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Machine Learning in Planning and Control of Robot Motion Workshop at the IEEE/RSJ International Conference on Intelligent Robots and Systems (iROS), pages: , , Machine Learning in Planning and Control of Robot Motion Workshop, October 2015 (conference)
Abstract
This paper proposes an automatic controller tuning framework based on linear optimal control combined with Bayesian optimization. With this framework, an initial set of controller gains is automatically improved according to a pre-defined performance objective evaluated from experimental data. The underlying Bayesian optimization algorithm is Entropy Search, which represents the latent objective as a Gaussian process and constructs an explicit belief over the location of the objective minimum. This is used to maximize the information gain from each experimental evaluation. Thus, this framework shall yield improved controllers with fewer evaluations compared to alternative approaches. A seven-degree-of-freedom robot arm balancing an inverted pole is used as the experimental demonstrator. Preliminary results of a low-dimensional tuning problem highlight the method’s potential for automatic controller tuning on robotic platforms.
This paper presents a convolutional layer that is able to process sparse input features. As an example, for image recognition problems this allows an efficient filtering of signals that do not lie on a dense grid (like pixel position), but of more general features (such as color values). The presented algorithm makes use of the permutohedral lattice data structure. The permutohedral lattice was introduced to efficiently implement a bilateral filter, a commonly used image processing operation. Its use allows for a generalization of the convolution type found in current (spatial) convolutional network architectures.
Deviations from rational decision-making due to limited computational resources have been studied in the field of bounded rationality, originally proposed by Herbert Simon. There have been a number of different approaches to model bounded rationality ranging from optimality principles to heuristics. Here we take an information-theoretic approach to bounded rationality, where information-processing costs are measured by the relative entropy between a posterior decision strategy and a given fixed prior strategy. In the case of multiple environments, it can be shown that there is an optimal prior rendering the bounded rationality problem equivalent to the rate distortion problem for lossy compression in information theory. Accordingly, the optimal prior and posterior strategies can be computed by the well-known Blahut-Arimoto algorithm which requires the computation of partition sums over all possible outcomes and cannot be applied straightforwardly to continuous problems. Here we derive a sampling-based alternative update rule for the adaptation of prior behaviors of decision-makers and we show convergence to the optimal prior predicted by rate distortion theory. Importantly, the update rule avoids typical infeasible operations such as the computation of partition sums. We show in simulations a proof of concept for discrete action and environment domains. This approach is not only interesting as a generic computational method, but might also provide a more realistic model of human decision-making processes occurring on a fast and a slow time scale.
In deterministic optimization, line searches are a standard tool ensuring stability and efficiency. Where only stochastic gradients are available, no direct equivalent has so far been formulated, because uncertain gradients do not allow for a strict sequence of decisions collapsing the search space. We construct a probabilistic line search by combining the structure of existing deterministic methods with notions from Bayesian optimization. Our method retains a Gaussian process surrogate of the univariate optimization objective, and uses a probabilistic belief over the Wolfe conditions to monitor the descent. The algorithm has very low computational cost, and no user-controlled parameters. Experiments show that it effectively removes the need to define a learning rate for stochastic gradient descent.
[You can find the matlab research code under `attachments' below. The zip-file contains a minimal working example. The docstring in probLineSearch.m contains additional information. A more polished implementation in C++ will be published here at a later point. For comments and questions about the code please write to mmahsereci@tue.mpg.de.]
Our goal is to understand the principles of Perception, Action and Learning in autonomous systems that successfully interact with complex environments and to use this understanding to design future systems | 2023-08-02T01:26:57.367551 | https://example.com/article/4638 |
Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis.
Alterations in the progesterone receptor (PR) are considered a risk factor for the development of endometriosis. In this study, the frequencies of the PROGINS and +331G/A polymorphisms of the PR gene were determined in deep infiltrating endometriosis and correlated with the expression of the PR protein. The frequencies of the PR polymorphisms were determined in women with deep infiltrating endometriosis (n = 72), women with adenomyosis in the uterine wall (n = 40), gynaecological patients without symptomatic endometriosis (n = 102) and healthy females (n = 93). Detection of +331G/A and PROGINS polymorphisms was performed using PCR-restriction fragment length polymorphism (RFLP) analysis. Expression of PR-A and PR-B protein was assessed with immunohistochemistry. The allelic frequency of the polymorphic allele +331A was lower in women with endometriosis (P < 0.01) and adenomyosis (P < 0.02) compared with healthy females. The frequency of the PROGINS polymorphism did not differ between the groups. The mean staining index (SI) for PR-B in endometriotic epithelium was higher in the presence of the +331A polymorphic allele (n = 2) (P < 0.001) compared with +331G/G individuals (n = 61). The PROGINS polymorphism did not affect the SI for PR-A and PR-B. The presence of the PR gene polymorphic allele +331A is associated with a reduced risk of deep infiltrating endometriosis and adenomyosis compared with healthy population controls. The PROGINS polymorphism does not seem to modify the risk of deep infiltrating endometriosis. | 2023-10-19T01:26:57.367551 | https://example.com/article/9955 |
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Classifications
C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
C07D301/04—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with air or molecular oxygen
C07D301/08—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with air or molecular oxygen in the gaseous phase
C07D301/10—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with air or molecular oxygen in the gaseous phase with catalysts containing silver or gold
B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
B01J37/02—Impregnation, coating or precipitation
B01J37/03—Precipitation; Co-precipitation
B01J37/031—Precipitation
B01J37/033—Using Hydrolysis
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
C07C45/32—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen
C07C45/33—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of CHx-moieties
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
C07C45/32—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen
C07C45/33—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of CHx-moieties
C07C45/34—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of CHx-moieties in unsaturated compounds
Abstract
The present invention provides hydro-oxidation catalysts for the oxidation of hydrocarbons, containing an organic-inorganic hybrid material as well as gold particles and/or silver particles, a process for the production thereof, and the use thereof as a catalyst.
Description
FIELD OF THE INVENTION
[0001]
The present invention provides hydro-oxidation catalysts, for the oxidation of hydrocarbons, containing an organic-inorganic hybrid material as well as gold particles and/or silver particles, a process for the production thereof, and methods of use thereof as a catalyst.
BACKGROUND OF THE INVENTION
[0002]
Akylene oxides such as propene oxide, for example, can be produced from alkenes such as propene. In this procedure, alkenes are reacted, in the presence of catalysts, with oxygen and with a reducing agent, e.g. hydrogen. This process is termed a hydro-oxidation process and the catalysts used therein are termed hydro-oxidation catalysts (abbreviated herein: HO catalysts).
[0003]
Purely inorganic catalysts that contain titanium and gold are known for the partial oxidation of hydrocarbons in the presence of oxygen and hydrogen. Catalysts of this type are disclosed, for example, in EP-A 0 709 360, EP-A 0 876 215, EP-A 0 827 779, WO 98/00414, WO 99/43431 and WO 99/52883.
[0004]
Such catalysts are mainly powdered catalysts produced by multi-stage processes. Suitable powdered support materials, which are generally based on silicon oxide, are impregnated with a titanium precursor, washed, dried and converted in a subsequent process step into insoluble gold hydroxides in the liquid phase by means of gold precipitation by deposition precipitation (soluble gold precursors are converted into insoluble gold hydroxides, by changing the pH from acidic to basic. This means that gold hydroxides are precipitated on the support surface) with gold precursors at a controlled pH.
[0005]
These so-called precursors are precursor compounds (salts and other compounds).
[0006]
The powdered material which contains the Ti and Au and which is obtained in this manner cannot yet be used in a fixed bed reactor without a molding step.
[0007]
Oxidation catalysts which contain noble metals and which are based on organic-inorganic hybrid materials, and a process of producing epoxides from olefins, oxygen and hydrogen using these oxidation catalysts, are known from WO 01/41921. Powdered catalysts are used. Organic-inorganic hybrid materials, which contain titanium are produced by a sol-gel process. The gold content of this hybrid process is imparted in a subsequent impregnation step. This impregnation is termed incipient wetness. Incipient wetness is an impregnation in which an accurately determined amount of solvent is used which corresponds to the pore volume of the support. This gives rise to a sponge effect, in which the support often remains dry on a macroscopic scale.
[0008]
Similar oxidation catalysts containing noble metals and which are based on organic-inorganic hybrid materials are described in DE-A 101 07 777, but differ from the systems described above in that noble metal particles are deposited on to the finished hybrid materials by spray-drying, namely in a subsequent step comprising a sol-gel process which includes gel work-up. Catalysts which range in size from powders to pellets are obtained (molding size <2 mm) depending on the process.
[0009]
DE-A 100 23 717 describes oxidation catalysts based on organic-inorganic hybrid materials which have a content of noble metals and which can be used for the production of epoxides from olefins. In a subsequent step, these powdered catalysts are formed into moldings, such as extrudates, granules, pellets, etc.
[0010]
As an alternative to the molding process described in DE-A 100 23 717 (conversion of organic-inorganic hybrid materials which contain gold and/or silver into moldings using binders, fillers and molding apparatuses such as extrusion presses, extruders, etc.), a route to HO catalysts is known in which an organic-inorganic hybrid material which does not contain noble metals is deposited on the inert moldings by impregnation, and the noble metal is deposited on the impregnated molding in a subsequent step.
[0011]
All the processes published heretofore have the disadvantage that the catalysts disclosed therein are produced by multi-stage syntheses, and are therefore associated with high manufacturing costs.
[0012]
For industrial processes, it is desirable to develop catalysts which achieve service lives of industrial interest, whilst exhibiting excellent selectivities and high productivities. Moreover, a pressure drop across the catalyst bed that is as low as possible is desirable. In order to produce catalysts on an industrial scale (a tonnage scale), the process steps for the preparation of the catalysts should be as reproducible and as simple as possible. To achieve an economic process, the cost of catalyst production should be very low.
The present invention further provides a process of producing these highly active catalysts.
[0015]
The present invention also provides a process of producing these highly active catalysts which is as reproducible as possible.
[0016]
The highly active catalysts of the present invention have a high mechanical strength.
[0017]
The present invention yet further provides a process of catalyst production, the cost of which is as low as possible. This is accomplished by having only a few preparation steps and the use of simple apparatus.
[0018]
The present invention still further provides a catalyst for the oxidation of hydrocarbons.
[0019]
The present invention greatly reduces or eliminates the disadvantages of known powdered catalysts (high pressure drop in tubular reactors, more rapid deactivation as a result of elevated local catalyst concentration).
[0020]
The present invention still further provides a technologically simple, gas phase hydro-oxidation process for the selective oxidation of hydrocarbons with a gaseous oxidizing agent and in the presence of a reducing agent on said catalysts, which results in high yields and low costs whilst achieving high catalyst productivities, very high selectivities and catalyst service lives of industrial interest.
DETAILED DESCRIPTION OF THE INVENTION
[0021]
The present invention will now be described for purposes of illustration and not limitation.
[0022]
The present invention provides a process for producing a catalyst comprising the provision of a support and impregnation of the support with an organic-inorganic hybrid sol which contains titanium and which contains gold and/or silver.
[0023]
The process may preferably include modifying the surface of the catalyst with silicon alkyl compounds, silicon aryl compounds and/or SiH compounds.
More preferably, the support is selected from the group consisting of alumina, silicon oxide, silicon carbide, carbon and a cordierite monolith.
[0026]
Most preferably, the support is α-alumina or silicon carbide.
[0027]
The process may also preferably include an annealing step at temperatures in the range from 100-1000° C., particularly from 200 to 600° C.
[0028]
The catalyst of the present invention comprises a support, an organic-inorganic hybrid material which is formed from the organic-inorganic hybrid sol, titanium in chemically bound form, and gold particles and/or silver particles.
[0029]
A preferred organic-inorganic hybrid material for the catalyst of the present invention is based on silicon oxide.
[0030]
In this respect, the organic-inorganic hybrid material may preferably contain terminal and/or bridging organic groups on the silicon atoms of the organic-inorganic hybrid material.
[0031]
The catalyst preferably contains gold and silver in the organic-inorganic hybrid material in an amount between 0.001 to 15% by weight.
[0032]
More preferably, the content of gold in the organic-inorganic hybrid material is 0.001-2% by weight.
[0033]
The catalyst may also preferably have a content of silver in the organic-inorganic hybrid material between 0.01-15% by weight.
[0034]
The catalyst preferably may contain gold particles that have a diameter less than 10 nm.
[0035]
Furthermore, in one embodiment of the present invention the catalyst that comprises other extraneous oxides (termed promoters).
[0036]
The method of the present invention also provides a process for the selective, partial oxidation of hydrocarbons in the presence of molecular oxygen and of a reducing agent, and in the presence of the catalyst according to the invention.
[0037]
One preferred process is a process of producing epoxides from alkenes in the presence of molecular oxygen and of a reducing agent and the catalyst according to the invention.
[0038]
The process in which the epoxide is propene oxide and the alkene is propene is preferred.
[0039]
The catalyst of the present invention preferably has titanium present as titanium oxide wherein the titanium oxide concentration is 0.1 to 10 mol % with respect to the amount of Si and Ti in the hybrid material.
[0040]
A process in which silicon hydride units are added during annealing is preferred.
[0041]
Hereinafter, the support is also termed a molding material. Catalysts according to the invention are hereinafter termed catalyst moldings.
[0042]
The catalyst moldings according to the invention, which contain organic-inorganic hybrid materials and gold and/or silver particles, have the advantage that moldings of high mechanical strength are obtained. The catalysts which are thus produced are hereinafter also termed hydro-oxidation catalysts (HO catalysts).
[0043]
Catalysts are described herein for the first time in which the generation of catalytically active titanium and gold species is achieved in a single process step.
[0044]
The catalysts of the present invention have longer catalyst lifetimes than the original powdered catalysts, whilst maintaining high selectivities and productivities. Moreover, the catalysts according to the invention enable very low pressure drops to be achieved in industrially relevant reactors, such as fixed bed reactors.
[0045]
HO catalysts are described herein for the first time in which the generation of catalytically active titanium and gold species is achieved in a single process step.
[0046]
The synthesis of these HO catalysts is surprising, because the gold clusters in the catalyst synthesis according to the invention do not agglomerate to form large, catalytically inactive gold particles.
[0047]
Further, according to the present invention the simultaneous synthesis of the correct Ti and Au species is effected for the first time on moldings which—optionally after thermal treatment—can be used directly in reactors (e.g. fixed bed reactors). It is thus possible to fulfill the requirement for HO catalysts by efficiently providing catalytically active Ti and Au species on suitable moldings in one process step.
[0048]
The HO catalysts according to the invention enjoy a considerable economic advantage compared with prior catalysts. Moreover, the systems according to the invention provide a considerably longer catalyst lifetime than that of conventional HO catalysts.
[0049]
The possibility, for the first-time, of depositing all the requisite HO species by single or multiple impregnation (e.g. spray impregnation, liquid phase impregnation, incipient wetness, etc) on all possible surfaces opens up diverse new OH catalysis reaction routes. Thus not only can palletized, inert moldings for fixed bed reactors be impregnated with HO species, but large surfaces can also be impregnated, such as those of monoliths for example.
[0050]
The Organic-Inorganic Gels are Described Below.
[0051]
Organic-inorganic hybrid materials as used in the description of the present invention are organically modified glasses based on silicon oxide, which are preferably produced in sol-gel processes by hydrolysis and condensation reactions of what are generally compounds of low molecular weight, and which contain terminal and/or bridging organic groups—preferably silicon organosilicon groups—in their network, and which advantageously contain free silicon hydride units. These are described in Assignee's copending US applications, Ser. No. 10/149,056 and Ser. No. 10/019,997, which are hereby incorporated in their entireties in the present application by reference.
[0052]
The catalytically active organic-inorganic hybrid materials which contain titanium and noble metals, and which are subsequently deposited on moldings, preferably contain, with respect to silicon oxide as the base component of the hybrid material, between 0.1 and 20 mol % titanium, preferably between 0.5 and 10 mol %, most preferably between 0.8 and 7 mol %. The titanium is preferably present in the form of an oxide and is preferably chemically incorporated or bonded in the silicon oxide lattice via Si—O—Ti and Si—O—Si bonds. Active catalysts of this type only comprise subordinate Ti—O—Ti domains.
[0053]
It is assumed that in active catalysts based on organic-inorganic hybrid materials, titanium is bonded to silicon via heterosiloxane bonds.
[0054]
Apart from titanium, the catalysts can also contain other extraneous oxides, which are termed promoters, namely those of Group 1 of the IUPAC Periodic Table (1985), such as sodium, potassium and caesium, of Group 2, preferably magnesium and calcium, of Group 5, such as vanadium, niobium and tantalum, preferably tantalum, of Group 6, preferably molybdenum and tungsten, of Group 3, preferably yttrium, of Group 4, preferably zirconium, of Group 8, preferably iron, of Group 9, preferably iridium, of Group 12, preferably zinc, of Group 15, preferably antimony, of Group 13, preferably aluminium, boron, thallium, and metals of Group 14, preferably germanium.
[0055]
The promoters, hereinafter denoted by M, are generally present in dispersed form in the organic-inorganic hybrid material. The chemical composition of these materials can be varied over wide ranges. The proportion of the promoter element with respect to silicon oxide preferably falls within the range from 0 to 10 mol %, more preferably 0 to 3 mol %. As those skilled in the art will appreciate, a plurality of different promoters can also be used. The promoters are preferably used in the form of promoter precursor compounds that are soluble in the respective solvent, such as promoter salts and/or organic promoter compounds and/or organic-inorganic promoter compounds.
[0056]
These promoters are capable of increasing both the catalytic activity of the organic-inorganic hybrid materials and the service life of the organic-inorganic hybrid materials in catalytic oxidation reactions of hydrocarbons.
[0057]
If these promoters are incorporated in or added to organic-inorganic hybrid materials which do not contain titanium oxide species, compositions are obtained after thermal activation which exhibit either no catalytic activity or a catalytic activity which is less than that of systems which contain titanium.
[0058]
The organic-inorganic hybrid materials which contain titanium can be produced either by impregnating an organic-inorganic silicon oxide matrix with a titanium precursor compound, or, preferably, via sol-gel processes. Sol gel production is effected, for example, by mixing suitable compounds, which are usually of low molecular weight, after which the hydrolysis and condensation reaction is initiated by adding water and optionally catalysts (e.g. acids, bases and/or organometallic compounds, electrolytes and/or ultrasound). Conducting sol-gel processes such as these is known in principle to one skilled in the art (L. C. Klein, Ann. Rev. Mar. Sci., 15 (1985) page 227, and S. J. Teichner, G. A. Nicolaon, M. A. Vicarini and G. E. E. Garses, Adv. Colloid Interface Sci., 5 (1976) page 245).
[0059]
The HO catalysts according to the invention preferably contain the following components on a suitable support: gold and/or silver particles and organic-inorganic hybrid materials that contain Ti and which optionally comprise Si—H groups. In their thermally treated state, the active components can be approximately described by the following empirical formula (I) (radicals formed after modification on the surface and any incompletely reacted groups are not taken into consideration here):
With respect to silicon oxide, the proportion of Org in mol percent can range between 0 and 200%. It is preferably between 1 and 200%, more preferably between 10 and 100%. The molar proportion of Si—H units with respect to silicon oxide can vary between 0 and 100 mol %. The proportion preferably ranges between 0.001 and 50%, more preferably between 0.001 and 20 mol %. The proportion of titanium oxide with respect to silicon oxide preferably ranges between 0.1 and 10 mol %, more preferably between 0.5 and 8.0%, most preferably between 0.5 and 7.0%. The proportion of MO with respect to silicon oxide preferably ranges between 0 and 12 mol %. The proportion of E with respect to the gold- and/or silver-free active component composition preferably ranges between 0.001 and 15% by weight. For gold it is preferably between 0.001 and 2% by weight, and for silver it is preferably between 0.01 and 15% by weight.
[0063]
Suitable precursor compounds for silicon, titanium and promoter species are mixed organic-inorganic compounds that are advantageously suitable for the sol-gel process, or are a combination of corresponding mixed inorganic and organic-inorganic compounds. As used in the description of the present invention, the term “low molecular weight” refers to monomeric or oligomeric compounds. Polymeric precursor compounds of silicon, titanium and promoters are also suitable if they are sufficiently soluble.
[0064]
The sol-gel process is based on the polycondensation of hydrolyzed, colloidally dissolved mixed metal components (sol) to form a network (gel).
[0065]
Hydrolysis is effected by mixing hydrolyzable silicon and titanium precursor compounds, optionally diluted in a solvent, with water (simultaneously or in succession). Because under normal conditions the hydrolysis of silicon precursor compounds is slow, catalysts are generally required so that it proceeds more rapidly and completely (J. Livage et al., Chemistry of Advanced Materials: An Overview Edited by: L. V. Interrante et al., VCH, New York, 1998, pages 389-448). The resulting silanols condense to form siloxane compounds. Dissolved polysiloxane networks are thus formed. Branching and crosslinking continue until the polymer is large enough for the gel transition to occur. The gel firstly consists of a solid polymer network that is permeated by a solvent. If the solvent is an alcohol, what are termed alcogels are formed. After ageing, the compositions according to the invention can be dried to form either xerogels, aerogels or cryogels. During drying, e.g. of alcogels, the network shrinks with loss of the solvent, whereupon a xerogel is formed. If the gel is dried under supercritical conditions (“High-Temperature Supercritical Drying” or “Low-Temperature Supercritical Drying”), the resulting network product is termed an aerogel (A. Baiker et al., Catal. Rev. Sci. Eng. 1995, 37, pages 515-556); cryogels are obtained when drying is effected by freeze-drying.
[0066]
The preferred solvents for the sol-gel process are alcohols such as isopropanol, butanol, t-butanol, ethanol or methanol, ketones such as acetone, and ethers such as THF or tert.-butyl methyl ether, for example.
[0067]
Suitable starting materials include all the soluble silicon and titanium compounds that are known to those skilled in the art and which can be employed as a starting material for the corresponding oxides or hydroxides. Silicon and titanium compounds of formula (II) are preferably used:
In the organically modified silanes, one or more hydrolyzable groups may be replaced by terminal and/or bridged, saturated (e.g. CH3, C2H5, C3H7, . . . ) or unsaturated (e.g. C2H3, C6H5) R group(s). Mixtures of different organically modified silanes or mixtures of organically modified silanes with purely inorganic silicon network formers, such as tetraalkoxysilanes, can also advantageously be used. Polyfunctional organosilanes, e.g. polysilsesquioxanes (polymethylsilsesquioxanes, polyvinylsilsesquioxanes, . . . ) silanols and alkoxides, can also be used. Silanes, which are optionally organically modified, can also be reacted in the presence of di- or polyhydric alcohols such as 1,4-butanediol, to form organically modified polysiloxanes. In the present invention, bridged R groups (alkylene radicals) are bridged structures such as chain-like, star-shaped (branched), cage-like or ring-like structural elements. “Alkyl” is to be understood to represent all terminal and/or bridged, linear or branched alkyl radicals comprising 1 to 12 carbon atoms which are known to those skilled in the art, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, hexyl and other homologes, which themselves can be further substituted. Suitable substituents include halogens, nitro, alkyl, hydroxide or alkoxy, as well as cycloalkyl or aryl, such as benzoyl, tris-methylphenyl, ethylphenyl, chloromethyl, chloroethyl and nitromethyl. Nonpolar substituents are preferably used, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and benzoyl.
[0072]
Higher molecular weight and/or oligomeric organic-inorganic silicon and titanium precursors are also suitable, such as gamma-glycidoxypropyltrimethoxysilane, 3,4-epoxycyclohexyl-ethyl-trimethoxysilane, 1-(triethoxysilyl)-2-(diethoxymethylsilyl)-ethane, tris(gamma)-trimethoxypropylsilyl isocyanurate, peralkylated cyclosiloxanes such as hexamethylcyclotrisiloxane, octamethyltetrasiloxane or decamethylpentasiloxane. Polyalkyl(aryl)siloxanes such as polydimethylsiloxane are also suitable.
[0073]
“Aryl” is to be understood to include all mono- or polynuclear radicals comprising 6 to 12 carbon atoms which are known to those skilled in the art, such as phenyl, naphthyl or fluorenyl, which themselves may be substituted. Suitable substituents here include a halogen, nitro, alkyl or alkoxyl, as well as cycloalkyl or aryl, such as bromophenyl, chlorophenyl, toloyl and nitrophenyl. Phenyl, fluorenyl, bromophenyl, chlorophenyl, toloyl and nitrophenyl are preferred.
[0074]
Even though salts such as halides, nitrates and hydroxides can be used, the alkoxides of these elements are preferred, e.g. the n-butoxides, t-butoxides, isopropoxides, n-propoxides, ethoxides and methoxides thereof.
[0075]
The titanium derivatives which are preferably used are those such as tetralkoxytitanates comprising C1-C12 alkyl groups such as iso-butyl, tert-butyl, n-butyl, i-propyl, n-propyl, ethyl, etc., or titanium alkoxy complexes such as those described in U.S. Pat. No. 6,090,961, e.g. (η5-tetramethylcyclopentadienyl)3-tert-butyl-5-methyl-2-phenoxy)-dimethylsilyl titanium dimethoxides, other organic titanium species such as titanium acetylacetonate, Ti(OSiPh3)4, dicyclopentadienyltitanium dihalides, titanium dihalogenodialkoxides, titanium halogenotrialkoxides, or titanium siloxanes such as diethoxysiloxane-ethyl titanate copolymer (available commercially from Gelest Inc). Chlorine is the preferred halogen substituent. Mixed alkoxides of titanium with other elements such as titanium triisopropoxide-tri-n-butyltin oxide can also be used. The titanium precursor compounds can also be used in the presence of complex-forming components such as acetylacetone or ethyl acetoacetate, for example.
[0076]
The organic-inorganic silicon and titanium precursor compounds can also be used in combination with inorganic network formers such as tetraethoxysilane (Si(OC2H5)4), tetramethoxysilane (Si(OCH3)4) or homologues thereof. Instead of monomeric alkoxides, condensation products thereof can also be used. Examples of the latter which are available commercially include Si(OC2H5)4 condensates, for example. Moreover, oligomeric or polymeric systems such as poly(diethoxysiloxane) can be used.
[0077]
The aforementioned silicon and titanium precursor compounds are reacted in a sol-gel process, preferably in combination with silanes, and contain silicon hydride units. Most silanes that contain silicon hydrides can be represented by formulae (IIIa) or (IIIb):
[RxSiHy(OR′)4−(x+y)] (IIIa)
[RxSiHy(Hal)4−(x+y)] (IIIb),
[0078]
wherein
[0079]
R and R′ independently represent C1-C12 alkyl and C6-C12 aryl, where x=0, 1, 2 or 3 and y=1, 2 or 3, and where R′ and R can also represent H.
[0080]
The silanes containing Si-H can also be generated in situ, e.g. from halosilanes in the presence of reducing agents such as magnesium hydride.
[0081]
The compounds of formulae (IIIa) and (IIIb) can be replaced, wholly or in part, by other silicon precursor compounds comprising proportions of Si-H units, such as 1,1,3,3-tetramethyidisiloxane, 1,3,5,7-tetramethylcyclotetrasiloxane, tri-n-hexylsilane or triphenylsilane.
Apart from low molecular weight precursors, oligomeric and polymeric precursors which contain silicon hydride can also be used, such as poly(methylhydrosiloxanes).
[0084]
The preferred trialkoxysilanes are those which comprise C1-C12 groups, such as trimethoxysilane, triethoxysilane, triisopropoxysilane, tripropoxysilane, triisopropoxysilane, tributoxysilane, and those which comprise oligomeric or polymeric SiH components, such as poly(methylhydrosiloxane).
[0085]
The sequence of operations during sol-gel synthesis is not fixed. The HO catalysts according to the invention are generated, for example, by the simultaneous hydrolysis and/or condensation of Si and Ti precursors or by the complete or partial reaction of silicon precursor compounds with water or with catalytic amounts of water and subsequent addition of the corresponding Ti compounds.
[0086]
In one embodiment of the present invention, the organic-inorganic silicon precursor compound is placed in a vessel, is initially or completely hydrolyzed with water with the addition of a catalyst, and the Ti precursor compound is subsequently added. The addition of silanes comprising free silane-hydride units is likewise not a fixed procedure. The SiH species can be added either before or after the addition of Ti.
[0087]
According to the invention, gel formation is effected directly on the support surface. One or more treatments of the moist and/or already dried gel with an excess of water or water vapor can optionally be effected in order to complete the hydrolysis and condensation reactions.
[0088]
The subsequent treatment of the “gel on support” system is not fixed. It can be dried (e.g. at 20-150° C. in an air current or in other atmospheres) and then annealed (150 to 450° C. in air, N2, H2, or in other atmospheres). The freshly impregnated molding can also be annealed directly, without drying.
[0089]
The hydrophobic character of the organic-inorganic hybrid materials according to the invention is essentially determined by the number and type of terminal and bridging Si—C bonds. Compared with other organic bonds, such as Si—O—C bonds for example, terminal and bridging Si—C bonds have the additional advantage of being substantially chemically inert, i.e. are insensitive to hydrolysis and oxidation reactions.
[0090]
The Noble Metals (Gold and/or Silver) are Described Below.
[0091]
In addition to the Si, Ti and possible promoter species, the HO catalysts according to the invention additionally contain noble metal clusters.
[0092]
The noble metals are added in the form of precursor compounds, such as salts, organic complexes or compounds, or as colloids, preferably during the sol-gel process. Alternatively, sol-gel-modified moldings can also be covered in a previous or subsequent step with noble metal clusters (e.g. by precipitation, impregnation in solution, incipient wetness, spray drying, sputtering, colloids, CVD).
[0093]
The noble metals are preferably gold and/or silver. In their catalytically active form, the moldings contain gold and/or silver particles which mainly have a particle size of <15 nm. In their catalytically active state, the gold and/or silver mainly exist as the elemental metals (analysis by X-ray absorption spectroscopy). Small proportions of gold and/or silver can also be present in a higher oxidation state. The gold and silver are preferably present as gold and/or silver clusters on a nanometer scale.
[0094]
The gold particles preferably have a diameter within the range from 0.5 to 50 nm, more preferably 0.8 to 15 nm, and most preferably 0.8 to 10 nm.
[0095]
The silver particles preferably have a diameter within the range from 0.5 to 100 nm, more preferably 0.5 to 40 nm, and most preferably 0.5 to 20 nm.
[0096]
It has been found that the selective hydro-oxidation reaction described above is very sensitive to the structure of the catalyst. In the presence of nano-dispersed gold and/or silver particles in or on HO catalyst moldings, an advantageous increase in productivity to form the selective oxidation product has been observed.
[0097]
With respect to the solid formed from the sol after hydrolysis/condensation/annealing, the gold concentration in the sol which contains silicon and titanium and with which the support is treated is preferably within the range from 0.001 to 2% by weight, preferably 0.001 to 1.5% by weight, and more preferably 0.005-1.0% by weight.
[0098]
The silver concentration should fall within the range from 0.005 to 20% by weight, preferably 0.01 to 15% by weight, and more preferably from 0.1 to 10% by weight of silver.
[0099]
For economic reasons, the noble metal content should be the minimum required to prolong the maximum catalyst activity.
[0100]
The production of the noble metal particles in the organic-inorganic hybrid sol that contains silicon and titanium or on the molding which is treated with the hybrid sol that contains noble metals is not restricted to one method.
[0101]
The catalytically active noble metal clusters can be generated either by reducing agents and/or by thermal treatment.
[0102]
Nano-scale gold particles may preferably be produced by thermal treatment in the presence of reducing agents.
[0103]
Nano-scale silver particles may preferably be produced by thermal treatment in the presence of reducing agents.
[0104]
It has surprisingly been found that the organic-inorganic hybrid materials which contain proportions of hydrogen silanes are particularly suitable for depositing metals such as gold and silver, with a high degree of dispersion, on external and internal surfaces. Ultrafine metal particles are generated in the course of this procedure.
[0105]
In contrast, on purely inorganic silica or SiO2—TiO2 mixed oxide surfaces (analogous to WO98/00415, WO-98/00414, WO-98/00413, EP-A 0 827 779), i.e. without organic modification and/or without proportions of hydrogen silanes, it is possible to synthesize nano-scale metal particles with a very narrow particle size distribution, but in a much less selective manner.
[0106]
The Impregnation of the Support with the Sol is Described Below.
[0107]
The methods by which the organic-inorganic hybrid sol with a content of noble metal precursors and/or noble metal colloids are deposited on suitable supports are not subject to any restrictions.
[0108]
Different catalysts can be produced depending on the method selected.
[0109]
Impregnating the support in a liquid phase often results in moldings which are impregnated homogeneously. Using dip coating (immersion) or spray impregnation, systems can be generated which cover the entire range from homogeneously impregnated to those comprising shell-like impregnation.
[0110]
The type of HO catalysts is also essentially determined by the viscosity of the hybrid sol which contains noble metals. In addition to the amount of solvent, the viscosity is also affected by the ageing of the sol-gel. A liquid, low-viscosity sol-gel system is preferably deposited on the molding.
[0111]
Impregnation of the molding with the hybrid sol can be effected as a single- or multi-stage process.
[0112]
The amount of hybrid sol on the support is not fixed. In many cases, the proportion of active ingredient after annealing ranges from 1 to 80%, preferably 1 to 60%, most preferably 3 to 30%.
[0113]
The further processing of the impregnated molding is not fixed. Excess hybrid sol can be removed or gelled by a plurality of routes, e.g. by drying, by vacuum treatment, in a centrifuge, in an air current, or by similar routes.
[0114]
Impregnation of the moldings with the hybrid sol can be conducted not only in a single step, i.e. using hybrid sols containing noble metals, but can also be conducted in two steps, by firstly impregnating the moldings with HO hybrid sols which are free from noble metals and subsequently covering them with noble metals or noble metal precursors, or vice versa.
[0115]
The catalytic activity of the HO catalysts according to the invention is often increased by subsequent thermal treatment.
[0116]
The Annealing Procedure is Described Below.
[0117]
The HO catalysts according to the invention are advantageously activated, before and/or after impregnation or immersion with the hybrid sols containing noble metals, by thermal treatment at temperatures within the range from 100-1000° C. in different atmospheres such as air, nitrogen, hydrogen, carbon monoxide or carbon dioxide.
[0118]
Thermal activation is preferably effected at temperatures within the range from 150-400° C. in gases which contain oxygen, such as air, oxygen-hydrogen or oxygen-inert gas mixtures or combinations thereof, or at temperatures within the range from 150-1000° C. under inert gases such as nitrogen and/or hydrogen and/or inert gases or combinations thereof. Activation of the organic-inorganic hybrid materials is most preferably effected under inert gases within the temperature range from 200-600° C.
[0119]
It may also be advantageous, however, to impregnate the moldings with hybrid sols which are free from noble metals, to anneal them at temperatures within the range from 200-1000° C. and subsequently to cover them with noble metal. The thermally activated (annealed) catalysts often exhibit a significantly higher catalytic activity and a prolonged service life compared with known catalysts.
[0120]
The Supports are Described Below.
[0121]
The selection of the support for the synthesis of the HO catalyst moldings is subject to no particular restriction as regards material, particle size, mechanical strength, size of surface, pore structure, absorption capacity, chemical inertness, etc., provided that it is possible effectively to impregnate said sols with the HO hybrid sols which contain noble metals, and provided that the support used does not give rise to secondary or subsequent reactions of the desired products.
[0122]
The preferred supports are mechanically stable, chemically inert, commercially available in industrial quantities and inexpensive. Particulate supports are particularly advantageous, and are used in the form of spheres, cylinders, hollow cylinders, saddles, extrudates, hollow extrudates, granules or rods, for example.
[0123]
Particulate catalyst moldings can be used in the form of a fixed bed of loose material or in the form of a fluidized bed. Instead of being deposited on a particulate support, the hybrid sol that contains noble metals can be deposited on monolithic support systems, for example. Examples thereof include ceramic honeycomb bodies (such as cordierite honeycomb bodies), ceramic sponges, knitted fabrics, etc.
[0124]
The particle size depends on how the reaction is conducted, e.g. in a fixed bed or fluidized bed, on the quantitative throughput, and on the type and size of the reactor. If a fixed bed reactor is used, a low pressure drop, good heat transfer and a low diffusion barrier are attained for moldings of sizes 2-10 mm. In fluidized bed processes, mechanically stable supports with a narrow particle size distribution of 50-300 μm are preferred.
[0125]
All materials that form mechanically stable moldings and which are inert or which only exhibit a slight activity with regard to gas phase oxidation can be used as supports. Suitable examples include oxides of aluminium (α-, γ-, etc.), silicon and zirconium. Carbon in various states, such as activated carbon, carbon black or graphite, can also be used. Carbides such as silicon carbide, or nitrides such as silicon nitride, are also suitable. Glasses and metals of all types can also be used.
[0126]
In principle, there is no restriction on the size and type of the surface of these moldings. The specific surface is advantageously 0.01-1000 m2/g, more advantageously 0.01-200 m2/g and most advantageously 0.01-100 m2/g.
[0127]
The pore structure can be micro-, meso- and/or macroporous. Both amorphous and crystalline molding systems can be selected.
[0128]
In some situations, particularly in order to achieve isothermal reaction conditions, it may be advantageous if the catalyst material is diluted uniformly or in layers with an inert or low-activity molding material. There is no restriction on the choice of dilution materials such as these. Examples include oxides of silicon, aluminum, zirconium, and materials made of glass such as coarse powder, spheres, etc. Silicates, ceramics, carbon and mineral particles are also suitable. By conducting the reaction isothermally, hot spots are often reduced, which has a favorable effect on the service life of the catalysts according to the invention. Moldings that have good thermal conductivities, such as graphite, carbon black and silicon carbide, for example, also reduce hot spots.
[0129]
The Modification of the Catalyst Surface is Described Below.
[0130]
The catalytic activity of the catalysts according to the invention can often be increased by modifying the surface.
[0131]
In the present invention, modification is to be understood in particular as the provision of groups selected from silicon-alkyl, silicon-aryl, silicon hydride, or alkyl or aryl groups which contain fluorine, on the surface of the supported composition, wherein these groups are often covalently or coordinately bonded to the functional groups (e.g. OH groups) on the surface. Any other surface treatment is also expressly included in the scope of the invention, however.
[0132]
The catalyst surface can be modified in many ways. The moldings can be modified either before impregnation with HO-active components or after impregnation. In some situations, modification before impregnation is preferred.
Suitable organosilicon compounds include all silylating agents which are known to those skilled in the art, such as organic silanes, organic silylamines, organic silylamides and derivatives thereof, organic silazanes, organic siloxanes and other organosilicon compounds, which of course can also be used in combination. The term “organosilicon compounds” also expressly includes compounds of silicon and partially fluorinated or perfluorinated organic radicals.
The HO catalyst moldings are preferably used in gas phase reactions for the partial oxidation of hydrocarbons in the presence of oxygen and hydrogen.
[0144]
The process parameters for this hydro-oxidation reaction can be varied over wide ranges.
[0145]
The catalyst moldings according to the invention are employed in particular at temperatures of 100 to 300° C., preferably 140 to 270° C. and more preferably 160 to 250° C.
[0146]
For gas phase reactions, it is often advantageous for economic reasons and for reasons relating to the construction of the apparatus to operate under elevated reaction pressures. The contact catalysts according to the invention exhibit particularly high catalytic activities over the pressure range from normal pressure to 70 bar. A pressure level of 2 to 50 bar is preferred, more preferably from 3 to 30 bar.
[0147]
The residence time can also be varied over a wide range. The residence time is advantageously <70 seconds. The HO catalyst moldings exhibit particularly high catalytic activities at residence times <20 sec, for example at 0.001 to 10 seconds. The present invention also expressly relates to extremely short residence times of the order of milliseconds (<0.001 seconds).
[0148]
The amount of feed gas or circulating gas, and thus the catalyst loading, is not fixed. In particular, the catalyst loading ranges from 1 to >1000 1 gas/(g active substance×h), preferably from 4 to 600 1 gas/(g catalyst×h), more preferably from 10-500 1 gas/(g active substance×h). The present invention likewise expressly relates to extremely high catalyst loadings, often associated with short catalyst contact times.
[0149]
The Feed Composition is Described Below.
[0150]
HO catalyst moldings are preferably used in gas phase reactions for the partial oxidation of hydrocarbons in the presence of oxygen and hydrogen.
[0151]
In reactions such as these, epoxides are obtained selectively from olefins, ketones are selectively obtained from saturated secondary hydrocarbons, and alcohols are selectively obtained from saturated tertiary hydrocarbons.
[0152]
The term “hydrocarbon” is to be understood to include unsaturated or saturated hydrocarbons such as olefins or alkanes which may also contain heteroatoms such as N, O, P, S or halogens. The organic component to be oxidized can be acyclic, monocyclic, bicyclic or polycyclic and can be monoolefinic, diolefinic or polyolefinic. In organic components that contain two or more double bonds, the double bonds may be conjugated or unconjugated. The hydrocarbons which are preferably oxidized are those from which oxidation products are formed at a partial pressure which is low enough for the product to be continuously removed from the catalyst. Unsaturated and saturated hydrocarbons are preferred which contain 2 to 20, preferably 2 to 10 carbon atoms, particularly ethene, ethane, propene, propane, isobutane, isobutylene, 1-butene, 2-butene, cis-2-butene, trans-2-butene, 1,3-butadiene, pentene, pentane, 1-hexene, 1-hexane, hexadiene, cyclohexene and benzene.
[0153]
The molar amount of hydrocarbon used with respect to the total number of moles of hydrocarbon, oxygen, hydrogen and dilution gas, as well as the relative molar ratios of the components, can be varied over wide ranges. An excess of hydrocarbon is preferably used with respect to the oxygen used (on a molar basis). The hydrocarbon content is typically greater than 1 mol % and less than 80 mol %. Hydrocarbon contents within the range from 4 to 90 mol % are preferably used, and are more preferably within the range from 8 to 70 mol %.
[0154]
Oxygen can be used in very different forms, such as molecular oxygen, air, nitrogen oxide or hydrogen peroxide. Molecular oxygen is preferred.
[0155]
The mole fraction of oxygen with respect to the total number of moles of hydrocarbon, oxygen, hydrogen and dilution gas can be varied over a wide range. Oxygen is preferably used in a molar deficit with respect to the hydrocarbon. Oxygen is preferably used within the range of 1-30% oxygen by volume, more preferably 5-25% oxygen by volume.
[0156]
In the absence of hydrogen, the moldings according to the invention only exhibit a slight activity and selectivity. In general, the productivity in the absence of hydrogen is low up to 180° C. At temperatures above 200° C., larger amounts of carbon dioxide are formed in addition to partial oxidation products.
[0157]
Any known source of hydrogen can be used, such as pure hydrogen, cracker hydrogen, synthesis gas or hydrogen from the dehydrogenation of hydrocarbons and alcohols. In another embodiment of the invention, the hydrogen can also be produced in situ in an upstream reactor, e.g. by the dehydrogenation of propane or isobutane or of alcohols such as methanol or isobutanol. Hydrogen can also be introduced into the reaction system as a complex-bonded species, e.g. as a catalyst-hydrogen complex.
[0158]
The mole fraction of hydrogen with respect to the total number of moles of hydrocarbon, oxygen, hydrogen and dilution gas, can be varied over a very wide range. Typical hydrogen contents are greater than 0.1% by volume, preferably within the range from 4-80% by volume, more preferably within the range from 5-75% by volume.
[0159]
A dilution gas such as nitrogen, helium, argon, methane, carbon dioxide, carbon monoxide, or similar gases that mainly exhibit inert behavior, can also optionally be used in addition to the essential gaseous starting materials described above. Mixtures of the inert components described above can also be used. Other inert hydrocarbons, such as fluorinated hydrocarbons (hexafluorethane, CF4, etc.) can also be used as components for diluting the feed or circulating gas. The addition of an inert component has a favorable effect on the transport of the heat evolved from the exothermic oxidation reaction and is often desirable for reasons of safety.
[0160]
If the process according to the invention is conducted in the gas phase, gaseous dilution components such as nitrogen, helium, argon, etc. are preferably used.
[0161]
When the invention is carried out in a liquid phase, an inert liquid which is stable to oxidation and which is thermally stable is advisedly used (e.g. alcohols, polyalcohols, polyethers, halogenated hydrocarbons, silicone oils).
[0162]
The catalysts according to the invention are also suitable for the oxidation of hydrocarbons in the liquid phase. For example, olefins are converted to epoxides in a highly selective manner on the catalysts described above in the liquid phase, either in the presence of organic hydroperoxides, in the presence of hydrogen peroxide, or in the presence of oxygen and hydrogen.
[0163]
It has surprisingly been found, compared with all the HO catalyst systems which were known hitherto for the catalytic partial oxidation of unsaturated and saturated hydrocarbons, that the catalysts according to the invention often exhibit a catalytic activity and a catalyst service life which are higher by several orders of magnitude.
[0164]
The catalysts according to the invention can be produced inexpensively on an industrial scale, without process technology problems.
[0165]
Catalysts which may have become slightly deactivated after months of use can often be regenerated either thermally or by washing them with suitable solvents such as alcohols or water, or by treating them with hot steam or dilute hydrogen peroxide solutions (e.g. a 3-10% solution of H2O2 in methanol).
[0166]
The present invention is illustrated by the examples given below. The present invention is not limited to these examples.
EXAMPLES
[0167]
Procedure for Testing HO Catalyst Moldings (Test Procedure)
[0168]
A metal tube reactor was used which had an inside diameter of 10 mm and a length of 20 cm, and which was heated at a controlled temperature by means of a thermostat. The reactor was supplied with the gaseous starting materials (propene, oxygen, hydrogen) by a set of three mass flow controllers.
[0169]
The reactor contained a HO catalyst molding (containing 0.5 g of a catalytically active HO component) at 180° C. and 2 bar pressure. The gaseous starting materials were metered into the reactor from above. The standard catalyst loading was 5 liters of gas per gram of HO molding per hour.
[0170]
A gas stream of the following composition (hereinafter called the standard gas composition) was used for carrying out oxidation reactions:
[0171]
H2/O2/propene: 60/10/30% by volume.
[0172]
The reaction gases were quantitatively analyzed by gas chromatography. Separation by gas chromatography of the individual reaction products was effected by a combined FID/TCD method in which the gas flowed through three capillary columns:
13.3 g methyltrimethoxysilane (98.1 mmol), 0.33 g triethoxysilane (2 mmol) and 1.15 g tetrapropoxy-titanium (4 mmol), dissolved in 7 g ethanol (absolute, analytical quality), were placed in a vessel, mixed with 2.9 g of an 0.1 N solution of p-toluenesulphonic acid in water and the mixture was stirred for 10 min. 2 g of a 1% solution of gold (HAuCl4×3H2O in ethanol) were then added with stirring.
This preparation was effected analogously to the preparation of hybrid sol-gel 1, except that 2 g of a 2% gold solution (HAuCl4×3H2O in ethanol) were used.
[0187]
Molding Impregnation; Variant 1:
[0188]
Preparation of an HO catalyst molding by impregnating commercially available moldings with a hybrid sol-gel solution by dip coating.
[0189]
The hybrid-sol-gel was in placed in a 100 ml glass beaker. 15 g moldings—pelletised moldings were placed in a sieve with a mesh aperture of 0.5 mm—were immersed for 30 seconds in a hybrid sol-gel solution, excess sol-gel was removed in a centrifuge (when monoliths were used, excess sol-gel was removed by means of compressed air), dried for 1 hour at room temperature and subsequently annealed for 4 hours at 400° C. under nitrogen. The molding contained about 3% by weight of HO-active components.
[0190]
To test the HO catalyst moldings by the procedure given above, 16 g of the catalyst moldings obtained in this manner, corresponding to about 0.5 g of HO-active substance, were used as a fixed bed catalyst.
[0191]
Molding Impregnation; Variant 2:
[0192]
Preparation of a HO catalyst molding by spray-impregnating commercially available moldings with a HO hybrid sol-gel solution.
[0193]
15 g of palletized moldings were placed in a drum (made of a plastics material, 15 cm diameter, inclined at 300, 50 rpm). The hybrid sol-gel solution was sprayed on to the rotating molding particles by means of a fine nozzle. After drying for 1 hour at 25° C., the material was annealed for 4 hours at 400° C. under nitrogen. The molding contained about 3% by weight of HO-active components.
[0194]
In order to test the HO catalyst moldings by the procedure given above, 16 g of the catalyst moldings obtained in this manner, corresponding to about 0.5 g of HO-active substance, were used as a fixed bed catalyst.
[0195]
The following Table gives the results obtained using the catalysts according to the invention (no comparative tests are given in the Table). (The supports were supplied by Condea, of Hamburg)
Productivity
Hybrid
Molding
gPO/(kgWS*
Ex.
sol-gel
impregnation
× h) after
No.
Moldings
method
method
PO selectivity [%]
48 h
7 days
1
α-A12O3 spheres,
1
1
95
200
183
2 mm spheres,
supplied by Condea,
Batch No. TKA 306
2
α-A12O3 spheres,
1
2
95
250
230
2 mm spheres,
supplied by Condea,
Batch No. TKA 306
3
α-A12O3 spheres,
2
2
95
265
250
2 mm spheres,
supplied by Condea,
Batch No. TKA 306
4
α-A12O3
1
2
95
185
170
hollow extrudate,
3-4 mm extrudate,
supplied by Condea,
Batch No. M908
6
α-Al2O3 spheres,
1
2
95
140
120
2-4 mm spheres,
supplied by
Procatalyse,
Description
SPH 512,
7
α-Al2O3 spheres,
3
2
95
180
140
2-4 mm spheres,
supplied by
Procatalyse,
Type SPH 512
8
SiC spheres,
1
2
96
230
220
3 mm spheres,
supplied by Norton,
Type XC 69374
9
SiC spheres, 3 mm
2
2
96
240
220
spheres,
supplied by Norton,
Type XC 69374
10
Cordierite honeycomb
3
1
96
200
190
body,
supplied by Dow
Corning
11
Metal wire grid rings,
1
1
95
150
145
4 mm
[0196]
Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
Claims (20)
What is claimed is:
1. A process for producing a catalyst comprising providing a support, and impregnating the support with an organic-inorganic hybrid sol containing titanium and at least one of gold and silver.
2. The process according to claim 1, further including modifying the surface of the catalyst with silicon alkyl compounds, silicon aryl compounds and/or SiH compounds.
11. The catalyst according to claim 8, wherein the sum of the contents of gold and silver in the organic-inorganic hybrid material totals 0.001 to 15% by weight.
12. The catalyst according to claim 11, wherein the content of gold in the organic-inorganic hybrid material is 0.001-2% by weight.
13. The catalyst according to claim 11, wherein the content of silver in the organic-inorganic hybrid material is 0.01-15% by weight.
14. The catalyst according to claim 8, containing gold particles having a diameter less than 10 nm.
15. The catalyst according to claim 8, wherein the catalyst comprises other extraneous oxides (termed promoters).
16. The process for the selective, partial oxidation of hydrocarbons in the presence of molecular oxygen and of a reducing agent, and in the presence of the catalyst according to claim 8.
17. The process for producing epoxides from alkenes in the presence of molecular oxygen and of a reducing agent and of the catalyst according to claim 8.
18. The process according to claim 17, wherein the epoxide is propene oxide and the alkene is propene.
19. The catalysts according to claim 8, wherein the titanium is present as titanium oxide and wherein the titanium oxide concentration is 0.1 to 10 mol % with respect to the amount of Si and Ti in the hybrid material.
20. The process according to one of claims 6 or 7, wherein silicon hydride units are added during annealing.
Nanoscale gold catalysts, activating agents, support media, and related methodologies useful for making such catalyst systems especially when the gold is deposited onto the support media using physical vapor deposition
Production of catalyst containing gold and-or silver and amorphous titanium-silicon oxide, used for selective hydrocarbon oxidation, e.g. propene to propene oxide, involves making the mixed oxide by a sol-gel process
Nanoscale gold catalysts, activating agents, support media, and related methodologies useful for making such catalyst systems especially when the gold is deposited onto the support media using physical vapor deposition
Catalysts, activating agents, support media, and related methodologies useful for making catalyst systems especially when the catalyst is deposited onto the support media using physical vapor deposition
Nanoscale gold catalysts, activating agents, support media, and related methodologies useful for making such catalyst systems especially when the gold is deposited onto the support media using physical vapor deposition
Catalysts, activating agents, support media, and related methodologies useful for making catalyst systems especially when the catalyst is deposited onto the support media using physical vapor deposition
Catalysts, activating agents, support media, and related methodologies useful for making catalyst systems especially when the catalyst is deposited onto the support media using physical vapor deposition
Catalysts, activating agents, support media, and related methodologies useful for making catalyst systems especially when the catalyst is deposited onto the support media using physical vapor deposition
Catalysts, activating agents, support media, and related methodologies useful for making catalyst systems especially when the catalyst is deposited onto the support media using physical vapor deposition
Catalysts, activating agents, support media, and related methodologies useful for making catalyst systems especially when the catalyst is deposited onto the support media using physical vapor deposition
Catalysts, activating agents, support media, and related methodologies useful for making catalyst systems especially when the catalyst is deposited onto the support media using physical vapor deposition | 2024-05-08T01:26:57.367551 | https://example.com/article/8800 |
Electrophysiological monitoring in a patient with an optic nerve glioma.
To report a case illustrating the value of pattern VEP and pattern ERG (PERG) in monitoring optic nerve gliomata (OG). A 15-year-old girl presented with a 3-year history of frontal headaches and a 5-month history of blurred vision in the right eye. MRI scanning revealed a thickened, right optic nerve extending to the cranial opening of the optic canal, consistent with an optic nerve glioma. Pattern VEP showed a mildly delayed major positive component consistent with optic nerve dysfunction. The PERG N95:P50 ratio was subnormal in keeping with retinal ganglion cell involvement. Visual acuity decreased over the following 2 years and repeat VEP objectively demonstrated marked deterioration in optic nerve function despite neuroradiology showing no significant change in the tumour. Pattern VEPs and pattern ERGs can provide early objective evidence of optic nerve/retinal ganglion cell dysfunction in optic nerve gliomata. Serial recordings can objectively demonstrate worsening function in the absence of significant neuroradiological change. | 2024-06-04T01:26:57.367551 | https://example.com/article/7488 |
Health on the Hill – briefs
Laws legalising euthanasia in the ACT and the Northern Territory would be reinstated under a Bill introduced to the Senate with the support of a group of MPs drawn from across the major parties.
In a rare display of cross-party action, Labor MPs including Alannah Mactiernan, Katy Gallagher and Nova Peris have joined with Liberal MP Sharman Stone and Australian Greens leader Richard Di Natale in backing legislation which would restore to the ACT and the NT the right to legislate around euthanasia.
The new laws would roll back a Private Member’s Bill, introduced by Liberal MP Kevin Andrews in 1996, that nullified NT euthanasia legislation and stripped the ACT of the power to legislate for euthanasia.
The issue is politically divisive, and the Labor caucus last month decided to allow ALP MPs a conscience vote on the matter.
The push to allow for euthanasia has gathered momentum in recent months and has the backing of several high-profile advocates including broadcaster Andrew Denton.
But even if the legislation is passed by the Senate, there are doubts it will attract sufficient support in the Lower House to become law.
Indecent disclosure
Health care providers are set to come under scrutiny over the adequacy of their information disclosure as the consumer watchdog vows to crack down on confusing and misleading conduct.
Australian Competition and Consumer Commission Chair Rod Sims said the agency had “important investigations underway” into the disclosure practices of health care providers amid concerns some were in breach of Australian Consumer Law.
Flushed with success after forcing Canberra’s Calvary Private Hospital to provide patients with more information about potential out-of-pocket costs, Mr Sims said the ACCC would focus on shortcomings in disclosure to consumers.
He said the Commission’s scathing report on the behaviour of the private health insurance industry, released last year, would provide a springboard for greater scrutiny regarding the provision of incomplete information that was not only confusing but potentially misleading.
Research boost
Research to develop an AIDS vaccine and reduce the incidence of over-diagnosis are among 96 projects sharing $130 million of funding in the latest round of grants from the nation’s peak medical research organisation.
Health Minister Sussan Ley said the money was part of $850 million that will be disbursed by the National Health and Medical Research Council to fund a wide range of projects.
There has been criticism that scientists starting their research career have often been unfairly overlooked in the race for funding, but NHMRC Chief Executive Officer Professor Anne Kelso said grants were awarded to a mix of both “outstanding new talent and experienced and internationally recognised researchers”.
TPP
Drug companies may effectively hold at least an eight-year monopoly on the supply of expensive biologic medicines under the terms of the controversial Trans Pacific Partnership trade deal, activists have warned.
Trade watchers have seized on remarks made by Australia’s Special Trade Envoy, Andrew Robb, during a visit to Washington DC late last month to claim the Government was looking at using administrative delays and other bureaucratic processes to effectively extend monopoly protection for biologic medicine manufacturers to eight years – three years longer than stipulated under the treaty.
The Washing-based Politico news service reported assurances from Mr Robb, who was visiting the US capital to help rally US Congress support for the TPP, that the trade agreement would effectively provide at least eight years market protection for biologic makers, as possibly as long as 17 years.
During negotiations for the TPP, Australia and other countries resisted US demands for at least 12 years of data protection for biologic manufacturers, and there was eventual agreement on a “five-plus” approach guaranteeing makers a minimum of five years’ monopoly on supply.
Though Mr Robb told Politico Australia would not be “a party to anything that would imply that we’ve changed our position”, he emphasised the importance of providing drug companies similar protection to that they received in the US: “We’ve got a very burgeoning biologics sector in Australia, [and] if they weren’t getting the protection that they could get in the United States, they wouldn’t be setting up in Australia”.
Health advocates warn this would effectively mean at least eight years before cheaper generic versions of expensive biologic medicines – gene and cellular-based therapies that are being developed to treat diseases long-considered intractable, such as cancer, HIV/AIDS, rheumatoid arthritis, diabetes, hepatitis B and multiple sclerosis – would become available.
Get moving
Teenage girls are being urged to ‘make your move’ following findings that they are, on average, only half as physically active as their male counterparts.
Health Minister Sussan Ley has launched the #girlsmakeyourmove campaign to encourage young women to play sport and engage in other activities amid concerns many are heading for a life of poor health.
Ms Ley said research showed almost 60 per cent of girls aged between 15 and 17 years undertook little or no exercise, compared with a third of boys in the same age group.
The Minister said such sedentary habits, particularly during the formative teenage years, could lead to a lifetime of chronic disease.
“[This campaign] aims to tackle this sliding door moment in a young woman’s life when they actually are laying down the foundation for the rest of their lives,” Ms Ley said. “Physical activity in the teenage years lays down the muscle and bone you need for the rest of your life.”
Many girls get put off playing sport or engaging in physical activity because of a lack of confidence, fear of being judged or a bad experience, and the campaign uses television ads and social media to feature girls enjoying playing sport and being active. | 2023-11-19T01:26:57.367551 | https://example.com/article/5250 |
#!/bin/bash
# ruleset_loads.sh ruleset
# Exits with 0 when the specified ruleset is able to load. Exits with 1 if
# it fails to load.
(echo "lua unsafe-file @abs_top_srcdir@/tests/rs_test_res/ruleset_is.lua" \
| (EXPECTED_RULESET=$1 @abs_top_builddir@/fcser \
--Announce none --ruleset $1)) \
|| exit 1
# The ruleset was able to load.
exit 0
| 2023-11-28T01:26:57.367551 | https://example.com/article/1328 |
package io.gatehill.imposter.plugin.openapi.service;
import io.gatehill.imposter.plugin.openapi.model.ContentTypedHolder;
import io.swagger.v3.oas.models.OpenAPI;
import io.swagger.v3.oas.models.media.Schema;
/**
* Collects examples from schema definitions.
*
* @author benjvoigt
*/
public interface SchemaService {
ContentTypedHolder<?> collectExamples(OpenAPI spec, ContentTypedHolder<Schema<?>> schema);
}
| 2024-01-13T01:26:57.367551 | https://example.com/article/3378 |
Crystals were once dismissed as hippy dippy nonsense. Now they are popping up on the catwalk and in the handbags of everyone from Adele to Naomi Campbell. Has mysticism gone mainstream?
Wellness is taking over the world. The latest figures from the Global Wellness Institute – a not-for-profit organisation that unpacks where we are at with health, wealth and self – values the industry at $3.7tn (£2.6tn) globally.
On one hand, this is not suprising. The tentacular reach of Goop, alongside a litany of yogas, meditation, supplements and books, have firmly rooted wellness into our everyday routines. But one thing that might surprise you is that the complementary/alternative medicine market alone is now worth almost $200bn.
Crystals are, arguably, one of the breakout stars of this whole business. There has also been a 40% increase in Google searches for “crystal healing” in the past four years, a percentage that generally spikes in January (“new year, new you”) and February (a combination of the winter doldrums and Valentine’s Day). Got a problem? There’s probably a crystal for that.
Facebook Twitter Pinterest Star print kimono, £89 from Topshop. Photograph: Topshop
She’s Lost Control is a modish, mystic shop in east London that stockpiles a wide range of crystals, including lemon-coloured citrine, which in certain circles is thought to boost power and attract wealth; City workers allegedly carry it in their suit pockets or sewn into their hems in the hope that it will bring them financial success. Today, in the store – which, owing to its proximity to London’s financial district, attracts bankers – the jar is half empty, which suggests the power of citrine is catching across the office blocks.
Regardless of whether crystals work, interest in them has deepened in so-called spiritual circles and among the business elite, but also in Vogue. Jessica Diner, the magazine’s beauty director, has them on her bedside table; Naomi Campbell carries black tourmaline and a rose quartz in her handbag; before her shows, Victoria Beckham lines the catwalk with black obsidian in an attempt to ward off negative energy. Adele attributed her hiccups at last year’s Grammys to losing her beloved collection. The model Munroe Bergdorf wears crystals in her clothes, following a strict rotation that includes labradorite, fluorite, and selenite – “The ones that really help me in transitional periods and elevate my spirit,” she told Vogue. “The whole witchy vibe is what I’m all about.”
Crystals fall under the umbrella of mysticism, which is itself an ill-defined catch-all for anything that discusses energy in terms that your gas bill doesn’t. In the past year, mysticism has begun to infiltrate the wellness market. Some would include meditation, reiki or yoga; others might mention gong baths or even magic – the latter have both appeared in fashion biannual the Gentlewoman. There’s arguably a special place, too, for astrology and horoscopes, which despite their dodgy rep in the print-classifieds section, feature online in Lena Dunham’s Lenny and Vice’s Broadly sites. Elsewhere, 13th-century Persian Sunni Muslim poet Rumi has become one of the most quoted scholars on Instagram (Cara Delevingne has been a longtime #fan) while others are diving even deeper into the occult, using tarot cards and the like. Crystals remain at the market’s beating heart, though, with people adding them to their water, face cream or interiors. Miranda Kerr’s Kora Organics beauty products are made from water that has been filtered through rose quartz “to give the vibration of self-love”.
Facebook Twitter Pinterest Cottweiler’s show at the Earth’s Treasury gallery at the London Natural History Museum. Photograph: Courtesy of Cottweiler
In the fashion industry, a mystic aesthetic has been building, piecemeal, over the past 18 months. At Vetements, long-lined coats come embroidered with horoscopes, while hip east-end label Blouse has made hoodies emblazoned with Champagne Mystic and The Vampire’s Wife has released hippy goddess T-shirts designed by Karen Constance. Stars are doing a roaring trade: Marks & Spencer’s biggest-selling dress for winter came covered in stars, as does a whole line of printed pieces from Topshop. Dilara Findikoglu’s entire spring 2018 line came with heavy, occultish overtones, inspired, she said, “by the illusion of the structure of our society”. Dior’s cruise collection has incorporated the Motherpeace symbol, and constellations in its couture, and even Gucci has a mystic cat-print scarf for men. Cottweiller, a cutting-edge streetwear brand, hosted its last show in the Earth’s Treasury Gallery in the London Natural History Museum, a room full of all types of crystals and minerals.
In keeping with the trend is ultraviolet, named the colour of 2018 by Pantone. UV, it says, represents the cosmos, the godly (papal purple), and the princely (um, Prince), and “communicates originality, ingenuity and visionary thinking,” says Leatrice Eiseman, executive director of the Pantone Color Institute. It’s an in-between colour, open to interpretation. And it was on the catwalk at Marni, Martine Rose and Kenzo. In fairness, we could have seen it coming: mysticism also falls under the concept of “chaos magic”, a loose and comprehensive idea drummed up by K-Hole (the agency responsible for making normcore happen). Greg Fong, one of its founders, told me in 2015 that it “was about the idea that magic could exist if you could hack your own brain and believe in an alternative”.
The appeal of mysticism seems to be that it is in fashion, it looks nice, and translates well on to social media. Crystals certainly carry a certain profundity. The stars, the motherpeace symbols, the rose quartz on Instagram stories, this is quasi-religion for the social media age. There was a time when all this “hippy dippy nonsense” was an alternative. But, as is the case with anything that purports to make our lives better, we democratise it, commodify it and thus it goes mainstream, and is sold online.
Facebook Twitter Pinterest Ultra-violet on the catwalk at (L to R) Marni, Martine Rose and Kenzo. Composite: Rex Features
I grew up in the West Country, where an interest in the occult was not trendy, but pretty normal. Some of my older friends were Wiccan, and they taught me spells involving red ribbons (which we tied around fingers), burning candles and, indeed, “smudging” (burning bundles of herbs to “clear bad energy”). At She’s Lost Control, I open-mindedly buy an amethyst (good for cleansing), calcite (good for cleaning bad energy) and rose quartz for love.
In the past six months, business has been booming. Until two years ago, Cheryl Eltringham and Jill Urwin worked in fashion as a jewellery designer and a buyer, respectively. Now they sell crystals, handmade jewellery, sage sticks and clothes in a shop that they periodically clear out to run tarot card readings and gong baths. Most of their customers are women, but bankers aside, men are beginning to drift in. “People come in because they’re stressed at work, in love, out of love or in mourning and these things can heal us.” I raise an eyebrow. The problem is, they say, “science doesn’t trust things it can’t measure”.
Facebook Twitter Pinterest Rose quartz, calcite and citrine. Photograph: Courtesy of She's Lost Control
Naturally, cynicism is high when it comes to crystals. They are natural conductors of energy. Yet the idea that they do any more than that is merely a placebo, says Tim Caulfield, a research director at the Health Law Institute, who has tried crystal healing. “Crystals don’t transmit a healing ‘vibratory frequency’,” he says. “I can say, without hesitation, that from a scientific perspective this is complete nonsense. Yep, some are attractive. But wearing a crystal isn’t going to help align some magical life-force energy.” The human desire for what religion can provide – a sense of comfort, community, purpose and the idea of there being something meaningful beyond the self – is still very much with us. We want rituals. We want to believe that someone or something is in control and that we can have some control over our life. Mysticism provides just that.
Clinical psychologist Cinzia Pezzolesi says that while “little scientific evidence exists to substantiate a crystal’s effectiveness”, and there are no proven medical benefits, “they appeal to people seeking calm in an otherwise chaotic world – for believers, their value may be in fulfilling the spirit, which suits them just fine”.
It turns out I’m late to the mystic party. Several of my most cynical friends use them. One held a crystal throughout her IVF treatment. The treatment proved successful and while she wouldn’t put it down to the crystals, she is sure they have had some positive effect. Another swears by waving clear quartz over your head if you have a headache (it is supposed to declutter). Another writer diagnosed with clinical depression found herself in a shop drawn to lepidolite, a soft-pink or lilac stone, and keeps it on her desk. She sees it as a distraction, something pretty, but that “sometimes you have to pursue all options, even though we have been made to feel cynical”. Whether any of it works is a moot point. As she explains: “When you feel let down, when you don’t want to get on a waiting list for CBT, you think, ‘Hey, why not?’” They are almost a last-resort therapy, reflective of the era in which they have risen.
This article contains affiliate links, which means we may earn a small commission if a reader clicks through and makes a purchase. All our journalism is independent and is in no way influenced by any advertiser or commercial initiative. By clicking on an affiliate link, you accept that third-party cookies will be set. More information. | 2023-09-23T01:26:57.367551 | https://example.com/article/9788 |
{
"images" : [
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"idiom" : "universal",
"filename" : "reply.png",
"scale" : "1x"
},
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"idiom" : "universal",
"filename" : "reply@2x.png",
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"info" : {
"version" : 1,
"author" : "xcode"
}
} | 2023-10-23T01:26:57.367551 | https://example.com/article/7558 |
Q:
Referencing a "partition table" foreign key in Multi-Tenant Code-First Entity Framework
I am creating a multi-tenant application that needs to be built in a single database. To partition the tables, we have a Tenant entity whose primary key will be referenced as part of the keys of other tables that need partitioning. The Tenant entity looks like this:
public class Tenant
{
[Key]
public string TenantId { get; set; }
public string TenantName { get; set; }
}
An example of where this partitioning is used is in a Store-Item scenario, where a tenant can have multiple stores as well as multiple items. Stores can have multiple items, and their relationships are maintained in a StoreItem entity. Our current implementation looks like this:
Store Entity
public class Store
{
[Key, Column(Order = 1)]
public string TenantId { get; set; }
[Key, Column(Order = 2)]
public string StoreId { get; set; }
[ForeignKey("TenantId")]
public virtual Tenant Tenant { get; set; }
}
Item Entity
public class Item
{
[Key, Column(Order = 1)]
public string TenantId { get; set; }
[Key, Column(Order = 2)]
public string ItemId { get; set; }
[ForeignKey("TenantId")]
public virtual Tenant Tenant { get; set; }
}
StoreItem Entity
public class StoreItem
{
[Key, Column(Order = 1)]
public string TenantId { get; set; }
[Key, Column(Order = 2)]
public string StoreId { get; set; }
[Key, Column(Order = 3)]
public string ItemId { get; set; }
[ForeignKey("TenantId")]
public virtual Tenant Tenant { get; set; }
[ForeignKey("StoreId")]
public virtual Store Store { get; set; }
[ForeignKey("ItemId")]
public virtual Item Item { get; set; }
}
When we try to build the database, I encounter the ff. error:
StoreItem_Item_Target_StoreItem_Item_Source: : The number of properties in the Dependent and Principal Roles in a relationship constraint must be identical.
StoreItem_Store_Target_StoreItem_Store_Source: : The number of properties in the Dependent and Principal Roles in a relationship constraint must be identical.
What is wrong with the way I structured my keys? Should TenantId not be referenced as part of the Key for other entities?
A:
The problem is that you're using [ForeignKey("ItemId")] to describe part of the relationship between StoreItem and Item but Item has multiple key columns. If you need the TenantId to be part of the key -- which you shouldn't if ItemId is enough to uniquely identify an Item record -- then I think you'd need to use the fluent API to define the relationship.
On the other hand, I'm guessing you don't need TenantId as a key column for either Item or Store, which would simplify things greatly.
| 2024-02-12T01:26:57.367551 | https://example.com/article/3741 |
About This Journal
Mission Statement
The mission of The Journal of Values-Based Leadership (JVBL) is to promote ethical and moral leadership and behavior by serving as a forum for ideas and the sharing of “best practices.” It serves as a resource for business and institutional leaders, educators, and students concerned about values-based
leadership. The JVBL defines values-based leadership to include topics involving ethics in leadership, moral considerations in business decision-making, stewardship of our natural environment, and spirituality as a source of motivation. JVBL strives to publish articles that are intellectually rigorous yet of practical use to leaders, teachers, and entrepreneurs. In this way, the JVBL serves as a high quality, international journal focused on converging the practical, theoretical, and applicable ideas and experiences of scholars and practitioners. The JVBL provides leaders with a tool of ongoing self-critique and development, teachers with a resource of pedagogical support in instructing values-based leadership to their students, and entrepreneurs with examples of conscientious decision-making to be emulated within their own business environs.
Submissions should be submitted electronically through the dedicated portal on the website home page in Word format. | 2024-07-22T01:26:57.367551 | https://example.com/article/5317 |
Haloalkane
The haloalkanes (also known as halogenoalkanes or alkyl halides) are a group of chemical compounds derived from alkanes containing one or more halogens. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely used commercially and, consequently, are known under many chemical and commercial names. They are used as flame retardants, fire extinguishants, refrigerants, propellants, solvents, and pharmaceuticals. Subsequent to the widespread use in commerce, many halocarbons have also been shown to be serious pollutants and toxins. For example, the chlorofluorocarbons have been shown to lead to ozone depletion. Methyl bromide is a controversial fumigant. Only haloalkanes which contain chlorine, bromine, and iodine are a threat to the ozone layer, but fluorinated volatile haloalkanes in theory may have activity as greenhouse gases. Methyl iodide, a naturally occurring substance, however, does not have ozone-depleting properties and the United States Environmental Protection Agency has designated the compound a non-ozone layer depleter. For more information, see Halomethane. Haloalkane or alkyl halides are the compounds which have the general formula "RX" where R is an alkyl or substituted alkyl group and X is a halogen (F, Cl, Br, I).
Haloalkanes have been known for centuries. Chloroethane was produced synthetically in the 15th century. The systematic synthesis of such compounds developed in the 19th century in step with the development of organic chemistry and the understanding of the structure of alkanes. Methods were developed for the selective formation of C-halogen bonds. Especially versatile methods included the addition of halogens to alkenes, hydrohalogenation of alkenes, and the conversion of alcohols to alkyl halides. These methods are so reliable and so easily implemented that haloalkanes became cheaply available for use in industrial chemistry because the halide could be further replaced by other functional groups.
While most haloalkanes are human-produced, non-artificial-source haloalkanes do occur on Earth, mostly through enzyme-mediated synthesis by bacteria, fungi, and especially sea macroalgae (seaweeds). More than 1600 halogenated organics have been identified, with bromoalkanes being the most common haloalkanes. Brominated organics in biology range from biologically produced methyl bromide to non-alkane aromatics and unsaturates (indoles, terpenes, acetogenins, and phenols). Halogenated alkanes in land plants are more rare, but do occur, as for example the fluoroacetate produced as a toxin by at least 40 species of known plants. Specific dehalogenase enzymes in bacteria which remove halogens from haloalkanes, are also known.
Classes
From the structural perspective, haloalkanes can be classified according to the connectivity of the carbon atom to which the halogen is attached. In primary (1°) haloalkanes, the carbon that carries the halogen atom is only attached to one other alkyl group. An example is chloroethane (). In secondary (2°) haloalkanes, the carbon that carries the halogen atom has two C–C bonds. In tertiary (3°) haloalkanes, the carbon that carries the halogen atom has three C–C bonds.
Haloalkanes can also be classified according to the type of halogen on group 7 responding to a specific halogenoalkane. Haloalkanes containing carbon bonded to fluorine, chlorine, bromine, and iodine results in organofluorine, organochlorine, organobromine and organoiodine compounds, respectively. Compounds containing more than one kind of halogen are also possible. Several classes of widely used haloalkanes are classified in this way chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs). These abbreviations are particularly common in discussions of the environmental impact of haloalkanes.
Properties
Haloalkanes generally resemble the parent alkanes in being colorless, relatively odorless, and hydrophobic. The melting and boiling points of chloro-, bromo-, and iodoalkanes are higher than the analogous alkanes, scaling with the atomic weight and number of halides. This is due to the increased strength of the intermolecular forces—from London dispersion to dipole-dipole interaction because of the increased polarizability. Thus carbon tetraiodide () is a solid whereas carbon tetrachloride () is a liquid. Many fluoroalkanes, however, go against this trend and have lower melting and boiling points than their nonfluorinated analogues due to the decreased polarizability of fluorine. For example, methane () has a melting point of -182.5 °C whereas tetrafluoromethane has a melting point of -183.6 °C .
As they contain fewer C–H bonds, halocarbons are less flammable than alkanes, and some are used in fire extinguishers. Haloalkanes are better solvents than the corresponding alkanes because of their increased polarity. Haloalkanes containing halogens other than fluorine are more reactive than the parent alkanes—it is this reactivity that is the basis of most controversies. Many are alkylating agents, with primary haloalkanes and those containing heavier halogens being the most active (fluoroalkanes do not act as alkylating agents under normal conditions). The ozone-depleting abilities of the CFCs arises from the photolability of the C–Cl bond.
Occurrence
Haloalkanes are of wide interest because they are widespread and have diverse beneficial and detrimental impacts. The oceans are estimated to release 1-2 million tons of bromomethane annually.
A large number of pharmaceuticals contain halogens, especially fluorine. An estimated one fifth of pharmaceuticals contain fluorine, including several of the most widely used drugs. Examples include 5-fluorouracil, fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine, and fluconazole. The beneficial effects arise because the C-F bond is relatively unreactive. Fluorine-substituted ethers are volatile anesthetics, including the commercial products methoxyflurane, enflurane, isoflurane, sevoflurane and desflurane. Fluorocarbon anesthetics reduce the hazard of flammability with diethyl ether and cyclopropane. Perfluorinated alkanes are used as blood substitutes.
Chlorinated or fluorinated alkenes undergo polymerization. Important halogenated polymers include polyvinyl chloride (PVC), and polytetrafluoroethene (PTFE, or Teflon). The production of these materials releases substantial amounts of wastes.
Nomenclature
IUPAC
The formal naming of haloalkanes should follow IUPAC nomenclature, which put the halogen as a prefix to the alkane. For example, ethane with bromine becomes bromoethane, methane with four chlorine groups becomes tetrachloromethane. However, many of these compounds have already an established trivial name, which is endorsed by the IUPAC nomenclature, for example chloroform (trichloromethane) and methylene chloride (dichloromethane). But now we use IUPAC nomenclature nowadays. For unambiguity, this article follows the systematic naming scheme throughout.
Production
Haloalkanes can be produced from virtually all organic precursors. From the perspective of industry, the most important ones are alkanes and alkenes.
From alkanes
Alkanes react with halogens by free radical halogenation. In this reaction a hydrogen atom is removed from the alkane, then replaced by a halogen atom by reaction with a diatomic halogen molecule. The reactive intermediate in this reaction is a free radical and the reaction is called a radical chain reaction.
Free radical halogenation typically produces a mixture of compounds mono- or multihalogenated at various positions. It is possible to predict the results of a halogenation reaction based on bond dissociation energies and the relative stabilities of the radical intermediates. Another factor to consider is the probability of reaction at each carbon atom, from a statistical point of view.
Due to the different dipole moments of the product mixture, it may be possible to separate them by distillation.
From alkenes and alkynes
In hydrohalogenation, an alkene reacts with a dry hydrogen halide (HX) like hydrogen chloride () or hydrogen bromide () to form a mono-haloalkane. The double bond of the alkene is replaced by two new bonds, one with the halogen and one with the hydrogen atom of the hydrohalic acid. Markovnikov's rule states that in this reaction, the halogen is more likely to become attached to the more substituted carbon. This is an electrophilic addition reaction. Water must be absent otherwise there will be a side product of a halohydrin. The reaction is necessarily to be carried out in a dry inert solvent such as or directly in the gaseous phase. The reaction of alkynes are similar, with the product being a geminal dihalide; once again, Markovnikov's rule is followed.
Alkenes also react with halogens (X2) to form haloalkanes with two neighboring halogen atoms in a halogen addition reaction. Alkynes react similarly, forming the tetrahalo compounds. This is sometimes known as "decolorizing" the halogen, since the reagent X2 is colored and the product is usually colorless and odorless.
From alcohols
Alcohol undergoes nucleophilic substitution reaction by halogen acid to give Haloalkanes. Tertiary alkanol reacts with hydrochloric acid directly to produce tertiary choloroalkane (alkyl chloride), but if primary or secondary alcohol is used, an activator such as zinc chloride is needed. This reaction is exploited in the Lucas test.
The most popular conversion is effected by reacting the alcohol with thionyl chloride () in the "Darzens halogenation", which is one of the most convenient laboratory methods because the byproducts are gaseous. Both phosphorus pentachloride () and phosphorus trichloride () also convert the hydroxyl group to the chloride.
Alcohols may likewise be converted to bromoalkanes using hydrobromic acid or phosphorus tribromide (PBr3). A catalytic amount of may be used for the transformation using phosphorus and bromine; is formed in situ.
Iodoalkanes may similarly be prepared using red phosphorus and iodine (equivalent to phosphorus triiodide). The Appel reaction is also useful for preparing alkyl halides. The reagent is tetrahalomethane and triphenylphosphine; the co-products are haloform and triphenylphosphine oxide.
From carboxylic acids
Two methods for the synthesis of haloalkanes from carboxylic acids are the Hunsdiecker reaction and the Kochi reaction.
Biosynthesis
Many chloro and bromoalkanes are formed naturally. The principal pathways involve the enzymes chloroperoxidase and bromoperoxidase.
By Rydons method
An alcohol on heating with halogen in presence of triphenyl phosphate produces haloalkanes or alkyl halides.
Reactions
Haloalkanes are reactive towards nucleophiles. They are polar molecules: the carbon to which the halogen is attached is slightly electropositive where the halogen is slightly electronegative. This results in an electron deficient (electrophilic) carbon which, inevitably, attracts nucleophiles.
Substitution
Substitution reactions involve the replacement of the halogen with another molecule—thus leaving saturated hydrocarbons, as well as the halogenated product. Haloalkanes behave as the R+ synthon, and readily react with nucleophiles.
Hydrolysis, a reaction in which water breaks a bond, is a good example of the nucleophilic nature of haloalkanes. The polar bond attracts a hydroxide ion, OH− (NaOH(aq) being a common source of this ion). This OH− is a nucleophile with a clearly negative charge, as it has excess electrons it donates them to the carbon, which results in a covalent bond between the two. Thus C–X is broken by heterolytic fission resulting in a halide ion, X−. As can be seen, the OH is now attached to the alkyl group, creating an alcohol. (Hydrolysis of bromoethane, for example, yields ethanol). Reaction with ammonia give primary amines.
Chloro- and bromoalkanes are readily substituted by iodide in the Finkelstein reaction. The iodoalkanes produced easily undergo further reaction. Sodium iodide is used thus as a catalyst.
Haloalkanes react with ionic nucleophiles (e.g. cyanide, thiocyanate, azide); the halogen is replaced by the respective group. This is of great synthetic utility: chloroalkanes are often inexpensively available. For example, after undergoing substitution reactions, cyanoalkanes may be hydrolyzed to carboxylic acids, or reduced to primary amines using lithium aluminium hydride. Azoalkanes may be reduced to primary amines by the Staudinger reduction or lithium aluminium hydride. Amines may also be prepared from alkyl halides in amine alkylation, the Gabriel synthesis and Delepine reaction, by undergoing nucleophilic substitution with potassium phthalimide or hexamine respectively, followed by hydrolysis.
In the presence of a base, haloalkanes alkylate alcohols, amines, and thiols to obtain ethers, N-substituted amines, and thioethers respectively. They are substituted by Grignard reagents to give magnesium salts and an extended alkyl compound.
Mechanism
Where the rate-determining step of a nucleophilic substitution reaction is unimolecular, it is known as an SN1 reaction. In this case, the slowest (thus rate-determining step) is the heterolysis of a carbon-halogen bond to give a carbocation and the halide anion. The nucleophile (electron donor) attacks the carbocation to give the product.
SN1 reactions are associated with the racemization of the compound, as the trigonal planar carbocation may be attacked from either face. They are favored mechanism for tertiary haloalkanes, due to the stabilization of the positive charge on the carbocation by three electron-donating alkyl groups. They are also preferred where the substituents are sterically bulky, hindering the SN2 mechanism.
Elimination
Rather than creating a molecule with the halogen substituted with something else, one can completely eliminate both the halogen and a nearby hydrogen, thus forming an alkene by dehydrohalogenation. For example, with bromoethane and sodium hydroxide (NaOH) in ethanol, the hydroxide ion HO− abstracts a hydrogen atom. Bromide ion is then lost, resulting in ethylene, H2O and NaBr. Thus, haloalkanes can be converted to alkenes. Similarly, dihaloalkanes can be converted to alkynes.
In related reactions, 1,2-dibromocompounds are debrominated by zinc dust to give alkenes and geminal dihalides can react with strong bases to give carbenes.
Other
Haloalkanes undergo free-radical reactions with elemental magnesium to give alkylmagnesium compounds: Grignard reagents. Haloalkanes also react with lithium metal to give organolithium compounds. Both Grignard reagents and organolithium compounds behave as the R− synthon. Alkali metals such as sodium and lithium are able to cause haloalkanes to couple in the Wurtz reaction, giving symmetrical alkanes. Haloalkanes, especially iodoalkanes, also undergo oxidative addition reactions to give organometallic compounds.
Applications
Haloalkanes are widely used as synthon equivalents to alkyl cation (R+) in organic synthesis. They can also participate in a wide variety of other organic reactions.
Short chain haloalkanes such as dichloromethane, trichloromethane (chloroform) and tetrachloromethane are commonly used as hydrophobic solvents in chemistry. They were formerly very common in industry; however, their use has been greatly curtailed due to their toxicity and harmful environmental effects.
Chlorofluorocarbons were used almost universally as refrigerants and propellants due to their relatively low toxicity and high heat of vaporization. Starting in the 1980s, as their contribution to ozone depletion became known, their use was increasingly restricted, and they have now largely been replaced by HFCs.
Bromochlorodifluoromethane (Halon 1211), and Bromotrifluoromethane (Halon 1301), as well as others are used in fire extinguishers. Due to their high ozone depletion potential, production has ended as of April 6, 1998 cost is high, and they are primarily used for critical applications such as aviation and military.
See also
Halogenation
Halomethane
Halogenoarene
Halon (disambiguation)
References
External links
Category:Organohalides
Category:Halogenated solvents
Category:Refrigerants
Category:Functional groups | 2024-07-28T01:26:57.367551 | https://example.com/article/4748 |
David Axelrod told CNN’s “State of the Union” that Obama would unveil a reasonable jobs plan in September calling for steps previously endorsed by both parties. However, he said, Republican leaders must put aside the kind of political gamesmanship that “brought us to the brink of default” during the debt ceiling negotiations to act in the best interest of the country.
“I think what you’ll find when the president unveils the entire program is that there’s nothing in there that reasonable people shouldn’t be able to agree on and if we make the House Republicans and particularly the tea party faction, if we make them the standard, we’re in deep trouble,” Axelrod said.
Short-term and long-term solutions are necessary to accelerate the U.S. economy that has taken recent hits from world events, including the Arab spring protest movement that has increased gas prices, the earthquake in Japan and shaky European economies, said Axelrod, who left the White House earlier this year to work on Obama’s re-election effort.
The president’s plan is expected to include an extension of the payroll tax cut passed in January as well as spending on infrastructure development, such as rebuilding or repairing roads and bridges, in an effort to help the long-term unemployed, Axelrod said.
He blamed politics for the lack of action in Congress, pointing specifically to conservative Republicans.
“I hope that over this break they’ve heard from their constituents, they’re ready to rethink this,” Axelrod told CNN Chief Political Correspondent Candy Crowley. “The only thing that keeps us from acting on this is pure politics.”
His comments follow the president’s three-day bus tour aimed at promoting the administration’s rural economic development initiatives and pivoting the national conversation toward job creation.
Obama has come under criticism from his liberal base for what they complain is yielding too quickly to Republican intransigence by moving to the political center instead of standing up for Democratic ideals.
Amid the president’s bus tour, members of the House Congressional Black Caucus, many of whom are strong Obama supporters, said he should also visit urban communities when traveling the country.
Democratic Rep. Maxine Waters of California was perhaps the loudest voice over the past week, telling CNN on Saturday that it’s time for Obama “to fight” for Democratic principles and focus on African American communities facing higher unemployment rates than elsewhere in the country. On Sunday, Rep. Elijah Cummings of Maryland echoed Waters’ call on CNN.
“On the one hand, they’re very protective, they really care,” said Cummings, the former chairman of the Black Congressional Caucus, of how African American members of Congress regard Obama, the nation’s first African American president. “On the other hand, almost every African American person I’ve talked to said they want him to fight and fight harder.”
Cummings summed up the attitude of African Americans as: “If the Republicans aren’t going to work with us, we’re just gong to have to go it alone and stand up to them. Don’t back down. Period.”
– CNN's Tom Cohen contributed to this report.
Watch State of the Union with Candy Crowley Sundays at 9am ET. For the latest from State of the Union click here.
soundoff(57 Responses)
RV1982
I have not heard tea party advocates not supporting spending on infrastructure. I have heard them complain about regulatory burdens that increase costs and delay projects. Maybe the best way to accomplish infrastucture construction is have the Fed buy up local, interest free bonds so localities can pay it off over the LONG HAUL. Not really sure it would create that many jobs, but it can't hurt.
August 21, 2011 03:01 pm at 3:01 pm |
FIELD1stSGT
You people are so stupid as to believe it's the Republicans or the Tea Party is stopping economic growth. I pity you for such stupid brainwork that you would even listen to a Axelrod. This man is a fool. He goes whereever the person can pay him this most money and says what they want him to say. What little control the House has is to approve things or in their quarter disapprove. If they ever receive anything of value from the preposed laws or admendments. The problem being is they aren't receiving anything from Obama. He didn't present a budget as his job called for, and now he is not working on economic growth. He is living it up on the rich people's tax dollars. If you think it's the little people that pay all the taxes your bigger fools than even I give you credit to be. Look at what you received back from the IRS last year. in most cases most received more than they even made. Who do you think is paying this money. OBAMA??? What a joke.
August 21, 2011 03:02 pm at 3:02 pm |
xav8ter
Those Georgia job fair lines are indicative of the failing policy's of this very administration. There is no light at the end of the tunnel....you just feel the heat. People....get off of your dead horse!
August 21, 2011 03:07 pm at 3:07 pm |
myfault
Oh...the tea party is just astro turf. They're aren't to be taken seriously. Oh. Wait. Oops. Never mind.
August 21, 2011 03:11 pm at 3:11 pm |
Elaine
In the 8 years that G.W.Bush was president, Republicans didn't care about the deficit; and for a goodly amount of that time, they controlled congress.President Clinton left the a strong, and solvent economy, with a surplus, and it was wrecked by
republicans, giving tax cuts to those who could do without them( and they are still now arguing for even more), in a time of war,while creating practically no jobs.Now that Barack Obama is president, they've become deficit hawks, and want to cut spending, and dismantle the Medicare, Social Security, and Education systems, as we have known them, and even want to deny unemployment benefits to people who have earned them.At least President Obama strengthened the jobs market, even though the growth has been slow.Instead of Republicans blocking every proposal , they need to compromise with the president on a jobs bill.
August 21, 2011 03:23 pm at 3:23 pm |
Henry Miller, Libertarian
Since, what?, 2006 when the Dems took control of Congress, the best that could be said about them is that they've been unbelievably irresponsible about America's economy. It's true they had a lot of help from George Bush and the neo-cons, but that doesn't minimise the spendthrift profligacy of the Dems.
So it's not just Republican "gamesmanship that“brought us to the brink of default.” It takes to play that kind of game. Both parties have been wasting insane amounts of taxpayer money for decades, and that's done enormous damage to the American economy.
It's time, next November, to vote every incumbent out of office.
August 21, 2011 03:34 pm at 3:34 pm |
Mike from MN
To all the right-wing Repubthugs:
The first thing Obama's administration did when it took office officially was passed bills to END THE GREAT RECESSION of 2008. The recession ended less than 3 months later.
The government can only effect the economy in two ways: 1) tax policy, and 2) spending
All of which the Obama administration did when taking office. All that needed and could have been done given the economic and political circumstances has been done.
Corporations have recorded profits. Executives have gotten record bonuses.
The reason not enough jobs are being created to reduce the unemployment rate can be blamed on CAPITALISM!
Corporations have no need to create more jobs! Why? When they are already making record profits!
Basic SUPPLY-DEMAND principles of a CAPITALISTIC economy is all one needs to understand why corporations do not need to create more jobs.
To understand, think of the OIL industry. Why has OPEC reduce the output of OIL SUPPLY, even though DEMAND for it is through the roof? | 2023-09-05T01:26:57.367551 | https://example.com/article/6816 |
Q:
How to fill tetris field
I create console tetris and I need to create tetris board, but i have no idea why my code doesn't works. I want to do something like
that
for(int i = 0; i < BOARD.GetLength(0); i++)
{
for (int j = 0; j < BOARD.GetLength(1); j++)
{
if (i == 0)
{
BOARD[i, j] = "=";
}
else if(i == 14)
{
BOARD[i, j] = "=";
}
else
{
BOARD[i, 0] = "|";
BOARD[i, 7] = "|";
}
}
}
}
private void Show()
{
for (int i = 0; i < BOARD.GetLength(0); i++)
{
for (int j = 0; j < BOARD.GetLength(1); j++)
{
Console.Write(BOARD[i, j]);
}
Console.Write("\n");
}
}
Result of my code
A:
for arrey [15,15]:
for (int i = 0; i < BOARD.GetLength(0); i++)
{
for (int j = 0; j < BOARD.GetLength(1); j++)
{
if (i == 0 || i == 14)
{
BOARD[i, j] = "=";
}
else if (j == 0 || j == 14)
{
BOARD[i, j] = "|";
}
else
{
BOARD[i, j] = " ";
}
}
}
| 2024-04-25T01:26:57.367551 | https://example.com/article/1278 |
play.application.loader = com.example.helloworld.impl.HelloWorldLoader
lagom.projection.auto-start.enabled = false
## Few hacks to speed up the test
## speed up the ensure-active-interval to distribute workers faster
lagom.persistence.cluster.distribution.ensure-active-interval = 2s
## reduce eventual consistency
cassandra-query-journal.eventual-consistency-delay = 2s
## set first-time-bucket to speed up unit tests (starting with no offset is faster with this.)
cassandra-query-journal {
first-time-bucket = "20190903T00:00"
}
## Below are some extra settings not having a direct impact on the test.
hello.cassandra.keyspace = helloscaladsl
cassandra-journal.keyspace = ${hello.cassandra.keyspace}
cassandra-snapshot-store.keyspace = ${hello.cassandra.keyspace}
lagom.persistence.read-side.cassandra.keyspace = ${hello.cassandra.keyspace}
| 2023-08-27T01:26:57.367551 | https://example.com/article/2865 |
Are you a fan of striking colours in fashion and artwork? If you find beige or ‘greige’ to be bland and boring, colourful kitchen renovations may be perfect for you. Colour can be difficult to manipulate in the interior design context, as a bright and impressive colour that looks great on paper can quickly become grating when you are faced with it every day. Colour can be even more difficult in kitchens, as having so many different surfaces with your appliances, sink and bench tops can easily make the space feel visually busy and messy.
With some clever planning and a measured approach, however, it is possible to fill your space with colour, and still enjoy using the room. The first step to finding a colour scheme for your kitchen renovations involves collecting colour guides and paint catalogues to get a feeling for what’s possible in your space. At this stage you can just pick out a few colours, and complements of those colours, that appeal to you as you can worry about matching the colours to your space later.
With new kitchen renovations, you can treat your space as a blank canvas on which you can splash any colour you like – unless your house is open plan there is no need to match your colour choices to anything else. This gives you a great opportunity to pick out one strong colour and use it as your overall theme. A striking and unusual colour such as watermelon pink can be used on the walls for high impact, or can be used as an accent colour on a few appliances and accessories and inside cabinets for a tasteful effect.
When planning new renovations for your home it is important to match the colours of your walls, flooring, appliances and cabinets to form a cohesive colour scheme. Choosing polished floorboards gives you more scope for other colour choices and also gives your space a warm and cosy feel.
No matter how keen you are on bright colour, it is always advisable to have a significant proportion of neutral tones in your space to balance the room out visually. Similarly, pale tones, whether a lemon yellow, china blue or creamy white, can make a room seem more spacious and will make the most of any natural light. There are no strict rules, however, for kitchen renovations, so feel free to trust your spirit of adventure and choose your favourite colours for your kitchen.
As the creator, Christine examines a venture inside the context in the total place, common. She understands the artwork and systems of standard of residing, environment and choice to make useful, stunning and personal places. Christine signifies a sense of individual design, processed style in addition to a essential eye for high-class, while turning into an inventor utilizing the character and enthusiasm for making and inspiring interactions. | 2023-10-05T01:26:57.367551 | https://example.com/article/7393 |
package org.liquidengine.legui.demo;
import org.joml.Vector2i;
import org.liquidengine.cbchain.impl.ChainErrorCallback;
import org.liquidengine.legui.animation.AnimatorProvider;
import org.liquidengine.legui.component.Frame;
import org.liquidengine.legui.listener.processor.EventProcessor;
import org.liquidengine.legui.listener.processor.EventProcessorProvider;
import org.liquidengine.legui.system.context.CallbackKeeper;
import org.liquidengine.legui.system.context.Context;
import org.liquidengine.legui.system.context.DefaultCallbackKeeper;
import org.liquidengine.legui.system.handler.processor.SystemEventProcessor;
import org.liquidengine.legui.system.handler.processor.SystemEventProcessorImpl;
import org.liquidengine.legui.system.layout.LayoutManager;
import org.liquidengine.legui.system.renderer.Renderer;
import org.liquidengine.legui.system.renderer.nvg.NvgRenderer;
import org.lwjgl.glfw.GLFW;
import org.lwjgl.glfw.GLFWErrorCallback;
import org.lwjgl.glfw.GLFWKeyCallbackI;
import org.lwjgl.glfw.GLFWWindowCloseCallbackI;
import org.lwjgl.opengl.GLCapabilities;
import java.util.concurrent.TimeUnit;
import static org.lwjgl.glfw.GLFW.*;
import static org.lwjgl.opengl.GL.createCapabilities;
import static org.lwjgl.opengl.GL.setCapabilities;
import static org.lwjgl.opengl.GL11.*;
import static org.lwjgl.system.MemoryUtil.NULL;
/**
* @author Aliaksandr_Shcherbin.
*/
public abstract class Demo {
private int width;
private int height;
private String title;
private volatile boolean running = false;
private Thread mainThread;
private Thread rendererThread;
private Thread eventProcessorThread;
private Thread leguiEventProcessorThread;
private Renderer renderer;
private EventProcessor leguiEventProcessors;
private CallbackKeeper keeper;
private SystemEventProcessor systemEventProcessor;
private GLCapabilities glCapabilities;
private long[] monitors;
private Context context;
private Frame frame;
private long window;
public Demo(int width, int height, String title) {
this.width = width;
this.height = height;
this.title = title;
}
public void run() {
System.setProperty("joml.nounsafe", Boolean.TRUE.toString());
System.setProperty("java.awt.headless", Boolean.TRUE.toString());
mainThread = new Thread(() -> {
initialize();
sleep(1000000000);
startRenderer();
startSystemEventProcessor();
startLeguiEventProcessor();
handleSystemEvents();
destroy();
}, "LEGUI_EXAMPLE");
mainThread.start();
// wait while not initialized
while (!running) {
Thread.yield();
}
}
private void sleep(long sleepTime) {
try {
TimeUnit.NANOSECONDS.sleep(sleepTime);
} catch (InterruptedException e) {
e.printStackTrace();
}
}
private void startSystemEventProcessor() {
eventProcessorThread = new Thread(() -> {
while (running) {
systemEventProcessor.processEvents(frame, context);
}
}, "GUI_SYSTEM_EVENT_PROCESSOR");
eventProcessorThread.start();
}
private void handleSystemEvents() {
while (running) {
glfwWaitEvents();
}
}
private void destroy() {
glfwDestroyWindow(window);
glfwTerminate();
}
private void startLeguiEventProcessor() {
leguiEventProcessorThread = new Thread(() -> {
while (running) {
EventProcessorProvider.getInstance().processEvents();
}
}, "GUI_EVENT_PROCESSOR");
leguiEventProcessorThread.start();
}
private void render() {
glfwMakeContextCurrent(window);
glCapabilities = createCapabilities();
glfwSwapInterval(0);
renderer = new NvgRenderer();
renderer.initialize();
glfwMakeContextCurrent(window);
setCapabilities(glCapabilities);
glfwSwapInterval(0);
while (running) {
try {
context.updateGlfwWindow();
Vector2i framebufferSize = context.getFramebufferSize();
glClearColor(1, 1, 1, 1);
glViewport(0, 0, framebufferSize.x, framebufferSize.y);
glClear(GL_COLOR_BUFFER_BIT | GL_STENCIL_BUFFER_BIT);
renderer.render(frame, context);
glfwSwapBuffers(window);
// update system. could be moved for example to game loop.
update();
// When everything done we need to relayout components.
LayoutManager.getInstance().layout(frame);
// also we need to run animations
AnimatorProvider.getAnimator().runAnimations();
} catch (Throwable e) {
e.printStackTrace();
}
}
renderer.destroy();
}
private void initialize() {
if (!GLFW.glfwInit()) {
throw new RuntimeException("Can't initialize GLFW");
}
ChainErrorCallback errorCallback = new ChainErrorCallback();
errorCallback.add(GLFWErrorCallback.createPrint(System.err));
errorCallback.add(GLFWErrorCallback.createThrow());
glfwSetErrorCallback(errorCallback);
glfwWindowHint(GLFW_DOUBLEBUFFER, GLFW_TRUE);
GLFWKeyCallbackI glfwKeyCallbackI = (w1, key, code, action, mods) -> running = !(key == GLFW_KEY_ESCAPE && action != GLFW_RELEASE);
GLFWWindowCloseCallbackI glfwWindowCloseCallbackI = w -> running = false;
frame = new Frame(width, height);
window = glfwCreateWindow(width, height, title, NULL, NULL);
glfwSetWindowPos(window, 50, 50);
glfwShowWindow(window);
createGuiElements(frame, width, height);
context = new Context(window);
keeper = new DefaultCallbackKeeper();
CallbackKeeper.registerCallbacks(window, keeper);
keeper.getChainKeyCallback().add(glfwKeyCallbackI);
keeper.getChainWindowCloseCallback().add(glfwWindowCloseCallbackI);
systemEventProcessor = new SystemEventProcessorImpl();
SystemEventProcessor.addDefaultCallbacks(keeper, systemEventProcessor);
running = true;
}
private void startRenderer() {
rendererThread = new Thread(this::render, "GUI_RENDERER");
rendererThread.start();
}
public void stop() {
running = false;
}
protected abstract void update();
protected abstract void createGuiElements(Frame frame, int width, int height);
}
| 2024-06-03T01:26:57.367551 | https://example.com/article/6453 |
Q:
Moved and symlinked usr
I foolishly moved usr on my Ubuntu 12.04 system
I did:
cp -rp /usr /home/usr
ln -s /home/usr /usr
Now networking has stopped working.
I don't know if anything else is broken (the launcher lost things, but that's easy to fix)
Can I recover from this without repartioning and starting over?
A:
Provided that nothing got severly screwed during the original operation, reversing the process should move things back to normal if a reboot is applied afterwards:
unlink /usr
cp -rp /home/usr /usr
If the above resolves the issue, you can safely delete /home/usr
| 2024-06-10T01:26:57.367551 | https://example.com/article/9353 |
Central corneal thickness is lower in osteogenesis imperfecta and negatively correlates with the presence of blue sclera.
Osteogenesis imperfecta (OI) is a rare, autosomal-inherited, connective tissue disorder characterised by bone fractures, deafness and blue sclera. Additional ocular findings are decreased ocular rigidity, myopia, glaucoma, keratoconus, corneal opacity, small corneal diameter and congenital Bowman's layer agenesis. This cross-sectional, masked, case-control study aimed to assess whether central corneal thickness (CCT) is affected in patients with OI and to focus on the clinical significance of scleral blueness. Twenty-three children with OI (13 boys, 10 girls) and 15 age-, sex- and refraction-matched healthy control subjects (eight boys, seven girls) were assessed for CCT by ultrasound pachymetry. The CCT was compared between two different patient subgroups (type-I OI with blue sclera, n = 12; type-IV OI without blue sclera, n = 11). Mann-Whitney U-test or analysis of variance was used as indicated and only right eyes of each subject were included in statistical analysis. Results were expressed as mean +/- S.D. and statistical significance was taken as p < 0.05. Mean age and sex distribution was similar between the groups (10.1+/-2.5 vs 9.8+/-1.8 years, p > 0.05). Patients with OI had significantly lower CCT (459.5+/-24.6 microm) than in control subjects (543.6+/-21.4 microm; p < 0.001). The CCT was below 500 microm in 22 of 23 children (95.6%) with OI, 15 of which (65.2%) were below 450 microm. In contrast, CCT was over 500 microm in all eyes in the control group. Type-I OI eyes with blue sclera had significantly (p = 0.005) lower CCT readings (446.5+/-16.3 microm) than type-IV OI eyes without blue sclera (473.6+/-25.0 microm). Mean keratometric values were similar between the groups (44.2+/-1.7 vs 43.8+/-1.6 dioptre, p > 0.05). Mean cycloplegic refraction was similar between the groups (-0.32+/-0.5 vs -0.18+/-0.4 dioptre; p > 0.05), although five of 23 OI patients had myopia, and mean intraocular pressure was lower in OI patients than controls (12.7+/-1.8 mmHg vs 15.6+/-1.9 mmHg; p < 0.001). The CCT is thinner and negatively correlated with the blueness of the sclera in patients with OI. The CCT readings may therefore be of utmost importance in the diagnosis of OI. An ophthalmologist should be aware of an artificially low intraocular pressure measurement in such patients. In addition, when considering a keratorefractive treatment, CCT must be evaluated carefully to avoid unexpected results or complications. Sturdy protective spectacles should be prescribed to those who are not bed bound. Possible correlation of low CCT with biochemical changes in scleral collagen or systemic parameters awaits further investigation. | 2024-07-13T01:26:57.367551 | https://example.com/article/1581 |
Q:
Batch script for multi-partition job?
I'm working on a project which runs programs on two different partitions of a large compute cluster. I'd like to run this using a batch script, but after searching, it's still unclear if/how I can allocate and run programs on two different partitions from within a single batch script. Here's the sort of thing I'd like to do
#!/bin/bash
#SBATCH --partition=<WHAT GOES HERE? I want to perform 100 processes on partition "batch" and 1 process on partition "gpu". I will alternate between the 2 during my jobs execution>
#SBATCH --ntasks=<100 on batch, 1 on gpu>
#SBATCH --mem-per-cpu=2G
#SBATCH --time=4-00:00:00
#SBATCH --exclude=nodeynode[003,016,019,020-023,026-030,004-015,017-018,020,024,031]
#SBATCH --job-name="lorem_ipsum"
filenames=("name1" "name2" "name3")
srun -p gpu python gpu_init.py
wait
for i in {0..100}
do
for name in "${filenames[@]}"
do
srun -p batch pythonexecutable &
done
srun -p gpu python gpu_iter.py
wait
done
Apologies for bash errors, I usually script in python but I can't here as I'm switching python modules (different versions) within my bash script (not shown). I saw that you can actually put a list of partitions in the header of a batch script, but from what I read that actually just tells the scheduler to allocate any available partitions from within the list, not multiple partitions.
Thanks!
A:
Slurm jobs are restricted to one partition so in your case, there are several courses of action:
submitting two job arrays --array=1..100 and splitting your submission script in one part for the batch partition and another part for the gpu partition and linking both arrays with --depedendcy=aftercorr:<job_id of the 'batch' job array>
use salloc to create an allocation on the gpu partition, and then use SSH explicitly to that node to run python gpu_iter.py in the submission script (if the cluster configuration permits)
modify the gpu_iter.py so that it can be signaled (with UNIX signals) that it has to run and then sleep until the next signal, and use scancel to signal the gpu job from within the batch job at each iteration.
| 2024-02-03T01:26:57.367551 | https://example.com/article/3316 |
1. Introduction {#sec1}
===============
Despite the progress in diagnosis and advancement in management of head and neck squamous cell carcinoma (HNSCC), long-term survival rates have not improved very much over the past decade. Even after combining chemotherapy and radiation for advanced stage disease, the treatment outcomes have marginally improved \[[@B1]\]. The prognosis of HNSCC still remains desolate and more than 50% of patients die of this disease or complications within 5 years under current therapies \[[@B2]\]. Recurrence and treatment failures continue to be a major concern of HNSCC patients and late stage diagnosis accounts to be the major cause still. The initiation, growth, recurrence, and metastasis of HNSCC and other cancers have recently been related to the presence of "cancer stem cells (CSCs)" or "tumor initiating cells (TICs)," They have been demonstrated as a distinct subpopulation of tumor cells, pertaining the ability to undergo self-renewal and differentiation which further initiates the properties of normal stem cells. Hence, they possess the capacity to promote tumorigenesis and tumor growth leading to recurrence also. HNSCC appears to be supported by such cells with stem-like properties making it a significant point to be further emphasized on for eliminating the disease \[[@B3]\]. We, the authors, have hereby put an effort through this minireview to correlate the CSCs properties, its efficacy for tumorigenesis in HNSCC, and how to manage this entity for treatment protocols.
2. Cancer Stem Cells (CSCs) in relation to Tumorigenesis {#sec2}
========================================================
2.1. CSCs Hypothesis in Tumorigenesis {#sec2.1}
-------------------------------------
A tumor can be seen as an "organ" composed of transformed cells that interact with stromal cells within the tumor microenvironment \[[@B4]\]. The process of tumorigenesis requires multistep initiation of cellular and molecular pathways leading to a series of mutations resulting in the acquisition of replication and growth factor independence, resistance to growth-inhibitory signals, tissue invasion, and metastasis \[[@B5]\]. Does every cancer cell within the tumor having the tumor/cancer-initiating capability? Related theories suggest that there are currently two accepted models for cancer development ([Figure 1](#fig1){ref-type="fig"}) \[[@B6]\] as follows.The stochastic model suggests that every cancer cell is able to initiate new tumor growth equally.The alternate hypothesis is that every tumor contains a rare population of cells termed CSCs or cancer-initiating cells (CICs) \[[@B7]--[@B9]\].
The most recent key features of the cancer stem cell hypothesis were described by Prince and Ailles in 2008 \[[@B10]\]:only a small fraction of the cancer cells within a tumor have tumorigenic potential when transplanted into immunodeficient mice;the cancer stem cell subpopulation can be separated from the other cancer cells by distinctive surface markers;tumors resulting from the cancer stem cells contain the mixed tumorigenic and nontumorigenic cells of the original tumor;the cancer stem cell subpopulation can be serially transplanted through multiple generations, indicating that it is a self-renewing population.
2.2. Concept of CSCs {#sec2.2}
--------------------
The concept of CSCs first began 150 years ago when Robert Virchow, a German pathologist, found similarities between embryonic and tumor tissues \[[@B11]\]. The CSC hypothesis postulates that tumor heterogeneity with regard to initiation, progression, response to therapy, and metastasis is the result of mutations which either render a normal somatic tissue stem cell cancerous or cause a cancer cell to become stem cell-like \[[@B12]\]. This population of tumor cells consists of rapidly dividing cells (similar to the transient amplifying (TA) cell population in normal tissue) as well as additional CSCs and more differentiated tumor cells. CSCs were first experimentally defined in hematopoietic malignancies by Lapidot and colleagues in 1994 \[[@B13]\]. Al-Hajj et al., in 2003, using breast tumors cells concluded that CSCs were heterogeneous in nature and a few cells isolated from primary breast cancers were capable of initiating tumors, whereas tens of thousands of phenotypically different cells did not \[[@B14]\].
The most common characteristics of CSCs were described as those cells having anchorage independent growth and metastasizing capacity, active membrane transporter activity, ability to survive for a long time, resistance to damaging agents, self-renewal capacity, active telomerase expression (telomere "shortening" leads to chromosomal instability), and differentiation capacity to mature progeny \[[@B15]\].
Gao in 2008 identified precancerous stem cells (pCSCs) in cancer and suggested that both pCSC and CSC might also serve as precursors of tumor stromal components such as tumor vasculogenic stem/progenitor cells (TVPCs). Thus, he suggested, the developing process of tumor-initiating cells (TIC) is initiated from pCSC leading to CSC and later cancer, a cellular process that parallels the histological process of hyperplasia/metaplasia (TIC) from precancerous lesions (pCSC) into malignant lesions (CSC → cancer) \[[@B16]\].
2.3. Signaling Pathways for Maintenance of CSCs {#sec2.3}
-----------------------------------------------
Some of the most important signals enumerated in maintaining stem cell proliferation in tumorigenesis are Oct-4, Notch, Wnt/Catenin, bone morphogenic protein (BMP), Sonic Hedgehog signalling pathway, Mushashi-1 (Msi-1), and so forth \[[@B17]\]. Oct-4 is normally expressed in the inner cell mass of the embryo and maintains totipotency. Notch, normally expressed in vasculature, activates endothelial cells and promotes angiogenesis. Wnt/Catenin affects orientation of chromosomes during mitotic divisions and plays a role in proliferation and inhibits apoptosis. Bone morphogenic proteins (BMP) are members of tissue growth factor-*β* (TGF-*β*) superfamily and function as oncogenes and tumour suppressors sometimes. Sonic Hedgehog signalling pathway is a major regulator of some of the fundamental processes including stem cell maintenance, cell differentiation, tissue polarity, and cell proliferation \[[@B18]\].
2.4. Methods of Identification of CSCs {#sec2.4}
--------------------------------------
CSC expresses specific markers that vary considerably depending on tumor type or tissue of origin---the discovery of a universal marker has not yet been made. General methods for the identification of CSCs in solid malignancies are similar to those strategies employed to differentiate normal stem cells from their differentiated progeny. The list of potential markers of CSCs includes CD133, CD44, CD24 (in combination with CD44) efflux of Hoechst or Rhodamine dyes, CD90, CD117, CD34, and CD20. This list also includes the efflux of vital dyes by multidrug transporters, the enzymatic activity of aldehyde dehydrogenase (ALDH), colony and sphere-forming assays utilizing specific culture conditions, and the expression of specific cell surface antigens known to enrich for stem cells \[[@B3]\].
The most commonly applied among them are as follows.Xenotransplantation assays, the gold-standard for identification of CSCs, are used to assess the tumorigenicity and self-renewing potential of the putative CSC population.CD44, the most well-recognized CSC marker, is a large cell surface glycoprotein that is involved in cell adhesion and migration.ALDH (aldehyde dehydrogenase, an intracellular enzyme normally present in the liver) activity is known to enrich hematopoetic stem/progenitor cells and recently has been revealed to enrich cells with increased stem like properties in solid malignancies \[[@B19]\].
2.5. Hypoxia and CSCs {#sec2.5}
---------------------
Hypoxia instigates cell demise by apoptosis/necrosis, it also prevents cell death by provoking adaptive responses that, in turn, facilitate cell proliferation or angiogenesis, causative to tumor progression \[[@B20]\]. In addition, studies confirm that hypoxia inhibits tumor cell differentiation and promotes maintenance of cancer stem cells and blocks the differentiation of mesenchymal stem/progenitor cells, a potential source of tumor-associated stromal cells. So an undifferentiated hypoxic microenvironment may be the initiator of cellular interactions and environmental signals for the preferential maintenance of cancer stem cells \[[@B21]\].
Evidence till date is suggestive of the fact that these hypoxic areas within a tumor are considered as a niche where CSCs reside. It is stated that effects of hypoxia on stem cell function are directly mediated by the hypoxia inducible factors (HIF). HIF function, as a master transcription factor, regulates hypoxia responsive genes. The molecular relationship between HIF signaling pathway with the biology of CSCs and epithelial mesenchymal transition (EMT) remains unclear although NF-*κ*B, PI3K/Akt/mTOR, Notch, Wnt/*β*-catenin, and Hedgehog signaling pathways have been recognized as important regulators of CSCs and EMT \[[@B22]\]. The links between the HIFs, Notch, and Oct-4 have revealed specific molecular mechanisms whereby oxygen responses can inhibit differentiation and promote stem cell identity \[[@B23]\]. By stimulating the expression or activity of Oct-4, Notch, and other critical signaling pathways, HIF stabilization in hypoxic tumor cells enhances stem cell properties, including self-renewal and multipotency \[[@B24]\].
Emerging experimental evidence indicates that hypoxia also plays an important role in the regulation of the phenotype and function of CSCs consistent with recent findings in glioma CSC. It has been shown that hypoxia is able to maintain the stem-like phenotypes in neuroblastomas and activate signaling pathways that are associated with undifferentiated phenotypes of normal stem cells, including sex determining region Y box 2 (Sox2), Oct-4, and Notch-1 signaling \[[@B25]\]. Both HIF-1*α* and HIF-2*α* are associated with tumor aggressiveness; HIF-1*α* promotes the phenotype and function of CSCs, whereas HIF-2*α* is highly expressed in CSCs; also known as TIC of neuroblastoma, glioblastoma, renal cell carcinoma, and breast carcinoma are associated with unfavorable disease outcome \[[@B24]\].
2.6. Metastatic Niche and CSCs {#sec2.6}
------------------------------
The CSC niche main role is to dedifferentiate nontumorigenic cells into tumorigenic CSCs and to induce the EMT, leading to dissemination of tumor cells from the primary tumor and further seeding at the metastatic place. Supporting cells of these niche release a number of molecular factors that have been identified to control stem cell identity. These factors include components of the BMP, Notch, Wnt, JAK-STAT, and Shh signaling pathways, which provide intercellular cues that regulate stem cell identity and differentiation \[[@B26], [@B27]\].
It has been unveiled that a premetastatic niche is established by the attraction of bone marrow derived cells to the future site of metastases by the secretion of factors from cancer cells \[[@B28]\]. The niche protects CSCs via differentiation and apoptosis and maintains self-regeneration via cell-cell and cell-matrix interactions which play a fundamental role in resistance to chemotherapy and radiotherapy and contribute to the genetic instability of CSCs \[[@B15]\]. The hypothesis of this niche, possibly for the arrival of CSCs to form a metastasis, appears to be a crucial step in metastatic spread.
3. CSCs Role in HNSCC Progression {#sec3}
=================================
3.1. CSCs and EMT Coexistence in HNSCC {#sec3.1}
--------------------------------------
EMT is a process by which epithelial cells lose their polarity and are converted to a migrant mesenchymal phenotype. In recent times, it has been considered as one of the fundamental steps that induces invasion and metastasis of tumors during cancer progression \[[@B29]\]. Similarly in HNSCC tumor microenvironment, connection between EMT and stem cell (SCs)/CSCs properties has drawn a great deal of research effort. In head and neck tumors, the overexpression of tyrosine kinase receptor B corresponds to an altered expression of the molecular mediators of EMT, including the downregulation of E-cadherin and the upregulation of Twist (a transcription factor that regulates differentiation, adhesion, and proliferation) \[[@B30]\]. Along with these modifications, the unique stem cell "niche" or environment is necessary to support the growth of stem cells \[[@B31]\].
3.2. CSCs Detection in HNSCC {#sec3.2}
----------------------------
Till date, very few studies have been conducted using HNSCC tissue for CSC marker identification. Markers such as aldehyde dehydrogenase (ALDH), CD133, and CD44 have been successfully used to identify highly tumorigenic cancer stem cells in HNSCC. Prince et al., in 2007, were the first ones to unveil the presence of highly tumorigenic, stem-like cells in HNSCC using primary tumor specimens as one-third of their samples \[[@B32]\]. In a follow-up study evaluating ALDH activity as a CSC marker in HNSCC, all samples were from primary tumors \[[@B33]\]. Later, Chen et al. showed that ALDH activity correlated with disease staging in HNSCC and that higher enzymatic activity correlated with expression of EMT genes as well as enriching cells with CSC properties \[[@B34]\]. In addition, ALDH activity appears to enrich CSCs in HNSCC to a higher degree than that currently provided by cell sorting based on surface antigen expression. In [Table 1](#tab1){ref-type="table"}, we have tried to summarize the molecular markers that have been used for detection of cancer stem cells mostly in head and neck region \[[@B35]--[@B43]\]. Though CD44 is generally accepted as a surrogate marker for head and neck squamous carcinoma cancer stem cells (HNSC CSCs) \[[@B32]\], in a recent study by Oh et al., in 2013, comparing in vitro stem-like cell characteristics, chemoresistance, and in vivo tumour formation capacity of CD44+ and CD44− HNSC cells obtained from primary HNSCC patient specimens, it was suggested that CSCs themselves hold the ability to be heterogenous due to various genetic alterations and hence cannot be used as a selective marker of spheroid-forming, tumour-initiating, or chemoresistant cell populations \[[@B44]\]. As suggested by Zhang et al., in 2009, Hoechst 33342 dye by the ATP-binding cassette transporter (ABC) can also be used to identify side-population cells in HNSCC which have been shown to increase clonality and tumorigenic potential \[[@B45]\].
Lim et al. later isolated sphere-forming cells (squamospheres) from primary HNSCCs and characterized their stem cell properties like self-renewal, stem cell marker expression, aberrant differentiation, and tumor-initiating potential. Furthermore, these HNSCC-driven squamospheres appeared to be chemoresistant to cisplatin, 5-fluorouracil (FU), paclitaxel, and doxetaxel and showed increased levels of ABCG2, one of the ATP-binding cassette (ABC) transporters. So accordingly the functional analysis of these squamospheres may provide a new insight into the tumorigenic process of HNSCC \[[@B46]\]. But irrespective of all the above data, another study by Ishizawa et al. demonstrated a counteracting result that TICs are rare in human pancreatic adenocarcinoma, lung squamous cell carcinoma, lung adenocarcinoma, and HNSCC, despite the use of highly permissive xenotransplantation conditions \[[@B47]\].
4. CSCs Responsibility in Progression of Oral Squamous Cell Carcinoma (OSCC) {#sec4}
============================================================================
4.1. CSCs Link with Oral Mucosa {#sec4.1}
-------------------------------
Oral mucosa consists of a number of distinct layers and has self-renewing capacity, such as bone marrow and skin. Mostly the basal layer cells are in the process of preparing for cell division, which later remain or move to a suprabasal position and become committed to terminal differentiation and stratification. The first hypothesis recommended that the CSCs in oral squamous cell carcinoma (OSCC) could be from local basal layer-derived adult SC or progenitor, which accumulate additional genetic alterations with time, within the tumor. The other proposed mechanism suggested the origin of CSCs to be either putative nonepithelial stem cell sources in the oral mucosa (which include vessel wall-derived cells, blood-derived stem cells, muscle-derived stem cells, and adipose-derived stem cell) or due to cell fusion between a hematopoietic stem cell and a mutated oral keratinocyte or can also originate through dedifferentiation of mature cells \[[@B48]\].
After understanding the possible role of CSCs in HNSCC, Oliveira et al. tried to find the possible influences of these CSCs in oral squamous cell carcinoma using CD44 and CD24. They suggested in their result that the absence of immunoexpression of these two investigated markers can be used in combination with other clinicopathologic information to improve the assessment of prognosis in OSCC \[[@B49]\].
4.2. CSCs, OSCC, EMT, and Hypoxia {#sec4.2}
---------------------------------
Costea et al. in their hypothesis suggested a potential involvement of the stromal microenvironment OSCC progression. As already known, the activated fibroblasts (myofibroblasts) inside the tumor stroma stimulate the transformed keratinocytes, thus influencing stem cell division patterns and with further genetic alterations of these keratinocytes leads to evolution of more invasive clones \[[@B50]\]. OSCC is found to rely on hypoxia cellular response system for tumor progression. Focal hypoxia which is found in OSCC also may be due to quantitative and qualitative alterations in tumor vasculature, leading to local reduction of oxygen availability \[[@B51]\].
5. Therapeutic Approach {#sec5}
=======================
CSCs seem to harbor mechanisms that are found to be responsible for therapy resistance in glioblastoma and pancreatic cancer, and recently in colon cancer as well \[[@B52]\]. It has been concluded that stromal environment and CSC niche play a vital role in the behavior of cancer cells. So, targeting the stem cell niche directly can weaken the source of nutrition and change the essential signals needed by CSCs to proliferate. Therapeutic strategies as suggested by Tang et al. included targeting candidate cancer stem cells and their microenvironmental niche, which contributes to self-renewal of these cells along with the reactive oxygen species (ROS) status of these cells, and tweaking their intracellular milieu to facilitate apoptotic death signals over proliferative effects may facilitate a new prospective towards target therapy in cancers \[[@B53]\]. Similarly, Krishnamurthy and Nor proposed a hypothetical model for the response of HNSCC to different therapeutic strategies. As earlier established, these slow-growing cancer stem cells in HNSCC evade conventional therapies, so targeting the cancer stem cells either directly or viatheir niche could lead to a more definitive response. They suggested an emerging concept of combining the use of conventional chemotherapy and cancer stem cell-targeted therapy \[[@B4]\].
Hypoxia has been understood to play a key role in tumor progression and hypoxic tumor microenvironment in turn has a control over the CSCs. So, when the antiangiogenic agents are administered in combination with CSC-targeted drugs, more effective results are attained in cancer therapy, along with inhibiting hypoxia inducible factors (HIF) \[[@B54]\]. CSCs are less sensitive to chemo- and radiotherapy and also have a lower immunogenicity. They contribute to tumor dormancy by having a slow cell cycle kinetics (quiescent state) which protects CSCs from chemoradiotherapy \[[@B55]\]. Iwasaki and Suda postulated that CSCs are resistant to traditional chemotherapy, because most of the current anticancer drugs target tumor growth by inhibiting DNA synthesis or cell division of actively dividing cancer cells, as CSCs are frequently in a quiescent state \[[@B56]\]. So missing these quiescent CSCs can lead to resistance and relapse and may even enrich CSCs for a more resistant state.
So, the therapeutic aspect should lead to target hypoxia curbing these hypoxic niches by HIF-inhibitors, NF*κ*B-inhibitors, nutraceuticals, and antioxidant therapy. NF*κ*B degradation by inhibitor of *κ*B (I*κ*B) proteins may be a useful therapeutic solution under such circumstances. It has also been suggested that treatment with echinomycin blocks the hypoxia-induced stroma \[[@B57]\].
6. Conclusions {#sec6}
==============
The confrontation in the years to come will be how to determine the contribution of each model to tumor growth in a given patient and how we can use that information to design more effective therapeutic strategy. Identification of reliable markers is required to characterize CSCs in HNSCC and OSCC in particular as this could ensure the clinical effectiveness of future targeted treatments, possibly resulting in a more effective outcome.
Conflict of Interests
=====================
The authors declare that there is no conflict of interests regarding the publication of this paper.
{#fig1}
######
Molecular markers implicated in HNSCC cancer stem cell detection.
Reference Stem cell marker Cancer cell lines studied
--------------------------------------- ------------------------------------------------------ -------------------------------------------------------
Barth et al., 2004 \[[@B35]\] CD34, CD117 (receptor of stem cell factor, SCF) Oral cavity, pharynx, and larynx (stromal fibrocytes)
Kojc et al., 2005 \[[@B36]\] CD34, transforming growth factor beta 1 (TGF beta 1) Larynx
Tan et al., 2006 \[[@B37]\] Stem cell factor Nasopharynx (plasma)
Prince et al., 2007 \[[@B32]\] CD44, BMI 1 HNSCC generated in immunodeficient mouse model
Zhou et al., 2007 \[[@B38]\] CD133 HNSCC cell lines (hep-2)
Pries et al., 2008 \[[@B39]\] CD44 Hypopharynx, larynx, and oropharynx
Chiou et al., 2008 \[[@B40]\] Oct-4, Nanog, and CD133 Oral squamous cell carcinoma stem like cells
Chen et al., 2009 \[[@B41]\] Bmi-1 1, Pakt (+) CD133, CD44, Nanog, and Oct-4 (−) Tongue (SASVO3)
Chen et al., 2009 \[[@B34]\] Aldehyde dehydrogenase 1 (ALDH) Immunodeficient mouse model
Y. Wu and P. Y. Wu, 2009 \[[@B42]\] CD133 Head and neck squamous cell carcinoma
Krishnamurthy et al., 2010 \[[@B43]\] Aldehyde dehydrogenase (ALDH) Head and neck squamous cell carcinoma
[^1]: Academic Editor: Malayannan B. Subramaniam
| 2023-10-16T01:26:57.367551 | https://example.com/article/3906 |
package com.handsomezhou.contactssearch.view;
import android.annotation.SuppressLint;
import android.content.Context;
import android.text.Editable;
import android.text.TextUtils;
import android.text.TextWatcher;
import android.util.AttributeSet;
import android.view.LayoutInflater;
import android.view.MotionEvent;
import android.view.View;
import android.view.View.OnClickListener;
import android.view.View.OnLongClickListener;
import android.widget.Button;
import android.widget.EditText;
import android.widget.LinearLayout;
import com.handsomezhou.contactssearch.R;
import com.handsomezhou.contactssearch.util.ViewUtil;
public class T9TelephoneDialpadView extends LinearLayout implements OnClickListener, OnLongClickListener {
private static final char DIAL_X_SECOND_MEANING = '+';
private static final char DIAL_0_SECOND_MEANING = ' ';
private static final char DIAL_J_SECOND_MEANING = '-';
/**
* Interface definition for a callback to be invoked when a
* T9TelephoneDialpadView is operated.
*/
public interface OnT9TelephoneDialpadView {
void onAddDialCharacter(String addCharacter);
void onDeleteDialCharacter(String deleteCharacter);
void onDialInputTextChanged(String curCharacter);
void onHideT9TelephoneDialpadView();
}
private Context mContext;
/**
* Inflate Custom T9 phone dialpad View hierarchy from the specified xml
* resource.
*/
private View mDialpadView; // this Custom View As the T9TelephoneDialpadView
// of children
private Button mTelephoneDialCloseBtn;
private Button mDialDeleteBtn;
private EditText mT9InputEt;
private OnT9TelephoneDialpadView mOnT9TelephoneDialpadView = null;
public T9TelephoneDialpadView(Context context, AttributeSet attrs) {
super(context, attrs);
mContext = context;
initView();
initData();
initListener();
}
public void show() {
ViewUtil.showView(this);
}
public void hide() {
ViewUtil.hideView(this);
}
private void initData() {
}
private void initView() {
LayoutInflater inflater = (LayoutInflater) mContext
.getSystemService(Context.LAYOUT_INFLATER_SERVICE);
mDialpadView = inflater.inflate(R.layout.t9_telephone_dialpad_layout,
this);
mTelephoneDialCloseBtn = (Button) mDialpadView
.findViewById(R.id.telephone_dial_close_btn);
mDialDeleteBtn = (Button) mDialpadView
.findViewById(R.id.dial_delete_btn);
mT9InputEt = (EditText) mDialpadView
.findViewById(R.id.dial_input_edit_text);
mT9InputEt.setCursorVisible(false);
}
private void initListener() {
mTelephoneDialCloseBtn.setOnClickListener(this);
mDialDeleteBtn.setOnClickListener(this);
mDialDeleteBtn.setOnLongClickListener(new OnLongClickListener() {
@Override
public boolean onLongClick(View v) {
deleteAllDialCharacter();
return true;
}
});
/**
* set click listener for button("0-9",'*','#')
*/
for (int i = 0; i < 12; i++) {
View v = mDialpadView.findViewById(R.id.dialNum1 + i);
v.setOnClickListener(this);
}
/**
* set long click listener for button('*','0','#')
* */
View viewX = mDialpadView.findViewById(R.id.dialx);
viewX.setOnLongClickListener(this);
View viewO = mDialpadView.findViewById(R.id.dialNum0);
viewO.setOnLongClickListener(this);
View viewJ = mDialpadView.findViewById(R.id.dialj);
viewJ.setOnLongClickListener(this);
mT9InputEt.addTextChangedListener(new TextWatcher() {
@Override
public void onTextChanged(CharSequence s, int start, int before,
int count) {
// TODO Auto-generated method stub
}
@Override
public void beforeTextChanged(CharSequence s, int start, int count,
int after) {
// TODO Auto-generated method stub
}
@Override
public void afterTextChanged(Editable s) {
if (null != mOnT9TelephoneDialpadView) {
String inputStr=s.toString();
mOnT9TelephoneDialpadView.onDialInputTextChanged(inputStr);
mT9InputEt.setSelection(inputStr.length());
// Toast.makeText(mContext,
// "onDialInputTextChanged[" + s.toString() + "]",
// Toast.LENGTH_SHORT).show();
}
}
});
mT9InputEt.setOnTouchListener(new OnTouchListener() {
@SuppressLint("ClickableViewAccessibility")
@Override
public boolean onTouch(View v, MotionEvent event) {
// In order to prevent the soft keyboard pops up,but also can
// not make EditText get focus.
return true; // the listener has consumed the event
}
});
}
@Override
public void onClick(View v) {
switch (v.getId()) {
case R.id.telephone_dial_close_btn:
hideT9TelephoneDialpadView();
if (null != mOnT9TelephoneDialpadView) {
mOnT9TelephoneDialpadView.onHideT9TelephoneDialpadView();
}
break;
case R.id.dial_delete_btn:
deleteSingleDialCharacter();
break;
case R.id.dial_input_edit_text:
break;
case R.id.dialNum0:
case R.id.dialNum1:
case R.id.dialNum2:
case R.id.dialNum3:
case R.id.dialNum4:
case R.id.dialNum5:
case R.id.dialNum6:
case R.id.dialNum7:
case R.id.dialNum8:
case R.id.dialNum9:
case R.id.dialx:
case R.id.dialj:
addSingleDialCharacter(v.getTag().toString());
break;
default:
break;
}
}
@Override
public boolean onLongClick(View v) {
switch (v.getId()) {
case R.id.dialx:
addSingleDialCharacter(String.valueOf(DIAL_X_SECOND_MEANING));
break;
case R.id.dialNum0:
addSingleDialCharacter(String.valueOf(DIAL_0_SECOND_MEANING));
break;
case R.id.dialj:
addSingleDialCharacter(String.valueOf(DIAL_J_SECOND_MEANING));
break;
default:
break;
}
return true;
}
public OnT9TelephoneDialpadView getOnT9TelephoneDialpadView() {
return mOnT9TelephoneDialpadView;
}
public void setOnT9TelephoneDialpadView(
OnT9TelephoneDialpadView onT9TelephoneDialpadView) {
mOnT9TelephoneDialpadView = onT9TelephoneDialpadView;
}
public EditText getT9InputEt() {
return mT9InputEt;
}
public void setT9InputEt(EditText t9InputEt) {
mT9InputEt = t9InputEt;
}
public void deleteSingleDialCharacter() {
String curInputStr = mT9InputEt.getText().toString();
if (curInputStr.length() > 0) {
String deleteCharacter = curInputStr.substring(
curInputStr.length() - 1, curInputStr.length());
if (null != mOnT9TelephoneDialpadView) {
mOnT9TelephoneDialpadView
.onDeleteDialCharacter(deleteCharacter);
}
String newCurInputStr=curInputStr.substring(0,curInputStr.length() - 1);
mT9InputEt.setText(newCurInputStr);
mT9InputEt.setSelection(newCurInputStr.length());
if(TextUtils.isEmpty(newCurInputStr)){
ViewUtil.hideView(mDialDeleteBtn);
}else{
ViewUtil.showView(mDialDeleteBtn);
}
}
}
public void deleteAllDialCharacter() {
String curInputStr = mT9InputEt.getText().toString();
if (curInputStr.length() > 0) {
String deleteCharacter = curInputStr.substring(0,
curInputStr.length());
if (null != mOnT9TelephoneDialpadView) {
mOnT9TelephoneDialpadView
.onDeleteDialCharacter(deleteCharacter);
}
mT9InputEt.setText("");
ViewUtil.hideView(mDialDeleteBtn);
}
}
private void addSingleDialCharacter(String addCharacter) {
String preInputStr = mT9InputEt.getText().toString();
if (!TextUtils.isEmpty(addCharacter)) {
mT9InputEt.setText(preInputStr + addCharacter);
mT9InputEt.setSelection(mT9InputEt.getText().length());
if (null != mOnT9TelephoneDialpadView) {
mOnT9TelephoneDialpadView.onAddDialCharacter(addCharacter);
}
ViewUtil.showView(mDialDeleteBtn);
}
// Toast.makeText(mContext, "addSingleDialCharacter[" + addCharacter +
// "]",
// Toast.LENGTH_SHORT).show();
}
public void showT9TelephoneDialpadView() {
if (this.getVisibility() != View.VISIBLE) {
this.setVisibility(View.VISIBLE);
}
}
public void hideT9TelephoneDialpadView() {
if (this.getVisibility() != View.GONE) {
this.setVisibility(View.GONE);
}
}
public int getT9TelephoneDialpadViewVisibility() {
return this.getVisibility();
}
public String getT9Input() {
return mT9InputEt.getText().toString();
}
public void clearT9Input() {
mT9InputEt.setText("");
}
}
| 2024-07-13T01:26:57.367551 | https://example.com/article/7062 |
The Fort Calhoun, Nebraska, Nuclear power plant is going down fast due to massive flooding.
The Omaha Public Power District has declared a Notification of Unusual Event (NOUE).
The FAA has issued the following directive, shutting down airspace over the plant:
FDC 1/6523 ZMP FLIGHT RESTRICTIONS FORT CALHOUN NUCLEAR POWER PLANT BLAIR,NE EFFECTIVE IMMEDIATELY UNTIL FURTHER NOTICE. PURSUANT TO 14 CFR SECTION 91.137(A)(3) TEMPORARY FLIGHT RESTRICTIONS ARE IN EFFECT FOR FLOOD RELIEF EFFORTS WITHIN A 2 NAUTICAL MILE RADIUS OF 413113N/0960438W OR THE OMAHA /OVR/ VORTAC 316 DEGREE RADIAL AT 26.1 NAUTICAL MILES AT AND BELOW 3500 FEET MSL. NEBRASKA STATE PATROL, LT. FRANK PECK TELEPHONE 402-450-1867 IS IN CHARGE OF THE OPERATION. MINNEAPOLIS /ZMP/ ARTCC TELEPHONE 651-463-5580 IS THE FAA COORDINATION FACILITY.
Location: Ft. Calhoun, NE (19 miles N of Omaha, NE) in Region IV
Operator: Omaha Public Power District
Operating License: Issued – 08/09/1973
Renewed License: Issued – 11/04/2003
License Expires: 08/09/2033
Docket Number: 05000285
Reactor Type: Pressurized Water Reactor
Electrical Output: 500 MWe
Reactor Vendor/Type: Combustion Engineering
Containment Type: Dry, Ambient Pressure
ref:
Electrical Fire Knocks Out Spent Fuel Cooling at Nebraska Nuclear Plant
Fort Calhoun Nuclear Power Plant Spent Fuel Pool Cooling System Stopped Working For Hours
Nebraska Nuclear Plant Lost Cooling System After Fire
NRC Monitors Second Event at Neb. Nuclear Plant Following Fire, Disruption of Spent-Fuel Cooling
No Fly Zone Over Fort Calhoun Nuclear Plant Due to “Hazards”
Dam Danger, Flooding and Ft. Calhoun Nuclear Power Plant
Electrical Fire Knocks Out Spent Fuel Cooling at Nebraska Nuclear Plant
NRC monitors declared fire alert, flood dangers at Fort Calhoun nuclear station | 2023-10-13T01:26:57.367551 | https://example.com/article/3126 |
A serological and virological survey for evidence of infection with Newcastle disease virus in Australian chicken farms.
To determine the prevalence and distribution of antibodies to Newcastle disease virus on Australian chicken farms and to determine the pathotype and relationships of the Newcastle disease viruses present on those farms. A cross-sectional survey of 753 commercial chicken farms. The survey comprised a detailed questionnaire and collection of venous blood samples. The titre of antibodies to Newcastle disease virus was determined by haemagglutination inhibition. Virus isolation was conducted from cloacal and tracheal swabs taken from chickens in serologically positive flocks. Virus isolates were pathotyped on the basis of the deduced Fusion protein cleavage site determined by nucleotide sequencing of a 265 bp region of the genome in the region of the cleavage site. Antibody evidence of Newcastle disease virus infection was found on 300 of the 753 surveyed farms throughout all 11 geographic regions of the survey. The highest prevalence occurred in the Sydney basin, New South Wales and Victoria east regions. Antibody titres were also highest in the regions where serologically positive flocks were most prevalent. The 259 virus isolates revealed nine different RNA sequences. Of the nine virus groups isolated, the most common group W was identical in sequence to the V4 vaccine strain. Five of the other groups had novel RNA sequences in the region of the F protein cleavage site. Antibodies to Newcastle disease virus are highly prevalent in the Australian chicken flock but all identified strains were avirulent in nature. | 2023-08-02T01:26:57.367551 | https://example.com/article/7900 |
Credit: John Wilcox
Joel Hanrahan transformed himself from a 6.00 ERA starter with poor command to an All-Star closer with one of the most unhittable sliders in baseball. The Red Sox would be wise to study his journey, because in many respects it reads like a road map to redemption for Daniel Bard. | 2024-02-28T01:26:57.367551 | https://example.com/article/5727 |
//---------------------------------------------------------------------------
// This software is Copyright (c) 2014 Embarcadero Technologies, Inc.
// You may only use this software if you are an authorized licensee
// of an Embarcadero developer tools product.
// This software is considered a Redistributable as defined under
// the software license agreement that comes with the Embarcadero Products
// and is subject to that software license agreement.
//---------------------------------------------------------------------------
unit BaaS_ToDoForm;
interface
uses
System.SysUtils, System.Types, System.UITypes, System.Classes, System.Variants,
FMX.Types, FMX.Controls, FMX.Forms, FMX.Graphics, FMX.Dialogs, IPPeerClient,
FMX.ListView.Types, Data.Bind.GenData, Data.Bind.EngExt, Fmx.Bind.DBEngExt,
System.Rtti, System.Bindings.Outputs, Fmx.Bind.Editors, Data.Bind.Components,
FMX.Layouts, FMX.Memo, FMX.StdCtrls, FMX.Edit, Data.Bind.ObjectScope,
FMX.TabControl, FMX.ListView, REST.Backend.KinveyProvider,
System.Generics.Collections,REST.Backend.ServiceTypes,
System.Actions, FMX.ActnList;
type
TBaaSToDoList = class(TForm)
ToolBar1: TToolBar;
TabControl1: TTabControl;
ListView1: TListView;
TabItemList: TTabItem;
TabItemDetails: TTabItem;
PrototypeBindSource1: TPrototypeBindSource;
BindingsList1: TBindingsList;
EditTitle: TEdit;
LinkControlToFieldTitle: TLinkControlToField;
MemoDescription: TMemo;
LinkControlToFieldDescription: TLinkControlToField;
LinkListControlToField1: TLinkListControlToField;
ButtonAdd: TButton;
TabItemAdd: TTabItem;
MemoAddDescription: TMemo;
EditAddTitle: TEdit;
ButtonSaveAdd: TButton;
Layout1: TLayout;
ButtonCancelAdd: TButton;
TabItemEdit: TTabItem;
EditEditTitle: TEdit;
Layout2: TLayout;
ButtonEditSave: TButton;
ButtonEditCancel: TButton;
MemoEditContent: TMemo;
LinkControlToField1: TLinkControlToField;
LinkControlToField2: TLinkControlToField;
ActionList1: TActionList;
ActionAdd: TAction;
ActionAddSave: TAction;
ActionAddCancel: TAction;
ActionEditSave: TAction;
ActionEditCancel: TAction;
ButtonBack: TButton;
ActionEdit: TAction;
ActionBack: TAction;
Layout3: TLayout;
Button2: TButton;
ActionDelete: TAction;
Label1: TLabel;
ActionLabel: TAction;
ActionRefresh: TAction;
ActionNext: TAction;
ActionPrior: TAction;
SpeedButton2: TSpeedButton;
SpeedButton1: TSpeedButton;
Button3: TButton;
Layout5: TLayout;
RefreshList: TButton;
BottomToolbar: TToolBar;
ToolBar2: TToolBar;
ToolBar3: TToolBar;
ToolBar4: TToolBar;
procedure ListView1ItemClick(const Sender: TObject;
const AItem: TListViewItem);
procedure PrototypeBindSource1CreateAdapter(Sender: TObject;
var ABindSourceAdapter: TBindSourceAdapter);
procedure FormCreate(Sender: TObject);
procedure ActionAddExecute(Sender: TObject);
procedure ActionAddUpdate(Sender: TObject);
procedure ActionAddCancelExecute(Sender: TObject);
procedure ActionAddSaveExecute(Sender: TObject);
procedure ActionAddSaveUpdate(Sender: TObject);
procedure ActionEditSaveExecute(Sender: TObject);
procedure ActionEditCancelExecute(Sender: TObject);
procedure ActionEditExecute(Sender: TObject);
procedure ActionEditUpdate(Sender: TObject);
procedure ActionBackExecute(Sender: TObject);
procedure ActionBackUpdate(Sender: TObject);
procedure ActionDeleteExecute(Sender: TObject);
procedure ActionLabelUpdate(Sender: TObject);
procedure ActionRefreshExecute(Sender: TObject);
procedure ActionNextExecute(Sender: TObject);
procedure ActionNextUpdate(Sender: TObject);
procedure ActionPriorExecute(Sender: TObject);
procedure ActionPriorUpdate(Sender: TObject);
procedure ActionEditSaveUpdate(Sender: TObject);
public
type
TView = (List, Details, Add, Edit);
private
FBindSourceAdapter: TBindSourceAdapter;
FViewStack: TStack<TView>;
procedure ShowView(AView: TView);
function CurrentView: TView;
procedure AddItem(const ATitle, AContent: string);
function GetAdapter: TBindSourceAdapter;
function GetTitleField: TBindSourceAdapterField;
function GetContentField: TBindSourceAdapterField;
procedure PopView;
procedure PushView(const AView: TView);
procedure ShowNavigation(const AAction: TAction);
{ Private declarations }
public
{ Public declarations }
constructor Create(AOwner: TComponent); override;
destructor Destroy; override;
end;
var
BaaSToDoList: TBaaSToDoList;
implementation
{$R *.fmx}
uses DataModuleUnit1, ToDoItemTypes;
procedure TBaaSToDoList.ListView1ItemClick(const Sender: TObject;
const AItem: TListViewItem);
begin
PushView(TView.Details);
end;
procedure TBaaSToDoList.PrototypeBindSource1CreateAdapter(Sender: TObject;
var ABindSourceAdapter: TBindSourceAdapter);
begin
Assert(FBindSourceAdapter = nil);
FBindSourceAdapter := DataModule1.ItemAdapter;
ABindSourceAdapter := FBindSourceAdapter;
end;
constructor TBaaSToDoList.Create(AOwner: TComponent);
begin
inherited;
FViewStack := TStack<TView>.Create;
end;
function TBaaSToDoList.CurrentView: TView;
begin
if Self.TabControl1.ActiveTab = TabItemAdd then
Result := TView.Add
else if Self.TabControl1.ActiveTab = TabItemList then
Result := TView.List
else if Self.TabControl1.ActiveTab = TabItemEdit then
Result := TView.Edit
else if Self.TabControl1.ActiveTab = TabItemDetails then
Result := TView.Details
else
raise Exception.Create('Unexpected');
end;
destructor TBaaSToDoList.Destroy;
begin
FViewStack.Free;
inherited;
end;
procedure TBaaSToDoList.PushView(const AView: TView);
begin
FViewStack.Push(CurrentView);
ShowView(AView);
end;
procedure TBaaSToDoList.PopView;
begin
if FViewStack.Count > 0 then
ShowView(FViewStack.Pop);
end;
procedure TBaaSToDoList.FormCreate(Sender: TObject);
begin
TabControl1.ActiveTab := TabItemList;
TabControl1.TabPosition := TTabPosition.None;
DataModule1.RefreshAdapter;
DataModule1.ItemAdapter.Active := True;
end;
function TBaaSToDoList.GetAdapter: TBindSourceAdapter;
begin
Result := Self.PrototypeBindSource1.InternalAdapter;
end;
function TBaaSToDoList.GetContentField: TBindSourceAdapterField;
begin
Result := GetAdapter.FindField(TToDoNames.ContentProperty);
if Result = nil then
raise Exception.Create('Field not found');
end;
function TBaaSToDoList.GetTitleField: TBindSourceAdapterField;
begin
Result := GetAdapter.FindField(TToDoNames.TitleProperty);
if Result = nil then
raise Exception.Create('Field not found');
end;
procedure TBaaSToDoList.ActionAddCancelExecute(Sender: TObject);
begin
PopView;
EditAddTitle.Text := '';
MemoAddDescription.Text := '';
end;
procedure TBaaSToDoList.ActionAddExecute(Sender: TObject);
begin
PushView(TView.Add);
end;
procedure TBaaSToDoList.ActionAddSaveExecute(Sender: TObject);
begin
AddItem(EditAddTitle.Text, MemoAddDescription.Text);
MessageDlg(Format('"%s" added', [GetTitleField.GetTValue.ToString]), TMsgDlgType.mtInformation, [TMsgDlgBtn.mbOK], 0);
PopView;
EditAddTitle.Text := '';
MemoAddDescription.Text := '';
end;
procedure TBaaSToDoList.ActionAddSaveUpdate(Sender: TObject);
begin
//
end;
procedure TBaaSToDoList.ActionAddUpdate(Sender: TObject);
begin
case CurrentView of
TView.List:
(Sender as TAction).Visible := True;
else
(Sender as TAction).Visible := False;
end;
end;
procedure TBaaSToDoList.ActionBackExecute(Sender: TObject);
begin
if FViewStack.Count > 0 then
PopView
else
ShowView(TView.List);
end;
procedure TBaaSToDoList.ActionBackUpdate(Sender: TObject);
begin
case CurrentView of
TView.Details:
begin
(Sender as TAction).Text := 'List';
(Sender as TAction).Visible := True;
end
else
(Sender as TAction).Visible := False
end;
end;
procedure TBaaSToDoList.ActionDeleteExecute(Sender: TObject);
var
LTitle: string;
begin
LTitle := GetTitleField.GetTValue.ToString;
if MessageDlg(Format('Delete "%s"?', [LTitle]), TMsgDlgType.mtConfirmation, mbOKCancel, 0) <> mrCancel then
begin
FBindSourceAdapter.Delete;
MessageDlg(Format('"%s" deleted', [LTitle]), TMsgDlgType.mtInformation, [TMsgDlgBtn.mbOK], 0);
if FBindSourceAdapter.ItemIndex = -1 then
// No more records
ShowView(TView.List);
end;
end;
procedure TBaaSToDoList.ActionEditCancelExecute(Sender: TObject);
begin
if (not FBindSourceAdapter.Modified) or (MessageDlg('Cancel changes?', TMsgDlgType.mtConfirmation, mbOKCancel, 0) <> mrCancel) then
begin
FBindSourceAdapter.Cancel;
PopView;
end;
end;
procedure TBaaSToDoList.ActionEditExecute(Sender: TObject);
begin
PushView(TView.Edit);
end;
procedure TBaaSToDoList.ActionEditSaveExecute(Sender: TObject);
begin
FBindSourceAdapter.Post;
MessageDlg(Format('"%s" saved', [GetTitleField.GetTValue.ToString]), TMsgDlgType.mtInformation, [TMsgDlgBtn.mbOK], 0);
PopView;
end;
procedure TBaaSToDoList.ActionEditSaveUpdate(Sender: TObject);
begin
(Sender as TAction).Enabled := GetAdapter.Modified;
end;
procedure TBaaSToDoList.ActionEditUpdate(Sender: TObject);
begin
case CurrentView of
TView.Details:
(Sender as TAction).Visible := True;
else
(Sender as TAction).Visible := False;
end;
end;
procedure TBaaSToDoList.ActionLabelUpdate(Sender: TObject);
begin
case CurrentView of
TView.List: (Sender as TAction).Text := 'To Do List';
TView.Details: (Sender as TAction).Text := 'To Do Item';
TView.Add: (Sender as TAction).Text := 'Add To Do Item';
TView.Edit: (Sender as TAction).Text := 'Edit To Do Item';
end;
end;
procedure TBaaSToDoList.ShowNavigation(const AAction: TAction);
begin
case CurrentView of
TView.Details: AAction.Visible := True;
else
AAction.Visible := False;
end;
end;
procedure TBaaSToDoList.ActionNextExecute(Sender: TObject);
begin
GetAdapter.Next;
end;
procedure TBaaSToDoList.ActionNextUpdate(Sender: TObject);
begin
ShowNavigation(Sender as TAction);
if TAction(Sender).Visible then
TAction(Sender).Enabled := not GetAdapter.Eof;
end;
procedure TBaaSToDoList.ActionPriorExecute(Sender: TObject);
begin
GetAdapter.Prior;
end;
procedure TBaaSToDoList.ActionPriorUpdate(Sender: TObject);
begin
ShowNavigation(Sender as TAction);
if TAction(Sender).Visible then
TAction(Sender).Enabled := not GetAdapter.BOF;
end;
procedure TBaaSToDoList.ActionRefreshExecute(Sender: TObject);
begin
DataModule1.RefreshAdapter;
DataModule1.ItemAdapter.Active := True;
end;
procedure TBaaSToDoList.AddItem(const ATitle, AContent: string);
var
LAdapter: TBindSourceAdapter;
begin
LAdapter := GetAdapter;
LAdapter.Append;
GetTitleField.SetTValue(ATitle);
GetContentField.SetTValue(AContent);
LAdapter.Post;
end;
procedure TBaaSToDoList.ShowView(AView: TView);
begin
case AView of
List: Self.TabControl1.ActiveTab := TabItemList;
Details: Self.TabControl1.ActiveTab := TabItemDetails;
Add: Self.TabControl1.ActiveTab := TabItemAdd;
Edit: Self.TabControl1.ActiveTab := TabItemEdit;
else
raise Exception.Create('Unexpected');
end;
end;
end.
| 2023-09-18T01:26:57.367551 | https://example.com/article/4739 |
Microelectronic substrates and substrate assemblies typically include a semiconductor material having features, such as memory cells, that are linked with conductive lines. The conductive lines can be formed by first forming trenches or other recesses in the semiconductor material and then overlaying a conductive material (such as a metal) in the trenches. The conductive material is then selectively removed to leave conductive lines extending from one feature in the semiconductor material to another.
One technique for forming microelectronic features, such as capacitors, is to dispose the features in isolated containers within the microelectronic substrate. One typical process includes forming an aperture in a substrate material (such as borophosphosilicate glass or BPSG), coating the microelectronic substrate (including the walls of the aperture) first with a barrier layer and then with a conductive layer, and then overfilling the aperture with a generally nonconductive material, such as a photoresist material. The excess photoresist material, conductive layer material, and barrier layer material located external to the aperture are then removed using chemical-mechanical planarization or polishing (CMP). The capacitor is then disposed within the photoresist material in the aperture and coupled to other features of the microelectronic substrate with an overlying network of vias and lines.
One drawback with the foregoing container technique for forming capacitors is that during the CMP process, small particles of the conductive material removed from the conductive layer can become embedded in the photoresist material within the aperture. The embedded conductive material can cause short circuits and/or other defects in the capacitor that is subsequently formed in the aperture, causing the capacitor to fail. | 2023-12-20T01:26:57.367551 | https://example.com/article/6597 |
Acids, Bases and Cocaine Addicts
Duke University Medical Center, The North Carolina School of Science and Mathematics
This interactive module introduces high school students to basic biology and chemistry principles using the pharmacokinetics of cocaine and crack cocaine. Students earn how the structure of a drug affects whether it can be smoked and whether it can pass through a biological membrane. Also included is how the connections between the circulatory system and the lungs govern the speed at which drugs are delivered to the brain and differences in effects of drug that enter the brain quickly and those that enter more slowly. This is one of six modules from the Pharmacology Education Partnership that helps high school students learn biology and chemistry concepts through the study of drugs.
What’s In the Lesson Plan:
1 interactive module
Teacher instructional guide and notes
Content background information
Student handout
Classroom activities
Additional resources
Grade Level(s):
9101112
Student Skills Targeted:
Basic principles of acids and bases
Knowledge of the properties of a drug that define it as a weak acid or a weak base
National Drug and Alcohol Facts Week® and the National Drug and Alcohol Facts Week® logo design are registered marks of the U.S. Department of Health and Human Services. SHATTER THE MYTHS® is a trademark and service mark of the U.S. Department of Health and Human Services. SHATTER THE MYTHS® is a registered trademark of the U.S. Department of Health & Human Services (HHS). | 2024-03-17T01:26:57.367551 | https://example.com/article/8762 |
Development of a real-time PCR assay to control the illegal trade of meat from protected capercaillie species (Tetrao urogallus).
A rapid and highly species-specific real-time polymerase chain reaction (PCR) assay has been developed for the detection of capercaillie DNA (Tetrao urogallus) in meat and meat mixtures. The method combines the use of capercaillie-specific primers, that amplify a 142bp fragment of the mitochondrial 12S rRNA gene, and a positive control primer pair that amplifies a 141bp fragment of the nuclear 18S rRNA gene from eukaryotic DNA. SYBR(®) Green dye or TaqMan(®) fluorogenic probes were used to monitor the amplification of the target genes. Results obtained with the use of TaqMan(®) probes as detection platform increased the specificity of the real-time PCR assay in comparison with the results obtained using SYBR(®) Green. The proposed real-time PCR assay represents a rapid and straightforward method for the accurate identification of capercaillie that could be used by law enforcement agencies as a tool for the control of poaching and illegal trade of meat from this protected species. | 2023-11-15T01:26:57.367551 | https://example.com/article/6318 |
Thursday, May 5, 2011
RIP JACKIE COOPER
Legendary actor-director-producer Jackie Cooper has passed away at the age of 88. I won't go into deep details on his career as I couldn't possibly cover it as eloquently as others who knew the man may end up doing. I for one am looking forward to seeing any articles that may be forthcoming from Leonard Maltin and/or Richard W. Bann, authors of the essential "Our Gang: the Life & Times of the Little Rascals."
Some Cooper highlights include at least three iconic roles: Jack/Jackie in the "Our Gang" theatrical short subjects from Hal Roach Studios (better known to generations who saw the films on TV as "The Little Rascals"), beleaguered boxer Wallace Beery's son in "The Champ," and Daily Planet newspaper editor (and boss to Clark Kent, Lois Lane and Jimmy Olsen) in the "Superman" movies from the 1970s and '80s.
Shortly after he left the Our Gang series Cooper was nominated for Best Actor for the title role in 1931's "Skippy" (at the age of 9!). On top of that he had the title role (and was nominated for two Emmy awards) portraying TV's "Hennesey" (a navy lieutenant doctor - Cooper also produced the show) and directed two Emmy-winning TV episodes - one each of "M*A*S*H*" and "The White Shadow."
Of course, here at "Scared Silly" we're most interested in his work as an Our Gang/Little Rascals kid. He is perhaps most famous for being smitten with teacher Miss Crabtree (the lovely June Marlowe) in a pair of shorts, "Teacher's Pet" and "School's Out." To really get on-topic here, I have to mention "Bouncing Babies," which takes place on Halloween Day and features the Gang in spooky costumes ("The Haunted Closet" blog features several great screen grabs from it) and "Moan & Groan, Inc." a bona-fide old dark house entry for the kids. "When the Wind Blows" gets an "horror-onable mention" for its brief scare moments as well.
Here's a clip of Jackie and the gang coming face-to-face with a gorilla from the public domain short, "Bear Shooters" (mislabeled as "Bear Hunters" by whoever posted this YouTube clip, but that happens sometimes). Jackie's the kid sliding the bear trap across the ground starting at approximately 2:20. Thanks for all the memories, Jackie!
3 comments:
Paul,First saw Jackie Cooper in 1929 "Moan and Groan, Inc." in 1963-3 on WPIX-11; loved the whole set-up w/ Offisa Kennedy & Max Davidson's "Whack-a-Mole", Chinese Finger-cuffs(wonder if this is Kevin Smith's inspiration for "Chasing Amy") and the general hijinks of the whole cast!Especially menacing Max with his thick accent, "...fine noodle zoop, and crrranberrry sauce..." to a mock-terrified Farina.Mr. On
ARE YOU READY TO BE SCARED SILLY?
This blog is a companion piece to Paul Castiglia's forthcoming book of the same name, all about horror-comedy films like the classic features "Abbott & Costello Meet Frankenstein," the Bowery Boys’ “Master Minds” and Bob Hope's "The Ghost Breakers;" plus short subject spook-spoofs by comedy legends including Laurel & Hardy, the Little Rascals and the 3 Stooges; and such low-budget gems as "Zombies on Broadway" and "Bela Lugosi Meets a Brooklyn Gorilla."
The book will include a foreword by noted film and TV character actor, monster movie memorabilia collector and spook show reenactor Daniel Roebuck.
About Me
Paul Castiglia is a veteran comic book creator, having written and edited several comic books as well as compiling trade paperback collections. He has also written pop culture articles and essays for magazine and book publications, and done research for special projects related to vintage entertainment.
His past forays into horror-comedy include providing a chapter to the book MIDNIGHT MARQUEE ACTOR SERIES: VINCENT PRICE about the comedic horror films that Mr. Price co-starred in with Peter Lorre, and writing the comic book series ARCHIE'S WEIRD MYSTERIES for several years (based on the animated cartoon show of the same name and recently collected in paperback form).
Oh yeah, Paul's dad is the godfather of The Misfits' Jerry Only, further cementing his "horror business" credentials. :) | 2024-04-07T01:26:57.367551 | https://example.com/article/2423 |
Novel Approach to Adoptive Immunotherapy Developed by NexImmune's Scientific Co-Founders
GAITHERSBURG, MD--(Marketwired - Jul 15, 2015) - NexImmune, an early stage biopharmaceutical company, today announced the publication of a study from the laboratory of Dr. Jonathan Schneck of The Johns Hopkins University, a Scientific Co-founder of NexImmune, that reports the development of a new approach for adoptive cellular therapy. In this study artificial Antigen Presenting Cells (aAPC) were used to stimulate rapid ex-vivo Enrichment and Expansion (E+E) of tumor-specific T cells. Within a two-week period, these cancer fighting cells were expanded to numbers that represent potentially therapeutic levels -- when they could be adoptively transfused back into a patient in the form of cellular immunotherapy. This new technology can also be used to validate patient-specific neoantigens. Neoantigens are formed as a result of mutations arising in cancer cells and can be detected by a patient's T cells with the same strength as they may detect microbial antigens. Neoantigens have recently been described as clinically desirable targets for the development of personalized cancer immunotherapies.
Dr. Mathias Oelke, Scientific Co-founder and Senior Director of Discovery at NexImmune and co-author on the publication, noted the broad potential of this approach for the development of more efficacious, cost-effective, and safe cellular therapies: "Despite recent advances in cancer immunotherapies, multiple challenges to increasing the rate of induction of durable responses remain. These challenges are complex, and primarily due to tumor heterogeneity, escape mechanisms, lack of tumor immunogenicity and the ability to deliver safe, timely treatments in a scalable cost effective manner." Dr. Oelke continued, "Adoptive T cell therapy is a highly promising approach for treating a range of cancers. However, the available methods can be prohibitively expensive or may be associated with severe side effects. We believe the E+E method using aAPC represents a significant step forward as it provides for rapid expansion of the patient's own repertoire of cancer-fighting T cells that does not rely on any genetic manipulation or re-engineering of the T cell."
Noting that this approach could also lead to highly personalized cancer therapy, Professor Pedro Romero of the Ludwig Cancer Research Center and Associate Director of the Department of Fundamental Oncology, University Hospital in Lausanne, Switzerland, a leading researcher in the area of antigen-specific T cell biology, added, "Several recent discoveries have pointed to neoantigens that are uniquely expressed on each patient's tumor as very promising targets for the development of cancer immunotherapy. The development of the E+E method for validation of these neoantigens represents a significant breakthrough that should lead to more effective, safer and more individualized treatments."
NexImmune, Inc. holds an exclusive worldwide license to the Artificial IMmune (AIM™) technology from The Johns Hopkins University based on the aAPC technology originally developed by Drs. Schneck and Oelke. The Company's CEO, Ken Carter, noted, "The development of this aAPC-based E+E technology greatly expands the potential for aAPC-based products. We had been solely focused on the development of our first product, AIM 101, an injectable aAPC treatment of cancer. But, E+E provides the opportunity to develop a complementary multi-antigen specific adoptive cellular therapy that could deliver safe and effective treatments in a scalable and cost effective manner. We believe this technology may overcome the problems of tumor heterogeneity and escape."
About NexImmuneNexImmune is an early stage biopharmaceutical company developing novel immuno-therapeutics based on the proprietary Artificial IMmune (AIM™) nanotechnology platform. Central to the AIM™ technology are artificial Antigen Presenting Cells (aAPCs) that can be engineered to orchestrate a highly targeted immune attack directed toward specific foreign substances or cell types in the body. In pre-clinical studies, aAPCs have demonstrated potential utility as therapeutic agents and can also be used for the development of diagnostic products. NexImmune is focusing the AIM technology platform to develop a pipeline of products to treat cancer. For more information visit: www.neximmune.com | 2023-09-21T01:26:57.367551 | https://example.com/article/9285 |
Image copyright Getty Images Image caption Ethan Ampadu's father, Kwame, was a professional footballer
Chelsea's Ethan Ampadu insists he will not change his mind about representing Wales on the international stage.
The 17-year-old is still eligible to play for Wales, England, Ireland and Ghana as he is yet to make his competitive international debut, despite winning his first Wales caps.
However, Ampadu says he is not looking to change his decision to represent Wales.
"I will be hanging around with Wales," he told S4C's 'Mwy o Sgorio' programme.
Ampadu, who made his Exeter City debut as a 15-year old before his transfer to Chelsea in the summer of 2017, says he has always felt comfortable in the Wales set-up.
"I first got invited to an under-16 camp with Wales, I went along with that and I just enjoyed it from the very first moment," he added.
"I thought Wales would be the one. The togetherness, throughout all the age groups is a good atmosphere."
Ampadu made his Wales debut against France and also featured in Chris Coleman's last match as manager, against Panama. | 2023-11-20T01:26:57.367551 | https://example.com/article/7221 |
Antipruritic Effect of Cold-induced and Transient Receptor Potential-agonist-induced Counter-irritation on Histaminergic Itch in Humans.
A frequent empirical observation is that cold-induced counter-irritation may attenuate itch. The aim of this randomized, single-blinded, exploratory study was to evaluate the counter-irritation effects of cold-stimulation and topical application of transient receptor potential TRPA1/M8-agonists (trans-cinnamaldehyde/L-menthol, respectively), on histamine-induced itch, wheals and neurogenic inflammation in 13 healthy volunteers. Histamine 1% was applied to the volar forearms using skin prick-test lancets. Recorded outcome-parameters were itch intensity, wheal reactions, and neurogenic inflammation (measured by laser-speckle perfusion-imaging). Homotopic thermal counter-irritation was performed with 6 temperatures, ranging from 4°C to 37°C, using a 3 × 3-cm thermal stimulator. Chemical "cold-like" counter-irritation was conducted with 40% L-menthol and 10% trans-cinnamaldehyde, while 5% doxepin was used as a positive antipruritic control/comparator. Cold counter-irritation stimuli from 4°C to 22°C inhibited itch in a stimulus-intensity-dependent manner (p < 0.05) and, to a lesser extent, also wheal reactions and neurogenic inflammation. Chemical "cold-like" counter-irritation with both L-menthol and trans-cinnamaldehyde had antipruritic efficacy similar to doxepin (p < 0.05). Cold-induced counter-irritation had an inhibitory effect on histaminergic itch, suggesting that agonists of cold transduction receptors could be of potential antipruritic value. | 2024-06-23T01:26:57.367551 | https://example.com/article/4628 |
package com.epam.coroutinecache.utils
import com.epam.coroutinecache.annotations.EntryClass
import java.lang.reflect.GenericArrayType
import java.lang.reflect.Modifier
import java.lang.reflect.ParameterizedType
import java.lang.reflect.Type
import java.lang.reflect.WildcardType
/**
* Factory methods for types.
*/
object Types {
private val EMPTY_TYPE_ARRAY = emptyArray<Type>()
fun obtainTypeFromAnnotation(annotation: EntryClass): Type {
return if (annotation.typeParams.isEmpty()) {
if (annotation.rawType.javaObjectType.isArray) {
arrayOf(annotation.rawType.javaObjectType)
} else {
annotation.rawType.javaObjectType
}
} else {
@Suppress("SpreadOperator")
newParameterizedType(annotation.rawType.javaObjectType, *annotation.typeParams.map { obtainTypeFromAnnotation(it) }.toTypedArray())
}
}
/**
* Returns a new parameterized type, applying {@code typeArguments} to {@code rawType}.
*/
@Suppress("SpreadOperator")
fun newParameterizedType(rawType: Type, vararg types: Type): ParameterizedType = ParameterizedTypeImpl(null, rawType, arrayOf(*types))
/**
* Returns an array type whose elements are all instances of `componentType`.
*/
fun arrayOf(componentType: Type): GenericArrayType = GenericArrayTypeImpl(componentType)
fun canonicalize(type: Type): Type {
var result = type
when (type) {
is Class<*> -> {
if (type.isArray) result = GenericArrayTypeImpl(canonicalize(type.componentType))
}
is ParameterizedType -> {
if (type !is ParameterizedTypeImpl) result = ParameterizedTypeImpl(type.ownerType, type.rawType, type.actualTypeArguments)
}
is GenericArrayType -> {
if (type !is GenericArrayTypeImpl) result = GenericArrayTypeImpl(type.genericComponentType)
}
is WildcardType -> {
if (type !is WildcardTypeImpl) result = WildcardTypeImpl(type.upperBounds, type.lowerBounds)
}
}
return result
}
private class ParameterizedTypeImpl(
private var ownerType: Type?,
private var rawType: Type,
private var typeArguments: Array<Type?>
) : ParameterizedType {
init {
if (rawType is Class<*>) {
val isStaticOrTopLevelClass = Modifier.isStatic((rawType as Class<*>).modifiers) || (rawType as Class<*>).enclosingClass == null
if (ownerType == null && !isStaticOrTopLevelClass) throw IllegalArgumentException()
}
this.ownerType = if (ownerType == null) null else canonicalize(this.ownerType!!)
this.rawType = canonicalize(this.rawType)
typeArguments = typeArguments.filter { it != null }.map { canonicalize(it!!) }.toTypedArray()
}
override fun getRawType(): Type = rawType
override fun getOwnerType(): Type? = ownerType
override fun getActualTypeArguments(): Array<Type?> = typeArguments.clone()
}
private class GenericArrayTypeImpl(private var componentType: Type) : GenericArrayType {
init {
this.componentType = canonicalize(componentType)
}
override fun getGenericComponentType(): Type = componentType
}
/**
* The WildcardType interface supports multiple upper bounds and multiple lower bounds. We only
* support what the Java 6 language needs - at most one bound. If a lower bound is set, the upper
* bound must be Object.class.
*/
private class WildcardTypeImpl(upperBounds: Array<Type?>, lowerBounds: Array<Type?>) : WildcardType {
private var upperBound: Type?
private var lowerBound: Type?
init {
if (upperBounds.size != 1) throw IllegalArgumentException()
if (lowerBounds.size > 1) throw IllegalArgumentException()
if (lowerBounds.size == 1) {
if (lowerBounds[0] == null) throw NullPointerException()
if (upperBounds[0] !== Any::class.java) throw IllegalArgumentException()
this.lowerBound = canonicalize(lowerBounds[0]!!)
this.upperBound = Any::class.java
} else {
if (upperBounds[0] == null) throw NullPointerException()
this.lowerBound = null
this.upperBound = canonicalize(upperBounds[0]!!)
}
}
override fun getLowerBounds(): Array<Type> = if (lowerBound != null) arrayOf<Type>(lowerBound!!) else EMPTY_TYPE_ARRAY
override fun getUpperBounds(): Array<Type> = arrayOf<Type>(upperBound!!)
}
} | 2024-06-16T01:26:57.367551 | https://example.com/article/6990 |
1. Field of the Invention
The present invention relates to a medical capsule for conducting sampling of a humor or dosage of a medicine at a desired location inside a living body. The present invention also is concerned with an apparatus for activating such a medical capsule from the outside of the living body.
2. Description of the Prior Art
Hitherto, a medical capsule has been known as a device which conducts sampling of, for example, intestinal liquid, or dosage of a medicine at a predetermined location in a living body, for the purpose of diagnosis or medical treatment.
The medical capsule has a capsule-like hermetic casing having an openable portion. When such a medical capsule swallowed by a patient has reached a predetermined position inside the patient's body, the openable portion is opened so as to sample a humor such as a gastric juice or to dose a medicine charged in the capsule. Then, the capsule is discharged through anus of the patient and collected. Such a medical capsule is disclosed, for example, in Japanese Patent Publication Nos. 53-53182, 55-9033. 55-49853, 57-1255, 57-39776 and 61-11104.
This medical capsule is very small and can easily swallow without any pain and, hence, is attracting attention in the medical fields. In particular, the medical capsule, when used for the purpose of dosage, can directly dose the medicine to the affected part of the body, thus attaining a great medical treating effect. For instance, when this capsule is used against a cancer in an alimentary system, a remarkable carcinostatic effect without side-effect, thus offering a desired treating effect.
A known medical capsule for sampling will be described in more detail. As shown in FIG. 10, a medical capsule used for the sampling purpose has a hermetic casing 103 composed of a frame 101 and an outer cylinder 102. A piston 104 is movably received in the outer cylinder 102. As the piston 104 is moved, a vacuum region is produced in the outer cylinder 102 so that a gastric juice around the casing is sucked into the capsule through ports 105, 106, whereby the sampling of the gastric juice is conducted. This medical capsule for sampling is disclosed in Japanese Utility Model Publication No. 57-57684.
The piston 104 in this medical capsule operates by the springing force of a spring 107. Initially, the spring 107 is compressed and held in the compressed state by a fixing thread 108. After the capsule is swallowed by a patient, the position of the capsule is traced and monitored by an external monitoring device such as a roentgen apparatus. When the capsule has reached a predetermined position inside the body, a resonance of a resonance circuit is caused by an externally given radio wave so as to supply an electrical current to a filament 109. The fixing thread 108 is then molten by the heat generated by the filament 109 so that the piston 104 is projected by the resilient force of the spring 107, whereby the capsule sucks a gastric juice to complete the sampling.
FIG. 11 illustrates a known medical capsule used for the purpose of dosage. This capsule has a medicine chamber 110 in one end of which a piston 104 is received slidably, whereas a discharge port 112 formed in the other end of the medicine chamber 110 is normally closed by a plug 111. This medical capsule is disclosed, for example, in Japanese Patent Publication No. 55-49853. Other portions are materially the same as those of the medical capsule shown in FIG. 10. For information, the same reference numerals are used to denote the same parts as those appearing in FIG. 10 and the description of such parts is omitted herein.
In operation, the fixing thread 108 is cut by the same method as that described before, so that the piston 104 moves inside the outer cylinder 102 so that the medicine Y in the medicine chamber is pressurized to forcibly remove the plug 111 so as to be discharged from the capsule.
Various other methods have been proposed for externally activating medical capsules. For instance, the following four methods have been proposed. | 2024-06-18T01:26:57.367551 | https://example.com/article/8064 |
110
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Living in South Florida we almost take for granted that so many people have made the insane voyage from Cuba to Florida on a raft. With his new short film The Rafter local filmmaker Jose Navas wanted to bring to life that most harrowing of immigrant journeys. In the 19 minute movie set to debut at the Miami Film Festival March 8, The Rafter recounts the true story of Reinaldo Cruz, one of the first Cuban refugees to arrive on U.S. shores on a homemade raft.
Navas learned of Cruz’s story after the success of producing his first documentary Miami Our City. “I got an e-mail (from Cruz’s son) telling me I’ve got to read up on this story. I did some research about his trip in 1964. There seemed to be something there.” Though Navas isn’t Cuban, as a Nicaraguan he could relate to an immigrant coming to America to make a better life. “Plus,” he joked, “you’re almost half Cuban just living in Miami.”
Before co-writing the script Navas interviewed the still alive Reinaldo Cruz. He was struck by the hardships Cruz suffered. For storytelling purposes he had Cruz taking a solo trek rather than making the trip with four other people as he did in real life, but the obstacles shown in the film were taken directly from Cruz’s account. “The waves stood out the most in his memory. The height of the waves during a thunderstorm shocked him. There were slow moving 40 foot waves that scared him more than the sharks. They could hit the sharks with paddles. There was nothing you could do about the waves.”
For the film Navas used special effects to depict the sharks and waves. One of the most impressive facets of the independent movie comes from how he captured 1964 Cuba and the vastness of the sea using South Florida locations from 2017. “There were ten guys carrying a crap load of equipment in the middle of summer to get to a point in Virginia Key where you can see the ocean line and there are no boats.”
Navas knows the struggles of a filmmaker are nothing compared to what Cruz went through. He was grateful that Cruz could also contribute with some off-screen narration. “He’s close to 80 now and gets very emotional talking about it. He’s an important part of the history of Cuba and Miami.”
Navas hopes his film which after its Miami Film Festival premiere and a screening in April at FIU, will be streaming on YouTube, might help viewers appreciate immigrants more. “So many people died coming over here. It’s important to remember them and remember that we’re a country with people from everywhere.”
. | 2024-01-22T01:26:57.367551 | https://example.com/article/5517 |
Q:
Using vinkla/hashids package in Laravel 5.2
I am using vinkla/hashids and i have followed the following steps
composer require vinkla/hashids
Add the service provider to config/app.php in the providers array
If you want you can use the facade. Add the reference in config/app.php to your aliases array.
php artisan vendor:publish this step does not create hashid.php in config file
use Vinkla\Hashids\Facades\Hashids;
Hashids::encode(4815162342);
And i get error that hashids class not found
A:
It seems that the provider is not booting.
Try to do this:
php artisan config:clear
php artisan clear-compiled
The first will clear any cached config files, and the later will clear the services cache.
It worked for me, hope it works for you too.
I found the solution here: Laravel 5.2 Service provider not booting
| 2024-04-20T01:26:57.367551 | https://example.com/article/8386 |
Niki Terpstra
Niki Terpstra (; born 18 May 1984) is a Dutch racing cyclist, who currently rides for UCI ProTeam . He is the brother of fellow racing cyclist Mike Terpstra. He is the third Dutch cyclist to have won both of the cobbled Monument spring classics, Paris-Roubaix and the Tour of Flanders, after Jan Raas and Hennie Kuiper.
Career
Early life and career
Niki Terpstra was born on 18 May 1984 in Beverwijk in the Netherlands.
He was part of the silver medal winning team in the team pursuit in the 2005 UCI Track Cycling World Championships, together with Levi Heimans, Jens Mouris and Peter Schep. With a 4th place in the Three Days of De Panne followed by a 14th place at the 2008 Tour of Flanders, young Terpstra showed signs of considerable talent.
Between 2007 and 2010, Terpstra rode for the German . In 2009 Terpstra won the 3rd stage in the Critérium du Dauphiné Libéré, gaining the yellow leader jersey at the same time, keeping it for a day.
Quick-Step (2011–2018)
2011–2014
In 2011, Terpstra joined the Belgian UCI World Tour team.
In 2012, Terpstra took a prestigious victory at the Dwars door Vlaanderen, winning in solo fashion after being on the attack all day. He detached himself from the break on the Oude Kwaremont with Jelle Wallays of . He dropped Wallays on the Paterberg and finished the race with an advantage of 47 seconds over Frenchman Sylvain Chavanel.
In 2014 he won his first short stage race with the victory in the Tour of Qatar. Terpstra continued his good form in the classics, placing fifth in Omloop Het Nieuwsblad, winning the Dwars door Vlaanderen for the second time in his career, and placing sixth in the Tour of Flanders. On 13 April 2014 he won the Paris–Roubaix race in solo fashion, after attacking from the leading group of 11 riders with remaining.
2015
In 2015, Terpstra defended his Tour of Qatar title, holding the race lead after winning the individual time trial on Stage 3. At Omloop Het Nieuwsblad, Terpstra made the decisive breakaway of four riders with teammates Tom Boonen and Stijn Vandenbergh, along with Ian Stannard (). After Stannard closed down a Boonen attack in the closing stages Terpstra tried to counterattack, but Vandenbergh closed the gap, allowing Stannard to attack with only Terpstra able to follow. Stannard went on to beat Terpstra in the sprint finish. In March Terpstra had some success, first by getting the second position in the Ronde van Zeeland Seaports. He then got on the second step of the podium of a very windy Gent–Wevelgem, as he won the two-man sprint for second position after Luca Paolini had crossed the line solo. In his next race, the Tour of Flanders, he broke away from the peloton with Alexander Kristoff from the finish but could not beat Kristoff in the final sprint, completing the race in second place. In June, he won the Dutch National Road Race Championships in a bunch sprint, surprising the pure sprinters.
2016
In 2016, Terpstra won the Eneco Tour after a dramatic rain-swept final stage that saw former race leader Rohan Dennis () crash out. The stage featured cobbles and bergs used in the Classics first saw Dennis lose time, and then drop out completely due to his injuries. Terpstra, who started the final stage in fifth place overall, formed part of a front group of three riders and finished second behind stage winner Edvald Boasson Hagen ().
2018
In 2018, Terpstra won E3 Harelbeke, soloing to the line after initially attacking on the Taaienberg with teammate Yves Lampaert with more than remaining. Terpstra finished 20 seconds clear of an elite group, led home by his team-mate Philippe Gilbert, and he became the first Dutchman to win E3 Harelbeke since Steven de Jongh in 2003.
Terpstra won the Tour of Flanders with a late solo attack. After following an attack by Vincenzo Nibali () over the Kruisberg climb, Terpstra dropped the Italian soon after, then caught and quickly dispatched a trio of riders from an earlier breakaway on the final climb of the Oude Kwaremont. Terpstra remained clear over the remaining , finishing 12 seconds ahead of 's Mads Pedersen from the earlier breakaway, and by teammate and defending race-winner Gilbert who led the bunch home in third. It was his second ‘Monument’ victory and he became the first Dutch rider since Adri van der Poel in 1986 to win the Tour of Flanders. The following week, Terpstra claimed third place at Paris–Roubaix, leading home a group 57 seconds behind winner Peter Sagan () and Silvan Dillier ().
Direct Énergie (2019–present)
In 2019, Terpstra joined French team .
Major results
Track
2004
1st Scratch race, National Championships
2005
National Championships
1st Scratch race
1st Points race
2nd Team pursuit, UCI World Championships
2006
National Championships
1st Individual pursuit
1st Madison (with Wim Stroetinga)
2007
National Championships
1st Scratch race
1st Madison (with Wim Stroetinga)
2011
2nd Madison (with Yoeri Havik), National Championships
2013
1st Six Days of Rotterdam (with Iljo Keisse)
2014
1st Six Days of Rotterdam (with Iljo Keisse)
1st Six Days of Amsterdam (with Yoeri Havik)
2015
1st Six Days of Rotterdam (with Iljo Keisse)
2016
3rd Six Days of Rotterdam (with Yoeri Havik)
2019
1st Six Days of Rotterdam (with Thomas Boudat)
Road
2004
1st Stage 2 Ronde van Midden-Brabant
1st GP Wielerrevue
2005
1st Omloop der Kempen
2006
1st Ronde van Midden-Nederland
1st Stage 4 Tour of Belgium
1st Stage 6 Tour de Normandie
1st Stage 2 OZ Wielerweekend
2nd Ronde van Overijssel
2007
1st Mountains classification Deutschland Tour
3rd Hel van het Mergelland
2008
3rd Overall Bayern–Rundfahrt
4th Overall Three Days of De Panne
5th Dutch Food Valley Classic
Combativity award Stage 13 Tour de France
2009
1st Ridderronde Maastricht
1st Stage 3 Critérium du Dauphiné Libéré
2nd Overall Ster ZLM Toer
1st Prologue
9th Omloop Het Nieuwsblad
2010
1st Road race, National Road Championships
1st Sparkassen Giro Bochum
3rd Dwars door Vlaanderen
6th Overall Tour of Oman
2011
2nd Overall Ster ZLM Toer
6th Overall Tour of Belgium
6th Omloop Het Nieuwsblad
10th Overall Tour of Beijing
Combativity award Stage 15 Tour de France
2012
1st Team time trial, UCI Road World Championships
National Road Championships
1st Road race
3rd Time trial
1st Dwars door Vlaanderen
1st Amstel Curaçao Race
3rd Overall Eneco Tour
3rd Paris–Tours
5th Overall Three Days of De Panne
5th Paris–Roubaix
6th Tour of Flanders
2013
1st Team time trial, UCI Road World Championships
1st Stage 1 (TTT) Tirreno–Adriatico
National Road Championships
2nd Time trial
5th Road race
3rd Overall Driedaagse van West–Vlaanderen
3rd Overall Three Days of De Panne
3rd Paris–Roubaix
6th Grand Prix Cycliste de Québec
9th Overall Tour of Belgium
10th Paris–Tours
2014
1st Overall Tour of Qatar
1st Stage 1
1st Paris–Roubaix
1st Dwars door Vlaanderen
1st Amstel Curaçao Race
2nd Road race, National Road Championships
2nd E3 Harelbeke
3rd Team time trial, UCI Road World Championships
4th Overall Three Days of De Panne
5th Omloop Het Nieuwsblad
6th Tour of Flanders
9th Overall Tour of Belgium
2015
1st Road race, National Road Championships
1st Overall Tour of Qatar
1st Stage 3 (ITT)
1st Overall Tour de Wallonie
1st Stage 1
2nd Team time trial, UCI Road World Championships
2nd Tour of Flanders
2nd Omloop Het Nieuwsblad
2nd Ronde van Zeeland Seaports
2nd Gent–Wevelgem
8th Road race, European Games
2016
UCI Road World Championships
1st Team time trial
9th Road race
1st Overall Eneco Tour
1st Le Samyn
1st Dwars door het Hageland
10th Overall Tour of Belgium
10th Tour of Flanders
2017
3rd Tour of Flanders
3rd Paris–Tours
4th Gent–Wevelgem
2018
1st Team time trial, UCI Road World Championships
1st Tour of Flanders
1st E3 Harelbeke
1st Le Samyn
1st Stage 1 (TTT) Adriatica Ionica Race
2nd Time trial, National Road Championships
2nd Paris–Tours
3rd Paris–Roubaix
9th Dwars door Vlaanderen
9th Overall BinckBank Tour
2019
2nd Dwars door het Hageland
3rd Overall Tour Poitou-Charentes en Nouvelle-Aquitaine
3rd Kuurne–Brussels–Kuurne
3rd Le Samyn
3rd Circuit de Wallonie
5th Time trial, National Road Championships
7th Antwerp Port Epic
10th Chrono des Nations
10th Tour de Vendée
Grand Tour general classification results timeline
Monuments results timeline
See also
List of Dutch Olympic cyclists
References
External links
Palmares at Cycling Base
Category:1984 births
Category:Living people
Category:Dutch male cyclists
Category:Dutch track cyclists
Category:People from Beverwijk
Category:Cyclists at the 2008 Summer Olympics
Category:Cyclists at the 2012 Summer Olympics
Category:Olympic cyclists of the Netherlands
Category:Tour de France cyclists
Category:Vuelta a España cyclists
Category:UCI Road World Champions (elite men)
Category:UCI Road World Championships cyclists for the Netherlands
Category:European Games competitors for the Netherlands
Category:Cyclists at the 2015 European Games
Category:Sportspeople from North Holland | 2023-08-03T01:26:57.367551 | https://example.com/article/4129 |
NEW - STRONG HOLD
Introducing the NEW NO GUNK Matte Lava Clay: A 100% natural chemical-free styling clay made with mineral rich Moroccan Lava Clay. Expect a textured natural look with a matte finish. It's an all-natural blend of nourishment and style that fits in your pocket, perfect for travel & on the go. With it's supple lightweight consistency, there's no residue on your hands or hair after use. It smells so good you might even be tempted to eat it. Join the Matt Lava Clay revolution Funky Fellas. JUST FUNK!
MADE IN UK 🇬🇧 NO CRUELTY 🐏 | 2024-04-20T01:26:57.367551 | https://example.com/article/3720 |
By Stylish with Your Eyeglasses
Sometimes people, especially teenager and kids do not like to wear prescribed eyeglasses. Even it helps them to get better sight; it seems that they are ashamed of it. Not just make your eyes get tired and hurts you, wearing eyeglasses is considered as silly and nerd things. You will be considered as weirdo and nerd boy and your opposite sex will not have interest on you.
But, Zennioptical.com will change this entire bad paradigm. In the first place, this web provides you high quality of prescription eyeglasses with comfortable and durable materials. Because it is sturdy and comfortable, you will not get tired to use it all the day. What makes it better is that here you can get new styles of prescription glasses. This web has all styles that fit your interest, starting from formal office looks frames, kids frames, colorful frames, sporty styles, and many more.
If you want to make your own glasses, you can simply buy the frames only. There is oval, round, and square model of frames. While for the lenses, you can find it by yourself with your own doctors. You can always change your style every month, because this web usually updates their collection faster every month. | 2024-01-02T01:26:57.367551 | https://example.com/article/2225 |
Pablo Daniel Osvaldo is set for a comeback against Juventus, sends Francesco Totti a birthday message and insisted Roma “are going for the win.”
The striker missed the last couple of games due to suspension and injury, but is training with the squad again and ready to play in Turin on Saturday night.
“These are two great teams and the ones who play the best football in Serie A,” Osvaldo told Sky Sport Italia.
“Obviously the Roma fans really want to beat Juve and at the end of the day the players also experience it like a fan.
“I already scored in Turin with an overhead kick for Fiorentina, so I’m feeling good.”
When asked which of the Bianconeri stars he would like to ‘steal’ from their team, he went for the attack.
“I really like Fabio Quagliarella. MirkoVucinic? He’s very strong, but has already played for Roma, so he’s had his turn! Did Juventus want me in the summer? I don’t know, I only read that in the papers.
“We are going for the win against Juventus, as we have a great squad and we can get the victory. What can we achieve this season? I’m a dreamer, but I don’t know if we’re targeting the title.” | 2023-11-07T01:26:57.367551 | https://example.com/article/3388 |
Q:
The scrollbar is disappeared when I add an alert and cancel event by javascript
I'm facing a problem is that when I use javascript to add an alert message to the page which has already had the vertical scrollbar, the message is shown perfectly but the vertical scrollbar is disappeared. When the alert message is dismissed, the scrollbar cannot appear again. Actually I don't want scrollbar disappearing anytime. I'm using bootstrap 3. Here is my code.
HTML:
... many HTML here ...
<div id="alertbox1"></div>
<div id="modal1">...stuff HTML here...</div>
... HTML here ...
Script:
$('#modal1').on("show.bs.modal", function (event) {
var ok = function_to_check_stuff_ok(); // ;)
if (!ok){
var myMessage = 'Lorem ipsum dolor sit amet...'
var htmlText = '<div class="alert alert-danger fade in">' +
' <button type="button" class="close" data-dismiss="alert" aria-hidden="true">×</button>' +
' <p>' + myMessage + '</p>' +
'</div>';
$('#alertbox1').html(htmlText);
event.prevenDefault();
}
});
A:
Problem: The call of event.prevenDefault() did affect on showing of the modal as well as alert.
Solution: check and validate data and show alert message before calling open modal by manual (by calling modal('show')) instead of checking inside show.bs.modal event.
| 2023-12-20T01:26:57.367551 | https://example.com/article/5812 |
Q:
APC needs restart to see changes
I have Apache2 with APC.
When I change something, I have to restart Apache to see the effect. I know 100% for sure it's because of APC.
What is wrong in my settings? (thanks for the help!)
extension=apc.so
apc.enabled = On
apc.optimization = 0
apc.shm_segments = 1
apc.shm_size = 2.6G
apc.ttl = 7200
apc.user_ttl = 720
apc.num_files_hint = 102400
apc.mmap_file_mask = /tmp/apc.XXXXXX
apc.enable_cli = 1
apc.cache_by_default = 1
apc.max_file_size = 220M
apc.stat = 0
A:
You have apc.stat set to 0. This means APC will not check whether the file is modified when it's requested, it will always serve it from cache after the first compilation.
To fix you problem either remove apc.stat = 0 or change it back to default apc.stat = 1
| 2023-11-13T01:26:57.367551 | https://example.com/article/2644 |
Ahmad Khan Rahami is taken into custody after a shootout with police Monday. Rahami was wanted for questioning in the bombings that rocked the Chelsea neighborhood of New York. (Source AP) Ahmad Khan Rahami is taken into custody after a shootout with police Monday. Rahami was wanted for questioning in the bombings that rocked the Chelsea neighborhood of New York. (Source AP)
A Sikh bar owner in the US is being hailed as a hero for helping capture the 28-year old Afghan-American wanted for the weekend bombings in New York and New Jersey.
Harinder Bains, the owner of a bar in Linden found Ahmad Khan Rahami sleeping in the doorway of his bar on Monday.
Bains said he was watching news on TV on his laptop from another business across the street.
At first, he thought he was some “drunk guy” resting in the vestibule but then recognised Rahami and called police.
“I’m just a regular citizen doing what every citizen should do. Cops are the real heroes, law enforcement are the real heroes,” Bains told.
When officers responded, Rahami pulled out a handgun and opened fire, striking an officer in the chest.
A foot chase ensued, during which Rahami shot at a police car, causing a bullet to graze another office in the face.
The chase ended when Rahami was shot multiple times.
He was taken to a hospital for surgery. Rahami was not initially cooperative with police who tried to interview him, a law enforcement official said.
Indian-American attorney Ravi Batra told PTI that Bains “dared to honour his Oath of Citizenship to protect & defend the Constitution from enemies foreign and domestic -and it’s turns out that the Chelsea Pressure Cooker Bomber suspect, a naturalised citizen, is caught by another immigrant, an Indian-American Hero-Sikh.”
Watch What Else is Making News
In a statement, the National Sikh Campaign said this was brave and courageous act by Bains.
“A Sikh helps police get to the terrorist involved in New York and New Jersey bombing over the weekend,” it said.
“He heroically helped save many innocent lives and yet gave credit to law enforcement officers. Harinder Bains certainly did what every responsible citizen in America ought to do. Brave and courageous act!” said the National Sikh Campaign.
📣 The Indian Express is now on Telegram. Click here to join our channel (@indianexpress) and stay updated with the latest headlines
For all the latest World News, download Indian Express App. | 2024-05-31T01:26:57.367551 | https://example.com/article/9061 |
TEWKSBURY, MA — Jennifer Kalicki posted $250 bail on Sept. 11 for her boyfriend Eric Griffin, who was charged with possession of a Class B drug with intent to distribute. It was two days after a domestic violence case against Griffin and involving Kalicki as the victim was dismissed, and four days before police found Kalicki dead at the couple's Tewksbury apartment.
Griffin is due back in court Friday for a dangerousness hearing on a charge of assault and battery on a family or household member, with more charges expected. "This is not believed to be a random incident of violence and there is no danger to the public," Tewksbury police said Monday in a statement announcing Griffin's arrest.
During Friday's hearing, a judge will rule whether there is enough evidence to hold Griffin, who pleaded not guilty to the charges Monday. He has two restraining orders and multiple violations of probation on his record. During his arraignment, a judge revoked his bail. Griffin called police Sunday morning and said Kalicki was cold to the touch and unresponsive. When police arrived, they found her in bed with her shirt ripped open, a bump and cut on her forehead, a red indentation near her left temple, red marks on both sides of her neck and on her upper chest, and bruising on the outside of her right hand, according to a police report. She was pronounced dead at the scene.
A day earlier, Kalicki sent a series of text messages to Griffin's sister between 8:35 a.m. and 10:42 a.m. She said she and Griffin had been fighting since the previous night and that Griffin was still angry and abusing her. "He's ripped the door open," Kalicki texted. "Choked me, slammed me to the ground. Please help me. He's losing it...I just need help. I'm tired of him making me the victim."
Griffin's sister did not call police.
"During those text messages, the victim was begging the defendant's sister for help," prosecutor Suzanne Wiseman said at the arraignment.
When police arrived at the Archstone Arms apartment around 8 a.m. on Sunday, Griffin said they had been arguing but claimed Kalicki's injuries were self-inflicted. In the police report, investigators said Kalicki's injuries were "not consistent" with the account Griffin offered. "He murdered her," Kalicki's mother, Kathy Gadd, told Boston 25. "He murdered her. There's no two ways about it."
| 2024-05-15T01:26:57.367551 | https://example.com/article/2327 |
Proton pathways in lysozyme.
Protonic conduction studies are reported for lysozyme as a function of the number of bound water molecules. Lysozyme samples employing proton-injecting palladium black electrodes exhibited conductivities up to eight orders of magnitude greater than those retained between control (copper) electrodes. The results indicate that water involved in multiple hydrogen bond contact with the enzyme together with hydrogen bonded segments of the enzyme structure provide a hydrogen bond network which is capable of supporting considerable protonic conduction. | 2024-05-04T01:26:57.367551 | https://example.com/article/8670 |
Filed 9/10/15 In re R.F. CA4/2
NOT TO BE PUBLISHED IN OFFICIAL REPORTS
California Rules of Court, rule 8.1115(a), prohibits courts and parties from citing or relying on opinions not certified for
publication or ordered published, except as specified by rule 8.1115(b). This opinion has not been certified for publication
or ordered published for purposes of rule 8.1115.
IN THE COURT OF APPEAL OF THE STATE OF CALIFORNIA
FOURTH APPELLATE DISTRICT
DIVISION TWO
In re R.F., a Person Coming Under the
Juvenile Court Law.
THE PEOPLE,
E061884
Plaintiff and Respondent,
(Super.Ct.Nos. J256006 & FJ52252)
v.
OPINION
R.F.,
Defendant and Appellant.
APPEAL from the Superior Court of San Bernardino County. Brian Saunders,
Judge. Affirmed.
Wayne C. Tobin, under appointment by the Court of Appeal, for Defendant and
Appellant.
Kamala D. Harris, Attorney General, Gerald A. Engler, Chief Assistant Attorney
General, Julie L. Garland, Assistant Attorney General, Eric A. Swenson, Lynne G.
1
McGinnis, and Jennifer B. Truong, Deputy Attorneys General, for Plaintiff and
Respondent.
Following a contested jurisdictional hearing, the Los Angeles County Juvenile
Court found true that defendant and appellant R.F. (minor) committed one count of
robbery (Pen. Code, § 211) with the use of a deadly and dangerous weapon, to wit, a
knife (Pen. Code, § 12022, subd. (b)(1)).1 After the matter was transferred to San
Bernardino County for disposition, the San Bernardino County Juvenile Court declared
minor a ward of the court and placed her on probation on various terms and conditions.
Minor’s sole contention on appeal is that the weapon use enhancement should be
reversed because there was insufficient evidence to show that minor’s offense was
committed during a carjacking and substitution of a lesser enhancement by the juvenile
court was not permitted. We reject these contentions and affirm the judgment.
I
FACTUAL AND PROCEDURAL BACKGROUND
On July 2, 2014, as Gustavo Garcia was leaving work and walking to his car,
minor put a knife to his neck and demanded his phone and wallet. Garcia removed his
wallet, which contained $800 in cash, and gave it to minor. Minor then ran away with
Garcia’s wallet. Garcia followed minor to a Laundromat in his car. When Garcia
entered, minor ran out. Garcia continued to pursue minor on foot, and at some point, a
bystander joined him. As the two men were chasing minor, minor threw items at them
1 All future statutory references are to the Penal Code unless otherwise stated.
2
from Garcia’s wallet, including $400 in cash. Police eventually arrived and arrested
minor. Garcia recovered his wallet and its contents except $320.
On July 7, 2014, a Welfare and Institutions Code section 602 petition was filed
charging minor with two counts of second degree robbery (§ 211)—one count as to
Gustavo Garcia (count 1) and the other as to James Nickerson (count 2). The petition
also alleged that in the commission of both offenses minor used a deadly and dangerous
weapon, to wit, a knife (§ 12022, subd. (b)(1)). As to the weapon enhancement, the
petition specifically cited in violation of subdivision (b)(2) of section 12022.
Following a contested jurisdictional hearing on August 12, 2014, the Los Angeles
County Juvenile Court found true the robbery allegation in count 1 as well as the weapon
enhancement alleged as to that count. The court dismissed count 2 and its attendant
enhancement as no evidence was presented on that count. In making its findings, the
juvenile court specifically stated, “Court finds count one to be true. 12022 (b) (one)
enhancement is true with a knife. Count two is dismissed. Minor is a person described
by section 602 of the Welfare and Institutions Code.” Because minor was living with her
mother in San Bernardino County, the juvenile court transferred the matter to San
Bernardino County for disposition.
On August 20, 2014, the San Bernardino County Juvenile Court accepted the
transfer. On September 3, 2014, the court declared minor a ward of the court and placed
her in the custody of the probation department on various terms and conditions while she
3
awaited placement in foster care. The court also ordered minor’s parents to comply with
a reunification plan and treatment program.
On September 8, 2014, minor filed a notice of appeal from the judgment.
II
DISCUSSION
In regard to the weapon enhancement allegation, the petition specifically
stated, “It is further alleged that in the commission and attempted commission of
the above offense [second degree robbery], the said minor, personally used a deadly
and dangerous weapon(s), to wit, knife, said use not being an element of the above
offense [second degree robbery], within the meaning of Penal Code Section 12022[,
subdivision] (b)(2) and causing the above offense to be a serious felony within the
meaning of Penal Code section 1192.7[, subdivision] (c)(24).” (Italics added.)
Section 12022, subdivision (b)(1), authorizes an additional and consecutive one-
year term of imprisonment for use of a dangerous weapon in the commission of a felony
or attempted felony. Section 12022, subdivision (b)(2), states, “If the person described in
paragraph (1) has been convicted of carjacking or attempted carjacking, the additional
term shall be in the state prison for one, two, or three years.” (§ 12022, subd. (b)(2).)
There is no dispute here that minor committed second degree robbery, and the juvenile
court correctly referred to subdivision (b)(1) of section 12022 when it found true the
deadly and dangerous weapon use enhancement.
4
According to minor, the weapon enhancement should be reversed because there
was no evidence to show her offense was committed during a carjacking and the juvenile
court erred in substituting the lesser enhancement. The People argue that the error in the
petition was a clerical error and that minor was on notice of the weapon enhancement
under subdivision (b)(1) of section 12022 because the petition stated the language from
that subdivision and the juvenile court found minor violated subdivision (b)(1) of
section 12022. The People therefore maintain that, under the circumstances of this case,
the weapon enhancement under section 12022, subdivision (b)(1), was properly pled and
proven.
An error in identifying the statute that renders a defendant’s acts unlawful is a
pleading defect, even if it continues throughout the proceedings. (People v. Thomas
(1987) 43 Cal.3d 818, 824-826 (Thomas).) As such, it is evaluated in light of the
statutory and due process requirements governing the preparation of accusatory
pleadings. (Thomas, at pp. 824-826.) The purpose of the due process notice requirement
is to afford an accused “ ‘ “a reasonable opportunity to prepare and present his defense
and not be taken by surprise by evidence offered at his trial.” ’ ” (People v. Lohbauer
(1981) 29 Cal.3d 364, 368; People v. West (1970) 3 Cal.3d 595, 612.)
The defendant also has the right to notice that the prosecution is seeking enhanced
punishment. (See § 1170.1, subd. (e); People v. Sok (2010) 181 Cal.App.4th 88, 96,
fn. 8; People v. Hopkins (1974) 39 Cal.App.3d 107, 113 (Hopkins); People v. Henderson
(1972) 26 Cal.App.3d 232, 238.) When the facts supporting such enhancement are
5
neither alleged nor found by the trier of fact, the aggravation of sentence cannot stand.
(People v. Ford (1964) 60 Cal.2d 772, 794, overruled on other grounds in People v.
Satchell (1971) 6 Cal.3d 28, 35-38; Hopkins, supra, at p. 113; People v. Henderson,
supra, at p. 238.)
The same reasoning applies in juvenile cases. “ ‘[Due] process requires that a
minor, like an adult, have adequate notice of the charge so that he may intelligently
prepare his defense. [Citation.]’ [Citation.] Compliance with this requirement has been
held by the Supreme Court to mandate that the minor ‘be notified, in writing, of the
specific charge or factual allegations to be considered at the hearing, and that such
written notice be given at the earliest practicable time, and in any event sufficiently in
advance of the hearing to permit preparation.’ [Citation.]” (In re Robert G. (1982) 31
Cal.3d 437, 442 (Robert G.).)
The “ ‘specific allegations of the accusatory pleading, rather than the statutory
definitions of offenses charged, constitute the measuring unit for determining what
offenses are included in a charge.’ [Citation.]” (Thomas, supra, 43 Cal.3d at p. 828;
§ 952.) Consequently, “ ‘even a reference to the wrong statute has been viewed of no
consequence under the circumstances there appearing [citations].’ [Citation.]” (Thomas,
at p. 826.)
Charging the defendant under the wrong statute is “of no consequence” when the
defendant has not been prejudiced by the error. (Thomas, supra, 43 Cal.3d at pp. 826-
827.) Prejudice in these circumstances implicates constitutional procedural due process
6
rights. “The ‘preeminent’ due process principle is that one accused of a crime must be
‘informed of the nature and cause of the accusation.’ (U.S. Const., Amend.VI.) Due
process of law requires that an accused be advised of the charges against him so that he
has a reasonable opportunity to prepare and present his defense and not be taken by
surprise by evidence offered at his trial. [Citation.] [¶] Thus, the right to defend has two
related components, namely, the right to notice of the charges, and the right to present a
defense to those charges.” (People v. Jones (1990) 51 Cal.3d 294, 317, italics omitted;
Thomas, supra, 43 Cal.3d at p. 823, and cases cited therein.) Further, “ ‘Notice of the
particular circumstances of the offense is given not by detailed pleading, but by the
transcript of the evidence before the committing magistrate . . . .’ [Citations.]” (Thomas,
supra, at p. 829.)
Here, the petition fully informed minor that she was charged with using a deadly
weapon, “to wit, knife,” in the commission of the second degree robbery. She, therefore,
could not be surprised by proof of such use, nor can she say that the preparation of her
defense to meet the facts would have been different if the petition had alleged use under
the provision of subdivision (b)(1) of section 12022, rather than subdivision (b)(2) of
section 12022. (See Hopkins, supra, 39 Cal.App.3d at pp. 112-113.) Minor was fully
informed that the People were seeking to enhance her sentence for use of a deadly
weapon. The question thus presented is whether the misstatement of the subdivision of
the code section in the petition, indicating a greater enhancement than that proven at the
7
jurisdictional hearing and found true by the juvenile court, requires reversal of the
weapon enhancement.
People v. Neal (1984) 159 Cal.App.3d 69 (Neal) is instructive. In Neal, the
information alleged the defendant used a deadly weapon during the commission of rape
and oral copulation, within the meaning of section 12022, subdivision (b), which allowed
an additional one-year imprisonment. (Neal, supra, 159 Cal.App.3d at p. 72.) The jury
found weapons enhancements true as to each crime. The trial court, however, increased
the imprisonment to three years per crime, relying on section 12022.3. Section 12022.3
provides an enhancement for using dangerous weapons during the commission or
attempted commission of certain sex crimes. (Neal, supra, 159 Cal.App.3d at p. 72.)
On appeal, the defendant argued the three-year enhancements should be modified
to one year because the information relied on section 12022, subdivision (b), rather than
section 12022.3. (Neal, supra, 159 Cal.App.3d at p. 72.) The Neal court held, “[W]here
the information puts the defendant on notice that a sentence enhancement will be sought,
and further notifies him of the facts supporting the alleged enhancement, modification of
the judgment for a misstatement of the underlying enhancement statute is required only
where the defendant has been misled to his prejudice. [Citations.]” (Id. at pp. 73-74.)
Because the defendant could not demonstrate prejudice, the sentence was not reduced.
(Id. at p. 74.)
Similarly, the petition alleged a weapon enhancement for carjacking, pursuant to
section 12022, subdivision (b)(2), but the court found true the enhancement based on
8
subdivision (b)(1) of section 12022. Minor was, or should have been aware, the
prosecutor was seeking the one-year additional enhancement for use of a deadly weapon
in the course of a robbery, based on the allegations in the petition and facts. Minor’s
challenge to the weapon enhancement is solely based on the fact that the accusatory
pleading specified the wrong subdivision of section 12022. She does not contend, nor
could she contend, that using a weapon in the commission of a robbery is not a proper
enhancement, or that there was no substantial evidence to support the juvenile court’s
true finding that minor used a knife in the commission of the robbery.
Minor’s reliance on Robert G., supra, 31 Cal.3d 437 is misplaced. Robert G.
involved a wardship petition which charged a 14-year-old minor with assault with a
deadly weapon. At the contested hearing, the People presented evidence that the minor
threw two rocks while he was in a junior high school parking lot, one of which hit a
school custodian in the back. (Id. at p. 439.) After the People completed their case, the
minor moved for acquittal on the ground that the rock was not a deadly weapon. The
juvenile court denied the motion, although it agreed that the rock was not a deadly
weapon. (Ibid.) After the minor rested without presenting evidence, the People argued
that the petition should be sustained because the evidence established that the minor
committed a battery. Over a defense objection, the juvenile court amended the petition to
charge a battery and then sustained the petition pursuant to that new charge. (Id. at
p. 440.) The Robert G. court reversed the judgment, holding that “a wardship petition
under section 602 may not be sustained upon findings that the minor has committed an
9
offense or offenses other than one specifically alleged in the petition or necessarily
included within an alleged offense, unless the minor consents to a finding on the
substituted charge.” (Id. at p. 445.)
Contrary to minor’s arguments on appeal, the purported amendment that occurred
in this case did not violate the due process principles elucidated in Robert G., supra,
31 Cal.3d 437. The juvenile court here did not add an enhancement that was not alleged
in the petition. The language in the petition alleged a weapon enhancement under
section 12022, subdivision (b)(1), despite its reference to subdivision (b)(2). The petition
alleged that minor “in the commission and attempted commission of the above offense
[second degree robbery], the said minor, personally used a deadly and dangerous
weapon(s), to wit, knife, said use not being an element of the above offense [second
degree robbery] . . . .” There was no dispute that minor was charged with, and the
juvenile court found true, that she had committed a robbery as opposed to a carjacking.
Accordingly, in making its true finding on the weapon use enhancement, the juvenile
court cited to the correct statutory provision. The court’s true finding on the weapon
enhancement under section 12022, subdivision (b)(1), was not a substitution of the
charged enhancement with an uncharged enhancement.
We also reject minor’s claim that substitution of a lesser enhancement violates the
California Supreme Court’s decision in People v. Wolcott (1983) 34 Cal.3d 92 (Wolcott).
In Wolcott, the court concluded that assault with a deadly weapon was not a lesser
included offense of a robbery charge with a special allegation that the defendant used a
10
firearm in the commission of the robbery. The Supreme Court determined that the
section 12022.5 allegation could not be considered in determining whether assault with a
deadly weapon was a lesser included offense of robbery. (Id. at pp. 98-102.) Here, the
juvenile court did not add an uncharged enhancement and minor was provided notice of
the weapon enhancement under section 12022, subdivision (b)(1). Accordingly, Wolcott
is not controlling authority in this case.
Under the circumstances of this case, minor has failed to establish that her right to
procedural due process was violated. The weapon enhancement allegation under
subdivision (b)(1) of section 12022 was properly pled and proven, and the juvenile court
properly cited that subdivision in finding the weapon enhancement allegation true.
III
DISPOSITION
The judgment is affirmed.
NOT TO BE PUBLISHED IN OFFICIAL REPORTS
RAMIREZ
P. J.
We concur:
HOLLENHORST
J.
CODRINGTON
J.
11
| 2023-12-16T01:26:57.367551 | https://example.com/article/5908 |
Q:
Rails 5 crash in .erb file but only when running on server
so i have this code in my erb file:
<% a = ["Apple","Orange","Banana","Carrot","Turnip","Rabbit","Lion"] %>
<% arr = @things.where(:active => 1).sort_by{|el| a.index(el[:name])}%>
<% for product in arr %>
and its crashing on line 2 with this error:
comparison of Fixnum with nil failed
I replaced it with this:
<% arr = @things.sort_by{|el| a.index(el[:name])}%>
and its still crashing... when i change the entire code block with this:
<% for thing in @things %>
the crash goes away.
its odd because it runs fine locally.
A:
It cannot find in array a element with el[:name] so it returns nil and cannot sort.
Put ternary operator and return -1 if not found:
<% a = ["Apple","Orange","Banana","Carrot","Turnip","Rabbit","Lion"] %>
<% arr = @things.where(:active => 1).select{|el| !a.index(el[:name]).nil?} %>
<% arr = arr.sort_by{|el| a.index(el[:name])} %>
or better filter it and then sort it:
<% a = ["Apple","Orange","Banana","Carrot","Turnip","Rabbit","Lion"] %>
<% arr = @things.where(:active => 1).select{|el| !a.index(el[:name]).nil?}.sort_by{|el| a.index(el[:name])} %>
| 2023-10-20T01:26:57.367551 | https://example.com/article/6277 |
Q:
The role of TFont.Charset in Delphi 2010
What is the role of TFont.Charset property of VCL controls in Delphi 2010? Isn't this property irrelevant now that all Delphi 2010 components support UNICODE?
A:
Setting different values for Charset property has no effect if a font under question supports these charsets; but if you set a charset not supported by a font Windows will use font substitution to find a font that supports the selected charset. Try to set SYMBOL_CHARSET for a text font like Tahoma and see the result.
So though font charsets are legacy in Unicode Delphi's they cannot be ignored completely.
| 2023-12-22T01:26:57.367551 | https://example.com/article/7831 |
Pretty soon I might have to create a Bruin of the Week poll without Bruins star forward Tyler Seguin. Because it doesn’t look like the second-year player plans on tailing off long enough to not be Boston’s best player over any seven-day period.
The Bruins’ leading scorer was again voted as the Bruin of the Week by readers of TheBruinsBlog.net.
Who should be the Bruin of the Week?
Tyler Seguin (76%, 138 Votes)
Brad Marchand (13%, 23 Votes)
Johnny Boychuk (8%, 15 Votes)
Joe Corvo (3%, 5 Votes)
Total Voters: 181
Loading ...
This honor comes on the same day the NHL picked Seguin as its First Star of the week. But no one knows how those stars get picked.
Seguin leads the Bruins with 20 points and 11 goals. Amazingly, he also leads the NHL with a plus-14 rating. After he was left off the All-Star ballot last week, Seguin made sure that when it comes time to pick the reserves for that contest he’s going to be hard to leave out.
I would take Corvo in a heartbeat over Kaberle. I do think he is capable of better play in his own end, however. I don’t expect him to give the bone-crunching checks of Chara, Sidenberg, or Boychuk, but I do expect him to have better positional play similar to Ference. He does have a good shot and appears to be a good passer. Since you remember Coffey, you know that he rarely killed penalties as well.
I wish sometimes defensive players would get a little more recognition on this blog. Glad to see two defenseman’s names on the ballot.
he has been the best player on the ice since game 1 of the season. it isn’t even close. it seems like there hasn’t been a shift of his that the bruins didn’t at least get a scoring chance. not only is he better than kessel but better than hall too.
B16 – Yes yes… I understand. When I bought my pick-up I didn’t expect it to corner hair-pins going 60 either. That doesn’t mean he didn’t have a great week or that he isn’t blossoming in the very area we traded for him to improve on this team. Paul Coffey wasn’t the baddest dude on the back-end either, but I’d still pick him for my pond hockey team.
I agree with Bruins16 on Corvo. A good puck mover, but not as good battling for the puck. He does make the effort. Still, way better than Kaberle. Watched him for a few games this year – and he looks weaker than last year.
You need to watch Corvo’s play in front of the net and his positioning defensively. As well, keep track of the number of times he wins battles along the boards. There is a reason why he is rarely on the penalty kill. | 2024-04-12T01:26:57.367551 | https://example.com/article/4170 |
Marko you must have the most tollerant cats on the planet! Twiggy is too cute for words, a little princess all pretty in pink.
My old red cat Whisker was very tollerant, my son's favourite game with him was to stack books on top of the cat when he was laying on the couch and see how high he could pile them. The cat just laid there and let him do it. He would have fit right in with your "dress up" games I think. | 2024-04-07T01:26:57.367551 | https://example.com/article/2727 |
I got this ring early for Christmas this year, it was something I'd asked for.
We aren't ready to get engaged just yet, so to kill 2 birds with 1 stone this ring is a promise ring for now and later will be my wedding band. I plan on ordering a 2nd ring to go on each side of the solitare that I'll eventually get. = )
The stones are a nice size, it's thin and feminine which is what I wanted.
The ring is sparkly, very pretty and I've gotten a lot of compliments on it already.
I'm pretty sure Zales sells this exact diamond band (just called something different) but it looks the exact same and it's more expensive at Zales. I'm happy with Overstock and I'm very happy with my Christmas present.
How did the image on site compare with the actual product? I think jewerly always looks bigger in online pictures.
How accurate was the sizing? The ring fits perfectly
Please tell us about the quality of the product. Good quality, is pretty!
I received this as a Christmas present from my husband to go along with my engagement diamond which is on a prong set diamond band, solid gold band, and diamond band that I stack. It fits in beautifully and really complements the stacking. I would very much recommend this to anyone. The value is almost too good to be true! I looked elsewhere and for the quality, bands were averaging much more in cost. It was a great buy, fabulous gift, and welcomed addition to my other three rings.
How did the image on site compare with the actual product? Looks exactly as pictured.
How accurate was the sizing? Although sizing was a bit large. I normally wear 4 3/4 and it was falling off my finger. Exchanged for a 4 1/2 and was still a bit big, but okay.
Please tell us about the quality of the product. The diamonds are beautiful, and complement each other.
My husband and I bought this ring as a wedding ring to be paired with my 1/2 carat diamond engagement ring and it was a stunning addition. They really did compliment each other well, so much in fact that I just ordered my second one so that I could use them as a wrap to my solitaire. I can't wait for it to get here!!
How did the image on site compare with the actual product? The image didn't do any justice for this ring.
How accurate was the sizing? If I could change one thing, it would be that it could have been ordered in 1/4 sizes.
This ring is so pretty and I really, really wish I did not have to return it. I bought two to go with my engagement ring but it just doesn't look right. My fiance could tell how upset I was and will most likely buy these rings or something very similar from Overstock for my birthday! I sincerely wish I did not have to return them.
How did the image on site compare with the actual product? pretty accurate
How accurate was the sizing? perfect
Please tell us about the quality of the product. i couldn't tell the difference in diamon quality with my engagement ring
This ring was amazing. I purchased (2) of them, one for each side of our wedding rings. Both were identical and sizing was perfect. The jewler that solder them togther ask where we got them and commented on how beautiful they were. Very impressed and first time ordering jewlery on line. Positive experience and would buy from here again.
Purchased this to add to with my wedding set . Wasn't sure if it would match up right but it did. I could wear it alone, with solitare or all 3 together.Looks awesome. I actually had the 3 soddered together & love it Have had many compliments on it. Love the Black & white diamonds they make each other stand out & it is something different. So glad I ordered it.
I bought this ring for my girlfriend for her birthday and her jaw literally dropped when she put it on. I wanted to go with something with black diamonds, but decided that the mix of both types was perfect. The diamonds are so shiny and are a great size. She told me that she loved the band because it's the perfect size. When we've been out, she's received so many compliments - decided to write a review because i was just so happy with it.
I received this band as an early Christmas gift and to accompany the 3 3/4 black solitaire ring that I also purchased from Overstock. My husband picked it out. This band is really beautiful and comfortable. Since the band is on the thinner side I'm thinking of purchasing another one when it comes back in my size to wear as ring guards. It would be perfect to surround the solitaire ring. The stones are very bright and they do sparkle.
This was purchased as my wedding band - my engagement ring has black diamonds so I wanted a band to match. This is beautiful! All of the non-black diamonds are clear and bright, and uniform. The settings seem good, but I haven't worn it yet since I am not yet married, but I can't wait to wear it every day!
My first impression, the stones were much smaller than expected. I placed the ring next to my wedding set and immediately fell in love with it. It's fun to have both black and white diamonds for a change. The ring is very feminine and I would call dainty. Very comfortable and a nice companion piece to a wedding set. I expected to send the ring back but can't part with it. Looks great and I think a pretty good value. Haven't seen anything else like it in a anniversary type band. I'm pleased. I think it would make a great pinky ring or right hand ring if you like simple but different. The stones have nice clarity and shine, they really sparkle. Another good choice from Overstock. Thanks!
I bought this to go with the 1ct black diamond solitaire I bought from this site and they look phenomenal together. We wanted something different for a wedding set and this has certainly provided that.
Shop Overstock™ and find the best online deals on everything for your home and your family. We work every day to bring you discounts on new products across our entire store. Whether you're looking for memorable gifts or everyday essentials, you can buy them here for less. | 2024-01-22T01:26:57.367551 | https://example.com/article/1065 |
Gluten-free and low-FODMAP sourdoughs for patients with coeliac disease and irritable bowel syndrome: A clinical perspective.
Wheat- and gluten-containing products are often blamed for triggering a wide range of gastrointestinal symptoms, and this has fueled demand for gluten-free products worldwide. The best studied 'gluten intolerance' is coeliac disease, an auto-immune disease that affects the small intestine. Coeliac disease occurs in 1% of the population and requires strict, life-long avoidance of gluten-containing foods as the only medical treatment. There is a larger group of individuals (around 10-15% of the population) who report a wide-range of gastrointestinal symptoms that respond well to a 'gluten-free diet', but who do not have coeliac disease - so called 'non-coeliac gluten sensitivity (NCGS)'. The team at Monash University has identified other factors in gluten-containing foods that may be responsible for symptoms in this group of individuals with so-called, NCGS. We have evidence that certain poorly absorbed short chain carbohydrates (called FODMAPs) present in many gluten-containing food products, induce symptoms of abdominal pain, bloating, wind and altered bowel habit (associated with irritable bowel syndrome, IBS). Our research has shown that FODMAPs, and not gluten, triggered symptoms in NCGS. Going forward, there are great opportunities for the food industry to develop low FODMAP products for this group, as choice of grain variety and type of food processing technique can greatly reduce the FODMAP levels in foods. The use of sourdough cultures in bread making has been shown to reduce the quantities of FODMAPs (mostly fructan), resulting in bread products that are well tolerated by patients with IBS. Greater interaction between biomedical- and food-scientists will improve understanding about the clinical problems many consumers face, and lead to the development of food products that are better tolerated by this group. | 2024-04-08T01:26:57.367551 | https://example.com/article/3062 |
k be -30*(h/(-10) - -1). Suppose 2*j = 2 + k. Is j a composite number?
False
Suppose 0*z - 22 = -z. Is z composite?
True
Let z = -586 + 849. Is z a composite number?
False
Is (-2)/(-4) - (-374)/4 a composite number?
True
Let p(h) = -95*h**3 + h**2 + h. Let q(w) = w**2 - 5*w - 7. Let t be q(6). Is p(t) a prime number?
False
Suppose 2*c - 5*i - 4010 = -3*i, -c = 2*i - 2005. Is c prime?
False
Suppose 3*t = -t + 12. Let z(r) = 19*r**2 + 10*r - 5. Let c(i) = -6*i**2 - 3*i + 2. Let l(b) = -7*c(b) - 2*z(b). Is l(t) prime?
False
Let v(o) = 5*o**2 - 2*o - 4. Is v(-3) a composite number?
False
Suppose -4119 = -5*c + 2*b + 1718, -3*c + 5*b + 3487 = 0. Is c a prime number?
False
Let g = 167 - -46. Is g a prime number?
False
Let c(d) = 12*d**3 + 2*d**2 + 2*d + 5. Is c(3) prime?
True
Let j = 210 + -117. Is j prime?
False
Let k(w) = 10*w + 3. Let s be k(-2). Let h = s + 132. Is h composite?
True
Let w(l) be the third derivative of 13*l**4/12 - 13*l**3/6 + 6*l**2. Is w(10) prime?
False
Let p(b) = b**2 - b + 1. Suppose 3*g = g + 8. Is p(g) composite?
False
Suppose -3*w + 5*k = -224, w - k - 30 = 48. Is w prime?
True
Let l = -4 - -1. Let a(b) = -b + 2. Let v be a(0). Is (l/6)/(v/(-84)) composite?
True
Let t be 4/5*(-1090)/4. Let o = t + 328. Suppose -v + o = v. Is v prime?
False
Is (2 - 1556/20)/((-3)/15) a composite number?
False
Let d be 1 + 257 - (3 - 0). Suppose 4*c = y + 465, 2*c - 4*c + d = -5*y. Suppose 345 = 3*w - 5*r, -2*w + c = -w - 4*r. Is w prime?
False
Let f(t) = 3*t**3 - 3*t**2 - 2*t. Let a be f(3). Let r = a + 185. Is r a prime number?
True
Let m be -2 + 93*-1*-1. Suppose -4 = -3*n + n. Suppose 2*s + m = x, 0*s - 346 = -4*x + n*s. Is x composite?
True
Let u(n) = n**2 + 2*n + 6. Is u(-9) composite?
True
Let b(u) = -u + 8. Let t be b(6). Suppose -t*v = -v - 122. Is v prime?
False
Let w(m) = 0*m + 5*m**3 - 3 - 2 - 6*m**2 + 0*m + 6*m. Let b(x) = x**3 - x**2 + x - 1. Let q(f) = -4*b(f) + w(f). Is q(4) a prime number?
False
Suppose 0 = -5*z + 10 + 10. Suppose -175 = -z*l - l. Is l prime?
False
Let s be (-6)/(0 + -2) - 11. Let k = s - -21. Is k composite?
False
Let d = -2 + 0. Let c be -423*d*(-2)/(-12). Let f = c - 86. Is f a composite number?
True
Suppose 3*j - 15 = 0, 2*r + j = -j + 3956. Is r composite?
False
Let k = 28 + 9. Is k a prime number?
True
Let u(q) = q**3 - 8*q**2 + 7*q + 9. Let x be u(7). Is (x/18)/((-1)/(-178)) a composite number?
False
Let l = 12 + -10. Suppose -5*c = 0, 3*w + 5*c - 16 + 4 = 0. Suppose w*v - 34 = l*f - 0*f, 4*v - 3*f - 37 = 0. Is v prime?
True
Let n = -616 + 2115. Is n a composite number?
False
Let z(u) = u + 2. Let m be z(0). Suppose -502 = m*i - 4*i. Is i a prime number?
True
Suppose 4*u - u = 10977. Is u a prime number?
True
Suppose 0*w - 18 = -3*w. Let m be 8 - w - (-1 + -1). Is 239/m + (-3)/4 composite?
False
Suppose -24 = c - 5*b - 100, -3*b + 15 = 0. Suppose 2*g = c - 7. Let w = g + -28. Is w prime?
True
Let i(r) = -6*r + 40. Is i(-7) a composite number?
True
Let x(m) = 4*m. Let c be x(1). Suppose b + c*b = 1885. Is b prime?
False
Let f(q) = -4*q. Let c be f(-1). Let j(n) = 10*n**2 - 5*n - 1. Is j(c) a prime number?
True
Suppose 0 = -p - 3, -r = p - 4 - 5. Suppose r*d - 1172 = 8*d. Is d composite?
False
Let c = 117 + 274. Suppose -h + 4*g + 85 = 0, 4*h - g = 8*h - c. Is h a composite number?
False
Suppose 225 + 81 = -2*b. Let z = -62 - b. Is z composite?
True
Suppose 4*t = 7*t - 9. Suppose 0*v = -5*m - v + 1586, 0 = -m + t*v + 314. Is m prime?
True
Let x be 4/(-10) + (-51)/(-15). Suppose -x*d + 4*a = -2*d - 183, -3*d + a + 604 = 0. Is d a prime number?
False
Is 2/3 - (-13692)/63 a composite number?
True
Let d = 130 + 131. Let u = -70 + d. Is u composite?
False
Let z = -69 + 143. Is z prime?
False
Suppose 5*q = 4*v + 1091, 3*q - 3*v - 2*v - 665 = 0. Is q composite?
True
Let w(f) = f**2 - f - 7. Let n be w(0). Let u = -913 + 526. Is u/n - 2/7 a composite number?
True
Let y(m) = -m**2 + 12*m - 11. Let h be y(11). Let j(s) = -71*s - 1. Let r be j(-2). Suppose h = 2*f + f - r. Is f a composite number?
False
Is 13/((-117)/(-25320)) + (-2)/6 a composite number?
True
Let b(k) be the second derivative of 7*k**4/12 + k**3/6 - k**2/2 + 2*k. Let a be (0/(-2) - 1)*-1. Is b(a) composite?
False
Let b be (8/(-10))/(12/90). Is 203/2*b/(-3) a prime number?
False
Let g = 12 - -22. Suppose -3 = q - 9. Suppose q*d - d - g = -4*c, 0 = 5*c - 5. Is d composite?
True
Let y = 932 + -663. Is y composite?
False
Suppose -4*q + 4*i = -9*q + 31, -q - i + 6 = 0. Let a(o) = -o**3 + 8*o**2 - 3*o + 9. Is a(q) composite?
False
Let b(y) = -1 + 0 - 1 + 21*y + 3. Is b(4) a prime number?
False
Suppose 158 = d - 371. Is d a prime number?
False
Suppose -13*d + 1010 = -11*d. Is d composite?
True
Is ((-1)/(-2))/((-1)/(-402)) composite?
True
Let p be 45/(-10)*8/6. Is (-42)/(-1)*(-3)/p a composite number?
True
Let f be (-9)/(-6)*(-3 + 1). Let i be 3*((-4)/f)/2. Suppose -98 = -2*c - 3*n, -3*c = i*c - 2*n - 207. Is c a composite number?
False
Suppose 4*c = s - 16, -2 = 5*c + 13. Let b(u) = -s - 1 - 4*u + 3. Is b(-4) a composite number?
True
Let u(y) = 3 - 3 + 3*y. Let j be u(-7). Let g = j - -31. Is g a prime number?
False
Let n be (5 + 0)*(-132)/(-10). Suppose 6*f + n = 2*p + 2*f, -5*p - 4*f + 193 = 0. Is p composite?
False
Let v(l) = -l**3 - 5*l**2 + 6*l + 2. Let w be v(-6). Let f(r) = 12*r**3 - 3*r**2 + 3*r - 1. Is f(w) a composite number?
False
Let m be ((-38)/8)/((-2)/8). Suppose 5*r + y - 12 = 0, 5*r - 2*y - 18 = -y. Is (r - (-1 + 3))*m a composite number?
False
Let g(p) = 29*p**2 + 3*p - 3. Let a = -4 + 6. Is g(a) a composite number?
True
Suppose 12 = 3*p - 0*p. Is p/((-6)/(-3)) - -1 prime?
True
Suppose -6*p - 94 = -3*p - 4*q, 4*q + 36 = -2*p. Let k = p + 237. Is k prime?
True
Suppose 0*a - 3*a + 15 = 0. Suppose 2*f - a = -1. Suppose f*b + 190 = 4*b + 5*d, 2*d - 93 = -b. Is b a prime number?
False
Suppose -5*k + 1732 = -1053. Let h = k + -198. Is h a prime number?
True
Suppose 8 = a + a. Suppose 0 = -c - a*c + 60. Is ((-1028)/(-6))/(c/18) a prime number?
True
Let n = 7 - -76. Is n a prime number?
True
Let o(d) = 13*d**2 - d + 22. Is o(-8) a composite number?
True
Let d = 506 - -2903. Is d a composite number?
True
Let c = 142 + -403. Let w = c - -512. Is w composite?
False
Let d = 106 + 7. Let t = d + 14. Is t prime?
True
Suppose -3*z = 3*w - 2232, 0*z - 2272 = -3*z + 5*w. Is z composite?
True
Let u(q) = 5*q - 1 - 3*q - 5 - q. Let g be u(6). Is (-179)/(g - (3 - 2)) a prime number?
True
Suppose 3*y + y - 8 = 0. Suppose -y*o - 112 = -3*o. Let i = o - 75. Is i composite?
False
Is (-142 + 2 + 2)/(-2) composite?
True
Let q = 375 + -161. Is q a prime number?
False
Is (-1)/(3453/(-12061) - (-14)/49) composite?
False
Let l = 7 - 6. Is (1 + -4)*-31*l prime?
False
Suppose -47 = -5*i + 2*x, -x = i + 4*x - 31. Let s = 6 - i. Is 2/s - (-74)/10 a prime number?
True
Suppose 0 = k + 5*m - 52, 2*k + 216 = 5*k - 5*m. Is k a prime number?
True
Let j(l) = l**2 - l + 4. Let n be j(0). Suppose n*h - 40 - 4 = 0. Is h a composite number?
False
Let w = 38 + 173. Is w a prime number?
True
Suppose -14*g + 13*g + 191 = 0. Is g a prime number?
True
Let l(u) = -u + 24 + 30 - 8. Is l(0) composite?
True
Let s(w) = -2*w**2 + 2*w - 6. Let c be s(6). Let u = c - 19. Let g = -2 - u. Is g composite?
False
Let w(t) be the second derivative of 3*t**4/2 + 5*t**3/6 + t**2 - 3*t. Is w(-3) prime?
True
Suppose 0 = 4*h - 3*o - 832, -3*h - 5*o + 508 = -145. Is h composite?
False
Suppose 651 = -a + 3106. Is a a composite number?
True
Let h = 4 - -33. Is h a prime number?
True
Let a be 3*-21*(-59 + 0). Suppose 5*h - a = k - 0*k, 2*k + 2233 = 3*h. Is h composite?
False
Suppose -5*v - i = -12, -i - 12 = -2*v - 5*i. Suppose -t - 2 = -3, v*t - 92 = 2*a. Let o = 80 + a. Is o composite?
True
Let i = 36 - 22. Let n = 8 - i. Let t = 1 - n. Is t composite?
False
Let t(u) = -u**3 - 3*u**2 - 2*u - 3. Let o be t(-3). Suppose -101 = 2*x - o*x + 2*s, -516 = -5*x - s. Is x a prime number?
True
Let k be 2 - 2 - (-4 + 1). Suppose 2*n = k*n - 150. Suppose 39 = -3*g + n. Is g a composite number?
False
Is ((-514)/(-2)*2)/2 a prime number?
True
Let s be -2 + 2 + (-2)/(-1). Let v = -35 - -137. Suppose -4*u = -s*x + v, 5*x = x - u + 195. Is x a composite number?
True
Let i be 0 - -2 - (-1 + 3). Suppose 0*v + 2*v - 6 = | 2023-08-06T01:26:57.367551 | https://example.com/article/1226 |
<?php
/************************************************************************/
/* ATutor */
/************************************************************************/
/* Copyright (c) 2002-2010 */
/* Inclusive Design Institute */
/* http://atutor.ca */
/* */
/* This program is free software. You can redistribute it and/or */
/* modify it under the terms of the GNU General Public License */
/* as published by the Free Software Foundation. */
/************************************************************************/
// $Id$
define('AT_INCLUDE_PATH', '../../../include/');
require (AT_INCLUDE_PATH.'vitals.inc.php');
admin_authenticate(AT_ADMIN_PRIV_PATCHER);
if (!isset($_REQUEST["myown_patch_id"]))
{
$msg->addError('NO_ITEM_SELECTED');
exit;
}
$myown_patch_id = $_REQUEST["myown_patch_id"];
// URL called by form action
$url = dirname($_SERVER['PHP_SELF']) . "/patch_creator.php?myown_patch_id=" . $myown_patch_id;
$sql_patches = "SELECT * from %smyown_patches m where myown_patch_id=%d";
$row_patches = queryDB($sql_patches, array(TABLE_PREFIX, $myown_patch_id), TRUE);
$sql_patch_dependent = "SELECT * from %smyown_patches_dependent m where myown_patch_id=%d";
$rows_patch_dependent = queryDB($sql_patch_dependent, array(TABLE_PREFIX, $myown_patch_id));
$sql_patch_files = "SELECT * from %smyown_patches_files m where myown_patch_id=%d order by myown_patches_files_id";
$rows_patch_files = queryDB($sql_patch_files, array(TABLE_PREFIX, $myown_patch_id));
require ('patch_edit_interface.tmpl.php');
?>
| 2023-08-17T01:26:57.367551 | https://example.com/article/5426 |
Guangzhou Underperforms First-tier Chinese Property Markets
Johnny Depp Sells First of Five Eclectic L.A. Penthouses for $2.5 million
Sliema, SLM 3112 - Malta
Address Not Disclosed
$1,288,236
Apartment
Waterfront lifestyle
Details
3
Bedrooms
2
Bathrooms (2 full)
3,292
sq ft
Description
This truly fabulous sea front Penthouse is situated on the Sliema promenade and has a massive 60 ft frontage and every imaginable luxury. Open stunning sea views as well as views of St. Julian’s and The Casino from the living room and terrace/roof top swimming pool. Located in the heart of Sliema, this wonderful property is surrounded by numerous cafes, restaurants and shops including Malta’s largest shopping mall - The Point. Yet high up on the 9th floor this excusive penthouse residence affords complete tranquility and peace.Modern layout consists of a bright, airy and spacious living room, with lovely open sea views leading out onto the front terrace which incorporates a swimming pool and entertainment and barbecue area enabling one to enjoy the beautiful sunsets. The Penthouse also accommodates a separate, fully fitted, modern kitchen. There is also a formal dining room with its own back terrace. The three bedrooms, one of which has an en suite shower room and guest bathroom, are secluded at the rear of the Penthouse where there is also a balcony and additional side terrace. The bathrooms have been finished using top quality materials of the latest styles using ‘Veneziana’ special paint effect. There is a two car garage included in the price and this beautiful property comes fully furnished with best quality, branded furniture and appliances and fully air conditioned throughout. There is more than 300 square meters of living space with over 130 square metres of outdoor area perfect for the Maltese climate.If you are looking for a tranquil yet exclusive, central yet private residence, look no further than the Penthouse at Sea Front Luxury Block, Sliema. | 2024-03-31T01:26:57.367551 | https://example.com/article/3498 |
My cousin’s 30-year-old daughter, Suzanne Nussbaum, is the quintessential crafter and thrifty do-it-your-selfer. She trolls Web sites looking for just the right items to give her small apartment in New York’s Hell’s Kitchen character and style. Last year she set out to find a sofa, the one piece of furniture — and arguably the most important piece — that was missing in her home. Suzanne, a television programmer, spent a couple of months searching Craigslist, Etsy, Krrb and various other used-furniture Web sites for a model that suited her style and her budget. She kept finding “gems,” as she calls them, but they were mostly in places she could not get to without a car, and renting one each time she wanted to check out a piece was financially unrealistic. She figured the best thing to do was to borrow her parents’ SUV and go on a big road trip, check out as many sofas as she could, and hopefully come home with one.
Suzanne began mapping out her trip by narrowing her search to one Web site, Craigslist. She quickly found that when searching for a specific item over a large geographic area, it was better to use the cPro Craigslist app rather than the site because the app allows you to search multiple cities at once. “Considering I was searching across eight or nine states, this was a huge timesaver,” she says. She also got smart about the keywords she used in her searches. For example a search for a “vintage sofa” will result in something more expensive and probably better quality than a search for a “blue sofa” or an “old couch.”
Another photo from the familiy’s road trip. (Family photo)
Part of the reason Suzanne cast a wide geographic net for her search was that she found prices differed from city to city, with the general rule of thumb that items in bigger cities such as New York and Chicago tended to be more expensive, and more rural areas were less expensive. The biggest differences in pricing tended to be between those sellers who knew what they had and what good vintage furniture was worth, and those who were moving, downsizing or just trying to get rid of their grandmother’s old couch. The cities tended to have higher concentrations of antique dealers and furniture aficionados.
Suzanne planned her road trip over Labor Day weekend, tacking on a couple of extra vacation days. Scheduling all of the appointments wasn’t easy. She had to remain flexible, and every so often she had to reschedule or cancel a meeting. She had planned on starting her trip in the Washington area (Suzanne grew up in Annandale, where her parents, Barry Nussbaum and Debbie Rachlin, still live) so that she could borrow her parents’ SUV and then work her way as far as Chicago, before stopping at home with her prize. Yet when she mentioned the trip to her parents, they said they wanted to join her and that the trip and sofa (if found) would be her birthday present. The three, in true road-trip fashion, set out not just to find her a sofa, but also to have fun. They planned on seeing and staying with friends and family along the way, plus they made sure they hit important stops like Jeni’s Splendid Ice Creams in Columbus, Ohio, and Walker Bros. Pancake House in Wilmette, Ill.
Suzanne’s parents picked her up in Allentown, Pa., where she had scheduled their first sofa-viewing. That sofa, she said in an e-mail, “was an absolute steal at $80, especially considering the cushions had all just been re-foamed (by an amateur, so not the best quality workmanship, but still a great deal) and the slipcovers recently dry-cleaned.” The sofa was priced low because the seller just needed to get it out of his house. Suzanne was tempted, especially because she knew she would never see a price like that in New York, but she ended up passing on it because it wasn’t exactly what she was looking for (an important lesson when bargain/thrift shopping: $80 spent on something you don’t like is just like flushing $80 down the drain). The trio continued on, making overnight stops in Dayton, Cincinnati and finally Chicago
It was there that Suzanne finally struck gold, checking out a sofa she had been tracking earlier in the summer. The first time she saw it, it was bought before she had the chance to inquire about it. But about a week before her trip, the listing popped up again with a note from the seller saying that he had bought it, but his girlfriend hated it, so he was now selling it again to get “out of the doghouse.”
After making sure the sofa would fit up the stairs and through her apartment’s front door, Suzanne happily helped save the seller’s relationship and ended up with exactly the sofa she wanted.
Craigslist tips
Online classifieds sites such as Craigslist are basically virtual yard sales; they both require some shopping savvy. Elizabeth Mayhew and Suzanne Nussbaum offer their lessons learned.
●Only search online when you are on the hunt for something specific — you don’t want to buy just to buy. When there’s something you want, search once a day. Any less and you will worry about missing out on things; any more and you might make yourself crazy. Bookmark furniture sites that you check every few days and check the Craigslist app daily.
●Do your homework. Study competing sites, including www.krrb.com and www.etsy.com as well as curated sites like www.1stdibs.com, www.chairish.com, and www.chairloom.com. The curated sites are very particular about what they sell (usually the items are more expensive and better quality), so you won’t typically find bargains, but the more you see, the more educated you will be.
●Always take a tape measure with you when viewing furniture; people don’t always post dimensions, and even if they do, they might not be accurate. Measure your door frames, stairwell and/or elevator to make sure you can get your purchases inside your home.
●Be open to bargaining. Some sellers add on a pre-bargaining markup because they know that for many buyers, bargaining is part of the game. But not everyone is comfortable with haggling. Suzanne says that she “doesn’t have that skill set.” Instead she looks only at items offered at a price she would be willing to pay in full. “I know a lot of people consider bargaining part of the game, but I find it so much more pleasant when everyone is just upfront to begin with.”
●Act quickly. Craigslist is about striking while the iron is hot. Chances are if you are interested in an item, so are a lot of other people. Plus, many sellers want to sell their stuff quickly — for them it’s less about making money than it is just getting the items out of their house.
●Unless you’re buying from a dealer, be prepared to pay in cash, and ideally with exact change. For a big purchase like a sofa, you should know your ATM’s daily withdrawal limits and either take out money ahead of time or going to the bank.
Chat Thursday at 11 a.m. Architect David Benton of Rill Architects, who designed the facade of this year’s D.C. Design House, joins staff writer Jura Koncius for our weekly online Q&A on decorating and household advice. Submit questions at washingtonpost.com/home
Mayhew, a “Today” show style expert and former magazine editor, is the author of “Flip! for Decorating.” | 2024-05-11T01:26:57.367551 | https://example.com/article/8013 |
© Erin Hooley / Chicago Tribune/Chicago Tribune/TNS With her parents, Matt and Megan Lassman, at left, 14-year-old Penelope Lassman, right, who has cerebral palsy, uses her iPad during a visit with cannabis specialist Farrah Zala, center, at at Innovative Wellness CBD Education Center and Store on Nov. 11, 2019, in Chicago.
The doctor’s appointment started like any other.
Dr. Rahul Khare asked his patient, a 44-year-old woman from Chicago’s North Side, if she was feeling fully recovered from a recent virus. He asked if she’d gotten her flu shot. Then the appointment veered into more unusual territory.
“Now, let’s talk about medical cannabis,” the Lincoln Park doctor said.
The patient, who is certified to take medical cannabis for fibromyalgia, said it had alleviated her chronic pain, helped her sleep and improved her mood, but the THC was making her feel “glazed” during the day. After listening to her breathing, Khare brought in the clinic’s medical marijuana consultant to discuss what type of cannabis product might work better.
Khare is one of at least a handful of Chicago-area doctors who have made medical cannabis a focus of their primary care practices — even as some physicians remain wary of its use. He and others say it’s the future of primary care, and they expect to see more doctors recommend it, especially as the legalization of recreational pot Jan. 1 lessens the stigma surrounding cannabis.
Medical marijuana has been available in Illinois since 2015. To get it, patients must have a doctor sign a certification that they have a qualifying condition, and patients can then get a card to buy cannabis at dispensaries. To certify patients, a doctor must have a physician-patient relationship with them, assess their medical history and have conducted a recent in-person exam.
© Erin Hooley / Chicago Tribune/Chicago Tribune/TNS Megan Lassman applies Lavender balm to her daughter Penelope, 14, during a visit with a Cannabis specialist at Innovative Wellness CBD Education Center and Store on Nov. 11, 2019, in Chicago.
Qualifying conditions include dozens of maladies, from autism to rheumatoid arthritis to migraines. The Illinois Department of Public Health has approved nearly 91,000 patients for medical cannabis use since the program started.
More than 4,500 Illinois doctors certified patients for medical marijuana between July 1, 2018 and June 30, 2019, the health department said.
Some doctors are making it clear that they don’t want to just certify patients in need of pot; they want to be those patients’ first call when they’re sick or in need of medical advice.
“The patient comes in for the medical (marijuana) card and then ends up staying,” said Dr. Mauricio Consalter, a primary care doctor at Medici Health Care in Chicago’s Wicker Park and Andersonville neighborhoods.
Consalter has been practicing at Medici for four years. His practice does not take health insurance, instead charging a flat fee for patients who receive certification. Marijuana use is still illegal at the federal level, and health insurance does not cover medical cannabis, meaning patients must pay out-of-pocket to purchase it from dispensaries.
“It’s going to be part of any family primary care practice in the future,” Consalter said.
Khare, a former hospital emergency room doctor, began offering cannabis-focused primary care as part of his Innovative Wellness practice about two months ago. He also has an urgent care facility and an office that’s been certifying patients for medical marijuana for about four years. He said his practice has certified about 10,000 patients.
Some have criticized doctors who certify large numbers of patients for medical marijuana — worrying that, for some, it may be little more than a money-making vehicle.
The state health department has sent requests for patient records to some doctors who have submitted suspicious physician certifications, spokeswoman Melaney Arnold said. The department has referred one doctor to the Illinois Department of Financial and Professional Regulation for inappropriately certifying patients, she said.
Khare said he’s never had a problem with the state. He said he fills a need for patients with valid medical problems.
“We’ve gotten a lot of patients who, lo and behold, use cannabis medically but because it was illegal (federally), they didn’t feel like they could tell their doctor,” Khare said. “People love it that they can come up to our doctors and say, ‘Hey, we use cannabis, can you help me with it?’”
Khare’s Lincoln Park office has an eastern feel to it, with small decorative elephants lining shelves and Indian artwork hanging from walls. The decorations reflect the practice’s focus on wellness, rather than just traditional western medicine, Khare said.
His office also sells cannabidoil, known as CBD, that patients can mix with medical cannabis as part of their treatment. CBD is legal and widely available. An in-office consultant meets with patients to suggest cannabis strains and dosages at area dispensaries that might work best and walk them through the process of how to use it.
Khare accepts health insurance, billing insurers for doctor visits and related services just as any other physician would, even though the cannabis products themselves aren’t covered.
Still, some physicians remain cautious about working with marijuana, and some question the doctors that are heavily involved in recommending its use.
The American Medical Association opposes the legalization of medical marijuana by states, saying in a policy statement that “scientifically valid and well-controlled clinical trials conducted under federal investigational new drug applications” are needed to assess the safety and effectiveness of all new drugs, including marijuana.
Thirty-two states and the District of Columbia have legalized medical marijuana. Illinois will become the 12th state to legalize recreational marijuana Jan. 1.
Some physicians also wonder whether primary care doctors should be the ones helping patients control symptoms such as pain through marijuana.
Medical marijuana is just one of many ways to treat pain, said Dr. Jay Joshi, owner of the National Pain Centers in Vernon Hills and Hoffman Estates, who is board-certified in anesthesiology and interventional spine and pain management.
“If you’re going to be managing pain, you better know how to manage it from a complex standpoint,” said Joshi, who certifies patients for medical cannabis. “If you’re not qualified to treat all aspects of pain, why are you treating any aspects of pain?”
It’s also possible, however, that some patients choose to see primary care docs who focus on medical cannabis because they can’t see pain specialists quickly enough or are confused about what pain specialists do, he said.
There’s also uncertainty about how the legalization of recreational marijuana on Jan. 1 will affect the practices of cannabis-focused doctors.
In California, many of the doctors who made businesses out of certifying medical marijuana patients found themselves out of luck when recreational use became legal in 2018, said Dale Gieringer, director of California NORML, a nonprofit that advocates for “sensible and fair” cannabis laws. Many patients preferred to go to dispensaries and get marijuana without the hassle of getting a doctor’s approval, he said.
But doctors who specialized in treating certain conditions with medical marijuana continued to see demand, he said.
In Illinois, there might be an initial drop-off in the number of patients seeking medical marijuana certification once recreational use becomes legal, said Dr. Leslie Mendoza Temple, a Glenview family and integrated medicine doctor who sees many medical marijuana patients. Mendoza Temple led the state’s former Medical Cannabis Advisory Board.
But she expects that doctors who integrate it into their practices will continue to see demand. Weed shortages are expected, and medical marijuana patients will have priority access.
Also, the state sales tax on medical cannabis is 1%, while the state sales tax on recreational marijuana will be between 10% and 25%, depending on the type of product and its potency.
Doctors such as Khare also believe their focus on treating patients with marijuana will set them apart even when patients no longer need their doctors’ consent to use it. Dispensaries typically provide advice on how to use medical marijuana, but many patients like to have a doctor’s input, he said.
“I think that there’s going to be way more people that are going to use cannabis medically now that it’s legal than ever before, and they’re going to be very confused on how to use it,” Khare said. “There’s going to be a huge influx of people wanting guidance.”
Megan and Matt Lassman, of Evanston, said they appreciated having a doctor’s assistance when they decided to put their 14-year-old daughter Penelope on medical cannabis. Parents seeking medical cannabis certifications for their children must get two doctors to certify them.
Penelope has cerebral palsy, vascular abnormalities and is nonverbal. Around the age of 9, she became violent, hitting herself in the mouth until she bled. She would scream and bite. Traditional medications weren’t controlling her behaviors and had troubling side effects, Megan Lassman said.
Running out of options, they found Khare’s practice. Penelope began taking medical cannabis every three hours, several months ago. Her mom visits her school each day to rub cannabis oil into her gums.
The difference has been dramatic, Megan Lassman said. The ninth-grader is now quick to smile and is hurting herself far less often, her mother said.
Megan Lassman said she wouldn’t have known, on her own, how to start her daughter on medical cannabis.
“I didn’t know what to try,” Lassman said. “It’s scary to think, ‘OK, I’m going to go into a dispensary and just wing it?’ That’s totally overwhelming. You need someone to hold your hand.”
lschencker@chicagotribune.com
———
©2019 the Chicago Tribune
Visit the Chicago Tribune at www.chicagotribune.com
Distributed by Tribune Content Agency, LLC. | 2023-08-14T01:26:57.367551 | https://example.com/article/2517 |
Nuclear Magnetic Relaxation Times and the Microdynamic Structure of Liquid Mixtures.
код для вставки на сайт или в блог
ссылки на документ
glucosamine ( [ K ] I=~ +32.3 ’) and the N-glycolylneuraminic
acid ([cr]’f
= -33.5 ”) can be obtained in crystalline from.
c H ,OH
II-C-OH
Hcl/ntirrli Fisclicv, Karlsruhe (Germany)
11-C -OH
OH
H
The intrinsic factor, a glycoprotein of human gastric mucosa,
contains N-acetylneurarninic acid, which protects the biologically active protein portion of this molecule from attack by
trypsin in the digestive tract (research in collaboration with
W. Pribilla). If N-acetylneuraminic acid is eliminated with
neuraminidase, the intrinsic factor is attacked by trypsin and
loses its power t o promote the resorption of vitamin BIZ in
the intestine. Protection against trypsin is also obtained if
N-acetylneuraminic acid in the intrinsic factor is replaced by
the cation exchanger poly(acry1ic acid vinyl pyrrolidone).
[GDCh-Ortsverband Miilheim/Ruhr (Germany),
January 6th, 19651
[VB 9041209 IE]
German version: Angew. Chem 77, 432 (1965)
Nuclear Magnetic Relaxation Times and the
Microdynamic StGcture of Liquid Mixtures
H . G. Hertz, Miinster (Germany)
There is relatively little knowledge, mostly from spectroscopic
investigations, about the preferred spatial arrangement of
molecules in liquid mixtures, i . e . about the “structure” of
mixtures. The “microdynamic structure” of a liquid is
characterized by dividing the liquid into microscopic regions
and ascribing to each of these regions a molecular reorientation and residence time. Thus it is possible, for example, to
correlate changes in the thermodynamic excess functions on
variation of the composition of the mixture with changes in
the microdynamic structure. The molecular reorientation
and residence times may be obtained by measuring the
nuclear magnetic relaxation times or the decay of the spinecho amplitude (self-diffusion coefficient).
This method was applied to the study of the hydration of
large, singly charged ions, e . g . Br-, I-, Rb+ [l]. By combining results of measurements of relaxation times for protons
with those for the large ions, it was shown that the range of
the increased fluidity, as compared with pure water, extends
right to the surface of the ion. I n other words, the hydration
sphere around the ions is not rigid. The activation energy
for reorientation of the water molecules in the hydration
sphere lies between 2 and 3 kcal/mole, i.e. below that for
pure water. Measurements of relaxation times also show
that the time for reorientation of the water molecules in the
hydration sphere around non-polar groups ( e . g . alkyl groups)
is about twice as high as in pure water 121. This effect has
been described as “iceberg formation”[3) or “hydration of the
second kind” [4]. The reorientation times of the dissolved
particles and the activation energy for this process can be
determined by isotopic substitution and extrapolation to
infinite dilution. Smaller particles containing alkyl groups
have a high mobility within their hydrate cages. These
relationships were studied for the systems acetonelwater and
methanol/water over the entire composition range.
[GDCh-Ortsverband Gottingen (Germany),
[VB 905/21! IE]
January 14th, 19651
German version: Angew. Chem. 77, 453 (1965)
. .
....
[ I ] H . G . Hertz, Ber. Bunsenges. physik. Chern. 67, 3 1 1 (1963);
H . G. Hertz and M. D.Zeidler, ibid. 67, 174 (1963).
[2] H. G . Hertz and M . D. Zeidler, Ber. Bunsengcs. physik.
Chem. 68, 821 (1964).
[3] ff. S. Frank and M . W. Evans, J . chem. Physics 13,507 (1945).
[4] ff. G. Hertz, Ber. Bunsenges. physik. Chem. 68, 907 (1964).
446
Control of Electrochemical Reactions by Means of
Foreign Sorbates
The sorption of foreign substances and their orientation on
a metallic surface largely depend on the surface charge of
the metal, which may be varied by means of a potential. This
constitutes the principal difference in the efficiency of such
sorbates in electrochemical and in non-electrochemical heterogeneous reactions. The following examples were given for
the effect, dependent on potential, of a sorbed foreign substance in electrode reactions:
1. During the dissolution of iron in acid, the anodic transfer
of iron into the solution, which is accelerated by sorbed hydroxide ions, may be inhibited by more strongly surface-active sorbates, e . g . chloride, other anions or polar molecules
such as phenylthiourea, as a function of the potential.
2. The drastic effect of a potential-controlled change from
adsorption to desorption (or vice versa) is shown, e.g. in the
evolution of H2 or in the deposition of Ni on a nickel
cathode (marked change in capacity, coverage of deposit,
and overvoltage).
3. A galvanostatic formation of rhythmic-lamellar structures,
coupled with periodic potential fluctuations, can be observed
when copper is deposited in the presence of o-phenanthroline. The overvoltage alters with the abrupt changes in the
sorptive coating, and in each period nucleation, specific crystal
growth, and levelling of the deposit occur in turn.
4. In the case of electro-crystallization, the sorbates may be
incorporated into the metal. Electron microscopy and spectrophotometry indicate occlusion densities of the same order,
e. g . 1018- 1020 molecules/cmz for o-phenanthroline in Ni.
5. The inhibition by sorbed 5,6-benzoquinoline, which varies
over a wide potential range (about 800 mV), was discussed
using the redox system V3”/VZc/Hg as an example. By
comparing the current density vs. potential curves in 0.1 N
HCl and in 0.1 N HCI + 0.9 N KCI, mechanical blocking of
the surface may be distinguished from a n electrokinetic effect
(repulsion between V3+ and VZ+). Potential vs. capacity curves, taken in vanadium-free electrolytes under otherwise
similar conditions, confirm the occurrence of inhibition and
sorption of foreign substances within the same potential
ranges.
IGDCh-Ortsverband Freiburg (Germany),
January 15th, 19651
[VB 906/213 IE]
German version: Angew. Chem. 77, 459 (1965)
Recent Investigations of Covalent
Inorganic Fluorides
0. Glemser, Gottingen (Germany)
Difluorodiazine N2Fz is obtained by direct fluorination of
NaN3 in a continuous process at room temperature. On
adding chlorine to the fluorine, highly explosive chlorofluorodiazine N2FCI is produced. On passing NO with
fluorine at 65OoC through a CaFz tube, nitrogen trifluoride
is formed:
2 N O + 2F2
+- N O p F f N F 3
NF3 is often considered to be only slightly reactive. On being
passed into molten sulfur at 200 OC it yields a little N3S3F3,
but at 400 OC good yields of thiazyl fluoride NSF and thiothionyl fluoride SSF2 are obtained. In this way NSF and
SSFz can be obtained easily on a preparative scale.
Nitrogen-sulfur-fluorine compounds can be divided into the
acyclic compounds NSF, S3NzF2, NSF3, and the cyclic
compounds N4S4F4, N3S3F3, S4N3F. Of the former, NSF3
can be reacted with diethylamine to give the stable compound
NSFzN(CzH& which contains an N E S triple bond as does
NSF3.
Angew. Chem. interntit. Edit. / Vol. 4(1965)
/
No. 5 | 2024-01-11T01:26:57.367551 | https://example.com/article/3842 |
Q:
How to disable the scrollbars is width and height of body bigger than 1000px and 600px?
Preferably with just javascript. But if that's too hard, jquery will be ok (I don't want to load jquery because the page has to load really fast).
A:
This question is pretty ambiguous, and I get the impression that you might be a little confused in your wording. This handler will disable the horizontal scrollbar if the body width exceeds 1000px, and the vertical scrollbar if the body height exceeds 600px. If this is really the functionality you're looking for, you should be aware that it's likely to frustrate users who are used to having full control over the scroll position of the page. Anyway, here's what (I think) you asked for:
function scrollStuff()
{
if (document.body.offsetHeight > 600)
{
document.body.style.overflowY = 'hidden';
}
else
{
document.body.style.overflowY = 'auto';
}
if (document.body.offsetWidth > 1000)
{
document.body.style.overflowX = 'hidden';
}
else
{
document.body.style.overflowX = 'auto';
}
}
window.onload = scrollStuff;
| 2024-04-26T01:26:57.367551 | https://example.com/article/2709 |
Conventionally known is the so-called tandem-type color laser printer having photosensitive drums forming electrostatic latent images, developing rollers developing the electrostatic latent images and toner boxes accommodating toners fed to the developing rollers, arranged correspondingly to four colors, i.e. yellow, magenta, cyan and black, respectively.
The tandem-type color laser printer forms generally simultaneously toner images of the respective colors on the respective photosensitive drums and sequentially transfers the toner images of the respective colors from the photosensitive drums to a sheet sequentially passing through the photosensitive drums, and therefore can form color images at a speed generally identical to that of a monochromatic laser printer.
For example, there has been proposed a tandem-type color laser printer having image forming stations, each including a photosensitive member, a developing unit having a developing roller and storing a developing agent and a transfer unit, provided correspondingly to respective colors, and forming color images by passing a transfer medium through the image forming stations of the respective colors.
In the tandem-type color laser printer, a set of four photosensitive members as well as a coroner charger and a cleaner arranged around the photosensitive member can be drawn out and detached from the printer body, and mounted on and attached to the printer body, as an integral photosensitive cartridge. Further, developing devices belonging to the photosensitive members are detachably mountable to the photosensitive cartridge.
Also known is a color image forming apparatus in which a plurality of developing machines are arranged correspondingly to respective colors and toner hoppers for supplementing toners to the developing machines are parallelly provided above side portions of the developing machines in a detachably mountable manner to the developing machines respectively.
However, each of the developing devices storing the toners corresponding to the respective colors must be increased in size in order to ensure sufficient volumes of the toners.
In the tandem-type color laser printer, on the other hand, the each developing device is attached/detached to/from the photosensitive cartridge. Therefore, if the developing devices are increased in size in order to ensure sufficient volumes of toners, the photosensitive cartridge must also be increased in size. Then, the printer body to/from which the photosensitive cartridge is attached/detached is inevitably increased in size.
In order to exchange each developing device in the tandem-type color laser printer, further, the photosensitive cartridge must be drawn out and detached from the printer body to exchange each developing device with a new one in the detached photosensitive cartridge, and must thereafter be mounted on and attached to the printer body again. In other words, the photosensitive cartridge including the photosensitive bodies, the coroner charger and the cleaner must be detached from and then attached to the printer body, in order to exchange each developing device. Thus, much labor is required for detaching the photosensitive cartridge from the printer body and thereafter attaching the photosensitive cartridge to the printer body.
Further, while each developing device storing the toner is provided with members such as a feed roller, a developing roller and a regulation blade necessary for developing a toner image, the developing device must be exchanged when the toner is used up, even if these members are still operable. Therefore, the running cost is increased.
The color laser printer can be undesirably increased in size due to the aforementioned structure including the plurality of photosensitive drums, the plurality of developing rollers and the plurality of toner boxes corresponding to the respective colors.
If the toner boxes are reduced in size in order to miniaturize the color laser printer, the volumes of the toners that can be accommodated in the toner boxes are reduced, so that the toner boxes must be frequently exchanged, leading to troublesome maintenance.
On the other hand, when sufficient volumes of toners are ensured in the toner boxes while miniaturizing the color laser printer, the toner boxes are limited in size reduction to inevitably occupy a large volume ratio in the color laser printer. Thus, arrangement of other parts in the color laser printer is restricted.
When the toner boxes are respectively provided with agitators for agitating the toners accommodated therein, for example, it is difficult to provide mechanisms for supplying driving force to the agitators on all the toner boxes in the limited space of the color laser printer.
When the developing machines and the toner hoppers are formed independently of each other as in the color image forming apparatus, for example, shutter members must be provided on all the toner hoppers respectively such that the toner hoppers communicate with the developing machines by opening the shutter members for feeding the toners to the developing machines and the toner hoppers are sealed by closing the shutter members for preventing the toners from leaking.
In this case, it is difficult to provide mechanisms for opening/closing the shutter members on all the toner hoppers in the limited space of the color laser printer. | 2023-12-12T01:26:57.367551 | https://example.com/article/9847 |
Q:
Error with changing color
I have the following code to change colors and store into the database... For some reason it only allows one color to be changed from the colorDialog...
if (colorDialog1.ShowDialog() == DialogResult.OK)
{
ColorDialog col = new ColorDialog();
//col.ShowDialog();
string color = col.Color.ToArgb().ToString("x");
color = color.Substring(2, 6);
color = "#" + color;
con.Open();
string sql2 = ("Update Employee SET PanelColor= '" + color + "' WHERE EID='" + 17002 + "' ");
SqlCommand cmd2 = new SqlCommand(sql2, con);
SqlDataReader dr2 = cmd2.ExecuteReader();
con.Close();
MessageBox.Show(color);
panel1.BackColor = ColorTranslator.FromHtml(color);
}
Step 1 green color was selected
Step 2 Messagebox showing the color codes(for testing purpose)(wrong color code)
Step 3 it uploads the wrong color into the panel...
I am not sure what is wrong with this... Please advice me thank you
A:
if (colorDialog1.ShowDialog() == DialogResult.OK)
{
string color = colorDialog1.Color.ToArgb().ToString("x");
color = color.Substring(2, 6);
color = "#" + color;
con.Open();
string sql2 = ("Update Employee SET PanelColor= '" + color + "' WHERE EID='" + 17002 + "' ");
SqlCommand cmd2 = new SqlCommand(sql2, con);
SqlDataReader dr2 = cmd2.ExecuteReader();
con.Close();
MessageBox.Show(color);
panel1.BackColor = ColorTranslator.FromHtml(color);
}
| 2023-09-28T01:26:57.367551 | https://example.com/article/3659 |
Introduction {#s1}
============
Liver sinusoidal endothelial cells (LSECs) act as a filter between the lumen of the hepatic sinusoid and the surrounding hepatocytes. A major role of the LSEC is to minimize any barrier for the bi-directional transfer of small or soluble substrates between blood and the extracellular space of Disse, while excluding larger circulating particles such as blood cells, platelets and chylomicrons. This physiological role is achieved by the presence of numerous transcellular pores in LSECs called fenestrations. Fenestrations are approximately 50--150 nm in diameter and most are aggregated into groups of 10--100, so-called liver sieve plates [@pone.0046134-Cogger1]. The diameter and number of fenestrations are altered by various liver diseases, diabetes mellitus and old age and are influenced by cytokines and hormones [@pone.0046134-Cogger1]. Alteration in the size and number of fenestrations influences the hepatic trafficking of lipoproteins [@pone.0046134-Hilmer1], clearance of pharmaceutical agents [@pone.0046134-LeCouteur1], liver regeneration [@pone.0046134-Furrer1] and interactions between lymphocytes and hepatocytes [@pone.0046134-Warren1].
No markers have been reported that specifically label fenestrations and the mechanisms for the regulation of their formation and size remain unclear. The most consistent findings of biological relevance are that fenestrations are increased by actin-disrupting agents [@pone.0046134-Steffan1], [@pone.0046134-Braet1] and by the angiogenic cytokine, vascular endothelial growth factor (VEGF) [@pone.0046134-Cogger1], [@pone.0046134-Funyu1], [@pone.0046134-Yokomori1]. The mechanisms that regulate fenestrations need to be clarified in order to develop strategies to improve lipoprotein metabolism in old age and liver disease [@pone.0046134-LeCouteur2], and to enhance liver regeneration [@pone.0046134-Furrer1].
Fenestrations are smaller than the limit of resolution of light microscopy and most studies have relied upon electron microscopy with inherent problems related to fixation of tissue. Recently three dimensional structured illumination fluorescence light microscopy (3D-SIM) was applied to LSECs and their fenestrations [@pone.0046134-Cogger2]. 3D-SIM is an ultra-high resolution light microscopy technique that uses interference patterns to convert structures below the resolution limit of light microscopy into observable ones by generating difference/beat frequencies called Moiré fringes. The morphology of the fenestrations and sieve plates was very effectively resolved by 3D-SIM, providing for the first time a detailed three-dimensional map of their structure. Using the plasma cell membrane stain Cell-Mask Orange, discrete membrane structures were identified between the sieve plates. On the basis of their size and appearance we postulated that these structures are membrane rafts and potentially involved in the regulation of sieve plates. Membrane rafts are lipid-ordered domains in cell membranes that vary in size from 10--200 nm, and may aggregate to form micrometer-sized structures [@pone.0046134-Lingwood1]. Rafts are enriched in sphingolipids and cholesterol which engenders membrane stability and provides a platform for many membrane proteins such as caveolin. Rafts are tethered to the actin cytoskeleton which has a pivotal role in maintaining their structure and integrity [@pone.0046134-Viola1], [@pone.0046134-Chichili1]. The size of membrane rafts, like that of fenestrations, is below the limits of resolution of light microscopy and their visualization has mostly been achieved with fluorescence microscopy [@pone.0046134-Owen1].
In this study, we used 3D-SIM to establish the three-dimensional structure of membrane rafts and liver sieve plates in the cell membranes of LSECs, and the topographical relationship between them. Furthermore, by manipulating membrane rafts and actin, we show how rafts might influence fenestrations, and conclude that rafts are the final regulatory step in the formation of transcellular pores, fenestrations and liver sieve plates.
Results {#s2}
=======
Visualization of Membrane Rafts and Fenestrations {#s2a}
-------------------------------------------------
To study the morphology and relationship between sieve plates and membrane rafts, we performed 3D-SIM on isolated LSECs. [Figure 1 (A--G)](#pone-0046134-g001){ref-type="fig"} shows representative 3D-SIM micrographs of sieve plates and membrane rafts in LSECs while Videos S1, S2, S3 demonstrate LSECs rotating in 3D space. The membrane rafts, which are stained with Bodipy FL C5 ganglioside GM1, are approximately 100 nm in size, occupy about one quarter of the surface area of the cell membrane, and protrude slightly from the cell membrane surface. They are distributed preferentially towards the perinuclear region where the rafts are aggregated in a large perinuclear ring. Several clustered rafts are apparent in the peripheral regions of the cell membrane. These are 1--2 µm in diameter, circular and have a more distinct morphology including a raised perimeter.
{ref-type="fig"} showing clustered membrane rafts with raised perimeters. (H) TIRFM of LSEC stained with NBD-cholesterol (green), a marker for rafts, and CellMask Orange (orange) showing perinuclear distribution of rafts (arrows). Fenestrations are not resolved within the sieve plates (\*) with TIRFM. (I) TIRFM of LSEC stained with Bodipy FL C5 ganglioside GM1, a marker for rafts, and CellMask Orange (orange) confirming mostly perinuclear distribution of rafts. Scale bar 5 µm (A, B, H, I), 1 µm (C--G).](pone.0046134.g001){#pone-0046134-g001}
The fenestrations and sieve plates are also well resolved by 3D-SIM. The fenestrations are approximately 50--150 nm in diameter and are mostly found in sieve plates containing about 10--100 fenestrations. The sieve plates are more frequent in the peripheral regions of the cell. There is an inverse relationship between the distribution of sieve plates and membrane rafts.
In order to confirm the distribution of membrane rafts in LSECs and their relationship with sieve plates we also performed total internal reflectance fluorescence microscopy (TIRFM) using two rafts stains, Bodipy FL C5 ganglioside GM1 and NBD-cholesterol. Representative micrographs are shown in [Figure 1 (H--I)](#pone-0046134-g001){ref-type="fig"}. Although TIRFM cannot visualize structures below the limit of resolution of light microscopy such as individual fenestrations, the distribution of the fluorescent raft stains confirmed the findings of 3D-SIM -- rafts are preferentially distributed in the perinuclear regions of LSECs and are inversely distributed with respect to sieve plates.
Effects of Manipulating Membrane Rafts on Fenestrations {#s2b}
-------------------------------------------------------
We used low concentrations of 7-ketocholesterol (7KC) in an attempt to reduce lipid-ordered membrane rafts [@pone.0046134-Kahn1]. We used low concentrations of Triton X-100 in an attempt to reduce non-raft lipid-disordered membranes [@pone.0046134-Chamberlain1]. Concentration-dependent effects on the morphology of LSECs of both agents are shown in [Figures S1](#pone.0046134.s001){ref-type="supplementary-material"} and [S2](#pone.0046134.s002){ref-type="supplementary-material"}. At high concentrations, both agents cause extensive cell damage. Representative figures from the low concentration experiments are shown in [Figure 2](#pone-0046134-g002){ref-type="fig"} and quantification of the results in [Figure 3](#pone-0046134-g003){ref-type="fig"}. We applied Triton X-100 to cells at 37°C rather than 4°C to maintain cell viability and preliminary experiments showed that this was associated with more effects on fenestrations ([Figure S1](#pone.0046134.s001){ref-type="supplementary-material"}). Fenestrations were quantified by measuring their diameter or their porosity (which is the percentage of the surface area of the cell membrane containing fenestrations). The effects of 7KC were initially studied at four concentrations. At the lowest concentration (9 µM) there was an increase in fenestrations while at the highest concentration (73 µM) typically used to study rafts in lymphocytes, cell membrane retraction and damage were apparent, however remaining fragments of cell membrane were highly fenestrated ([Figure S2](#pone.0046134.s002){ref-type="supplementary-material"}). Therefore the 9 µM concentration was used in all subsequent experiments. LAURDAN (6-lauroyl-2-dimethylaminonaphthalene) was used to visualize rafts with ratiometric two-photon fluorescence microscopy. LAURDAN undergoes a spectral shift when in lipid-disordered non-raft regions versus lipid-ordered raft domains, thus can identify both raft and non-raft regions simultaneously and is a widely accepted method for identifying lipid-disordered and lipid-ordered regions of cell membranes [@pone.0046134-Owen2], [@pone.0046134-Rentero1]. This is quantified with Generalized Polarization values (GP) which range from −1 to 1, where −1 represents most lipid disordered and 1 represents the most lipid ordered membranes [@pone.0046134-Owen2]. LAURDAN-stained LSECs confirmed that 7KC increased lipid disordered, non-raft regions in the cell membrane. The GP values decreased from −0.259 in controls to −0.320 in 7KC-treated cells. These results were confirmed using NBD-cholesterol where it was found that Triton X-100 increased raft staining while 7KC reduced staining ([Figure S3](#pone.0046134.s003){ref-type="supplementary-material"}). Scanning electron microscopy (SEM) revealed that 7KC caused a marked increase in both the diameter of fenestrations and total porosity in isolated LSECs ([Figure 2](#pone-0046134-g002){ref-type="fig"} and [3](#pone-0046134-g003){ref-type="fig"}). 7KC was associated with the development of some gaps which presumably represent deficits in the cell membrane where the rafts have been depleted. On the other hand, Triton X-100 was associated with a marked decrease in fenestration porosity as assessed by SEM ([Figure 2](#pone-0046134-g002){ref-type="fig"} and [3](#pone-0046134-g003){ref-type="fig"}). GP values did not statistically significantly change following treatment with Triton X-100 however the distribution was more homogeneous and fewer sieve plates were apparent.
{#pone-0046134-g002}
{#pone-0046134-g003}
Effects of Manipulating Actin on Fenestrations {#s2c}
----------------------------------------------
Actin influences both membrane rafts [@pone.0046134-Viola1] and fenestrations [@pone.0046134-Steffan1],[@pone.0046134-Braet1], therefore the effect of the actin-disrupting agent, cytochalasin D [@pone.0046134-Rubtsova1] was studied. Representative micrographs are shown in [Figure 4](#pone-0046134-g004){ref-type="fig"}. SEM showed that cytochalasin D increased number of fenestrations. The effect of cytochalasin D on LAURDAN staining in LSECs was studied using two-photon fluorescence microscopy. It was associated with more sieve plates and an increase in lipid-disordered staining. Then it was determined whether the effect of cytochalasin D to increase fenestrations could be abrogated by pretreating the cells with Triton X-100 to reduce non-raft regions of the membrane. We found no increase in fenestrations following co-treatment with Triton X-100 and cytochalasin D, in fact porosity was reduced substantially (porosity 0.87±0.22% following dual treatment vs 9.05±0.84% following treatment with only cytochalasin D). The results indicate that actin influences fenestrations via its effects on membrane rafts. Finally we assessed the effects of 7KC with cytochalasin D on fenestrations. As expected there was an increase in fenestrations which indicates that the disruption of rafts and actin both act via a linked or similar mechanism to increase fenestrations.
{#pone-0046134-g004}
The Presence of Membrane Pores Adjacent to Sieve Plates {#s2d}
-------------------------------------------------------
It has been reported that vesicles form in cell membranes when the membrane-stabilizing effects of actin and rafts are depleted [@pone.0046134-VindKezunovic1]. Therefore we examined iso-rendered 3D-SIM micrographs and SEM of fenestrations to determine whether there was any evidence for the formation of fenestrations from pores or vesicles. Pores including ones with small fenestrations at their base were apparent adjacent to the sieve plates on both 3D-SIM and SEM ([Figure 5](#pone-0046134-g005){ref-type="fig"}).
{#pone-0046134-g005}
Effects of VEGF on Membrane Rafts in LSECs {#s2e}
------------------------------------------
VEGF increases fenestrations in LSECs [@pone.0046134-Funyu1], [@pone.0046134-Yokomori1]. Therefore, the effects of VEGF on fenestrations and membrane rafts in LSECs were studied ([Figure 6](#pone-0046134-g006){ref-type="fig"}). LSECs were stained with LAURDAN and studied using two-photon fluorescence microscopy. VEGF was associated with increased blue staining indicating an increase in non-raft, lipid disordered regions of the cell membrane (median −0.365 vs −0.259 in controls, P\<0.001).
{#pone-0046134-g006}
Effect of 7KC on LSECs in the Perfused Liver {#s2f}
--------------------------------------------
In light of these *in vitro* results indicating that 7KC manipulates fenestrations via its effects on rafts, we tested the effect of perfusing intact livers with 9 µM of 7KC for 8 minutes ([Figure 7](#pone-0046134-g007){ref-type="fig"}). Treatment with 7KC caused ruffling of LSEC membranes and increased the diameter of fenestrations from 80.9±0.8 nm in perfused untreated control mice to 85.8±1.0 nm in those perfused with 7KC (P\<0.001). However porosity of the LSEC was unaffected by treatment with 7KC (7KC 1.79±0.25% vs control 1.72±0.17%).
{#pone-0046134-g007}
Discussion {#s3}
==========
Fenestrations and rafts are both cell membrane structures that are below the limit of resolution of light microscopy [@pone.0046134-Cogger1]. The morphology of fenestrations has been studied primarily using electron microscopy while that of rafts has been studied using fluorescence microscopy [@pone.0046134-Owen1]. 3D-SIM is a super-resolution fluorescence microscopy technique that provides the opportunity to simultaneously study both membrane rafts and fenestrations and their distribution in isolated LSECs. 3D-SIM provides high resolution images of fenestrations and associated structures, such as the cellular cytoskeleton [@pone.0046134-Cogger2]. Here, we also applied 3D-SIM to visualize membrane rafts. Using the fluorescent raft stain, Bodipy FL C5 ganglioside GM1, membrane rafts were found to be aggregated preferentially in the perinuclear region of LSECs, with a more diffuse distribution in the peripheral cytoplasmic extensions, and were generally thicker than the surrounding cell membrane. This pattern of distribution of rafts was confirmed using TIRFM with two raft stains, Bodipy FL C5 ganglioside GM1 and NBD-cholesterol. With 3D-SIM, a few clustered rafts sections were also apparent in the peripheral regions of the cells. These were about 1--2 µm in diameter and some had a raised perimeter, consistent with predictions based on line tension [@pone.0046134-Kuzmin1]. As reported previously [@pone.0046134-Cogger2], 3D-SIM revealed that fenestrations are clustered in groups of 10--100 fenestrations called liver sieve plates that occupy 5--10% of the entire cell membrane. Moreover, the SIM images revealed that there is a distinct inverse distribution between liver sieve plates and membrane rafts. On the basis of this observation, we investigated whether manipulating membrane rafts had any effect on fenestrations.
Most studies of membrane rafts have used various agents to isolate raft or non-raft membranes. At low concentrations, 7KC disrupts membrane rafts by disordering lipid membranes [@pone.0046134-Kahn1], [@pone.0046134-Rentero1], while at much higher concentrations than we used 7KC can also induce apoptosis [@pone.0046134-Kahn2]. Triton X-100 is a detergent that has been used to separate detergent-resistant membranes from cells [@pone.0046134-Chamberlain1]. This has usually been undertaken using high concentrations above the Critical Micelle Concentration which are associated with cell lysis. In our experiments we used a much lower concentration in order to study cell membranes that have remained intact. Triton X-100 still penetrates cell membranes in the monomeric form [@pone.0046134-Mrowczynska1] and also increases the formation of rafts [@pone.0046134-Heerklotz1]. Here we used these two agents to assess their effect on the morphology of the LSEC cell membrane. Treatment with 7KC was associated with increased number and diameter of fenestrations *in vitro* and increased diameter of fenestrations i*n vivo.* Triton X-100 was associated with a reduced number of fenestrations. The fluorescent stains, LAURDAN and NBD-cholesterol confirmed an effect of low concentrations of 7KC and Triton X-100 on membrane rafts. The inverse distribution of rafts and sieve plates observed with 3D-SIM combined with the effects of Triton X-100 and 7KC on fenestrations, suggest that rafts prevent the formation of fenestrations and sieve plates in LSECs.
To study this further, we then investigated the effects of the actin disrupter, cytochalasin D. The actin cytoskeleton is bound to membrane rafts via a range of proteins and this serves to tether and maintain raft structure [@pone.0046134-Viola1], [@pone.0046134-Chichili1]. Cytochalasin D has been shown to disrupt membrane rafts through its effects on the actin cytoskeleton [@pone.0046134-Head1]. Furthermore, cytochalasin D and other actin disrupters have been reported to increase fenestrations [@pone.0046134-Steffan1], [@pone.0046134-Braet1]. Indeed we found that cytochalasin D reduced rafts in LSECs and that this was associated with increased fenestrations. However, the effect of cytochalasin D on fenestrations was blocked and reversed by Triton X-100. On the other hand the effects of 7KC and cytochalasin D were possibly synergistic in increasing fenestrations. Although this is most likely to indicate the addition of two sub-maximal responses, it is not inconsistent with two separate mechanisms.
The results of these experiments suggest that actin and rafts reduce the formation of fenestrations in LSECs, and that fenestrations form in non-raft regions of the LSEC membrane. Disruption of actin increases fenestrations through its effect on rafts and can be prevented by the removal of non-raft regions. The processes leading to the formation of fenestrations may be similar to the generation of membrane vesicles. It has been reported that disruption of actin cytoskeleton associated with increased lipid-disordered, non-raft membrane is required for the formation of microvesicles [@pone.0046134-VindKezunovic1]. Vesiculation occurred spontaneously in membranes when line tension associated with rafts was reduced and the tethering by actin cytoskeleton released. We were able to identify small pores in the non-raft regions of the LSEC and adjacent to the sieve plates that might represent early development of fenestrations, although it is not possible to determine what happens to these pores over time. Thus here we propose that a sieve-raft theory to explain the formation of fenestrations. Fenestrations form in non-raft membranes once the stabilizing effects of actin and rafts are depleted. Because the cytoplasmic extensions of LSECs are very thin (approximately 100 nm thick), fenestrations form rather than vesicles. The fact that small pores can develop spontaneously in lipid bilayers under appropriate conditions has been established [@pone.0046134-Bicout1], [@pone.0046134-Loison1] and sieve-like sets of small pores generate increased stability for rafts [@pone.0046134-Bicout1].
Other pathways have been reported to be involved in the regulation and formation of fenestrations. Most of these are consistent with the sieve-raft theory because they act via the actin cytoskeleton, such as serotonin [@pone.0046134-Furrer1], VEGF [@pone.0046134-Yokomori1] and rho [@pone.0046134-Yokomori2]. There has also been a report that fenestrations might be a type of caveolae [@pone.0046134-Cogger3], [@pone.0046134-Yokomori3] which would suggest that they reside in rafts, rather than non-rafts. However we believe that this is unlikely because caveolin-1 knockout mice have normal fenestrations [@pone.0046134-Warren2]. To test whether VEGF exerts its action on fenestrations via rafts, we studied the effects of VEGF on LAURDAN staining in isolated LSECs. VEGF was associated with an increase in lipid-disordered membranes, consistent with this hypothesis.
In conclusion 3D-SIM revealed the three dimensional morphology of fenestrations and rafts and identified their inverse distribution in LSECs. The experiments reported here are consistent with a sieve-raft interaction, where fenestrations form in non-raft regions of LSECs once the membrane-stabilizing effects of actin cytoskeleton and membrane rafts are diminished. Agents that regulate fenestrations might act via their effects on actin and rafts.
Materials and Methods {#s4}
=====================
Animals {#s4a}
-------
3--4 and 12 month old C57/Bl6 mice were obtained from the Animal Resource Centre in Perth Western Australia. Animals were housed at the ANZAC Research Institute on a 12 hour light/dark cycle and provided with *ad libitum* access to food and water. The study was approved by the Animal Welfare Committee of the Sydney South Western Area Health Service.
Materials {#s4b}
---------
Reagents included: Liberase TM Research Grade (Roche, Basel, Switzerland); RPMI (Gibco Grand Island, NY), Percoll, Cytochalasin D, Triton X-100, methyl-β-cyclodextrin, 7-ketocholesterol, mouse recombinant vascular endothelial growth factor VEGF (Sigma Aldrich, St Louis, MO). Stains included 6-lauroyl-2-dimethylaminonaphthalene LAURDAN, Cell-Mask Orange, Bodipy FL C5 ganglioside GM1 and NBD-cholesterol (Invitrogen, Eugene, OR).
LSEC Isolation {#s4c}
--------------
Mouse LSEC isolation was performed as described previously [@pone.0046134-Hansen1] by perfusion of the liver with Liberase TM (0.15 Wünsch units/ml). Non-parenchymal cells were removed by a two-step Percoll gradient and Kupffer cells were removed by selective adherence to plastic. LSECs (seeded at 0.5×10^6^ cells/cm^2^) were cultured (37°C, 5% CO~2~) in serum free RPMI-1640 for 3 hours before use.
LSEC Treatments {#s4d}
---------------
Cells were treated with a variety of agents and probes to elucidate the relationship between rafts, actin and fenestrations. Membrane rafts were disrupted using 7KC [@pone.0046134-Kahn1] while non-raft regions were removed using Triton X-100 [@pone.0046134-Chamberlain1]. Actin was disrupted using cytochalasin D [@pone.0046134-Rubtsova1]. All experiments were performed in triplicate. 7KC stock solution was prepared by drop-wise adding 15 mg/ml 7KC solution in ethanol to 50 mg/ml methyl-β-cyclodextrin in PBS at 80°C to a final sterol concentration of 1.5 mg/ml. 5, 10 or 20 µl of this solution were then added to 1 ml of cell medium to obtain 9, 18, 36 or 73 µM 7KC concentrations respectively. LSECs were treated for 7 min. For Triton X-100 experiments, LSECs were incubated with 0.001% Triton X-100 in RPMI for 1 minute. For cytochalasin D experiments, LSECs were incubated with 0.5 µg/ml cytochalasin D in RPMI for 30 minutes. Experiments were also performed with both cytochalasin D with Triton X-100, and cytochalasin D with 7KC. In addition, experiments were performed where LSECs were incubated with VEGF (100 ng/ml) for 4 hours.
Liver Perfusion with 7KC {#s4e}
------------------------
Liver perfusions were performed in 12 month old mice as previously described [@pone.0046134-LeCouteur3]. The perfusate was Krebs-Henseleit bicarbonate buffer (10 mmol/L glucose, *p*H 7.4, saturated with 95% O~2~/5% CO~2~, 1% bovine serum albumin, 37°C). The perfusate flow rate was maintained at approximately 2 mL/min/g of liver using a cartridge pump (Masterflex L/S, model 794-32; Cole-Palmer, Extech Equipment, Boronia, Australia) in a non-recirculating system. Viability was confirmed by macroscopic appearance, portal venous pressure, light microscopy and electron microscopy. Control animals (n = 3) were perfused with Krebs Henseleit buffer for 10 min and 7KC treatment animals (n = 3) were perfused for 2 min with Krebs Henseleit buffer alone followed by 8 min with 9 µM 7KC solution in Krebs Henseleit buffer. After completion of treatment experiments, liver specimens were fixed for electron microscopy by gravity-fed perfusion with 2% glutaraldehyde/3% paraformaldehyde in 0.1 mol/L sodium cacodylate buffer (0.1 mol/L sucrose, 2 mmol/L CaCl~2~). Randomly selected specimens were analysed by SEM as described below.
Fixation, Staining and Imaging of LSECs {#s4f}
---------------------------------------
SEM was performed as described [@pone.0046134-Cogger4], [@pone.0046134-OReilly1]. Isolated LSECs were fixed in 2.5% glutaraldehyde in 0.1 mol/L sodium cacodylate buffer, osmicated, dehydrated in ethanol and hexamethyl-disilazane, mounted on stubs, sputter coated with platinum, and examined using a JEOL 6380 Scanning Electron Microscope. Figures at 10,000× magnification were used to measure fenestration diameter and LSEC porosity using Image J (<http://rsb.info.nih.gov/ij/>, between 464--2483 fenestrations assessed in each treatment group). Porosity is defined as the percentage of cell membrane covered by fenestrations.
3D-SIM was performed as described previously [@pone.0046134-Cogger2]. LSECs were stained with Cell-Mask Orange (Life Technologies, Carlsbad, CA) which is a cell membrane marker, and Bodipy FL C5 ganglioside GM1 which is a marker of membrane rafts then fixed with 4% fresh paraformaldehyde in PBS. The cells were imaged with a structured illumination microscope based on the Deltavision/OMX V2.0 (Applied Precision Inc, Issaquah, WA). Image reconstructions were made with the OMX specific SoftWoRx v4.5.0 software package (Applied Precision Inc, Issaquah, WA). Three dimensional figures were generated by iso-surface rendering (iso-rendering) which builds up a 3D model from multiple two dimensional images (Volocity 3D Image Analysis Software, PerkinElmer, MA).
TIRFM was performed as described previously [@pone.0046134-Owen2] using Bodipy FL C5 ganglioside GM1 or NBD-cholesterol. A custom built microscope was used with excitation at 473 nm from a diode-pumped solid-state laser delivered via a single mode optical fibre and a rotatable mirror. Excitation was delivered into the backport of an inverted epifluorescence IX71 Olympus microscope equipped with a 60×1.45 NA oil-immersion TIRF objective. Fluorescence was collected on an electron-multiplying CCD camera in the range 500--593 nm and 600--680 nm using a two-channel imager.
Two-photon fluorescence microscopy was performed as described [@pone.0046134-Owen2]. LAURDAN undergoes a spectral blue-shift from 490 nm when in lipid-disordered non-raft regions to 440 nm when in lipid-ordered raft domains, thus can identify both raft and non-raft regions simultaneously [@pone.0046134-Owen2]. Two-channel time-resolved live cell imaging was performed using a confocal laser-scanning microscope (TCS SP5, Leica Microsystems GmbH, Wetzlar, Germany) with a 1.2NA 63× water-immersion objective and multiphoton excitation from a mode-locked, femtosecond-pulsed Ti:Sapphire laser (Mai-Tai, Spectra Physics, Mountain View, CA). LAURDAN was excited at 800 nm and fluorescence was split using a dichroic mirror (458 nm) passed through a bandpass filter centered on 425 and 483 nm. Fluorescence was quantified using ImageJ and converted to generalized polarization (GP) values (n = 30--143 cells for each group) [@pone.0046134-Owen2].
Statistics {#s4g}
----------
Results are presented as mean ± SEM or median. Multiple groups were compared with either ANOVA with a post-hoc Student-Newman-Keuls test, or Kruskal-Wallis test with a post hoc Dunn's method (Sigmastat v11, Systat Software Inc).
Supporting Information {#s5}
======================
######
Concentration-dependent effects of Triton X-100 on isolated LSECs. Scanning electron micrographs of LSECs after treatment with 0.1, 0.01 and 0.001% Triton X-100 at 25C. The effects of Triton X-100 were diminished when performed at 4C, while cell damage occurred with higher concentrations of Triton X-100. (scale bar 1 µm)
(TIFF)
######
Click here for additional data file.
######
Concentration-dependent effects of 7KC on isolated LSECs. Scanning electron micrographs of LSECs after treatment with 18, 36 and 73 µM 7KC. Cell damage occurred at higher concentrations of 7KC. (scale bar 1 µm)
(TIFF)
######
Click here for additional data file.
######
The effects of 7KC (9 µM) and Triton X-100 (0.0001%) on NBD-cholesterol staining in isolated LSECs. There was an increase in staining with Triton X-100 and a reduction with 7KC.
(TIFF)
######
Click here for additional data file.
######
3D-SIM of LSECs stained with Bodipy FL C5 ganglioside GM1, a marker for rafts (green) and Cell-Mask Orange, a cell membrane marker (orange). There is an inverse distribution between liver sieve plates and membrane rafts.
(MOV)
######
Click here for additional data file.
######
3D-SIM of LSECs stained with Bodipy FL C5 ganglioside GM1, a marker for rafts (green) and Cell-Mask Orange, a cell membrane marker (orange). There is an inverse distribution between liver sieve plates and membrane rafts.
(MOV)
######
Click here for additional data file.
######
3D-SIM of LSECs stained with Bodipy FL C5 ganglioside GM1, a marker for rafts (green) and Cell-Mask Orange, a cell membrane marker (orange). There is an inverse distribution between liver sieve plates and membrane rafts.
(MOV)
######
Click here for additional data file.
[^1]: **Competing Interests:**The authors have declared that no competing interests exist.
[^2]: Conceived and designed the experiments: DLC VC BS TH RQ DS AW. Performed the experiments: DS AW GM DO DZ SZ HC. Analyzed the data: DS AW GM DO DZ SZ HC RQ TH BS DLC VC. Contributed reagents/materials/analysis tools: RQ TH BS DLC VC. Wrote the paper: DLC VC DS DO GM.
| 2024-03-17T01:26:57.367551 | https://example.com/article/6848 |
using Demo.StoreExample.RulesPattern.Refactor;
namespace Demo.StoreExample.RulesPattern.Rules
{
public class NewCustomerRule : IDiscountRule
{
public decimal CalculateCustomerDiscount(Customer customer)
{
return !customer.IsExisting() ? 0.15m : 0;
}
}
}
| 2023-09-23T01:26:57.367551 | https://example.com/article/2424 |
Q:
how to query two column of same table with two condition with groupby
Table :tbl_user
dateofregistration ID registrationstate
6-03-11 3 0
6-03-11 1 0
6-03-11 2 1
7-03-11 2 1
7-03-11 1 1
how can I display result like this for sql server 2008 express
date TotalID(count) Total State(0 only)
6-03-11 3 2
7-03-11 2 0
I have tried with this
SELECT CONVERT(varchar(10), dateofregistration, 103) AS Date,
(select COUNT(ID)) AS Subbase,
(Select Count(ID)from tbl_User where (registrationstate='0')) AS Totalchurn
FROM tbl_User
GROUP BY CONVERT(varchar(10), dateofregistration, 103);
but wrong result.Any help plz.
A:
How about;
select
cast(dateofregistration as date),
count(distinct id), --or * for all
sum(
case registrationstate when '0' then 1 else 0 end
)
from tbl_user
group by cast(dateofregistration as date)
order by 1
2011-06-03 3 2
2011-07-03 2 0
| 2024-03-16T01:26:57.367551 | https://example.com/article/1930 |
1,N2-cyclic deoxyguanosine adducts and guanine adducts of 2-haloacroleins. Isolation, characterization, isomerization and stability.
The reaction of the mutagenic 2-haloacroleins, 2-fluoroacrolein, -2-chloroacrolein and 2-bromoacrolein, with nucleosides and 5'-mononucleotides was studied. We found two different regioisomers of 1,N2-cyclic deoxyguanosine adducts of 2-chloroacrolein and 2-bromoacrolein: type A, the 6-hydroxy, 7-haloadduct in which the OH-substituent is vicinal to the N2-atom of the guanine moiety and type B, the 8-hydroxy, 7-haloadduct in which the OH-group is adjacent to the N1-atom of the guanine moiety. The major adducts were the trans pairs of diastereomers of type A and type B in which the 6,7-substituents as well as the 7,8-substituents are in the energetically favoured diaxial position of the newly formed tetrahydropyrimidine ring. In the case of the type A regioisomers, the cis pairs of diastereomers (traces with chloroacrolein and about 4% with bromoacrolein) were also found in which the halosubstituent probably takes the equatorial position. Due to the anomeric effect, the OH-group takes the axial position in both regioisomers. No cis isomers of the type B regioisomers could be isolated. Acid hydrolysis of the deoxyguanosine adducts released deoxyribose, and the respective guanine adducts were isolated and characterized. Besides the vicinal halo, hydroxy adducts, trace amounts of the corresponding dihydroxy adducts were formed by hydrolysis of the chlorine or bromine substituents. The dihydroxy compounds possess the same structures and conformations in the newly formed tetrahydropyrimidine ring as do the halo, hydroxy adducts. Under our conditions no adducts other than those with deoxyguanosine and guanine could be identified.(ABSTRACT TRUNCATED AT 250 WORDS) | 2023-08-07T01:26:57.367551 | https://example.com/article/4876 |
As the value and use of information continue to increase, individuals and businesses seek additional ways to process and store information. One option available to users is information handling systems. An information handling system generally processes, compiles, stores, and/or communicates information or data for business, personal, or other purposes, thereby allowing users to take advantage of the value of the information. Because technology and information handling needs and requirements vary between different users or applications, information handling system's may also vary regarding what information is handled, how the information is handled, how much information is processed, stored, or communicated, and how quickly and efficiently the information may be processed, stored, or communicated. The variations in IHSs allow for IHSs to be general or configured for a specific user or specific use such as financial transaction processing, airline reservations, enterprise data storage, or global communications. In addition, an information handling system may include a variety of hardware and software components that may be configured to process, store, and communicate information and may include one or more computer systems, data storage systems, and networking systems.
An information handling system can be configured in several different configurations. The information handling system can range from a single, stand-alone computer system to a distributed, multi-device computer system, to a networked computer system with remote or cloud storage systems. Both local computer storage systems and remote or cloud storage systems can support RAID configurations that use hard disk drives or solid state storage drives. Various “levels” of RAID configurations are well known to those in the field of data storage systems.
Historically, RAID driver development and support has been concentrated on traditional mass storage protocols, including SATA, SCSI, SAS, FC, ATA, and IDE. More recently, PCIe-based storage drives, including NVMe drives, have raised the prospect of RAID volumes spanning multiple PCI/PCIe devices, including systems that employ PCI/PCIe based RAID volumes as a boot disk. Whereas traditional mass storage bus protocols recognize the concept of a storage controller associated with two or more physical drives, PCIe treats each connected device as an individual controller. This distinction must be addressed to accommodate PCI/PCIe-based RAID volumes. | 2024-02-27T01:26:57.367551 | https://example.com/article/2679 |
Q:
Strange behaviour of TypeScript String.split() function
I have TypeScript model like this:
export class Product {
id:number;
name:string;
brand:Brand;
price:number;
shippingPrice:number;
description:string;
photoName:string;
productType:ProductType;
purchaseCounter:number;
rating:number;
volume:string;
ingredients:string;
}
and json file which populate this model:
{
"id": 1,
"name": "xxx",
"description": "xxx",
"price": 12.34,
"purchaseCounter": 12,
"photoName": "xx",
"shippingPrice": 12.99,
"volume": "xxx",
"rating": 4.7,
"ingredients": "A,B,C",
"brand": {
"id": 1,
"name": "xx"
},
"productType": {
"id": 3,
"name": "xxx"
}
}
Now in my TypeScript component I have function like this :
public getIngredients():String [] {
return this.product.ingredients.split(",");
}
Everytime when I am invoking this function I have error:
"TypeError: Cannot read property 'split' of undefined"
but when i change body of function to sth like this:
public getIngredients():String [] {
if (this.product.ingredients == null) {
return null;
}
return this.product.ingredients.split(",");
}
then eveyrthing is ok and split function work properly. Have You got any idea why checking if ingredients is not null fix it? I have to admin that I just start my adventure with js and ts. Thanks
UPDATE
I instantiating this Product variable here:
export class ProductOverviewComponent implements OnInit {
private product:Product;
private errorMessage:string;
constructor(private productService:ProductService) {
this.product = new Product();
}
ngOnInit():void {
this.productService.getProduct()
.subscribe(
product => this.product = product,
error => this.errorMessage = <any>error);
}
}
For now I hit to the json file but in future I will hit to server. Another think is that I pass product to another comopnent using @Input().
And this is how i call getIngredients function
<div class="col-md-12">
<div class="property-text">
<!--<h3 class="h3style">Ingredients</h3>-->
<ul>
<li *ngFor="let ingredient of getIngredients()">
{{ ingredient }}
</li>
</ul>
</div>
</div>
A:
The TypeError that you get is a JavaScript error raised at runtime and has nothing to do with TypeScript. It happens because this.product.ingredients is undefined. Your "fix" works because undefined == null is true in JavaScript which results in an early return inside getIngredients(). If you used the === operator to compare against null your fix would no longer work.
However, the question is then why this.product.ingredients is undefined? It may be because the TypeScript this context is lost inside getIngredients(). From the code you have provided it is impossible to determine if that is the case but there is a nice write-up about the problem in the 'this' in TypeScript article on Github which might help you solve your problem. A simple first check could be to add console.log(this) inside getIngredients() to see what this really is.
| 2023-09-12T01:26:57.367551 | https://example.com/article/7366 |
name = "PCRE2"
uuid = "c9310f65-a42c-5928-aca3-d34f64192029"
repo = "https://github.com/JuliaString/PCRE2.jl.git"
| 2023-10-12T01:26:57.367551 | https://example.com/article/8731 |
Teaching German
Opinion
Opinion: Iceland's pullout is a wake up call
Life as an islander must be pretty good, as Iceland has now withdrawn its bid for EU accession. Christoph Hasselbach says that the reasons for this retraction should give all Europeans something to think about.
In 2008, the water swelled to the top of the retaining wall at Reykjavik harbor. An overinflated banking sector went bust overnight as a result of the global financial collapse, and threatened to take the North Atlantic island state with it on its descent into the abyss. Panic gripped the Icelanders. Credit was extended by the International Monetary Fund and others, but the remote island suddenly didn't feel so comfortable with its splendid isolation, rather it felt lost and alone. With that uneasy feeling in their gut, the Icelanders swallowed the pride of their independence and came knocking on the EU's door. Over the years they had seen it help several member states that had also gone into debt.
Now Iceland has withdrawn its application. Many Icelanders are angry that the government did so without holding a referendum, but that would not have changed the final outcome. The departure from the EU is not a surprise, and has been looming for quite some time.
Enjoy advantages, avoid drawbacks
How did this change of heart come about? The questions around fishing quotas are only one part of the equation, perhaps not even the most important one. It was clear what they were getting into from the beginning. True, fishing is extremely important for Iceland, and as an EU member, the island would have had to integrate itself into the quota system of the Common Fisheries Policy. On the other hand, Iceland belongs to the European Economic Area (EEA) and can export its fish to the EU duty free. Beyond that, as part of the Nordic Passport Union, Iceland is also a member of the checkpoint free Schengen Area. This greatly simplifies tourism - which is just as important as a source of income. In other words, even as a non-member state, Iceland enjoys a number of European Union advantages, and it wants to avoid membership's disadvantages.
Christoph Hasselbach
If you've got money, you stay out
The Icelanders have been able to observe from afar many of these disadvantages over the last several years. For instance, they could see how the EU, and especially eurozone countries, invested vast sums of money into helping debt-ridden members. Which, for instance in the case of Greece, has resulted in the country being hardly better off than before the bailout, resisting reforms, and now even insulting the helpers. Nobody wants to join that kind of club unless they absolutely have to. Like many EU states, Iceland helped itself out of its financial crisis and is now on pretty solid footing. Is Norway thinking about joining the EU? Switzerland? Why should they? Are Sweden, Denmark, or Great Britain contemplating introducing the euro? Now less than ever. All of these states could easily fulfill membership requirements. But they don't want to. What do they have in common? They are all wealthy and competitive.
Fear of the bottomless pit
That all leads to a scary conclusion: the EU is only attractive for have-nots and those who resist reform. Those who can afford to stay completely outside of the union, or at least maintain their own currency to avoid having to join in throwing money into a bottomless pit. At least that is the popular impression. The EU welcomed Iceland with open arms. Yet, that is where most Icelanders see the problem. Because Iceland would be welcome above all as one who could pay. But who wants to be taken advantage of? Iceland's retraction will not go unnoticed in Great Britain either. The euroskeptics will be emboldened in their opinion that they are better off outside of the EU, but in the European Economic Area - just like Norway, Denmark, and now Iceland.
If there were only more Irelands
The Icelandic withdrawal has to be a wake-up call. The less competitive countries of the south - which unfortunately also includes Italy, and despite its geographic centrality, France - have to make more of an effort. Otherwise there will eventually have to be a rift between north and south. The fact that financial help does not have to be extended forever is best exemplified by Ireland. Like Iceland, Ireland was in rough shape due in great part to the debt incurred by its banks. With help from the EU and IMF, and the implementation of a radical austerity and reform agenda, Ireland is once again financially fit and has the highest economic growth rates in the entire EU. By the way, there was very little whining there. One simply did what one had to do. If there were more Irelands in the EU, perhaps the attitude in Iceland would be different today. | 2023-10-06T01:26:57.367551 | https://example.com/article/6703 |
Q:
How does Chaum style e-cash work? (all the Wiki links are broken)
I'm trying to learn how Chaum-style ecash worked specifically how:
"the issuer does a blind signature on a serial number"
I tried looking up on Wikipedia but the page is pretty light on the details, and all the pages don't work (even the Wayback machine pages are broken)
A:
Here's the basic idea of blind signing in Chaumian e-cash:
Let's suppose that a central issuer (Chaumian e-cash is centralised) has an account in my name with a value of 10 dollars. In order to "withdraw" this money as 1-dollar "bills" I begin by generating ten random serial numbers, each long enough that I can be reasonably sure no one else will generate the same numbers.
I am going to have the central issuer sign a message saying these are now worth one dollar each, only I don't want the issuer to know which bill is which (otherwise they could just match up outgoing and incoming serial numbers to know who I spent it with, since Chaumian e-cash can only be spent once before it has to be re-issued).
So in addition to the serial numbers I also choose secret 'blinding factors' and combine them with my serial numbers. I give these blinded serial numbers to the central issuer, and they sign each one with their 1-dollar key (they have different keys for different denominations) and reduce the amount in my account with them accordingly. They know how many 1-dollar bills they signed, but they don't know what serial numbers were on each bill they signed.
Now, the trick with "blind signing" comes in. Because of how blind signing works, I can now remove the blinding factor, but I still have a valid signed message which can be verified using the issuer's public key. This gives me a signed one dollar bill with its own serial number that the bank doesn't know (but they do know how many one dollar bills they have signed, because each one can only be un-blinded to a single serial number).
Now, to spend the bills to someone else, I simply show them the un-blinded, signed serial number. They must now immediately "cash in" this token by going to the central issuer and showing them the signed serial number. The central issuer verifies the signature using their "1 dollar" key, records the serial number, and credits the new person's account. From their perspective, this dollar is indistinguishable from any other they have issued in the past.
However, if someone else shows up and tries to cash in the same dollar again, they will not honour it because they have already recorded the serial number as spent. You also cannot spend a $1 serial number as a $50 serial number because $50 serial numbers use a different key.
More details about e-cash, including an "offline mode" that relies on trusted hardware, can be found here. They use a different method of ensuring a $1 bill is not spent as a $50 bill--I don't remember which variant is whose but there are several of them which basically accomplish the same thing in slightly different ways.
| 2024-01-06T01:26:57.367551 | https://example.com/article/7957 |
Epidemiological Aspects of Osteosarcoma, Giant Cell Tumor and Chondrosarcoma Musculoskeletal Tumors--Experience of the National Rehabilitation Institute, Mexico City.
Primary bone neoplasms are rare, contributing only 0.2% of the global burden of all human malignancies. Osteosarcoma (OS) and chondrosarcoma (CS) are the most common malignancies of bone. The giant cell tumor of bone (GCTb) is a benign tumor with behavior characterized by osteolytic bone destruction. The OS, CS and GCTb affect both sexes, all races and generally have incidence peaks regarding the age of the patient which vary according to the tumor type. We analyzed the incidences of OS, CS and GCTb and their relations with gender and age in patients treated in the National Rehabilitation Institute (INR, for its acronym in Spanish) over a period of nine years. In the study period, clinic pathological data for 384 patients were obtained with clinical, radiological and histopathological diagnosis for OS, GCTb and CS. Data analysis was performed using the chi-square and Fisher's exact tests. From 2006 to 2014 were recorded 384 cases of bone malignancies in the database of INR. The GCTb had the highest incidence (53.1%), followed by OS (31.3%) and finally the CS (15.6%). The overall average age was 33.6±15.8 years and the overall frequency of gender had a ratio of 1/1.03 male/female. The states with the highest incidence were Distrito Federal and Estado de Mexico with 29.2% and 25.3% respectively. Malignant neoplasms of bone assessed in the course of nine years show three significant increases in 2008, 2011 and 2014 (p=0.14). We found association between sex and tumor type (p=0.03), GCTb and CS predominated in females (54.9% and 56.6% respectively), while for the OS males were most affected (59.1%). Age was different in relation with tumor type (p=0.0001), average age was 24.3±11.2 years for OS, 34.5±13 years for GCTb and 49.2±18.5 years for CS. Furthermore, associations of tumor type with topographic location of the primary tumor (P=0.0001) were found. In this study we can see that incidence of musculoskeletal tumor in our population is continuously increasing and in nine years an approximately 200% increase of musculoskeletal tumor cases was observed. | 2024-05-27T01:26:57.367551 | https://example.com/article/9228 |
Based on observations from brainstem tissue of SIDS cases, we hypothesize, as a program, that an important subset of SIDS result from medullary defects in serotonin (5-HT)-producing neurons and related neurotransmitter systems such as GABA. Evidence suggests that these defects arise during gestation and affect specific subtypes of, as opposed to all, 5-HT neurons. From this, we reason that SIDS is an embryonic developmental disorder affecting specific subtypes of 5-HT and/or GABA neurons of the medulla. Towards understanding the differential basis for SIDS, we propose experiments designed to decode the developmental and molecular origins of different neuron subtypes within the medullary 5-HT and GABA neural systems in the mouse, and determine the specific properties of these subtypes as relates to homeostatic control. These experiments are made possible via recent, powerful advances: 1) a developmental map of the mature brainstem 5-HT system that, for the first time, resolves the system into molecularly separable, and therefore genetically accessible, 5-HT neuron subtypes; 2) the identification of embryonic genetic programs that are instructive for different GABAergic fates and which are likely employed in the developing medulla; and 3) tools with sufficient specificity to perturb the activity of (for example, silence) select 5-HT or GABA subtypes in the living mouse. Using these tools, we will plot cellular functions and electrophysiological properties onto the developmental maps of medullary 5-HT and GABA neuron subtypes (Aims 1 and 3, respectively). Because our goal is to identify neuron subtypes most relevant pathophysiologically to SIDS, we will focus on 5-HT and GABA neuron subtypes of the medulla and their properties as relates to sensing acidosis and/or hypoxia (in collaboration with Project 4) and their functions as relates to control of breathing, heart rate, blood pressure and reflex apnea (in collaboration with Project 2). These are functions which, if impaired, might plausibly contribute to sudden death. Further, we propose investigating a possible mechanism for regulating 5-HT neuron production, our goal being to decipher the basis for the increased number of 5-HT neurons in SIDS cases. The ability to redefine medullary 5-HT and GABA neuron subtypes and their production based on a constellation of criteria - molecular, developmental, electrophysiological, and functional- is a major strength and innovation of this proposal and program. | 2024-05-10T01:26:57.367551 | https://example.com/article/3199 |
Watch OFA's immigration campaign manager Pedro Morillas explain.
From one on one conversations to powerful public displays of support, OFA volunteers fought for reform in 2013.
We came a long way toward achieving comprehensive immigration reform in 2013, including passing a landmark bill in the Senate. Take a look at OFA organizers' favorite moments in the fight for reform this year
OFA calls on seven more lawmakers to act on reform.
Today we're going public with the next seven names on our list of representatives who can play a key role in passing reform. These legislators have a choice: side with their constituents and be leaders on reform, or defend the broken status quo.
Will one of these representatives stand up?
The reality is that immigration reform could pass today if House leaders just held a vote. So today, OFA is adding five more members of Congress to the list of representatives who should be leading on immigration reform.
A group of activists has set up camp at the foot of the Capitol.
The strength and bravery of the individuals on the National Mall right now stands in stark contrast to the stalling and foot dragging in the House of Representatives. Their activities on the ground have sparked solidarity across the country, and prompted visits from leaders as diverse as Vice President Joe Biden, the Reverend Jesse Jackson, and Representative Jeff Denham.
Supporters rally to keep pressure on Congress in nationwide Day of Action.
The fight for immigration reform continues, with OFA volunteers organizing on the ground and online to pressure the House of Representatives to hold a vote. Check out photos and stories from the field.
Here are five more members of Congress who need to take action.
These members of Congress can either stand with the American people or stand in the way. And let’s be clear: There is no gray area. The House's inaction is hurting American families and costing our economy millions every day. | 2024-06-15T01:26:57.367551 | https://example.com/article/7689 |
Q:
Подгрузка только части полей модели Asp.net mvc 5
Нужно подгрузить только часть модели, например убрать пару полей, который не нужны в данный момент. Как это можно реализовать? Что-то типа этого не работает:
_dbContext.News.Where(n => n.Id != newsId && n.IsActive).OrderBy(n => n.CreatedAt).Skip(1).Take(4).Select(n => _mapper.Map<PreviewNewsViewModel>(n)).ToListAsync();
PreviewNewsViewModel - такая же как модель, которую хочу вытащить, но без одного поля. Крашится именно на этой строчке.
A:
Так как информации предоставлено в вопросе не так много, то есть предположение, что вам просто необходимо сказать AutoMapper-у, чтобы он при меппинге заигнорил поле, которое отсутствует в объекте PreviewNewsViewModel. Это можно сделать так
Mapper.CreateMap<NewsType, PreviewNewsViewModel>()
.ForSourceMember(x => x.NewsField, y => y.Ignore());
Как вытащить определенные столбцы?
Чтобы вытащить из БД не всю сущность целиком, а только определенные поля сущности, то вы можете в select-е создать анонимный тип со специфичными свойствами, которые должны быть вытащены из таблицы.
Это будет выглядеть примерно так:
_dbContext.News.Where(n => n.Id != newsId && n.IsActive).Select(n => new {
Id = n.Id
Property1 = n.Property1
}).ToListAsync();
Это будет транслировано в SQL запрос примерно такой
SELECT p.Id, p.Property1 FROM News p WHERE p.Id != newsId && p.IsActive
Далее уже можете данную коллекцию с элементами анонимного типа преобразовать в объекты типа PreviewNewsViewModel либо с помощью AutoMapper-а, либо руками.
| 2023-10-25T01:26:57.367551 | https://example.com/article/3831 |
Extrapulmonary tuberculosis: experience at Veterans General Hospital-Taipei, 1985 to 1987.
From 1985 to 1987, 343 cases of extrapulmonary tuberculosis (TB) were identified, representing about 20% of all the newly diagnosed TB cases at Veterans General Hospital-Taipei. Bacteriological and histopathological examinations were of equal importance in making a diagnosis of extrapulmonary TB. However, 79% of the cases of TB meningitis were diagnosed only by positive cerebrospinal fluid cultures for Mycobacterium tuberculosis. The pleura, lymph nodes, urinary and osteoarticular systems were the most commonly affected locations. Male patients predominated except for TB lymphadenitis. However, female patients with TB are more likely to have non-respiratory TB than are male patients. The peak number of cases by age occurred in the seventh decade of life, and the mean age of male patients was older than that of female patients. Pulmonary lesions suggestive of TB and age over 60 years were the two most common risk factors. Anti-TB chemotherapy alone was enough in many patients. However, more than 50% of the patients with osteoarticular TB, pericardial TB, TB lymphadenitis, and TB enteritis or peritonitis underwent surgical intervention for either diagnosis or treatment. The results of adequate anti-TB chemotherapy or surgical treatment were usually satisfactory. About 32% of the patients were lost to follow-up before completing anti-TB chemotherapy. In this series, 34 deaths occurred, of which 7 were TB-unrelated and 10 occurred before a diagnosis of TB was made or proper therapy initiated. Although TB meningitis was uncommon in this series, it had the highest mortality rate (67%). | 2024-01-05T01:26:57.367551 | https://example.com/article/4180 |
The Swedish Employment Service has warned that migrant unemployment rates are set to dramatically increase to the worst levels since the 1990s in a new report.
The agency stated that as the trend of overall unemployment in Sweden continues to grow, structural unemployment will increase and that migrants will be especially likely to be jobless, Sydsvenskan reports.
“The Employment Service believes that those born abroad with the highest level of upper secondary education will suffer a sharp rise in unemployment and long-term unemployment in the coming years,” the agency said.
“The group that is most severely affected is foreign-born women who do not have upper secondary education,” it added.
The report comes just a month after Swedish bank Handelsbanken predicted that the country’s economy would remain sluggish for the rest of the year and that overall unemployment numbers could reach as high as 7.2 per cent this year and 7.4 per cent in 2023.
The agency also demanded 800 million Swedish krona (£63,680,071/$82,220,880) in added cash from 2021 to 2023 to cope with added administrative costs.
In Sweden, Just One in Sixteen New Migrants Have a Job That Isn’t Being Subsidised by Taxpayers https://t.co/FTEigeBTP7 — Breitbart London (@BreitbartLondon) February 4, 2020
Migrant unemployment rates have been far higher than rates fior native Swedes rates for years, with a 2018 report revealing that while native unemployment was just 3.6 per cent that year the migrant rate was 19.9 per cent.
Migrants also make up the majority of those who sign up with the Employment Service, according to another 2018 report, which noted that six in ten people registered with the agency are born overseas.
The Employment Service has several programmes designed to get migrants into work including the use of government-subsidised jobs — and figures released in early February showed that just 6.1 per cent of newly-arrived migrants were able to find work not subsidised by the government after 90 days in an Employment Service programme.
In total, just 31 per cent of migrants in the programme were able to get any sort of job at all.
Swedish Municipality That Took Too Many Migrants Faces Bankruptcy https://t.co/TiW53eVPCX — Breitbart London (@BreitbartLondon) August 3, 2019 | 2024-05-10T01:26:57.367551 | https://example.com/article/2255 |
I'm really fat/large/heavy/big-boned/glandular. Will your PFDs float me?If you are within the chest size chart dimensions, then a Stohlquist PFD will float you. Most adults only need between 7-12 pounds of additional buoyancy to keep their heads out of the water. Stohlquist adult PFDs provide a minimum of 15.5 pounds of buoyancy. The amount of additional buoyancy that you require depends on your body density (e.g. fat or muscle?), lung size, clothing, and water conditions (calm or aerated). As a rule of thumb, the more physically fit you are (e.g. trim and lean), the more buoyancy you need to stay afloat.
Why do some PFDs have mesh in the back?Several types of kayaks, like Sit-On-Top kayaks have high back seats to provide extra support and comfort. Many of our recreational PFD models are specifically designed with mesh backs that position flotation elements above the "high-back" seats found in today's boats. The mesh back designs also allow for increased ventilation.
What is the best PFD for canoeing, sailing, whitewater, etc.?The best choice for any type of paddling (or sailing) depends on the conditions you expect to face when on the water. Rescue PFDs are just as useful to canoeists as they are to kayakers. Fishing PFD's have lots of extra storage capabilities, even if you are not going fishing. Whitewater vests offer side-zip entry zippers so pockets may be maximized, and centrally located for quick access and maximum mobility. Please contact us if you have any questions, and we will be happy to help you pick a PFD that best suits your needs.
How long will a PFD last?The USCG/Transport Canada, as well as Stohlquist, advises checking your PFD at the beginning of each season to check the degree of buoyancy remaining (and for degradation or wear). Proper treatment is the key to PFD longevity.
Protect your PFD from extended Ultraviolet light exposure (sun), and the extremes of hot and cold to minimize premature aging. There are many products available that may be used on the exterior of the vest to help guard against UV degradation.
Sitting on your PFD or stuffing it under deck rigging will ruin/compress the soft foam quickly. This can lead to premature wear or loss of buoyancy.
PFD models with higher denier shell fabrics are the most resilient and wear resistant. All of Stohlquist's top of the line whitewater/touring/and recreational PFDs use highly durable 500D fabrics.
A PFD can last you 3 months or 5-10 years depending on use. The average life of a vest, for average paddlers, is about 5 years given normal wear and care.
Is there a PFD that will fit everyone in my family, including my kids?The O.S.F.A. (One Size Fits All) will fit everyone in your family as long as they are within the chest size range (30"-54") and at least 90 lbs or more. PFDs for individuals below 90 lbs are broken into Youth, Child, and Infant sizes, and are based on user weight not chest size.
Do you sell direct?To ensure the highest level of customer service, we have chosen to sell only through select retailers. If you have no local dealer, you may make purchases from the Stohlquist website or other online retailers. Simply click the "BUY NOW" button on the Stohlquist site, and the sale will be automatically routed directly through our dealer network for prompt fulfillment and speedy delivery to your door.
Does Stohlquist accept custom orders?Unfortunately no, we cannot custom make or custom fit any of our products at this time. Some drysuit modifications (e.g. gasket sizes) are available. Please feel free to contact us at This email address is being protected from spambots. You need JavaScript enabled to view it. with any questions.
Where can I purchase Stohlquist products?Stohlquist products are available at over 500 retail outlets nationwide, as well as through online retailers. For a list of dealers in your area, enter your zip code into our Dealer Locator located in the top right of this page and hit enter.
Pro-Sales and SponsorshipStohlquist is pleased to offer our products at special pricing to outdoor professionals who are actively working in the outdoor industry as guides, outfitters, or related industry employees. Please contact This email address is being protected from spambots. You need JavaScript enabled to view it. for more information. | 2024-07-28T01:26:57.367551 | https://example.com/article/4740 |
Mandy Stokes far left along with her husband John Stokes, to her right and her brother-in-law Kevin Jenkins and his two teenage children, Savannah Jenkins, 16, and Parker Jenkins, 14, all of Thomaston, Ala., killed a 1,000-pound alligator. (SHARON STEINMANN/AL.COM /Landov) | 2024-04-26T01:26:57.367551 | https://example.com/article/6510 |
It’s no secret that while Daredevil, Jessica Jones, and Luke Cage all enjoyed positive buzz when they debuted on Netflix, the fourth installment in the Defenders franchise, Iron Fist, was not so lucky. But despite the poor (and controversy-tinged) reaction to Danny Rand, Netflix was already locked into Finn Jones’s embattled martial artist appearing in this summer’s all-star team-up event titled, what else, The Defenders. It was too late to write Rand out—but as this first trailer proves, it’s not too late to have fun with him.
When Rand shows up in the trailer, he’s quickly slammed to the ground by Mike Colter’s Luke Cage. And while the other Defenders are each given a moment to crack wise and play it cool, Danny is only given three rather bland lines of dialogue. His self-important declaration of “I’m the immortal Iron Fist” is met with an incredulous “you’re what??” from Cage. And, sure, Danny gets to land a solid punch on Cage’s face that plays out a little differently than it does for your average goon. . .
. . .but when Scott Glenn’s Stick lists off the various heroic monikers of the show’s four leads, poor Danny is stuck with the least impressive one. “The kid with the glowing fist” doesn’t have quite the same ring as “the devil of Hell’s Kitchen, the smart-ass detective, and the righteous ex-con,” does it? Just wait until the sardonic Jessica Jones gets ahold of Danny. He’s going to need a lot of ice for those burns.
Of course, this trailer—scored to a crunchy version of Nirvana’s “Come as You Are”—has a lot more than Danny Rand jokes going for it. Sigourney Weaver makes her debut as the arch-villain poised to take Jessica, Matt, Luke, and Danny down, while Élodie Yung’s Elektra is back from the dead and, presumably, evil. Or does she have a good reasons for throwing Matt Murdock through plate glass?
But chiefly, the trailer teases some potential future pairings for Netflix’s popular Marvel installment. Krysten Ritter and Charlie Cox have some brief fizz-pop banter that might promise more Jessica/Matt collaborations in the future. Meanwhile, if anyone can make more Danny Rand look appealing, it’s Luke Cage—and the trailer hints that a “heroes for hire” team-up might be coming soon. But before we play mix and match with these heroes, perhaps we should see if they all survive this brand-new battle for New York. The Defenders premieres on August 18. | 2023-12-03T01:26:57.367551 | https://example.com/article/1540 |
Manufacturer Part # MMRAD-MUS-94AAvailability: Usually Ships in 1 to 2 Days
Product Code:01390
Qty:
Key Product Specs
Technical Specs
Overall Size: 34.8" x 20.5" x 4.2"
Core Size: 24.02" x 15.28"
Rows: 2
Inlet: 1.5"
Outlet: 1.77"
Core Thickness: 1.57"
Tank Wall Thickness: .08"
Fill Neck: 1.61"
Drain Plug Thread Size: M12x1.5
Purchase Includes:
Mishimoto Radiator
Mishimoto Radiator Cap
Magnetic Drain Plug w/Dowty oil seal
Left and right brackets
(4) rubber bushings and metal collars
(4) M8 Flange head bolts
(4) M8 Washers
Limited Lifetime Warranty
Key Product Specs
The Mishimoto performance aluminum radiator for the Ford Mustang is the ideal upgrade to the stock Mustang radiator. Their new patent-pending floating bracket system eliminates damage to the radiator from high torque applications. The new design ensures the endtanks will not separate from the cores in your high horsepower/torque Mustang. This new set up is still designed and specifically engineered to maximize cooling efficiency by up to 30%, boost engine functions and protect your car from overheating. Whether you use your Mustang for daily driving or take it to the track, many people overlook the importance of installing an upgraded radiator in their engine. A stock radiator can not handle the heat that comes along with having a great deal of horsepower. The Mishimoto Ford Mustang radiator features a lightweight triple core, 100% brazed aluminum, and polished end tanks. Every Mishimoto Performance Radiator is a direct OEM fit, making installation effortless, no cutting or modification is required. All Mishimoto radiators come with a high pressure 1.3 bar Mishimoto radiator cap and an excellent warranty. | 2024-02-05T01:26:57.367551 | https://example.com/article/4306 |
RE-1 Valley Board of Education tables endorsed diploma discussion
Approves Sterling Middle School Promotion/Retention Plan for 2013-14 school year
Marty Smock is sworn into office by board secretary Kim Krier after being appointed to fill the District 6 seat on the RE-1 Valley Board of Education at Tuesday's business meeting. (Callie Jones/Journal-Advocate)
STERLING — The RE-1 Valley Board of Education welcomed a new board member during their business meeting on Tuesday. Marty Smock was appointed to fill the District 6 vacancy left by Dorcas Brekel.
Among the first items that Smock took action on was the endorsed diploma. The board voted 4-2 to table the topic until further notice. Smock and George Hernandez were the only no votes; Eric Windom was absent from the meeting.
The decision came after Superintendent Betty Summers presented possible dates in March for the community meetings regarding the endorsed diploma.
“I certainly believe in the long-term that there are benefits,” Myra Westfall said. “I'm not sure that all of those benefits at the state level have been identified or how they're going make some of those things happen.”
She pointed out there are strong emotions both for and against it, which is why she wanted to table it and regroup as the state finalizes their plan.
“With the end of the year coming, with different leadership, I think it would be appropriate to table it.”
Tona Felzien agreed.
“I do think there's a lot of emotion involved in this,” she said. “I think we're starting to get a lot of people that are just flat shutting down and I don't think that is going to benefit us when we're talking about the engagement piece.”
She commended the Response to Intervention (RtI) Committee and all the staff for all the work they've put into the endorsed diploma.
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“I do think that it has some great potential,” Felzien said. “It is not something I want to see us lose; it's not something that I'm saying we just throw by the wayside. I think we have to realize that there is a lot of knowledge and information there and we have got to step back and figure out how to get that knowledge and information out.”
Assistant Superintendent Ron Marostica noted that any benefits the district would have garnered as a pilot district, they won't have now.
He also pointed out that the part that was difficult for those that worked on this is they were “asked so many times, to do it again and again and again. They gave it there all; they spent weeks and weeks answering the same questions again and again and this decision could have been made.”
Westfall pointed out they want people to know the board recognizes there is some value in the endorsed diploma and the work that was done will be beneficial when they decide to look at it again.
“I think the one piece to keep in mind in that value is when you ask the professional staff to put a plan together, that consideration for the professional approach to what's good for kids does have true merit in making decisions,” Summers said.
Cody Engelhaupt pointed out that sometimes the board has to do things that the community doesn't agree with.
“Is this one of the things that we go forth and try to explain the best we can to the community? I don't know,” he said.
In other business, the board unanimously approved adopting a Sterling Middle School Promotion/Retention Plan for implementation during the 2013-14 school year, utilizing the 2013-14 Transitional Colorado Assessment Program (TCAP) results.
The plan was approved earlier in the day by the RtI Committee.
Sandy Underwood, Jana Lock and Lori Atkin, members of the SMS leadership team, presented the plan to the board.
Underwood pointed out that the promotion policy has no economic impact and can be implemented with no additional funding.
The policy focuses on points earned for academics, assessment and attendance.
“These expectations let students know exactly what they need for ultimate success,” Underwood said. “We believe this policy will increase academic achievement for all. It will also provide guidance to staff, parents, students regarding promotion and retention.”
In developing the policy, they looked at schools across Colorado with promotion policies, including Cortez, Windsor, Douglas County and Florence.
Students will be able to earn points in a number of ways.
They can earn one point in academics by passing three of their five classes. This is based on the two semester grades -- if they flunk one semester and got a D the next semester that would be considered passing, an F and a D- would not be passing.
Students can also earn one point on assessments by scoring at least one partially proficient on the TCAP.
Additionally, they can earn one point for 90 percent attendance, which allows for 17 days missed. Lock said they could probably easily get three points in that area.
Plus, students can receive a point for getting a C average in unified art classes.
For struggling students there are things in place to assist them, including the extended day, a den program for sixth graders and before and after school help.
It was also noted that extenuating circumstances will be taken into consideration by the promotion/retention committee.
The teachers will review the student's points with them during Tiger Time, when they review their grades and attendance.
One con that was pointed out is the possibility this may increase class sizes.
“We don't think there will be lots of kids staying back. We really think once they know what they need, there shouldn't be too many, but there could be some,” Lock said.
Among the pros is that it will help students would be more prepared for the next grade level, especially jumping from middle school to high school.
“This is such a nice, we believe, segue into credits at the high school,” Underwood said.
Principal Bob Hall has sent out two to three letters letting parents know this was impending. They also have a plan for grade level assemblies to inform students about what this entails. Plus, information will be posted on the school website and go into the registration packets next year.
Hall has also had a conversation with Campbell Elementary Dennis Klein. There will be a plan to talk to students in the coming days about what TCAP scores will mean for them next year and information will be shared when they tour SMS later this school year.
ODESSA, Texas (AP) — A West Texas man has been charged with impersonating an officer by using sirens and flashing lights to skip to the head of the drive-thru line at a fast-food restaurant. Full Story
Sufjan Stevens, "Carrie & Lowell" (Asthmatic Kitty) Plucked strings and pulsing keyboards dominate the distinctive arrangements on Sufjan Stevens' latest album, and in the absence of a rhythm section, they serve to keep time. Full Story | 2023-10-18T01:26:57.367551 | https://example.com/article/9955 |
The raven has piercing eyes. It is standing on an ornate ledge under an archway overlooking a waning crescent moon and superimposed planet. Inbetween these 2 extremes of distance stands a white-coloured mountain peak, perhaps too far forward in the picture to be making use of the depth perceptuality. | 2023-08-19T01:26:57.367551 | https://example.com/article/6801 |
Taos Told You So
Black
Women's
The women’s Taos® Untold is a casual slip-on flat for everyday wear. A premium soft leather upper with elastic goring provides perfect fit, while a leather lining ensures comfort. A removable footbed with suede lining also provides exceptional comfort, while a flexible, durable rubber outsole means this shoe can take on any street. | 2024-02-01T01:26:57.367551 | https://example.com/article/2909 |
1. Statement of the Technical Field
The present invention relates to unsolicited commercial electronic messages and more particularly to controlling the receipt of unsolicited instant messages.
2. Description of the Related Art
Historically, the print medium served as the principal mode of unsolicited mass advertising on the part of the direct marketing industry. Typically referred to as “junk mail”, unsolicited print marketing materials could be delivered in bulk to a vast selection of recipients, regardless of whether the recipients requested the marketing materials. With an average response rate of one to two percent, junk mail has been an effective tool in the generation of new sales leads. Nevertheless, recipients of junk mail generally find the practice to be annoying. Additionally, postage for sending junk mail can be expensive for significant “mail drops”. Consequently, the direct marketing industry constantly seeks equally effective, but less expensive modalities for delivering unsolicited marketing materials.
The advent of electronic mail has provided much needed relief for direct marketers as the delivery of electronic mail to a vast number of targeted recipients requires no postage. Moreover, the delivery of unsolicited electronic mail can be an instantaneous exercise and the unsolicited electronic mail can include embedded hyperlinks to product or service information thus facilitating an enhanced response rate for the “mail drop”. Still, as is the case in the realm of print media, unsolicited electronic mail, referred to commonly as “spam”, remains an annoyance to consumers worldwide. As a result, an entire cottage industry of “spam filters” has arisen whose task solely is the eradication of spam.
Like electronic mail, instant messaging has proven to be fertile ground for the mass marketer. Referred to in the art as “spim”, unsolicited instant messages have proven to be even a greater annoyance than spam. When received in an e-mail server, spam is not noticed by the recipient until the inbox for the e-mail server has been scanned. At worst, a “new message” notification can be activated pending the review of the newly received spam message by the recipient. In the case of instant messaging, however, the impact is immediate.
Specifically, spim when received causes the activation of a viewer which can “pop up” and distract the recipient. Moreover, spim like spam can consume network resources which can drain user productivity. Even workplace issues can arise where spim includes sexually explicit materials which can be viewed by unsuspecting passersby in proximity to the instant messenger client. Importantly, unlike e-mail based spam, instant messaging based spim cannot be merely deleted. Rather, the spim can become part of the record of the instant messaging session.
Spim often can be generated by “bots”—automated logic charged with the task of identifying possible instant messenger recipients and forwarding instant messages to the recipients as if the instant messages originated from an actual instant message user. Often, the list of instant messenger recipients can be generated randomly, or harvested through Internet probing operations. Given the level of automation available to the spim artist, estimates now place spim at epidemic levels in excess of 500 million spims per day.
Several products have attempted to address the spim epidemic. For example, anti-spim filters have been developed to identify keywords in spim in order to quash the receipt of spim messages. Additionally, it is known to block the receipt of an incoming instant message from a particular instant messenger identifier or screen name. Some systems restrict the receipt of instant messages to those which originate from within a specified domain or network. Yet other systems identify instant messenger sources which have added the recipient to a buddy list. Consequently, a “reverse buddy list” can be generated based upon which subsequent messages can be blocked which originate from users in the reverse buddy list. In all cases, however, spim remains a troublesome element of computer communications. | 2023-10-18T01:26:57.367551 | https://example.com/article/7518 |
Review: ‘His & Hers’
A rumination on infancy, adolescence, infirmity, mortality and relations between the sexes.
Simple ideas are often the best — and sometimes turn out not to be so simple. “His & Hers,” a delightful, disarming documentary, consists on a very basic level of soundbites from 70 Irish women, through whom we learn about potato peeling, naming babies and the very domestic politics of the TV remote. But it’s also a profound rumination on infancy, adolescence, infirmity, mortality and, most emphatically, the relations between the sexes. With the kind of marketing calculation that seems foreign to this gentle, charming film, “His & Hers” could easily find a niche and possibly pots o’ arthouse gold.
Filmed in the Irish midlands, “His & Hers” begins, naturally enough, with a baby girl, whose face registers the full spectrum of human emotion before she settles down and lets the story begin — one story, as it turns out, albeit told by 70 mouths. It’s a movie of women talking about their men, candidly and humorously, via a progression from young speakers to old: The little girls we see scurrying down a hallway are replaced by children, adolescents, young marrieds, mothers, matrons and elderly widows; they talk of dads, their boyfriends, their husbands, their sons; they speak in tenses future, present and, sadly, past. There are no revelations, irritations or explosions. And yet the overall effect of the collective story — the one we all lead — is orchestral.
As deceptively moving as it may be, helmer Ken Wardrop’s directorial debut is also rigorously and remarkably cinematic: The colors, the placement of objects (often in pairs), and the interplay of camera angles, light and movement are all choreographed to provide fluidity from subject to subject and home to home. There are no startling differences among the women — all are white, Irish and middle-class, but that’s not entirely an accident of geography. “His & Hers” is about the universality of experience and the subtlety of differences among people who may at first glance seem homogenous, but who are individuated by their manner, stories and even accents.
The idea of transition permeates “His & Hers” — the limited way the subjects move about their homes, cut the grass or perform domestic chores between the interviews are shot straight-on, as well as in mirrors and through windows. There is a geometric precision in the visual compositions here that, if one were so inclined, might recall the ancient Greeks.
Production values, from cinematography to sound to Denis Clohessy’s music, are tops. And all the ladies are charming.
His & Hers
Docu - Ireland
Production
A Venom Film presentation. Produced by Andrew Freedman. Directed, edited by Ken Wardrop. | 2024-04-27T01:26:57.367551 | https://example.com/article/7254 |
This invention relates to semiconductor memory devices and methods of manufacture, and more particularly to an improved method for making one-transistor dynamic read/write memory devices of the N-channel silicon gate type.
Dynamic read/write memory devices made by the single-level or double-level polysilicon, N-channel, self-aligned processes commonly used in the industry are shown in my U.S. Pat. No. 4,055,444 and my pending application Ser. No. 132,703, filing date Mar. 21, 1980 as well as in U.S. Pat. No. 4,240,092, by C-K Kuo, all assigned to Texas Instruments; these processes are also shown in Electronics: Feb. 19, 1976, pp. 116-121; May 13, 1976, pp. 81-86; and Sept. 28, 1978, pp. 109-116.
In prior dynamic RAM devices, the cell array and peripheral circuitry is usually formed by a process which leaves thick field oxide surrounding MOS transistors of the silicon-gate, self-aligned type on the face of a silicon bar. The field oxide is created in a high-temperature operation using nitride as an oxidation mask; to reduce capacitance between overlying conductors and underlying heavily-doped silicon regions, the field oxide is thick, but the process of growing the oxide results in moat encroachment beneath the edges of the nitride. This is in a continuing problem in large arrays as the capacitor and transistor sizes are scaled down for maximum density.
It is the principal object of this invention to provide an improved high-speed, high-density, dynamic read/write memory device and method of making, particularly for minimizing problems caused by moat encroachment. Another object is to provide a dynamic memory device of reduced cell size yet high speed. An additional object is to provide a high density DRAM memory device, made by an improved method which provides a reduction in capacitance for the peripheral circuitry, compared to the cell array. | 2023-08-09T01:26:57.367551 | https://example.com/article/8985 |
Introduction {#Sec1}
============
Osteoid osteoma (OO) is a relatively common benign skeletal lesion. It is the third most common primary benign skeletal neoplasm, accounting for approximately 10--12% of benign bone tumors \[[@CR1]\]. Although reported in almost every bone, it most commonly occurs in the long bones of the lower extremity, with 50% of the cases in the tibia and femur \[[@CR2], [@CR3]\]. Male patients are affected more than female patients at a ratio of 2--3:1 \[[@CR1]--[@CR4]\]. Osteoid osteoma is uncommonly seen in patients before age 5 years or after age 30 years, although a range from 8 months to 70 years has been reported \[[@CR2], [@CR5]\].
Most patients present with pain, which worsens at night and is relieved by nonsteroidal anti-inflammatory drugs (NSAIDs). The characteristic radiographic findings of OO include a cortical based central nidus of vascular osteoid tissue surrounded by reactive sclerotic bone \[[@CR1]\]. The clinical and radiological picture may be characteristic, but occasionally it is unclear, contributing to delay in diagnosis, especially in a young patient who may not be able to communicate his or her symptoms. Although there are reports of OO undergoing spontaneous regression, early diagnosis enables timely treatment, avoids unnecessary suffering, and minimizes morbidity including bone deformity and leg-length discrepancy \[[@CR6]\]. We report a 7-month-old female infant with osteoid osteoma, who presented with limited use of the right lower extremity and exhibited atypical imaging findings. After biopsy tissue confirmation of the diagnosis of OO, she was subsequently treated with radiofrequency ablation (RFA). The patient demonstrated signs of recurrent pain 3 months after the initial procedure and was treated successfully with a second RFA.
Case report {#Sec2}
===========
A 7-month-old girl was referred to our institution in December 2009 with a right femoral lesion, with concerns of neoplasm or osteomyelitis. Her parents noticed that she had shown a decrease in the use of her right lower extremity especially at about 3 months of life when the patient would not bear weight on her right lower extremity when held up in an upright position. The patient's ability to sit upright was also somewhat limited because she preferred to have her right hip and knee extended. At age 7 months, her pediatrician obtained a roentgenogram that showed a lytic lesion in the right proximal femur. The past medical history was unremarkable. Clinical examination showed an afebrile infant who moved her right lower extremity much less than the left and preferred keeping her right hip and right knee extended with external rotation. There was no erythema, warmth or mass in the right lower extremity. The results of routine laboratory studies were normal.
Roentgenograms of the right femur showed an osteolytic area in the intertrochanteric region, surrounded by a sclerotic rim and lamellar periosteal reaction (Fig. [1](#Fig1){ref-type="fig"}). A magnetic resonance imaging (MRI) study showed a focal, 1.1 × 0.9 × 1.2 cm, high T2 signal lesion centered in the intertrochanteric region of the proximal right femur. There was marked lamellar periosteal reaction involving the proximal right femoral metaphysis extending to the mid diaphysis, with extensive, ill-defined intra- and extraosseous edema (Fig. [2](#Fig2){ref-type="fig"}). The differential diagnosis included chronic osteomyelitis with a Brodie's abscess, eosinophilic granuloma, osteoid osteoma, and small round blue cell tumor such as Ewing sarcoma or metastatic neuroblastoma. Fig. 1Roentgenogram of the right hip shows a lytic lesion with sclerotic rim centered in the intertrochanteric region of the proximal right femur (*arrowhead*). There is lamellar periosteal reaction involving the proximal femur extending to the mid diaphysis (*arrow*)Fig. 2Axial T1-weighted pre-contrast (**a**) and fat-saturated post-contrast (**b**) MR images of the right femur show a tumor nidus (*arrows*) associated with extensive bone marrow edema pattern and extra-osseous edema pattern involving the proximal metadiaphysis and diaphysis
A CT-guided core needle biopsy of the lesion was performed. The axial CT scan at the time of biopsy showed a 1-cm lucent lesion eccentrically located within the medial aspect of the proximal femur with marked periosteal new bone formation (Fig. [3](#Fig3){ref-type="fig"}). Cultures of the biopsy tissue were negative for fungal and bacterial organisms. Histological examination of the biopsy tissue showed an area of new woven bone formation with prominent osteoblastic rimming in a background of loose, cellular, fibrous stroma (Fig. [4](#Fig4){ref-type="fig"}). There were no features of acute osteomyelitis, small round blue cell tumor, or eosinophilic granuloma. A diagnosis of OO was considered. Fig. 3Axial CT scan (bone window) during percutaneous RFA shows a radiolucent intramedullary nidus with central calcification surrounded by a dense rim of sclerosis. There is a marked periosteal reaction around the cortex (*arrows*). Note a marker for planning the skin entry pointFig. 4The tumor consisted of delicate trabeculae of woven bone with osteoblastic rimming. The intertrabecular space was occupied by a loose, hypocellular, vascular stroma. (Hematoxylin and eosin stain, 400× original magnification)
The infant subsequently underwent an RFA procedure, performed under CT guidance and general anesthesia. To reduce radiation exposure, only 20 mAs with 80 kVp was used, which resulted in markedly increased image noise, however, still allowing visualization of the lesion. Cefazolin sodium was administered during the procedure as a prophylactic to avoid osteomyelitis. After placement of the electrode-grounding pads and marking the entrance site on the skin, a 14G Bonopty penetration set (AprioMed, Uppsala, Sweden) was inserted and attached to the cortical bone. Then a 16G drill and extended drill (AprioMed) were advanced to the lesion.
Subsequently, RFA was performed using a Cool-tip™ RFA system (Tyco Valleylab, Boulder, CO) in a noncooled mode. A 17G 15 cm RFA probe with a 0.7 cm active tip was inserted. Using this probe and a standard heating procedure by heating the tip of the electrode to 90°C for a period of 6 min, a tissue area of 0.5 cm around the active tip was ablated. No complications were observed during or immediately after the procedure. The patient was discharged the next day.
At the follow-up 1 week later, the patient was able to place weight on her right leg when held up in an upright position and sit, unassisted, for several minutes. The patient presented again 3 months later with signs of recurrence, including inability to bear weight and decrease in the use of her right lower extremity. The follow-up radiographs showed persistent osteolytic area in the intertrochanteric region but less prominent periosteal reaction as compared to the radiographs prior to treatment. A second CT-guided RFA was performed 4 months after the initial procedure by using again a 0.7 cm active tip RFA probe with the same standard technique. The CT images showed a decrease in size of the nidus, which measured 0.7 cm in diameter (Fig. [5](#Fig5){ref-type="fig"}). Additionally, the periosteal reaction has improved when compared to the initial scans. One month after the second ablation, the patient still did not show signs of pain and began to stand on her legs. Fig. 5Axial CT scan (bone window) obtained during the RFA of the recurrent OO. Note mild decrease in size of the nidus (*arrow*) and periosteal bone formation
Discussion {#Sec3}
==========
There are numerous reports in the literature of osteoid osteomas occurring in patients younger than 5 years of age, but only rarely in those under 1 year of age \[[@CR2], [@CR5], [@CR7], [@CR8]\]. Habermann and Stern \[[@CR5]\] reported a case of OO in an 8-month-old infant whose onset of symptoms began at 4 months. A case of possible congenital OO involving a distal phalanx of the left long finger was reported by Szabo and Smith \[[@CR9]\]. That patient was diagnosed when she was 15 years old. However, deformity of the affected phalanx and its nail apparently had existed from birth and gone unnoticed.
Pain is the most common clinical manifestation of OO, with limp, tenderness, swelling, and atrophy the next most frequent findings in children \[[@CR7], [@CR8]\]. The symptoms may be present for periods ranging from weeks to several years before diagnosis \[[@CR2]\]. Although the clinical features of OO in children are similar to those in adults, greater clinical discernment is required for diagnosis, as children might not be able to accurately communicate their symptoms. In our patient, the most prominent sign was decreased use of the affected leg. Although this was first noted by the parents shortly after birth, the appropriate radiologic evaluation of the lesion was delayed until other indications of disease became evident.
The most characteristic and most common radiologic finding of OO includes a radiolucent, intracortical nidus, containing a variable amount of mineralization, surrounded by an area of dense fusiform reactive sclerosis \[[@CR1], [@CR10]\]. Approximately 20% of osteoid osteomas involve the medulla. The intramedullary lesions are often barely visible and usually induce only mild or no reactive bone formation \[[@CR11]\]; diagnosis of these osteoid osteomas may be challenging as shown by our case.
The nidus of an osteoid osteoma rarely exceeds 1.5 cm in the greatest dimension. The reactive periosteal bone formation is usually solid. CT scan is generally regarded as the preferred cross-sectional technique to locate the lesion. In children, an MRI study is often performed first in order to limit radiation exposure. The tumor nidus, however, may be difficult to identify on MR imaging \[[@CR12]\]. The great sensitivity of MR imaging to detect nonspecific, reactive changes in the bone marrow and soft tissue may result in a misleading aggressive appearance \[[@CR13]\]. In our patient, intramedullary location, extensive bone marrow, and soft tissue edema adjacent to the lesion, as well as lamellar periosteal new bone formation, made the diagnosis more difficult; because of this imaging appearance and the unusual age of our patient, other entities, such as osteomyelitis and aggressive tumors, were included in the differential radiologic diagnosis.
Osteoid osteoma and osteoblastoma are considered as closely related processes. Histologically, osteoid osteoma is similar to osteoblastoma and the difference between these two entities is established on the basis of the size of the nidus (\>2 cm is generally considered as osteoblastoma), skeletal distribution, radiographic appearance, and clinical presentation \[[@CR14]\].
A rare complication of osteoid osteoma is localized overgrowth and deformity of bone. It has been found most frequently in children with symptom onset before 5 years of age, emphasizing the importance of prompt definitive treatment to prevent leg length discrepancy and deformity in infants and very young children \[[@CR15]\]. Radiofrequency ablation for the treatment of OO was first described in 1992 \[[@CR16]\], and is currently the therapeutic treatment of choice for OO in both adult and pediatric cases; it is minimally invasive, safe and has a high technical and clinical success rate \[[@CR17]--[@CR19]\]. Successful treatment of OO with RFA was reported in a 1-year-old boy by Egstrom et al. \[[@CR20]\], but reviewing international medical literature our patient was the youngest child with OO to have been treated with RFA. In some studies, a higher recurrence of osteoid osteoma following treatment with RFA has been suggested in children or younger patients \[[@CR17], [@CR21]\] and association of recurrence with large nidus diameter (1.0--1.5 cm) has also been reported \[[@CR18], [@CR22]\]. Our case demonstrates potential problems with RFA in very young patients with relatively large lesions (1.2 cm in maximum diameter of the nidus). Although our patient developed a recurrence after the primary treatment, with a short follow-up after the second ablation, she is currently doing well. Whether there are any long-term consequences of the OO or the RFA procedure remains to be seen.
In summary, osteoid osteoma can be a diagnostic challenge when it presents with atypical clinical features in a very young patient. But also in very young patients, RFA is a safe procedure and should be considered as the treatment of choice. However, recurrence after the procedure is more frequently observed and close follow-up is recommended.
We would like to thank Dr. Daniel I. Rosenthal, Department of Radiology, Massachusetts General Hospital for his kind advice and support with the management of this patient.
**Open Access** This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
| 2024-05-15T01:26:57.367551 | https://example.com/article/5172 |
The National Association of REALTORS® (NAR) announced this morning that President Donald J. Trump will address members at 1 p.m. Central Daylight Savings Time Friday at the Marriott Wardman Park Hotel in Washington, D.C.
Today is the first day of the NAR Legislative Meetings & Trade Expo, May 13-18. Throughout the week, REALTORS® will attend educational sessions, participate in forums and discuss key legislative and regulatory issues with members of Congress, regulatory agency officials and top industry leaders. Login and read more.
“The National Association of REALTORS® is honored to welcome President Donald J. Trump to our annual Legislative Meetings & Trade Expo in Washington,” said NAR President John Smaby. “As thousands of REALTORS® descend on Capitol Hill to highlight our support of the housing industry, private property rights and policies that ensure the American Dream is accessible to everyone in this country, we know there are countless opportunities for collaboration between NAR and the Trump administration. While we hear how we can work together to secure these priorities and promote real estate in America, REALTORS® also look forward to showing the President ‘Who We R’ and what we care about as REALTORS®.” | 2023-10-18T01:26:57.367551 | https://example.com/article/3566 |
Mount Thompson (Queensland)
Mount Thompson is a mountain in Brisbane, Queensland, Australia. It is within the suburbs of Mount Gravatt East and Holland Park.
It is well-known within Brisbane because Queensland's first crematorium (and only crematorium until the 1970s), Mount Thompson crematorium, was built on its north-west slope in 1934.
References
Category:Mountains of South East Queensland
Category:Holland Park, Queensland
Category:Mount Gravatt East, Queensland | 2024-05-22T01:26:57.367551 | https://example.com/article/9163 |
<?php
declare(strict_types=1);
namespace Brick\Math\Tests;
use Brick\Math\BigDecimal;
use Brick\Math\BigInteger;
use Brick\Math\BigRational;
use PHPUnit\Framework\TestCase;
/**
* Base class for math tests.
*/
abstract class AbstractTestCase extends TestCase
{
/**
* @param string $expected The expected value, as a string.
* @param BigInteger $actual The BigInteger instance to test.
*
* @return void
*/
final protected static function assertBigIntegerEquals(string $expected, BigInteger $actual) : void
{
self::assertSame($expected, (string) $actual);
}
/**
* @param string $expected The expected string representation.
* @param BigDecimal $actual The BigDecimal instance to test.
*
* @return void
*/
final protected static function assertBigDecimalEquals(string $expected, BigDecimal $actual) : void
{
self::assertSame($expected, (string) $actual);
}
/**
* @param string $expected The expected string representation.
* @param BigRational $actual The BigRational instance to test.
*
* @return void
*/
final protected static function assertBigRationalEquals(string $expected, BigRational $actual) : void
{
self::assertSame($expected, (string) $actual);
}
/**
* @param string $unscaledValue The expected unscaled value, as a string.
* @param int $scale The expected scale.
* @param BigDecimal $actual The BigDecimal instance to test.
*
* @return void
*/
final protected static function assertBigDecimalInternalValues(string $unscaledValue, int $scale, BigDecimal $actual) : void
{
self::assertSame($unscaledValue, (string) $actual->getUnscaledValue());
self::assertSame($scale, $actual->getScale());
}
/**
* @param string $numerator The expected numerator, as a string.
* @param string $denominator The expected denominator, as a string.
* @param BigRational $actual The BigRational instance to test.
*
* @return void
*/
final protected static function assertBigRationalInternalValues(string $numerator, string $denominator, BigRational $actual) : void
{
self::assertSame($numerator, (string) $actual->getNumerator());
self::assertSame($denominator, (string) $actual->getDenominator());
}
/**
* @param string $name
*
* @return bool
*/
final protected static function isException(string $name) : bool
{
return \substr($name, -9) === 'Exception';
}
}
| 2024-03-10T01:26:57.367551 | https://example.com/article/6832 |
First-person shooter games as a way of connecting to people: "brothers in blood".
This work seeks to understand young adults' motives for online gaming and extends previous research concerning social interaction in virtual contexts. The focus of the study is on Counter-Strike and World of Warcraft. Drawing on Baudrillard's concept of simulacra, an analysis of young gamers' motivation for gaming is carried out. The empirical data was generated employing a mix of qualitative methods such as researcher introspection, observation, and interviews with young adults in two different online gaming centers in Stockholm during 2006 and 2007. The results show that online gaming is foremost motivated by social reasons providing the gamers with a possibility of cooperation and communication. Some of the gamers in the study were motivated by escapism. Online gaming also provides gamers with an experience in which "flow" can be obtained and serves as a "hallucination of the real," making it possible to do things and try out behaviors that would be impossible to do or try in real life. The gamers felt that online gaming gave them more experiences than real life could provide. For research purposes, this work provides a better understanding of the motivational aspects for gamers. | 2024-07-04T01:26:57.367551 | https://example.com/article/3868 |
Introduction {#Sec1}
============
Prostate cancer (PCa), is the most frequent solid cancer in aging males, and the third leading cause of cancer death in the US^[@CR1]^. The metastatic disease is the most important cause of increasing morbidity and mortality of PCa. The development of the metastasis stage of the disease involves multiple events, including the progression to hormone-independent status, which leaves physicians with very few treatment options. Although there are effective treatments of local PCa, such as radiation therapy, surgery, and androgen ablation therapy, only a few drugs have demonstrated some efficacy against hormone-refractory metastatic disease, such as docetaxel, abiraterone, and enzalutamide^[@CR2]--[@CR4]^. One major prerequisite to develop more effective targeted therapies is the identification of the most relevant cellular targets and enhancing understanding of the key pathophysiological pathways driving PCa progression. In this context, our group recently demonstrated that Axl is a relevant therapeutic target for metastatic castration-resistant PCa (mCRPCa)^[@CR5]^.
The receptor tyrosine kinase Axl belongs to the TAM (Tyro-3, Axl, and Mer) family and possesses transforming potential when overexpressed^[@CR6],[@CR7]^. Activation of Axl occurs subsequent to the binding of growth arrest-specific gene 6 (Gas6) which contains an N-terminal γ-carboxyl-glutamic acid domain, in a vitamin K-dependent event^[@CR8]--[@CR11]^. Axl expression has been associated with pathways closely related to progression and development of tumors and inhibition of apoptosis, such as the phosphatidylinositol 3-OH kinase (PI3K) pathway, MAP kinases, STAT, and NF-κB signal transduction pathway^[@CR5],[@CR12],[@CR13]^. Furthermore, Axl plays a role in the epithelial-mesenchymal transition (EMT), which is an important feature for the initiation of metastasis^[@CR14]--[@CR17]^.
Axl is deregulated in cancers such as prostate, breast, lung, and oesophageal carcinomas^[@CR5],[@CR8],[@CR18]--[@CR25]^. Its expression predicts poor overall patient survival in breast and pancreatic cancer patients^[@CR26],[@CR27]^ and is linked to increased resistance to therapy^[@CR28]--[@CR32]^, indicating that targeting Axl may represent a novel therapeutic approach for cancer treatment.
Here, we evaluated a library of natural compounds to identify and characterize specific Axl-inhibitors. We identified dihydroartemisinin (DHA), the active metabolite of artemisinin, which has been used as an anti-malarial drug, as a strong Axl-inhibitor. We demonstrated that DHA inhibits Axl expression, leading to decreased proliferation, migration, and invasion, induction of apoptosis of PCa cells and inhibition of tumor development in vivo. Moreover, DHA synergizes with docetaxel, a standard of care in mCRPC treatment, and increases the survival of mice with PCa xenografts. We provide strong evidence that DHA treatment effects on Axl expression are mediated by inhibition of microRNAs (miR-34a and miR-7) that regulate Axl expression. DHA regulation of miR-34a and miR-7 expression is dependent on JARID 2 and EZH2, components of the Polycomb Complex Repressor 2 (PRC2), a complex of proteins involved in proliferation, pluripotency, and maintenance of the developmental stage in adults, that acts through the regulation of the chromatin structure mainly by methylation of histone H3 lysine 27 residue (H3K27)^[@CR33],[@CR34]^. In summary, we have characterized a novel mechanism of action for DHA as a specific Axl-inhibitor in PCa, providing insights into the signaling pathways underlying the anticancer effects of DHA in PCa cells.
Results {#Sec2}
=======
Screening of natural compounds and identification of dihydroartemisinin as an inhibitor of prostate cancer cell proliferation {#Sec3}
-----------------------------------------------------------------------------------------------------------------------------
We previously demonstrated the expression and pathophysiological function of Axl in a panel of PCa cells^[@CR5]^. Here, we extended our analysis by investigating the expression of Axl in an additional panel of PCa cells. The castration-resistant PCa cells, DU145 and PC-3 lack androgen receptor (AR), PSA, and 5α-reductase^[@CR35],[@CR36]^, while C4, C4-2 and C4-2B are castration-resistant LNCaP clones. We observed that Axl mRNA and protein levels are expressed in C4, C4-2 and C4-2B cells at higher levels than LNCaP cells, but lower than in DU145 and PC-3 cells. LNCaP cells express very low levels of Axl compared to DU145 and PC-3 cells (Fig. [S1A and B](#MOESM1){ref-type="media"}).
We performed several cell-based assays utilizing a Natural Product Library (Selleck Chemicals) comprising of 144 natural compounds (Table [S1](#MOESM1){ref-type="media"}), to identify inhibitors of PCa cell proliferation (Fig. [S2](#MOESM1){ref-type="media"}). We analysed the solubility of the compounds in the media used to grow the panel of PCa cells and observed issues in 10 compounds (Table [S2](#MOESM1){ref-type="media"}). The remaining 134 compounds were tested for inhibition of proliferation in PCa cells (DU145, PC-3, C4, C4-2, and C4-2B). Our analysis revealed a similar pattern of proliferation inhibition for PC-3, C4, C4-2, and C4-2B, but not DU145 (Fig. [S3A](#MOESM1){ref-type="media"}). To select the most effective inhibitors of PCa cell proliferation, we ranked individual cells based on the inhibitory effects of the compounds (Fig. [S3B](#MOESM1){ref-type="media"}). Amongst the top 10 most effective compounds, eight were common to PC-3, C4, C4-2, and C4-2B (Table [S3](#MOESM1){ref-type="media"}). Only DHA demonstrated consistent inhibitory effects across all PCa cells tested. Consequently, we focused on the further evaluation of PCa proliferation inhibition by DHA. We previously demonstrated that Axl is a relevant therapeutic target for mCRPCa; Axl blockage inhibits the proliferation and migration of PCa cells as well as tumor formation in vivo^[@CR5]^, we tested the hypothesis that DHA inhibits proliferation of mCRPCa cells via Axl modulation. We found that DHA reduced Axl mRNA expression in all PCa cell lines tested (Fig. [1a](#Fig1){ref-type="fig"}). Additionally, we analysed the impact of DHA treatment on the protein levels and phosphorylation status of Axl and other members of the TAM family (Mer and Tyro3) in different PCa cell lines (Fig. [1b](#Fig1){ref-type="fig"}). DHA leads to inhibition of both Axl protein expression and phosphorylation, without affecting the expression of Mer and Tyro3 proteins.Fig. 1DHA treatment inhibits Axl expression and proteins involved in the Axl signaling pathway, reduces cell migration and invasion and induces apoptosis in mCRPCa cell lines.**a** qRT-PCR for Axl in PCa cells treated with 5 μM of DHA for 24 h. Values were normalized to Gapdh levels and to DMSO control. The experiment was performed in triplicate. Data are representative of 3 independent experiments; \**p* \< 0.05 two-tailed Student's *t*-test. **b** Immunoblot analysis of protein extracts obtained from DU145 and PC-3 treated with 5 μM DHA for 24 h using anti-phospho-Axl, anti-phospho-Akt and anti-phospho-Stat3 and anti-Axl, anti-Akt, anti-Stat3 and anti- GAPDH. **c** Migration and **d** invasion analysis of mCRPC cell lines 24 h post treatment with 5 μM of DHA. Cells were fixed and stained, and 3--5 random microscopic fields were counted. Data are representative of three independent experiments and all values shown are mean ± SD from a representative experiment; \*\**p* \< 0.01, two-tailed Student's *t*-test. **e** Apoptosis assay for mCRPCa cell lines treated with 5 μM of DHA for 8 h. DMSO 0.05% was used as a control. Data are representative of three independent experiments and all values shown are mean ± SD from a representative experiment; \**p* \< 0.05, two-tailed Student's *t*-test
We, and others, have shown that Axl regulates the Akt/NF-κB pathway in cancer^[@CR5],[@CR12],[@CR24]^. We evaluated the expression levels of components of the Akt/NF-κB signaling pathway by western blot analysis. As predicted, DHA reduces Akt and Stat3 protein phosphorylation, indicating Akt activation and inactivation of Stat3 signaling (Fig. [1b](#Fig1){ref-type="fig"}). Dose-response experiments to determine DHA concentration needed to inhibit PCa proliferation established the IC~50~ ranging from 3.9 to 5.1 µM in the panel tested (Table [1](#Tab1){ref-type="table"}). Interestingly PCa cells expressing comparatively very low levels of Axl, such as LNCaP, exhibit higher IC~50~ when compared with cells expressing higher levels of Axl (DU145, PC-3, C4, C4-2, and C4-2B), suggesting that DHA acts in an Axl-dependent manner in PCa cell lines.Table 1Analysis of DHA effect in PCa cell linesCell lineIC~50~ ± SD (µM)95% Confidence interval**DU145**4.8 ± 0.893.49--6.96**PC-3**5.1 ± 0.912.75--5.41**C4**3.9 ± 0.452.78--4.46**C4-2**4.9 ± 0.523.07--5.75**C4-2B**5.1 ± 0.553.59--5.86**LNCaP**22.1 ± 1.8915.2--30.5A dose-response curve was performed and inhibition of proliferation was analyzed. IC~50~ = 4.8 µM in DU145; 5.1 µM in PC-3; 3.9 µM in C4, 4.9 µM in C4-2, 5.1 μM in C4-2B and 22.1 μM in LNCaP
Other than proliferation, the Axl signaling pathway is important in inducing migration and invasion^[@CR5],[@CR8],[@CR14]^. Transwell assays demonstrated that DHA treatment significantly inhibits migration and invasion of PCa cells (Fig. [1c, d](#Fig1){ref-type="fig"}). Moreover, the treatment of PCa cells for 4 h with DHA induces apoptosis (Fig. [1e](#Fig1){ref-type="fig"}). In contrast, DHA treatment of the non-cancer cells, CCD-18, PNT1A, and Cos-7, did not significantly reduce proliferation (Fig. [S4A](#MOESM1){ref-type="media"}), indicating non-toxicity for non-cancer cells. Remarkably, analysis of Axl mRNA in this panel of non-cancer cell lines demonstrated lower levels of Axl transcript when compared to DU145 cells (Fig. [S4B](#MOESM1){ref-type="media"}).
DHA inhibition of prostate cancer cell proliferation and tumor formation in vivo is dependent on Axl expression {#Sec4}
---------------------------------------------------------------------------------------------------------------
We observed that inhibition of the proliferation effect elicited by DHA is more prominent in PCa cell lines expressing higher levels of Axl. We hypothesized that DHA effects on PCa proliferation are Axl-dependent. We evaluated DHA effects on PCa cell lines upon knockdown of Axl expression by lentivirus encoding shRNA-Axl-gene^[@CR5]^, compared to wild type cells. Lentivirus-shRNA-Axl as well as a lentivirus-shRNA-GFP (control) were used to infect PCa cells, resulting in \~90% reduction of Axl expression (Fig. [S5](#MOESM1){ref-type="media"})^[@CR5]^.
DHA treatment inhibits DU145shGFP cell proliferation after 24 h incubation compared to cells treated with DMSO by 44% (*p* \< 0.05), but has no effect on DU145shAxl (Fig. [2a](#Fig2){ref-type="fig"}). These findings confirm that DHA elicits its anti-proliferative effect at least partially in an Axl-dependent manner.Fig. 2DHA inhibition of PCa proliferation and tumor formation in vivo is dependent on Axl expression.**a** Proliferation assay. DU145shGFP and DU145 shAxl cells were treated with DHA (5 μM) or DMSO (0.05%) for 24 h. Data were normalized to DU145shGFP treated with control and represented as percentage. Data shown are mean ± SD of triplicate independent experiments. Data are representative of 3 independent experiments. **b** DU145shGFP and DU145shAxl cells (5 × 10^6^) were implanted subcutaneously into the right flank of MF-1 mice. Mice were submitted to daily treatment with 40 mg/kg of DHA or DMSO (2 mL/kg). Tumor weight was measured 48 days after implantation. Values are represented as mean ± SD of six individuals; \**p* \< 0.05, two-tailed Student's *t*-test
Previously, we demonstrated that Axl plays an important role in PCa tumor growth in vivo^[@CR5]^. To determine whether DHA treatment impacts tumor formation in vivo, DU145 cells infected with LV-shRNA-GFP or LV-shRNA-Axl were subcutaneously implanted into the prostate of MF-1 nude mice. Mice were treated with DHA (40 mg/kg) or vehicle control (DMSO at 2 mL/kg) injected intraperitoneally for 50 days and examined for tumor formation and tumor weight. Treatment of mice implanted with the DU145shGFP cell line (control cells) with DHA significantly reduced tumor growth by 46% (Fig. [2b](#Fig2){ref-type="fig"}, *p* \< 0.05) compared to DMSO vehicle-treated mice. Interestingly, treatment of mice implanted with the DU145shAxl cell line with DHA showed no significant difference in tumor burden when compared to DMSO vehicle-treated mice (Fig. [2b](#Fig2){ref-type="fig"}), reinforcing the notion that DHA acts in an Axl-dependent manner.
DHA treatment enhances docetaxel efficacy in prostate cancer {#Sec5}
------------------------------------------------------------
Docetaxel is a semisynthetic taxane employed as a standard of care in mCRPCa treatment^[@CR2],[@CR37]^. To test whether the treatment of docetaxel synergizes with DHA in reducing tumor growth, we evaluated the effect of DHA on docetaxel response in PCa cells. We defined the docetaxel IC~50~ in DU145 cells as 2 nM (Fig. [S6](#MOESM1){ref-type="media"}). We evaluated the effect of docetaxel on the proliferation of PCa cells with siRNA-mediated knockdown of Axl (DU145shAxl) and showed that DU145shAxl cells are more sensitive to docetaxel treatment than DU145shGFP cells. Docetaxel IC~50~ in DU145shAxl cells is 0.6 nM, 3-fold lower in shAxl than in Axl+/+ (Fig. [S6A](#MOESM1){ref-type="media"}). Isobologram analysis of PCa cells with combined docetaxel and DHA treatment using Calcusyn software revealed that the two drugs synergize (Fig. [S6B](#MOESM1){ref-type="media"}). Pre-treatment of PCa cells for 24 h with DHA (2 µM) sensitized PCa cells to docetaxel and enhanced the growth-inhibitory effect of docetaxel (Fig. [S6C](#MOESM1){ref-type="media"}). Cells pre-treated with DHA require 14-times lower concentrations of docetaxel compared to DMSO. These data reinforce the hypothesis that DHA treatment sensitizes PCa cells to and enhances docetaxel response in PCa. Furthermore, targeted Axl-inhibition could be an effective therapy for enhancing docetaxel efficacy in mCRPC.
DHA synergizes with docetaxel to inhibit tumor formation in vivo {#Sec6}
----------------------------------------------------------------
To determine whether DHA treatment has a synergistic effect on tumor formation in vivo when co-administrated with docetaxel, DU145 cells were implanted into MF-1 nude mice. Balanced cohorts with established mCRPC xenograft tumors were treated with vehicle DMSO (2 mL/kg) daily, DHA (40 mg/kg) daily, docetaxel (15 mg/kg) on days 1, 8, 15, 38, 45, 52 post inoculation, or DHA (40 mg/kg) daily combined with docetaxel (15 mg/kg) on days 1, 8, 15, 38, 45, 52 by intraperitoneal injection. 50 days later, mice were examined for tumor formation, tumor weight and IL-6 expression in the serum.
DHA or docetaxel treatment resulted in a significant reduction of tumor growth and volume in mice when compared to those treated with DMSO. As observed in Fig. [3a](#Fig3){ref-type="fig"}, tumor growth is reduced by the use of docetaxel, DHA or a combination of both. At the end of the 50 days of the experiments, we observed reduction of 49.9% (*p* \< 0.05) after treatment with DHA, 55.10% (*p* \< 0.05) after treatment with docetaxel and 76.10% (*p* \< 0.001) when combining both compounds. Analysis of dissected tumor at the end 50 days, demonstrated that tumor weight was reduced by 44.27% (*p* \< 0.05) and 51.35% (*p* \< 0.05) after treatment with DHA or docetaxel, respectively. Combination therapy with both compounds increased tumor weight reduction to 68.75% (*p* \< 0.001) (Fig. [3b](#Fig3){ref-type="fig"}).Fig. 3Synergistic effects of combinatorial therapy with DHA and docetaxel in vivo.DU145shGFP cells (5 × 10^6^) were implanted subcutaneously into the right flank of MF-1 mice. Mice were randomly divided into 4 groups (*n* = 6/group): Mice submitted to treatment with DMSO (2 mL/kg/daily), DHA (40 mg/kg/daily), docetaxel or combination of DHA (40 mg/kg/daily) and docetaxel (15 mg/kg/daily) as described in Material and methods. **a** Analysis of **a** tumor volume progression and **b** tumor volume. Values are represented as mean ± SD of six individuals; \**p* \< 0.05 and \*\**p* \< 0.001, two-tailed Student's *t*-test. **c** Analysis of IL-6 levels in the blood of mice. Values are represented as mean ± SD of six individuals; \* *p* \< 0.05, two-tailed Student's *t-*test. **d** Survival curve of mice treated DMSO (2 mL/kg/daily), DHA (40 mg/kg/daily), docetaxel (15 mg/kg/daily) or combination of DHA (2 mL/kg/daily) and docetaxel (15 mg/kg/daily)
We evaluated the levels of IL-6 secreted in the blood of animals. IL-6 levels in blood predict poor outcomes in patients with localized tumors^[@CR38]^. Previously, we demonstrated that Axl/Akt/NF-κB cascade via constitutive activation of NF-κB leads to IL-6 secretion in PCa^[@CR5]^. We observed that treatment of mice with DHA, docetaxel or a combination of both, drastically reduced the levels of IL-6 secreted in mouse blood. The reduction in secreted levels of IL-6 in mice was 38.12% for DHA (*p* \< 0.05), 42.77% for docetaxel (*p* \< 0.05) and 58.41% for the combination of docetaxel and DHA (*p* \< 0.05) compared to control (Fig. [3c](#Fig3){ref-type="fig"}). In an independent experiment utilizing the same cohorts, treatments, and conditions as described above, we evaluated the overall survival of mice submitted to the different treatment regimens. The experiment ended when tumors reached institutional limits (1500 mm^3^). Treatment with DHA and docetaxel prolonged overall survival compared with vehicle-treated controls. Treatment with DHA led to a median survival of 58 days compared to 48 days of the control group (Fig. [3d](#Fig3){ref-type="fig"}). This is similar to the survival seen for the docetaxel treated group (60 days). Moreover, the co-treatment of mice with DHA and docetaxel enhances survival to 64 days. Together, these results suggest that an Axl specific inhibitor may impact PCa treatment, leading to prolonged survival.
Kinase screening and profiling indicates that DHA treatment does not affect Axl-kinase activity {#Sec7}
-----------------------------------------------------------------------------------------------
We evaluated whether DHA treatment directly inhibits the Axl-kinase domain, or whether the decrease of Axl phosphorylation is directly linked to the decrease in Axl expression, as well as investigated the effect of DHA treatment on other tyrosine kinases. We performed a kinase screening and profiling assay, using the KINOME scanTK Kinase Assay Panel (DiscoverX).
It has three components: a kinase-tagged phage, a test compound, and an immobilized ligand that the compound competes with to displace the kinase. The amount of kinase bound to the immobilized ligand is determined using quantitative PCR of the DNA tag. The readout from assay is "percent of control", where the control is DMSO and where a 100% result means no inhibition of the kinase by the test compound.
Under the conditions tested, DHA did not inhibit the kinase activity of any of the kinases screened, including Axl. (Fig. [S7A](#MOESM1){ref-type="media"}). These results suggest that inhibition of Axl phosphorylation by DHA treatment is due to the inhibition of Axl protein expression. Furthermore, we investigated whether DHA-elicited inhibition of Axl protein expression is mediated by the proteasome pathway. DU145 cells were treated with DHA, MG132 (proteasome pathway inhibitor), and a combination of both. Four hour post-treatment, protein was extracted and Axl expression was analyzed by western blot. Treatment with MG132 did not affect the inhibition of Axl protein expression by DHA (Fig. [S7B](#MOESM1){ref-type="media"}), indicating that DHA inhibition of Axl expression is not mediated by the proteasome pathway.
DHA inhibits Axl expression by inducing miR-7 and miR-34a expression {#Sec8}
--------------------------------------------------------------------
Several reports demonstrated the involvement and deregulation of micro-RNAs in cancer^[@CR39]--[@CR41]^. Axl has been shown to be regulated by miR34a, miR199a, and miR199b^[@CR42]^. To evaluate whether DHA treatment of PCa cells affects the expression of these miRNAs, we quantified their expression in PCa cell lines treated with DHA by qPCR. DHA treatment leads to a significant induction in miR-34a expression levels (2.18 fold), but not in miR-199a and miR-199b levels (Fig. [S8A](#MOESM1){ref-type="media"}). To evaluate DHA treatment effects on other non-coding RNA, we performed microarray analysis using the GeneChip miRNA 3.0 Array (Affymetrix). Treatment of PCa cells with DHA led to differential expression of a distinct set of miRNAs (Fig. [4a](#Fig4){ref-type="fig"}). Validation of microarray data was performed by expression evaluation of some of the top regulated miRNAs by qRT-PCR. We confirmed that miR-7, miR-550, miR-548, miR-663, and miR-4634 exhibited the same trend of expression as observed in the microarray data (Fig. [S8B](#MOESM1){ref-type="media"}). In order to identify non-coding RNAs that are likely to directly target Axl expression among this set of deregulated non-coding RNAs, we applied a bioinformatics approach to screen the 3′-UTR of the Axl transcript for complementary seed sequences of miRNAs. Using the *microRNA.org--Targets and Expression* database^[@CR43],[@CR44]^ we identified miR-7 as an Axl repressor candidate (Fig. [4b](#Fig4){ref-type="fig"}).Fig. 4DHA regulates the expression of miRNAs in PCa cell lines.Cells were treated with DHA (5 μM) or DMSO (0.05%) for 24 h. **a** Heat map of miRNA microarray expression data. Cluster analysis classified the samples into groups based on miRNA expression levels in each sample. Red indicates high expression and green indicates relatively low expression of miRNA. **b** Schematic representation of the location of the putative miR-7 target site is shown in the Axl 3′-UTR. **c** RT-PCR analysis of miR-34 expression levels (left) and miR-7 (right) expression levels in PCa cell lines. ΔCt values graphed are relative to the endogenous control RNU6B small RNA and data were normalized to normal cell PNT1A. Data are representative of three independent experiments and all values shown are mean ± SEM from a representative experiment; \**p* \< 0.05, two-tailed Student's *t-*test. **d** RT-PCR analysis of expression levels of miR-34a, miR-7, and Axl in human PCa samples. Total RNA was collected from human tissue consisting of paired normal and tumor samples and was analyzed for miR-7, miR-34a, and Axl expression levels. ΔCt values graphed are relative to the endogenous control RNU6B small RNA (for miR-34a and miR-7) and GAPDH for Axl. Data are shown as the triplicate independent experiments; \**p* \< 0.05, two-tailed, nonparametric Mann--Whitney test. **e** RT-PCR analysis of expression levels of miR-34a (right), miR-7 (left) and Axl (bottom) in tumor extracted from mice treated with 40 mg/kg of DHA or DMSO (2 mL/kg). Total RNA was collected from tumor and analyzed for miR-7 and miR-34a expression levels. ΔCt values graphed are relative to the endogenous control RNU6B small RNA. Data are representative of three independent experiments and all values shown are mean ± SD from a representative experiment; \**p* \< 0.05, two-tailed, nonparametric Mann--Whitney test
We evaluated miR-7 and miR-34a expression levels in a panel of PCa cell lines. PCa cell lines expressing higher levels of Axl (DU145 and PC-3) express lower levels of miR-34a and miR-7, while PCa cells expressing lower levels of Axl (LNCaP, C4, C4-2, and C4-2B) express higher levels of these miRNAs (Fig. [4c](#Fig4){ref-type="fig"}). Likewise, we evaluated the relevance of miR-7 and miR-34a expression and its inverse correlation with Axl expression levels in clinical PCa samples. We analyzed 16 matched pairs of normal and PCa tumor patient samples. Characteristics of each sample including Gleason score, stage, and grade are described in Table [S4](#MOESM1){ref-type="media"}. While Axl mRNA levels are consistently upregulated in tumor samples compared with matched normal tissue, miR-7 and miR-34a are downregulated (Fig. [4d](#Fig4){ref-type="fig"}) independent of tumor stage (Fig. [S9](#MOESM1){ref-type="media"}). The observation that miR-7 and miR34a are inversely correlated to Axl levels in both PCa cell lines and clinical tissues, together with our finding that DHA treatment leads to inhibition of Axl and induction of miR-7 and miR-34a, persuaded us to determine whether treatment of mice with DHA affects levels of miR-7 and miR-34a in vivo. This analysis demonstrated significant increase in miR-7 and miR-34a levels, as well as reduction in the levels of Axl in tumors from mice treated with DHA (Fig. [4e](#Fig4){ref-type="fig"}).
To gain further insights into Axl regulation by miR-7 and miR-34a, DU145 and PC-3 cells were transfected with miR-7 and miR-34a expression vectors as well as a control vector. Axl protein expression was analyzed in whole-cell extracts by western blot analysis. Expression of miR-7 or miR-34a results in the inhibition of Axl protein expression (Fig. [5a](#Fig5){ref-type="fig"}). Additionally, we evaluated the effect of the expression of miR-7 and miR-34a on proliferation and migration of PCa cells. As observed in Fig. [5b](#Fig5){ref-type="fig"}, both miR-7 and miR-34a reduce cell proliferation. The proliferation of PC-3 and DU145 cells are reduced by 32.2% (*p* \< 0.05) and 42.3% (*p* \< 0.05) after expression of miR-7. Likewise, the proliferation of PC-3 and DU145 cells are reduced by 38.8% (*p* \< 0.05) and 56.3% (p \< 0.05) after the expression of miR-34. Analysis of cell migration (Fig. [5c](#Fig5){ref-type="fig"}) demonstrated that the expression of miR-7 leads to inhibition of 39.7% (*p* \< 0.05) in PC-3 and 56.3% (*p* \< 0.05) in DU145. Migration of PC-3 and DU145 was similarly reduced by 41.6% (*p* \< 0.05) and 54.2% (*p* \< 0.05) after miR34a expression. These data provide strong evidence that miR-7 and miR-34a play critical roles in the DHA-mediated inhibition of Axl expression.Fig. 5Expression of miR-7 and miR-34a inhibits Axl protein expression as well as proliferation and migration of in PCa cells.**a** Western blot analysis of Axl expression in DU145 and PC-3 cells transfected with miR-7 or miR-34a expression vectors and a vector control. **b** Proliferation assay of DU145 and PC-3 cells transfected with miR-7 or miR-34a expression vectors. Proliferation was measured 48 h post transfection. Data are representative of three independent experiments and all values shown are mean ± SD from a representative experiment; \**p* \< 0.05, two-tailed Student's *t*-test. **c** Migration assay of DU145 and PC-3 cells transfected with miR-7 or miR-34a expression vectors. Migration was measured 24 h post transfection. Migrating cells were fixed and stained, and three to five random microscopic fields were counted. Data are representative of three independent experiments and all values shown are mean ± SD from a representative experiment; \**p* \< 0.05, two-tailed Student's *t-*test
DHA regulation of miR-7 and miR-34 and inhibition of Axl expression is mediated by polycomb repress complex 2 system {#Sec9}
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To gain insight into the functional and biological pathways that are involved in the DHA-mediated regulation of miRNAs and inhibition of Axl expression, we performed transcriptional profiling of DU145 cells treated with DHA (5 µM) or DMSO (0.05%) for 6 h. Transcriptional profiling analysis revealed 422 genes as differentially expressed in DHA-treated DU145 cells (Excel Spreadsheet 1 in [Supplementary Information](#MOESM1){ref-type="media"}). Systems biology analysis of the genes differentially expressed upon DHA treatment indicates that DHA treatment interferes with a set of genes involved in proliferation and cell growth as well as cell and tissue development functions (Fig. [S10](#MOESM1){ref-type="media"}). Our analysis indicates inhibition of JARID2 (Jumonji, AT-rich interaction domain containing 2) expression (data not shown), a DNA-binding component of the polycomb repress complex proteins (PRC2)^[@CR45],[@CR46]^. PRC2 is one of the two classes of the polycomb group (PcG) proteins that are required for establishing and maintaining cellular memory and are involved in cellular processes such as proliferation and pluripotency^[@CR33]^. PcG proteins form several complexes that function primarily through the regulation of chromatin structure^[@CR34],[@CR47]^. PRC2 is a methyltransferase complex that acts specifically on histone H3 lysine 27 (H3K27) and is composed of four core components: enhancer of zeste homolog 2 (EZH2), Eed, Suz12, and JARID2^[@CR45],[@CR46],[@CR48]^. EZH2 is the catalytic component of PRC2 and functions as a histone methyltransferase for H3K27 residues which is associated with repressed chromatin states and is widely distributed among genes encoding developmental regulators^[@CR49]--[@CR51]^. JARID2 interacts with EZH2 in the chromatin, stimulating its histone H3K27 methyltransferase activity^[@CR52]^. In the absence of JARID2, PRC2 is recruited late to its target genes and its enzymatic function is diminished^[@CR52]^.
We performed western blot analysis of JARID2 and EZH2 protein expression in DU145 and PC-3 cells treated with 5 µM of DHA for 24 h. DHA treatment resulted in the inhibition of JARID2 expression and reduced levels of p-EZH2 expression, the phosphorylated form of EZH2 (Fig. [6a](#Fig6){ref-type="fig"}). Furthermore, we investigated whether DHA treatment interferes with JARID2-EZH2 interaction, Immunoprecipitation of JARID2 or EZH2 proteins followed by detection with anti-EZH2 or anti-JARID2 antibodies in cells treated with DHA (5 µM) or DMSO (0.05%). Control demonstrates that JARID2 or EZH2 are not co-immunoprecipitated in cells treated with DHA, thus inhibition of JARID2 by DHA disrupts the formation of this complex (Fig. [6b](#Fig6){ref-type="fig"}).Fig. 6DHA inhibits proteins involved in the polycomb repressive complex.**a** Immunoblot analysis of protein extracts obtained from DU145 and PC-3 treated with DHA (5 μM) using anti-phospho EZH2, and anti-JARID2, anti-EZH2 and anti-GAPDH. **b** DHA Treatment of PCa cells inhibits JARID2-EZH2 interaction. DU145 cells were treated with 5 µM of DHA and DMSO (0.05%) and protein extracts were immunoprecipitated using anti-JARID2 or anti-EZH2 antibodies. The interaction between the proteins was detected by anti-EZH2 (right) or anti-JARID2 antibodies. **c** Inhibition of JARID2 protein regulates miR-34a and miR-7 expression and Axl expression. RT-PCR analysis of miR-34a, miR-7, and Axl expression levels of in DU145 cells lacking JARID2 expression. DU145 were transfected with JARID2 siRNA or GFP siRNA duplexes (50 nM). Total RNA was collected and was analyzed 24 h post transfection. ΔCt values graphed are relative to the endogenous control RNU6B small RNA (for miR-34a and miR-7) and GAPDH for Axl. Data are representative of three independent experiments and all values shown are mean ± SD from a representative experiment; \**p* \< 0.05, two-tailed Student's *t-*test. **d** ChIP-qPCR analysis demonstrating the effect of DHA treatment on DU145 and C4-2 cells on H3K27me3 at specific gene loci. PCa cell lines were treated with 5 uM of DHA or DMSO and subjected to ChIP analysis using antibodies against H3K27me3 or control IgG. The signals of H3K27me3 at the indicated genomic locations were normalized to that obtained from IgG ChIP at the same location to calculate their enriched signal. **e** Schematic representation of DHA inhibition of Axl expression via regulation of microRNAs and proteins of the polycomb repressive complex 2
We knocked down JARID2 in DU145 using siRNA (Fig. [S10A](#MOESM1){ref-type="media"}) and evaluated miR-7, miR-34a, and Axl expression levels. Cells lacking JARID2 expression exhibit higher levels of miR-7 (2.72 fold) and miR-34a (2.68 fold) and lower levels of Axl (0.533 fold) (Fig. [6c](#Fig6){ref-type="fig"}). We did not observe any significant differences in miR-7 and miR-34a levels when JARID2 knockdown cells are treated with DHA (Fig. [S10B and C](#MOESM1){ref-type="media"}), indicating that DHA modulation of miR-7 and miR-34a levels is JARID2 dependent.
Considering the above, we investigated the effect of DHA-mediated inhibition of JARID2 and JARID2-EZH2 interaction on EZH2 H3K27 methyltransferase activity. We performed Chromatin Immunoprecipitation (ChIP) analysis using H3K27me3 antibodies, followed by qPCR from the immunoprecipitated DNA of DU145 and C4-2 cells treated with DHA or DMSO. PCa cells treated with DHA presented decreased levels of H3K27me3 at specific gene loci (ANKRD30BL, Dnmt3A, KIF21A and MYC promoter) compared with cells treated with DMSO (Fig. [6d](#Fig6){ref-type="fig"} and Fig. [S11](#MOESM1){ref-type="media"}), suggesting that DHA affects H3K27me3 methyltransferase activity.
Discussion {#Sec10}
==========
Identifying relevant cellular targets and patient populations is necessary for developing and testing targeted therapies. Previously, we identified the tyrosine kinase receptor Axl as a potential target for PCa therapy^[@CR5]^. Increased Axl levels have been linked to resistance to Imatinib in gastrointestinal stromal tumors, Lapatinib in HER-2 positive breast tumor cells^[@CR53]^, BMS-754087 in Rhabdomyosarcoma^[@CR54]^, and metformin in PCa^[@CR55]^, as well as erlotinib in non-small cell lung cancer (NSCLC)^[@CR32]^. Moreover, Axl overexpression has been described as mediating resistance to PI3K inhibitors^[@CR30]^.
Numerous studies have described the development of Axl-inhibitors^[@CR26],[@CR56],[@CR57]^. The development of small molecules such as R428 (also known as BGB324)^[@CR26]^ and monoclonal antibodies such as YW327.6S2^[@CR58]^ are promising. However, the development of specific Axl-inhibitors represents a major challenge due to the lack of an Axl structure and the fact that it shares high structural similarity with the rest of the TAM family and other kinases of the human kinome^[@CR57]^. Therefore, screening of biologically and/or pharmacologically active natural compounds is a viable alternative approach, as several natural products and their semisynthetic derivatives are used in cancer chemotherapy.
In this study, the screening of a natural compound library has identified dihydroartemisinin (DHA) as a potent Axl-inhibitor in PCA cells. Our findings demonstrate that DHA inhibits proliferation and migration of PCa cells and tumor formation in vivo in an Axl-dependent manner. It leads to reduction of IL-6 levels, a mediator of morbidity and mortality in patients with mCRPCa^[@CR38]^. Moreover, our group has shown that DHA regulates NF-κB and Akt in PCa which is in line with the previous reports^[@CR59]^.
Co-treatment with DHA and docetaxel demonstrated synergistic effects against PCa both in vitro and in vivo. Docetaxel improves survival in patients with metastatic PCa. However, side-effects are observed in patients treated with this drug and patients become resistant to docetaxel^[@CR37]^. Side-effects to docetaxel treatment may be minimized if combined with DHA, since DHA treatment can decrease docetaxel dosage needed for efficacy, leading to improved quality of life during treatment. As Axl plays a role in resistance to various cancer drugs, and DHA reduces Axl expression in PCa, combination of docetaxel with DHA may also delay or prevent resistance to docetaxel.
Besides some evidence of the anticancer potential of artemisinin and its derivatives, particularly DHA, for different types of cancers, there is little information about its mechanism of action, thus our findings are novel. We demonstrated that DHA does not inhibit Axl-kinase itself or via proteasome degradation. In fact, DHA-induced inhibition of Axl expression appears to be mediated by regulating specific micro RNAs. DHA treatment leads to increased expression of miR-34a and miR-7. MiR-34a has been shown to be a tumor suppressor in different types of cancers such as glioma, breast and PCa, and a part of the p53 tumor suppressor network, and regulates Axl expression^[@CR42],[@CR60]^. MiR-7 targets and downregulates oncogenic factors in cancer-associated signaling pathways including EGF, Bcl-2, Raf1, and Akt/PI3K^[@CR61]^. Using bioinformatics analysis, we identified miR-7 as having complementary seed sequences to the 3′-UTR of the Axl-gene. Ectopic expression of miR-7 and miR-34a inhibits Axl expression. miR-7 and miR-34a expression levels are inversely correlated with Axl expression in clinical PCa samples. Tumor samples derived from xenograft mice treated with DHA exhibit higher levels of miR-7 and miR-34a expression, suggesting that these miRNAs play a critical role in PCa.
Further gene expression and bioinformatics analysis in PCa cells treated with DHA indicates that DHA inhibits the expression of JARID2, a DNA-binding protein which is a component of the polycomb repressive complex 2 (PRC2)^[@CR46]^. PRC2 regulates gene silencing through chromatin reorganization and histone methylation^[@CR45],[@CR48]^. EZH2, another component of the PRC2 complex, has been described as an oncogene which is deregulated in prostate and breast cancer, and implicated in cancer progression and poor prognosis^[@CR62],[@CR63]^. EZH2 catalyses trimethylation of H3K27, creating repressive chromatin structures over long genomic distances^[@CR64]^. In fact, H3K27me3 is a signature of PRC2 activity and is involved in gene silencing through several mechanisms^[@CR65]^. Treatment of PCa cells with DHA decreases the enrichment of trimethylation of H3K27 in specific gene loci, reinforcing the notion that DHA inhibits the formation of the PRC2 complex.
Regulation of miRNAs by PRC2 proteins is pivotal in cancer^[@CR66]^. Nevertheless, a recent report has described a positive regulation of Axl by EZH2, independent of histone or DNA methylation in glioblastoma^[@CR67]^. Induction of miR-7 and miR-34a in cells treated with DHA or cells not expressing JARID2 may indicate a role of PRC2 in the regulation of these miRNAs. In fact, we have demonstrated that inhibition of JARID2 by DHA treatment causes inhibition of EZH2, avoiding the establishment of PRC2 and inducing miR-7 and miR-34a, which in turn inhibits Axl (Fig. [6e](#Fig6){ref-type="fig"}). Even though we demonstrated a direct link between inhibition of PRC2 complex components i.e., JARID2 by DHA, it is important to note that the exact mechanism by which DHA inhibits JARID2, which may include direct interaction, remains unclear and is under investigation by our group. In conclusion, we provide strong evidence that DHA inhibits Axl expression in PCa via regulation of microRNAs and proteins of the polycomb repressive complex 2.
Materials and methods {#Sec11}
=====================
Cell lines and culture {#Sec12}
----------------------
Human PCa cell lines C4, C4-2, and C4-2B were kindly provided by Dr. Steven Balk (Beth Israel Deaconess Medical Center and Harvard University); DU145, PC-3, and LNCaP, as well as non-cancer cell lines CCD-18 and Cos-7, were purchased from ATCC. PNT1A, a normal prostate epithelial cell line, was purchased from Sigma Aldrich. Knockdown cell lines DU145shGFP and DU145shAxl cells were previously described^[@CR5]^. Details from authentication and culture methods are described in [Supplementary data](#MOESM1){ref-type="media"}.
Plasmids and transfection assays {#Sec13}
--------------------------------
Transfection was performed as previously described^[@CR5],[@CR68],[@CR69]^ using Lipofectamine plus reagent (Invitrogen) and plasmids, allowing expression of microRNA precursors; pCMV-miR-7 (Origene, SC400648), pCMV-miR-34a (Origene, SC400356) and pCMV as a control.
Reagents {#Sec14}
--------
Library of Natural Products (Cat No.L1400Selleck Chemicals). Dihydroartemisinin (D7439), docetaxel (01885) from Sigma-Aldrich, MG132 (474791), Calbiochem San Diego, CA, USA) were dissolved in DMSO (Sigma-Aldrich). siRNA-JARID2 (sc-60872, Santa Cruz Biotechnology) was used following the manufacturer's recommendation.
Isobologram {#Sec15}
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Analysis of docetaxel and DHA combinatorial treatment was demonstrated by isobologram, and calculated using Calcusyn software (Biosoft) as previously described^[@CR70]^.
Immunoprecipitation and western blot {#Sec16}
------------------------------------
Immunoprecipitation and Western blot analyses were performed as previously described^[@CR5],[@CR68],[@CR69]^ using the primary antibodies Mer (\#9178), Tyro3 (\#5585), Axl (\#4977), p-Akt (\#92765), Akt (\#9272), p-Stat3 (\#9132), Stat3 (\#9131), EZH2 (\#4905), p-EZH2 (\#27888) and GAPDH (Cell Signalling Technology, Beverly, MA, USA), JARID2 (sc-134548 - Santa Cruz Biotechnology) and p-Axl (AF2228) (R&D Systems, Minneapolis, MN, USA). For immunoprecipitation assays, 500 µg of total protein were immunoprecipitated using anti-JARID2 or anti-EZH2 antibodies coupled to protein-G agarose.
Proliferation and apoptosis assays {#Sec17}
----------------------------------
Proliferation and apoptosis assays were performed using Cell Proliferation Kit I (MTT; Roche, Basel, Switzerland) and Apoptotic Cell Death Detection ELISA (Roche), respectively, according to the manufacturer's protocol.
Drug treatment {#Sec18}
--------------
Cells were treated with compounds in their particular medium for 24 h (proliferation analysis) or 6 h (apoptosis analysis). For determination of IC~50~, cells were incubated with different concentrations of DHA (0.0048--5 µM) and Docetaxel (2.4--625 nM of docetaxel) for 24 h. Proliferation was analyzed. For combinatorial effect analysis, PCa cells were pre-treated with DHA (2 µM) for 24 h and treated with different concentrations (2.4--625 nM) of docetaxel. Proliferation was measured 24 h after docetaxel treatment.
Invasion and migration assays {#Sec19}
-----------------------------
Cell migration and invasion assays were performed as previously described^[@CR38]^, using a modified transwell chamber migration assay and invasion assay matrigel-coated membrane (BD Biosciences, Bedford, MA, USA).
Real-time PCR {#Sec20}
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Total RNA was harvested using QIAshredder (Qiagen, Valencia, CA, USA) and the RNeasy mini kit (Qiagen) from tissue samples or cells, as recommended by the manufacturer. Primers used for real-time PCR are described in [Supplementary information](#MOESM1){ref-type="media"}, and conditions were as described previously^[@CR5]^.
Quantification of miRNA by RT-PCR {#Sec21}
---------------------------------
Quantification of miRNAs was performed using specific and sensitive quantitative RT-PCR^[@CR71]^ on LightCycler®480 InstrumentII (Roche). Primers and adaptors sequence are described in [Supplementary information](#MOESM1){ref-type="media"}.
Animal experiments {#Sec22}
------------------
Eight-week-old male MF-1 nude mice, obtained from the University of Cape Town, were bred at the University's animal facility and housed in a pathogen-free environment. Details of procedures, groups, and treatment schedule are described in details in [Supplementary information](#MOESM1){ref-type="media"}. All procedures with animals were reviewed and approved by the Animal Research Ethics Committee of the University of Cape Town.
IL-6 detection {#Sec23}
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IL-6 was assayed as described^[@CR5],[@CR38]^ using ELISA (InvitrogenKHC0061C, Carlsbad, CA, USA) according to the manufacturer's protocol.
Tissue samples {#Sec24}
--------------
Histopathological-confirmed PCa biopsies and the corresponding adjacent normal tissue samples were obtained from the Rhode Island Hospital, Brown University, Providence, Rhode Island, USA. Informed consent was obtained from all participants, while ethical approval for this study was obtained from the Ethics Committee of the Brown University (approved protocol number 015/005). Samples were stored in RNA later solution (Qiagen) at −80 °C until nucleic acid extraction was performed following the manufacturer's instructions.
Kinase screening and profiling {#Sec25}
------------------------------
Kinase screening and profiling were performed using the *scan*TK^℠^ Kinase Assay Panel (DiscoverX). We used 7 μM of DHA and the experiment was performed according to the manufacturer's instructions.
Microarrays analysis {#Sec26}
--------------------
RNA samples for microarray analysis were obtained using QIAshredder (Qiagen) and RNeasy Mini Kit (Qiagen) and converted into cRNA following the manufacturer's instructions (Affymetrix, Santa Clara, CA, USA). Details of analyses are described in [Supplementary material](#MOESM1){ref-type="media"}.
Microarray data deposition {#Sec27}
--------------------------
Dataset have been deposited in the Gene Expression Omnibus under GSE122625
Chromatin immunoprecipitation {#Sec28}
-----------------------------
Chromatin immunoprecipitation was performed as previously described^[@CR72]^. Details are described in [Supplementary Information](#MOESM1){ref-type="media"}.
Statistical analysis {#Sec29}
--------------------
Unpaired Student *t*-test was used for comparison of drug treatment in PCa cell lines. Gehan-Breslow-Wilcoxon test was used for analysis of the survival curve. All were performed using GraphPad Prism 5.00 (GraphPad Software).
Supplementary information
=========================
{#Sec30}
Supplementary Information.
**Publisher's note:** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
=========================
**Supplementary information** accompanies this paper at (10.1038/s41389-019-0122-6).
Financial Support: International Centre for Genetic Engineering and Biotechnology (L.F.Z.); ICGEB post-doctoral fellowship (J.D.P. and D.S.). UICC Yamagiwa-Yoshida Memorial International Cancer Study Grant (J.D.P.). 1R21 CA187843--01 (T.A.L. and L.F.Z.). The University of Cape Town, South African Medical Research Council, and South African Research Chairs Initiative of the Department of Science and Technology, administered through the South African National Research Foundation are gratefully acknowledged for support (K.C.).
Conflict of interest {#FPar1}
====================
The authors declare that they have no conflict of interest.
| 2023-10-31T01:26:57.367551 | https://example.com/article/8870 |
On the ab initio solution of the phase problem for macromolecules at very low resolution: the few atoms model method.
A method is proposed for the solution of the phase problem at very low resolution for macromolecules. It generates randomly a very large number of models, each consisting of a few (two to ten) pseudo-atoms. The corresponding amplitudes are used for selecting a subset of 'best' models by choosing those with the highest correlation with experimental values. The phases calculated from these 'best' models are analysed by a clusterization procedure leading to a few possible solutions, from which the correct one can be recognized by simple additional criteria. This method has been successfully applied to the neutron diffraction data of the AspRS-tRNA(Asp) complex at 50 A resolution and to data calculated from a model ribosome crystal at 60 A resolution. | 2023-08-17T01:26:57.367551 | https://example.com/article/5112 |
Master's Program Enhances Relevance of Physics to Zimbabwe
Ed. Note: This story was written for APS News by Jordan Raddick.
Xavier Carelse speaking in College Park and (inset) working with students in Zimbabwe. Jessica Clark/APS
"We are progressively making physics irrelevant by focusing on what physics is and what it isn't," claimed Xavier Carelse, professor of physics at the University of Zimbabwe, in a talk given at APS headquarters in February.
Carelse contrasted this general situation with the Master's of Applied Physics program that he founded at the university in 1994. His students work with industry to learn new machines and techniques, and most graduates go on to jobs with industries in Zimbabwe. "What we're trying to do is to make physics relevant to our country," Carelse said.
Carelse grew up in South Africa. He has worked in eight different countries, and has been at the University of Zimbabwe in Harare for twenty years. Last September, Carelse gave a presentation at an international conference on physics and economic development in Durban, South Africa. There, he met Roman Czujko, Director of the Statistical Research Center of the American Institute of Physics (AIP). When Czujko heard that Carelse was coming to Washington, he invited him speak at the American Center for Physics, the common home of APS and AIP, in College Park, MD. "His talk and the slides that he used put a face on physics in Zimbabwe," Czujko said.
In his talk, Carelse explained that his university is currently experiencing the same decline in physics enrollment that many western universities have experienced. He attributes the decline to an excessive focus by professors on defining 'pure' physics and steering students away from jobs in government or industry.
To solve this problem, Carelse founded his two-year master's of applied physics program. In the first year, students take classes and pick one of four areas of concentration. One course involves practice in a workshop that Carelse built for the students. Students make devices in the workshop; by the end of the course, all must be able to design and build a circuit. One student built a solar cooker - he now uses it to cook all his food, and he sells it in the countryside. "You can't train physicists to be useful in industry unless you train them to use their hands," Carelse said. One of his PhD students turned a broken electron microscope into a plasma focus machine, and he now uses it to conduct fusion experiments. Carlese said he knows when the machine is running because it makes a loud bang that can be heard throughout the building.
In the second year of the master's program, students are matched up with local companies for an internship, where they work as full-time industrial physicists. Since 1993, 30 students have graduated from the master's program. Many have gone on to other industrial jobs, both in Zimbabwe and abroad. Half of the graduates have taken teaching jobs. "To me, that is gratifying," Carelse said. "They will produce the next generation of physicists who are relevant to Zimbabwe." One recent graduate has gone to the nearby country of Malawi, where he is setting up a similar university master's program
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INTRODUCTION {#s1}
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Christianson syndrome (CS, OMIM 300243) is a rare, X-chromosome-linked neurodevelopmental and neurological disorder characterized in males by non-verbal status, intellectual disability, epilepsy, craniofacial dysmorphology with microcephaly, truncal ataxia and hyperkinesis. These core phenotypic features (present in \>85% of patients) can be accompanied by secondary symptoms, such as signs of autism and behavioral abnormalities mimicking Angelman syndrome, eye movement problems, hypotonia or gastroesophageal reflux disease (for further information see [@DMM022780C22]). Magnetic resonance imaging studies have suggested hippocampal and/or progressive cerebellar atrophy in male CS patients ([@DMM022780C13]; [@DMM022780C26]; [@DMM022780C19]). Furthermore, neuropathological reports on male CS brains have demonstrated widespread neurodegeneration, including loss of Purkinje cells (PCs), dystrophic neuritic changes, gliosis and tau deposition ([@DMM022780C4]; [@DMM022780C12]).
CS develops as a result of mutations in the solute-carrier 9A6 gene (*SLC9A6*, Xq26.3; [@DMM022780C13]). *SLC9A6* codes a multipass transmembrane protein (NHE6) that is believed to co-regulate the luminal pH of early/recycling endosomes by its sodium (potassium)-hydrogen antiporter activity ([@DMM022780C20]; [@DMM022780C16]). A significant fraction of the reported *SLC9A6* mutations are nonsense or shift the open reading frame of *SLC9A6* and result in introduction of premature stop codons (reviewed by [@DMM022780C22]).
As a result of X-chromosome inactivation (XCI), female heterozygotes presumably express *SLC9A6* mutations in their cells and tissues mosaically. Although several female heterozygotes have presented with clinical symptoms reminiscent of those identified in their CS-affected male relatives ([@DMM022780C4]; [@DMM022780C13]; [@DMM022780C26]; [@DMM022780C22]), conclusive information about the range of the probably mitigated and/or variable clinical phenotype in this particular group still remains to be considered systematically.
Previous studies by us and others have demonstrated the relevance of the knockout of the murine S*lc9a6* gene (*Slc9a6* KO) for studies exploring the human CS phenotype. Our analyses of mutant *Slc9a6* KO males (*Slc9a6^−/Y^* 'mutant' males) and homozygous mutant *Slc9a6* KO females (*Slc9a6^−/−^* 'mutant' females), both of which serve as models with uniform tissue distribution of the (transcriptionally) active mutant *Slc9a6* allele, indicated late endosomal/lysosomal dysfunction characterized by intraneuronal accumulation of GM2 ganglioside and unesterified cholesterol in the amygdala and the CA3/CA4 and fascia dentata regions of the hippocampus ([@DMM022780C30]). In addition, both mutant males and mutant females expressed progressive, patterned PC degeneration associated with axonal spheroid formation. Behavioral testing in mutant males revealed mild but significantly increased locomotor activity and motor coordination deficits, suggesting further overlap with the human CS clinical condition ([@DMM022780C22]). Importantly, a subsequent study using *in vitro* experimental approaches in neuronal cultures derived from the *Slc9a6* KO model proposed that abnormal endosomal acidification caused by the NHE6 deficit attenuates tropomyosin related kinase B (TrkB) signaling and results in underdeveloped cortical and hippocampal neuritic arborization ([@DMM022780C21]).
Although different in specific molecular details from the human situation, the random XCI and its propagation in the tissues of the developing embryo are replicated in mice ([@DMM022780C7]). In the murine female brain, XCI topography generates intra- and inter-individual diversity that ranges from individual cells to the entire organ. Crucially, however, it was shown that specific neuronal populations in female mice can tend, as a result of the complex neurodevelopment, to be inactivated non-randomly on a functionally relevant spatial scale ([@DMM022780C34]). Crucial for our studies, the murine KO model carries an insertion of the *lacZ-Neo* cassette into exon 6 of the *Slc9a6* gene (X.A5; [@DMM022780C30]). *lacZ*, which codes nuclear-targeted β-galactosidase (β-Gal) from *E.coli*, thus serves both as a mutagen that obliterates the *Slc9a6* open reading frame and as a transcriptional reporter that allows effective tracing of the cellular expression of the mutant *Slc9a6* allele. Important for utility of the β-Gal reporter, its expression patterns correspond to the endogenous expression of the protein as identified by mRNA expression studies ([@DMM022780C15]) and/or a specific anti-NHE6 antibody ([@DMM022780C6]; [@DMM022780C21]). As a further important prerequisite, the murine *Slc9a6* gene was not previously identified, similarly to humans ([@DMM022780C5]), among X-linked genes that escape XCI ([@DMM022780C35]). Therefore, crucial for the present study, β-Gal expression can also be considered to reflect the inactivation of the wild-type (WT) *Slc9a6* allele in tissues of heterozygous *Slc9a6* KO female (*Slc9a6^−/+^*) mice.
Given the relevance of the murine model for CS and with the purpose of providing insights into the potential disease phenotype in human female heterozygotes carrying *SLC9A6* mutations, we performed a study to evaluate the neuropathology and behavioral presentation in heterozygous *Slc9a6* KO female mice. Here, we focused on delineating the mosaic patterns of abnormal intraneuronal lysosomal GM2 ganglioside accumulation in amygdala and hippocampus, characterizing the extent of cerebellar PC degeneration and comparing the range of motor coordination and cognitive deficits with the abnormalities observed in mutant *Slc9a6* KO males.
RESULTS {#s2}
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Expression of the mutant *Slc9a6* allele is mosaic in the brains of heterozygous female mice {#s2a}
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Cellular and tissue expression of the mutant *Slc9a6* allele can be tracked by the *lacZ*-encoded β-Gal reporter. Using the histochemical X-GAL-based approach, we previously documented the brain-specific expression patterns of β-Gal in mutant males and mutant females ([@DMM022780C30]). Being aware of the limitations of the histochemical technique and aiming to assess β-Gal expression qualitatively and quantitatively in the brains of heterozygous females, we tested the utility of a specific antibody for detection of the reporter protein. To allow multi-immunofluorescence (IF) tissue-labeling experiments, we selected a specific anti-*E.coli* β-Gal antibody raised in chickens.
In order to assess the progression of disease at later ages than previously reported ([@DMM022780C30]) and to fully document the reference neuropathology resulting from uniform tissue distribution of the (transcriptionally) active mutant *Slc9a6* allele, we optimized IF staining conditions in the brains of X-chromosome hemizygous mutant males (aged 4, 20-22 and 32-34 weeks). We compared the results with negative findings in age-matched WT males (shown in the cerebellar PC layer in [Fig. S1C](Fig. S1C)) and WT females (data not shown). The anti-β-Gal antibody generated a nuclear staining pattern in the brains of mutant males, allowing us to confirm that the expression patterns of β-Gal by IF corresponded to those previously identified by X-GAL histochemistry ([@DMM022780C30]; [@DMM022780C21]).
In agreement also with studies by others ([@DMM022780C6]; [@DMM022780C15]; [@DMM022780C21]), the versatility of the multi-IF technique allowed us to demonstrate that β-Gal expression was not limited exclusively to nuclei of neurons, but could be identified also in GFAP^+^ astrocytes and APC^+^ oligodendroglial cells ([Fig. 1](#DMM022780F1){ref-type="fig"}A,C) in the cerebra of the mutant males. As a result of the small nuclear size and relatively high levels of the endogenous cytoplasmic autofluorescence, we were not able to identify β-Gal expression unambiguously in CD68^+^ microglia/macrophages (data not shown). Crucial for progression of the neuropathological changes in mutant males, we also specifically assessed β-Gal in the cerebella and confirmed a strong expression in nuclei contained within the PC layer. Despite slight variability, β-Gal expression was uniform in PCs. Expression was also strong in the GFAP^+^ astrocytes (Bergmann glia) adjacent to PCs ([Fig. S1A](Fig. S1A)). Fig. 1.**Expression of the mutant (β-Gal^+^) *Slc9a6* allele is mosaic in heterozygous females.** Nuclear expression patterns of the β-Gal reporter in the brain of an X-chromosome hemizygous mutant male (A) are mosaically replicated in a heterozygous female (B). Unlike mutant males (C), heterozygous females express β-Gal mosaically in neurons (NeuN^+^), astrocytes (GFAP^+^) and oligondrendroglial cells (APC^+^) (D). Arrowheads depict β-Gal^−^ astrocytes and oligodendroglial cells. Cerebellar β-Gal expression in mutant males and heterozygous females is shown in Fig. 4 and [Fig. S1](Fig. S1)*.* fimbria hipp., hippocampal fimbria; rad. CA1, radiatum layer of the (CA1) hippocampus. The *z*-thickness of MIP projections is 15 µm in C,D. Scale bars: 1 mm in A,B; 50 µm in C,D.
At the level of individual cells and regardless of the particular cell type, nuclear β-Gal expression was either comparable to the levels observed in mutant males or was altogether absent in *Slc9a6* heterozygous females ([Fig. 1](#DMM022780F1){ref-type="fig"}B,D; [Fig. S1B](Fig. S1B)). Although the overall mosaic patterning was variable between individual heterozygous female brains, it did not have a tendency to focal clustering of cells with either of the two disparate β-Gal expression profiles. Importantly, the mosaic β-Gal expression was detected in neuroanatomical locations previously identified as crucial (brain cortex, hippocampus, amygdala and cerebellar PC layer) for initiation and progression of the abnormal phenotype in mutant males.
Intracellular accumulation of GM2 ganglioside is mosaic in heterozygous females and develops in cells expressing the mutant *Slc9a6* allele {#s2b}
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The vacuolar intracellular GM2 ganglioside accumulation previously identified in specific neuronal populations in cerebra of mutant males and mutant females was believed to reflect late endosomal/lysosomal dysfunction. This particular subcellular pathology develops in CA3/CA4 regions of hippocampus and amygdala of these animals as early as at 3 weeks of age ([@DMM022780C30]). Utilizing the IF-based β-Gal detection, we evaluated the presence of the abnormal GM2 accumulation and correlated it with the mosaic expression of β-Gal in the brains of heterozygous females. Moreover, we assessed the timing and progression of GM2 accumulation by analyzing animals aged 4 weeks and significantly older (32-34 weeks) mutant males and heterozygous females.
Serving as a reference phenotype, mutant males showed GM2 accumulation in neurons of hippocampal CA3/CA4 regions and amygdala at 4 weeks of age ([Fig. 2](#DMM022780F2){ref-type="fig"}A). In neurons of the CA3/CA4 region of hippocampus, the nuclear β-Gal expression and GM2 ([Fig. 2](#DMM022780F2){ref-type="fig"}E) accumulation were uniform, with both signals co-occurring in individual cells. On the contrary, the number of β-Gal^+^ cells/neurons in amygdala was larger than the number of cells accumulating GM2. Nevertheless, nuclei of the GM2-accumulating neurons ([Fig. 2](#DMM022780F2){ref-type="fig"}C) consistently stained with anti-β-Gal antibody. To explore this numerical difference, we searched the amygdala of mutant males using electron microscopy to identify the abnormal glycolipid-containing concentric lamellar bodies. In agreement with the multi-IF staining, we found that a number of neurons lacked the specific lysosomal storage structures ([Fig. 2](#DMM022780F2){ref-type="fig"}C). Altogether, these observations suggest that in mutant males only a subpopulation of neurons ([Fig. S2](Fig. S2)) in amygdala abnormally accumulates GM2 (and probably also other glycolipids) despite expressing the mutant *Slc9a6* allele from their single X-chromosome.
We further assessed the age-related persistence of GM2 accumulation by co-staining cerebra of significantly older mutant males (32-34 weeks). In these, we found that the patterns of β-Gal expression and the abnormal GM2 accumulation ([Fig. 2](#DMM022780F2){ref-type="fig"}G) corresponded to those identified in 4-week-old brains.
In heterozygous females ([Fig. 2](#DMM022780F2){ref-type="fig"}B,D,F,H), the neuronal GM2 pathology and its timing corresponded to the findings in mutant males. Crucially, the occurrence of GM2 accumulation was, in individual neurons, linked to mosaic nuclear expression of the β-Gal reporter. The correlation of the mosaic β-Gal expression and GM2 accumulation could easily be discerned in the hippocampal CA3/CA4 region ([Fig. 2](#DMM022780F2){ref-type="fig"}F,H). In amygdala, β-Gal expression was also mosaic (Fig. 1B; [Fig. 2](#DMM022780F2){ref-type="fig"}D). Identical to mutant males ([Fig. 2](#DMM022780F2){ref-type="fig"}C), nuclei of neurons accumulating GM2 in amygdala were also β-Gal^+^ in heterozygous females; nonetheless, some of the β-Gal^+^ cells did not accumulate GM2 ([Fig. 2](#DMM022780F2){ref-type="fig"}D).
As controls, age- and sex-matched WT littermate brains were negative for β-Gal expression and did not show intraneuronal GM2 accumulation. As an additional check for possible neurodegeneration in the regions affected by the glycolipid accumulation in mutant males and heterozygous females, we IF co-stained cerebra of animals of both these genotypes with antibodies targeting neurons (anti-NeuN) and microglia/macrophages (anti-CD68). In contrast to the cerebellum (see the section below) and when compared with WT controls, none of these stains directly or indirectly suggested widespread neurodegeneration at 4 and/or 32-34 weeks of age (data not shown).
Purkinje cells in *Slc9a6* KO heterozygous females exhibit degeneration that is ameliorated compared with mutant males {#s2c}
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Degeneration of PCs that is associated with spheroid formation on their axons is another feature consistently discernible in mutant males. The spatial patterning of this process follows cerebellar zonal organization with Zebrin II-positive PCs being the most resistant to decay ([@DMM022780C30]). Transformed to (para)sagittal projection ([@DMM022780C28]), PCs in the anterior (lobules I-V) and posterior (lobule VIII) cerebellar zones tend to degenerate earlier than those localized to the central (lobule VI/VII) and nodular (lobules IX/X) zones. The molecular and developmental basis of this pattern remains to be understood fully; nonetheless, as observed in mutant males, it is replicated in other murine disease models that develop PC degeneration (e.g. Niemann--Pick disease type A/B or C; [@DMM022780C25]; [@DMM022780C17]).
We evaluated cerebellar pathology both in 4- and 32- to 34-week-old animals. Neurono/dendritophagic clustering of CD68^+^ macrophages/microglia in the PC and molecular layers of cerebellar lobules I-II, III and VIII ([Fig. 3](#DMM022780F3){ref-type="fig"}A,C) suggested ongoing PC loss (visualized by calbindin IF staining) in these areas already in 4-week-old mutant males. Identical but less profound changes than those identified in mutant males were also detected in 4-week-old heterozygous females ([Fig. 3](#DMM022780F3){ref-type="fig"}B,D).
At 32 weeks, cerebella of mutant males showed extensive PC loss in anterior and posterior zones ([Fig. 3](#DMM022780F3){ref-type="fig"}E). This pathology was also associated with atrophy and gliosis of the cerebellar molecular layer in these zones (shown for lobule I-II in [Fig. S1A](Fig. S1A)). CD68^+^ cells were frequent in these cerebellar cortical areas; nonetheless, they did not form PC neuronophagic clusters comparable to 4-week-old animals (data not shown). To document the major quantitative difference in a cohort of 32-week-old mutant males, we sampled the density of PCs in lobule I-II and lobule X selected as representative of zones affected and spared from PC degeneration, respectively. The density of PCs in lobule I-II was significantly lower in mutant compared with WT males (*F*~(1,7)~=227.4, *P*\<0.0001; [Fig. 3](#DMM022780F3){ref-type="fig"}G).
Crucial for 32-week-old heterozygous females, the extent of PC degeneration was not histologically as discernible ([Fig. 3](#DMM022780F3){ref-type="fig"}F) as in mutant males. The secondary gliosis in the molecular layer of lobules affected by PC degeneration was also less profound in heterozygous females ([Fig. S1B](Fig. S1B)) than in mutant males. Despite these mitigated histological findings, the density of PCs in lobule I-II in heterozygous compared with WT females was significantly lower (*F*~(1,21)~=24.9, *P*\<0.0001; [Fig. 3](#DMM022780F3){ref-type="fig"}H).
Although β-Gal expression could be considered uniform in mutant males ([Fig. 4](#DMM022780F4){ref-type="fig"}A; [Fig. S1A](Fig. S1A)), in heterozygous females at 32 weeks of age the β-Gal expression was mosaic in the PC layer and was also confined both to PCs and to nuclei of GFAP^+^ astrocytes (Bergmann glia; [Fig. S1B](Fig. S1B)). Unlike mutant males, however, PC densities and the numbers of β-Gal^+^ PCs varied between individual heterozygous female cerebella (compared in two selected animals in [Fig. 4](#DMM022780F4){ref-type="fig"}B,C). To reiterate, and contrary to lobule X, the overall density of PCs was significantly lower in lobule I-II of heterozygous females when compared with their WT littermates ([Fig. 3](#DMM022780F3){ref-type="fig"}H). To quantify the likely selection against β-Gal^+^ PCs, we compared the fractional (percentage) content of β-Gal^+^ PCs in lobules I-II (mean value was 12.8±1.4%) and X (mean value was 32.4±2.8%) among heterozygous females and found that this fraction was significantly lower in lobule I-II (*F*~(1,29)~=44.6, *P*\<0.0001; [Fig. 4](#DMM022780F4){ref-type="fig"}D).
As a last, but important detail, spheroid formation affected axons of (β-Gal^+^) PCs both in mutant males ([Fig. 4](#DMM022780F4){ref-type="fig"}A) and in heterozygous females ([Fig. 4](#DMM022780F4){ref-type="fig"}C).
*Slc9a6* KO heterozygous females have cognitive deficits and sensorimotor dysfunction {#s2d}
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In behavioral tests, we found that heterozygous females generally demonstrated similar motor incoordination and cognitive deficits as did male mutants, albeit some of the phenotypes were less profound in the female mice. Mutant males (32-34 weeks old) had significantly higher locomotor activity in the open field (total track length, *F*~(1,59)~=5.7, *P*\<0.05; [Fig. 5](#DMM022780F5){ref-type="fig"}A) and exploration (number of rears, *F*~(1,59)~=12.5, *P*\<0.05; [Fig. 5](#DMM022780F5){ref-type="fig"}B) than WT males. Similar to the previous study in younger (20- to 24-week-old) animals ([@DMM022780C30]), we identified no differences in the anxiety-like behavior (ratio of track length in center zone to total track length; [Fig. 5](#DMM022780F5){ref-type="fig"}C). Unlike the males, heterozygous and WT females at the age of 32-34 weeks did not differ in track length, rears or anxiety-like behavior ([Fig. 5](#DMM022780F5){ref-type="fig"}D-F).
Consistent with the substantial cerebellar pathology, mutant males also had significant motor coordination deficits assessed as an increased number of slips in the balance beam assay (*F*~(genotype 1,84)~=32.9, *P*\<0.0001 and *F*~(age 1,86)~=11.9, *P*\<0.001; [Fig. 5](#DMM022780F5){ref-type="fig"}G). Similar to the previous study ([@DMM022780C30]), gross ataxia and motor incoordination were not detectable at 20-22 weeks in mutant males but could be identified readily in animals aged 32-34 weeks. Given the mitigated cerebellar neuropathology, female heterozygotes also had significant motor coordination deficits in the balance beam compared with age-matched WT controls (*F*~(genotype 1,105)~=5.3, *P*\<0.05 and *F*~(age 1,105)~=8.4, *P*\<0.01; [Fig. 5](#DMM022780F5){ref-type="fig"}G). Importantly, none of the evaluated heterozygous females presented with obvious ataxia even at 32-34 weeks of age.
Given the hippocampal neuropathology of both mutant males ([@DMM022780C30]; [@DMM022780C21]) and heterozygous females (shown in the present study), we evaluated visuospatial memory in the hippocampus-dependent object placement test ([@DMM022780C10]; [@DMM022780C8]) and found deficits in both mutant males and heterozygous females at 20-22 weeks of age ([Fig. 5](#DMM022780F5){ref-type="fig"}H). Mutant males (*T*~(d.f.=23)~=1.15, *P*\<0.26) and heterozygous females (*T*~(d.f.=24)~=0.33, *P*\<0.75) failed to display a preference for a relocated object (new position not significantly greater than old position). In contrast, their age-matched WT littermates (WT males, *T*~(d.f.=14)~=5.3, *P*\<0.0001; WT females, *T*~(d.f.=16)~=2.3, *P*\<0.05) displayed the normal preference for a relocated object (new position significantly greater than old position). The preference for the relocated object (new position) in the testing phase was not confounded in animals of either sex by any non-specific alteration in the reactivity to novelty as assessed by the total exploration time in the training phase when no memory is involved (data provided in [Fig. S3](Fig. S3)).
DISCUSSION {#s3}
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Our study demonstrates that expression of the mutant *Slc9a6* allele in heterozygous female mice mosaically follows the neuroanatomical distribution and cell-type-specific patterns identified in the brains of X-chromosome hemizygous mutant males. As a consequence, heterozygous females develop behavioral and neuropathological abnormalities that are, albeit milder, comparable to defects identified in mutant males. As a follow-up to our previous studies, by analyzing animals up to 8 months old we document that specifically the sensorimotor dysfunction and the cerebellar PC degenerative pathology are progressive with age both in mutant males and in heterozygous females.
Overall, we propose that *Slc9a6* KO heterozygous female mice represent a relevant and crucial model for future studies aimed at understanding the pathogenesis of human CS. As the second pathology-expressing genotype relevant to human X-linked CS, heterozygous female mice should complement the experimental use of mutant males. As a result of the mosaic expression of the mutant *Slc9a6* allele, we expect heterozygous females to become particularly useful for testing the cell-autonomous nature of specific (neuro)pathologies and/or exploring the roles of intercellular interactions (neuronal circuitry dysfunction included) in the onset and progression of the abnormal phenotype. Similarly important will be studies aimed at exploring the embryonic and developmental impacts of XCI on overall and site-specific brain (dys)function in heterozygous female mice.
The bacterial β-galactosidase that reports the expression of the mutant *Slc9a6* allele can be identified in murine tissues by a specific antibody. With IF, we confirmed cerebral and cerebellar β-Gal expression in large populations of neurons and astrocytes ([@DMM022780C30]; [@DMM022780C6]; [@DMM022780C15]; [@DMM022780C21]) in mutant males and identified the mosaic presence of β-Gal in these cell types and locations in heterozygous females. Knowing the expression patterns in mutant males, presuming that the murine *Slc9a6* gene does not escape XCI ([@DMM022780C35]) and comparing our results with the recently published XCI topography maps of the female murine brain ([@DMM022780C34]), we explain the mosaic β-Gal expression patterns in the brains of heterozygous female mice by XCI. Previously unreported, we found β-Gal in APC^+^ oligodendrocytes of both mutant males and heterozygous females. In fact, this suggests that another glial cell type is theoretically compromised by the *Slc9a6* deficit both in the mouse model and in CS patients.
Although the neuropathological findings in human hippocampi are relatively mild ([@DMM022780C12]) and hippocampal atrophy was identified by neuroimaging studies only in some male individuals ([@DMM022780C26]), dysfunction of hippocampus and amygdala can be presumed based on the clinical CS phenotype ([@DMM022780C30]). Lysosomal accumulation of GM2 in neurons of hippocampal CA3/CA4 regions and basolateral amygdala is one of the early occurring abnormalities in *Slc9a6* mutant male mice. In the present study, we found that only a subpopulation of neurons in amygdala accumulates GM2. Molecular, structural and, most importantly, functional/connectivity characteristics ([@DMM022780C3]; [@DMM022780C14]) of these neurons, the determinants of their sphingolipid pathology and its contribution to the overall phenotype remain to be established. Crucially, however, in heterozygous female mice, the timing, neuroanatomical distribution and ultrastructural appearance of GM2 pathology are replicated. As an anticipated effect, GM2 accumulation in neurons of both hippocampus and amygdala were correlated with the mosaically expressed mutant *Slc9a6* allele in heterozygous females.
The early-onset degeneration of PCs and ataxia present in older mutant male mice correspond to the clinical, neuroimaging and cerebellar pathology in male CS patients ([@DMM022780C4]; [@DMM022780C13]; [@DMM022780C12]; [@DMM022780C26]; [@DMM022780C19]). More specifically, PC loss and consequent atrophic changes in the cerebellar cortex of mutant males follow a previously described and conserved cerebellar developmental/gene-expression pattern ([@DMM022780C30]). In heterozygous female mice, the mosaic β-Gal expression profiles in the cerebellar cortex correspond at the cellular level to the uniform expression found in mutant males. PC degeneration in heterozygous females is initiated at the same age as in mutant males, and a selection against (β-Gal^+^) PCs is likely in heterozygous females in cerebellar cortical zones that are affected by degeneration in mutant males. Importantly, the mean values (and distribution of individual values among heterozygous females) of the percentage fraction of β-Gal^+^ PCs in the cerebellar zone(s) not affected by degeneration even in older (32- to 34-week-old) mice suggest random XCI in this particular neuronal population. This result shows that direct detection of the β-Gal reporter in the brains of heterozygous females allows *Slc9a6* allelic expression quantification even in numerically limited or anatomically restricted specific cellular types/populations. Besides neurons, we also found that GFAP^+^ cells (Bergmann glia) in the cerebellar cortex express β-Gal. Aware of the intimate developmental, structural and functional association between PCs and Bergmann glia ([@DMM022780C2]; [@DMM022780C33]) that encompasses regulation of synaptic transmission and/or plasticity and buffering of extracellular K^+^ and neurotrophin levels by astrocytes ([@DMM022780C16]), we hypothesize that the PC degeneration in mutant male or heterozygous female mice might not be an exclusively cell-autonomous event. If valid, the variable extent of XCI in PCs and cerebellar cortical astrocytes would probably, in conjunction with the microdomain and overall zonal organization of cerebellar cortex, represent a crucial determinant of the cerebellar degenerative pathology in heterozygous females.
Crucial for human CS, dominance and recessivity allelic relations valid for autosomal genes do not apply to X-chromosome-linked traits ([@DMM022780C9]). Whereas X-linked phenotypes are penetrant in X-chromosome hemizygous male CS patients, the clinical presentation in heterozygous female patients/carriers is mitigated and often variable. One of the principal underlying mechanisms for such variability in females is XCI in their tissues ([@DMM022780C36]; [@DMM022780C7]). Unlike in males, data on the frequency of the mutations in X-linked genes associated with intellectual disability (ID) among females is largely unavailable as a likely result of the diversity of their clinical phenotype(s). Interestingly, it was shown that female heterozygotes in families with X-linked ID have significantly skewed XCI ratios in peripheral white blood cells ([@DMM022780C23]). However, the relation of the skewed XCI status in leukocytes to the range and severity of the neurodevelopmental, neurological and psychiatric disease(s) still remains to be understood fully ([@DMM022780C32]). Consistent with cellular abnormalities, *Slc9a6* heterozygous female mice showed the same cognitive and sensorimotor abnormalities, albeit mitigated, that were compromised in mutant males. It remains for future studies, however, to attempt to establish neuroanatomical XCI thresholds for the behavioral pathologies and determine the sources of inter-individual variability in heterozygous female mice.
[@DMM022780C22] defined the core and secondary clinical features of CS by evaluating the largest cohort of affected families and male patients. Although reported inconsistently, a variable and mitigated phenotype seems likely also in female heterozygotes for *SLC9A6* mutations. Here, some females have presented with neurodevelopmental delays, problems with speech, learning and/or behavioral difficulties, aggressiveness in childhood and adolescence, hyperkinesis or truncal ataxia ([@DMM022780C4]; [@DMM022780C13]; [@DMM022780C26]; [@DMM022780C22]). Intriguingly for interpretation of these observations, [@DMM022780C13] partly excluded XCI as a contributor to the clinical CS presentation because several female heterozygotes in their pedigrees presented with normal XCI ratios in lymphocytes.
Several recent genomic projects ([@DMM022780C31]; [@DMM022780C27]; [@DMM022780C32]) demonstrated that CS is one of the most frequent X-linked neurodevelopmental ID disorders. However, the patient cohorts in these studies either consisted exclusively of male ID patients and their female relatives or included females with penetrant ID phenotypes. As a possible result of disqualifying individuals with mitigated or variable abnormalities (applicable specifically to female heterozygotes), the CS population frequency that was estimated based on some of these data sets as 1 in 16,000-100,000 ([@DMM022780C22]) could, in fact, be higher. Also relevant to the occurrence of CS, a substantial fraction of male CS probands develop the *SLC9A6* mutations *de novo* ([@DMM022780C26]; [@DMM022780C22]). This lack of maternal inheritance in CS pedigrees has not yet been specifically explored for post-zygotic mutagenic events or low-level maternal somatic/germinal mosaicism, both of which result in variable non-homogeneous tissue distribution of *SLC9A6* mutations. As these phenomena are relatively frequent in the general population ([@DMM022780C1]), they could theoretically represent an additional and disparate source of phenotypic variability contributing to the likely under-diagnosis of CS.
Here, we have provided evidence for a behavioral and neuropathological phenotype in *Slc9a6* KO heterozygous female mice. Such findings, we believe, indicate a crucial need to gain detailed insight into the range of potential phenotypes in heterozygous female CS patients/carriers. Although we acknowledge that the homogenous genetic background of murine *Slc9a6* KO model might not necessarily reflect the complex and heterogeneous human genomics and X-linked epigenetics, we hypothesize that the expected XCI-driven expression ([@DMM022780C5]) of *SLC9A6* mutations in the brains of human female heterozygotes contributes to the diversity of their resultant clinical presentation. Defining the full phenotypic spectrum in this potentially underappreciated patient group is, to us, a key prerequisite to delineate the population frequency of CS, avoid diagnostic neglect and allow efficient genetic counseling and screening in affected families. Moreover, an evidence-based recognition of female CS heterozygotes as at risk or affected by a variable or mitigated disease could be an additional strong argument advocating further experimental and clinical research, including the development of therapy for this disorder.
MATERIALS AND METHODS {#s4}
=====================
Mice and tissue collection {#s4a}
--------------------------
All procedures used in experiments involving animals were approved by the Institutional Animal Care and Use Committee of the Albert Einstein College of Medicine. The study used B6.129P2-Slc9a6^tm1Dgen/J^ (*Slc9a6* KO) mice originally acquired from the Jackson Laboratory (Bar Harbor, ME, USA). Genotyping of litters was performed as previously reported ([@DMM022780C30]). In this study, we used *Slc9a6* wild-type male (*Slc9a6^+/Y^* or 'WT' males) and female (*Slc9a6^+/+^* or 'WT' females) mice, X-chromosome hemizygous (mutant) *Slc9a6* KO male mice (*Slc9a6^−/Y^* or 'mutant' males) and X-chromosome heterozygous *Slc9a6* KO females (*Slc9a6^−/+^* or 'heterozygous' females). Homozygous (mutant) *Slc9a6* KO females (*Slc9a6^−/−^* or 'mutant' females) were not tested. If not stated otherwise, results were compared between genotypes and separately for sexes of the animals (mutant males×WT males and heterozygous females×WT females). For tissue collection, mice were deeply anesthetized with ketamine and xylazine and perfused transcardially with saline and subsequently with 4% paraformaldehyde (PFA). Dissected organs were further immersion fixed overnight in 4% PFA and then transferred to ice-cold phosphate buffer and stored at 4°C. This study did not use any data or material generated in our previous study ([@DMM022780C30]). Behavioral and tissue studies were performed in parallel and in identical conditions in all sex and genotype groups.
Antibodies and immunofluorescence {#s4b}
---------------------------------
For immunofluorescence (IF) labeling, brains were divided along the midline and then split into cerebral and cerebellar-brainstem parts at the mesencephalic level. The separated fragments were embedded into 8.0% sucrose and 3.5% agarose, and serial sections 35 µm thick (coronal in cerebrum and sagittal in cerebellum) were cut using a Leica VT-1000S Vibratome (Leica Microsystems, Wetzlar, Germany). Sections representing rostral-caudal bregma (−1.94 to −2.30) and lateral (0.40-0.84) ranges ([@DMM022780C11]) were selected from cerebra and cerebella, respectively. Matched sections were stained by multi-IF protocols as described before ([@DMM022780C18]). The following primary antibodies were used for staining of specific epitopes: chicken anti-*E.coli* β-galactosidase (β-Gal) Ab (ab9361, 1:2000; Abcam, Cambridge, MA, USA), mouse anti-calbindin (Purkinje cells) mAb D-28K (C9848, 1:2000; Sigma-Aldrich, St Louis, MO, USA), rabbit anti-calbindin pAb (AB1778, 1:800; Chemicon, Temecula, CA, USA), rat anti-CD68 mAb (MCA1957, 1:1000; AbD Serotec, Kidlington, UK), mouse anti-glial fibrillary acidic protein (GFAP) mAb G-A-5 (G3893, 1:3000; Sigma-Aldrich), mouse anti-neurofilament (anti-NF) medium chain mAb (NB300-134, 1:500; Novus Biologicals, Littleton, CO, USA), mouse anti-APC (oligodendroglial cells; OP80, 1:100; Calbiochem, San Diego, CA, USA), mouse anti-NeuN (neuronal nuclei) IgG mAb (MAB377, 1:1000; Chemicon) and mouse anti-GM2 ganglioside IgM mAb (mab 10-11, 1:15; cell culture supernatant was produced in-house from the 10-11 hybridoma line by Progenics Pharmaceuticals, Tarrytown, NY, USA). Species-specific secondary antibodies conjugated to Alexa Fluor (AF) 488, 546 and 633 dyes (Invitrogen, Carlsbad, CA, USA) were used for detection of primary antibodies. A minimum of three animals were evaluated for all sex and genotype groups aged 4 and 32-34 weeks. The number of cerebella analyzed in the quantitative studies in 32-week-old animals is listed in the legends to [Figs 3](#DMM022780F3){ref-type="fig"},[4](#DMM022780F4){ref-type="fig"} and [Fig. S1](Fig. S1).
Light microscopy {#s4c}
----------------
Overview images ([Fig. 1A,B](#DMM022780F1){ref-type="fig"}; [Fig. 2A,B](#DMM022780F2){ref-type="fig"}; [Fig. 3A,B,E,F](#DMM022780F3){ref-type="fig"}) of the cerebral and cerebellar IF-labeled sections were acquired using an IX70 microscope (Olympus, Tokyo, Japan) equipped with an HQ2 camera (Photometrics, Britannia, AZ, USA) and a Proscan II-encoded *xyz* stage (Prior Scientific, Rockland, MA, USA) equipped with 10 position excitation-emission *Smart*Shutters filter wheels (Sutter, Novato, CA, USA). The exposure time for all antibody combinations was 750 ms (gain 2×) per channel. Excitation/emission conditions for the AF488 and AF546 dyes were excitation (exc.) 490/20/beamsplitter (b.s.) 480-513/emission (em.) 535/40 and exc.572/23/b.s.555-588/em.630/60 nm, respectively. Individual but partly overlapping double-channeled 14-bit images (downsampled to 8-bit) were acquired with a Plan 10× (NA 0.25) objective and digitally stitched in Metamorph/MetaFluor (Molecular Devices, Sunnyvale, CA, USA) and subsequently in Photoshop CS6 (Adobe, San Jose, CA, USA) software. Selected areas of the IF-labeled sections ([Figs 1](#DMM022780F1){ref-type="fig"}-[4](#DMM022780F4){ref-type="fig"}; [Fig. S1](Fig. S1)) were imaged by laser scanning confocal microscope (Zeiss Meta Duo V2, Oberkochen, Germany) using a Plan Apochromat 20× (NA 0.8) objective. Conditions of image acquisition (pinhole size, excitation laser intensity, scanning speed, dichroic mirrors, excitation and emission (band)pass filters and photomultiplier gains) were kept constant for individual combinations of primary and secondary antibodies. Excitation and emission filtering was set to minimize crosstalk, and individual dyes were excited and their emission was collected sequentially. The final *z*-stacks (thickness is reported in the legends of the individual figures) were transformed into single-plane maximal intensity projection (MIP) images using the Zeiss LSM Image Browser (Zeiss). Images of amygdala and CA3 brain regions ([Fig. 2](#DMM022780F2){ref-type="fig"}C-H) represent scans with an open confocal pinhole, allowing collection of the fluorescence information from the entire thickness of the section (35 µm). Fig. 2.**The abnormal intraneuronal accumulation of GM2 ganglioside in amygdala and CA3 region of hippocampus is found in the neurons expressing the mutant (β-Gal^+^) *Slc9a6* allele in heterozygous females.** At 4 weeks of age, GM2 accumulation is conspicuously present in the neurons of CA3 region of hippocampus (white arrowheads) and amygdala (blue arrowheads) of mutant males (A) and in heterozygous females (B). In mutant males, only a fraction of β-Gal^+^ neurons in amygdala accumulates GM2. The intracellular glycolipid accumulation adopts the form of concentric lamellar bodies by electron microscopy (C; [Fig. S2](Fig. S2)). In heterozygous females, β-Gal^+^ and β-Gal^+^/GM2^+^ neurons are less frequent than in mutant males. The lysosomal ultrastructural abnormalities found in heterozygous females (D) are equivalent to findings in mutant males. Whereas CA3 neurons in mutant males express β-Gal and accumulate GM2 uniformly (E,G), GM2 accumulation in CA3 neurons of heterozygous females is mosaic and reflects the expression of the mutant (β-Gal^+^) *Slc9a6* allele (F,H). amyg., amygdala; CA3, CA3 region of hippocampus. Scale bars: 1 mm in A,B; 200 µm (IF images) and 5 µm (electron micrographs) in C,D; 100 µm in E-H. Panels A,B showing GM2 accumulation originate from sections co-labeled for β-Gal shown in [Fig. 1](#DMM022780F1){ref-type="fig"}A,B. Fig. 3.**Cerebellar pathology in heterozygous** **females.** Degeneration of Purkinje cells (visualized by calbindin IF staining) in anterior and posterior zones is initiated in mutant males (A) and heterozygous females (B) as early as at 4 weeks of age and is highlighted by the abnormal population of CD68^+^ microglia in both genotypes (arrowheads). (C,D) Neuronophagy of PC cell bodies (arrowheads) and dendrites in the molecular cerebellar layer can be readily identified at this age by confocal microscopy in both sex/genotype groups by clusters of CD68^+^ microglia/macrophages. (E) At 32 weeks of age, mutant males present with advanced and widespread loss of Purkinje cells in anterior (lobule I-V) and posterior (lobule VIII) cerebellar zones (arrowheads). (F) In heterozygous females, PC degenerative patterns are not as evident as in mutant males and vary among individual animals. (G,H) PC density quantification in lobules I-II (representative of the anterior zone) and X (representative of the nodular zone) showed significant PC loss in lobule I-II of 32-week-old mutant males and heterozygous females (*n*=4 WT and 5 mutant males and 6 WT and 17 heterozygous females) in contrast to lobule X (*n*=4 WT and 4 mutant males and 6 WT and 14 heterozygous females). \**P*\<0.0001. The *z*-thickness of MIP projections in C,D is 15 µm, and these images correspond to areas outlined by white rectangles in A,B. Scale bars: 1 mm in A,B,E,F; 50 µm in C,D. Panel A reviews the numbering of individual cerebellar lobules. Fig. 4.**Percentage fractions of (β-Gal^+^) PCs in 32-week-old heterozygous females differ between cerebellar lobules affected and spared from degeneration of Purkinje cells.** (A) Similar to lobule X, PCs that remain in lobule I-II uniformly express β-Gal (white arrowheads) in mutant males. Small β-Gal^+^ non-PC nuclei largely correspond to the population of (Bergmann glia) astrocytes ([Fig. S1A](Fig. S1A)). Axons of these remaining PCs in lobule I-II develop spheroids (blue arrowhead in the inset). (B,C) β-Gal expression in PCs is mosaic (white arrowheads) in heterozygous females and varies among individual animals. The fraction of β-Gal^+^ PCs is lower in lobule I-II compared with lobule X. β-Gal expression is also mosaic in other cell types within the PC layer (Bergmann glia astrocytes; [Fig. S1B](Fig. S1B)). (C) β-Gal^+^ PCs in heterozygous females also develop spheroids on their axons (blue arrowhead in the inset). (D) The percentage fraction of β-Gal^+^ PCs in lobule I-II (*n*=17) is significantly lower than in lobule X (*n*=14) of heterozygous females. \**P*\<0.0001. Images shown for lobule I-II and X in A,B were collected from cerebella of a single mutant male and heterozygous female, respectively. Lobule I-II PC densities and percentages of β-Gal^+^ PCs in A-C represent values for the particular animals shown. The *z*-thickness of MIP projections in A-C is 18-22 µm. Scale bars: 50 µm.
Electron microscopy {#s4d}
-------------------
For electron microscopy, cerebra of 4- to 5-week-old WT and mutant males and heterozygous females were coronally sectioned (250 µm) using a Vibratome. Sections containing hippocampal CA3 and amygdala regions were selected, and these regions were manually dissected. The tissue blocks were first transferred to 0.1 M cacodylate buffer and post-fixed in 2% glutaraldehyde. Samples were further washed and post-fixed in osmium (1% osmium in 0.1% cacodylate buffer), dehydrated and embedded in Epon-araldite. Ultrathin sections were stained with uranyl acetate and lead citrate and examined with a Philips CM10 electron microscope (Philips Electron Optics, Eindhoven, The Netherlands).
Purkinje cell density counts {#s4e}
----------------------------
Serial cerebellar sagittal sections (35 µm thick) were visually searched for the first occurrence of the deep cerebellar nuclei (∼0.48 mm lateral; Fig. 105 of [@DMM022780C11]). Such a section was considered as section +1. This and three consecutive sections in lateral sequence (+3, +5 and +7) were stained with a combination of anti-calbindin (PC marker) and anti-β-Gal antibodies and secondary antibodies conjugated to AF488 and AF546, respectively (protocol modified for IF from [@DMM022780C24]). The total number of Purkinje cells (PC\#), the number of PCs with β-Gal-positive nuclei (β-Gal^+^ PCs) and the overall lengths of PC layers (in millimetres) were manually counted/traced in at least three out of the four selected sections in lobules I-II and X. The number of 32-week-old animals analyzed is provided in legends to [Figs 3](#DMM022780F3){ref-type="fig"},[4](#DMM022780F4){ref-type="fig"} and [Fig. S1](Fig. S1). Stereo Investigator software (MBF Bioscience, Williston, VT, USA) installed in an Olympus Bx51 microscope was used for outlining the PC layers and counting PCs. PC\# and β-Gal^+^ PC\# were assessed using a PlanFL 20× (NA 0.5) objective. Although nuclei were co-detected by DAPI in all the double-IF-stained sections, the parallel triple fluorescent quantification proved technically difficult because of unbalanced intensities and fluorescence bleaching of the three dyes. The total number of PCs with structurally identifiable nuclei in lobules I-II and X was first assessed using the fluorescence filter set discerning AF488 (exc.480/40/b.s.510LP/em.505LP). β-Gal^+^ PCs were subsequently quantified by changing the excitation and emission to a triple excitation/emission (DAPI/FITC/TRITC) filter cube (Chroma set \#61000v2, Bellows Falls, VT, USA). The overall PC density (PC\#/1 mm of the length of the PC layer) and percentage fractions of β-Gal^+^ PCs in individual animals were calculated in lobules I-II and X from values in the 35-µm-thick sections.
Behavioral studies {#s4f}
------------------
The strategy for behavioral testing was designed according to our previous analyses performed in mutant and WT males aged ∼20-24 weeks ([@DMM022780C30]). Expecting a mitigated, delayed and also variable phenotype in heterozygous females compared with the reference abnormality in X-chromosome hemizygous mutant males, we decided to increase substantially the number of tested animals in all compared sex and genotype groups and to perform some of the behavioral tests at an older age (weeks 32-34). Animals were tested for their voluntary locomotor and exploratory activities and anxiety-like (exploration of the center zone) behavior in an open field. Motor coordination was assessed by the balance beam test. Spatial memory of the animals was tested in the object placement test. The timeline of the tests and ages of animals when tested were as follows: balance beam at 20-22 weeks, repeated at 32-34 weeks; object placement at 20-22 weeks; and open field at 32-34 weeks.
Motor coordination was evaluated by counting the number of slips made while crossing a round balance beam (16 mm diameter; 120 cm long; [@DMM022780C29]). Before each testing session, mice were trained to walk over a 6-cm-wide, flat wooden plank to diminish anxiety. Owing to the time scale of the study (8 months) and tissue collection, some animals were tested only once (at either 20-22 or 32-34 weeks old), whereas most were tested longitudinally.
Locomotor activity, exploration and thigmotaxis (anxiety-like behavior) of the animals were assayed in the open-field arena (37 cm×42 cm) for 6 min. The total track length traveled in the entire arena was used as a measure of locomotor activity. Anxiety-like behavior was assessed as the proportion of the center zone (15 cm×15 cm) exploration (center zone track) from the total track traveled. Both measures were assessed automatically using Viewer software (Biobserve, Bonn, Germany). Rears (exploration) were counted manually.
For the object placement test ([@DMM022780C10]; [@DMM022780C8]), animals were first allowed to explore a pair of identical, non-toxic objects for 5 min (training phase) in an open field with high-contrast visual cues placed on each wall of the arena. Animals were then placed back into their home cages for 16 min (retention interval). Subsequently, one of the objects was moved to a new position, whereas the position of the other object remained unchanged (old position), and the animals were allowed to explore both objects for 3 min (testing phase). Exploration of the objects was defined as any physical contact with an object (whisking, sniffing, rearing on or touching the object) or orienting to the object from within 5 cm. Viewer software (Biobserve) was used to record the sessions. Care was taken to ensure that the intrinsic relationship between the objects and the relative position of the objects to the visual cues was altered. The total times (in seconds) spent exploring the objects in the old and new positions during the testing phase were compared. Animals with cumulative exploration times \<2 s in either training or testing phases were excluded from further analyses.
Statistical analyses and figure preparation {#s4g}
-------------------------------------------
JMP statistical software (v.11; SAS, Cary, NC, USA) was used to analyze the results of the behavioral and PC quantification analyses. The balance beam data were analyzed by a mixed-effects analysis including random and fixed factors, similar to a standard repeated-measures analysis, but with the advantage that missing data can be accommodated in a mixed-effects model that thus analyzed both between (fixed)- and within (random)-subject variability while preserving the correct sample sizes and degrees of freedom (d.f.) when some animals were tested twice ([Fig. 5](#DMM022780F5){ref-type="fig"}G). The results of the object placement test require analysis of the time exploring the object in both the new and the old position by each mouse (measured during the testing phase). Thus, to preserve the sample size and because the values represent two data points from each individual animal, these data were matched and analyzed by paired *t*-tests in each sex/genotype group. The rest of the statistical analyses (total track lengths, ratios of center and total track lengths, number of rears, total exploration time in the training phase of the object placement test, PC densities and comparisons of fractions of β-Gal^+^ PCs in lobules I-II and X) were evaluated by one-way ANOVA. *P*-values \<0.05 were considered statistically significant. Data in [Figs 3](#DMM022780F3){ref-type="fig"},[4](#DMM022780F4){ref-type="fig"} (shown also as individual values) and [5](#DMM022780F5){ref-type="fig"}, in the text and [supplementary material](supplementary material), are presented as arithmetic mean values±s.e.m. Figures were prepared in Photoshop CS6 (Adobe, San Jose, CA, USA) and graphs were plotted in GraphPad Prism version 6.05 software (GraphPad Software, La Jolla, CA, USA). For better contrast and visibility without altering the biological information, images were stretched to fill the full dynamic 8-bit ranges. Fig. 5.**Behavioral abnormalities in *Slc9a6* animals.** Open field (A-F) in 32- to 34-week-old animals \[*n*=31 wild-type (WT) males, 30 mutant males, 22 WT females and 33 heterozygous females\]. (A,B) When compared with WT littermates, mutant males demonstrated significantly higher locomotor activity (A; total track in centimeters) and exploration (B; number of rears). (C) Anxiety-like behavior was assessed as center zone exploration (center zone/total track length). (D-F) No significant differences were identified between WT and heterozygous females. \*Significant differences between WT and mutant males (*P*\<0.05). (G) Balance beam test in 20- to 22-week-old animals (*n*=25 WT males, 21 mutant males, 22 WT females and 34 heterozygous females) and 32- to 34-week-old animals (*n*=25 WT males, 21 mutant males, 17 WT females and 38 heterozygous females). \*Significant main effect of age; ^\#^significant main effect of genotype. (H) Object placement test in 20- to 22-week-old animals (*n*=15 WT males, 24 mutant males, 17 WT females and 25 heterozygous females). Both WT males and WT females had intact visuospatial memory, indicated by a clear preference (exploration in seconds) for the relocated (New position) object. On the contrary, both mutant males and heterozygous females demonstrated cognitive deficits because there was no preference for the object in the New position. \*Significant difference between exploration of an object in a New and Old position (*P*\<0.05). For additional details see [Fig. S3](Fig. S3).
The authors would like to acknowledge Kostantin Dobrenis and Cristin Davidson for crucial discussions and Gloria Stephney and Bin Cui for technical assistance. Behavioral studies were conducted at the Behavioral Core Facility Dominick P. Purpura Department of Neuroscience (director M.G.), Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine.
**Competing interests**
The authors declare no competing or financial interests.
**Author contributions**
J.S. conceived and designed the study, performed light and electron microscopic imaging, participated in the cell quantification studies, analyzed the data, wrote the first draft and co-edited the final version of the manuscript. J.L. performed the behavioral testing, tissue staining and cell quantification analyses and co-edited the manuscript. M.G. designed and supervised the behavioral testing and statistical analyses and co-edited the manuscript. S.U.W. conceived and designed the study, analyzed the data and co-edited and submitted the final version of the manuscript.
**Funding**
This project was supported by National Institute of Child Health and Human Development grants \[R01 HD045561 and P30 HD071593 to S.U.W.\]. J.S. was supported by National Institute of Neurological Disorders and Stroke Award \[1F05 NS074790\] and by the research project \[IGA MZ NT14015-3/2013\] from the Ministry of Health of the Czech Republic.
**Supplementary information**
Supplementary information available online at <http://dmm.biologists.org/lookup/suppl/doi:10.1242/dmm.022780/-/DC1>
| 2024-04-18T01:26:57.367551 | https://example.com/article/3702 |
Q:
Setting Line Breakpoints in Intellij 15.02 doesn't work
Since yesterday I'm on IntelliJ 15.02 and cannot set any line breakpoints any longer. Neither by clicking on the side bar, nor by "Run -> Toggle Line Breakpoint". Is that a Bug in IntelliJ? Or is there any way to disable / enable this feature? I appreciate any help.
A:
This seems to be an issue with the python plugin. I uninstalled the python plugin, and the line breakpoints were available again. Then I reinstalled the plugin and still everything is fine. I use the python plugin because I have Jython scripts that I call from the Java code.
| 2024-03-21T01:26:57.367551 | https://example.com/article/2327 |
Q:
How to loop and array's index by day in xcode
I know the question sounds a little funny.
I am trying to move down the list of array in my iPhone project.
I have an array of 100 items:
[0][1]...[99]
I would like to select index[0] today, index[1] tomorrow... index[99] 100 days from now. And then on day 101, back to index [0].
Maybe I need to convert NSDate and get todays date in a day format? So today would be 285/365 and then do something with my array to loop it according to today's date/day?
A:
Got the answer from a friend. Modulo Operation is the answer!
a = Today's Date in Day format 286/365
n = Number or items in my array array.count (100)
a % n
day 1 % 100 = array[1];
day 2 % 100 = array[2];
day 99 % 100 = array[99];
day 100 % 100 = array[0];
day 101 % 100 = array[1];
day 286 % 100 = array[86];
Now I just need to research on how to convert NSDate into days of the year.
October 13th = 286
| 2023-10-14T01:26:57.367551 | https://example.com/article/5200 |
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"name": "S3",
"tier": "Standard"
}
},
{
"sku": {
"name": "S4",
"tier": "Standard"
}
}
]
}
}
}
}
| 2023-12-15T01:26:57.367551 | https://example.com/article/3913 |
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