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Moisture recycling In hydrology, moisture recycling or precipitation recycling refer to the process by which a portion of the precipitated water that evapotranspired from a given area contributes to the precipitation over the same area. is thus a component of the hydrologic cycle. The ratio of the locally derived precipitation (formula_1) to total precipitation (formula_2) is known as the recycling ratio, formula_3: formula_4. The recycling ratio is a diagnostic measure of the potential for interactions between land surface hydrology and regional climate. Land use changes, such as deforestation or agricultural intensification, have the potential to change the amount of precipitation that falls in a region. The recycling ratio for the entire world is one, and for a single point is zero. Estimates for the recycling ratio for the Amazon basin range from 24% to 56%, and for the Mississippi basin from 21% to 24%. The concept of moisture recycling has been integrated into the concept of the precipitationshed. A precipitationshed is the upwind ocean and land surface that contributes evaporation to a given, downwind location's precipitation. In much the same way that a watershed is defined by a topographically explicit area that provides surface runoff, the precipitationshed is a statistically defined area within which evaporation, traveling via moisture recycling, provides precipitation for a specific point.
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https://en.wikipedia.org/wiki?curid=3560122
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Peder Oluf Pedersen (19 June 1874 – 30 August 1941) was a Danish engineer and physicist. He is notable for his work on electrotechnology and his cooperation with Valdemar Poulsen on the developmental work on Wire recorders, which he called a telegraphone, and the arc converter known as the Poulsen Arc Transmitter. Pedersen became a professor of telegraphy, telephony and radio in 1912. He became principal of the College of Advanced Technology ("Den Polytekniske Læreanstalt") in 1922, a title he held until his death. He was a Fellow of the American Institute of Electrical Engineers and was a member of the British Institution of Electrical Engineers. In 1915 he became a Fellow of the Institute of Radio Engineers.
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https://en.wikipedia.org/wiki?curid=3561195
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Coalescence (physics) Coalescence is the process by which two or more droplets, bubbles or particles merge during contact to form a single daughter droplet, bubble or particle. It can take place in many processes, ranging from meteorology to astrophysics. For example, it is seen in the formation of raindrops as well as planetary and star formation. In meteorology, its role is crucial in the formation of rain. As droplets are carried by the updrafts and downdrafts in a cloud, they collide and coalesce to form larger droplets. When the droplets become too large to be sustained on the air currents, they begin to fall as rain. Adding to this process, the cloud may be seeded with ice from higher altitudes, either via the cloud tops reaching , or via the cloud being seeded by ice from cirrus clouds. In cloud physics the main mechanism of collision is the different terminal velocity between the droplets. The terminal velocity is a function of the droplet size. The other factors that determine the collision rate are the droplet concentration and turbulence.
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Power history Power History refers to the power of a nuclear reactor over an extended period of time. is important for calculations and operations that involve decay heat and fission product poisons and to avoid the iodine pit during reactor shutdowns. For example, a nuclear reactor that has operated at 100% power for 100 hours and then has dropped down to 20% power for 5 hours will have a different amount of decay heat and fission product poisons than the same nuclear reactor operating at 20% power for 105 hours. This is because the second reactor has a different power history.
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https://en.wikipedia.org/wiki?curid=3577039
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T. Neil Davis Thomas Neil Davis (February 1, 1932 – December 10, 2016) was a professor of geophysics from the University of Alaska Fairbanks and the author of several books. Born in Greeley, Colorado, Davis received his B.S in geophysics from University of Alaska Fairbanks in 1955, an M.S. in geophysics from California Institute of Technology in 1957, and a Ph.D in geophysics from University of Alaska Fairbanks in 1961. Davis spent most of his working career at the Geophysical Institute, pioneering the use of all-sky and low-level light cameras for the study of the aurora borealis and conducting rocket studies of the aurora. With Masahisa Sugiura (while both were at NASA Goddard Space Flight Center) he introduced the AE (auroral electrojet) index now commonly used as a measure of solar-terrestrial interaction. A student of Beno Gutenberg and Charles Richter at Caltech, he also has done work in observational seismology.
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https://en.wikipedia.org/wiki?curid=3577676
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Nectar guide Nectar guides are markings or patterns seen in flowers of some angiosperm species, that guide pollinators to their rewards. Rewards commonly take the form of nectar, pollen, or both, but various plants produce oil, resins, scents, or waxes. Such patterns also are known as "pollen guides" and "honey guides", though some authorities argue for the abandonment of such terms in favour of floral guides (see for example Dinkel & Lunau). These patterns are sometimes visible to humans; for instance, the Dalmatian toadflax ("Linaria genistifolia") has yellow flowers with orange nectar guides. However, in some plants, such as sunflowers, they are visible only when viewed in ultraviolet light. Under ultraviolet, the flowers have a darker center, where the nectaries are located, and often specific patterns upon the petals as well. This is believed to make the flowers more attractive to pollinators such as honey bees and other insects that can see ultraviolet. This page on butterflies shows an animated comparison of black-eyed Susan ("Rudbeckia hirta") flowers in visible and UV light. The ultraviolet color, invisible to humans, has been referred to as "bee violet", and mixtures of greenish (yellow) wavelengths (roughly 540 nm) with ultraviolet are called "bee purple" by analogy with purple in human vision.
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https://en.wikipedia.org/wiki?curid=3579392
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OTS 44 is a free-floating planetary-mass object or brown dwarf located at in the constellation Chamaeleon near the reflection nebula IC 2631. It is among the lowest-mass free-floating substellar objects, with approximately 11.5 times the mass of Jupiter, or approximately 1.1% that of the Sun. Its radius is not very well known and is estimated to be 23–57% that of the Sun. was discovered in 1998 by Oasa, Tamura, and Sugitani as a member of the star-forming region Chamaeleon I. Based upon infrared observations with the Spitzer Space Telescope and the Herschel Space Observatory, emits an excess of infrared radiation for an object of its type, suggesting it has a circumstellar disk of dust and particles of rock and ice. This disk has a mass of at least 10 Earth masses. Observations with the SINFONI spectrograph at the Very Large Telescope show that the disk is accreting matter at the rate of approximately 10 of the mass of the Sun per year. It could eventually develop into a planetary system. Observations with ALMA detected the disk in millimeter wavelengths. The observations constrained the dust mass of the disk between 0.07 and 0.63 , but these mass estimates are limited by assumptions on poorly constrained parameters.
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https://en.wikipedia.org/wiki?curid=3583044
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Interface (matter) In the physical sciences, an interface is the boundary between two spatial regions occupied by different matter, or by matter in different physical states. The interface between matter and air, or matter and vacuum, is called a surface, and studied in surface science. In thermal equilibrium, the regions in contact are called phases, and the interface is called a phase boundary. An example for an interface out of equilibrium is the grain boundary in polycrystalline matter. The importance of the interface depends on the type of system: the bigger the quotient area/volume, the greater the effect the interface will have. Consequently, interfaces are very important in systems with large interface area-to-volume ratios, such as colloids. Interfaces can be flat or curved. For example, oil droplets in a salad dressing are spherical but the interface between water and air in a glass of water is mostly flat. Surface tension is the physical property which rules interface processes involving liquids. For a liquid film on flat surfaces, the liquid-vapor interface keeps flat to minimize interfacial area and system free energy. For a liquid film on rough surfaces, the surface tension tends to keep the meniscus flat, while the disjoining pressure makes the film conformal to the substrate. The equilibrium meniscus shape is a result of the competition between the capillary pressure and disjoining pressure. Interfaces may cause various optical phenomena, such as refraction
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Interface (matter) Optical lenses serve as an example of a practical application of the interface between glass and air. One topical interface system is the gas-liquid interface between aerosols and other atmospheric molecules.
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Yasha Rosenfeld Yaakov (Yasha) Rosenfeld (February 16, 1948 – July 21, 2002) was a condensed-matter theorist who made outstanding contributions to the statistical mechanics of liquids and dense plasmas. He was a leading figure in theories of liquids and his fundamental measure approach to classical density functional theory has been a very significant contribution to the subject. He received the Alexander von Humboldt Prize , which is Germany's highest research award for scientists and scholars in all disciplines. He was born in Harbin, China to Rosa and Yehiel Rosenfeld. When he was two years of age the family immigrated to Israel, where he grew up. Yasha died in 2002 from lung cancer at the age of 54.
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https://en.wikipedia.org/wiki?curid=3614758
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Friedrich Ritter (9 May 1898 – 9 April 1989) was a German botanist who collected and described many species of cacti. "Ritterocereus" is named in his honour.
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Cratonic sequence A cratonic sequence is a very large-scale lithostratographic sequence that covers a complete marine transgressive-regressive cycle across a craton. They are also known as "megasequences", "stratigraphic sequences", "sloss sequence", "supersequence" or simply "sequences". In plain English, it is the geological evidence of the sea level rising and then falling, thereby depositing layers of sediment onto an area of ancient rock called a craton. Places such as the Grand Canyon are a good visual example of this, apparent in the layers deposited over time. Cratonic sequences were first proposed by Lawrence Sloss in 1963; each one represents a time when epeiric seas deposited sediments across the craton, while the upper and lower edges of the sequence are bounded by craton-wide unconformities eroded when the seas receded. These sequences may in part represent eustatic or global change in sea level; however, when the proper names are used they usually refer to the North American continent. The most likely causes of these cycles is change in mid-ocean ridge volume, which is related to spreading rates. When Earth's mid-ocean ridges spread rapidly, the ridges tend to be longer than usual; also, the greater heat elevates the lithosphere over the ridges. This elevated lithosphere reduces ocean-basin volume and displaces water onto the continents; conversely, when spreading rates decline, the ridges subside, and the seas drain from the cratons
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Cratonic sequence It is also possible that other mechanisms, such as dynamic topography related to mantle mass anomalies, and intraplate stress related to episodes of contractional and extensional tectonics, play a part by causing significant tectonic uplift and subsidence across the craton. There have been six cratonic sequences since the beginning of the Cambrian Period. For North America, from oldest to youngest, they are the Sauk, Tippecanoe, Kaskaskia, Absaroka, Zuñi, and the Tejas. Attempts to identify equivalent cratonic sequences on other continents have met with only limited success, suggesting that eustasy is unlikely to be the sole responsible mechanism.
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Neural computation is the hypothetical information processing performed by networks of neurons. is affiliated with the philosophical tradition known as Computational theory of mind, also referred to as computationalism, which advances the thesis that neural computation explains cognition. The first persons to propose an account of neural activity as being computational was Warren McCullock and Walter Pitts in their seminal 1943 paper, A Logical Calculus of the Ideas Immanent in Nervous Activity. There are three general branches of computationalism, including classicism, connectionism, and computational neuroscience. All three branches agree that cognition is computation, however they disagree on what sorts of computations constitute cognition. The classicism tradition believes that computation in the brain is digital, analogous with digital computing. Both connectionism and computational neuroscience do not require that the computations which realize cognition are necessarily digital computations. However, the two branches greatly disagree upon which sorts of experimental data should be used to construct explanatory models of cognitive phenomena. Connectionists rely upon behavioral evidence to construct models to explain cognitive phenomenon, whereas computational neuroscience leverages neuroanatomical and neurophysiological information to construct mathematical models which explain cognition
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Neural computation When comparing the three main traditions of the computational theory of mind, as well as the different possible forms of computation in the brain, it is helpful to define what we mean by computation in a general sense. Computation is the processing of vehicles, otherwise known as variables or entities, according to a set of rules. A rule in this sense is simply an instruction for executing a manipulation on the current state of the variable, in order to produce an specified output. In other words, a rule dictates which output to produce given a certain input to the computing system. A computing system is a mechanism whose components must be functionally organized to process the vehicles in accordance with the established set of rules. The types of vehicles processed by a computing system determines which type of computations it performs. Traditionally, in cognitive science there have been two proposed types of computation related to neural activity - digital and analog, with the vast majority of theoretical work incorporating a digital understanding of cognition. Computing systems which perform digital computation are functionally organized to execute operations on strings of digits with respect to the type and location of the digit on the string. It has been argued that neural spike train signaling implements some form of digital computation, since neural spikes may be considered as discrete units or digits, like 0 or 1 - the neuron either fires an action potential or it does not
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Neural computation Accordingly, neural spike trains could be seen as strings of digits. Alternatively, analog computing systems perform manipulations on non-discrete, irreducibly continuous variables, that is, entities which vary continuously as a function of time. These sorts of operations are characterized by systems of differential equations. can be studied for example by building models of neural computation. There is a scientific journal dedicated to this subject, "Neural Computation". Artificial neural networks (ANN) is subfield of the research area machine learning. Work on ANNs has been somewhat inspired by knowledge of neural computation.
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E. C. Jeffrey Edward Charles Jeffrey (May 21, 1866 – April 19, 1952) was a Canadian-American botanist who worked on vascular plant anatomy and phylogeny. From 1892 to 1902 Jeffrey was a lecturer at the University of Toronto. While on leave of absence, he received his Ph.D. from Harvard University in 1899. In 1902 he became there an assistant professor of vegetable histology. In 1907 he was promoted to a full professorship of plant morphology. In 1933 he retired from Harvard University as professor emeritus. died on 1952-04-19.
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https://en.wikipedia.org/wiki?curid=3634131
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Kobald is a name for pyrites of copper-nickel-cobalt-iron given by German miners of the 15th century. The name (similar to kobold) means goblin. See cobalt.
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Magellanic Bridge The (MBR) is a stream of neutral hydrogen that links the two Magellanic Clouds, with a few known stars inside it. It should not be confused with the Magellanic Stream, which links the Magellanic Clouds to the Milky Way. It was discovered in 1963 by J. V. Hindman et al. There is a continuous stream of stars throughout the Bridge linking the Large Magellanic Cloud (LMC) with the Small Magellanic Cloud (SMC). This stellar bridge is of greater concentration in the western part. There are two major density clumps, one near the SMC, the other midway between the galaxies, referred to as the "OGLE Island".
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https://en.wikipedia.org/wiki?curid=3641069
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René Dahinden (August 22, 1930 - April 18, 2001) was a well-known Bigfoot (Sasquatch) researcher. Dahinden was born in Switzerland but moved to Canada at the end of October 1953, where he would live for the rest of his life. He became interested in the Bigfoot phenomenon shortly after arriving in Canada, and during the next few decades he conducted many field investigations and interviews throughout the Pacific Northwest. Dahinden was a major advocate for the controversial Patterson–Gimlin film, which was taken in 1967 and supposedly provides photographic evidence of Bigfoot. He also co-wrote a book, "Sasquatch", with Don Hunter, which was published in 1973 in a hardcover edition. In 1975, the book would be issued as a paperback. This title would then be revised and renamed in 1993 as "Sasquatch/Bigfoot: The Search for North America's Incredible Creature, Revised Edition". David Suchet's French Canadian Bigfoot-hunting character in the 1987 film "Harry and the Hendersons" is based on Dahinden. For a year, Dahinden acted as spokesman for Kokanee beer, and appeared in commercials in Canada. Dahinden died of prostate cancer at approximately 8:40 p.m. PDT on April 18, 2001, in British Columbia. In an obituary in the "National Post", his friend Christopher Murphy remembered a remark of Dahinden's. "One day he said to me: 'You know, I've spent over 40 years — and I didn't find it. I guess that's got to say something.'"
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Sommerfeld identity The is a mathematical identity, due Arnold Sommerfeld, used in the theory of propagation of waves, where is to be taken with positive real part, to ensure the convergence of the integral and its vanishing in the limit formula_3 and Here, formula_5 is the distance from the origin while formula_6 is the distance from the central axis of a cylinder as in the formula_7 cylindrical coordinate system. Here the notation for Bessel functions follows the German convention, to be consistent with the original notation used by Sommerfeld. The function formula_8 is the zeroth-order Bessel function of the first kind, better known by the notation formula_9 in English literature. This identity is known as the Sommerfeld Identity [Ref.1,Pg.242]. In alternative notation, the can be more easily seen as an expansion of a spherical wave in terms of cylindrically-symmetric waves, Where [Ref.2,Pg.66]. The notation used here is different form that above: formula_6 is now the distance from the origin and formula_13 is the radial distance in a cylindrical coordinate system defined as formula_14. The physical interpretation is that a spherical wave can be expanded into a summation of cylindrical waves in formula_13 direction, multiplied by a two-sided plane wave in the formula_16 direction; see the Jacobi-Anger expansion. The summation has to be taken over all the wavenumbers formula_17. The is closely related to the two-dimensional Fourier transform with cylindrical symmetry, i.e., the Hankel transform
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Sommerfeld identity It is found by transforming the spherical wave along the in-plane coordinates (formula_18,formula_19, or formula_13, formula_21) but not transforming along the height coordinate formula_16. <br>
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Ground substance is an amorphous gel-like substance in the extracellular space that contains all components of the extracellular matrix (ECM) except for fibrous materials such as collagen and elastin. is active in the development, movement, and proliferation of tissues, as well as their metabolism. Additionally, cells use it for support, water storage, binding, and a medium for intercellular exchange (especially between blood cells and other types of cells). provides lubrication for collagen fibers. The components of the ground substance vary depending on the tissue. is primarily composed of water and large organic molecules, such as glycosaminoglycans (GAGs), proteoglycans, and glycoproteins. GAGs are polysaccharides that trap water, giving the ground substance a gel-like texture. Important GAGs found in ground substance include hyaluronic acid, heparan sulfate, dermatan sulfate, and chondroitin sulfate. With the exception of hyaluronic acid, GAGs are bound to proteins called proteoglycans. Glycoproteins are proteins that attach components of the ground substance to one another and to the surfaces of cells. Components of the ground substance are secreted by fibroblasts. Usually it is not visible on slides, because it is lost during staining in the preparation process. Link proteins such as vinculin, spectrin and actomyosin stabilize the proteoglycans and organize elastic fibers in the ECM. Changes in the density of ground substance can allow collagen fibers to form aberrant cross-links
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Ground substance Loose connective tissue is characterized by few fibers and cells, and a relatively large amount of ground substance. Dense connective tissue has a smaller amount of ground substance compared to the fibrous material. The meaning of the term has evolved over time.
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Allogamy "Allogamy" (cross-fertilization) is a term used in the field of biological reproduction describing the fertilization of an ovum from one individual with the spermatozoa of another. By contrast, autogamy is the term used for self-fertilization. In humans, the fertilization event is an instance of allogamy. Self-fertilization occurs in hermaphroditic organisms where the two gametes fused in fertilization come from the same individual. This is common in plants (see Sexual reproduction in plants) and certain protozoans. In plants, allogamy is used specifically to mean the use of pollen from one plant to fertilize the flower of another plant and usually synonymous with the term "cross-fertilization" or "cross-pollination" (outcrossing), though the latter term can be used more specifically to mean pollen exchange between different plant strains or even different plant species (where the term "cross-hybridization" can be used) rather than simply between different individuals. Parasites having complex life cycles can pass through alternate stages of allogamous and autogamous reproduction, and the description of a hitherto unknown allogamous stage can be a significant finding with implications for human disease. ordinarily involves cross-fertilization between unrelated individuals leading to the masking of deleterious recessive alleles in progeny
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Allogamy By contrast, close inbreeding, including self-fertilization in plants and automictic parthenogenesis in hymenoptera, tends to lead to the harmful expression of deleterious recessive alleles (inbreeding depression). In dioecious plants, the stigma may receive pollen from several different potential donors. As multiple pollen tubes from the different donors grow through the stigma to reach the ovary, the receiving maternal plant may carry out pollen selection favoring pollen from less related donor plants. Thus post-pollination selection may occur in order to promote allogamy and avoid inbreeding depression. Also, seeds may be aborted selectively depending on donor–recipient relatedness.
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https://en.wikipedia.org/wiki?curid=3647987
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Ursa Major Cluster The (Ursa Major I Cluster, UMa I ClG) is a spiral-rich galaxy cluster of the Virgo Supercluster. Some of its largest members are NGC 3631, NGC 3953, M109 on North (M109 Group) and NGC 3726, NGC 3938 NGC 4051 on South. The Ursa Major cluster is located at a distance of 18.6 megaparsecs (60 million light-years) and contains about 30% of the light but only 5% of the mass of the nearby Virgo Cluster.
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Concise International Chemical Assessment Document Concise International Chemical Assessment Documents (CICADs) are published by the World Health Organization within the framework of the International Programme on Chemical Safety (IPCS). They describe the toxicological properties of chemical compounds. CICADs are prepared in draft form by one or two experts from national bodies such as the US CDC, and then peer reviewed by an international group of experts. They do not constitute the official policy of any of the bodies which contribute to their publication.
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NGC 7752 and NGC 7753 are a pair of galaxies approximately 272 million light-years away in the constellation Pegasus. NGC 7753 is the primary galaxy. It is a barred spiral galaxy with a small nucleus. NGC 7752 is the satellite galaxy of NGC 7753. It is a barred lenticular galaxy that is apparently attached to one of NGC 7753's spiral arms. They resemble the Whirlpool Galaxy (M51A) and its satellite NGC 5195 (M51B). The first supernova detected in NGC 7753 was SN 2006A in January 2006. It was followed four months later by SN 2006ch, a Type Ia supernova. In January 2013 another Type Ia supernova, SN 2013Q, was detected, and in August 2015 a Type II supernova, SN 2015ae, was discovered.
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Specific kinetic energy is kinetic energy of an object per unit of mass. It is defined as formula_1. Where formula_2 is the specific kinetic energy and formula_3 is velocity. It has units of J/kg, which is equivalent to m/s.
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Genome Valley is an Indian high-technology business district spread across 600 km² in Hyderabad, India. It is located across the suburbs, Turkapally, Shamirpet, Medchal, Uppal, Patancheru, Jeedimetla, Gachibowli and Keesara, the Valley has developed as a cluster for Biomedical research, training and manufacturing. Genome valley was commissioned in 1999 as "S. P. Biotech Park" in a public-private partnership with Bharat Biotech International, and its founder Krishna Ella, alongside private infrastructure companies such as Shapoorji Pallonji Group and ICICI Bank. In 2009, U.S.-based infrastructure giant "Alexandria Real Estate Equities" has announced its plans to invest in the bio-cluster, which led to the Alexandria Knowledge Park SEZ. The biocluster at Shamirpet holds Certification mark by the United States Patent and Trademark Office and the European Union. The IKP Knowledge Park is spread over 200 acres in Turakapally, is an initiative of ICICI Bank with five "innovation corridors" - a first of its kind knowledge-nurturing centre for Indian companies and a knowledge gateway for multinational companies". The first phase of Innovation Corridor I, comprising 10 laboratories, around 3,000 ft² (300 m²) each, is operational and fully occupied. The second phase of Innovation Corridor I, comprising 16 laboratory modules of 1,700 ft² (170 m²) each, is ready for operation. In 2016, Mission Neutral Park has acquired specialized R&D assets in from US based Alexandria REIT and rechristened it as MN Park
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Genome Valley It is a collaborative life sciences ecosystem in Genome Valley, Hyderabad consisting of Grade A R&D facilities. It is spread over 400 acres including build-up facilities of around 600,000 sq.ft. provided to global tenants like Novartis, GlaxoSmithKline, Mylan and Ashland Inc. MN’s focus area: Preleased industrial assets and specialized office spaces to sectors including specialized warehousing, logistics, food processing, light manufacturing, pharmaceutical R&D, biotechnology etc.
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Dreikanter A is a type of ventifact that typically forms in desert or periglacial environments due to the abrasive action of blowing sand. Dreikanters exhibit a characteristic pyramidal shape with three wind-abrased facets. The word "Dreikanter" is German for "three-edged." Similarly, a zweikanter ("two-edged") has two wind facets, an einkanter ("one-edged"), has only one wind facet. Most places on the planet have several weathering processes acting at the same time, so finding good examples of Dreikanters is often difficult. Antarctica is a good location for finding such ventifacts since wind is usually the only active weathering agent. Many specimens in the Northeastern United States were formed during the Pleistocene era when the absence of vegetation made for little cover from wind-blown sediment. Some common features of Dreikanters include fluting, high polish, sharp ridges, pits, grooves, and helical forms. In areas where there is a prevailing wind, sand and debris cause a rock face to become flattened and polished. This changes the mass distribution of the rock, and may cause it to turn another surface toward the wind. If this process continues undisturbed, the resulting rock will have three distinct flattened and polished faces. Dreikanters generally form in dry, arid environments from hard rocks.
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Capacitor-spring analogy There are several formal analogies that can be made between electricity, which is invisible to the eye, and more familiar physical behaviors, such as the flowing of water or the motion of mechanical devices. In the case of capacitance, one analogy to a capacitor in mechanical rectilineal terms is a spring where the compliance of the spring is analogous to the capacitance. Thus in electrical engineering, a capacitor may be defined as an ideal electrical component which satisfies the equation where formula_2 = voltage measured at the terminals of the capacitor, formula_3 = the capacitance of the capacitor, formula_4 = current flowing between the terminals of the capacitor, and formula_5 = time. The equation quoted above has the same form as that describing an ideal massless spring: formula_7 is the force applied between the two ends of the spring, formula_8 is the stiffness, or spring constant (inverse of compliance) defined as force/displacement, and formula_9 is the speed (or velocity) of one end of the spring, the other end being fixed. Note that in the electrical case, current ("I") is defined as the rate of change of charge ("Q") with respect to time: While in the mechanical case, velocity ("v") is defined as the rate of change of displacement ("x") with respect to time: Thus, in this analogy: Also, these analogous relationships apply: This analogy of the capacitor forms part of the more comprehensive impedance analogy of mechanical to electrical systems.
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Tadpole Galaxy The is a disrupted barred spiral galaxy located 420 million light-years from Earth in the northern constellation Draco. Its most dramatic feature is a massive trail of stars about 280,000 light-years long; the size of the galaxy has been attributed to a merger with a smaller galaxy that is believed to have occurred about 100 million years ago. The galaxy is filled with bright blue star clusters. It is hypothesized that a more compact intruder galaxy crossed in front of the Tadpole Galaxy—from left to right from the perspective of Earth—and was slung around behind the Tadpole by their mutual gravitational attraction. During this close encounter, tidal forces drew out the spiral galaxy's stars, gas, and dust, forming the conspicuous tail. The intruder galaxy itself, estimated to lie about 300 thousand light-years behind the Tadpole, can be seen through foreground spiral arms at the upper left. Following its terrestrial namesake, the will likely lose its tail as it grows older, the tail's star clusters forming smaller satellites of the large spiral galaxy.
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Retarder (chemistry) A retarder is a chemical agent that slows down a chemical reaction. For example, retarders are used to slow the chemical reaction hardening of plastic materials such as wallboard, concrete, and adhesives. Sugar water acts as a retarder for the curing of concrete. It can be used to retard the chemical hardening of the surface, so that the top layer can be washed off to expose the underlying aggregate.
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Rudolf Ruedemann (October 16, 1864–June 18, 1956) was a German American paleontologist, widely known as an expert in graptolites, enigmatic fossil animals. He worked at the New York State Museum for over 40 years, including a decade as State Paleontologist of New York. and was elected to the U.S. National Academy of Sciences in 1928. Born in Georgenthal, Germany, he was educated in Europe, earning a PhD in 1887 from the University of Jena (Ph.D., 1887), and a second doctorate in 1889 from France's University of Strasbourg where he was an assistant in geology from 1887 to 1892. He emigrated to the United States in 1892 and taught at the high schools of Lowville and Dolgeville, New York for several years before joining the State Museum in 1899, where he worked for the remainder of his career. Although his primary interests were in graptolites he also made contributions to other areas of invertebrate paleontology, describing new species of fossil corals, eurypterids ("sea scorpions"), trilobites, and cephalopods. He was married with a daughter and six sons, and retired in 1937.
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Inorganic Crystal Structure Database (ICSD) is a chemical database founded in 1978 by Günter Bergerhoff (University of Bonn) and I.D.Brown (University of McMaster, Canada). It is now produced by FIZ Karlsruhe in Europe and the U.S. National Institute of Standards and Technology. It seeks to contain information on all inorganic crystal structures published since 1913, including pure elements, minerals, metals, and intermetallic compounds (with atomic coordinates). ICSD contains 161,030 entries and is updated twice a year. A Windows-based PC version has been developed in co-operation with the National Institute of Standards and Technology (NIST), and a PHP-MySQL web based version in co-operation with the Institut Laue–Langevin (ILL) Grenoble.
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Kao Ping-tse (; 23 December 1888 - 23 March 1970) was a Chinese astronomer. He was entirely self-taught in this field. The crater Kao on the Moon is named in his honor. Kao was born in Shanghai. His father was a revolutionary, a Jǔrén 舉人, and a key figure of the "Nan Society" ("South Society", ) in the late Qing Dynasty. He worked at Qingdao Observatory, received from the Japanese after the Washington Naval Conference in 1924. He then worked at the Academia Sinica Institute of Astronomy & Astrophysics, one of the founders of Purple Mountain Observatory. During World War II, he lived in Shanghai. He moved to Taiwan in 1948, during the Chinese Civil War. He died in Taipei.
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Abrahão de Moraes Abrahão De Moraes (1916–1970) was a Brazilian astronomer and mathematician. He taught at the Escola Politécnica and also served as director of the Instituto Astronômico e Geofísico. The Observatório (OAM) is named after him. Founded in 1972, it is situated in the municipality of Valinhos, 90 km from São Paulo. The crater De Moraes on the Moon is named after him.
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Michigan Life Sciences Corridor The (MLSC) is a $1 billion biotechnology initiative in the U.S. state of Michigan. The MLSC invests in biotech research at four Michigan institutions: the University of Michigan in Ann Arbor; Michigan State University in East Lansing; Wayne State University in Detroit; and the Van Andel Institute in Grand Rapids. The Michigan Economic Development Corporation administers the program. It began in 1999 with money from the state's settlement with the tobacco industry. When the program's funds distributions are completed in 2019, the goal is that the investments in high tech research will have notably expanded the state's economic base. In 1998, the State of Michigan, along with 45 other states, reached the $8.5 billion Tobacco Master Settlement Agreement, a settlement with the U.S. tobacco industry. Former Governor John Engler created the in 1999 when he signed Public Act 120 of 1999. The bill appropriated money from the state's settlement with the tobacco industry to fund biotech research at four of Michigan's largest research institutions. Under the management of the Michigan Economic Development Corporation, the MLSC allocated $1 billion over the course of 20 years, including $50 million in 1999 to fund research on aging. The following year, the MLSC awarded $100 million to 63 Michigan universities. In 2002, Governor Jennifer Granholm incorporated the MLSC into the Michigan Technology Tri-Corridor, adding funding for homeland security and alternative fuel research
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Michigan Life Sciences Corridor In 2009, the University of Michigan added a 30-building, North Campus Research Complex by acquiring the former Pfizer pharmaceutical corporation facility. A BioEnterprise Midwest Healthcare Venture report found that Michigan attracted $451.8 million in new biotechnology venture capital investments from 2005 to 2009.
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Fine chemical Fine chemicals are complex, single, pure chemical substances, produced in limited quantities in multipurpose plants by multistep batch chemical or biotechnological processes. They are described by exacting specifications, used for further processing within the chemical industry and sold for more than $10/kg (see the comparison of fine chemicals, commodities and specialties). The class of fine chemicals is subdivided either on the basis of the added value (building blocks, advanced intermediates or active ingredients), or the type of business transaction, namely standard or exclusive products. Fine chemicals are produced in limited volumes (< 1000 tons/year) and at relatively high prices (> $10/kg) according to exacting specifications, mainly by traditional organic synthesis in multipurpose chemical plants. Biotechnical processes are gaining ground. The global production value is about $85 billion. Fine chemicals are used as starting materials for specialty chemicals, particularly pharmaceuticals, biopharmaceuticals and agrochemicals. Custom manufacturing for the life science industry plays a big role; however, a significant portion of the fine chemicals total production volume is manufactured in house by large users. The industry is fragmented and extends from small, privately owned companies to divisions of big, diversified chemical enterprises. The term "fine chemicals" is used in distinction to "heavy chemicals", which are produced and handled in large lots and are often in a crude state
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Fine chemical Since their inception in the late 1970s, fine chemicals have become an important part of the chemical industry. The total production value of $85 billion is split about 60 / 40 among in-house production by the main consumers, the life science industry, on the one hand, and the fine chemicals industry on the other hand. The latter pursues both a “supply push” strategy, whereby standard products are developed in-house and offered ubiquitously, and a “demand pull” strategy, whereby products or services determined by the customer are provided exclusively on a “one customer / one supplier” basis. The products are mainly used as building blocks for proprietary products. The hardware of the top tier fine chemical companies has become almost identical. The design, lay-out and equipment of the plants and laboratories has become practically the same all over the world. Most chemical reactions performed go back to the days of the dyestuff industry. Numerous regulations determine the way labs and plants have to be operated, thereby contributing to the uniformity. The term "fine chemicals" was in use as early as 1908. The emergence of the fine chemical industry as a distinct entity dates back to the late 1970s, when the overwhelming success of the histamine H receptor antagonists Tagamet (cimetidine) and Zantac (ranitidine hydrochloride) created a strong demand for advanced organic chemicals used in their manufacturing processes
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Fine chemical As the in-house production capacities of the originators, the pharmaceutical companies Smith, Kline, & French and Glaxo, could not keep pace with the rapidly increasing requirements, both companies (now merged as GlaxoSmithKline) outsourced part of the manufacturing to chemical companies experienced in producing relatively sophisticated organic molecules. Lonza, Switzerland, which already had supplied an early intermediate, methyl acetoacetate, during drug development, soon became the main supplier of more and more advanced precursors. The signature of a first, simple supply contract is generally acknowledged as the historical document marking the beginning of the fine chemical industry. In the subsequent years, the business developed favorably and Lonza was the first fine chemical company entering in a strategic partnership with SKF. In a similar way, Fine Organics, UK became the supplier of the thioethyl-N’-methyl-2-nitro-1,1-ethenediamine moiety of ranitidine, the second H2 receptor antagonist, marketed as Zantac by Glaxo. Other pharmaceutical and agrochemical companies gradually followed suit and also started outsourcing the procurement of fine chemicals. An example in case is F.I.S., Italy, which partnered with Roche, Switzerland for custom manufacturing precursors of the benzodiazepine class of tranquilizers, such as Librium (chlordiazepoxide HCl) and Valium (diazepam)
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Fine chemical The growing complexity and potency of new pharmaceuticals and agrochemicals requiring production in multipurpose, instead of dedicated plants and, more recently, the advent of biopharmaceuticals had a major impact on the demand for fine chemicals and the evolution of the fine chemical industry as a distinct entity. For many years, however, the life science industry continued considering captive production of the active ingredients of their drugs and agrochemicals as a core competency. Outsourcing was recurred to only in exceptional cases, such as capacity shortfalls, processes requiring hazardous chemistry or new products, where uncertainties existed about the chance of a successful launch. In terms of molecular structure, one distinguishes first between low-molecular-weight (LMW) and high-molecular-weight (HMW) products. The generally accepted threshold between LMW and HMW is a molecular weight of about 700. LMW fine chemicals, also designated as small molecules, are produced by traditional chemical synthesis, by microorganisms (fermentation or biotransformation), or by extraction from plants and animals. In the production of modern life science products, total synthesis from petrochemicals prevails. The HMW products, respectively large molecules, are obtained mainly through biotechnology processes. Within LMWs, the N-heterocyclic compounds are the most important category; within HMWs they are the peptides and proteins
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Fine chemical As aromatic compounds have been exhausted to a large extent as building blocks for life science products, N-heterocyclic structures prevail nowadays. They are found in many natural products, such as chlorophyll; hemoglobin; and the vitamins biotin, folic acid, niacin (PP), pyridoxine (vitamin B), riboflavin (vitamin B), and thiamine (vitamin B). In synthetic life science products, N-heterocyclic moieties are widely diffuses both pharmaceuticals and agrochemicals. Thus, β-lactams are structural elements of penicillin and cephalosporin antibiotics, imidazoles are found both in modern herbicides, e.g. Arsenal (imazapyr) and pharmaceuticals, e.g. the antiulcerants Tagamet (cimetidine. see above) and Nexium (omeprazole), the antimycotics Daktarin (miconazole), Fungarest (ketoconazole) and Travogen (isoconazole). Tetrazoles and tetrazolidines are pivotal parts of the “sartan” class of hypertensives, e.g. Candesartan cilexetil (candesartan), Avapro (irbesartan), Cozaar (losartan) and Diovan (valsartan). A vast array of pharmaceuticals and agrochemicals are based on pyrimidines, such as Vitamin B1 (thiamine), the sulfonamide antibiotics, e.g. Madribon (sulfadimethoxime) and –half a century later– the sulfonyl urea herbicides, e.g. Eagle (amidosulfuron) and Londax (bensulfuron-methyl). Benzodiazepine derivatives are the pivotal structural elements of breakthrough CNS Drugs, such as Librium (chlordiazepoxide) and Valium (diazepam)
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Fine chemical Pyridine derivatives are found in both well-known Diquat and Chlorpyrifos herbicides, and in modern nicotinoid insecticides, such as Imidacloprid. Even modern pigments, such as diphenylpyrazolopyrazoles, quinacridones, and engineering plastics, such as polybenzimidazoles, polyimides, and triazine resins, exhibit an N-heterocyclic structure. "Big molecules", also called "high molecular weight", HMW molecules, are mostly oligomers or polymers of small molecules or chains of amino acids. Thus, within pharma sciences, peptides, proteins and oligonucleotides constitute the major categories. "Peptides and proteins" are oligomers or polycondensates of amino acids linked together by a carboxamide group. The threshold between the two is as at about 50 amino acids. Because of their unique biological functions, a significant and growing part of new drug discovery and development is focused on this class of biomolecules. Their biological functions are determined by the exact arrangement or sequence of different amino acids in their makeup. For the synthesis of peptides, four categories of fine chemicals, commonly referred to as peptide building blocks (PBBs), are key, namely amino acids (=starting materials), protected amino acids, peptide fragments and peptides themselves. Along the way, the molecular weights increase from about 10 up to 10 and the unit prices from about $100 up to $10 per kilogram. However, only a small part of the total amino acid production is used for peptide synthesis
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Fine chemical In fact, L-glutamic acid, D, L-methionine, L-aspartic acid and L-phenylalanine are used in large quantities as food and feed additives. About 50 peptide drugs are commercialized. The number of amino acids that make up a specific peptide varies widely. At the low end are the dipeptides. The most important drugs with a dipeptide (L-alanyl-L-proline) moiety are the “-pril” cardiovascular drugs, such as Alapril (lisinopril), Captoril (captopril), Novolac (imidapril) and Renitec (enalapril). Also the artificial sweetener Aspartame (N-L-α-Aspartyl-L-phenylalanine 1-methyl ester) is a dipeptide. At the high end there is the anticoagulant hirudin, MW ≈ 7000, which is composed of 65 amino acids. Apart from pharmaceuticals, peptides are also used for diagnostics and vaccines. The total production volume (excl. Aspartame) of chemically synthesized, pure peptides is about 1500 kilograms and sales approach $500 million on the active pharmaceutical (API) level and $10 billion on the finished drug level, respectively. The bulk of the production of peptide drugs, which comprise also the first generation anti-AIDS drugs, the “…navirs”, is outsourced to a few specialized contract manufacturers, such as Bachem, Switzerland; Chengu GT Biochem, China; Chinese Peptide Company, China; Lonza, Switzerland, and Polypeptide, Denmark. "Proteins" are “very high-molecular-weight” (MW > 100,000) organic compounds, consisting of amino acid sequences linked by peptide bonds
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Fine chemical They are essential to the structure and function of all living cells and viruses and are among the most actively studied molecules in biochemistry. They can be made only by advanced biotechnological processes; primarily mammalian cell cultures. Monoclonal antibodies (mAb) prevail among human-made proteins. About a dozen of them are approved as pharmaceuticals. Important modern products are EPO (Binocrit, NeoRecormon, erythropoietin), Enbrel (etanercerpt), Remicade (infliximab); MabThera/Rituxin (rituximab), and Herceptin (trastuzumab). PEGylation is a big step forward regarding administration of peptide and protein drugs. The method offers the two-fold advantage of substituting injection by oral administration and reducing the dosage, and therefore the cost of the treatment. The pioneer company in this field is Prolong Pharmaceuticals which has developed a PEGylated erythropoietin (PEG-EPO). "Oligonucleotides" are a third category of big molecules. They are oligomers of nucleotides, which in turn are composed of a five-carbon sugar (either ribose or desoxyribose), a nitrogenous base (either a pyrimidine or a purine) and 1–3 phosphate groups. The best known representative of a nucleotide is the coenzyme ATP (=Adenosine triphosphate), MW 507.2. Oligonucleotides are chemically synthesized from protected phosphoramidites of natural or chemically modified nucleosides. The oligonucleotide chain assembly proceeds in the direction from 3’- to 5’-terminus by following a procedure referred to as a “synthetic cycle”
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Fine chemical Completion of a single synthetic cycle results in the addition of one nucleotide residue to the growing chain. The maximum length of synthetic oligonucleotides hardly exceeds 200 nucleotide components. From its current range of applications in basic research as well as in drug target validation, drug discovery, and therapeutic development, the potential use of oligonucleotides is foreseen in gene therapy (antisense drugs), disease prevention and agriculture. "Antibody-drug conjugates (ADC)" constitute a combination between small and big molecules. The small molecule parts, up to four different APIs, are highly potent cytotoxic drugs. They are linked with a monoclonal antibody, a big molecule which is of little or no therapeutic value in itself, but extremely discriminating for its targets, the cancer cells. The first commercialized ADCs were Isis’s Formivirisen and, more recently, Pfizer’s (formerly Wyeth) Mylotarg (gemtuzumab ozogamicin). Examples of ADCs in phase III of development are Abbott’s / Isis’s Alicaforsen and Eli Lilly’s Aprinocarsen. Several key technologies are used for the production of fine chemicals, including Chemical synthesis and biotechnology are most frequently used; sometimes also in combination. A large toolbox of chemical reactions is available for each step of the synthesis of a fine chemical
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Fine chemical The reactions have been developed on laboratory scale by academia over the last two centuries and subsequently adapted to industrial scale, for instance for the manufacture of dyestuffs & pigments. The most comprehensive handbooks describing organic synthetic methods is "Methods of Molecular Transformations". About 10% of the 26,000 synthetic methods described therein are currently used on an industrial scale for fine chemicals production. Amination, condensation, esterification, Friedel–Crafts, Grignard, halogenation (esp. chlorination), and hydrogenation, respectively reduction (both catalytic and chemical) are most frequently mentioned on the websites of individual companies. Optically active cyanohydrins, cyclopolymerization, ionic liquids, nitrones, oligonucletides, peptide (both liquid- and solid-phase), electrochemical reactions (e.g., perfluorination) and steroid synthesis are promoted by only a limited number of companies. With the exception of some stereospecific reactions, particularly biotechnology, mastering these technologies does not represent a distinct competitive advantage. Most reactions can be carried out in standard multipurpose plants. The very versatile organometallic reactions (e.g., conversions with lithium aluminum hydride, boronic acids) may require temperatures as low as -100 °C, which can be achieved only in special cryogenic reaction units, either by using liquefied nitrogen as coolant or by installing a low-temperature unit
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Fine chemical Other reaction-specific equipment, such as filters for the separation of catalysts, ozone or phosgene generators, can be purchased in many different sizes. The installation of special equipment generally is not a critical path on the overall project for developing an industrial-scale process of a new molecule. Since the mid-1990s the commercial importance of "single-enantiomer" fine chemicals has increased steadily. They constitute about half of both existing and developmental drug APIs. In this context, the ability to synthesize chiral molecules has become an important competency. Two types of processes are used, namely the physical separation of the enantiomers and the stereo specific synthesis, using chiral catalysts. Among the latter, enzymes and synthetic BINAP (2,2´–Bis(diphenylphosphino)–1,1´–binaphthyl) types are used most frequently. Large volume (> 103 mtpa) processes using chiral catalysts include the manufacture of the perfume ingredient l-Menthol and Syngenta’s Dual (metolachlor) as well as BASF’s Outlook (dimethenamid-P) herbicides. Examples of originator drugs, which apply asymmetric technology, are AstraZeneca’s Nexium (esomeprazole) and Merck & Co’s Januvia (sitagliptin)
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Fine chemical The physical separation of chiral mixtures and purification of the desired enantiomer can be achieved either by classical fractional crystallization (having a “low-tech” image but still widely used), carried-out in standard multipurpose equipment or by various types of chromatographical separation, such as standard column, simulated moving-bed (SMB) or supercritical fluid (SCF) techniques. For "peptides" three main types of methods are used, namely chemical synthesis, extraction from natural substances, and biosynthesis. Chemical synthesis is used for smaller peptides made of up to 30–40 amino acids. One distinguishes between “liquid phase” and “solid phase” synthesis. In the latter, reagents are incorporated in a resin that is contained in a reactor or column. The synthesis sequence starts by attaching the first amino acid to the reactive group of the resin and then adding the remaining amino acids one after the other. In order to ascertain a full selectivity, the amino groups have to be protected in advance. Most developmental peptides are synthesized by this method, which lends itself to automation. As the intermediate products resulting from individual synthetic steps cannot be purified, a selectivity of effectively 100% is essential for the synthesis of larger-peptide molecules. Even at a selectivity of 99% per reaction step, the purity will drop to less than 75% for a dekapeptide (30 steps)
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Fine chemical Therefore, for industrial quantities of peptides not more than 10–15 amino acid peptides can be made using the solid-phase method. For laboratory quantities, up to 40 are possible. In order to prepare larger peptides, individual fragments are first produced, purified, and then combined to the final molecule by liquid phase synthesis. Thus, for the production of Roche’s anti-AIDS drug Fuzeon (enfuvirtide), three fragments of 10–12 amino acids are first made by solid-phase synthesis and then linked together by liquid-phase synthesis. The preparation of the whole 35 amino acid peptide requires more than 130 individual steps. Microreactor "Technology" (MRT), making part of “process intensification”, is a relatively new tool that is being developed at several universities, as well as leading fine chemical companies, such as Bayer Technology Services, Germany; Clariant, Switzerland; Evonik-Degussa, Germany; DSM, The Netherlands; Lonza, Switzerland; PCAS, France, and Sigma-Aldrich, US. The latter company produces about 50 fine chemicals up to multi-kilogram quantities in microreactors. From a technological point of view, MRT, a.k.a. continuous flow reactors, represents the first breakthrough development in reactor design since the introduction of the stirred-tank reactor, which was used by Perkin & Sons, when they set up a factory on the banks of what was then the Grand Junction Canal in London in 1857 to produce mauveïne, the first-ever synthetic purple dye
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Fine chemical For a comprehensive coverage of the subject see "Micro Process Engineering". Examples for reactions that have worked in microreactors include aromatics oxidations, diazomethane conversions, Grignards, halogenations, hydrogenations, nitrations, and Suzuki couplings. According to experts in the field, 70% of all chemical reactions could be done in microreactors, however only 10-15% are economically justified. With the exception of some stereospecific reactions, particularly biotechnology, mastering these technologies does not represent a distinct competitive advantage. Most reactions can be carried out in standard multipurpose plants. Reaction-specific equipment, such as ozone or phosgene generators, is readily available. The installation generally is not a critical path on the overall project for developing an industrial-scale process of a new molecule. Whereas the overall demand for outsourced pharmaceutical fine chemicals is expected to increase moderately ("see" Chapter 8), the estimated annual growth rates for the above-mentioned niche technologies are much higher. Microreactors and the SMB separation technology are expected to grow at a rate of even 50–100% per year. However, the total size of the accessible market typically does not exceed a few hundred tons per year at best
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Fine chemical "Industrial biotechnology", also called "“white biotechnology”" is increasingly impacting the chemical industry, enabling both the conversion of renewable resources, such as sugar or vegetable oils, and the more efficient transformation of conventional raw materials into a wide range of commodities (e.g., cellulose, ethanol and succinic acid), fine chemicals (e.g. 6-aminopenicillanic acid), and specialties (e.g., food and feed additives). As opposed to green and red biotechnology, which relate to agriculture and medicine, respectively, white biotechnology enables the production of existing products in a more economic and sustainable fashion on the one hand, and provides access to new products, especially biopharmaceuticals, on the other hand. It is expected that revenues from white biotechnology will account for 10%, or $250 billion, of the global chemical market of $2,500 billion by 2013. In ten to 15 years it is expected that most amino acids and vitamins and many specialty chemicals will be produced by means of biotechnology Three very different process technologies -biocatalysis, biosynthesis (microbial fermentation), and cell cultures- are used. Biocatalysis, a.k.a. biotransformation and bioconversion, makes use of natural or modified isolated enzymes, enzyme extracts, or whole-cell systems for enhancing the production of small molecules. It has much to offer compared to traditional organic synthesis
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Fine chemical The syntheses are shorter, less energy intensive and generate less waste and hence, are both environmentally and economically more attractive. About 2/3 of chiral products produced on large industrial scale are already made using biocatalysis. In the manufacture of fine chemicals, enzymes represent the single most important technology for radical cost reductions. This is particularly the case in the synthesis of molecules with chiral centres. Here, it is possible to substitute the formation of a salt with a chiral compound, e.g., (+)-α-phenylethylamine, crystallization, salt breaking and recycling of the chiral auxiliary, resulting in a theoretical yield of not more than 50%, with a one step, high yield reaction under mild conditions and resulting in a product with a very high enantiomeric excess (ee). An example is AstraZeneca’s blockbuster drug Crestor (rosuvastatin), see Chemical / Enzymatic Synthesis of Crestor. Further examples of modern drugs, where enzymes are used in the synthesis, are Pfizer’s Lipitor (atorvastatin), where the pivotal intermediate R-3-Hydroxy-4-cyanobutyrate is now made with a nitrilase, and Merck & Co.’s Singulair (montelukast), where the reduction of a ketone to S-alcohol, which had required stoichiometric amounts of expensive and moisture sensitive “(-)-DIP chloride” is now replaced by a ketoreductase enzyme catalyst step. Similar rewarding switches from chemical steps to enzymatic ones have also been achieved in steroid synthesis
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Fine chemical Thus, it has been possible to reduce the number of steps required for the synthesis of Dexamethasone from bile from 28 to 15. Enzymes differ from chemical catalysts particularly with regard to stereoselectivity, regioselectivity, and chemoselectivity. They can also be modified (“reshuffled”) for specific reactions, for use in chemical synthesis. “Immobilized enzymes” are those fixed on solid supports. They can be recovered by filtration after completion of the reaction. Conventional plant equipment can be used with no, or only modest, adaptations. The "International Union of Biochemistry and Molecular Biology" (IUBMB) has developed a classification for enzymes. The main categories are Oxidoreductases, Transferases, Hydrolases, Lipases (subcategory), Lyases, Isomerases and Ligases, Companies specializing in making enzymes are Novozymes, Danisco (Genencor). Codexis is the leader in modifying enzymes to specific chemical reactions. The highest-volume chemicals made by biocatalysis are bio-ethanol (70 million metric tons), high-fructose corn syrup (2 million metric tons); acrylamide, 6-aminopenicillanic acid (APA), L-lysine and other amino acids, citric acid and niacinamide (all more than 10,000 metric tons). "Biosynthesis" i.e. the conversion of organic materials into fine chemicals by microorganisms, is used for the production of both small molecules (using enzymes in whole cell systems) and less complex, non-glycosylated big molecules, including peptides and simpler proteins
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Fine chemical The technology has been used for 10,000 years to produce food products, like alcoholic beverages, cheese, yogurt, and vinegar. In contrast to biocatalysis, a biosynthetic process does not depend on chemicals as starting materials, but only on cheap natural feedstock, such as glucose, to serve as nutrient for the cells. The enzyme systems triggered in the particular microorganism strain lead to the excretion of the desired product into the medium, or, in the case of HMW peptides and proteins, to the accumulation within so-called inclusion bodies in the cells. The key elements of fermentation development are strain selection and optimization, as well as media and process development. Dedicated plants are used for large-scale industrial production. As the volume productivity is low, the bioreactors, called fermenters, are large, with volumes that can exceed 250 m3. Product isolation was previously based on large-volume extraction of the medium containing the product. Modern isolation and membrane technologies, like reverse osmosis, ultra- and nano-filtration, or affinity chromatography can help to remove salts and by-products, and to concentrate the solution efficiently and in an environmentally friendly manner under mild conditions. The final purification is often achieved by conventional chemical crystallization processes
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Fine chemical In contrast to the isolation of small molecules, the isolation and purification of microbial proteins is tedious and often involves a number of expensive large-scale chromatographic operations. Examples of large-volume LMW products made by modern industrial microbial biosynthetic processes are monosodium glutamate (MSG), vitamin B2 (riboflavin), and vitamin C (ascorbic acid). In vitamin B2, riboflavin, the original six- to eight-step synthetic process starting from barbituric acid has been substituted completely by a microbial one-step process, allowing a 95% waste reduction and an approximately 50% manufacturing cost reduction. In ascorbic acid, the five-step process (yield ≈ 85%) starting from D-glucose, originally invented by Tadeus Reichstein in 1933, is being gradually substituted by a more straightforward fermentative process with 2-ketogluconic acid as pivotal intermediate. After the discovery of penicillin in 1928 by Sir Alexander Fleming from colonies of the bacterium Staphylococcus aureus, it took more than a decade before a powdery form of the medicine was developed. Since then, many more antibiotics and other secondary metabolites have been isolated and manufactured by microbial fermentation on a large scale. Some important antibiotics besides penicillin are cephalosporins, azythromycin, bacitracin, gentamycin, rifamycin, streptomycin, tetracycline, and vancomycin
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Fine chemical "Cell Cultures" Animal or plant cells, removed from tissues, will continue to grow if cultivated under the appropriate nutrients and conditions. When carried out outside the natural habitat, the process is called cell culture. "Mammalian cell culture" fermentation, also known as recombinant DNA technology, is used mainly for the production of complex big molecule therapeutic proteins, a.k.a. biopharmaceuticals. The first products made were interferon (discovered in 1957), insulin, and somatropin. Commonly used cell lines are Chinese hamster ovary (CHO) cells or plant cell cultures. The production volumes are very small. They exceed 100 kg per year for only three products: Rituxan (Roche-Genentech), Enbrel (Amgen and Merck & Co. [formerly Wyeth]), and Remicade (Johnson & Johnson). production by mammalian cell culture is a much more demanding operation than conventional biocatalysis and –synthesis. The bioreactor batch requires more stringent controls of operating parameters, since mammalian cells are heat and shear sensitive; in addition the growth rate of mammalian cells is very slow, lasting from days to several months. While there are substantial differences between microbial and mammalian technologies (e.g., the volume / value relationships are 10 $/kg and 100 tons for microbial, 1,000,000 $/kg and 10 kilograms for mammalian technology; the cycle times are 2–4 and 10–20 days, respectively), they are even more pronounced between mammalian and synthetic chemical technology (see Table 1)
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Fine chemical The mammalian cell production process, as used for most biopharmaceuticals, is divided into the four main steps: (1) Cultivation, i.e. reproduction of the cells; (2) Fermentation, i.e. the actual production of the protein, typically in 10,000 Liter, or multiples, bioreactors; (3) Purification, i.e. separation of the cells from the culture medium and purification, mostly by chromatography, (4) Formulation, i.e. conversion of the sensitive proteins to a stable form. All steps are fully automated. The low productivity of the animal culture makes the technology expensive and vulnerable to contamination. Actually, as a small number of bacteria would soon outgrow a larger population of animal cells. Its main disadvantages are low volume productivity and the animal provenance. It is conceivable that other technologies, particularly plant cell production, will gain importance in future. Given the fundamental differences between the two process technologies, plants for mammalian cell culture technologies have to be built ex novo. The pro’s and con’s of an involvement of a fine chemical company in cell culture technology are listed below: Pros: Cons: The inherent risks of the mammalian cell technology led several companies to opt out of mammalian cell technology or to substantially reduce their stake. Examples are Cambrex and Dowpharma in the US, Avecia, DSM and Siegfried in Europe and WuXi App Tech in China. In conclusion, biocatalysis should be, or become, part of the technology toolbox of any fine chemical company
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Fine chemical Mammalian cell culture fermentation, on the other hand, should be considered only by large fine chemical companies with a full war chest and a long-term strategic orientation. Within the chemical universe, the fine chemical industry is positioned between the commodity, their suppliers, and specialty chemical industries, their customers. Depending on the services offered, there are two types of fine chemical companies. The "Fine Chemical Companies" are active in industrial scale production, both of standard and exclusive products. If the latter prevails, they are referred to as Fine Chemical / "Custom Manufacturing Organizations (CMOs)". The main assets of the Contract Research Organizations (CROs) are their research laboratories. CRAMS; Contract Research and Manufacturing Organizations are hybrids (see section 4.2). "/ Custom Manufacturing companies" in the narrower sense are active in process scale up, pilot plant (trial) production, industrial-scale exclusive and non-exclusive manufacture and marketing. Their product portfolios comprise exclusive products, produced by custom manufacturing, as main activity, non-exclusive products, e.g. API-for Generics, and standard products. Characteristics are high asset intensity, batch production in campaigns in multipurpose plants, above-industry-average R&D expenditures and close, multi-level and multi-functional relationships with industrial customers. The industry is very fragmented
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Fine chemical 2000 – 3000 fine chemical companies exist globally, extending from small, “garage-type” outfits in China making just one product, all the way to the big, diversified enterprises, resp. units. The main reason for the fragmentation is the lack of economy of scale (see below). The industry is subject to a high degree of regulation even more so than the chemical industry as a whole, particularly if pharmaceutical fine chemical production is involved. The most important regulatory authorities are the "(US) Food and Drug Administration (FDA)" and "(Chinese) State Food & Drug Administration (SFDA)", respectively. Their main responsibilities comprise formulating comprehensive supervision policies (“Good Manufacturing Practice”) and control the implementation, to be in charge of drug registration, draw up criteria for marketing authorization and formulate national essential medicines lists. The European correspondent is the "European Medicines Agency (EMEA)", which is manly responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union. The role of REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) is self-explanatory. The "U.S. Pharmacopeia" codifies quality standards for Active Pharmaceutical Ingredients. As these standards are observed worldwide, they contribute also to the emergence of a uniform worldwide set-up of the top tier fine chemical companies
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Fine chemical In terms of size, resources, and complexity of the chemical process technologies mastered, the fine chemical companies can be broadly divided into three segments, each of them accounting for approximately the same turnover, namely about $10 billion. The top tier, about twenty, has sales in excess of $250 million per year (see Table 3). Most are not pure players but divisions or b.u.’s of large, multinational companies. Their share varies between one percent or less for BASF and Pfizer, all the way to 100% for Cambrex, USA; Divi’s Laboratories, India, and F.I.S. Italy. All have extensive resources in terms of chemists and other specialists, plants, process knowledge, backwards integration, international presence, etc. The combined revenues of the top 20 fine chemical companies amounted to $10 billion in 2009, representing about 30% of the figure for the whole industry. The leading companies are typically divisions of large, diversified chemical companies. In terms of geography, 9 of the top 20 are located in Europe, which is recognized as the cradle of the fine chemical industry. This is e.g. the case for the world’s #1 company, Lonza, headquartered in Basel. Switzerland. Custom manufacturing prevails in northern Europe; the manufacture of active substances for generics, in southern Europe. The second largest geographic area is Asia, housing 7 of the top 20. With 4 large companies, the US rank last. Whereas the European and U.S
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Fine chemical pharma industry constitutes the main customer base for most fine chemical companies, some have a significant share of products and services for the agrochemical industry. Examples are Archimica, CABB, Saltigo (all Germany), DSM (The Netherlands) and Hikal, India. Several large pharmaceutical companies market fine chemicals as subsidiary activity to their production for captive use, e.g. Abbott, USA; Bayer Schering Pharma, Boehringer-Ingelheim, Germany; Daiichi-Sankyo (after the takeover of Ranbaxy), Japan; Johnson & Johnson, USA; Merck KGaA, Germany; Pfizer (formerly Upjohn), US. Large fine chemical companies, in contrast to mid-sized and small ones, are characterized by A comprehensive list of about 1400 fine chemical companies (including traders) can be found in the “event catalogue” of the CPhI exhibition. The "second tier" consists of several dozens of "midsized" companies with sales in the range of $100–$250 million per year. Their portfolios comprise both custom manufacturing and API-for-generics. They include both independents and subsidiaries of major companies. A number of these companies are privately owned and have grown mainly by reinvesting the profits. Examples are Bachem, Switzerland; Dishman, India; F.I.S. and Poli Industria Chimica, Italy; Hikal, India, and Hovione, Portugal. Customers prefer to do business with mid-sized companies, because communications are easier —they typically deal directly with the decision maker— and they can better leverage their purchasing power
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Fine chemical The "third tier" includes thousands of "small independents" with sales below $100 million per year. Most of them are located in Asia. They often specialize in niche technologies. The minimum economical size of a fine chemical company depends on the availability of infrastructure. If a company is located in an industrial park, where analytical services; utilities, safety, health, and environmental (SHE) services, and warehousing are readily available, there is practically no lower limit. New fine chemical plants have come on-stream mostly in Far East countries over the past few years. Their annual turnover rate rarely exceeds $25 million. All big and medium-size fine chemical companies have cGMP-compliant plants that are suitable for the production of pharmaceutical fine chemicals. With the exception of biopharmaceuticals, which are manufactured by only a few selected fine chemical companies, (see section 3.2.2), the technology toolboxes of all these companies are similar. This means that they can carry out practically all types of chemical reactions. They differentiate on the basis of the breadth and quality of the service offering. Contract research organizations (CROs) provide services to the life science industries along product development. There are more than 2000 CROs operating worldwide, representing revenues of more than $20 billion. One distinguishes between "Product" and "Patient" CROs
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Fine chemical Whereas the production sites of CMOs are multipurpose plants, allowing for the production of tens to hundreds of tons of fine chemicals, the work places of patient CROs are the test persons (volunteers) for the clinical trials and those of the product CROs are the laboratory benches. Major customers for CRO services are the large global pharmaceutical companies. Half a dozen companies (Pfizer, GlaxoSmithKline, Sanofi-Aventis, AstraZeneca, Johnson & Johnson, and Merck & Co.) alone absorb about one third of all CRO spending. As for CMOs also for CROs, biotech start-up companies with their dichotomy between ambitious drug development programs and limited resources are the second most promising prospects. Product CROs (chemical CROs) are providing primarily sample preparation, process research and development services. An overlap between the latter and CMOs exists with regard to pilot plants (100 kg quantities), which are part of the arsenal of both types of enterprise. There are more 100 product CROs. Most of them are privately held and have revenues of $10–$20 million per year or less, adding up to a total business in the range of $1.5-$2 billion. Their tasks are described in Chapter 5, Examples of are: The business of CROs is usually done through a “pay for service” arrangement. Contrary to manufacturing companies, invoicing of CROs is not based on unit product price, but on full-time equivalents (FTEs), that is, the cost of a scientist working one year on a given customer assignment
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Fine chemical Companies offering both contract research and manufacturing services (CRAMS) combine the activities of CROs and CMOs. Their history is either a forward integration of a CRO, which adds industrial scale capabilities or backwards integration of a CMO. As there are only limited synergies (e.g. > 90% of the projects end at the sample preparation stage). It is questionable, though, whether one-stop shops really fulfil a need. Actually, the large fine chemical companies consider the preparation of samples more as marketing tool (and expense ...) rather than a profit contributor. The offerings of Patient CROs (Clinical CROs) comprise more than 30 tasks addressing the clinical part of pharmaceutical development at the interface between drugs, physicians, hospitals, and patients, such as the clinical development and selection of lead new drug compounds. As clinical trials represent the largest expense in pharmaceutical research, the market for patient CROs is larger than for their product counterparts. Thus, the sales of the top tier firms, Charles River Laboratories, Covance, Parexel, PPD, Quintiles Transnational, all USA, and TCG Lifescience, India; are in the $1–$2 billion range, whereas the largest product CROs have revenues of a few 100 million dollars. The overall emphasis of fine chemical R&D is more on development than on research
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Fine chemical The main tasks are (1) designing, respectively duplicating and adapting in case of custom manufacture, and developing laboratory procedures for new products or processes; (2) transferring the processes from the laboratory via pilot plant to the industrial scale (the scale up factor from a 10g sample to a 1-ton batch is 100,000); and (3) to optimize existing processes. At all times during this course of action it has to be ensured that the four critical constraints, namely, economics, timing, safety, ecology and sustainability are observed . R&D expenditures in the fine chemical industry are higher than in the commodities industry. They represent around 5–10% versus 2–5% of sales. On the business side, product innovation must proceed at a more rapid pace, because life cycles of fine chemicals are shorter than those of commodities. Therefore, there is an ongoing need for substitution of obsolete products. On the technical side, the higher complexity of the products and the more stringent regulatory requirements absorb more resources. Many economic and technical parameters have been proposed to enable a meaningful assessment of single projects and project portfolios. Examples are attractiveness, strategic fit, innovation, gross/net present value, expected profits, R&D expenditures, development stage, probability of success, technology fit, potential conflicts with other activities of the company and realization time
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Fine chemical Most of these parameters cannot be determined quantitatively, at least during the early phases of a project. The best way to take advantage of a project portfolio is to develop and use it in an iterative way. By comparing the entries at regular intervals, for instance, every 3 months, the directions that the projects take can be visualized. If a negative trend persists with one particular project, the project should be put on the watch list. R&D has to manage the following functions in order to deliver the requested services: "Literature and Patent Research". Provisions have to be made for a periodic examination of all acquired research results to safeguard Intellectual Property Rights (IPR) and to determine whether patent applications are indicated. Patent research is particularly important for evaluation of the feasibility of taking up R&D for new APIs-for-generics. "Process Research" has to design new synthetic routes and sequences. Two approaches are feasible. For simple molecules, the “bottom-up” approach is the method of choice. The researcher converts a commercially available starting material and sequentially adds more reagents until the target molecule is synthesized. For more complex molecules, a “top-down” approach, also known as retro synthesis, or de-construction, is chosen. Key fragments of the target molecule are first identified, then synthesized individually, and finally combined to form the desired molecule through convergent synthesis
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Fine chemical "Process Development" focuses on the design of new, efficient, stable, safe, and scalable synthetic routes to a target fine chemical. It represents an essential link between process research and commercial production. The resulting “base process” description provides the necessary data for the determination of preliminary raw material and product specifications, the manufacture of semi commercial quantities in the pilot plant, the assessment of the ecological impact, the regulatory submissions and technology transfer to manufacture at industrial scale, and an estimate of the manufacturing costs in an industrial-scale plant. If the base process is provided by the customer as part of the technology transfer, process, research has to optimize it so that it can be transferred to the bench-scale laboratory or pilot plant. Furthermore, it has to be adapted to the specific characteristics of available production trains. "Bench-scale Laboratory, kg-lab and Pilot Plant Development". Depending on the volume requirements, three different types of equipment are used for process research, development and optimization, namely bench-scale laboratories for gram to 100 gram, kilo-labs for kg to 10 kg and pilot plants for 100 kg to ton quantities. Particularities of laboratory processes that have to be eliminated include the use of large numbers of unit operations, dilute reaction mixtures, vast quantities of solvents for extraction, evaporation to dryness, drying of solutions with hygroscopic salts
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Fine chemical Although modern reaction calorimeters consent to foresee the effects of these different conditions to a certain extent, a direct transfer of a process from the laboratory to the industrial scale is not recommended, because of the inherent safety, environmental, and economic risks. In development, the viability of the process on a semi commercial scale has to be demonstrated. Trial quantities of the new fine chemical have to be manufactured for market development, clinical tests, and other requirements. The necessary data have to be generated to enable the engineering department to plan the modifications of the industrial-scale plant and in order to calculate production costs for the expected large-volume requirements. Both equipment and plant layout of the pilot plant reflect those of an industrial multipurpose plant, except for the size of reaction vessels (bench-scale laboratory ~10–60 liters; pilot plant ~100–2500 liters) and the degree of process automation. Before the process is ready for transfer to the industrial-scale plant, the following activities have to be completed: Adaptation of the laboratory process to the constraints of a pilot plant, hazard and operability (HAZOP) analysis, execution of demonstration batches. The main differences between laboratory synthesis and industrial scale production are shown in Table 4. In case of cGMP fine chemicals also a process validation is required. It consists of the three elements process design, process qualification and continued process verification
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Fine chemical "Process Optimization". Once a new chemical process has been introduced successfully on an industrial scale, process optimization is called upon to improve the economics. As a rule of thumb it should be attempted to reduce the costs of goods sold (COGS) by 10-20%, every time the yearly production quantity has doubled. The task extends from fine tuning the currently used synthetic method all the way to the search for an entirely different second generation process. Specific provisions are the increase of overall yield, the reduction of the number of steps, raw material cost, solvent, catalyst, enzyme consumption, environmental impact. There are two main sources of new research projects, namely ideas originating from the researchers themselves (“supply push”) and those coming from customers (“demand pull”). Ideas for new processes typically originate from researchers, ideas for new products from customers, respectively customer contacts. Particularly in custom manufacturing, “demand pull” prevails industrial reality. The “new product committee” is the body of choice for evaluating new and monitoring ongoing research activities. It has the assignment to evaluate all new product ideas. It decides whether a new product idea should be taken up in research, reassesses a project at regular intervals and, last but not least decides also about the abandonment of a project, once it becomes evident that the objectives cannot be reached
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Fine chemical In a typical project the overall responsibility for the economic and technical success lies with the project champion. He is assisted by the project manager, who is responsible for the technical success. In custom manufacturing, a typical project starts with the acceptance of the product idea, which originates mainly from business development, by the new product committee, followed by the preparation of a laboratory process, and ends with the successful completion of demonstration runs on industrial scale and the signature of a multiyear supply contract, respectively. The input from the customer is contained in the “technology package”. Its main constituents are (1) reaction scheme, (2) target of project & deliverables (product, quantity, required dates, specifications), (3) list of analytical methods, (4) process development opportunities (stepwise assessment), (5) list of required reports, (6) Safety, Health and Environment (SHE) issues, (7) materials to be supplied by customer and (8) packaging & shipping information The technical part of a project usually determines its duration. Depending on the quality of the information contained in the “technology package” received from the customer and the complexity of the project as such, particularly the number of steps that have to be performed; it can be any time between 12 and 24 months. Depending on the number of researches involved, the total budget easily amounts to several million US dollars
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Fine chemical Fine chemicals are used as starting materials for specialty chemicals. The latter are obtained either by direct formulation or after chemical/biochemical transformation of intermediates to active substances. Life sciences, primarily pharmaceutical, agrochemical and food and feed industries are the main consumers of fine chemicals. Fine chemicals account for about 4% of the universe of chemicals. The latter, valued at $2,500 billion, is dominated mainly by oil-, gas-, and mineral-derived commodities (~40%) on one hand and a large variety of specialty chemicals at the interface between industry and the public on the other hand (~55%). The global production value of fine chemicals is estimated at $85 billion, of which about 2/3, or $55 billion are produced captively and $30 billion represent the global revenues of the fine chemical industry. The corresponding figures for the major user, the pharmaceutical industry, are $32 billion and $23 billion, respectively. For a number of reasons, such as the lack of statistical data and the somewhat equivocal definition it is not possible to exactly determine the size of the fine chemical market. In Table 5, the approximately $85 billion fine chemical market is subdivided into major applications according to their relevance, namely, fine chemicals for pharmaceuticals, agrochemicals and specialty chemicals outside life sciences. Furthermore, a distinction is made between captive (in-house) production and merchant market
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Fine chemical Pharmaceutical fine chemicals (PFCs) account for two-thirds of the total. Out of the PFC value of $55 billion, about $23 billion (~40%) are traded, and $32 billion (~60%) are the production value of the pharma industry’s in-house production. Within life science products, fine chemicals for agro, and —at a distance— for veterinary drugs follow in importance. The production value for fine chemicals used for specialty chemicals other than pharmaceuticals and agrochemicals is estimated at $15 billion. As the leading specialty chemical companies, Akzo Nobel, Dow, Du Pont, Evonik, Chemtura and Mitsubishi are backward-integrated, the share of in-house production is estimated at 75%, leaving a merchant market of approximately $5 billion. The pharmaceutical industry constitutes the most important customer base for the fine chemical industry (see Table 4). The largest companies are Pfizer, USA; Roche, Switzerland, GlaxoSmithKline, UK; Sanofi Aventis, France, and Novartis, Switzerland. All are active in R&D, manufacturing and marketing. Pharmaceuticals containing more than 2000 different active ingredients are in commerce today; a sizable number of them are sourced from the fine chemical industry. The industry also has a track record of above-average growth. The fine chemical industry has a keen interest in the top-selling or “blockbuster drugs”, i.e. those with worldwide annual sales in excess of $1 billion. Their number has increased steadily, from 27 in 1999 to 51 in 2001, 76 in 2003, and then levelled off
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Fine chemical Sales of the top 20 blockbuster drugs are reported in Table 6. The APIs of 12 of them are “small” (LMW) molecules. Averaging a MW of 477, they have quite complex structures. They typically show three cyclic moieties. 10 of them exhibit at least one N-heterocyclic moiety. Five of the top 10, up from none in 2005, are biopharmaceuticals. The largest-selling non-proprietary drugs are paracetamol, omeprazole, ethinylestradiol, amoxicillin, pyridoxine, and ascorbic acid. The innovator pharma companies require mainly custom manufacturing services for their proprietary drug substances. The demand is driven primarily by the number of new drug launches, the volume requirements and the industry’s “make or buy” strategy. A summary of the pro’s and con’s for outsourcing from the pharma industry’s perspective is given in Table 7. As extended studies at the Stern Business School of the New York City University have shown, financial considerations clearly favor the “buy” option. Teva and Sandoz are by far the largest "generics companies" (see also chapter 6.3.2). They differ from their competitors not only in sales revenues but also because they are strongly backwards integrated and have proprietary drugs in their portfolios. They also vie for the promising biosimilars market. Several thousand "smal"l or "virtual pharma" companies focus on R&D. albeit on just a few lead compounds. They typically originate mostly from academia
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Fine chemical Therefore, their R&D strategy is more focused on the elucidation of the biological roots of diseases rather than developing synthesis methods. Agrochemical companies are the second largest users of fine chemicals. Most products have a “pharmaceutical heritage”. As a consequence of an intensive M&A activity over the past 10–20 years, the industry now is more consolidated than the pharmaceutical industry. The top 10 companies, led by Syngenta, Switzerland; Bayer Cropsciences, Germany: Monsanto, USA; BASF Crop Protection, Germany, and Dow Agrosciences, USA have a share of almost 95% of the total 2,000,000 tons / $48.5 billion pesticide output in 2010. Since the 1990s the R&D effort is focused mainly on gene modified (GM) seeds. At both Monsanto and DuPont’s seed subsidiary, Pioneer Hi-Bred, GM seed businesses already account for more than 50% of total sales. 100 new LMW agrochemicals have been launched in the period 2000–2009. However, only 8 products achieved sales in excess of $100 million per year. Generics play a bigger role in the agro than in the pharma industry. They represent some 70% of the global market. China National Chemical Corp, a.k.a. ChemChina Group, is the world's largest supplier of generic farm chemicals. Mahkteshim Agan, Israel, and Cheminova, Denmark follow on the ranks 2 and 3. Apart from these multibillion-dollar companies, there are hundreds of smaller firms with sales of less than $50 million per year, mainly in India and China
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Fine chemical The incidence of the cost of the active ingredient is about 33%; i.e., much higher than in drugs. Depending on the climatic conditions affecting crop yields, consumption and prices of agrochemicals are subject to wide fluctuations from year to year, impacting also the suppliers. The molecular structures of modern agrochemicals are much more complex than in older products, but lower than of their pharma counterparts. The average molecular weight of the top 10 is 330, as compared with 477 for the top 10. In comparison to reagents used in pharmaceutical fine chemical syntheses, hazardous chemicals, e.g. sodium azide, halogens, methyl sulfide, phosgene, phosphorus chlorides, are more frequently used. Agrochemical companies sometimes outsource just these steps, which require specialized equipment, on toll conversion deals. With exception of the pyrethroids, which are photostable modifications of naturally occurring pyrethrums, active ingredients of agrochemicals rarely are chiral. Examples within "herbicides" are the world’s longstanding top-selling product, Monsanto’s round-up (glyphosate). Syngenta’s cyclohexadione-type mesotrione and paraquat dichloride. Within "insecticides", the traditional organophosphates, like malathion, and pyrethroids such as γ-cyhalotrin are being substituted for by neonicotinoids, like Bayer’s imidacloprid and Syngenta’s thiamethoxam and pyrazoles, such as BASF’s fipronil
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Fine chemical Chloranthaniliprole is the most important representative of Du Pont’s award-winning anthranilic diamide family of broad spectrum insecticides. Within "fungicides", the strobilurins, a new class, are growing rapidly and already have captured more than 30% of the $10 billion global fungicide market. Syngenta’s azoxystrobin was the first product launched. Also BASF’s F-500 Series, a.o. pyraclostrobin and kresoxim-methyl, Bayer CropScience, and Monsanto are developing new compounds in this class. Combination pesticides, such as Monsanto’s Genuity and SmartStax are more and more frequently used. Apart from life sciences, specialty chemicals -and therefore also their active ingredients, commodities or fine chemicals, as the case may be- are used ubiquitously, in both industrial applications, such as biocides and corrosion inhibitors in cooling water towers, and consumer applications, such as personal care and household products. The active ingredients extend from high-price / low-volume fine chemicals, used for liquid crystal displays to large-volume / low-price amino acids used as feed additives. <nowiki>*</nowiki>fine chemicals merchant market size, growth potential Examples of applications in eight areas, ranging from adhesives to specialty polymers, are listed in Table 8. Overall, the attractiveness for the fine chemical industry is smaller than the life science industry. The total market, expressed in finished product sales, amounts to $150–200 billion, or about one fourth of the pharma market
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Fine chemical The embedded fine chemicals account for an estimated $15 billion (see Table 5). Further disadvantages are the backward integration of the big players, e.g. Akzo-Nobel, Netherlands; Ajinomoto, Japan; Danone, France; Everlight Chemical Industrial Corp., Taiwan; Evonik-Degussa, Germany; Givaudan and Nestlé, Switzerland, Novozymes, Denmark, Procter & Gamble, and Unilever USA. Last but not least, innovation is rather based on new formulations of existing products, rather than the development of new fine chemicals. It is most likely to happen in application areas unrelated to human health (where NCEs are subject to very extensive testing). Global sales of proprietary drugs are estimated $735 billion in 2010, or almost 90% of the total pharma market. Global sales of generics are about $100 billion, or just over 10% of the total pharma market. Due to the much lower unit price, their market share will be close to 30% on an API volume/volume basis. The products and services offered by the fine chemical industry fall into two broad categories: (1) “Exclusives”, a.k.a. custom manufacturing (CM) and (2) “standard” or “catalogue” products. “Exclusives”, provided mostly under contract research or custom manufacturing arrangements, prevail in business with life science companies; “standards” prevail in other target markets. Service-intense custom manufacturing (CM) constitutes the most prominent activity of the fine chemical industry. CM is the antonym of outsourcing
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Fine chemical In custom manufacturing, a specialty-chemicals company outsources the process development, pilot plant, and, finally, industrial-scale production of an active ingredient, or a predecessor thereof, to one, or a few, fine chemical companies. The intellectual property of the product, and generally also the manufacturing process, stay with the customer. The customer-supplier relationship is governed by an exclusive supply agreement. At the beginning of cooperation, the customer provides a “tech package,” which in its simplest version, includes a laboratory synthesis description and SHE recommendations. In this case, the whole scale up, which comprises a factor of about one million (10 gram → 10 ton quantities), is done by the fine chemical company. Non-exclusives, ”standard” or “catalogue products” constitute the second most important outlet for fine chemicals after custom manufacturing. API-for-Generics are the most important sub-category. Because of patent expiries, over 60 of the top 200 drugs alone, representing aggregated sales of over $150 billion, have fallen into the public domain within the past decade. This, along with government-backed incentives, are causing global sales of generics to rapidly increase. Asian companies currently dominate the API-for-Generics business. They have multiple advantages of their low cost basis, their large home markets, and significant previous manufacturing experience compared to western manufacturers in producing for their domestic and other non-regulated markets
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Fine chemical Investment costs for multipurpose plants are high in comparison with product output. However, they vary considerably, depending on the location, size of equipment and degree of sophistication (e.g., automation, containment, quality of equipment, complexity of infrastructure). An example for a cGMP multipurpose plant built in the US is shown in Table 9. The investment cost of $21 million comprises just the equipment and installation. The building, property and external services are excluded. For comparison purposes, the investment cost per m reactor volume is used. In this case, it is $0.9 million. The amount includes the cost of the reaction vessel itself plus an equitable part of the ancillary equipment, like feeding tanks, piping, pumps & process control. If larger or smaller reactors were installed, the unit cost per m would decrease or decrease with the exponent 0.5, respectively. Hence, by increasing the equipment size manufacturing costs on a per kilogram (kg) basis typically decrease substantially. Also, costs for a plant that is used for the production of non regulated intermediates only would be substantially lower. Pharma companies tend to spend up to ten times more for a plant with the same capacity. In contrast, investment costs in developing countries, particularly in India or China, are considerably lower. The raw material consumption and the conversion cost are the two elements that establish the manufacturing cost for a particular fine chemical
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Fine chemical The former is determined primarily by the unit consumption and the purchasing cost of the materials used; the latter, by the throughput in kilograms per day in a given production bay. A precise calculation of the conversion cost is a demanding task. Different products with widely differing throughputs are produced in campaigns in multipurpose plants, occupying the equipment to different extents. Therefore, both the production capacity and the equipment utilization for a specific fine chemical are difficult to determine. Moreover, cost elements such as labor, capital, utilities, maintenance, waste disposal, and quality control cannot be allocated unambiguously. An approximative calculation can be done by an experienced process development or pilot plant chemist on the basis of (1) the laboratory synthesis procedure and (2) by breaking down the process into unit operations, the standard costs of which have been determined previously Controlling has to be involved for a more in-depth costing.. The problems it has to address are how to fairly allocate costs for production capacity, which is not used. This can be due to the fact that part of a production bay is idle, because of lack of demand or because e.g., a reactor is not required for a particular process. Manufacturing costs usually are reported on a per kilogram product basis. For the purpose of benchmarking (both internal and external), the volume x time / output (VTO), as mentioned above, is a useful aid
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Fine chemical An indicative cost structure for a fine chemical company is shown in Table 10. Nowadays, a full 7-day/week operation, consisting of four or five shift teams, each working 8h per day, has become the standard. In terms of production costs, this is the most advantageous scheme. Higher salaries for night work are more than offset by better fixed cost absorption. As part of the budgeting process, standard costs for a production campaign of a particular fine chemical are determined on the basis of past experience. The actual results of the campaign are then compared with the standard. The capability of a fine chemical company to make dependable manufacturing cost forecasts is a distinct competitive advantage. The fine chemical industry has undergone several boom and bust phases during its almost 30 years of existence. The biggest boom took place in the late 1990s, when high-dosage, high volume anti-AIDS drugs and COX-2 inhibitors gave a big boost to custom manufacturing. After the end of the “irrational exuberance” in 2000, the industry suffered a first bust in 2003, as a result of capacity expansions, the advent of Asian competitors and a ruinous M&A activity, several billion dollars of shareholder value were destroyed. The most recent –minor- boom is associated with stockpiling of GlaxoSmithKline’s Relenza (zanamivir) and Roche’s Tamiflu (oseltamivir phosphate) by many countries in order to prepare for a possible avian flu epidemic
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Fine chemical Surprisingly, the main cause for the 2009 slump had not been the general recession, but slow-downs of the growth and, even more so, inventory adjustments by the pharma industry. They resulted in postponements or cancellations of orders. The unfavorable development was in sharp contrast to the very optimistic growth forecasts, which many fine chemical companies, had announced. They had been based on equally promising sector reports from investment banks, which in turn had evolved from forward projections of the preceding boom period. In most cases, these projections have been missed by a large margin. At the end of the “irrational exuberance” at the turn of the millennium and again in 2009 almost half of the industry achieved a return on sales (ROS) of more than 10%, and less than 10% an ROS below 5%. In the worst years, 2003 and 2009, almost half of the companies suffered from an ROS of less than 5%. Whereas during the period under review, 2000–2009. the average EBITDA / sales and EBIT / sales ratios of representative companies, resp. divisions were 15% and 7½%, respectively, in the period 2000–2009, the numbers were 20% and 10–13% in the boom, and 10% and 5% in the bust phases. The factor 2 between the high and low numbers reflects the volatility of the industry’s profitability. All in all, the average Western fine-chemical firms have been making a return below the cost of capital, i.e. they are not reinvestment grade. Two main trends impinge on the industry
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Fine chemical On the "supply side", biotechnology is rapidly gaining importance. In the synthesis of small molecule fine chemicals, the use of biocatalysts and microbial fermentation enable both a more sustainable and economic production than conventional organic chemistry. In the synthesis of big molecules, such as biopharmaceuticals, it is the method of choice. Biopharmaceuticals are expected to grow 15% per year, three times as fast as small molecule drugs. Five of the top ten drugs were biopharmaceuticals in 2010 (see table 6), and this is expected to grow to eight by 2016 (see table 2). On the "demand side", the main customer base for fine chemicals, the pharmaceutical industry, is faced with slower growth of demand, patent expirations of many lucrative blockbuster drugs and stalling new product launches. In order to restrain these challenges, the leading companies are implementing restructuring programs. They comprise a reduction of in-house chemical manufacturing and plant eliminations. Outsourcing is moving up from a purely opportunistic to a strategic approach. It is difficult to make a judgment, whether the positive or negative effects of these initiatives will prevail. In a worst-case scenario, a condition could develop, whereby even top-tier mid-sized, family-owned fine-chemical companies with state-of-the-art plants and processes could be relegated to producing small quantities of fine chemicals for new life-science products in late stage of development
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https://en.wikipedia.org/wiki?curid=3694845
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Fine chemical In agro fine chemicals, the active ingredients become more sophisticated and performing. Therefore, they require multipurpose instead of dedicated plants prevailing in the industry so far. At the same token, outsourcing is gaining ground. "Globalization" results in a shift of fine chemical production from the industrialized to developing countries. The latter benefit not only from a “low cost / high skill” advantage, but also from a rapidly rising domestic demand for Western medicine. Despite the mantras of Western industry leaders, the cost advantage of the Asian producers is going to persist. As the pharmemerging countries mainly use generics, their market share continues to grow to the detriment of originator pharmaceuticals and agrochemicals. This is also the case for biosimilars, the generic versions of biopharmaceuticals. As a consequence of the harsh business climate, many Western fine chemical companies or divisions created during the “irrational exuberance” at the end of the 20th century already have exited from the sector. Others will follow suit or will be acquired by private equity firms. Survival strategies include implementation of lean production principles originally developed by the automotive industry and extending the business model to include also contract research at the beginning and active drug formulation towards the end of the added value chain. This latter strategy, however, is not finding unanimous approval by industry experts
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https://en.wikipedia.org/wiki?curid=3694845
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Fine chemical Although the demand for fine chemicals on the merchant market has not grown to the extent originally anticipated, fine chemicals still provide attractive opportunities for well-run companies, which are fostering the critical success factors, namely running fine chemicals as a core business, pursuing niche technologies—primarily biotechnology—and taking advantage of the opportunities offered by the Asian market. Pollak, Peter (2011). Fine Chemicals – The Industry and the Business (2nd. rev. ed.). J. Wiley & Sons. .
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https://en.wikipedia.org/wiki?curid=3694845
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Jörgen Lehmann Jörgen Erik Lehmann (15 January 1898 – 26 December 1989) was a Danish-born Swedish physician and chemist best known for his discovery in the 1940s that para-amino salicylic acid (PAS) would make an excellent orally-available tuberculosis therapy. PAS was, together with streptomycin, the first efficacious anti-microbial therapy for tuberculosis and remained in clinical use for several decades. In 1941, Lehmann also developed the anti-coagulant dicumarol, which is used for the prevention of blood clots and in the treatment of deep venous thrombosis. Lehmann studied under Torsten Thunberg, professor of physiology in Lund, who discovered the dehydrogenases. Lehmann was appointed professor of physiology in Aarhus in 1937, and became head of the central laboratory at the Sahlgrenska University Hospital in Gothenburg 1938. After retiring in 1963, Lehmann continued his research at the Nobel Laureate Arvid Carlsson's institution at the University of Gothenburg. was son of Edvard Lehmann, professor of History of Religions at Lund University and grandnephew of the Danish politician Orla Lehmann.
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https://en.wikipedia.org/wiki?curid=3694890
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Karl Grobben (27 August 1854, in Brno – 13 April 1945, in Salzburg) was an Austrian biologist. He graduated from, and later worked at, the University of Vienna, chiefly on molluscs and crustaceans. He was also the editor of a new edition of Carl Friedrich Wilhelm Claus' "Lehrbuch der Zoologie", and the coiner of the terms "protostome" and "deuterostome". Taxa named by Grobben include: Taxa named in Grobben's honour include:
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https://en.wikipedia.org/wiki?curid=3697442
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Geological resistance is a measure of how well minerals resist erosive factors, and is based primarily on hardness, chemical reactivity and cohesion. The more hardness, less reactivity and more cohesion a mineral has, the less susceptible it is to erosion. Over time, differences in geological resistance in the same geological formation can lead to the formation of columns and arches, like those in Moab, Utah; and of bridges, like Utah's Rainbow Bridge.
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https://en.wikipedia.org/wiki?curid=3700900
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Peter Pulay (Born September 20, 1941 in Veszprém, Hungary) is a theoretical chemist. He is the Roger B. Bost Distinguished Professor of Chemistry in the Department of Chemistry and Biochemistry at the University of Arkansas, U.S. One of his most important contributions is the introduction of the gradient method in quantum chemistry. This allows the prediction of the geometric structure of a molecule using computational chemical programs to be almost routine. He is the main author of the PQS computational chemistry program. His work was cited in the official background material for the 1998 Nobel Prize in chemistry. Among many honors he was made a Foreign Member of the Hungarian Academy of Sciences in 1993. He is a member of the International Academy of Quantum Molecular Science.
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https://en.wikipedia.org/wiki?curid=3707012
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Solvent exposure occurs when a chemical, material, or person comes into contact with a solvent. Chemicals can be dissolved in solvents, materials such as polymers can be broken down chemically by solvents, and people can develop certain ailments from exposure to solvents both organic and inorganic. Some common solvents include acetone, methanol, tetrahydrofuran, dimethylsulfoxide, and water among countless others. In biology, the solvent exposure of an amino acid in a protein measures to what extent the amino acid is accessible to the solvent (usually water) surrounding the protein. Generally speaking, hydrophobic amino acids will be buried inside the protein and thus shielded from the solvent, while hydrophilic amino acids will be close to the surface and thus exposed to the solvent. However, as with many biological rules exceptions are common and hydrophilic residues are frequently found to be buried in the native structure and vice versa. can be numerically described by several measures, the most popular measures being accessible surface area and relative accessible surface area. Other measures are for example: Lee B, Richards F. (1971) The interpretation of protein structures: estimation of static accessibility. J. Mol. Biol. 55:379-400 Greer J, Bush B. (1978) Macromolecular shape and surface maps by solvent exclusion. Proc. Natl. Acad. Sci. USA 75:303-307. Connolly M. (1983) Solvent-accessible surfaces of proteins and nucleic acids. Science 221:709-713 Chakravarty S, Varadarajan R
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Solvent exposure (1999) Residue depth: a novel parameter for the analysis of protein structure and stability. Structure Fold. Des. 7:723-732. Pintar A, Carugo O, Pongor S. (2003) Atom depth in protein structure and function. Trends Biochem. Sci. 28:593-597. Hamelryck T. (2005) An amino acid has two sides: A new 2D measure provides a different view of solvent exposure. Proteins Struct. Func. Bioinf. 59:38-48.
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https://en.wikipedia.org/wiki?curid=3708060
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Erwin Lindner (7 April 1888 – 30 November 1988) was a German entomologist mainly interested in Diptera. He was born in Böglins, Memmingen and died in Stuttgart, aged 100 years. In 1913 joined the State Museum of Natural History Stuttgart and was head of the Department of Entomology there until 1953. He edited "Die Fliegen der paläarktischen Region" (the Flies of the Palaearctic Region), a twelve-volume seminal work on the systematics and anatomy of the flies of the Palearctic ecozone. Lindner, a passionate collector, participated in several expeditions traveled to Dalmatia, the Gran Chaco, Anatolia, Liguria, East Africa, Italy, Spain and the regions of the Alps.
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https://en.wikipedia.org/wiki?curid=3708919
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SIGMET SIGMET, or Significant Meteorological Information AIM 7-1-6 , is a weather advisory that contains meteorological information concerning the safety of all aircraft. There are two types of SIGMETs: convective and non-convective. The criteria for a non-convective to be issued are severe or greater turbulence over a area, severe or greater icing over a area or IMC over a area due to dust, sand, or volcanic ash. This information is usually broadcast on the ATIS at ATC facilities, as well as over VOLMET stations. They are assigned an alphabetic designator from N through Y (excluding S and T). SIGMETs are issued as needed, and are valid up to four hours. SIGMETS for hurricanes and volcanic ash outside the CONUS are valid up to six hours. A Convective is issued for convection over the Continental U.S. Convective SIGMETs are issued for an area of embedded thunderstorms, a line of thunderstorms, thunderstorms greater than or equal to VIP level 4 affecting 40% or more of an area at least 3000 square miles, and severe surface weather including surface winds greater than or equal to 50 knots, hail at the surface greater than or equal to 3/4 inches in diameter, and tornadoes. Severe thunderstorms are characterized by tornado(s), hail 3/4 inches or greater, or wind gusts 50 knots or greater. A Convective is valid for no more than 2 hours and they are issued hourly at Hour+55.
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https://en.wikipedia.org/wiki?curid=3709962
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Anemoscope An anemoscope is a device invented to show the direction of the wind, or to foretell a change of wind direction or weather. Hygroscopic devices, in particular those utilizing catgut, were considered as very good anemoscopes, seldom failing to foretell the shifting of the wind. The ancient anemoscope seems, by Vitruvius's description of it, to have been intended to show which way the wind actually blew, rather than to foretell into which quarter it would change. Otto von Guericke gave the title "anemoscope" to a machine invented by him to foretell the change of the weather, as to fair and rain. It consisted of a small wooden man who rose and fell in a glass tube as the atmospheric pressure increased or decreased. Accordingly, M. Comiers has shown that this was simply an application of the common barometer. This form of the anemoscope was invented by Leonardo da Vinci.
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https://en.wikipedia.org/wiki?curid=3710466
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