Hypotaurine dehydrogenase

In enzymology, a hypotaurine dehydrogenase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are hypotaurine, H2O, and NAD+, whereas its 3 products are taurine, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on a sulfur group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is hypotaurine:NAD+ oxidoreductase. This enzyme participates in taurine and hypotaurine metabolism. It has 2 cofactors: heme, and Molybdenum.


Vernalis Research

Vernalis Research develops and applies fragment and structure-based methods to drug discovery, and has generated cell active lead compounds and development candidates against biological targets in oncology, neurodegeneration, anti-infectives and inflammation.
History.
Following the sale of Vernalis plc on 10 October 2018, Vernalis Research became a subsidiary of Ligand Holdings UK Ltd, wholly owned by Ligand Pharmaceuticals, Inc. On 2nd December 2020, HitGen (Chengdu, China), acquired the entire issued share capital of Vernalis (R&D) Limited.
Their scientists, based at Granta Park, Cambridge UK, integrate fragment-based approaches, structural biology, biophysics, assay technology, drug metabolism, pharmacokinetics, cheminformatics, molecular modelling and computational, synthetic organic and medicinal chemistry to enable drug discovery on both established and novel targets, progressing projects from target identification through to clinical candidate. They have generated lead compounds on enzymes, protein-protein interactions and GPCRs, leading to clinical candidates for targets such as Chk1, Hsp90, Bcl-2, Mcl-1, FAAH and A2A.
As well as an internal portfolio of drug discovery projects, Vernalis Research has a number of research collaborations on targets with large pharmaceutical companies and academic partners. Recently disclosed collaborations include those with Servier, Daiichi Sankyo, Lundbeck and Asahi Kasei Pharma. In 2014, the Company was awarded a Queen's Award for Enterprise, for outstanding achievement in International Trade, endorsing both the talent and capabilities of its research group, and recognition of the growing overseas earnings it has achieved.
Vernalis Research has delivered a number of drug candidates into clinical development, some of which remained as part of the Ligand Pharmaceuticals, Inc. portfolio following the sale of the research business to HitGen. These include V158866, the lead molecule arising from an in-house FAAH research programme, which completed a phase II study in spinal cord injury patients in July 2015. Additionally, luminespib (AUY922) is a novel intravenous Hsp90 inhibitor with the potential to target a range of cancers, which arose from a research collaboration starting in 2004, originally between Vernalis plc, the Institute of Cancer Research and Cancer Research Technology, and then with Novartis. A further example is V158411, the lead intravenous molecule arising from an in-house structure-based Chk1 oncology research programme.


Glycine dehydrogenase (cytochrome)

In enzymology, a glycine dehydrogenase (cytochrome) () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are glycine, H2O, and ferricytochrome c, whereas its 4 products are glyoxylate, NH3, ferrocytochrome c, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH2 group of donors with a cytochrome as acceptor. The systematic name of this enzyme class is glycine:ferricytochrome-c oxidoreductase (deaminating). This enzyme is also called glycine---cytochrome c reductase. This enzyme participates in glycine, serine and threonine metabolism.


Mycena

Mycena is a large genus of small saprotrophic mushrooms that are rarely more than a few centimeters in width. They are characterized by a white spore print, a small conical or bell-shaped cap, and a thin fragile stem. Most are gray or brown, but a few species have brighter colors. Most have a translucent and striate cap, which rarely has an incurved margin. The gills are attached and usually have cystidia. Some species, like "Mycena haematopus", exude a latex when the stem is broken, and many species have a chlorine-like odor.
Overview.
"Mycenas" are hard to identify to species and some are distinguishable only by microscopic features such as the shape of the cystidia. Some species are edible, while others contain toxins, but the edibility of most is not known, as they are too small to be useful in cooking. "Mycena pura" contains the mycotoxin muscarine.
Over 33 species are known to be bioluminescent, creating a glow known as foxfire. These species are divided among 16 lineages, leading to evolutionary uncertainty in whether the luminescence developed once and was lost among many species, or evolved in parallel by several species. One advantage of bioluminescence may lie in its potential to attract insects that can disperse the mushroom's spores.
Alexander Smith's 1947 "Mycena" monograph identified 232 species; the genus is now known to include about 500 species worldwide. Maas Geesteranus divided the genus into 38 sections in 1992, providing keys to each for all the species of the Northern Hemisphere. Many new species have been discovered since then, and four new sections have been proposed. Taxonomy is complex, as most sections are not truly homogeneous, and the keys fail for some species, especially those that satisfy some criteria for only part of their life cycle. Some sections contain only one species.
The name "Mycena" comes from the Ancient Greek μύκης ', meaning "fungus." Species in the genus "Mycena" (and in "Hemimycena") are commonly known as bonnets.


Sugar signal transduction

Sugar signal transduction is an evolutionarily conserved mechanism used by organisms to survive. Sugars have an overwhelming effect on gene expression. In yeast, glucose levels are managed by controlling the mRNA levels of hexose transporters, while in mammals, the response to glucose is more tightly controlled with glucose metabolism and is therefore much more complex. Several glucose-responsive DNA motifs and DNA binding protein complexes have been identified in liver and b-cells. Although not proven, glucose repression appears to be conserved in plants because in many cases, both sugar induction and sugar repression are initiated by turning off transcription factors.


Mary Bernheim

Mary Lilias Christian Bernheim (née Hare; 28 June 1902 – 19 November 1997) was a British biochemist best known for her discovery of the enzyme tyramine oxidase, which was later renamed as monoamine oxidase. Bernheim discovered the enzyme system of tyramine oxidase during her doctorate research at the University of Cambridge in 1928, and her research has been referred to as "one of the seminal discoveries in twentieth century neurobiology".
Early life and education.
Bernheim was born under the name Mary Lilias Christian Hare in Gloucester, England on 28 June 1902. However, she was referred to as "Molly" by those around her. As a child, Bernheim was raised in India. She obtained higher degrees of BA, MA, and PhD from the University of Cambridge in England. After finishing her undergraduate, Bernheim received the Bathurst Studentship to work on her PhD research in the Department of Biochemistry at the Newnham College of the University of Cambridge.
Discovery of monoamine oxidase.
As a doctoral student, Bernheim was aware of the limited research which had been conducted on the catabolism of tyramine, a naturally occurring monoamine compound obtained from the amino acid tyrosine. Keeping in mind the availability of newly enhanced techniques for the analysis of oxidative processes, she decided to study the manner in which the addition of tyramine affected oxygen uptake in tissues.
During the course of her work, Bernheim used rabbit liver extracts and obtained the enzyme by adding kaolin to the liver extracts at pH 6.5. Following this, crude tyramine was procured by heating tyrosine in the presence of the catalyst diphenylamine. The extracted enzyme was added to tyramine, in the presence of water and buffer, and the Barcroft technique was used to observe the amount of oxygen consumed by tyramine. She discovered that the oxidation of tyramine did take place, with the observation that one atom of oxygen was absorbed per molecule of tyramine present. This observation indicated the presence of an enzyme system within the studied liver extracts, which Bernheim named tyramine oxidase, since it was involved in the oxidation of tyramine.
In addition to the discovery of the enzyme system, Bernheim observed several unique properties of the tyramine oxidase system. She noted that the methylene blue dye used in the experiment was not reduced. This observation indicated that the tyramine oxidase system, unlike other enzyme systems, was not able to use the dye as a hydrogen acceptor. Additionally, the oxidative process within this enzyme system was seen to be resistant to the addition of cyanide. This observation showed that the tyramine oxidase system was an exception to Warburg's statement, which claimed that direct oxidation could not occur unless atmospheric oxygen was activated by iron. Instead, the system was seen to produce hydrogen peroxide, indicating that molecular oxygen acted as a hydrogen acceptor in the system. Bernheim also detected that the enzyme facilitated the occurrence of deamination in tyramine, along with the process of oxidation.
Prior to her discovery, tyramine had not been studied extensively from a biochemical perspective.
Importance of monoamine oxidase discovery.
Following her discovery, Bernheim predicted that tyramine oxidase was important for the oxidative deamination of tyramine, thus allowing for the detoxification of extra amines absorbed from the intestines. This prediction was proven correct by later research, which showed that patients treated with monoamine oxidase inhibitors had toxic reactions to the consumption of food rich in tyramine. However, subsequent research indicated that the enzyme was involved in the oxidative deamination of additional monoamine neurotransmitters, including Catecholamines and histamine, as shown in the figure. The enzyme was eventually renamed as monoamine oxidase, indicating that the enzyme catalysed the oxidative deamination of the class of monoamines.
After the discovery of monoamine oxidase (MAO), numerous studies were conducted to determine the biological importance of monoamines. Due to the significance of MAO in the inactivation of monoamine neurotransmitters, MAO dysfunction is believed to cause several psychiatric and neurological disorders, including depression and schizophrenia. Upon the discovery that the MAO inhibitor iproniazid resulted in mood elevation, and thus could be used as an effective anti-depressant, there was a marked increase in pharmacological research on drugs regulating monoamine activity.
Despite the fact that MAO inhibitors were eventually replaced by tricyclic antidepressants and serotonin reuptake inhibitors in the treatment of depression, there is still enormous interest in the function of MAO. The discovery of different MAO subtypes has led to research on selective MAO subtype inhibitors, which have been shown to exhibit reduced side effects and greater specificity during inhibition. These MAO subtype inhibitors are being used in the treatment of geriatric depression and as potential replacements for MAO reuptake inhibitors. Additionally, the discovery of MAO in blood platelets has led to research on the function of platelet enzyme activity as an indicator of MAO dysfunction.
Duke Medical School faculty.
In 1930, Bernheim was appointed as a member of the original faculty of Duke Medical School. When she began at Duke, Bernheim was notably one of few women in the Department of Biochemistry, either as a student or faculty member. She eventually became a full professor at Duke, and was teaching graduate students, medical students, and nursing students. During her time at Duke, the number of women in the medical school classes increased significantly from one or two women in a class of seventy-five students to women comprising more than half of the class. At the time of her death in 1997, she was the final surviving member of the original faculty of Duke Medical School.
Personal life.
While at Cambridge, Hare met fellow graduate student Frederick Bernheim, and eventually married him on 17 December 1928. Over the course of her career, Bernheim had authored over sixty papers.
Beyond biochemistry, Bernheim had interests in botany and flying. She published a book "A Sky of My Own," in which she details her journey into the field of flying, and describes her experience as a pilot and flight instructor.
Bernheim was recognised for her contributions to scientific research, and she was honoured at the Ciba Foundation symposium held in 1975 for her discovery of monoamine oxidase. Although she retired in 1983, she remained in a teaching position until her death on 19 November 1997 at the age of 95.


Kyriacos A. Athanasiou

Kyriacos A. Athanasiou (; born 1960) is a Cypriot-American bioengineer who has contributed significantly to both academic advancements as well as high-technology industries. He is currently a Distinguished Professor at the University of California, Irvine. He joined UCI from the University of California, Davis where he also served as the Chair of the Biomedical Engineering department. Before joining the University of California in 2009, he was the Karl F. Hasselmann Professor at Rice University. He has published hundreds of scientific articles detailing structure-function relationships and tissue engineering approaches for articular cartilage, the knee meniscus, and the temporomandibular joint.
Early life and education.
Athanasiou was born in Larnaca, Cyprus in 1960. He went to Sotir Elementary School and St. George High School. In 1978, he graduated valedictorian from high school and then joined the army for 26 months as part of his mandatory military duty. During that time, he trained at an infantry cadet school eventually becoming a second lieutenant. In August 1980, he came to the United States to attend college. He spent his first year at Brescia College in Owensboro, Kentucky. He then moved with relatives in Long Island, New York.
Athanasiou received his bachelor's degree in Mechanical Engineering from New York Institute of Technology at Old Westbury in 1984. He then attended Columbia University where he obtained his master's degree in 1985, his Ph.M in 1987, and his Ph.D in 1989.
Research.
Upon obtaining his Ph.D. in early 1989, Athanasiou became an assistant professor at the University of Texas Health Science Center at San Antonio. He became an associate professor in 1994. He was recruited to Rice University as a full professor of bioengineering at the end of 1999. Athanasiou established a research group in bioengineering, specializing in the cartilages of the musculoskeletal system. His group has worked extensively on cartilages of the musculoskeletal system both in terms of characterization but also in efforts to achieve healing or repair of the clinically complex problems of cartilage afflictions, including trauma and osteoarthritis.
Athanasiou and his colleagues published the book "Articular Cartilage". He published one of the first papers on the use of biodegradable scaffolds as carriers of growth factors to heal cartilage defects "in vivo". His group has directed its attention to tissue engineering the jaw joint disc (TMJ disc) and the knee meniscus, whose degradation is responsible for a large number of debilitating problems. (TMJ disc degeneration and meniscus injuries result in arthritic-like diseases that strike otherwise healthy young adults.) In addition to tissue-level work, Athanasiou has established a program to understand how single cartilage cells behave under direct and controlled biomechanical loads, not only in terms of deformation but also in terms of changes in gene expression. This work represents the first measurement of gene levels at the single cell level under varying biomechanical conditions. His group has also demonstrated the fabrication of entire sections of articular cartilage by self-assembly of cells, without the use of any scaffolds. Their group also demonstrated that hydrostatic pressure in conjunction with growth factors can have synergistic effects on the functional properties of engineered cartilage. The biomechanical, histological, transcriptional, and biochemical properties of this engineered cartilage approach those of native articular cartilage. More recently, the Athanasiou group showed the engineering of articular cartilage with biomechanical tensile properties on par with native tissue; the work was published in Nature Materials. In a study published in the Proceedings of the National Academy of Sciences Athanasiou showed that the matrix of a number of musculoskeletal tissues can be crosslinked with exogenous methods using lysyl oxidase L2. In a paper published in "Science," the Athanasiou group described why cartilage healing is so difficult.
High-technology companies.
In addition to his academic accomplishments, Athanasiou is known for his significant contributions in co-founding fifteen companies based on technologies co-developed by his group. His first company Osteobiologics, founded in 1993, was based, among other inventions, on the development of acellular scaffolds for the treatment of focal cartilage lesions. This was the first ever implant for this application. The company was acquired by Smith & Nephew in 2006. Another company co-founded by Athanasiou is Vidacare based on Athanasiou et al.'s patents on intraosseous infusion; this company was acquired by Teleflex Medical in 2013.
Service to the biomedical engineering profession.
In the summer of 2002, Athanasiou was elected President of the Biomedical Engineering Society. He served as BMES President from 2003 through 2004. He has also served as editor-in-chief of the Society's flagship journal, the "Annals of Biomedical Engineering."
Honors.
Among other awards and recognitions, Athanasiou has been elected to the National Academy of Inventors. He is a Fellow of the American Association for the Advancement of Science, the American Society of Mechanical Engineers, and the Biomedical Engineering Society.


Chryseobacterium frigidisoli

Chryseobacterium frigidisoli is a Gram-negative, rod-shaped, psychrotolerant and aerobic bacteria from the genus of Chryseobacterium which has been isolated from the permafrost of a glacier from the Larsemann Hills in the Antarctica.


Armillaria

Armillaria is a genus of fungi that includes the "A. mellea" species known as honey fungi that live on trees and woody shrubs. It includes about 10 species formerly categorized summarily as "A. mellea". "Armillarias" are long-lived and form the largest living organisms in the world. The largest known organism (of the species "Armillaria ostoyae") covers more than in Oregon's Malheur National Forest and is between 1900 and 9600 years old. Some species of "Armillaria" display bioluminescence, resulting in foxfire.
"Armillaria" can be a destructive forest pathogen. It causes "white rot" root disease (see Plant pathology section) of forests, which distinguishes it from "Tricholoma", a mycorrhizal (non-parasitic) genus. Because "Armillaria" is a facultative saprophyte, it also feeds on dead plant material, allowing it to kill its host, unlike parasites that must moderate their growth to avoid host death.
In the Canadian Prairies (particularly Manitoba), "Armillaria" is referred to often as "" (), meaning "near the stump" in Ukrainian.
Description.
The basidiocarp (reproductive structure) of the fungus is a mushroom that grows on wood, typically in small dense clumps or tufts. Their caps (mushroom tops) are typically yellow-brown, somewhat sticky to touch when moist, and, depending on age, may range in shape from conical to convex to depressed in the center. The stipe (stalk) may or may not have a ring. All "Armillaria" species have a white spore print and none have a volva (cup at base) (compare "Amanita").
Similar species include "Pholiota" spp. which also grow in cespitose (mat-like) clusters on wood and fruit in the fall. "Pholiota" spp. are separated from Armillaria by its yellowish to greenish-yellow tone and a dark brown to grey-brown spore print. Mushroom hunters need to be wary of "Galerina " spp. which can grow side by side with "Armillaria" spp. on wood. "Galerina" have a dark brown spore print and are deadly poisonous (alpha-amanitin) – see: mushroom poisoning.
Plant pathology.
Honey fungus is a "white rot" fungus, which is a pathogenic organism that affects trees, shrubs, woody climbers and, rarely, woody herbaceous perennial plants. Honey fungus can grow on living, decaying, and dead plant material.
Honey fungus spreads from living trees, dead and live roots and stumps by means of reddish-brown to black rhizomorphs (root-like structures) at the rate of approximately a year, but infection by root contact is possible. Infection by spores is rare. Rhizomorphs grow close to the soil surface (in the top ) and invade new roots, or the root collar (where the roots meet the stem) of plants. An infected tree will die once the fungus has girdled it, or when significant root damage has occurred. This can happen rapidly, or may take several years. Infected plants will deteriorate, although may exhibit prolific flower or fruit production shortly before death.
Initial symptoms of honey fungus infection include dieback or shortage of leaves in spring. Rhizomorphs (also called mycelial cords) appear under the bark and around the tree, and mushrooms grow in clusters from the infected plant in autumn and die back after the first frost. However these symptoms and signs do not necessarily mean that the pathogenic strains of honey fungus are the cause, so other identification methods are advised before diagnosis. Thin sheets of cream colored mycelium, beneath the bark at the base of the trunk or stem indicated that honey fungus is likely the pathogen. It will give off a strong mushroom scent and the mushrooms sometimes extend upward. On conifers honey fungus often exudes a gum or resin from cracks in the bark.
Taxonomy.
The linkage of morphological, genetic, and molecular characters of "Armillaria" over the past few decades has led to the recognition of intersterile groups designated as “biological species”. Data from such studies, especially those using molecular diagnostic tools, have removed much uncertainty for mycologists and forest pathologists. New questions remain unanswered regarding the phylogeny of North American "Armillaria" species and their relationships to their European counterparts, particularly within the “"Armillaria mellea" complex”. Some data suggest that North American and European "A. gallica" isolates are not monophyletic. Although North American and European isolates of "A. gallica" may be interfertile, some North American isolates of "A. gallica" are more closely related to the North American taxon "A. calvescens" than to European isolates of "A. gallica". The increase in genetic divergence has not necessarily barred inter-sterility between isolated populations of "A. gallica". Although the relationships among some groups in the genus seem clearer, the investigation of geographically diverse isolates has revealed that the relationship between some North American species is still unclear (Hughes et al. 2003).
Intersterile species of "Armillaria" occurring in North America (North American Biological Species = NABS) were listed by Mallett (1992):
and XI taxonomically undescribed
NABS I, V, VII, IX, X, and XI have been found in British Columbia; I, III, V have been found in the Prairie Provinces, with I and V occurring in both the boreal and subalpine regions; I, III, V, and VII have been found in Ontario; and I, II, III, V, and VI have been found in Quebec. "Armillaria ostoyae" is the species most commonly found in all Canadian provinces surveyed (Mallett 1990). "Armillaria" root rot occurs in the Northwest Territories, and was identified on white spruce at Pine Point on Great Slave Lake prior to NABS findings.
Edibility.
Honey fungus are regarded in Ukraine, Russia, Poland, Germany and other European countries as one of the best wild mushrooms. They are commonly ranked above morels and chanterelles and only the cep/porcini is more highly prized. However, honey fungus must be thoroughly cooked as they are mildly poisonous raw. One of the four UK species can cause sickness when ingested with alcohol. For those unfamiliar with the species, it is advisable not to drink alcohol for 12 hours before and 24 hours after eating this mushroom to avoid any possible nausea and vomiting. However, if these rules are followed this variety of mushroom is a delicacy with a distinctive mushroomy and nutty flavour. Reference texts for identification are "Collins Complete British Mushrooms and Toadstools" for the variety of field pictures in it, and Roger Philips' "Mushrooms" for the quality of his out of field pictures and descriptions.
In Norway, few mycologists have started to regard honey fungus as poisonous, because the Norway health department is moving away from the parboiling practice.
Hosts.
Potential hosts include conifers and various monocotyledonous and dicotyledonous trees, shrubs, and herbaceous species, ranging from asparagus and strawberry to large forest trees (Patton and Vasquez Bravo 1967). "Armillaria" root rot enters hosts through the roots. In Alberta, 75% of trap logs (Mallett and Hiratsuka 1985) inserted into the soil between planted spruce became infected with the distinctive white mycelium of "Armillaria" within one year. Of the infestations, 12% were "A. ostoyae", and 88% were "A. sinapina" (Blenis et al. 1995). Reviews of the biology, diversity, pathology, and control of "Armillaria" in Fox (2000) are useful.


Sister chromatids

A sister chromatid refers to the identical copies (chromatids) formed by the DNA replication of a chromosome, with both copies joined together by a common centromere. In other words, a sister chromatid may also be said to be 'one-half' of the duplicated chromosome. A pair of sister chromatids is called a dyad. A full set of sister chromatids is created during the synthesis (S) phase of interphase, when all the chromosomes in a cell are replicated. The two sister chromatids are separated from each other into two different cells during mitosis or during the second division of meiosis.
Compare sister chromatids to homologous chromosomes, which are the two "different" copies of a chromosome that diploid organisms (like humans) inherit, one from each parent. Sister chromatids are by and large identical (since they carry the same alleles, also called variants or versions, of genes) because they derive from one original chromosome. An exception is towards the end of meiosis, after crossing over has occurred, because sections of each sister chromatid may have been exchanged with corresponding sections of the homologous chromatids with which they are paired during meiosis. Homologous chromosomes might or might not be the same as each other because they derive from different parents.
There is evidence that, in some species, sister chromatids are the preferred template for DNA repair.
Sister chromatid cohesion is essential for the correct distribution of genetic information between daughter cells and the repair of damaged chromosomes. Defects in this process may lead to aneuploidy and cancer, especially when checkpoints fail to detect DNA damage or when incorrectly attached mitotic spindles don't function properly.
Mitosis.
Mitotic recombination is primarily a result of DNA repair processes responding to spontaneous or induced damages. Homologous recombinational repair during mitosis is largely limited to interaction between nearby sister chromatids that are present in a cell subsequent to DNA replication but prior to cell division. Due to the special nearby relationship they share, sister chromatids are not only preferred over distant homologous chromatids as substrates for recominational repair, but have the capacity to repair more DNA damage than do homologs.
Meiosis.
Studies with the budding yeast "Saccharomyces cerevisiae" indicate that inter-sister recombination occurs frequently during meiosis, and up to one-third of all recombination events occur between sister chromatids.


DNA-binding domain

A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a general affinity to DNA. Some DNA-binding domains may also include nucleic acids in their folded structure.
Function.
One or more DNA-binding domains are often part of a larger protein consisting of further protein domains with differing function. The extra domains often regulate the activity of the DNA-binding domain. The function of DNA binding is either structural or involves transcription regulation, with the two roles sometimes overlapping.
DNA-binding domains with functions involving DNA structure have biological roles in DNA replication, repair, storage, and modification, such as methylation.
Many proteins involved in the regulation of gene expression contain DNA-binding domains. For example, proteins that regulate transcription by binding DNA are called transcription factors. The final output of most cellular signaling cascades is gene regulation.
The DBD interacts with the nucleotides of DNA in a DNA sequence-specific or non-sequence-specific manner, but even non-sequence-specific recognition involves some sort of molecular complementarity between protein and DNA. DNA recognition by the DBD can occur at the major or minor groove of DNA, or at the sugar-phosphate DNA backbone (see the structure of DNA). Each specific type of DNA recognition is tailored to the protein's function. For example, the DNA-cutting enzyme DNAse I cuts DNA almost randomly and so must bind to DNA in a non-sequence-specific manner. But, even so, DNAse I recognizes a certain 3-D DNA structure, yielding a somewhat specific DNA cleavage pattern that can be useful for studying DNA recognition by a technique called DNA footprinting.
Many DNA-binding domains must recognize specific DNA sequences, such as DBDs of transcription factors that activate specific genes, or those of enzymes that modify DNA at specific sites, like restriction enzymes and telomerase. The hydrogen bonding pattern in the DNA major groove is less degenerate than that of the DNA minor groove, providing a more attractive site for sequence-specific DNA recognition.
The specificity of DNA-binding proteins can be studied using many biochemical and biophysical techniques, such as gel electrophoresis, analytical ultracentrifugation, calorimetry, DNA mutation, protein structure mutation or modification, nuclear magnetic resonance, x-ray crystallography, surface plasmon resonance, electron paramagnetic resonance, cross-linking and microscale thermophoresis (MST).
DNA-binding protein in genomes.
A large fraction of genes in each genome encodes DNA-binding proteins (see Table). However, only a rather small number of protein families are DNA-binding. For instance, more than 2000 of the ~20,000 human proteins are "DNA-binding", including about 750 Zinc-finger proteins.
Types.
Helix-turn-helix.
Originally discovered in bacteria, the helix-turn-helix motif is commonly found in repressor proteins and is about 20 amino acids long. In eukaryotes, the homeodomain comprises 2 helices, one of which recognizes the DNA (aka recognition helix). They are common in proteins that regulate developmental processes (PROSITE HTH).
Zinc finger.
The zinc finger domain is mostly found in eukaryotes, but some examples have been found in bacteria. The zinc finger domain is generally between 23 and 28 amino acids long and is stabilized by coordinating zinc ions with regularly spaced zinc-coordinating residues (either histidines or cysteines). The most common class of zinc finger (Cys2His2) coordinates a single zinc ion and consists of a recognition helix and a 2-strand beta-sheet. In transcription factors these domains are often found in arrays (usually separated by short linker sequences) and adjacent fingers are spaced at 3 basepair intervals when bound to DNA.
Leucine zipper.
The basic leucine zipper (bZIP) domain is found mainly in eukaryotes and to a limited extent in bacteria. The bZIP domain contains an alpha helix with a leucine at every 7th amino acid. If two such helices find one another, the leucines can interact as the teeth in a zipper, allowing dimerization of two proteins. When binding to the DNA, basic amino acid residues bind to the sugar-phosphate backbone while the helices sit in the major grooves. It regulates gene expression.
Winged helix.
Consisting of about 110 amino acids, the winged helix (WH) domain has four helices and a two-strand beta-sheet.
Winged helix-turn-helix.
The winged helix-turn-helix (wHTH) domain is typically 85-90 amino acids long. It is formed by a 3-helical bundle and a 4-strand beta-sheet (wing).
Helix-loop-helix.
The basic helix-loop-helix (bHLH) domain is found in some transcription factors and is characterized by two alpha helices (α-helixes) connected by a loop. One helix is typically smaller and due to the flexibility of the loop, allows dimerization by folding and packing against another helix. The larger helix typically contains the DNA-binding regions.
HMG-box.
HMG-box domains are found in high mobility group proteins which are involved in a variety of DNA-dependent processes like replication and transcription. They also alter the flexibility of the DNA by inducing bends. The domain consists of three alpha helices separated by loops.
Wor3 domain.
Wor3 domains, named after the White–Opaque Regulator 3 (Wor3) in "Candida albicans" arose more recently in evolutionary time than most previously described DNA-binding domains and are restricted to a small number of fungi.
OB-fold domain.
The OB-fold is a small structural motif originally named for its oligonucleotide/oligosaccharide binding properties. OB-fold domains range between 70 and 150 amino acids in length. OB-folds bind single-stranded DNA, and hence are single-stranded binding proteins.
OB-fold proteins have been identified as critical for DNA replication, DNA recombination, DNA repair, transcription, translation, cold shock response, and telomere maintenance.
Unusual.
Immunoglobulin fold.
The immunoglobulin domain () consists of a beta-sheet structure with large connecting loops, which serve to recognize either DNA major grooves or antigens. Usually found in immunoglobulin proteins, they are also present in Stat proteins of the cytokine pathway. This is likely because the cytokine pathway evolved relatively recently and has made use of systems that were already functional, rather than creating its own.
B3 domain.
The B3 DBD (, ) is found exclusively in transcription factors from higher plants and restriction endonucleases EcoRII and BfiI and typically consists of 100-120 residues. It includes seven beta sheets and two alpha helices, which form a DNA-binding pseudobarrel protein fold.
TAL effector.
TAL effectors are found in bacterial plant pathogens of the genus "Xanthomonas" and are involved in regulating the genes of the host plant in order to facilitate bacterial virulence, proliferation, and dissemination. They contain a central region of tandem 33-35 residue repeats and each repeat region encodes a single DNA base in the TALE's binding site. Within the repeat it is residue 13 alone that directly contacts the DNA base, determining sequence specificity, while other positions make contacts with the DNA backbone, stabilising the DNA-binding interaction. Each repeat within the array takes the form of paired alpha-helices, while the whole repeat array forms a right-handed superhelix, wrapping around the DNA-double helix. TAL effector repeat arrays have been shown to contract upon DNA binding and a two-state search mechanism has been proposed whereby the elongated TALE begins to contract around the DNA beginning with a successful Thymine recognition from a unique repeat unit N-terminal of the core TAL-effector repeat array.
Related proteins are found in bacterial plant pathogen "Ralstonia solanacearum", the fungal endosymbiont "Burkholderia rhizoxinica" and two as-yet unidentified marine-microorganisms. The DNA binding code and the structure of the repeat array is conserved between these groups, referred to collectively as the TALE-likes.
RNA-guided.
The CRISPR/Cas system of "Streptococcus pyogenes" can be programmed to direct both activation and repression to natural and artificial eukaryotic promoters through the simple engineering of guide RNAs with base-pairing complementarity to target DNA sites. Cas9 can be used as a customizable RNA-guided DNA-binding platform. Domain Cas9 can be functionalized with regulatory domains of interest (e.g., activation, repression, or epigenetic effector) or with endonuclease domain as a versatile tool for genome engineering biology. and then be targeted to multiple loci using different guide RNAs.


Walter Kaufmann (physicist)

Walter Kaufmann (June 5, 1871 – January 1, 1947) was a German physicist. He is best known for the first experimental proof of the velocity dependence of mass, which was an important contribution to the development of modern physics, including special relativity.
Life.
Of Jewish descent, in 1890/91 Kaufmann studied mechanical engineering at the technical universities of Berlin and Munich. From 1892 he studied physics at the Universities of Berlin and Munich, attaining a doctorate in 1894. From 1896 he was an assistant at the physical institutes of the Universities of Berlin and Göttingen. Kaufmann habilitated in 1899 and became a professor extraordinarius of physics in at the University of Bonn. After further work at the Berliner Physikalisches Institut he became professor ordinarius for experimental physics and leader of the physical institute at the Albertina in Königsberg, where he taught until he retired in 1935. Later, he was guest lecturer at the University of Freiburg.
Measurements of velocity dependence of mass.
Kaufmann's early work (1901–1903) confirmed for the first time the velocity dependence of the electromagnetic mass (later called relativistic mass) of the electron. However, the measurements were not accurate enough to differentiate between the Lorentz ether theory and that of Max Abraham.
At the end of 1905 Kaufmann carried out more accurate measurements. He was the first to discuss Albert Einstein's theory of special relativity and argued that, although Einstein's theory is based on quite different conditions and is logically more satisfying, it is observationally equivalent to Lorentz's theory. Therefore, he spoke of the "Lorentz-Einstein" theory. It is notable that Kaufmann himself interpreted his experimental results as confirmation of Abraham's theory, refuting the Lorentz-Einstein principle of relativity. For some years this weighed heavily against the latter. However, Kaufmann's results were criticized by Max Planck, Adolf Bestelmeyer (1906) and Walter Ritz (1908). The experiments were repeated by Alfred Bucherer (1908), Neumann (1914) and others, with results which appeared to confirm the Lorentz-Einstein theory and to disprove that of Abraham. However, it was pointed out later that the results were not accurate enough to distinguish between the theories. The uncertainty continued until 1940, when such experiments were accurate enough to rule out competing models. Today, the relativistic Lorentz-Einstein relations for momentum and energy are confirmed routinely in particle accelerators, see Tests of relativistic energy and momentum.
Note, however, that this uncertainty concerned only the relativistic mass of the electron. Even in 1917, investigations of the fine structure of the hydrogen lines provided confirmation of the Lorentz-Einstein formula, contradicting that of Abraham.


Unsinkable Sam

Unsinkable Sam (also known as Oskar or Oscar) is, according to a possibly apocryphal story, the nickname of a ship's cat who purportedly served during World War II with both the Kriegsmarine and the Royal Navy and survived the sinking of three ships.
History.
The cat's original name is unknown. The name "Oscar" was given by the crew of the British destroyer HMS "Cossack" that rescued him from the sea following the sinking of the German battleship "Bismarck". "Oscar" was derived from the International Code of Signals for the letter 'O', which is code for "Man Overboard" (the German spelling, "Oskar", was sometimes used since he was a German cat).
"Bismarck".
The black and white patched cat was supposedly owned by an unknown crewman of the German battleship "Bismarck" and was on board the ship on 18 May 1941 when he set sail on Operation "Rheinübung" (German for Rhine Exercise), "Bismarck"s only mission. "Bismarck" was sunk after a fierce sea-battle on 27 May, from which only 115 from her crew of over 2,100 survived. Hours later, Oscar was found floating on a board and picked from the water by the British destroyer HMS "Cossack". Unaware of what his name had been on "Bismarck", the crew of "Cossack" named their new mascot "Oscar".
HMS "Cossack".
The cat served on board "Cossack" for the next few months as the ship carried out convoy escort duties in the Mediterranean Sea and north Atlantic Ocean. On 24 October 1941, "Cossack" was escorting a convoy from Gibraltar to Great Britain when she was severely damaged by a torpedo fired by the . Crew were transferred to the destroyer , and an attempt was made to tow the badly listing "Cossack" back to Gibraltar. However, worsening weather conditions meant the task became impossible and had to be abandoned. On 27 October, a day after the tow was slipped, "Cossack" sank to the west of Gibraltar. The initial explosion had blown off one third of the forward section of the ship, killing 159 of the crew, but Oscar survived this too and was brought to the shore establishment in Gibraltar.
HMS "Ark Royal".
Now nicknamed "Unsinkable Sam", the cat was soon transferred to the aircraft carrier , which coincidentally had been instrumental in the destruction of "Bismarck" (along with "Cossack"). However, Sam was to find no more luck there, and when returning from Malta on 14 November 1941 this ship too was torpedoed, this time by . Attempts were also made to tow "Ark Royal" to Gibraltar, but the unstoppable inflow of water made the task futile. The carrier rolled over and sank 30 miles from Gibraltar. The slow rate at which the ship sank meant that all but one of the crew could be saved. The survivors, including Sam, who had been found clinging to a floating plank by a Motor Launch and described as "angry but quite unharmed", were transferred to HMS "Lightning" and the same HMS "Legion" which had rescued the crew of "Cossack". "Legion" would itself be sunk in 1942, and "Lightning" in 1943.
The loss of "Ark Royal" proved the end of Sam's shipborne career. He was transferred first to the offices of the Governor of Gibraltar and then sent back to the United Kingdom, where he saw out the remainder of the war living in a seaman's home in Belfast called the "Home for Sailors". Sam died in 1955. A pastel portrait of Sam (titled "Oscar, the Bismarck's Cat") by the artist Georgina Shaw-Baker is in the possession of the National Maritime Museum in Greenwich.
Historicity.
Some authorities question whether Oskar/Sam's biography might be a "sea story", because – for example – there are pictures of two different cats identified as Oskar/Sam. The sinking of "Bismarck" and rescue of a limited number of survivors took place in desperate conditions; British ships were ordered not to stop as there was believed to be a U-boat in the area, and many survivors were left to die of exposure. Pointedly, there is no mention of this incident in Ludovic Kennedy's detailed account of the sinking, suggesting that information later gleaned from sailors regarding the cat's true service were apocryphal.


Bisnortilidine

Bisnortilidine is an opioid metabolite. It is formed from tilidine by demethylation in the liver.


Tulobuterol

Tulobuterol (INN) is a long-acting beta2-adrenergic receptor agonist, marketed in Japan as a transdermal patch under the name Hokunalin tape (ホクナリンテープ).
Currently, it is only legal in 7 countries: Japan, Germany, China, South Korea, Bangladesh, Pakistan, and Venezuela. It is available in India also.


Phoriospongin

Phoriospongin A and B are Australian sea sponge isolates with nematocidal activity. They are depsipeptides and were obtained from Phoriospongia species and Callyspongia bilamellata.


Avian HBV RNA encapsidation signal epsilon

The Avian HBV RNA encapsidation signal epsilon (AHBV epsilon) is an RNA structure that is shown to facilitate encapsidation of the pregenomic RNA required for viral replication. There are two main classes of encapsidation signals in avian hepatitis B viruses - "Duck hepatitis B virus" (DHBV) and "Heron hepatitis B virus" (HHBV) like. DHBV is used as a model to understand human "Hepatitis B virus". Although studies have shown that the HHBV epsilon has less pairing in the upper stem than DHBV, this pairing is not absolutely required for DHBV infection in ducks.
DHBV epsilon consists of a stem structure, a bulge and an apical loop (Fig. 1). The RNA structure was determined by chemical probing, NMR analysis and by mutagenesis.
HHBV epsilon also consists of a stem structure, a bulge and an apical loop (Fig. 2). The RNA structure has been determined by chemical probing and by mutagenesis. However, it has less base pairing in the upper stem than DHBV epsilon.
Recent NMR analysis of both the HHBV and DHBV epsilon have shown that the apical loop to be capped by a stable well-structured UGUU tetraloop.
In the Rfam database a single covariation model (AHBV_epsilon box right) best discriminates between the true instances of the element in sequence databases and background. The secondary structure diagram is a computer generated view of the structure with highly conserved bases shown in red. It includes the major elements shown in Figures 1 and 2.


Listeria Hfq binding LhrA

Listeria Hfq binding LhrA is a ncRNA that was identified by screening for RNA molecules which co-immunoprecipitated with the RNA chaperone Hfq. This RNA is transcribed from a region overlapping with a predicted protein of unknown function (Lmo2257) and is located between a putative intracellular protease and a putative protein of the ribulose-phosphate 3 epimerase family. It is highly expressed in the stationary growth phase but the function is unknown. It is proposed to be a regulatory RNA which controls gene expression at the post transcriptional level by binding the target mRNA in an Hfq dependent fashion. This RNA molecule appears to be conserved amongst Listeria species but has not been identified in other bacterial species.


Master regulator

In genetics, a master regulator is a gene at the top of a gene regulation hierarchy, particularly in regulatory pathways related to cell fate and differentiation.
Examples.
Most genes considered master regulators code for transcription factor proteins, which in turn alter the expression of downstream genes in the pathway. Canonical examples of master regulators include Oct-4 (also called POU5F1), SOX2, and NANOG, all transcription factors involved in maintaining pluripotency in stem cells. Master regulators involved in development and morphogenesis can also appear as oncogenes relevant to tumorigenesis and metastasis, as with the Twist transcription factor.
Other genes reported as master regulators code for SR proteins, which function as splicing factors, and some noncoding RNAs.
Criticism.
The master regulator concept has been criticized for being a "simplified paradigm" that fails to account for the multifactorial influences on some cell fates.


RNA-Seq

RNA-Seq (named as an abbreviation of "RNA sequencing") is a sequencing technique which uses next-generation sequencing (NGS) to reveal the presence and quantity of RNA in a biological sample at a given moment, analyzing the continuously changing cellular transcriptome.
Specifically, RNA-Seq facilitates the ability to look at alternative gene spliced transcripts, post-transcriptional modifications, gene fusion, mutations/SNPs and changes in gene expression over time, or differences in gene expression in different groups or treatments. In addition to mRNA transcripts, RNA-Seq can look at different populations of RNA to include total RNA, small RNA, such as miRNA, tRNA, and ribosomal profiling. RNA-Seq can also be used to determine exon/intron boundaries and verify or amend previously annotated 5' and 3' gene boundaries. Recent advances in RNA-Seq include single cell sequencing and in situ sequencing of fixed tissue.
Prior to RNA-Seq, gene expression studies were done with hybridization-based microarrays. Issues with microarrays include cross-hybridization artifacts, poor quantification of lowly and highly expressed genes, and needing to know the sequence "a priori". Because of these technical issues, transcriptomics transitioned to sequencing-based methods. These progressed from Sanger sequencing of Expressed Sequence Tag libraries, to chemical tag-based methods (e.g., serial analysis of gene expression), and finally to the current technology, next-gen sequencing of cDNA (notably RNA-Seq).
Methods.
Library preparation.
The general steps to prepare a complementary DNA (cDNA) library for sequencing are described below, but often vary between platforms.
Small RNA/non-coding RNA sequencing.
When sequencing RNA other than mRNA, the library preparation is modified. The cellular RNA is selected based on the desired size range. For small RNA targets, such as miRNA, the RNA is isolated through size selection. This can be performed with a size exclusion gel, through size selection magnetic beads, or with a commercially developed kit. Once isolated, linkers are added to the 3' and 5' end then purified. The final step is cDNA generation through reverse transcription.
Direct RNA sequencing.
Because converting RNA into cDNA, ligation, amplification, and other sample manipulations have been shown to introduce biases and artifacts that may interfere with both the proper characterization and quantification of transcripts, single molecule direct RNA sequencing has been explored by companies including Helicos (bankrupt), Oxford Nanopore Technologies, and others. This technology sequences RNA molecules directly in a massively-parallel manner.
Single-cell RNA sequencing (scRNA-Seq).
Standard methods such as microarrays and standard bulk RNA-Seq analysis analyze the expression of RNAs from large populations of cells. In mixed cell populations, these measurements may obscure critical differences between individual cells within these populations.
Single-cell RNA sequencing (scRNA-Seq) provides the expression profiles of individual cells. Although it is not possible to obtain complete information on every RNA expressed by each cell, due to the small amount of material available, patterns of gene expression can be identified through gene clustering analyses. This can uncover the existence of rare cell types within a cell population that may never have been seen before. For example, rare specialized cells in the lung called pulmonary ionocytes that express the Cystic Fibrosis Transmembrane Conductance Regulator were identified in 2018 by two groups performing scRNA-Seq on lung airway epithelia.
Experimental procedures.
Current scRNA-Seq protocols involve the following steps: isolation of single cell and RNA, reverse transcription (RT), amplification, library generation and sequencing. Early methods separated individual cells into separate wells; more recent methods encapsulate individual cells in droplets in a microfluidic device, where the reverse transcription reaction takes place, converting RNAs to cDNAs. Each droplet carries a DNA "barcode" that uniquely labels the cDNAs derived from a single cell. Once reverse transcription is complete, the cDNAs from many cells can be mixed together for sequencing; transcripts from a particular cell are identified by the unique barcode.
Challenges for scRNA-Seq include preserving the initial relative abundance of mRNA in a cell and identifying rare transcripts. The reverse transcription step is critical as the efficiency of the RT reaction determines how much of the cell's RNA population will be eventually analyzed by the sequencer. The processivity of reverse transcriptases and the priming strategies used may affect full-length cDNA production and the generation of libraries biased toward 3’ or 5' end of genes.
In the amplification step, either PCR or in vitro transcription (IVT) is currently used to amplify cDNA. One of the advantages of PCR-based methods is the ability to generate full-length cDNA. However, different PCR efficiency on particular sequences (for instance, GC content and snapback structure) may also be exponentially amplified, producing libraries with uneven coverage. On the other hand, while libraries generated by IVT can avoid PCR-induced sequence bias, specific sequences may be transcribed inefficiently, thus causing sequence drop-out or generating incomplete sequences.
Several scRNA-Seq protocols have been published:
Tang et al.,
STRT,
SMART-seq,
CEL-seq,
RAGE-seq,
, Quartz-seq.
and C1-CAGE. These protocols differ in terms of strategies for reverse transcription, cDNA synthesis and amplification, and the possibility to accommodate sequence-specific barcodes (i.e. UMIs) or the ability to process pooled samples.
In 2017, two approaches were introduced to simultaneously measure single-cell mRNA and protein expression through oligonucleotide-labeled antibodies known as REAP-seq, and CITE-seq.
Applications.
scRNA-Seq is becoming widely used across biological disciplines including Development, Neurology, Oncology, Autoimmune disease, and Infectious disease.
scRNA-Seq has provided considerable insight into the development of embryos and organisms, including the worm "Caenorhabditis elegans", and the regenerative planarian "Schmidtea mediterranea". The first vertebrate animals to be mapped in this way were Zebrafish and "Xenopus laevis". In each case multiple stages of the embryo were studied, allowing the entire process of development to be mapped on a cell-by-cell basis. Science recognized these advances as the 2018 Breakthrough of the Year.
Experimental considerations.
A variety of parameters are considered when designing and conducting RNA-Seq experiments:
Analysis.
Transcriptome assembly.
Two methods are used to assign raw sequence reads to genomic features (i.e., assemble the transcriptome):
"A note on assembly quality:" The current consensus is that 1) assembly quality can vary depending on which metric is used, 2) assemblies that scored well in one species do not necessarily perform well in the other species, and 3) combining different approaches might be the most reliable.
Gene expression quantification.
Expression is quantified to study cellular changes in response to external stimuli, differences between healthy and diseased states, and other research questions. Gene expression is often used as a proxy for protein abundance, but these are often not equivalent due to post transcriptional events such as RNA interference and nonsense-mediated decay.
Expression is quantified by counting the number of reads that mapped to each locus in the transcriptome assembly step. Expression can be quantified for exons or genes using contigs or reference transcript annotations. These observed RNA-Seq read counts have been robustly validated against older technologies, including expression microarrays and qPCR. Examples of tools that quantify counts are HTSeq, FeatureCounts, Rcount, maxcounts, FIXSEQ, and Cuffquant. The read counts are then converted into appropriate metrics for hypothesis testing, regressions, and other analyses. Parameters for this conversion are:
Absolute quantification.
Absolute quantification of gene expression is not possible with most RNA-Seq experiments, which quantify expression relative to all transcripts. It is possible by performing RNA-Seq with spike-ins, samples of RNA at known concentrations. After sequencing, read counts of spike-in sequences are used to determine the relationship between each gene's read counts and absolute quantities of biological fragments. In one example, this technique was used in "Xenopus tropicalis" embryos to determine transcription kinetics.
Differential expression.
The simplest but often most powerful use of RNA-Seq is finding differences in gene expression between two or more conditions ("e.g.", treated vs not treated); this process is called differential expression. The outputs are frequently referred to as differentially expressed genes (DEGs) and these genes can either be up- or down-regulated ("i.e.", higher or lower in the condition of interest). There are many tools that perform differential expression. Most are run in R, Python, or the Unix command line. Commonly used tools include DESeq, edgeR, and voom+limma, all of which are available through R/Bioconductor. These are the common considerations when performing differential expression:
Downstream analyses for a list of differentially expressed genes come in two flavors, validating observations and making biological inferences. Owing to the pitfalls of differential expression and RNA-Seq, important observations are replicated with (1) an orthogonal method in the same samples (like real-time PCR) or (2) another, sometimes pre-registered, experiment in a new cohort. The latter helps ensure generalizability and can typically be followed up with a meta-analysis of all the pooled cohorts. The most common method for obtaining higher-level biological understanding of the results is gene set enrichment analysis, although sometimes candidate gene approaches are employed. Gene set enrichment determines if the overlap between two gene sets is statistically significant, in this case the overlap between differentially expressed genes and gene sets from known pathways/databases ("e.g.", Gene Ontology, KEGG, Human Phenotype Ontology) or from complementary analyses in the same data (like co-expression networks). Common tools for gene set enrichment include web interfaces ("e.g.", ENRICHR, g:profiler) and software packages. When evaluating enrichment results, one heuristic is to first look for enrichment of known biology as a sanity check and then expand the scope to look for novel biology.
Alternative splicing.
RNA splicing is integral to eukaryotes and contributes significantly to protein regulation and diversity, occurring in >90% of human genes. There are multiple alternative splicing modes: exon skipping (most common splicing mode in humans and higher eukaryotes), mutually exclusive exons, alternative donor or acceptor sites, intron retention (most common splicing mode in plants, fungi, and protozoa), alternative transcription start site (promoter), and alternative polyadenylation. One goal of RNA-Seq is to identify alternative splicing events and test if they differ between conditions. Long-read sequencing captures the full transcript and thus minimizes many of issues in estimating isoform abundance, like ambiguous read mapping. For short-read RNA-Seq, there are multiple methods to detect alternative splicing that can be classified into three main groups:
Differential gene expression tools can also be used for differential isoform expression if isoforms are quantified ahead of time with other tools like RSEM.
Coexpression networks.
Coexpression networks are data-derived representations of genes behaving in a similar way across tissues and experimental conditions. Their main purpose lies in hypothesis generation and guilt-by-association approaches for inferring functions of previously unknown genes. RNA-Seq data has been used to infer genes involved in specific pathways based on Pearson correlation, both in plants and mammals. The main advantage of RNA-Seq data in this kind of analysis over the microarray platforms is the capability to cover the entire transcriptome, therefore allowing the possibility to unravel more complete representations of the gene regulatory networks. Differential regulation of the splice isoforms of the same gene can be detected and used to predict and their biological functions.
Weighted gene co-expression network analysis has been successfully used to identify co-expression modules and intramodular hub genes based on RNA seq data. Co-expression modules may correspond to cell types or pathways. Highly connected intramodular hubs can be interpreted as representatives of their respective module. An eigengene is a weighted sum of expression of all genes in a module. Eigengenes are useful biomarkers (features) for diagnosis and prognosis. Variance-Stabilizing Transformation approaches for estimating correlation coefficients based on RNA seq data have been proposed.
Variant discovery.
RNA-Seq captures DNA variation, including single nucleotide variants, small insertions/deletions. and structural variation. Variant calling in RNA-Seq is similar to DNA variant calling and often employs the same tools (including SAMtools mpileup and GATK HaplotypeCaller) with adjustments to account for splicing. One unique dimension for RNA variants is allele-specific expression (ASE): the variants from only one haplotype might be preferentially expressed due to regulatory effects including imprinting and expression quantitative trait loci, and noncoding rare variants. Limitations of RNA variant identification include that it only reflects expressed regions (in humans, <5% of the genome) and has lower quality when compared to direct DNA sequencing.
RNA editing (post-transcriptional alterations).
Having the matching genomic and transcriptomic sequences of an individual can help detect post-transcriptional edits (RNA editing). A post-transcriptional modification event is identified if the gene's transcript has an allele/variant not observed in the genomic data.
Fusion gene detection.
Caused by different structural modifications in the genome, fusion genes have gained attention because of their relationship with cancer. The ability of RNA-Seq to analyze a sample's whole transcriptome in an unbiased fashion makes it an attractive tool to find these kinds of common events in cancer.
The idea follows from the process of aligning the short transcriptomic reads to a reference genome. Most of the short reads will fall within one complete exon, and a smaller but still large set would be expected to map to known exon-exon junctions. The remaining unmapped short reads would then be further analyzed to determine whether they match an exon-exon junction where the exons come from different genes. This would be evidence of a possible fusion event, however, because of the length of the reads, this could prove to be very noisy. An alternative approach is to use pair-end reads, when a potentially large number of paired reads would map each end to a different exon, giving better coverage of these events (see figure). Nonetheless, the end result consists of multiple and potentially novel combinations of genes providing an ideal starting point for further validation.
History.
RNA-Seq was first developed in mid 2000s with the advent of next-generation sequencing technology. The first manuscripts that used RNA-Seq even without using the term includes those of prostate cancer cell lines (dated 2006), "Medicago truncatula" (2006), maize (2007), and "Arabidopsis thaliana" (2007), while the term "RNA-Seq" itself was first mentioned in 2008 The number of manuscripts referring to RNA-Seq in the title or abstract (Figure, blue line) is continuously increasing with 6754 manuscripts published in 2018 (link to PubMed search). The intersection of RNA-Seq and medicine (Figure, gold line, link to PubMed search) has similar celerity.
Applications to medicine.
RNA-Seq has the potential to identify new disease biology, profile biomarkers for clinical indications, infer druggable pathways, and make genetic diagnoses. These results could be further personalized for subgroups or even individual patients, potentially highlighting more effective prevention, diagnostics, and therapy. The feasibility of this approach is in part dictated by costs in money and time; a related limitation is the required team of specialists (bioinformaticians, physicians/clinicians, basic researchers, technicians) to fully interpret the huge amount of data generated by this analysis.
Large-scale sequencing efforts.
A lot of emphasis has been given to RNA-Seq data after the Encyclopedia of DNA Elements (ENCODE) and The Cancer Genome Atlas (TCGA) projects have used this approach to characterize dozens of cell lines and thousands of primary tumor samples, respectively. ENCODE aimed to identify genome-wide regulatory regions in different cohort of cell lines and transcriptomic data are paramount in order to understand the downstream effect of those epigenetic and genetic regulatory layers. TCGA, instead, aimed to collect and analyze thousands of patient's samples from 30 different tumor types in order to understand the underlying mechanisms of malignant transformation and progression. In this context RNA-Seq data provide a unique snapshot of the transcriptomic status of the disease and look at an unbiased population of transcripts that allows the identification of novel transcripts, fusion transcripts and non-coding RNAs that could be undetected with different technologies.


Oxidative deamination

Oxidative deamination is a form of deamination that generates α-keto acids and other oxidized products from amine-containing compounds, and occurs primarily in the liver. Oxidative deamination is stereospecific, meaning it contains different stereoisomers as reactants and products; this process is either catalyzed by L or D- amino acid oxidase and L-amino acid oxidase is present only in the liver and kidney. Oxidative deamination is an important step in the catabolism of amino acids, generating a more metabolizable form of the amino acid, and also generating ammonia as a toxic byproduct. The ammonia generated in this process can then be neutralized into urea via the urea cycle.
Much of the oxidative deamination occurring in cells involves the amino acid glutamate, which can be oxidatively deaminated by the enzyme glutamate dehydrogenase (GDH), using NAD or NADP as a coenzyme. This reaction generates α-ketoglutarate (α-KG) and ammonia. Glutamate can then be regenerated from α-KG via the action of transaminases or aminotransferase, which catalyze the transfer of an amino group from an amino acid to an α-keto acid. In this manner, an amino acid can transfer its amine group to glutamate, after which GDH can then liberate ammonia via oxidative deamination. This is a common pathway during amino acid catabolism.
Another enzyme responsible for oxidative deamination is monoamine oxidase, which catalyzes the deamination of monoamines via addition of oxygen. This generates the corresponding ketone- or aldehyde-containing form of the molecule, and generates ammonia. Monoamine oxidases MAO-A and MAO-B play vital roles in the degradation and inactivation of monoamine neurotransmitters such as serotonin and epinephrine. Monoamine oxidases are important drug targets, targeted by MAO inhibitors (MAOIs) such as selegiline.


Variola minor virus


Lacto-usp RNA motif

The Lacto-"usp" RNA motif is a conserved RNA structure identified in bacteria by bioinformatics. Lacto-"usp" RNAs are found exclusively in lactic acid bacteria, and exclusively in the possible 5′ untranslated regions of (5′ UTRs) operons that contain a hypothetical gene and a "usp" gene. The "usp" gene encodes the universal stress protein. It was proposed that the Lacto-"usp" might correspond to the 6S RNA of the relevant species, because four of five of these species lack a predicted 6S RNA, and 6S RNAs commonly occur in 5′ UTRs of "usp" genes. However, given that the Lacto-"usp" RNA motif is much shorter than the standard 6S RNA structure, the function of Lacto-"usp" RNAs remains unclear.


Jennifer Moyle

Jennifer Moyle (April 30, 1921 - August 1, 2016) was a British biochemist who helped discover the chemiosmotic mechanism of ATP synthesis. She also conducted research on the properties of purified isocitric enzymes and calcium import in the mitochondria during cellular respiration.
Biography.
Jennifer Moyle was born in Norwich, England and attended Norwich High School for Girls. She was the daughter of S.H. Leonard Moyle and Olive M. Dakin. She had a sister named Vivian, who also studied biochemistry.
Moyle began schooling at Norwich High School for Girls in 1926 where she remained until entering Girton College of Cambridge University in 1939. While studying there, she earned a "Title of Bachelor of Arts Degree", the equivalent of modern-day Bachelor of Arts, in 1942. She specialized in Biochemistry, and also attended many lectures on philosophy.
In 1955, Moyle began her PhD work at the University of Edinburgh, and was awarded a PhD in zoology in 1958.
Moyle conducted a lot of research regarding cellular respiration, oxidative phosphorylation, and properties of purified isocitric enzymes. She was a major contributor to the development of the chemiosmotic theory regarding ATP synthesis.
Military service.
Shortly after earning her degree, Moyle entered the Auxiliary Territorial Service during World War II. She went into military intelligence, where she soon become an intelligence officer in MI8. There, she was promoted to second in command of a section dealing with intelligence obtained from ciphers breaking German codes.
After World War II, she continued service for another year helping teach servicemen how to return to civilian life.
Research.
Moyle began her career in biochemistry research in 1964 when she joined a Cambridge biochemistry lab. She began as an assistant to Marjory Stephenson, but after a few years Stevenson introduced Moyle to Peter D. Mitchell, with whom Moyle worked for the majority of her research career. Jennifer's main research focus was cellular respiration. for a short period, Moyle worked with Malcolm Dixon, and the two focused their work on the purification of isocitric enzymes.
Purified isocitric enzymes.
Jennifer Moyle published an article on the properties of purified isocitric enzymes in August 1956 with Malcolm Dixon. The article describes the chemical and physical properties of isocitric enzymes, various reactions they are involved in, causes for their inactivation, and a hypothesis for the mechanism of reaction. Moyle and Dixon authored another paper regarding the isocitric enzyme Triphosphopyridine Nucleotide-linked isoCitric Dehydrogenase-Oxalosuccinic Carboxylase. The paper outlines the proper method of the purification of that enzyme.
Chemiosmotic theory.
One of Moyle's major contributions to the field of biochemistry is her contribution to the development of the chemiosmotic theory. Moyle conducted research with Peter Mitchell on chemiosmotic reactions and reaction mechanisms, which led to the development of the theory in 1967. The chemiosmotic theory explained the mechanism for oxidative phosphorylation, stating that ATP synthesis requires chemiosmosis to function. The proton gradient across the inner membrane of the mitochondria is created by the electron transport chain. This causes protons to re-enter the mitochondrial matrix through the protein ATP synthase. The movement of protons through this enzyme causes mechanical movement and a conformational change in the enzyme that combines ADP and inorganic phosphate to produce ATP. The proposal of the chemiosmotic theory was not accepted in the scientific community for over ten years until. When It finally was accepted, Peter Mitchell received a nobel prize for their work. While the nobel committee recognized Moyle's contributions, she did not receive a nobel prize.
Mitochondria and cellular respiration.
The chemiosmotic theory was radical at the time, and it was not immediately accepted by the scientific community. One experiment that Moyle and Mitchell conducted in 1967 was an investigation of ways to improve the precision at which the quotients of translocation of a proton to oxygen can be measured, and what the optimum conditions are for these measurements. Their goal was to improve the precision of that measurement in order to allow others to confirm their findings in the proposed chemiosmotic hypothesis. They conducted this experiment because the arrangement of the electron transport chain was only a hypothesis at the time, and it had been inferred from a quotient of protons translocated to oxygen in the chain (→H+/O). Moyle and Mitchell isolated mitochondria from a rat liver, measured pH displacement across the mitochondrial membrane, and computed the relationship between proton translocation and changes in pH. They found that the pulses of acidification of the inner membrane space of the mitochondria are due to the transport of H+ ions from the mitochondrial matrix into the inner membrane space, and can't be attributed to the formation and breakdown of an intermediate as was previously hypothesized. Their work provided sufficient detail for others to reproduce their experiment and confirm their previous findings regarding the chemiosmotic theory.
An article published jointly with Peter Mitchell in 1977 outlines their work regarding calcium import into mitochondria in the rat's liver during cellular respiration. In the article, they state that this import of calcium happens electrophoretically, and that evidence had already been obtained showing that one electric charge is translocated through a lanthanide-sensitive transporter system per a single calcium ion (Ca2+) imported. Moyle and Mitchell isolated rat liver mitochondria to investigate their hypothesis that the calcium transporter is in fact a calcium phosphate transporter, defined in the article as a "(Ca2)4+--HPO42- symporter." Their results were consistent with their hypothesis, showing that a lanthanide-sensitive (Ca2)4+--HPO42- symporter that is insensitive to NEM and mersalyl catalyzed calcium translocation in the mitochondria of the rat liver.
Research colleagues.
Peter D. Mitchell.
Jennifer Moyle and Peter Mitchell were research colleagues for over thirty years, beginning around 1948 and continuing until Moyle's retirement in 1983. They worked together on many research projects, including the development of the chemiosmotic theory. Moyle designed many of the experiments that were fundamental in testing the theory's hypothesis, and she helped Mitchell win the Nobel Prize in chemistry in 1978.
Moyle and Mitchell also cofounded charitable research company known as Glynn Research Ltd., a research institute that promoted biological research from 1964 to 1987.
Malcolm Dixon.
Jennifer Moyle and Malcolm Dixon worked together for roughly two years. During this time together, they researched the properties of purified isocitric enzymes and published their findings.


Neldazosin

Neldazosin is an alpha adrenoreceptor antagonist.


Michael Somogyi

Dr. Michael Somogyi (March 7, 1883 – July 21, 1971) was a Hungarian-American professor of biochemistry at Washington University and the Jewish Hospital of St. Louis. He prepared the first insulin treatment given to a child with diabetes in the USA in October 1922. Somogyi later showed that excessive insulin makes diabetes unstable in the Chronic Somogyi rebound to which he gave his name.
Career.
Michael Somogyi was born on March 7, 1883 in the village of Zsámánd in Hungary, (today Reinersdorf, part of Heiligenbrunn, Austria). He graduated in chemical engineering from the University of Budapest in 1905.
After an additional year as an assistant in biochemistry, Somogyi went to the United States, where he eventually found a position as an assistant in biochemistry at Cornell University (1906–1908). He returned to Budapest where he worked at the Municipal Laboratory for the next decade. In 1914, he received his Ph.D. from the University of Budapest, submitting a dissertation on catalytic hydrogenation. During World War I he was in charge of providing food to the destitute.
Somogyi was invited to return to the United States by Philip A. Shaffer, whom he had known at Cornell. In 1922 Somogyi became an instructor in biochemistry at Washington University Medical School, St. Louis, Missouri. There Somogyi worked with Shaffer and Edward Adelbert Doisy on insulin preparation and insulin's use in the treatment of diabetes. In 1926, Somogyi became the first biochemist on the staff of the new Jewish Hospital of St. Louis where he worked closely with physicians. He directed the hospital's clinical laboratory until he retired in 1957.
Research.
Insulin was discovered in 1921, by Frederick G. Banting, Charles Herbert Best and John James Rickard Macleod at the University of Toronto. At a time when most child diabetics lived no more than months or a few years, insulin offered the hope of extending lives.
Somogyi worked with Philip A. Shaffer and Edward Adelbert Doisy on insulin preparation and insulin's use in the treatment of diabetes. He developed a method for extracting insulin from the pancreases of dogs. In 1922 doctors treated the first diabetic American child, a baby boy, with Somogyi’s insulin.
Somogyi also developed a quicker, less expensive method for screening for diabetes, using sodium carbonate, urine, and heat. This led to the development of popular tests, including several varieties of urine sugar comparator from the Aloe Company of Saint Louis, Missouri. Urine Sugar Test kits were also produced by Eli Lilly & Company.
In 1938 Somogyi published findings showing that excessive insulin can make diabetes management unstable and increase the difficulty of treatment. The Chronic Somogyi rebound, a form of post-hypoglycemic hyperglycemia that Somogyi theorized could occur as a defensive mechanism, is named for him. It can be confused with the Dawn phenomenon and whether or not Somogyi's theory is actually correct is still contested.
In 1949, Somogyi argued against the use of high doses of insulin on the grounds that it was a potentially dangerous form of treatment. He also argued that many diabetic patients could successfully manage their conditions through a combination of diet and weight loss.
In 1969, Michael Somogyi suffered a stroke. He died on 21 July 1971.


Pyrroline-5-carboxylate reductase

In enzymology, a pyrroline-5-carboxylate reductase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are -proline, NAD+, and NADP+, whereas its 4 products are 1-pyrroline-5-carboxylate, NADH, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is -proline:NAD(P)+ 5-oxidoreductase. Other names in common use include proline oxidase, -proline oxidase, 1-pyrroline-5-carboxylate reductase, NADPH-L-Delta1-pyrroline carboxylic acid reductase, and -proline-NAD(P)+ 5-oxidoreductase. This enzyme participates in arginine and proline metabolism.
Structural studies.
As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes , , , , and .


SecY protein

The SecY protein is the main transmembrane subunit of the bacterial Sec or Type II secretory pathway and a protein-secreting ATPase complex, also known as a SecYEG translocon. Homologs of the SecYEG complex are found in eukaryotes and in archaea, where the subunit is known as Sec61α.
Secretion of some proteins carrying a signal-peptide across the inner membrane in Gram-negative bacteria occurs via the preprotein translocase pathway. Proteins are produced in the cytoplasm as precursors, and require a chaperone subunit to direct them to the translocase component within the membrane. From there, the mature proteins are either targeted to the outer membrane, or remain as periplasmic proteins. The translocase protein subunits are encoded on the bacterial chromosome.
The translocase pathway comprises 7 proteins, including a chaperone protein (SecB), an ATPase (SecA), an integral membrane complex (SecY, SecE and SecG), and two additional membrane proteins that promote the release of the mature peptide into the periplasm (SecD and SecF). The chaperone protein SecB is a highly acidic homotetrameric protein that exists as a "dimer of dimers" in the bacterial cytoplasm. SecB maintains preproteins in an unfolded state after translation, and targets these to the peripheral membrane protein ATPase SecA for secretion. The structure of the Escherichia coli SecYEG assembly revealed a sandwich of two membranes interacting through the extensive cytoplasmic domains. Each membrane is composed of dimers of SecYEG. The monomeric complex contains 15 transmembrane helices.
The eubacterial SecY protein interacts with the signal sequences of secretory proteins as well as with two other components of the protein translocation system: SecA and SecE. SecY is an integral plasma membrane protein of 419 to 492 amino acid residues that apparently contains 10 transmembrane (TM), 6 cytoplasmic and 5 periplasmic regions.
Cytoplasmic regions 2 and 3, and TM domains 1, 2, 4, 5, 7 and 10 are well conserved: the conserved cytoplasmic regions are believed to interact with cytoplasmic secretion factors, while the TM domains may participate in protein export. SecY is also encoded in the chloroplast genome of some algae where it could be involved in a prokaryotic-like protein export system across the two membranes of the chloroplast endoplasmic reticulum (CER) which is present in chromophyte and cryptophyte algae.
Human proteins containing this domain.
SEC61A1; SEC61A2;


Tentoxin

Tentoxin is a natural cyclic tetrapeptide produced by phytopathogenic fungus "Alternaria alternata". It selectively induces chlorosis in several germinating seedling plants. Therefore, tentoxin may be used as a potential natural herbicide.
Tentoxin was first isolated from "Alternaria alternata" (syn. "tenuis") and characterized by George Templeton "et al." in 1967.
Tentoxin has also been used in recent research to eliminate the polyphenol oxidase (PPO) activity from seedlings of higher plants.


Countercurrent multiplication

A countercurrent mechanism system is a mechanism that expends energy to create a concentration gradient.
It is found widely in nature and especially in mammalian organs. For example, it can refer to the process that is underlying the process of urine concentration, that is, the production of hyperosmotic urine by the mammalian kidney.
The ability to concentrate urine is also present in birds.
Countercurrent multiplication is frequently mistaken for countercurrent exchange, a similar but different mechanism where gradients are maintained, but not established.
Physiological principles.
The term derives from the form and function of the loop of Henle, which consists of two parallel limbs of renal tubules running in opposite directions, separated by the interstitial space of the renal medulla.
Details.
Countercurrent multiplication was originally studied as a mechanism whereby urine is concentrated in the nephron. Initially studied in the 1950s by Gottschalk and Mylle following Werner Kuhn's postulations, this mechanism gained popularity only after a series of complicated micropuncture experiments.
Pump: The Na+/K+/2Cl− transporter in the ascending limb of the loop of Henle helps to create a gradient by shifting Na+ into the medullary interstitium. The thick ascending limb of the loop of Henle is the only part of the nephron lacking in aquaporin—a common transporter protein for water channels. This makes the thick ascending limb impermeable to water. The action of the Na+/K+/2Cl− transporter therefore creates a hypoosmolar solution in the tubular fluid and a hyperosmolar fluid in the interstitium, since water cannot follow the solutes to produce osmotic equilibrium.
Equilibration: Since the descending limb of the loop of henle consists of very leaky epithelium, the fluid inside the descending limb becomes hyperosmolar.
Shift: The movement of fluid through the tubules causes the hyperosmotic fluid to move further down the loop. Repeating many cycles causes fluid to be near isosmolar at the top of Henle's loop and very concentrated at the bottom of the loop. Animals with a need for very concentrated urine (such as desert animals) have very long loops of Henle to create a very large osmotic gradient. Animals that have abundant water on the other hand (such as beavers) have very short loops.
The vasa recta have a similar loop shape so that the gradient does not dissipate into the plasma.
The mechanism of counter current multiplication works together with the vasa recta's counter current exchange to prevent the wash out of salts and maintain a high osmolarity at the inner medulla.


Empire Genomics

Empire Genomics is a cancer molecular diagnostics company. They make genetic tests for over 200 different types of health concerns. It is based in Buffalo, New York in the United States.
Dr. Norma J. Nowak founded Empire Genomics in 2006 in Buffalo, New York. It developed out of a project at Roswell Park Comprehensive Cancer Center. Their headquarters is located in Buffalo at the Buffalo Niagara Medical Campus.
The company develops non-invasive tests that focus around health concerns such as cancer, autism and Down syndrome.
In 2012, Empire Genomics released a test for multiple myeloma and opened a new laboratory to focus on the test. As of 2012, Anthony Johnson is chief executive officer. That same year, the company received a $400,000 grant from the Empire State Development Corporation.
On February 19, 2019, the company announced the appointments of Andy Watson as CEO and Anthony Scarpello to CCO, and the opening of its new headquarters in Williamsville, NY.


Ionian Technologies

Ionian Technologies Inc. was a United States Biotechnology Company focused on molecular diagnostics development for the detection of infectious diseases and biothreat agents. It was established in 2000 in Upland, California as the first spin-off company to commercialize technology developed at the Keck Graduate Institute. Since its inception Ionian has expanded its isothermal amplification technology. Ionian was acquired in July 2010 by Alere Inc.
History.
Ionian traces its origins to Dr. David Galas who was previously Chancellor, Chief Scientific Officer and Norris Professor of Applied Life Science at the Keck Graduate Institute of Applied Life Sciences. During his development of KGI he spun off Ionian Technologies from work done in his lab, based upon a 2003 PNAS paper.
In 2001, Ionian was incorporated in Delaware.
Corporate governance.
Current members of the board of directors of Ionian Technologies are: David Galas and Paul Tardif.
Technology.
Ionian's proprietary isothermal technology, termed the Nicking Enzyme Amplification Reaction Assay, is claimed to be capable of amplifying extremely low amounts of starting material to easily detectable levels in just a few minutes. The proprietary technology is based on the very rapid detection of small DNA or RNA fragments generated directly from the target nucleic acid. The amplification products can be detected by a variety of standard methods, including LC-MS, real-time fluorescence, lateral flow and capillary electrophoresis detection. Ionian's assay technology is therefore ideally suited for portable and handheld detectors and sensors.
Mission.
Ionian Technologies Inc. describes itself as a private company focused on molecular diagnostics and advanced biomedical research tools based on proprietary isothermal systems for DNA and RNA amplification and detection. This technology is currently focused on the development of products for the medical diagnostics, agricultural (GMO), veterinary, food hygiene and biodefense markets.
Ionian has made significant efforts for providing rapid and economical systems for third world countries and have received funding from the Bill and Melinda Gates Foundation to achieve these goals.


Protocatechuate 4,5-dioxygenase

In enzymology, a protocatechuate 4,5-dioxygenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are protocatechuate and O2, whereas its product is 4-carboxy-2-hydroxymuconate semialdehyde.
This enzyme belongs to the family of oxidoreductases, specifically those acting on single donors with O2 as oxidant and incorporation of two atoms of oxygen into the substrate (oxygenases). The oxygen incorporated need not be derived from O2. The systematic name of this enzyme class is protocatechuate:oxygen 4,5-oxidoreductase (decyclizing). Other names in common use include protocatechuate 4,5-oxygenase, protocatechuic 4,5-dioxygenase, and protocatechuic 4,5-oxygenase. This enzyme participates in benzoate degradation via hydroxylation and 2,4-dichlorobenzoate degradation. It employs one cofactor, iron.
Structural studies.
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes and .


Xylomannan

Xylomannan is an antifreeze molecule, found in the freeze-tolerant Alaskan beetle "Upis ceramboides". Unlike antifreeze proteins, xylomannan is not a protein. Instead, it is a combination of a sugar (saccharide) and a fatty acid that is found in cell membranes. As such is expected to work in a different manner than AFPs. It is believed to work by incorporating itself directly into the cell membrane and preventing the freezing of water molecules within the cell.
Xylomannan is also found in the red seaweed "Nothogenia fastigiata". Fraction F6 of a sulphated xylomannan from Nothogenia fastigiata was found to inhibit replication of a variety of viruses, including Herpes simplex virus types 1 and 2 (HSV-1, HSV-2), Human cytomegalovirus (HCMV, HHV-5), Respiratory syncytial virus (RSV), Influenzavirus A, Influenzavirus B, Junin and Tacaribe virus, Simian immunodeficiency virus, and (weakly) Human immunodeficiency virus types 1 and 2.


Mycena zephirus

Mycena zephirus is a species of agaric fungus in the family Mycenaceae. It is bioluminescent.


Elosulfase alfa

Elosulfase alfa (trade name Vimizim) is a drug for the treatment of Morquio syndrome which is caused by a deficiency in the enzyme N-acetylgalactosamine-6-sulfatase. Elosulfase alfa is a synthetic version of this enzyme.
Elosulfase alfa was developed by BioMarin Pharmaceutical Inc. and approved for use in the US by the Food and Drug Administration in 2014.
The drug is used in enzyme replacement therapy; a 2014 study confirmed it was effective on young patients with Morquio syndrome type A. Treatment with this medication was most effective upon respiratory symptoms, activities of daily living and growth, as confirmed in a 2015 paper.
The cost of elosulfase alfa in some countries is $400,000 a year, which has made it difficult for some health systems to afford it.
In June 2019, a Belgian court issued a preliminary injunction forcing BioMarin to continue supplying Vimizim to a young girl suffering from Morquio syndrome free of charge. BioMarin stopped providing the drug for free at the beginning of the year after negotiations with Belgian health authorities regarding reimbursement of the product repeatedly failed. This caused the parents to start legal proceedings to force the company to keep providing the medicine free of charge. BioMarin was ordered to keep doing so until a definitive judgment would be rendered, or until the medicine would be available on the Belgian market at a reasonable price.


Psychroflexus

Psychroflexus is a psychrophilic bacteria genus from the family of Flavobacteriaceae.


Jack D. Keene

Jack D. Keene (born June 22, 1947, Jacksonville, Florida) is a James B. Duke Professor of Molecular Genetics and Microbiology at Duke University.
Keene studies the regulation of RNA and the mechanisms of RNA-protein interactions. He identified RNA recognition motif (RRM) proteins, which are the largest family of RNA-binding proteins. He isolated the first human autoimmune antigen. He formalized the posttranscriptional operon and regulon (PTRO) model to describe global gene regulation, and proposed the RNA regulon hypothesis to better understand post-transcriptional regulation of mRNAs encoding proteins. Keene introduced the RIP (ribonucleoprotein immunoprecipitation) protocol for isolating specific mRNPs, which has become a tool for the mapping of mRNA targets of specific RBPs.
Early life and education.
Jack Donald Keene was born in Jacksonville, Florida on June 22, 1947. His father worked for the RAND Corporation. Keene attended Redlands High School in Redlands, California, graduating in 1965.
Initially a student at University of California, Los Angeles (UCLA),
he transferred to the University of California, Riverside, where he majored in biology, working with Carlton Bovell. He received his A.B. degree in 1969.
Next, Keene studied with Helen Riaboff Whiteley at the University of Washington in Seattle, Washington, graduating in 1975 with a doctorate in microbiology and Immunology.
He did postdoctoral work in molecular virology with Robert A. Lazzarini in the Laboratory for Molecular Genetics at the National Institutes of Health in Bethesda, Maryland from 1974-1978.
Career.
In 1979, Keene was recruited by Wolfgang Joklik to the Department of Microbiology and Immunology at Duke University Medical Center. At that time the department was ranked one of the top three in the United States by the National Research Council.
Keene was the chairman of the Department of Microbiology from 1992-2002, and
Director of Basic Sciences for the Duke Comprehensive Cancer Center from 1995-2003.
As of 1997 he became the James B. Duke Professor of Molecular Genetics and Microbiology at Duke University.
In 1999 Keene founded the Duke Center for RNA Biology.
Research.
Keene studies the regulation of RNA and the mechanisms of RNA-protein interactions.
In his work on molecular genetics, he and his coworkers have examined the role of DNA and RNA-binding proteins (RBPs) in the pathogenesis of autoimmunity.
In the late 1970s and early 1980s he identified genomic sequences for vesicular stomatitis virus (VSV) and rabies virus (RABV), members of the Rhabdoviridae family of viruses,
and for Ebola virus and Marburg virus from the broader group of negative-strand RNA viruses (NSRV).
He identified the origins of defective interfering particles of negative-strand RNA viruses.
Through combinatorial studies of viral and bacterial systems, he has identified targets for novel pharmacological studies.
Later in the 1980s, Keene identified RNA recognition motif (RRM) proteins. RRM proteins are the largest family of RNA-binding proteins and the seventh largest protein family of the human genome. RRM is a prevalent RNA-binding fold involving proteins implicated in RNA biogenesis, processing, transport, and degradation.
In 1987, Query and Keene first identified a B-cell epitope within the U1-70K protein.
Keene isolated the first human autoimmune antigen and elucidated its autoimmune epitopes, the parts of an antigen to which antibodies in the immune system can bind.
He cloned rheumatological autoimmune protein genes. He developed a diagnostic test for systemic lupus erythematosus using recombinant antigens.
Keene's lab has identified functions of the ELAV/Hu posttranscriptional regulators HuB, HuC and HuD and their roles and that of HuR in processes of growth, proliferation, differentiation, and immune response.
The study of RNA-binding proteins such as HuR and the determination of the binding of specific sequences have informed Keene's later post-transcription theory and his coordination theory of RNA operons.
RNA-binding proteins appear to be implicated in the functioning of many posttranscriptional processes. As of 1994, Keene suggested that RNA-binding proteins could be involved in the regulation of messenger RNA that encode cytokines.
In 2000, he was able to apply this approach to demonstrate neuronal differentiation. He also introduced the first use of the RIP (ribonucleoprotein immunoprecipitation) protocol, isolating specific mRNPs using immunoprecipitation, and identifying the mRNA component with microarray or deep sequencing. This method has become a tool for the mapping of mRNA targets of specific RBPs.
In 2001-2002, Keene formalized the posttranscriptional operon and regulon (PTRO) model for global gene regulation.
By 2007, Keene proposed the RNA regulon hypothesis, "that mRNAs encoded by functionally related genes may be coordinately regulated as posttranscriptional RNA regulons by specific mRNP processing machineries".
The purpose of the RNA regulon model was to better understand post-transcriptional regulation, to answer the question "How does the cell coordinate metabolism and regulation of mRNAs encoding proteins in the same biological process so that the proteins can be coordinately produced?"


Variola minor


Adiphenine

Adiphenine is an inhibitor of nicotinic receptors.


MAbs (journal)

mAbs is a peer-reviewed multi-disciplinary scientific journal established in 2009, published by Taylor & Francis and dedicated to the art and science of antibody research and development. Its editor-in-chief is Janice M. Reichert and it is affiliated with The Antibody Society. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics. It is indexed in MEDLINE, PubMed, the Science Citation Index Expanded, Biological Abstracts, BIOSIS Previews, and Scopus.


Drishti (client)

Drishti (from Sanskrit दृष्टि "dr̥ṣţi", meaning "vision" or "insight") is a multi-platform, open-source volume-exploration and presentation tool. Written for visualizing tomography data, electron-microscopy data and the like, it aims to ease understanding of data sets and to assist with conveying that understanding to the research community or to lay persons. From the website: "The central idea about Drishti is that the scientists should be able to use it for exploring volumetric datasets as well as use it in presentations."
The Commonwealth Scientific and Industrial Research Organisation (CSIRO) in Australia has used Drishti for a number of purposes, such as volumetric visualisation of various computer-tomography datasets. The Australian National University (ANU) Physics Department, along with the author of the software, has used it for (amongst other things) the analysis of immiscible flow in massive 3D systems. Further uses were presented at the APAC '07.
Among other software, Drishti uses Qt for the GUI widgets and OpenGL Extension Wrangler Library (GLEW).
Features.
Drishti provides a number of features that would otherwise require several proprietary volume visualisation programs or that are simply not available together in other software: