Guanosine pentaphosphate

(p)ppGpp, guanosine pentaphosphate or tetraphosphate is an alarmone which is involved in the stringent response in bacteria, causing the inhibition of RNA synthesis when there is a shortage of amino acids present. This causes translation to decrease and the amino acids present are therefore conserved. Furthermore, ppGpp causes the up-regulation of many other genes involved in stress response such as the genes for amino acid uptake (from surrounding media) and biosynthesis.
Discovery.
ppGpp and pppGpp were first identified by Michael Cashel in the 1960s. These nucleotides were found to accumulate rapidly in "Escherichia coli" cells starved for amino acids, and inhibit synthesis of ribosomal and transfer RNAs. It is now known that (p)ppGpp is also produced in response to other stressors, including carbon and phosphate starvation.
Absence of (p)ppGpp.
A complete absence of (p)ppGpp causes multiple amino acid requirements, poor survival of aged cultures, aberrant cell division, morphology, and immotility, as well as being locked in a growth mode during entry into starvation.
Synthesis and degradation of (p)ppGpp.
The synthesis and degradation of (p)ppGpp have been most extensively characterized in the model system "E. coli". (p)ppGpp is created via pppGpp synthase, also known as RelA, and is converted from pppGpp to ppGpp via pppGpp phosphohydrolase. RelA is associated with about every one in two hundred ribosomes and it becomes activated when an uncharged transfer RNA (tRNA) molecule enters the A site of the ribosome, due to the shortage of amino acid required by the tRNA. If a mutant bacterium is "relA"− it is said to be relaxed and no regulation of RNA production due to amino acid absence is seen.
"E. coli" produces a second protein responsible for degradation of (p)ppGpp, termed SpoT. When the amino acid balance in the cell is restored, (p)ppGpp is hydrolysed by SpoT. This protein also has the capacity to synthesize (p)ppGpp, and seems to be the primary synthase under certain conditions of stress. Most other bacteria encode a single protein that is responsible for both synthesis and degradation of (p)ppGpp, generally homologs of SpoT.
Targets of (p)ppGpp.
Targets of (p)ppGpp include rRNA operons, of which there are seven in "Escherichia coli" (a commonly used bacterial model organism), all of which have 2 promoters. When (p)ppGpp associates with the promoter it affects the RNA polymerase enzyme's ability to bind and initiate transcription. It is thought that (p)ppGpp may affect the stability of the open complex formed by RNA polymerase on DNA and therefore affect promoter clearance. Its presence also leads to an increase in pausing during transcription elongation and it competes with nucleoside triphosphate substrates.
There is now a consensus that (p)ppGpp is a determinant of growth rate control rather than nucleoside triphosphate (NTP) substrate concentrations.
Impact of (p)ppGpp on bacterial physiology.
Inhibition of growth by inhibition of protein synthesis.
ppGpp inhibits IF2-mediated fMet-Phe initiation dipeptide formation, probably by interfering with 30S and 50S subunit interactions. E. coli accumulates more ppGpp than pppGpp during amino acid starvation, and ppGpp has about 8-fold greater efficiency than that of pppGpp. While B. subtilis accumulates more pppGpp than ppGpp.
Inhibition of DNA replication.
In E. coli amino acid starvation inhibited DNA replication at the initiation stage at oriC, most probably owing to the lack of the DnaA replication initiation protein. In B. subtilis, the replication arrest due to (p)ppGpp accumulation is caused by the binding of an Rtp protein to specific sites about 100-200kb away from oriC in both directions. DNA primase (DnaG) was directly inhibited by (p)ppGpp. Unlike E. coli, B. subtilis accumulates more pppGpp than ppGpp; the more abundant nucleotide is a more-potent DnaG inhibitor. ppGpp can bind with Obg protein which belongs to the conserved, small GTPase protein family. Obg protein interacts with several regulators (RsbT, RsbW, RsbX) necessary for the stress activation of sigma B.
Impact on phage replication and development.
The (p)ppGpp levels of the host seem to act as a sensor for phage lambda development, primarily affecting transcription. Modest ppGpp levels inhibit pR and active pE, pI, and paQ promoters in vivo and have effects in vitro that seem to favor lysogeny. In contrast, absent or high concentrations of (p)ppGpp favor lysis. Modest ppGpp levels favor lysogeny by leading to low HflB (FtsH). When ppGpp is either absent or high, HflB protease levels are high; this leads to lower CII (a lysogeny-promoting phage protein)
and favors lysis.
Impact on transcription.
Characteristics of affected promoters.
One of the key elements of promoters inhibited by (p)ppGpp is the presence of a GC-rich discriminator, defined as a region between TATA-box (-10 box) and +1 nt (where +1 is the transcription start site). Promoters negatively regulated by ppGpp have a 16-bp linker, in contrast with the 17-bp consensus. Promoters activated by ppGpp seem to have an AT-rich discriminator and linger linkers (for example, the "his" promoter linker is 18 bp).
RNAP is the target.
Genetic evidence suggesting that RNAP was the target of ppGpp came from the discovery that M+ mutants (also called stringent RNAP mutants) display in vitro and in vivo mimicry of physiology and transcription regulation conferred by (p)ppGpp, even in its absence. Cross-linking ppGpp to RNAP reinforced this notion. Structural details of an association between ppGpp and RNAP came from the analysis of cocrystals that positioned ppGpp in the secondary channel of RNAP near the catalytic center.
DksA augments regulation.
DksA is a 17-kDa protein, its structure is similar to GreA and GreB, which are well-characterized transcriptional elongation factors. GreA and GreB bind directly to RNAP rather than DNA and act by inserting their N-terminal coiled-coil finger domain through the RNAP secondary channel. Two conserved acidic residues at the tip of the finger domain are necessary to induce RNAP's intrinsic ability to cleave backtracked RNA. DksA also possesses two acidic residues at its finger tip, but it does not induce nucleolytic cleavage activity. Instead, these residues are proposed to stabilize ppGpp binding to RNAP by mutual coordination of an Mg2+ ion that is crucial for polymerization.
Transcription inhibition and activation.
ppGpp directly inhibits transcription from ribosomal promoters. One model is ppGpp and DksA together and independently decrease the stability of the open complexes formed on DNA by RNAP. Another model is the trapping mechanism. In this model, RNAP is trapped by ppGpp in closed complexes and is unable to initiate transcription. Thus, ppGpp seems to act at many levels, and the mechanism of its action is a complex outcome of several factors, intrinsic promoter properties not being the least of them. The transcription activation by ppGpp can be direct or indirect. Direct activation occurs when RNAP interacts with effectors, such as ppGpp, DksA or both, to increase transcription from a given promoter. Indirect activation by these effectors of one promoter relies on inhibition of other (strong) promoters, leading to increased availability of RNAP that indirectly activates transcription initiation. The promoters that activated directly by ppGpp include P"argI", P"thrABC", P"livJ", and P"hisG". The indirectly activation promoters include these dependent on sigma factors: S, H, N, E. When strong promoters, such as "rrn", are inhibited, there more RNAP are available for these alternative sigma factors.
Pathogenesis and (p)ppGpp.
When (p)ppGpp is absent, pathogenicity is compromised for reasons that vary with the organism studied. Deleting "rel"A and "spo"T genes, but not "rel"A alone, gave a (p)ppGpp0 state that resulted in strong attenuation in mice and noninvasiveness in vitro. Vaccine tests reveal that 30 days after single immunization with the (p)ppGpp0 strain, mice were protected from challenge with wild-type Salmonella at a dose 106-fold above the established LD50.
Polyphosphate accumulation.
It was proposed that increased synthesis of (p)ppGpp would cause polyphosphate (PolyP) accumulation in "E. coli" and . The alarmone could interact with exopolyphospahatase PPX, which would inhibit the hydrolysis of PolyP, thus causing its accumulation in bacteria. Although it has recently been shown that it is actually DksA and not (p)ppGpp that causes this buildup. It has been shown in "Pseudomonas aeruginosa" that the "phoU" mutant ("phoU" belongs to the Pho Regulon) synthesizes more (p)ppGpp and this would be one of the reasons that it accumulates more polyphosphate.


Xenorhabdus

Xenorhabdus is a genus of motile, gram-negative bacteria from the family of the Morganellaceae. All the species of the genus are only known to live in symbiosis with soil entomopathogenic nematodes from the genus "Steinernema".
Although no free-living forms of Xenorhabdus have ever been isolated outside of the nematode host, the benefits for the bacteria are still unknown.
However, it has been demonstrated that the nematode can't establish within his insect host without the bacteria.
The tripartite Xenorhabdus-nematode-insect interaction represents a model system in which both mutualistic and pathogenic processes can be studied in a single bacterial species.
In laboratory, some species are virulent directly injected within the insect host, whereas others species need the nematode to penetrate into the insect.
Lifecycle.
"Xenorhabdus" like "Photorhabdus" bacteria has a striking feature of phase variation. Phase I variants are involved in the symbiotic relationship with entomopathogenic nematodes and are isolated from the nonfeeding infective stage nematodes and the body cavities of insects killed by these nematodes. No role in symbiosis has yet been determined for phase II, which is associated only with entomopathogenic nematodes under laboratory conditions.
Biological pest control.
The mutualistic association between "Xenorhabdus" and "Steinernema" represent an insectidical complex, active against a large range of insect pests.
Indeed, the complex is used in biological pest control, and is very efficient against insects such as "Spodoptera exigua" (Lepidoptera), "Cydia pomonella" (Lepidoptera), "Leptinotarsa decemlineata" (Coleoptera), family Tipulidae (Diptera). These bacteria inhabit the gut of the Asian corn borer, a moth pest of maize in East Asia, and kills it within 48 hours.
"Xenorhabdus nematophila" is the most widely used species in biological control, in association with "Steinernema carpocapsae" and "S. feltiae".
The pathogenicity of the complex is "species-specific", which means that the complex can only be active against a specific range of insects.
The Steinernema-Xenorhabdus association is currently sold as a biocontrol agent by private companies, like Biobest, SUMI AGRO, and Biosafe.
Perspectives.
A study carried out by Furgani G. & Al
suggests that the antibiotic compounds produced by Xenorhabdus to preserve the insect cadaver from others bacteria may be used in the aim of controlling mastitis caused by bacteria. Indeed, "X. budapestensis", "X. szentirmaii" and "X. nematophila" appear to be efficient against pathogens such as "Staphylococcus aureus" and "Escherichia coli".


Cell Biology International

Cell Biology International is a peer-reviewed scientific journal published by Portland Press for the International Federation for Cell Biology. The journal was established in 1977 as "Cell Biology International Reports" () and published by Elsevier, obtaining its current name in 1993. The journal was transferred to Portland Press in 2010. It covers all aspects of cell biology.
Abstracting and indexing.
The journal is abstracted and indexed in:
According to the "Journal Citation Reports", the journal has a 2010 impact factor of 1.747.


Christopher J. Hardy

Christopher J. Hardy (born 1955) is an American physicist and inventor of several magnetic resonance imaging (MRI) subsystem technologies for use in real time MRI and cardiac MR imaging and spectroscopy.
Biography.
Hardy obtained his Ph.D. from the University of Illinois at Urbana-Champaign in March, 1983. He is currently a principal scientist and Coolidge Fellow at General Electric. He developed the first graphical approach that allowed physicians to explore anatomy in real time during cardiac MRI, as opposed to viewing groups of images at a later time, and he also developed a technique that improved imaging speed. Both accomplishments have gained widespread use. He has also led the teams that developed 32 channel and 128 channel General Electric MRI systems.
Hardy has written 98 research papers and 54 patents.


Four-toed elephant shrew

The four-toed elephant shrew or four-toed sengi is the only living species in the genus Petrodromus, which together with five other extant genera "Rhynchocyon", "Macroscelides", "Petrosaltator", "Galegeeska" and "Elephantulus" constitutes the order Macroscelidea. This species is only found in particular regions in Africa and is smaller in size compared to its relatives. A comprehensive recording of this species is lacking.
As its name suggests, the species has four toes on its hind feet, and like other elephant shrews, it has been named for its elephant-like, mobile proboscis.
Geographic location and habitat.
The four-toed elephant shrew is located in Central and Southern East Africa, notably in Angola, Democratic Republic of the Congo, Kenya, Malawi, Mozambique, South Africa, Tanzania, Zambia, Zimbabwe, and possibly Namibia. Its natural habitats are subtropical or tropical dry forests, montane forests, and moist savannas lowland forests.
 Throughout these countries, they are the second most widespread species, following the short-snouted elephant shrew.
Specifically, they thrive in dense forests (notably in dense evergreen growths), woodlands and thickets, with suitable cover and protection, as well as invertebrates for food. In these areas, they are the second most common species. During the night, they prefer to sleep under dense brush (as opposed to a nest).
In some areas, their habitats are being destroyed and four-toed elephant shrews are being hunted, but their conservation status is of least concern.
Physical characteristics.
A four-toed elephant shrew has long, soft fur and its color varies from greyish pale brown to dark brown with white rings around its eyes, and wide dark stripes on its back.
Markings of the four-toed elephant shrew vary in colour: the upper parts of its feet are brownish-yellow; its ears are dark brown, with pure white hair on the base of the inner margin; the tail is black on the upper side and pale yellow-brown on the underside, darkening in the middle and almost black at tip.
The four-toed elephant shrew has a long, pointed, flexible and sensitive snout, which it uses to hunt. It also has short forelimbs and long back limbs.
The differences between the regular elephant shrew and the four-toed elephant shrew can be seen in facial features, body length and weight. Compared to the regular elephant shrew, which has small eyes and ears, a four-toed elephant shrew has broad, upstanding ears and large eyes. The elephant shrew generally varies in size from about .
However, the body length of the four-toed elephant shrew is less variable, . Similarly, the tail length of the regular elephant shrew is , while tail length of the four-toed species is .
The elephant shrew is a small mammal weighing from , while the four-toed elephant shrew is one of largest elephant shrews, weighing between .
Behaviour.
The four-toed elephant shrew is mostly active during the day and early evening, whereas during the night or midday, it tends to be less active. When the four-toed elephant shrew runs, its tail points upwards; it also makes a noise through its hind feet. Ants react to this sound, which helps the four-toed elephant shrew to locate its prey.
When four-toed elephant shrews fight, they usually fight in pairs of the same gender. They fight in a "boxing" motion, supporting themselves on their rear legs and boxing with their front limbs to tackle one another. Four-toed elephant shrews have good senses of sight, smell and hearing, but their vocal capacity is not well developed. In captivity, they make different kinds of sounds, such as screaming, purring or clucking for help.
Diet.
Four-toed elephant shrews are heavily dependent on rich leaf litter composition for their food and nests. Their main prey are small invertebrates. Ants and termites are most common, as well as crickets, grasshoppers, spiders, centipedes, millipedes, and earthworms. Seeds, fruits, buds, and other plant material also form part of their diets. Four-toed elephant shrews eat much like anteaters; they flick small foods into their mouths.
Based on where these four-toed elephant shrews live, their main diets can vary. In Kenya, their diets include termites, plant matter, centipedes, ants, crickets and cockroaches, millipedes, spiders, and other similar creatures.
Some of the predators of the four-toed shrews are snakes, raptors, and carnivores, and in some cases, domestic cats.
Reproduction.
Depending on the quality of the habitat, four-toed elephant shrews breed throughout the year, showing an increase in reproduction when more feeding grounds are accessible. The lowland forests and savannas offer shelter from the midday heat and resting places, as well as suitable birth places. Copulation typically occurs on land, and they are monogamous in nature. Their mating patterns involve sexual intercourse over several days, after which each mate returns to its solitary lifestyle. Gestation lasts between 40 and 60 days and one or two offspring are born. The young are born in a highly developed state and are weaned by their mothers after 15–25 days; the young reach full sexual maturity close to 50 days after birth.


Lesser hedgehog tenrec

The lesser hedgehog tenrec ("Echinops telfairi") is a species of mammal in the family Tenrecidae.
It is the only species in the genus Echinops and is named in honour of Charles Telfair.
Distribution and habitat.
It is endemic to Madagascar. Its natural habitats are subtropical or tropical dry forests, dry savanna, subtropical or tropical dry shrubland, and subtropical or tropical dry lowland grassland.
Description.
The lesser hedgehog tenrec is a small, stout-bodied animal similar to the hedgehog, hence the name. Their tails are short, their limbs and muzzles are of moderate length, and their ears are prominent. The entire dorsum is covered with sharp spines. Color is usually yellow buff; individuals range from near white to almost black. Head and body length is . Weight is about .
Tenrecs have a cloaca (common uro-genital opening), like a bird or a reptile.
Behavior.
This tenrec is terrestrial. It spends its daytime hours resting under a log, a pile of branches, leaves, straws or in a hollow tree, although trees are widely scattered in its native habitat. In hot weather, it sleeps with its body extended, but otherwise lies in a curled position to rest. It enters a state of torpor in the winter time.
They mostly feed upon insects but may prey on small vertebrates, and usually forage alone, except for a mother with her young.
Breeding is known to occur in October but may depend on warm weather first arousing the animals from winter torpor and on an available food supply.
The Lesser hedgehog tenrec is a host of the Acanthocephalan intestinal parasite "Promoniliformis ovocristatus".
Captivity.
The lesser hedgehog tenrec has become popular in the exotic pet industry.


Metabolic pathway

In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reactions catalyzed by enzymes. In most cases of a metabolic pathway, the product of one enzyme acts as the substrate for the next. However, side products are considered waste and removed from the cell. These enzymes often require dietary minerals, vitamins, and other cofactors to function.
Different metabolic pathways function based on the position within a eukaryotic cell and the significance of the pathway in the given compartment of the cell. For instance, the, electron transport chain, and oxidative phosphorylation all take place in the mitochondrial membrane. In contrast, glycolysis, pentose phosphate pathway, and fatty acid biosynthesis all occur in the cytosol of a cell.
There are two types of metabolic pathways that are characterized by their ability to either synthesize molecules with the utilization of energy (anabolic pathway), or break down complex molecules and release energy in the process (catabolic pathway). The two pathways complement each other in that the energy released from one is used up by the other. The degradative process of a catabolic pathway provides the energy required to conduct the biosynthesis of an anabolic pathway. In addition to the two distinct metabolic pathways is the amphibolic pathway, which can be either catabolic or anabolic based on the need for or the availability of energy.
Pathways are required for the maintenance of homeostasis within an organism and the flux of metabolites through a pathway is regulated depending on the needs of the cell and the availability of the substrate. The end product of a pathway may be used immediately, initiate another metabolic pathway or be stored for later use. The metabolism of a cell consists of an elaborate network of interconnected pathways that enable the synthesis and breakdown of molecules (anabolism and catabolism).
Overview.
Each metabolic pathway consists of a series of biochemical reactions that are connected by their intermediates: the products of one reaction are the substrates for subsequent reactions, and so on. Metabolic pathways are often considered to flow in one direction. Although all chemical reactions are technically reversible, conditions in the cell are often such that it is thermodynamically more favorable for flux to proceed in one direction of a reaction. For example, one pathway may be responsible for the synthesis of a particular amino acid, but the breakdown of that amino acid may occur via a separate and distinct pathway. One example of an exception to this "rule" is the metabolism of glucose. Glycolysis results in the breakdown of glucose, but several reactions in the glycolysis pathway are reversible and participate in the re-synthesis of glucose (gluconeogenesis).
Major metabolic pathways.
Catabolic pathway (catabolism).
A catabolic pathway is a series of reactions that bring about a net release of energy in the form of a high energy phosphate bond formed with the energy carriers adenosine diphosphate (ADP) and guanosine diphosphate (GDP) to produce adenosine triphosphate (ATP) and guanosine triphosphate (GTP), respectively. The net reaction is, therefore, thermodynamically favorable, for it results in a lower free energy for the final products. A catabolic pathway is an exergonic system that produces chemical energy in the form of ATP, GTP, NADH, NADPH, FADH2, etc. from energy containing sources such as carbohydrates, fats, and proteins. The end products are often carbon dioxide, water, and ammonia. Coupled with an endergonic reaction of anabolism, the cell can synthesize new macromolecules using the original precursors of the anabolic pathway. An example of a coupled reaction is the phosphorylation of fructose-6-phosphate to form the intermediate fructose-1,6-bisphosphate by the enzyme phosphofructokinase accompanied by the hydrolysis of ATP in the pathway of glycolysis. The resulting chemical reaction within the metabolic pathway is highly thermodynamically favorable and, as a result, irreversible in the cell.
<chem>Fructose-6-Phosphate + ATP -> Fructose-1,6-Bisphosphate + ADP</chem>
Cellular respiration.
A core set of energy-producing catabolic pathways occur within all living organisms in some form. These pathways transfer the energy released by breakdown of nutrients into ATP and other small molecules used for energy (e.g. GTP, NADPH, FADH). All cells can perform anaerobic respiration by glycolysis. Additionally, most organisms can perform more efficient aerobic respiration through the citric acid cycle and oxidative phosphorylation. Additionally plants, algae and cyanobacteria are able to use sunlight to anabolically synthesize compounds from non-living matter by photosynthesis.
Anabolic pathway (anabolism).
In contrast to catabolic pathways, anabolic pathways require an energy input to construct macromolecules such as polypeptides, nucleic acids, proteins, polysaccharides, and lipids. The isolated reaction of anabolism is unfavorable in a cell due to a positive Gibbs Free Energy (+Δ"G"). Thus, an input of chemical energy through a coupling with an exergonic reaction is necessary. The coupled reaction of the catabolic pathway affects the thermodynamics of the reaction by lowering the overall activation energy of an anabolic pathway and allowing the reaction to take place. Otherwise, an endergonic reaction is non-spontaneous.
An anabolic pathway is a biosynthetic pathway, meaning that it combines smaller molecules to form larger and more complex ones. An example is the reversed pathway of glycolysis, otherwise known as gluconeogenesis, which occurs in the liver and sometimes in the kidney to maintain proper glucose concentration in the blood and supply the brain and muscle tissues with adequate amount of glucose. Although gluconeogenesis is similar to the reverse pathway of glycolysis, it contains three distinct enzymes from glycolysis that allow the pathway to occur spontaneously. An example of the pathway for gluconeogenesis is illustrated in the image titled "Gluconeogenesis Mechanism".
Amphibolic pathway.
An amphibolic pathway is one that can be either catabolic or anabolic based on the availability of or the need for energy. The currency of energy in a biological cell is adenosine triphosphate (ATP), which stores its energy in the phosphoanhydride bonds. The energy is utilized to conduct biosynthesis, facilitate movement, and regulate active transport inside of the cell. Examples of amphibolic pathways are the citric acid cycle and the glyoxylate cycle. These sets of chemical reactions contain both energy producing and utilizing pathways. To the right is an illustration of the amphibolic properties of the TCA cycle.
The glyoxylate shunt pathway is an alternative to the tricarboxylic acid (TCA) cycle, for it redirects the pathway of TCA to prevent full oxidation of carbon compounds, and to preserve high energy carbon sources as future energy sources. This pathway occurs only in plants and bacteria and transpires in the absence of glucose molecules.
Regulation.
The flux of the entire pathway is regulated by the rate-determining steps. These are the slowest steps in a network of reactions. The rate-limiting step occurs near the beginning of the pathway and is regulated by feedback inhibition, which ultimately controls the overall rate of the pathway. The metabolic pathway in the cell is regulated by covalent or non-covalent modifications. A covalent modification involves an addition or removal of a chemical bond, whereas a non-covalent modification (also known as allosteric regulation) is the binding of the regulator to the enzyme via hydrogen bonds, electrostatic interactions, and Van Der Waals forces.
The rate of turnover in a metabolic pathway, also known as the metabolic flux, is regulated based on the stoichiometric reaction model, the utilization rate of metabolites, and the translocation pace of molecules across the lipid bilayer. The regulation methods are based on experiments involving 13C-labeling, which is then analyzed by Nuclear Magnetic Resonance (NMR) or gas chromatography-mass spectrometry (GC-MS)-derived mass compositions. The aforementioned techniques synthesize a statistical interpretation of mass distribution in proteinogenic amino acids to the catalytic activities of enzymes in a cell.


Andrew Kennedy (American politician)

Andrew Kennedy (July 24, 1810 – December 31, 1847) was a U.S. Representative from Indiana, cousin of Case Broderick.
Born in Dayton, Ohio, Kennedy moved with his parents to a farm on the Indian reserve near Lafayette, Indiana. He soon afterward moved to Connersville, Indiana, where he became a blacksmith's apprentice. Kennedy attended the common schools and later studied law. He was admitted to the bar in 1833 and commenced practice in Connersville. Kennedy then moved to Muncie (then Muncytown or Muncietown), Indiana, in 1834 and continued the practice of law. He served as member of the Indiana House of Representatives in 1835 and served in the Indiana Senate in 1838.
Kennedy was elected as a Democrat to the Twenty-seventh, Twenty-eighth, and Twenty-ninth Congresses (March 4, 1841 – March 3, 1847). He served as Democratic caucus nominee for United States Senator in 1847. He was stricken with smallpox on the eve of the legislative joint convention and died in Indianapolis, Indiana, December 31, 1847. He was interred in Greenlawn Cemetery. He was reinterred in Beech Grove Cemetery, Muncie, Indiana.


Manu Platt

Manu Omar Platt (born 1980) is an American biomedical engineer who is a Professor at the Georgia Institute of Technology Wallace H. Coulter Department of Biomedical Engineering. He serves as Diversity Director of the Center on Emergent Behaviors of Integrated Cellular Systems.
Early life and education.
Platt is the son of a veteran of the United States Air Force. He spent his high school years in Dover, Delaware. As a high school student, Platt took part in science enrichment programmes at Delaware State University. He earned his undergraduate degree at Morehouse College, where he studied biology as an ARCS Foundation scholar. At Morehouse, Platt was mentored by Robert M. Nerem, and he took part in the Morehouse SPACE scholar programme. On Nerem's advice Platt moved to the Georgia Institute of Technology for his graduate studies, where he worked with Hanjoong Jo on endothelial cell biology. His doctoral research was performed in collaboration with Emory University School of Medicine, as one of the first students to be part of the newly established biomedical engineering program. After earning his doctoral degree he joined Massachusetts Institute of Technology (MIT).
Research and career.
In 2009 Platt was appointed to the faculty of the Coulter Department of Biomedical Engineering at Georgia Tech, where he investigates the proteolytic mechanisms of disease, with a focus on conditions that impact Black communities. He has concentrated on reducing the occurrence of stroke in patients with sickle cell disease.
Platt has investigated how scientific discoveries have impacted the governmental response to HIV/AIDS. He studied the various bills introduced by the United States Congress, and found that whilst the number of bills was related to breakthroughs in scientific research, it did not impact the passage of laws.
Platt is the founding director of "Engaging New Generations at Georgia Tech through Engineering and Science" (ENGAGES), a biotechnology and engineering research scheme for African American high school students. He delivered the 2017 Biomedical Engineering Society lecture, where he spoke about being from an underrepresented group in science, “Often, if you are the first or the only of a particular demographic category, the path is neither well paved, nor well lit,”. He remarked that scientists can feel like they are waiting for the “perfect time,” to be impactful in promoting diversity and inclusion. In 2019 he was selected as a Keystone Symposia Fellow. In response to the George Floyd protests, universities released statements that called out racism within their research institutions. Platt wrote a perspective piece for "Nature Reviews Materials" on racism within academia, in which he wrote, “It is said that science is a meritocracy; however, that only holds true if Black professors’ existence is accepted,”.
Personal life.
Platt is one of six sons, including political science researcher Matthew B. Platt. He is a master of origami.


RNA of unknown function

RNA of unknown function (RUF) is a generic name, often appended with a numeric identifier, for a non-coding RNA molecule which has been partially characterised or predicted but the biological function has yet to be determined. The same convention is used for proteins, they can be named domains of unknown function (DUFs).
Examples of RUFs include:


Toeprinting assay

The toeprinting assay, also known as the primer extension inhibition assay, is a method used in molecular biology that allows one to examine the interactions between messenger RNA and ribosomes or RNA-binding proteins. It is different from the more commonly used DNA footprinting assay. The toeprinting assay has been utilized to examine the formation of the translation initiation complex.
To do a toeprint assay, one need the mRNA of interest, ribosomes, a DNA primer, free nucleotides, and reverse transcriptase (RT), among other reagents. The assay involves letting the RT generate cDNA until it gets blocked by any bound ribosomes, resulting in shorter fragments called toeprints when the results are observed on a sequencing gel.


Autoantigen

autoantigen
[ô′tō·an′tijin]
Etymology: Gk, autos + anti, against, genein, to produce
an endogenous body constituent that stimulates the production of autoantibodies and an autoimmune reaction. An autoantigen associated with Addison's disease has been identified as the enzyme 17 α-hydroxylase. Also called self-antigen. See also antibody-specific model, autoantibody, autoimmune disease.


LPAR4

Lysophosphatidic acid receptor 4 also known as LPA4 is a protein that in humans is encoded by the "LPAR4" gene. LPA4 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).


Hwasong-6

The Hwasong-6 () is a North Korean tactical ballistic missile. It is derived from the Hwasong-5, itself a derivative of the Soviet R-17 Elbrus. It carries the NATO reporting name Scud.
History.
Work on an extended-range version of the Hwasong-5 began in 1988, and with only relatively minor modifications, a new type was produced from 1989, designated Hwasong-6 ("Scud Mod. C" or "Scud-C"). It was first tested in June 1990, and entered full-scale production the same year, or in 1991. It was superseded by the Rodong-1.
To increase range over its predecessor, the Hwasong-6 has its payload decreased to and the length of the rocket body extended to increase the propellant by 25%; accuracy is 700–1,000 meters circular error probability (CEP). Such range is sufficient to strike targets as far away as western Japan. Its dimensions are identical to the original Hwasong-5. Due to difficulties in procuring MAZ-543 TELs, mobile launchers were produced in North Korea. By 1999, North Korea was estimated to have produced 600 to 1,000 Hwasong-6 missiles, of which 25 had been launched in tests, 300 to 500 had been exported, and 300 to 600 were in service with the Korean People's Army. Hwasong-6 was delivered to United Arab Emirates in 1999.
Variant with terminal maneuverability was tested in May 2017. U.S. intelligence referred to the upgraded missile as the KN-18.
Export.
The Hwasong-6 was exported to Iran, where it is designated as the Shahab-2, to Syria, where it is manufactured under licence with Chinese assistance and to Yemen.Myanmar also imported Scud-type Hwasong-6 ballistic missiles in 2009.Uncertain status of Hwasong-6 export to Vietnam.


Insys Therapeutics

Insys Therapeutics was an American specialty pharmaceutical company based in Chandler, Arizona. Its main product was Subsys, a sublingual liquid form of the drug fentanyl. Fentanyl is an extremely fast-acting and powerful opioid used to relieve peaks of pain in cancer patients.
Founded in 1990, the company and its executives are facing legal issues related to the opioid crisis and marketing activities by the company, including accusations of bribes and misleading advertising. Several company executives were convicted of racketeering in a jury trial rendered in May 2019.
Products.
In addition to Subsys, Insys Therapeutics marketed Syndros, a synthetic THC product, and was working toward approval of other cannabis derivatives. Despite delta-9 THC being classified as a Schedule I substance by the U.S. Drug Enforcement Administration, Syndros was classified as a Schedule II substance used in adults to treat loss of appetite (anorexia) in people with AIDS who have lost weight, as well as nausea and vomiting caused by anti-cancer medicines (chemotherapy) in people whose nausea and vomiting have not improved with usual anti-nausea medicines. Syndros was the first and only FDA-approved liquid THC formulation, which allows for fast absorption, flexible dosing, and a potential solution for patients who may prefer a liquid medication. The disparity between the US DEA scheduling of THC and of Syndros is pre- and post-formulation, respectively, according to Title 21 United States Code of Controlled Substances Act.
History.
The company was founded in 1990 by American multi-millionaire John Kapoor, who served as CEO and president after former CEO Michael Babich was arrested. Kapoor retired from Insys in 2017 and was ultimately replaced by Saeed Motahari.
In 2016, the company was ranked No. 52 on the Deloitte Fast 500 North America list.
Legal issues.
Seven former executives and managers employed by Insys were taken into custody by law enforcement on Thursday, December 13, 2016. U.S. Attorney for the District of Massachusetts, Carmen Ortiz, alleged that several former employees of Insys Therapeutics, Inc. – including the former CEO and president of the company – conspired to bribe medical staff in several states to prescribe a specific pain medication to their patients. The accusations were the topic of an NBC special feature report on Megyn Kelly's "Sunday Night" on Sunday, June 4, 2017.
In August 2017, Insys Therapeutics was sued by Arizona Attorney General Mark Brnovich for misleading patients and doctors about the dangers of the drug Subsys, and for lying to insurers about the condition of the patients in a bid to get payment for the drug. He said the firm deceived insurers and pharmaceutical benefit companies into agreeing to pay for the expensive drug by misleading them to believe that the payment request was coming from a doctor's office and not the company making the drug. Brnovich also said those Insys employees misrepresented the medical conditions of the patients, lying that they had breakthrough pain, lying that the patients had tried other medications, and lying that the patients needed the sublingual spray rather than less expensive pills marketed by other firms because they had difficulty swallowing. Insys Therapeutics issued a response to the Arizona filing on their website, stating, in part, that "[t]he allegations contained in the Arizona Attorney General's complaint relate to former employees and physicians that are no longer associated with our Company or our speaker bureau."
In October 2017, Insys founder John Kapoor was arrested in Arizona and charged with RICO conspiracy, conspiracy to commit wire fraud, and conspiracy to violate the anti-kickback law related to Insys' effort to secure prescriptions of Subsys. Kapoor is also alleged to have conspired to defraud health insurance providers.
In December 2018, former Insys CEO Michael Babich agreed to plead guilty to one count of conspiracy and one count of mail fraud, in connection to bribes paid to doctors and their assistants. In April 2019, Alec Burlakoff, the former vice president of sales for Insys, agreed to pay the State of Arizona $9.5 million in a civil settlement with Attorney General Mark Brnovich for his role in the alleged bribery campaign of doctors to prescribe Insys products to patients. Brnovich had accused Burlakoff of operating a program that paid doctors lucrative "speaking fees" in order to encourage them to prescribe more Subsys, Insys' fentanyl-based pain medication. Burlakoff is required to pay the state $5.2 million from the proceeds he made from the operation, as well as $4.3 million in civil penalties. As part of the settlement, Burlakoff agreed to testify against Insys in ongoing litigation and will be permanently banned from advertising or selling any pharmaceutical drugs in Arizona.
On May 2, 2019, a federal jury found top executives of Insys Therapeutics guilty of racketeering charges. The jury, after deliberating for 15 days, issued guilty verdicts against the company's founder, the one-time billionaire John Kapoor, and four former executives, finding they had conspired to fuel sales of its highly potent drug, Subsys, by not only bribing doctors to prescribe their product but also by misleading insurers about patients' need for the drug. Other Insys employees also found guilty included Richard M. Simon, former national director of sales; Sunrise Lee, regional sales director; Joseph A. Rowan, regional sales director; and Michael J. Gurry, former vice president of managed markets. A sentencing hearing has not been scheduled but is expected to take place in early August 2019. In June 2019, Insys Therapeutics agreed to pay $225 million to settle the federal government's criminal and civil investigations into the company's marketing practices. In January 2020, Kapoor was sentenced by a federal court to five and a half years in prison.
Insys filed for bankruptcy in Delaware Bankruptcy Court on June 10, 2019. Andrew Long, the company's CEO, claims the company is struggling due to: 1) extensive litigation, and 2) declining revenues relating to its Subsys product. The bankruptcy filing came just 10 days after the company reached a settlement with the U.S. Justice Department. The U.S. government has agreed to accept an unsecured claim of $190 million in the case.
Political issues.
In 2016, Insys donated $500,000 to Arizonans for Responsible Drug Policy, a group opposing a marijuana legalization ballot initiative in the state of Arizona. Investor filings confirm the company was concerned about the impact of legalization on sales for a cannabis-based drug it was developing. The reason publicly given for opposing the measure was to "protect children". However, medical marijuana advocates have criticized Insys' position as hypocritical, profit-driven, and an appeal to emotion, as the company actively developed its own cannabis-derived products. In a September 2016 statement, J.P. Holoyak, a representative from the pro-legalization campaign, commented, "It appears they are trying to kill a non-pharmaceutical market for marijuana in order to line their own pockets." That same month, the opposition campaign defended Insys' involvement, stating: "We are grateful that Insys Therapeutics – an Arizona-based company – has chosen to join Governor Ducey, the Arizona Association of County School Superintendents, the Arizona Small Business Association, the Arizona Hospital and Healthcare Association, the Arizona Catholic Conference of Bishops, the Arizona Chamber of Commerce and several other community organizations in defeating Prop. 205 in November." The ballot measure eventually failed to pass, losing 51.32% to 48.68%.
In 2017, U.S. Senator Claire McCaskill released a report and audio recording of an Insys representative allegedly falsely claiming to represent a doctor's office and lying about a patient's diagnosis in order to circumvent prescribing rules for Subsys. The patient later died due to an adverse reaction to her medications.


Cloranolol

Cloranolol (Tobanum) is a beta blocker.
Synthesis.
β-Adrenergic blocker. Prepn:


Ceruletide

Ceruletide (INN), also known as cerulein or caerulein, is a ten amino acid oligopeptide that stimulates smooth muscle and increases digestive secretions. Ceruletide is similar in action and composition to cholecystokinin. It stimulates gastric, biliary, and pancreatic secretion; and certain smooth muscle. It is used in paralytic ileus and as diagnostic aid in pancreatic malfunction. It is used to induce pancreatitis in experimental animal models.
Ceruletide was discovered and its structure elucidated in 1967 by Australian and Italian scientists from dried skins of the Australian green tree frog ("Litoria caerulea", formerly "Hyla caerulea"). Its amino acid sequence is Pglu-Gln-Asp-Tyr[SO3H]-Thr-Gly-Trp-Met-Asp-Phe-NH2.
Induction of pancreatitis.
Ceruletide upregulates pancreatic acinar cell intercellular adhesion molecule-1 (ICAM-1) proteins through intracellular upregulation of NF-κB. Surface ICAM-1 in turn promotes neutrophil adhesion onto acinar cells enhancing pancreatic inflammation. In addition to promoting the inflammatory cell reaction to acinar cells, ceruletide induces pancreatitis through dysregulation of digestive enzyme production and cytoplasmic vacuolization, leading to acinar cell death and pancreatic edema. Ceruletide also activates NADPH oxidase, a source of reactive oxygen species contributing to inflammation, as well as the Janus kinase/signal transducer, another inflammation inducer.


Virander Singh Chauhan

Virander Singh Chauhan is an Indian scientist and a Rhodes Scholar working in the fields of genetic engineering and biotechnology and known for his contributions to the development of a recombinant vaccine for malaria. He was honored by the Government of India in 2012 with the fourth highest Indian civilian award of Padma Shri.
Biography.
Virander Singh Chauhan, born on 3 March 1950, graduated in Chemistry (BSc) from the University of Delhi in 1969 and secured his post graduation (MSc) from the same university in 1971. His career started as the faculty member of Chemistry at the St. Stephen's College, Delhi and continued his research at Delhi University. In 1974, he obtained a Ph.D., after which he moved to Oxford University, on temporary leave from the college, on a Rhodes Scholarship where he stayed till 1977. On his return from the Oxford, he resumed his duties at St. Stephen's College where he worked till 1979. In between, he had a brief stay of one year as a post doctoral fellow at the University of Georgia during 1977-78.
In 1979, Chauhan joined the Indian Institute of Technology, Kanpur as an Assistant Professor and returned to Delhi University in 1982 as the Reader of the Department of Chemistry. In 1986, he was promoted as the Professor and worked there till 1988. Resigning from the university, Chauhan joined the International Centre for Genetic Engineering and Biotechnology (ICGEB), a non profit research organization under the aegis of United Nations Industrial Development Organization as senior scientist and was entrusted the leadership of the workgroup involved in the research on Malaria. In 1998, he was appointed as the Director of the institute, a post he held till 2014.
Positions.
Virander Chauhan is the secretary of the Indian arm of Rhodes Scholarships UK and is a member of the selection committees of such as Inlaks, Felix and Dr. Manmohan Singh scholarships. A former president of the Society of Biological Chemists during 2009-2011, Chauhan is an elected member (1992) of the Indian National Science Academy (INSA), Guha Research Conference and The World Academy of Sciences TWAS. He has served as the president of Indian Peptide Society and as a member of scientific institutions such as New York Academy of Sciences, American Society of Microbiology, Indian Biophysical Society and Indian Immunology Society. He has been a member of the executive councils of Jawaharlal Nehru University, Delhi and the Department of Biotechnology (DBT) for their Indo-US Vaccine Action Programme. He has also been a part of other initiatives by Department of Biotechnology, "Rotaviral Diarrhoea Vaccine Product Development Project" and "Molecular Biophysics and Biochemistry Programme" and has served as the part-time chairman of "Bharat Immunologicals and Biologicals Corporation Limited", a vaccine manufacturing company under DBT.
Chauhan has been associated with international bodies such as the World Health Organization (WHO) as the member of the "Expert Advisory Panel on Vaccines and Biological Standards", International Union of Biochemistry and Molecular Biology (IUBMB) and Asia-Pacific International Molecular Biology Network (A-IMBN), South Korea, as a member of their "Technical Research Groups". He has also been a part of the editorial boards of several national and international journals like "International Journal of Biomedical Science", "Journal of Biomedicine and Biotechnology", Journal of Peptide Science, "Asian Biotechnology and Development Review", "Pakistan Journal of Biological Sciences", "Indian Journal for Biochemistry and Biophysics", Journal of Molecular Structure and "The Open Vaccine Journal".
Legacy.
Virander Chauhan was the leader of the workgroup engaged in the development of a vaccine during his early years in the International Centre for Genetic Engineering and Biotechnology. His team is known to have developed a recombinant vaccine, the first time such vaccine developed entirely in India, which is now in its clinical trials stage. His research has also assisted in the understanding of artemisinin and chloroquine, drugs used in the treatment of Malaria. It is also reported to have helped in the development of "high throughput screens" for the discovery of drugs for Malaria. He has also done research on conventionally defined Peptides, which is of significance for developing antibiotic peptides as well as anti-fibrillizing structures (anti amyloids) that may help in finding treatment protocols for diseases like HIV and Diabetes mellitus type 2. The work has also led to the formation of nanostructures to be used as biomolecule vehicles for site delivery.
Virander Singh Chauhan is known to have guided over 50 research students and is credited with over 200 research papers, published in peer reviewed national and international journals. PubMed, an international knowledge repository, has listed 203 research articles by Chauhan. His papers are also featured on known research databases such as Microsoft Academic Search, PubFacts and Pubget. He has also delivered keynote addresses at many seminars and conferences.
Awards and recognitions.
Virander Chauhan, a Rhodes Scholar of 1974 and a Fellow of the Academy of Sciences for the Developing World (TWAS), received Dr. MOT Iyengar Memorial Award from the Indian Council of Medical Research (ICMR) in 1995. This was followed by Ranbaxy Research Award in 2001, Om Prakash Bhasin Award in 2002 and ICMR Basanti Devi Amir Chand Prize in 2003. He is also a recipient of Raj Kristo Dutt Memorial Award of the Indian Science Congress Association in 2010 and the BioSpectrum Person of the Year Award in 2011. In 2012, the Government of India awarded him the civilian honor of Padma Shri. He also holds the Fellowships of Indian Academy of Sciences, National Academy of Sciences, India, and Indian Society for Parasitology.


Alan J. Russell

Alan J. Russell, Ph.D (born August 8, 1962 in Salford, Greater Manchester UK), is Vice President of Biologics for Amgen, one of the world’s leading Biopharmaceutical companies. Until 2020, Alan was the Highmark Distinguished Career Professor and Director of the Disruptive Health Technology Institute at Carnegie Mellon University. From 2013 through spring of 2016 he was also the Chief Innovation Officer, Allegheny Health Network.
He is married to Maria Caruso and has five children: Hannah, Nessa, Christian, Trevor, and Emily.
Education.
Russell earned his bachelor's degree in Biochemistry and Applied Molecular Biology from the University of Manchester Institute of Science and Technology in 1984, graduating with Honors, First Class. In 1987, he completed his Ph.D. in Biological Chemistry from the Imperial College of Science and Technology, University of London. Russell also served as a NATO Research Fellow in Chemistry at MIT (Massachusetts Institute of Technology) from 1987-1989.
Research.
Russell's initial research centered on enzymes and from that study, Russell and his team described the first use of enzymes in ionic liquids. In addition, the team was the first to describe the use of pressure to control enzyme activity in supercritical fluids, the first stabilization of enzymes for chemical weapon defense and the first use of ATRP to grow polymers from the surface of proteins. Russell also discovered a route to stabilize enzymes by multipoint attachment to polyurethane foams.
His research into ruggedizing enzymes has led to the development of polymer-based protein engineering using ATRP. Russell’s enzyme stabilization technology was singled out for the U.S. Army's Top Ten Greatest Invention Award and products containing the core chemistry (such as the Agentase Chemical Agent Detection Kit) are now used to monitor activities in countries suspected of developing and using chemical weapons.
Russell's expertise in regenerative medicine led to an invite to speak at TED2006. There, Dr. Russell spoke on the potential of regenerative medicine to engineer new tissue and organs to replace sick ones.
Career.
In 1989, Russell joined the faculty of the Department of Chemical Engineering at the University of Pittsburgh as an assistant professor. Promoted to Associate Professor in 1993, Dr. Russell then went on in 1995 to serve as the Chairman of the Department of Chemical and Petroleum Engineering at the university.
In 1999, Russell became the Founding President of the Tissue Engineering and Regenerative Medicine International Society.
In 2001, Russell joined the McGowan Institute for Regenerative Medicine as its founding director. In 2012 Russell joined Carnegie Mellon University as the Highmark Distinguished Career Professor in the Department of Biomedical Engineering, as well as, the founding director of the Disruptive Health Technology Institute or DHTI. DHTI is focused on transformational improvements in the affordability, accessibility, quality, and simplicity of health care solutions. Also in 2012 Russell served as Chair of the College of Fellows for the American Institute for Medical and Biological Engineering, an elected body consisting of the top 2% of medical and bioengineers in the U.S.
Selected works.
Russell is the author of over 200 published works (h-index 62/i10-index 124).
Patents.
Russell’s work has led to the awarding of over 20 patents such as:
Honors.
Russell has received many awards and honors, including the following:
Publication editorial boards.
Dr. Russell serves and has served on the editorial board on many industry publications, such as:
Advisory boards.
In 2015 Dr. Russell was the longest serving member on the FDA’s Science Board. He currently is serving on the board of:
Active in the community, he also serves on the boards of the British-American Connections Pittsburgh and the Pittsburgh Symphony Orchestra.


Gelidibacter algens

Gelidibacter algens is a species of psychrophilic, yellow-pigmented bacteria. It is saccharolytic, exhibits rapid gliding motility, and its cells are rod-like to filamentous. Its type strain is ACAM 536.


GeneCalling

In the field of genomics, GeneCalling is an open-platform mRNA transcriptional profiling technique. The GeneCalling protocol measures levels of cDNA, which are correlated with gene expression levels of specific transcripts. Differences between gene expression in healthy tissues and disease or drug responsive tissues are examined and compared in this technology. The technique has been applied to the study of human tissues and plant tissues.
Method.
In the GeneCalling protocol, mRNAs are first isolated from a given sample and processed into fragments for analysis. This usually involves the synthesis and subdivision of double-stranded cDNAs from polyA RNA. Distinct sets of restriction enzymes can then be used to digest sets of the divided cDNAs and resulting fragments ligated to labelled adapters to be amplified by PCR. PCR products are then purified and subjected to gel electrophoresis on a mounted platform employing stationary laser excitation and a multi-colour charge-coupled device imaging system. A fluorescent label at the 5' end of one of the PCR primers allows for visualization of the PCR fragments, and the cDNAs are subjected to several isolated and identical restriction digests to generate a merged profile based on peak height and variance. The merged digestion profiles from the cDNA preparations are then compared to locate differentially expressed fragments (such as between normal tissue and diseased or drug responsive tissue); these profiles are compared by means of various internet-ready databases such as GeneScape.


Hwasong-5

The Hwasong-5 () is a North Korean tactical ballistic missile derived from the Soviet R-17 Elbrus missile. It is one of several missiles with the NATO reporting name Scud.
History.
North Korea obtained its first R-17 missiles from Egypt in 1979 or 1980, in return for assistance during the Yom Kippur War. As relations with the Soviet Union were rather strained at the time, and Chinese assistance had proven unreliable, the North Koreans set about reverse engineering the Egyptian missiles. This process was accompanied by the construction of a missile-building infrastructure, of which the main elements were the 125 factory at Pyongyang, a research and development institute at Sanum-dong and the Musudan-ri Launch Facility.
The first missile prototypes were completed in 1984. Designated Hwasong-5, and known in the West as the "Scud Mod. A", they were identical to the R-17Es obtained from Egypt. The first test flights occurred in April 1984, but the first version saw only limited production, and no operational deployment, as its purpose was only to validate the production process.
Production of the definitive version of the Hwasong-5 ("Scud Mod. B" or "Scud-B") began at a slow rate in 1985. The type incorporated several minor improvements over the original Soviet design. The range with a 1000 kilogram warhead was increased from 300 to 340 kilometres, and the Isayev engine was slightly modified. An array of payloads was developed, including high explosive (HE), cluster, chemical, and possibly biological warheads. Throughout the production cycle, until it was phased out in favour of the Hwasong-6 in 1989, North Korean manufacturers are thought to have carried out small enhancements, in particular to the guidance system, but the exact details are unknown.
A variant with terminal maneuverability was tested on August 26, 2017. U.S. intelligence referred to the upgraded missile as the KN-21. Although the missile's maneuverability would make it more accurate, few tests were conducted and it wasn't seen after August 2017, suggesting little progress was made and North Korea may have moved on to wholly new missile designs like the KN-23.
Export.
In 1985, Iran acquired 90 to 100 Hwasong-5 missiles from North Korea in a deal worth US$500 million. As part of the deal, North Korea agreed on a missile technology transfer, and it helped Iran establish a production line. In Iran, the Hwasong-5 was produced as the Shahab-1.
The United Arab Emirates purchased a number of Hwasong-5 missiles in 1989. The missiles were decommissioned, allegedly due to unsatisfactory quality yet UAE ordered Hwasong-6 ballistic missiles from North Korea.
In 2008, North Korea made a technology transfer with Myanmar. In December 2006, South Korean press reported that Daewoo signed a deal with the Myanmar government in May 2002 to build an arms factory near Pyi(Bago Division), worth US$133.8 million. Some analysts believe that this deal included the supply of some parts for missile development in Myanmar. In 2014, China confirmed to UN monitors that North Korean-made ballistic, missile-related alloy rods destined for Myanmar had been found on a ship docked in China.


Scaffold/matrix attachment region

The term S/MAR (scaffold/matrix attachment region), otherwise called SAR (scaffold-attachment region), or MAR (matrix-associated region), are sequences in the DNA of eukaryotic chromosomes where the nuclear matrix attaches. As architectural DNA components that organize the genome of eukaryotes into functional units within the cell nucleus, S/MARs mediate structural organization of the chromatin within the nucleus. These elements constitute anchor points of the DNA for the chromatin scaffold and serve to organize the chromatin into structural domains. Studies on individual genes led to the conclusion that the dynamic and complex organization of the chromatin mediated by S/MAR elements plays an important role in the regulation of gene expression.
Overview.
It has been known for many years that a polymer meshwork, a so-called "nuclear matrix" or "nuclear-scaffold" is an essential component of eukaryotic nuclei. This nuclear skeleton acts as a dynamic support for many specialized events concerning the readout a spread of genetic information (see below).
S/MARs map to non-random locations in the genome. They occur at the flanks of transcribed regions, in 5´-introns, and also at gene breakpoint cluster regions (BCRs). Being association points for common nuclear structural proteins S/MARs are required for authentic and efficient chromosomal replication and transcription, for recombination and chromosome condensation. S/MARs do not have an obvious consensus sequence. Although prototype elements consist of AT-rich regions several hundred base pairs in length, the overall base composition is definitely not the primary determinant of their activity. Instead, their function requires a pattern of "AT-patches" that confer the propensity for local strand unpairing under torsional strain.
Bioinformatics approaches support the idea that, by these properties, S/MARs not only separate a given transcriptional unit (chromatin domain) from its neighbors, but also provide platforms for the assembly of factors enabling transcriptional events within a given domain. An increased propensity to separate the DNA strands (the so-called 'stress induced duplex destabilization' potential, SIDD) can serve the formation of secondary structures such as cruciforms or slippage structures, which are recognizable features for a number of enzymes (DNAses, topoisomerases, poly(ADP-ribosyl) polymerases and enzymes of the histone-acetylation and DNA-methylation apparatus). S/MARs have been classified as either being constitutive (acting as permanent domain boundaries in all cell types) or facultative (cell type- and activity-related) depending on their dynamic properties.
While the number of S/MARs in the human genome has been estimated to approach 64,000 (chromatin domains) plus an additional 10,000 (replication foci), in 2007 still only a minor fraction (559 for all eukaryotes) had met the standard criteria for an annotation in the S/MARt database SMARtDB.
Context-dependent properties.
Current views of the nuclear matrix envision it as a dynamic entity, which changes its properties along the requirements of the cell nucleus—much the same as the cytoskeleton adapts its structure and function to external signals. In retrospect it is of note that the discovery of S/MARs has two major routes:
Subsequent work demonstrated both the constitutive (SAR-like) and the facultative (MAR-like) function of the elements depending on the context. Whereas constitutive S/MARs were found to be associated with a DNase I hypersensitive site in 'all' cell types (whether or not the enclosed domain was transcribed), DNAse I hypersensitivity of the facultative type depended on the transcriptional status. The major difference between these two functional types of S/MARs is their size: the constitutive elements may extend over several kilobasepairs whereas facultative ones are at the lower size limit around 300 base pairs.
The figure shows our present understanding of these properties and it incorporates the following findings:
Additional information.
Recently, Tetko has found a strong correlation of intragenic S/MARs with spatiotemporal expression of genes in "Arabidopsis thaliana". On a genome scale, pronounced tissue- and organ-specific and developmental expression patterns of S/MAR-containing genes have been detected. Notably, transcription factor genes contain a significant higher portion of S/MARs. The pronounced difference in expression characteristics of S/MAR-containing genes emphasizes their functional importance and the importance of structural chromosomal characteristics for gene regulation in plants as well as within other eukaryotes.


Liver X receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.
Two isoforms of LXR have been identified and are referred to as LXRα and LXRβ. The liver X receptors are classified into subfamily 1 (thyroid hormone receptor-like) of the nuclear receptor superfamily, and are given the nuclear receptor nomenclature symbols NR1H3 (LXRα) and NR1H2 (LXRβ) respectively.
LXRα and LXRβ were discovered separately between 1994-1995. LXRα isoform was independently identified by two groups and initially named RLD-1 and LXR, whereas four groups identified the LXRβ isoform and called it UR, NER, OR-1, and RIP-15. The human LXRα gene is located on chromosome 11p11.2, while the LXRβ gene is located on chromosome 19q13.3.
Expression.
While the expression of LXRα and LXRβ in various tissues overlap the tissue distribution pattern of these two isoforms differ considerably. LXRα expression is restricted to liver, kidney, intestine, fat tissue, macrophages, lung, and spleen and is highest in liver, hence the name liver X receptor α (LXRα). LXRβ is expressed in almost all tissues and organs hence the early name UR (ubiquitous receptor). The different pattern of expression suggests that LXRα and LXRβ have different roles in regulating physiological function.
Structure.
Crystal structure of human liver X receptor β (LXRβ) forms a heterodimer with its partner retinoid X receptor α (RXRα) on its cognate element an AGGTCA direct repeat spaced by 4 nucleotides showing an extended X-shaped arrangement with DNA- and ligand-binding domains crossed. In contrast, the parallel domain arrangement of other NRs bind an AGGTCA direct repeat spaced by 1 nucleotide. The LXRβ core binds DNA via canonical contacts and auxiliary DNA contacts that enhance affinity for the response element.
Activation/ligands.
LXRα and LXRβ form heterodimers with the obligate partner retinoid X receptor (RXR), which is activated by 9-cis-13,14-dihydroretinoic acid. The LXR/RXR heterodimer can be activated with either an LXR agonist (oxysterols) or a RXR agonist (9-cis-13,14-dihydroretinoic acid). Oxysterols, the oxygenated derivatives of cholesterol, such as 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 27-hydroxycholesterol, and cholestenoic acid, are the natural ligands for LXR. After activation, LXR binds to LXR response element (LXRE), usually a variant of the idealized sequence AGGTCAN4AGGTCA, in the promoters of LXRs' target genes. Some synthetic LXR agonists have been developed, including nonsteroidal LXR agonists T0901317 and GW3965.
The hexacyclic aromatic ketones, (-)anthrabenzoxocinone and (-)bischloroanthrabenzoxocinone ((-)-BABX) derived from a "Streptomyces sp." have micromolar affinity for LXR-α.
LXR-623 (WAY 252623) CAS: [875787-07-8].
Target genes.
Target genes of LXRs are involved in cholesterol and lipid metabolism regulation, including:
Role in metabolism.
The importance of LXRs in physiological lipid and cholesterol metabolism suggests that they may influence the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Evidence for this idea has been observed by recent studies that linked LXR activity to the pathogenesis of atherosclerosis. LXRα knockout mice are healthy when fed with a low-cholesterol diet. However, LXRα knockout mice develop enlarged fatty livers, degeneration of liver cells, high cholesterol levels in liver, and impaired liver function when fed a high-cholesterol diet. LXRβ knockout mice are unaffected by a high-cholesterol diet, suggesting that LXRα and LXRβ have separate roles. LXRs regulate fatty acid synthesis by modulating the expression of sterol regulatory element binding protein-1c (SREBP-1c). LXRs also regulate lipid homeostasis in the brain. LXRα and LXRβ double knockout mice develop neurodegenerative changes in brain tissue. LXRβ knockout mice results in adult-onset motor neuron degeneration in male mice.
Adiponectin induces ABCA1-mediated reverse cholesterol transport by activation of PPAR-γ and LXRα/β.
Potential therapeutic applications of LXR agonists.
LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, anti-inflammation, Alzheimer's disease, and cancer.
Cardiovascular.
Treatment with LXR agonists (hypocholamide, T0901317, GW3965, or N,N-dimethyl-3beta-hydroxy-cholenamide (DMHCA)) lowers the cholesterol level in serum and liver and inhibits the development of atherosclerosis in murine disease models. Synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance by regulating genes involved in glucose metabolism in liver and adipose tissue. GW3965 inhibits the expression of inflammatory mediators in cultured macrophage and inflammation in mice.
Aberrant LXR signaling in macrophages due to the oxidized cholesterol 7-ketocholesterol promotes the inflammation that leads to atherosclerosis. For this reason, 7-ketocholesterol is a therapeutic target for the prevention and treatment of atherosclerosis.
When lipogenesis is increased by pharmacological activation of the liver X receptor, hepatic VLDL production is increased 2.5-fold, and the liver produces large TG-rich VLDL particles. Glucose induces expression of LXR target genes involved in cholesterol homeostasis like ABCA1 which is defective in Tangier disease. A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. LXR heterodimerises with RXR. Promiscuous RXR also heterodimerises with PPAR members. PPAR-α plays a pivotal role in fatty acid catabolism in liver by upregulating the expression of numerous genes involved in mitochondrial fatty acid oxidation. Thus RXR is a common partner of two nuclear receptors acting in opposite directions with regard to fatty acid metabolism. So both LXR and PPAR-α compete for the limited pool of RXR and this dynamic equilibrium determines the direction of lipid metabolism.
Developing new potent and effective LXR agonists without the undesirable side effects may be beneficial for clinical usage. In this regard, DMHCA was reported to reduce atherosclerosis in apolipoprotein E-deficient mice without inducing hypertriglyceridemia and liver steatosis.
Alzheimer's disease.
Treatment with T0901317 decreases amyloidal beta production in an Alzheimer's disease mouse model. However, both T0901317 and GW3965 have been reported to increase plasma and liver triglycerides in some mice models, indicating that T0901317 and GW3965 may not be a good candidate for a therapeutic agent.
Cancer.
LXR agonists (T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol) were also shown to suppress the proliferation of prostate cancer and breast cancer cells as well as delay progression of prostate cancer from androgen-dependent status to androgen-independent status.


Alpha,N-DMT

Alpha,"N"-DMT, or α,"N"-dimethyltryptamine, is a lesser-known psychedelic drug. It is the α,"N"-dimethyl analog of DMT. α,"N"-DMT was first synthesized by Alexander Shulgin. In his book "TiHKAL" ("Tryptamines I Have Known and Loved"), Shulgin lists the dosage as 50-100 mg, and the duration as 6–8 hours. α,"N"-DMT causes an unpleasant body load. Very little data exists about the pharmacological properties, metabolism, and toxicity of α,"N"-DMT.


Cryoprotectant

A cryoprotectant is a substance used to protect biological tissue from freezing damage (i.e. that due to ice formation). Arctic and Antarctic insects, fish and amphibians create cryoprotectants (antifreeze compounds and antifreeze proteins) in their bodies to minimize freezing damage during cold winter periods. Cryoprotectants are also used to preserve living materials in the study of biology and to preserve food products.
For years, glycerol has been used in cryobiology as a cryoprotectant for blood cells and bull sperm, allowing storage at liquid nitrogen temperatures. However, glycerol cannot be used to protect whole organs from damage. Instead, many biotechnology companies are researching the development of other cryoprotectants more suitable for such uses. A successful discovery may eventually make possible the bulk cryogenic storage (or "banking") of transplantable human and xenobiotic organs. A substantial step in that direction has already occurred. Twenty-First Century Medicine has vitrified a rabbit kidney to -135 °C with their proprietary vitrification cocktail. Upon rewarming, the kidney was successfully transplanted into a rabbit, with complete functionality and viability, able to sustain the rabbit indefinitely as the sole functioning kidney.
Mechanism.
Cryoprotectants operate by increasing the solute concentration in cells. However, in order to be biologically viable they must easily penetrate and must not be toxic to cells.
Glass transition temperature.
Some cryoprotectants function by lowering the glass transition temperature of a solution or of a material. In this way, the cryoprotectant prevents actual freezing, and the solution maintains some flexibility in a glassy phase. Many cryoprotectants also function by forming hydrogen bonds with biological molecules as water molecules are displaced. Hydrogen bonding in aqueous solutions is important for proper protein and DNA function. Thus, as the cryoprotectant replaces the water molecules, the biological material retains its native physiological structure and function, although they are no longer immersed in an aqueous environment. This preservation strategy is most often utilized in anhydrobiosis.
Toxicity.
Mixtures of cryoprotectants have less toxicity and are more effective than single-agent cryoprotectants. A mixture of formamide with DMSO (dimethyl sulfoxide), propylene glycol, and a colloid was for many years the most effective of all artificially created cryoprotectants. Cryoprotectant mixtures have been used for vitrification (i.e. solidification without crystal ice formation). Vitrification has important applications in preserving embryos, biological tissues and organs for transplant. Vitrification is also used in cryonics, in an effort to eliminate freezing damage.
Conventional.
Conventional cryoprotectants are glycols (alcohols containing at least two hydroxyl groups), such as ethylene glycol , propylene glycol and glycerol. Ethylene glycol is commonly used as automobile antifreeze; while propylene glycol has been used to reduce ice formation in ice cream. Dimethyl sulfoxide (DMSO) is also regarded as a conventional cryoprotectant. Glycerol and DMSO have been used for decades by cryobiologists to reduce ice formation in sperm, oocytes, and embryos that are cold-preserved in liquid nitrogen. Cryoconservation of animal genetic resources is a practice that involves conventional cryoprotectants to store genetic material with the intention of future revival. Trehalose is non-reducing sugar produced by yeasts and insects in copious amounts. Its use as a cryoprotectant in commercial systems has been patented widely.
Examples in nature.
Arctic fish use antifreeze proteins, sometimes appended with sugars, as cryoprotectants.
Insects.
Insects most often use sugars or polyols as cryoprotectants. One species that uses cryoprotectant is "Polistes exclamans" (a wasp). In this species, the different levels of cryoprotectant can be used to distinguish between morphologies.
Amphibians.
Cold-adapted arctic frogs (e.g., wood frog) and some other ectotherms in polar and subpolar regions naturally produce glucose, but southern brown tree frogs and Arctic salamanders create glycerol in their livers to reduce ice formation.
When glucose is used as a cryoprotectant by arctic frogs, massive amounts of glucose are released at low temperature and a special form of insulin allows for this extra glucose to enter the cells. When the frog rewarms during spring, the extra glucose must be rapidly eliminated, but stored.
Food preservation.
Cryoprotectants are also used to preserve foods. These compounds are typically sugars that are inexpensive and do not pose any toxicity concerns. For example, many (raw) frozen chicken products contain a sucrose and sodium phosphates solution in water.


Hypermetabolism

Hypermetabolism is defined as an elevated resting energy expenditure (REE) > 110% of predicted REE. Hypermetabolism is accompanied by a variety of internal and external symptoms, most notably extreme weight loss, and can also be a symptom in itself. This state of increased metabolic activity can signal underlying issues, especially hyperthyroidism. Patients with Fatal familial insomnia, an extremely rare and strictly hereditary disorder, also presents with hypermetabolism; however, this universally fatal disorder is exceedingly rare, with only a few known cases worldwide. The drastic impact of the hypermetabolic state on patient nutritional requirements is often understated or overlooked as well.
Signs and symptoms.
Symptoms may last for days, weeks, or months until the disorder is healed. The most apparent sign of hypermetabolism is an abnormally high intake of calories followed by continuous weight loss. Internal symptoms of hypermetabolism include: peripheral insulin resistance, elevated catabolism of protein, carbohydrates and triglycerides, and a negative nitrogen balance in the body.
Outward symptoms of hypermetabolism may include:
Pathophysiology.
During the acute phase, the liver redirects protein synthesis, causing up-regulation of certain proteins and down-regulation of others. Measuring the serum level of proteins that are up- and down-regulated during the acute phase can reveal extremely important information about the patient's nutritional state. The most important up-regulated protein is C-reactive protein, which can rapidly increase 20- to 1,000-fold during the acute phase.
Hypermetabolism also causes expedited catabolism of carbohydrates, proteins, and triglycerides in order to meet the increased metabolic demands.
Diagnosis.
Quantitation by indirect calorimetry, as opposed to the Harris-Benedict equation, is needed to accurately measure REE in cancer patients.
Differential diagnosis.
Many different illnesses can cause an increase in metabolic activity as the body combats illness and disease in order to heal itself.
Hypermetabolism is a common symptom of various pathologies. Some of the most prevalent diseases characterized by hypermetabolism are listed below.
Treatment.
Ibuprofen, polyunsaturated fatty acids, and beta-blockers have been reported in some preliminary studies to decrease REE, which may allow patients to meet their caloric needs and gain weight.


Chryseobacterium solincola

Chryseobacterium solincola is a Gram-negative, strictly aerobic halotolerant and psychrotolerant bacteria from the genus of Chryseobacterium which has been isolated from soil which was polluted with hydrocarbon in Meftah in Algeria.


Variola virus minor


Cyclic di-GMP-II riboswitch

Cyclic di-GMP-II riboswitches (also c-di-GMP-II riboswitches) form a class of riboswitches that specifically bind cyclic di-GMP, a second messenger used in multiple bacterial processes such as virulence, motility and biofilm formation. Cyclic di-GMP II riboswitches are structurally unrelated to cyclic di-GMP-I riboswitches, though they have the same function.
Cyclic di-GMP-II riboswitches were discovered by bioinformatics, and are common in species within the class Clostridia and the genus "Deinococcus". They are also found in some other bacterial lineages. There is significant overlap between species that use cyclic di-GMP-I and cyclic di-GMP-II riboswitches, as both riboswitch classes are common in Clostridia.
In "Clostridium difficile" strains, a cyclic di-GMP-II riboswitch is found adjacent to a group I catalytic intron. Group I introns are ribozymes that catalyze the splicing of the RNA molecule in which they are embedded. In the riboswitch-associated case, the outcome of the splicing reaction catalyzed by the intron is controlled by the riboswitch in response to cyclic di-GMP levels. The splicing reaction is also regulated "in vitro" by levels of guanosine triphosphate, since group I introns require a guanosine derivative for their activity.
Group I introns function as part of selfish elements, where they reduce the likelihood that the element will negatively impact the fitness of the host by interrupting a protein-coding gene. However, the group I intron associated with a cyclic di-GMP-II riboswitch is not selfish since it seems to perform a useful function for the cell. They also show that natural cells use allosteric ribozymes to regulate gene expression, a mechanism commonly used in engineered aptamers but not previously observed in nature.
Cyclic di-GMP-II riboswitches are a pseudoknotted structure. Most of these riboswitches conserve a kink turn structural motif that permits a bend in the relevant stem, presumably facilitating the pseudoknot. Several nucleotide positions are highly conserved, with many around the terminal loops involved in the pseudoknot interaction.


Tina Henkin

Tina Henkin is a professor of microbiology at Ohio State University and member of the National Academy of Sciences. She was elected a member of the National Academy of Sciences in 2012. In 2019, she was reappointed to her professorship. In her research, Henkins studies how cells respond to change in their environment through gene expression, using "Bacillus subtilis" as a model.


Pulmonary agent

A pulmonary agent, or choking agent, is a chemical weapon agent designed to impede a victim's ability to breathe. They operate by causing a build-up of fluids in the lungs, which then leads to suffocation. Exposure to the eyes and skin tends to be corrosive, causing blurred vision and severe deep burns. Inhalation of these agents cause burning of the throat, coughing, vomiting, headache, pain in chest, tightness in chest, and respiratory and circulatory failure.
Examples of pulmonary agents include:
Phosgene is the most dangerous commonly used pulmonary agent (although disulfur decafluoride and perfluoroisobutene are both even more dangerous, with respectively 4 and 10 times the lethality of phosgene, neither is widely used). It is a colorless gas under ordinary conditions. It has a vapor density 3.4 times greater than that of air, allowing it to remain low in the air for long periods of times. Phosgene leads to massive pulmonary edema, which reaches maximum symptoms in 12 hours after exposure, followed by death within 24 to 48 hours.
Chlorine is an element used in industry. It is one of the most commonly manufactured chemicals in the United States. It is used to make pesticides, rubber, and solvents. It is also used in drinking water and swimming pools to kill bacteria. The extent of poisoning chlorine causes depends on the amount of chlorine to which a person is exposed.
History.
The first major use of these agents came on April 22, 1915, at the Second Battle of Ypres in Belgium. The Germans opened up 168 tons of chlorine gas on the French, Canadian and British troops which created a wind-borne cloud of chemical gas that opened up a breach in the lines. However, the Germans were not prepared to exploit the opening. In 1917 the Germans also introduced the agent phosgene. By then both sides had mastered the techniques of new choking agents such as diphosgene, chloropicrin, and perfluoroisobutene which allowed numerous attacks to be made. By the end of World War I, phosgene was responsible for roughly 80% of all deaths related to chemical attacks.


Mouse Genome Informatics

Mouse Genome Informatics (MGI) is a free, online database and bioinformatics resource hosted by The Jackson Laboratory, with funding by the National Human Genome Research Institute (NHGRI), the National Cancer Institute (NCI), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). MGI provides access to data on the genetics, genomics and biology of the laboratory mouse to facilitate the study of human health and disease. The database integrates multiple projects, with the two largest contributions coming from the Mouse Genome Database and Mouse Gene Expression Database (GXD). , MGI contains data curated from over 230,000 publications.
The MGI resource was first published online in 1994 and is a collection of data, tools, and analyses created and tailored for use in the laboratory mouse, a widely used model organism. It is "the authoritative source of official names for mouse genes, alleles, and strains", which follow the guidelines established by the International Committee on Standardized Genetic Nomenclature for Mice. The history and focus of Jackson Laboratory research and production facilities generates tremendous knowledge and depth which researchers can mine to advance their research. A dedicated community of mouse researchers, worldwide enhances and contributes to the knowledge as well. This is an indispensable tool for any researcher using the mouse as a model organism for their research, and for researchers interested in genes that share homology with the mouse genes. Various mouse research support resources including animal collections and free colony management software are also available at the MGI site.
Mouse Genome Database.
The "Mouse Genome Database" collects and curates comprehensive phenotype and functional annotations for mouse genes and alleles. This is an NHGRI-funded project which contributes to the Mouse Genome Informatics database.
Mouse gene expression database.
The "Gene Expression Database" is a community resource of mouse developmental expression information.


Small heterodimer partner

The small heterodimer partner (SHP) also known as NR0B2 (nuclear receptor subfamily 0, group B, member 2) is a protein that in humans is encoded by the "NR0B2" gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.
Function.
The principal role of SHP appears to be repression of other nuclear receptors through association to produce a non-productive heterodimer. The protein has also been identified as a mediating factor in the metabolic circadian clock Research shows that it interacts with retinoid and thyroid hormone receptors, inhibiting their ligand-dependent transcriptional activation. In addition, interaction with estrogen receptors has been demonstrated, leading to inhibition of function. Studies suggest that the protein represses nuclear hormone receptor-mediated transactivation via two separate steps: competition with coactivators and the direct effects of its transcriptional repressor function.
Structure and ligands.
A crystal structure of the LBD-only SHP, generated by co-crystallisation with EID1, has been obtained. Instead binding to the usual AF-2 site, EID1 fills in the place of what is usually helix α1 of an LBD and makes SHP more soluble. The overall structure resembles the "apo" (ligandless) form of other LBDs. Some synthetic retinoid ligands can bind to SHP's LBD and promote its interaction with LXXLL-containing corepressors using the AF-2 site.
Interactions.
Large and medium scale Y2H experiments as well as text mining of the NR literature have highlighted the important role of SHP in the Nuclear Receptor dimerization network and its relatively highly connected status, compared to other NRs.
Small heterodimer partner has been shown to interact with:


Nancy T. Chang

Nancy Tang Chang (born 1950), née Tang Nanshan (), is a biochemist who cofounded Tanox in 1986 to address medical needs in the areas of allergy, asthma, inflammation and diseases affecting the human immune system. Tanox took an innovative approach in developing an asthma drug that focused on the allergy-related basis of asthma, Xolair. In June 2003, the U.S. Food and Drug Administration (FDA) approved Xolair, the first biotech product cleared for treating those with asthma related to allergies. Tanox was also active in the development of TNX-355, an antibody for the treatment of HIV/AIDS.
In 2007, Tanox was sold to Genentech for $919 million. Dr. Chang grew Tanox from an idea to a substantial publicly traded company, doing innovative science. Following her success with Tanox, she has become an angel investor in health-care entrepreneurships and performs philanthropic work in community health-education projects.
Biography.
Nancy Chang was born in Taiwan in 1950. Her parents were from mainland China, and had traveled to Taiwan after their marriage. Due to political unrest in China, they were not allowed to return, and stayed in Taiwan. Nancy attended Taipei First Girls' High School in Taipei, where "we were trained to compete with the boys". She studied college chemistry the first year in high school and college physics the second year.
Nancy attended Taiwan's National Tsing Hua University, where she took undergraduate classes from future Nobel Prize winner Yuan T. Lee. There she also met a fellow budding scientist, Tse Wen Chang. They married just a few days before traveling to the United States, where both had received scholarships for graduate school: Nancy at Brown University and Tse Wen at Harvard University. On the plane ride to the United States, Nancy read James Watson’s book on the discovery of the double helix. This sparked her interest in biology, which she had not previously studied. Nancy subsequently changed her academic focus to biology and transferred to the Division of Medical Sciences, Harvard University. The Changs were among the first international students at the Division of Medical Sciences, and Nancy had to work extremely hard due to her unfamiliarity with English. Nancy earned her Ph.D. in biological chemistry from Harvard University.
Work.
Her interest in interferon led her to approach Dr. Sidney Pestka at Roche Pharmaceutical Company and be hired at Hoffman-La Roche. For a time, the Changs endured the difficulties of a commuter marriage: Nancy lived and worked in Parsippany, NY; Tse Wen commuted to Pennsylvania each week to work at Centocor. Eventually Nancy joined Centocor as a bench-level diagnostician. Her heart was still in research, and she took part in Centocor's involvement in therapeutic research. She brought in several new projects, including HIV/AIDS research. Nancy's team participated in a consortium, which sequenced the HIV genome structure. Nancy was instrumental in developing the first diagnostic assay to detect HIV infection by employing a peptide segment of HIV as the solid-phase antigen in the immunoassay. She was Director of Research at Centocor from 1982 to 1986.
In 1986, the Changs moved to Houston, TX. Baylor College of Medicine in Houston offered Tse Wen a faculty position, and Nancy was able to obtain a position as well. She became Associate Professor of Virology at Baylor College of Medicine, serving from 1986 to 1991.
Both Nancy and Tse Wen suffered severely from allergies. Tse Wen had an idea for treating allergies by blocking IgE (immunoglobulin E), and the Changs founded the biotechnology company Tanox. Tse Wen continued his preferred work as a professor, and Nancy served as president of the new company. In 1992, the Changs separated. Tse Wen returned to Taiwan in 1996 to teach, while remained as a board member of Tanox until the company was acquired by Genentech. Nancy continued her work with Tanox, serving as CEO as well as president.
Tanox focused on addressing medical needs in the areas of allergy, asthma, inflammation, and diseases affecting the human immune system, developing an asthma drug that targeted the allergy-related basis of asthma, Xolair.
Tanox's initial public offering in 2000 was the second largest IPO ever for a biotechnology company, raising $244 million. In June 2003, the U.S. Food and Drug Administration (FDA) approved Xolair, the first biotech product cleared for treating those with asthma related to allergies. In 2007, Tanox was sold to Genentech for $919 million. Nancy continued to be involved, as chairman of Tanox's board of directors.
Tanox was also active in the development of TNX-355, an antibody for the treatment of HIV/AIDS. Nancy has said that she is passionate about AIDS because of her work as a young researcher in one of the first laboratories to confront the disease.
Nancy Chang's published research includes over 35 papers on topics including monoclonal antibodies and HIV. She has been awarded seven patents.
Chang has served on the boards of directors of the Federal Reserve Bank in Houston, of BioHouston, of Project Hope, of Charles River Laboratories, and of the Board of Visitors of the University of Texas M.D. Anderson Cancer Center, among others. Nancy is an angel investor in health-care entrepreneurships and performs philanthropic work in community health-education projects. As part of Project Hope's China programs, she has had the responsibility of assessing annual progress in programs at Wuhan University School of Medicine, Shanghai Children's Medical Center, and educational programs and treatments for diabetes and HIV/AIDS. As of 2009, Dr. Chang was the chairman and managing director of OrbiMed's Caduceus Asia partner fund and a member of Orbimed Advisors, the largest investment firm focused entirely on the healthcare sector. As of 2013, Nancy Chang was president of Apex Enterprises.
Honors and awards.
During her career, Dr. Chang has received numerous academic, national and international awards for her leadership and contributions to the biopharmaceutical industry.
Nancy Chang was inducted into the Texas Science Hall of Fame in 2001, for exemplary achievement in science.
In 2005, she was named a Most Respected Woman in Biotechnology (MedAd News, 2005), and also received the Global Business Achievement Hall of Fame Governor's Award from the Global Federation of Chinese Business Women in the Southern U.S.
In 2008 Nancy was named to the Forbes Twenty-Five Notable Chinese Americans list.
In 2012, she became the first woman to receive the 14th annual Biotechnology Heritage Award, conferred by the Biotechnology Industry Organization (BIO) and the Chemical Heritage Foundation.
She is the recipient of several additional awards, such as the Association of Women in Computing: Top 20 Houston Women in Technology and Houston Entrepreneur of the Year.


Kantavati Devi

Kantavati Devi (Kantawati Devi Jha) (?–31 October 1799) was the favourite wife of Rana Bahadur Shah, King of Kingdom of Nepal. She was the mother of Girvan Yuddha Bikram Shah. She died of smallpox.


Photoaffinity labeling

Photoaffinity labeling is a technique used to attach "labels" to the active site of a large molecule, especially a protein. The "label" attaches to the molecule loosely and reversibly, and has an inactive site which can be converted using photolysis into a highly reactive form, which causes the label to bind more permanently to the large molecule via a covalent bond. The technique was first described in the 1970s. Molecules that have been used as labels in this process are often analogs of complex molecules, in which certain functional groups are replaced with a photoreactive group, such as an azide, a diazirine or a benzophenone.


Donald Rix

Donald Blake Rix, (1931 – November 6, 2009) was a Canadian pathologist, philanthropist, community volunteer, and businessman. He was the founder and chair of MDS Metro Laboratory Services (now known as LifeLabs Medical Laboratory Services), the largest private medical laboratory in Western Canada.
He was a member of several organizations and foundations including the BC Innovation Council, BC Cancer Agency Foundation, BC Medical Services Foundation, and the BC Children’s Hospital Foundation and was the Chairman of the Board of Governors of UNBC.
Dr. Rix earned a specialty certificate in general pathology in 1968 from the University of Western Ontario. He was a fellow of the College of American Pathologists, the Royal College of Physicians and Surgeons of Canada, the Royal Society of Medicine, and the American Society of Clinical Pathologists. He was awarded honorary doctorates by the British Columbia Institute of Technology (BCIT) and the University of Western Ontario, Simon Fraser University, University of British Columbia, and University of Victoria. He was the former chair of the Vancouver Board of Trade, a senior member of both the British Columbia and Canadian Medical Associations, and was awarded the BCMA Silver Medal of Service Award in 2004. On August 19, 2009 Dr. Rix was awarded the Canadian Medical Association's 2009 F.N.G. Starr Award.
Donald Rix died on November 6, 2009.