedance of the input or output to be determined.","5.Process according to claim 1, characterised in that for measuring the switching time of the outputs or transition time of the protection diode, a variable time is introduced in the simulated model, so as to obtain different patterns of the reflected signal, given the same stimulus signal, to find the pattern which best reproduces the measured pattern by subsequent approximation, the simulated switching or transition time corresponding to the value to be determined."],["This invention relates to measurement methods for evaluating electromagnetic compatibility, and particularly relates to a process for the electromagnetic modelling of electronic components and systems.","With the increased level of integration and operating frequency of electronic components and systems, the need to check the electromagnetic compatibility between different parts of any one system, or between different systems in conditions of mutual interference, and the integrity of signals exchanged in electronic systems between the various components is becoming increasingly important.","The integrity of signals is particularly important in digital systems, where the treated signals are essentially binary signals.","For the good operation of systems, these signals must satisfy certain minimum quality requirements.","Particularly, two voltage levels, corresponding to bit 1 and 0, and the transition times between the levels must be preserved.","Furthermore, interference between adjacent conductors, skin effect attenuation and spurious signals originated from reflection of the original signals in the presence of discontinuous impedance must be minimised.","In digital systems, the increase in signal switching front steepness and dock frequency increases the intensity of the electromagnetic field radiated by the various component parts, such as conductors and active and passive components, with the consequent possibility of exceeding the limits established in the emission standard.","As a consequence, the device may not be type-approved or, consequently, marketed.","These problems can be obviated by an accurate system design, which accounts for the electromagnetic performance of the various components employed.","The validity of design can be verified before system construction by exploiting the possibilities offered by simulation programs readily available on the market.","Electromagnetic compatibility data, which can be provided by such programs, will be closer to reality the more the component and system models employed for describing the entire device to be simulated are accurate.","Standard model definition processes have existed for several years.","These processes guide technicians in identifying the parameters of the model and describing the model Of such processes, the most common is that proposed by the IBIS (Input-output Buffer Information Specification) Association, which consists in describing the static V-I characteristics of all component inputs and outputs, the output transition times in particular conditions of load, the parasite parameters associated to all inputs and outputs, such as the capacitance with respect to a reference potential, and other parameters.","At this time, there are not many available electronic component models.","The few available models essentially refer to integrated circuits and are widely incomplete and not very accurate.","These models are obtained by simulation employing known methods (SPICE), using technological parameters, in some cases provided by the manufacturers, or by using the scarce information provided by component data sheets.","In other cases, the models are made by means of measurements using single instruments, with considerable waste of time for preparing the bench and for making settings and measurements.","The process illustrated in this invention obviates these disadvantages and solves the technical problem described above by allowing automatic electronic component and system modelling using normal electronic test machines in an original way, without requiring costly modifications.","All access points of the device under test can be characterised rapidly also when dealing with very complex stimulation signals.","The test machine can be used in a conventional way for conducting functional tests or, according to this invention, for modelling in the same test session, without the need for additional manual interventions on behalf of the operator.","Specifically, object of this invention is a process for the electromagnetic modelling of electronic components and systems the characteristics of which are described in claim 1.This invention will be better explained by the following detailed description with reference to the accompanying drawings as non-limiting example, wherein: FIG.","1 is a flow chart illustrating a typical measurement session; FIGS.","2 and 3 are flow charts illustrating the process for conducting the measurements by means of the test machine; FIG.","4 is a flow chart illustrating the process which is used to extract the output switching time and the capacitance of the input or output ports of the component or system under test.","The process for the electromagnetic modelling of electronic components and systems employs a test machine of the commercial type, designed for conducting parametric measurements in direct current, functional tests and digital integrated circuit timing.","The characteristics required for the machine to be used in this process are: the possibility of generating digital signals with sufficiently steep switching fronts, typically lower than 300 ps; impedance controlled along all interconnections in the device under test; possibility of monitoring all signals output by the device under test by sampling, with time resolution lower than 300 ps.","Various types of such machines are made by various manufacturers, e.g.","the machine identified by code ITS9000 IX, made by Schlumberger.","In normal use for integrated circuit functional tests, signals with a suitable pattern are sent to the device inputs and the output signals are measured, checking that such signals are as required in a precise instant of the clock cycle.","The sampling method is used to measure the signals.","Specifically, at input port level transition, the signal at the output port is compared with a pre-programmed reference threshold and the time instant in which the threshold was exceeded is recorded.","By using a sufficiently high sampling frequency, the signal can be closely reconstructed.","A subsequent study can be conducted to evaluate the response of the device, checking that the parametric, functional and timing characteristics, the output signal time delays and the input and output signal threshold values are within the tolerance range permitted in specifications.","The test machine according to this invention is used in a different way with respect to that described above: it is used as a time domain reflectometer, i.e.","the test machine is used to send specific signals to the component ports and the reflections due to impedance offset are measured.","This method is not exploited in normal test machine use.","Only in the initial machine channel calibration and characterisation phase, a signal is sent to the device support and the delay of the corresponding reflected signal is measured to determine the delay introduced by the device interconnection channel.","The consequent compensations can be implemented, if required.","However, the time pattern of the reflected signal is not studied in detail, to the extent that the integrated circuit under test is not present: in other words, the conditions are those of total reflection.","By extending the possibility of reconstructing signals, also to involve the signals reflected by the access ports of the device under test, the respective electric parameters can be obtained.","These are essential for the electromagnetic modelling of the entire device according to the IBIS standard process mentioned above.","In detail, the following parameters can be obtained: the static voltage-current (V-I) characteristics at inputs and outputs; the output switching times in the specific conditions of load; the input and output capacitance; the tripping times of the protection and clamp diode circuits, normally present in input ports; various parasite parameters.","For the use according to this invention, the stimulus signals generated by the test machine must be sufficiently steep and present a sufficient amplitude, so as to allow high frequency measurements, preserving a good signal/noise ratio.","For example, to measure the typical input capacitance of a digital integrated circuit, an amplitude of approximately 1 V is conveniently selected for obtaining a transition time of approximately 400 ps, which suitably adapts to the amplitude resolution of the test machine comparators.","The signal offset can be set at a suitable level for the device, e.g.","2.5 V for an integrated circuit powered at 5 V. Since impedance offset is measured, naturally the output impedance of the test machine must be controlled and fixed at a suitable value, e.g.","50 Ohms, as the impedance of all the interconnections between the generator and the access port of the device.","As mentioned above, the reflected signals are reconstructed using the periodical sampling method.","The sampling input phase can be very finely tuned, e.g.","with a resolution of 20 ps.","After stablising the sampling phase, the comparison threshold is used to identify the internal comparator switching value, by using a suitable search algorithm, eg.","dichotomy, linear etc., according to the morphology of the signal.","After reconstructing the pattern of the reflected signal, it is compared with the pattern obtained by simulating the measurement configuration in the time domain with a circuit simulator.","The simulated model must include the same stimulus signal, the same impedance and the same interconnection channel delay and a variable load impedance, which is the unknown quantity to be determined.","By varying the simulated impedance parameters (e.g.","capacitance), various reflected signal patterns are obtained, given the same stimulus signal, to find the pattern which best reproduces the measured pattern by subsequent approximation.","The value of the simulated impedance parameters thus corresponds to that associated to the device port.","Other parasite effects in the interconnection channel between generator and device, due to discontinuous impedance between support and connection cable, between support and device, etc., or loss due to skin effect in the cable and in the support, which are intrinsic to the test machine, can be accounted for in the model used for simulation and consequently compensated.","A similar process can be applied to the measurement of protection circuit and clamps on device access ports, by suitably arranging the voltage levels of the stimulus signal.","For example, to characterise the protection circuit at input of an integrated circuit to the earth terminal, a stimulus signal passing from 0 V to −1 V and then from −1 V to 0 V can be used.","By measuring the waveform reflected by the diode, which firstly conducts and then cuts off the stimulus signal, the characteristic transition time of the diode can be determined.","The subsequent approximation process herein described can also be applied to more conventional types of measurements, i.e.","measurements based on the use of the test machine as a stimulus signal generator and respective output signal sampler, instead of as a time domain reflectometer.","The component is programmed, by means of the test machine, so to generate repetitive output signals, which can be measured by means of the sampling procedure.","The measured waveforms are not those of the component under test but those effected by the distortion introduced in the entire measurement system, consisting of the machine, the interconnections, the physical component support, etc.","Consequently, a system model is required, for simulating the measurement providing the output waveform to be compared with those resulting from the measurements.","In this case, in the model used for the simulation, the unknown quantity to be identified consists of the intrinsic switching times of the device.","A sequence of increasing switching times within a predefined range is set in the model for each output port so that the simulated waveform output by the measurement system model better approximates the measured waveform.","The set switching time leading to the best approximation of the waveforms, is the unknown quantity sought.","The entire procedure, comprising the measurement phases, the simulation phases and the comparison phases, can be easily automated by implementing a specific test machine management and result processing application.","A typical measurement session according to the process of this invention is illustrated in the flow chart in FIG.","1.Test device 101, with respective data sheet 102 and JTAG data 103, where relevant, form the starting data of phase 100.As known, JTAG is a standard according to which some component pins are dedicated to functional tests.","For example, thanks to this standard, some parts of the device, deemed particularly critical, can be isolated and individually operated, during testing or trouble-shooting.","Consequently, the test support is prepared during phase 104.The test support is specific for the device under test and suitable to the test machine.","The device is fitted in phase 105.According to the type of parameters to be extracted, suitable stimulus signals 106, to be used in the test machine in phase 107 for the measurements, must be prepared.","According to the resulting measurements, the device input and output voltage-current static characteristics are extracted in phase 108, the output switching times in certain conditions of load are extracted in phase 109, and the input or output port capacitance reactance is extracted in phase 110.Particularly, the switching time measurements are made according to the measured waveforms and the capacitance on the basis of reflected signals.","During the subsequent phase 111, the IBIS model containing all the measurement parameters is finally created.","The measurement process implementing the test machine, indicated with numeral 107, is illustrated in greater detail in FIGS.","2 and 3.In FIG.","2, the various operations, indicated with numerals 201, .",".",".","206, consist in: measuring the input static characteristics; output conditioning by means of JOAG functions; measuring output static characteristics; generating and measuring input reflectometer signals; output conditioning by means of JTAG functions; measuring the output fronts.","The reflectometer and output waveform front measurement process is illustrated in FIG.","3.In phase 301 “Generate one input or output waveform front”, the test machine controls the device under test.","If measurements are carried out on the output signals, the machine programs the component to switch the outputs.","In the next phase 302, the starting point of the switching front is established.","This determines the start instant of the level measurement.","This measurement is conducted in phase 303, by comparing the signal with a variable threshold by means of a machine comparator to check correspondence of values.","Consequently, the measurement instant is increased by one time unit defined in phase 304 and, if the measurement time window is not over because the switching transient is not complete, the cycle is repeated to measure the new signal level in phase 305.The succession of levels obtained, which reproduces the pattern of the waveform, is finally stored in a file during phase 306.During reflectometer measurements, the output signal of the circuit under test is no longer considered in phase 301.In this case, the signal is reflected on an input port The process is similar and the result is the pattern of the reflected signal.","The process in which the output switching times and the input and output port capacitance, indicated with numerals 109 and 110, are extracted is illustrated in greater detail in FIG.","4.In phase 410 “setup model”, an electric simulator model representing the measurement configuration is created, specifically including the interconnection cables with respective loss and impedance discontinuity, where relevant, the physical support and the stimulus signals.","This model can be created on the basis of the reflectometer response obtained from the test machine in the configuration in which the support plate of the device under test is not inserted and is specific for each measurement channel available on the machine.","Said responses contain all the information (characteristics impedance levels, propagation delay, etc.)","required for the description by means of circuit simulation primitives.","The circuit model completed in phase 402 can be obtained by connecting the measurement system model to the device model containing one or more circuit parameters on circuit simulation level (for example capacitance, switching time, etc.)","which value is to be extracted.","In phase 402, the model is updated with a first hypothesis of parameter, for example the switching time, which is then simulated in phase 404 and compared with the measurements provided by the test machine in phase 405.If the error exceeds a predefined threshold, the parameter is changed in phase 403 and the approximation cycle is repeated to obtain the minimal discrepancy between the measurement and the simulation.","Finally, the resulting parameter is used for constructing the IBIS model.","The description herein is provided as a non-limiting example and obviously variations and changes are possible within the scope of protection of this invention."]],"string":"[\n [\n \"Process for the electromagnetic modelling of electronic components and systems\",\n \"Process for the electromagnetic modelling of electronic components and systems, for the extraction of certain electrical parameters, such as the static V-I characteristics and the input and output impedance, the output switching times in particular conditions of load and the transition times of the protection diodes.\",\n \"A test machine of the commercial type is used for these measurements, by generating stimulus signals and measuring the correlated signals, the test machine being suitable for parametric direct current measurements, functional tests and digital integrated circuit timing and also being used as a time domain reflectometer.\",\n \"The measurement phase is followed by a simulation phase during which the electric parameters used for modelling electronic components and systems are extracted.\"\n ],\n [\n \"1.Process for the electromagnetic modelling of electronic components and systems, in particular for the extraction of certain electrical parameters, such as the static V-I characteristics and the input and output impedance, the output switching times in particular conditions of load and the transition times of the protection diodes of said electronic components and systems, to ports of these components and systems suitable stimulus signals are sent and the correlated signals are measured, reconstructing the respective time patterns, characterised in that a test machine of the commercial type is used for generating the stimulus signals and measuring the correlated signals, the test machine being suitable for parametric direct current measurements, functional tests and digital integrated circuit timing and also being used as a time domain reflectometer, in which case the test machine sends said stimulus signals to the component or system inputs or outputs, fitted on a suitable support and connected by means of suitable interconnection channels, and detects the reflection due to impedance offset, providing the respective time patterns, which are then compared with those provided by a simulated measurement system model, comprising the test machine signal generation and measurement part, the interconnection channels and the support, to verify the coincidence between the measure time pattern and that provided by the simulated model obtained by setting different values with respect to the electric parameters to be determined.\",\n \"2.Process according to claim 1, characterised in that the model simulated by the measurement system is obtained by the reflectometer response of each channel of the test machine in the situation in which the support of the component or system is not connected to the machine.\",\n \"3.Process according to claim 1, characterised in that the reflected signals are reconstructed by means of the periodical sampling method, by fine tuning the sampling pulse phase and operating on the comparison threshold of the measurement part of the test machine to identify the succession of values assumed in time by the reflected signal, so as to obtain the time pattern.\",\n \"4.Process according to claim 1, characterised in that for measuring the electronic component and system input and output impedance, a variable load impedance is introduced in the simulated model, so as to obtain various patterns of the reflected signal, following the same stimulus signal, to find the pattern which best reproduces the measured pattern by subsequent approximation, the simulated impedance value corresponding to the impedance of the input or output to be determined.\",\n \"5.Process according to claim 1, characterised in that for measuring the switching time of the outputs or transition time of the protection diode, a variable time is introduced in the simulated model, so as to obtain different patterns of the reflected signal, given the same stimulus signal, to find the pattern which best reproduces the measured pattern by subsequent approximation, the simulated switching or transition time corresponding to the value to be determined.\"\n ],\n [\n \"This invention relates to measurement methods for evaluating electromagnetic compatibility, and particularly relates to a process for the electromagnetic modelling of electronic components and systems.\",\n \"With the increased level of integration and operating frequency of electronic components and systems, the need to check the electromagnetic compatibility between different parts of any one system, or between different systems in conditions of mutual interference, and the integrity of signals exchanged in electronic systems between the various components is becoming increasingly important.\",\n \"The integrity of signals is particularly important in digital systems, where the treated signals are essentially binary signals.\",\n \"For the good operation of systems, these signals must satisfy certain minimum quality requirements.\",\n \"Particularly, two voltage levels, corresponding to bit 1 and 0, and the transition times between the levels must be preserved.\",\n \"Furthermore, interference between adjacent conductors, skin effect attenuation and spurious signals originated from reflection of the original signals in the presence of discontinuous impedance must be minimised.\",\n \"In digital systems, the increase in signal switching front steepness and dock frequency increases the intensity of the electromagnetic field radiated by the various component parts, such as conductors and active and passive components, with the consequent possibility of exceeding the limits established in the emission standard.\",\n \"As a consequence, the device may not be type-approved or, consequently, marketed.\",\n \"These problems can be obviated by an accurate system design, which accounts for the electromagnetic performance of the various components employed.\",\n \"The validity of design can be verified before system construction by exploiting the possibilities offered by simulation programs readily available on the market.\",\n \"Electromagnetic compatibility data, which can be provided by such programs, will be closer to reality the more the component and system models employed for describing the entire device to be simulated are accurate.\",\n \"Standard model definition processes have existed for several years.\",\n \"These processes guide technicians in identifying the parameters of the model and describing the model Of such processes, the most common is that proposed by the IBIS (Input-output Buffer Information Specification) Association, which consists in describing the static V-I characteristics of all component inputs and outputs, the output transition times in particular conditions of load, the parasite parameters associated to all inputs and outputs, such as the capacitance with respect to a reference potential, and other parameters.\",\n \"At this time, there are not many available electronic component models.\",\n \"The few available models essentially refer to integrated circuits and are widely incomplete and not very accurate.\",\n \"These models are obtained by simulation employing known methods (SPICE), using technological parameters, in some cases provided by the manufacturers, or by using the scarce information provided by component data sheets.\",\n \"In other cases, the models are made by means of measurements using single instruments, with considerable waste of time for preparing the bench and for making settings and measurements.\",\n \"The process illustrated in this invention obviates these disadvantages and solves the technical problem described above by allowing automatic electronic component and system modelling using normal electronic test machines in an original way, without requiring costly modifications.\",\n \"All access points of the device under test can be characterised rapidly also when dealing with very complex stimulation signals.\",\n \"The test machine can be used in a conventional way for conducting functional tests or, according to this invention, for modelling in the same test session, without the need for additional manual interventions on behalf of the operator.\",\n \"Specifically, object of this invention is a process for the electromagnetic modelling of electronic components and systems the characteristics of which are described in claim 1.This invention will be better explained by the following detailed description with reference to the accompanying drawings as non-limiting example, wherein: FIG.\",\n \"1 is a flow chart illustrating a typical measurement session; FIGS.\",\n \"2 and 3 are flow charts illustrating the process for conducting the measurements by means of the test machine; FIG.\",\n \"4 is a flow chart illustrating the process which is used to extract the output switching time and the capacitance of the input or output ports of the component or system under test.\",\n \"The process for the electromagnetic modelling of electronic components and systems employs a test machine of the commercial type, designed for conducting parametric measurements in direct current, functional tests and digital integrated circuit timing.\",\n \"The characteristics required for the machine to be used in this process are: the possibility of generating digital signals with sufficiently steep switching fronts, typically lower than 300 ps; impedance controlled along all interconnections in the device under test; possibility of monitoring all signals output by the device under test by sampling, with time resolution lower than 300 ps.\",\n \"Various types of such machines are made by various manufacturers, e.g.\",\n \"the machine identified by code ITS9000 IX, made by Schlumberger.\",\n \"In normal use for integrated circuit functional tests, signals with a suitable pattern are sent to the device inputs and the output signals are measured, checking that such signals are as required in a precise instant of the clock cycle.\",\n \"The sampling method is used to measure the signals.\",\n \"Specifically, at input port level transition, the signal at the output port is compared with a pre-programmed reference threshold and the time instant in which the threshold was exceeded is recorded.\",\n \"By using a sufficiently high sampling frequency, the signal can be closely reconstructed.\",\n \"A subsequent study can be conducted to evaluate the response of the device, checking that the parametric, functional and timing characteristics, the output signal time delays and the input and output signal threshold values are within the tolerance range permitted in specifications.\",\n \"The test machine according to this invention is used in a different way with respect to that described above: it is used as a time domain reflectometer, i.e.\",\n \"the test machine is used to send specific signals to the component ports and the reflections due to impedance offset are measured.\",\n \"This method is not exploited in normal test machine use.\",\n \"Only in the initial machine channel calibration and characterisation phase, a signal is sent to the device support and the delay of the corresponding reflected signal is measured to determine the delay introduced by the device interconnection channel.\",\n \"The consequent compensations can be implemented, if required.\",\n \"However, the time pattern of the reflected signal is not studied in detail, to the extent that the integrated circuit under test is not present: in other words, the conditions are those of total reflection.\",\n \"By extending the possibility of reconstructing signals, also to involve the signals reflected by the access ports of the device under test, the respective electric parameters can be obtained.\",\n \"These are essential for the electromagnetic modelling of the entire device according to the IBIS standard process mentioned above.\",\n \"In detail, the following parameters can be obtained: the static voltage-current (V-I) characteristics at inputs and outputs; the output switching times in the specific conditions of load; the input and output capacitance; the tripping times of the protection and clamp diode circuits, normally present in input ports; various parasite parameters.\",\n \"For the use according to this invention, the stimulus signals generated by the test machine must be sufficiently steep and present a sufficient amplitude, so as to allow high frequency measurements, preserving a good signal/noise ratio.\",\n \"For example, to measure the typical input capacitance of a digital integrated circuit, an amplitude of approximately 1 V is conveniently selected for obtaining a transition time of approximately 400 ps, which suitably adapts to the amplitude resolution of the test machine comparators.\",\n \"The signal offset can be set at a suitable level for the device, e.g.\",\n \"2.5 V for an integrated circuit powered at 5 V. Since impedance offset is measured, naturally the output impedance of the test machine must be controlled and fixed at a suitable value, e.g.\",\n \"50 Ohms, as the impedance of all the interconnections between the generator and the access port of the device.\",\n \"As mentioned above, the reflected signals are reconstructed using the periodical sampling method.\",\n \"The sampling input phase can be very finely tuned, e.g.\",\n \"with a resolution of 20 ps.\",\n \"After stablising the sampling phase, the comparison threshold is used to identify the internal comparator switching value, by using a suitable search algorithm, eg.\",\n \"dichotomy, linear etc., according to the morphology of the signal.\",\n \"After reconstructing the pattern of the reflected signal, it is compared with the pattern obtained by simulating the measurement configuration in the time domain with a circuit simulator.\",\n \"The simulated model must include the same stimulus signal, the same impedance and the same interconnection channel delay and a variable load impedance, which is the unknown quantity to be determined.\",\n \"By varying the simulated impedance parameters (e.g.\",\n \"capacitance), various reflected signal patterns are obtained, given the same stimulus signal, to find the pattern which best reproduces the measured pattern by subsequent approximation.\",\n \"The value of the simulated impedance parameters thus corresponds to that associated to the device port.\",\n \"Other parasite effects in the interconnection channel between generator and device, due to discontinuous impedance between support and connection cable, between support and device, etc., or loss due to skin effect in the cable and in the support, which are intrinsic to the test machine, can be accounted for in the model used for simulation and consequently compensated.\",\n \"A similar process can be applied to the measurement of protection circuit and clamps on device access ports, by suitably arranging the voltage levels of the stimulus signal.\",\n \"For example, to characterise the protection circuit at input of an integrated circuit to the earth terminal, a stimulus signal passing from 0 V to −1 V and then from −1 V to 0 V can be used.\",\n \"By measuring the waveform reflected by the diode, which firstly conducts and then cuts off the stimulus signal, the characteristic transition time of the diode can be determined.\",\n \"The subsequent approximation process herein described can also be applied to more conventional types of measurements, i.e.\",\n \"measurements based on the use of the test machine as a stimulus signal generator and respective output signal sampler, instead of as a time domain reflectometer.\",\n \"The component is programmed, by means of the test machine, so to generate repetitive output signals, which can be measured by means of the sampling procedure.\",\n \"The measured waveforms are not those of the component under test but those effected by the distortion introduced in the entire measurement system, consisting of the machine, the interconnections, the physical component support, etc.\",\n \"Consequently, a system model is required, for simulating the measurement providing the output waveform to be compared with those resulting from the measurements.\",\n \"In this case, in the model used for the simulation, the unknown quantity to be identified consists of the intrinsic switching times of the device.\",\n \"A sequence of increasing switching times within a predefined range is set in the model for each output port so that the simulated waveform output by the measurement system model better approximates the measured waveform.\",\n \"The set switching time leading to the best approximation of the waveforms, is the unknown quantity sought.\",\n \"The entire procedure, comprising the measurement phases, the simulation phases and the comparison phases, can be easily automated by implementing a specific test machine management and result processing application.\",\n \"A typical measurement session according to the process of this invention is illustrated in the flow chart in FIG.\",\n \"1.Test device 101, with respective data sheet 102 and JTAG data 103, where relevant, form the starting data of phase 100.As known, JTAG is a standard according to which some component pins are dedicated to functional tests.\",\n \"For example, thanks to this standard, some parts of the device, deemed particularly critical, can be isolated and individually operated, during testing or trouble-shooting.\",\n \"Consequently, the test support is prepared during phase 104.The test support is specific for the device under test and suitable to the test machine.\",\n \"The device is fitted in phase 105.According to the type of parameters to be extracted, suitable stimulus signals 106, to be used in the test machine in phase 107 for the measurements, must be prepared.\",\n \"According to the resulting measurements, the device input and output voltage-current static characteristics are extracted in phase 108, the output switching times in certain conditions of load are extracted in phase 109, and the input or output port capacitance reactance is extracted in phase 110.Particularly, the switching time measurements are made according to the measured waveforms and the capacitance on the basis of reflected signals.\",\n \"During the subsequent phase 111, the IBIS model containing all the measurement parameters is finally created.\",\n \"The measurement process implementing the test machine, indicated with numeral 107, is illustrated in greater detail in FIGS.\",\n \"2 and 3.In FIG.\",\n \"2, the various operations, indicated with numerals 201, .\",\n \".\",\n \".\",\n \"206, consist in: measuring the input static characteristics; output conditioning by means of JOAG functions; measuring output static characteristics; generating and measuring input reflectometer signals; output conditioning by means of JTAG functions; measuring the output fronts.\",\n \"The reflectometer and output waveform front measurement process is illustrated in FIG.\",\n \"3.In phase 301 “Generate one input or output waveform front”, the test machine controls the device under test.\",\n \"If measurements are carried out on the output signals, the machine programs the component to switch the outputs.\",\n \"In the next phase 302, the starting point of the switching front is established.\",\n \"This determines the start instant of the level measurement.\",\n \"This measurement is conducted in phase 303, by comparing the signal with a variable threshold by means of a machine comparator to check correspondence of values.\",\n \"Consequently, the measurement instant is increased by one time unit defined in phase 304 and, if the measurement time window is not over because the switching transient is not complete, the cycle is repeated to measure the new signal level in phase 305.The succession of levels obtained, which reproduces the pattern of the waveform, is finally stored in a file during phase 306.During reflectometer measurements, the output signal of the circuit under test is no longer considered in phase 301.In this case, the signal is reflected on an input port The process is similar and the result is the pattern of the reflected signal.\",\n \"The process in which the output switching times and the input and output port capacitance, indicated with numerals 109 and 110, are extracted is illustrated in greater detail in FIG.\",\n \"4.In phase 410 “setup model”, an electric simulator model representing the measurement configuration is created, specifically including the interconnection cables with respective loss and impedance discontinuity, where relevant, the physical support and the stimulus signals.\",\n \"This model can be created on the basis of the reflectometer response obtained from the test machine in the configuration in which the support plate of the device under test is not inserted and is specific for each measurement channel available on the machine.\",\n \"Said responses contain all the information (characteristics impedance levels, propagation delay, etc.)\",\n \"required for the description by means of circuit simulation primitives.\",\n \"The circuit model completed in phase 402 can be obtained by connecting the measurement system model to the device model containing one or more circuit parameters on circuit simulation level (for example capacitance, switching time, etc.)\",\n \"which value is to be extracted.\",\n \"In phase 402, the model is updated with a first hypothesis of parameter, for example the switching time, which is then simulated in phase 404 and compared with the measurements provided by the test machine in phase 405.If the error exceeds a predefined threshold, the parameter is changed in phase 403 and the approximation cycle is repeated to obtain the minimal discrepancy between the measurement and the simulation.\",\n \"Finally, the resulting parameter is used for constructing the IBIS model.\",\n \"The description herein is provided as a non-limiting example and obviously variations and changes are possible within the scope of protection of this invention.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_10297634"}}}],"truncated":false,"partial":false},"paginationData":{"pageIndex":0,"numItemsPerPage":100,"numTotalItems":4495096,"offset":0,"length":100}},"jwt":"eyJhbGciOiJFZERTQSJ9.eyJyZWFkIjp0cnVlLCJwZXJtaXNzaW9ucyI6eyJyZXBvLmNvbnRlbnQucmVhZCI6dHJ1ZX0sImlhdCI6MTc3MzQ2MjY3OCwic3ViIjoiL2RhdGFzZXRzL2hvd2V5L2h1cGQiLCJleHAiOjE3NzM0NjYyNzgsImlzcyI6Imh0dHBzOi8vaHVnZ2luZ2ZhY2UuY28ifQ.rrkfWNQqrfKV2EC_i2udSyU6P4UIX3urXlOqYBv2yAlFMUuMyuBrGtvyIB1Lou-3RCvvHyyLGtjz78VLRBxiDQ","displayUrls":true,"splitSizeSummaries":[{"config":"default","split":"train","numRows":4495096,"numBytesParquet":108339066781}]},"discussionsStats":{"closed":0,"open":0,"total":0},"fullWidth":true,"hasGatedAccess":true,"hasFullAccess":true,"isEmbedded":false,"savedQueries":{"community":[],"user":[]}}">
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"Stable expression of polymorphous forms of human cytochrome p450 2d6",
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"Maintenance system for an equipment set",
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[
"Force -transmision unit comprising speed -dependent hydraulic clutch and centrifugal force compensation",
"A power transmission unit with a hydraulic coupling dependent on a rotational-speed difference, in which, when a rotational-speed difference occurs between the input member (1) and the output member... | Patent_10149078 |
[
[
"Encasing arrangement for a semicoductor component",
"A semiconductor component package configuration includes a semiconductor chip mounted to a printed circuit board, and a substrate arranged between the semiconductor chip and the printed circuit board.",
"The substrate is for routing the wiring term... | Patent_10149892 |
[
[
"Termination device e.g. for a multiconnector",
"A termination device e.g.",
"for a multiconnector comprises a cover (2) which is rotatably hinged to a housing (1), and which has a hole for receiving a cable containing a plurality of wires (5a-e).",
"When the individual wires are arranged in respe... | Patent_10168605 |
[
[
"Electrical circuit board and a multiconnector",
"An electrical circuit board and multiconnector having protruding contact pins, which together form contact areas for providing contact with a complementary connector, are arranged such that the contact pins (6-13) extend out from one of the sides of the ci... | Patent_10168606 |
[
[
"System for reproducing three-dimensional images",
"The present invention describes a system that is able to reproduce images in three dimensions, that is, stereoscopic, three-dimensional or integral, without the need for glasses or any other device in front of observer's eyes.",
"The number of images... | Patent_10168652 |
[
[
"Compounds and methods for the treatment of pain",
"2-substituted 7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione compounds, pharmaceutical compositions and methods for the treatment of pain are disclosed."
],
[
"1.A compound selected from: 7-chloro-4-hydroxy-2-(4-[1,3,... | Patent_10168755 |
[
[
"Repressible sterility of animals",
"A construct which allows animals to be bred in captivity but renders them infertile in the wild by allowing reversible control over fertility and reproduction.",
"The construct comprises: a first promoter that is activated in a defined spatial (tissue specific) or ... | Patent_10169050 |
[
[
"Compositions and methods for gene silencing",
"DNA constructs are provided for disrupting gene expression in targeted organisms."
],
[
"1.An IR gene construct encoding an inverted repeat gene, said construct comprising: a) a promoter element operably linked in a 5′ to 3′ direction to a first codi... | Patent_10169287 |
[
[
"Image pickup device, and image pickup device assembling method",
"The invention integrally arranges a lens, an optical filter, a semiconductor imaging device, on-chip components, and a printed circuit board on a three-dimensional circuit board and contrives the lens attachment structure, bonding method, ... | Patent_10169359 |
[
[
"Vessel provided with a sealing ring",
"A vessel for containing a fluid is provided.",
"A composite wall encloses the fluid chamber and is connected, at at least one location, to a shaft-like body which traverses the fluid chamber and extends through the composite wall.",
"A sealing ring is furthe... | Patent_10169529 |
[
[
"Method for preparing hydroxypicolinic scid derivatives",
"The invention concerns a method for preparing compounds of general formula (I) wherein: n, Q1, Q2, X1, X2, Y and Z are as defined in the description."
],
[
"1.A process for preparing compounds of general formula (I): in which: n represents... | Patent_10169855 |
[
[
"Ultrasonic diagnosing apparatus",
"An ultrasonic diagnostic apparatus transmits an ultrasonic beam into an object to be examined using a multi-ring arrangement formed with transducer elements arrayed two-dimensionally in concentric rings and receives an echo so as to create a tomogram or a three-dimensio... | Patent_10169979 |
[
[
"Quad cable",
"The invention relates to a cable (10) having an elongate core (20) made of a first dielectric material and having a core outer surface (25); and a plurality of elongate conducting elements (30) arranged about the elongate core (20).",
"The elongate conducting elements (30) have an inner... | Patent_10181667 |
[
[
"TORSION SENSOR",
"The invention relates to a device for providing an axial force subject to a torque, which device has a first shaft with a friction surface comprising at least a radial directional component; a second shaft which is placed parallel with at least an axial directional component to the firs... | Patent_10181796 |
[
[
"Purifying polyoxyethylated castor oils with activated charcoal and pharmaceutical formulations thereof",
"Disclosed are polyoxyethylated castor oils produced by preparing a suspension of activated charcoal and a polyoxyethylated castor oil; and separating the activated charcoal from the polyoxyethylated ... | Patent_10182041 |
[
[
"Christmas tree stand comprising securing wedges",
"The invention relates to a Christmas tree stand with a holding body which surrounds the lower end of the trunk of a Christmas tree and with securing wedges for the trunk which are connected to the holding body via blade wedges."
],
[
"1-8.",
... | Patent_10182325 |
[
[
"Method and apparatus for signal transduction pathway profiling",
"An assay device for determining the presence of analytes in a cell lysate comprises a porous support member and a plurality of binding reagents arranged and immobilized at multiple reaction sites on the support member.",
"The binding r... | Patent_10182354 |
[
[
"Defoaming agent for liquid hydrocarbons II",
"A process for inhibiting a liquid hydrocarbon from foaming involving: (a) providing a liquid hydrocarbon; (b) providing a defoamer additive containing: (i) an ester corresponding to formula (I) R1—COO—R2 (I) wherein R1 and R2 are, independent of each other, s... | Patent_10203859 |
[
[
"Stretch film and method for producing a stretch film",
"A stretch film for the packing of goods, particularly for the packing of goods stacked on a pallet, comprises a prestretched main film (10).",
"The main film (10) is reinforced by reinforcement strips (12) extending in the longitudinal direction... | Patent_10203952 |
[
[
"Alloy for use in bonded magnet, isotropic magnet powder and anisotropic magnet powder and method for production thereof, and bonded magnet",
"An alloy for bonded magnet alloy of the present invention includes at least Fe as a main component, 11-15 at % rare-earth element (R) that includes yttrium (Y) and... | Patent_10204426 |
[
[
"Methods for producing a light emitting semiconductor body with a liminescence converter element",
"The invention describes two methods of fabricating semiconductor components in which a luminescence conversion element is applied directly to the semiconductor body (1).",
"In the first method, a suspen... | Patent_10204576 |
[
[
"Method And Apparatus For Processing Electronic Documents",
"A computer-implemented method of generating an input to be used by a classifying apparatus based on an electronic document comprising a plurality of elements, said method comprising: analyzing said electronic document to obtain one or more of sa... | Patent_10204756 |
[
[
"Apparatus and method for water treatment by adsorption",
"The present invention relates to an apparatus and method for removal of arsenic or other metal salts from drinking water.",
"The invention uses a bed of granulated ferric hydroxide to adsorp the metal in a pressurized adsorption chamber.",
... | Patent_10204998 |
[
[
"Method for accommodating large movements in a mooring system",
"A method of operating a mooring system exemplified by active mooring devices having attractive attachment elements fixable to a ship's hull.",
"Each mooring device includes active means for moving the attachment element vertically and in... | Patent_10220010 |
[
[
"Method for reversing the immunosuppressive effects of the melanoma inhibitory activity \"mia\"",
"A method for stimulating immune cells and/or the immune system, and/or reducing invasion and/or metastasis of tumor cells by inhibiting expression and/or functional activity of “Melanoma Inhibitory Activity”... | Patent_10220265 |
[
[
"Waxes for producing printing inks",
"The invention relates to mixtures for producing printing inks, wherein the mixtures comprise a homopolymerizate or copolymerizate of C2-C18-α-olefins, which are produced by means of metallocene catalysis, and of decomposing waxes, which are prepared from polyolefins o... | Patent_10220411 |
[
[
"Model transition sensitivity analysis system and method",
"A method and system for analyzing an infectious disease uses computer based simulation engines.",
"The method and system utilizes at least two computer-based simulation engines of the transmission of the infectious disease.",
"The transmi... | Patent_10220874 |
[
[
"Ergonomic Chair",
"A work station chair is enabled to shift in response to a person leaning forward in the chair when in a working mode and leaning back in a rest position.",
"The chair includes a seat, a backrest and supportive structure.",
"The seat is resiliently supported on the supportive st... | Patent_10221186 |
[
[
"Compounds for pdt",
"A tetrakis(hydroxyphenyl)chlorin, bacteriochlorin or isobacteriochlorin, derivatised at one or more of the hydroxy groups by addition reaction with a diisocyanate, diisothiocyanate or isocyanate-isothiocyanate at one isocyanate or isothiocyanate group thereof, the other isocyanate or... | Patent_10221218 |
[
[
"Method for producing an electric machine subassembly produced according to said method, and electric machine with said subassembly",
"The invention relates to a method for the manufacture of an assembly of an electric machine with the steps of: manufacturing at least one portion of a coil of a rotor or s... | Patent_10221816 |
[
[
"Molecular weight markers for western blot",
"A method for the preparation of molecular weight standards having peroxidase activity which can be directly identified at the time of the detection of the antigen in all western blot techniques based on the use of peroxidase."
],
[
"1.A method per the ... | Patent_10221854 |
[
[
"Circuit arrangement for operating electric or electronic components in a motor vehicle having an electric system comprising two voltages",
"The invention relates to a circuit arrangement for operating electric or electronic components in a motor vehicle with a two-voltage onboard network, with a direct c... | Patent_10221980 |
[
[
"Process for forming plastic, apparatuses for forming plastic,and articles made therefrom",
"Process and apparatus for forming plastics by heating an open mold and contacting the open mold with plastic particulate material to form a melted skin on the mold, and resulting articles made therefrom.",
"Si... | Patent_10239039 |
[
[
"Electronic apparatus",
"In the structure of an electronic apparatus, in which cooling of an heat-generating element is achieved through circulation of a liquid, in particular, for providing the structure of being high in cooling performance and reliability, wherein a heat-radiation pipe 9 is connected to... | Patent_10239156 |
[
[
"Composite building components",
"A structural insulated panel having a core (40) of expanded polystyrene sandwiched between, and bonded to, two facings (52).",
"The facings are attached to faces of the core formed by moulding.",
"Preferably the core is an expanded polymer moulding and the preferr... | Patent_10239276 |
[
[
"Device for adjusting the components of a chair",
"The invention relates to a device for adjusting a first component of a chair, in particular an office chair, with respect to a second component of the chair, the said device being provided with a latching unit by means of which one of the two components c... | Patent_10240160 |
[
[
"Optical device for simultaneous multiple measurement using polarimetry and spectrometry and method for regulating/monitoring physical-chemical and biotechnical processes using said device",
"The invention relates to a device, especially an optical flow-through measuring cell, for the combined use of spec... | Patent_10240165 |
[
[
"Attenuation material",
"An attenuation material and a method of making such an attenuation material.",
"The attenuation material includes a matrix of elastomer having mixed therewith particulate vulcanised rubber and particulate magnetisable material, the mixture being substantially free of sublimabl... | Patent_10240298 |
[
[
"Organic field emission device and emission device",
"The present invention provides an organic electroluminescence light emitting device capable of preventing a color (hue) of light and a luminous efficiency from being varied depending on a concentration of a luminous material contained in a light emissi... | Patent_10240328 |
[
[
"Plasma system and method of producing a functional coating",
"A plasma system has at least one inductively coupled high-frequency plasma jet source having a burner body delimiting a plasma generating space, having an outlet orifice for the plasma jet, and a chamber communicating with the plasma jet sourc... | Patent_10240474 |
[
[
"Plasma system and method of producing a functional coating",
"A plasma system has at least one inductively coupled high-frequency plasma jet source having a burner body delimiting a plasma generating space having an outlet orifice for the plasma jet, a coil surrounding the plasma generating space in some... | Patent_10240477 |
[
[
"System and method for establishing eletronic business systems for supporting communications servuces commerce",
"A comprehensive electronic business support system comprises three layers: (1) the business layer, including various smart components which unify data and business processes across all custome... | Patent_10240614 |
[
[
"Electronic device, communication system and method, information processing terminal and method, and information processing apparatus and method",
"An electronic device, a communication system and method, an information processing terminal and method, and an information processing apparatus and method cap... | Patent_10250341 |
[
[
"Soft restraining system",
"A device for restraining a miscreant includes a bell shaped tubular body adapted to envelop the torso of a miscreant.",
"Openings at each end allow the body to be passed over the head to surround the torso of the miscreant.",
"Restraining straps are each adapted to enci... | Patent_10250409 |
[
[
"Recombinant viral switches for the control of gene expression in plants",
"The invention describes a method of controlling a biochemical process or a biochemical cascade in plants utilizing a process of interaction between a heterologous DNA sequence in a transgenic plant, on one side, and a heterologous... | Patent_10250413 |
[
[
"Process and device for desulphurizing hydrocarbons containing thiophene derivatives",
"The invention relates to a selective desulphurisation method for thiophene derivatives contained in the hydrocarbons emitted from the distillation of crude oil, refined or not, consisting in oxidising the atoms of thio... | Patent_10250431 |
[
[
"Orbital implant",
"An orbital implant includes a body of bioactive material having macropores of at least 400 μm, and a cap of bioactive material having substantially no pores or only micropores smaller than 50 μm.",
"The cap covers a portion of the body."
],
[
"1.An orbital implant which inc... | Patent_10250525 |
[
[
"Bumper airbag and system",
"An airbag (10) for mounting in the bumper (18) of a motor vehicle (12) is provided.",
"The airbag can have an up-side-down “L” shape or a cylindrical shape.",
"Further, multiple bags can be combined within one system.",
"The airbag is configured to cover substantia... | Patent_10250602 |
[
[
"5-azido-laevulinic acid, method for the production thereof and its use",
"The present invention relates to 5-azido levulinic acid, a process for its preparation, its use.",
"Using 5-azido levulinic acid as starting material for the synthesis of 5-amino levulinic acid hydrochloride it is possible to o... | Patent_10250708 |
[
[
"Medical metal implants that can be decomposed by corrosion",
"An in vivo, decomposable medical implant is provided and comprises a metal material that contains, as a main alloying constituent, tungsten or a metal from the group rhenium, osmium, and molybdenum.",
"The method for decomposing the implan... | Patent_10250784 |
[
[
"Piezoelectric actuator",
"An apparatus for actuating a brake comprising force transmission means for transmitting force to a friction pad of a brake, at least one piezo-electric device operable when energised to change shape and/or size so as to apply a force to the force transmission means in a directio... | Patent_10250881 |
[
[
"Autonomous bird predation reduction device",
"A self-guided apparatus for repelling birds through various means of deterrence.",
"The device comprises a chassis, a floatation assembly, a propulsion system, and a guidance and control system.",
"The device may operate in either of at least two mode... | Patent_10250973 |
[
[
"Pole climber",
"The pole climber is designed to allow an individual to move vertically up and down a tree or pole with little physical exertion, depending instead on the power and design of the device.",
"An electrically powered motor and pair of metal drums set on opposite ends of a bar-like compone... | Patent_10251413 |
[
[
"Method of designing addressable array for detection of nucleic acid sequence differences using ligase detection reaction",
"The present invention is directed to a method of designing a plurality of capture oligonucleotide probes for use on a support to which complementary oligonucleotide probes will hybr... | Patent_10257158 |
[
[
"Progressive distributor comprising displaceable pistons",
"The invention relates to a progressive distributor comprising three or more control pistons (SA to SD), each of which can be displaced in a respective housing bore (A to D) of a distributor housing (G).",
"According to the invention, said pis... | Patent_10257417 |
[
[
"Lactic acid bacteria overproducing exopolysaccharides",
"The invention concerns lactic acid bacteria overproducing exopolysaccharides following mutation in the gene coding for α-phosphoglucomutase.",
"Said mutants are useful, in particular for preparing fermented products or for producing exopolysacc... | Patent_10257737 |
[
[
"Method for measuring cylinder specific parameters in a combustion engine",
"The invention concerns a method to measure parameters in the combustion chamber of a piston engine that comprises an ignition system.",
"An alternating voltage is applied across the secondary winding of the ignition coil and ... | Patent_10257820 |
[
[
"Method and apparatus to measure flow rate",
"A method and apparatus for measuring the flow rate of a single phase fluid, particularly a gas, through a conduit.",
"A pulse of tracer fluid is discharged or injected into a first fluid flowing through a conduit, the concentration of the tracer fluid is m... | Patent_10257953 |
[
[
"Closing system for plastic shaped parts",
"The present invention relates to a seal system for plastic moldings and to the use of the seal system in the engine fluid sector."
],
[
"1.A seal system for plastic moldings, comprising.",
"a plastic molding, wherein said plastic molding has an openi... | Patent_10258177 |
[
[
"Substituted Benzoic Acid Amides and Use thereof for the Inhibition of Angiogenesis",
"Substituted benzoic acid amides of formula (I) and their use as pharmaceutical agents for treating diseases that are triggered by persistent angiogenesis as well as their intermediate products for the production of benz... | Patent_10258345 |
[
[
"Conductive gasket and material therefor",
"A conductive gasket and a paste for the electrical industry based on at least one elastomer (10) and on an admixture of conductive particles in the form of fibers (20), in which the fibers (20) are flexible and have been embedded in the elastomer (10) in random ... | Patent_10258426 |
[
[
"Photovoltaic cell",
"A photovoltaic cell is described having a photoactive layer (4) made of two components, namely a conjugated polymer component as an electron donor and a fullerene component as an electron acceptor.",
"In order to provide advantageous conditions, it is suggested that the two compo... | Patent_10258713 |
[
[
"Method and apparatus for manufacturing composite sheet-like materials",
"A method of producing a composite laminate comprises the steps of feeding ground reclaimed material, for example carpet backing, to a dispersing station (16), dispersing the reclaimed material on a moving web (10), bringing an inter... | Patent_10258838 |
[
[
"Method and device for the mechanical-thermal separation of different materials",
"The invention relates to a method and system for the mechanical-thermal separation of different materials such as textile flat structures, threads, and plastic films by heating and simultaneously compacting the material.",
... | Patent_10258986 |
[
[
"Heterocyclic cyclopentyl tetrahydroisoquinoline and tetrahydropyridopyridine modulators of chemokine receptor activity",
"The present invention is directed to compounds of the formula I: Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, n and the broken lines are as defined herein which are useful as modula... | Patent_10260008 |
[
[
"Production of high grade and high concentration of free fatty acids from residual residual oils, fats and greases",
"The present invention relates to a process for the production of unsaturated and saturated free fatty acids.",
"The process comprises the steps of: (a) selecting a starting material fr... | Patent_10275077 |
[
[
"Micro-arrayed organization of transcription factor target genes",
"The following invention outlines methodologies for the construction and utilization of transcription factor direct target gene microarrays of both DNA and corresponding protein/peptide target origin.",
"The technology entails the arra... | Patent_10275845 |
[
[
"Transcription factor target gene discovery",
"The ability to rapidly define transcription factor target genes allows for the study of genetic cascades involved in development, physiology and disease.",
"The presently descibed invention outlines the combination of novel chromosomal immunoprecipitation... | Patent_10275846 |
[
[
"Process for the puritication of a salt of clavulanic acid",
"A process in which a salt of clavulanic acid, typically an amine salt or an alkali metal salt is exposed to conditions, particularly a pH of less than 6.0, which reduces the quantity of contaminating impurities.",
"The process may be a wash... | Patent_10275852 |
[
[
"Eeg feedback controlled sound therapy for tinnitus",
"An automated method for treating tinnitus by habituation through use of neurological feedback, comprising the steps of connecting a subject through a set of attached headphones to an electronic sound player that is connected to a PC workstation presen... | Patent_10276018 |
[
[
"Method for applying a layer containing at least polymeric material",
"In a method for applying a layer containing at least polymer material to a substrate, there is applied to the substrate a film of polymer particles dispersed in a non-reactive liquid.",
"By subjecting these at least polymer materia... | Patent_10276106 |
[
[
"Optical recording medium and its manufacturing method",
"A multi-layered film made of sequentially stacked first dielectric layer, recording layer, record-assist layer, second dielectric layer and first reflection layer on a disc substrate having a concavo-convex structure at least on one surface thereof... | Patent_10276126 |
[
[
"Bellows for consant-velocity joints",
"A convoluted boot for sealing an annular gap between two parts which are connected to one another in a rotationally fast way, which can be articulated relative to one another and which are axially displaceable relative to one another, especially of a constant veloci... | Patent_10276208 |
[
[
"Method and apparatus of dsp resource allocation and use",
"Certain embodiments of the invention support the distribution and control of multiple instruction streams going to multiple steps of modules supporting arithmetic and memory, as well as method for numeric data processing optimizing non-additive f... | Patent_10276414 |
[
[
"Centrifugal pump, in particular a spirally-housed centrifugal pump for a heat exchange medium",
"In a centrifugal pump—in particular a spiral-casing centrifugal pump—for a heat carrier medium, comprising a spiral casing (14) having an impeller (40), a casing cover (18) and an associated casing attachment... | Patent_10276581 |
[
[
"Allocating access across shared communication medium",
"A method of providing network access across a shared communications medium between competing users (86) includes the step of allocating network access for each user for a future time interval (102).",
"Features include forecasting network access... | Patent_10276654 |
[
[
"Novel nucleic acids and polypeptides",
"The present invention provides novel nucleic acids, novel polypeptide sequences encoded by these nucleic acids and uses thereof."
],
[
"1.An isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-8051, a ... | Patent_10276817 |
[
[
"Automatic scanning system, shoppers scanpass system",
"The checkout system described herein is to show a system how to eliminate the lines at the regiters, to eliminate the removal of items from shopping cart in order to “ring” them at the checkout counters.",
"As clients lowering their goods into sh... | Patent_10292688 |
[
[
"Thermoplastic Hydraulic Composition, Formed Article Prepared From The Composition By Hydration- Hardening And Method For Preparing The Hydration- Hardened Former Article",
"The object of the present invention is to produce general machine parts, OA machine part, and the like which can be produced by inje... | Patent_10296092 |
[
[
"Combinations of enzyme inhibitor-containing preparations and the use thereof",
"The invention comprises a process wherein the DNA synthesis and, thus, the proliferation of mononuclear cells (MNZ) and of T cells as well is inhibited by the simultaneous and combined inhibition of the enzyme activity (I) of... | Patent_10296102 |
[
[
"Induction heating of rail welds",
"An apparatus (10) and method for preheating welds uses a centered induction plate (12) having preferably a plurality of induction coils (30, 32) to impart the generation of heat in the materials to be welded (14), being interactively controlled by at least a temperature... | Patent_10296635 |
[
[
"Carboxylate salts in heat-storage applications",
"The use of an alkali metal salt or alkaline earth metal salt or of a bring solution of a C1-C16 carboxylic acid, or a mixture thereof, as a medium for the storage and use of thermal energy.",
"The salts or solution can be used in a heat exchange fluid... | Patent_10296826 |
[
[
"Stabiliser for radiopharmaceuticals",
"The present invention provides an improved stabiliser for radiopharmaceuticals which inhibits impurities from being produced by two kinds of decomposition mechanisms and exhibits such an effect that the shelf life of a radiopharmaceutical after its preparation is pr... | Patent_10296952 |
[
[
"METHODS FOR MEDIATING GENE SUPPRESSION",
"The present invention is concerned with methods for enhancing gene suppression in cells and in particular it is concerned with improved methods for enhancing RNAi-mediated gene silencing by manipulation of factors associated with RNAi.",
"The present inventio... | Patent_10297167 |
[
[
"Ligands of Integrin Receptors",
"The invention relates to the use of cyclic compounds as ligands of integrin receptors, in particular as ligands of the αVβ3 integrin receptor, the novel compounds themselves, their use, and pharmaceutical preparations comprising these compounds."
],
[
"1.The use o... | Patent_10297202 |
[
[
"Method, apparatus and system for building a compact language model for large vocabulary continous speech recognition (lvcsr) system",
"According to one aspect of the invention, a method is provided in which a set of probabilistic attributes in an N-gram language model is classified into a plurality of cl... | Patent_10297354 |
[
[
"Refrigeration unit",
"The refrigerating unit can be operated by means of a thermal solar system as energy source.",
"Therein it is provided that the refrigerating unit is formed as a diffusion-absorption refrigerating unit.",
"The refrigerating unit has an expeller, a triple heat exchanger, a con... | Patent_10297462 |
[
[
"Acetyl glucosaminyl inositol deacetylase, a mycothiol biosynthetic enzyme, and methods of use",
"The present invention provides a family of bacterial acetyl glucosaminyl inositol deacetylases (MshB) with deacetylase activity against acyl glucosaminyl inositol and which play a key role in mycothiol biosyn... | Patent_10297512 |
[
[
"Process for the electromagnetic modelling of electronic components and systems",
"Process for the electromagnetic modelling of electronic components and systems, for the extraction of certain electrical parameters, such as the static V-I characteristics and the input and output impedance, the output swit... | Patent_10297634 |