Enhancer (genetics)

In genetics, an enhancer is a short (50–1500 bp) region of DNA that can be bound by proteins (activators) to increase the likelihood that transcription of a particular gene will occur. These proteins are usually referred to as transcription factors. Enhancers are cis-acting. They can be located up to 1 Mbp (1,000,000 bp) away from the gene, upstream or downstream from the start site. There are hundreds of thousands of enhancers in the human genome. They are found in both prokaryotes and eukaryotes.
The first discovery of a eukaryotic enhancer was in the immunoglobulin heavy chain gene in 1983. This enhancer, located in the large intron, provided an explanation for the transcriptional activation of rearranged Vh gene promoters while unrearranged Vh promoters remained inactive.
Locations.
In eukaryotic cells the structure of the chromatin complex of DNA is folded in a way that functionally mimics the supercoiled state characteristic of prokaryotic DNA, so although the enhancer DNA may be far from the gene in a linear way, it is spatially close to the promoter and gene. This allows it to interact with the general transcription factors and RNA polymerase II. The same mechanism holds true for silencers in the eukaryotic genome. Silencers are antagonists of enhancers that, when bound to its proper transcription factors called repressors, repress the transcription of the gene. Silencers and enhancers may be in close proximity to each other or may even be the same region only differentiated by the transcription factor the region binds to.
An enhancer may be located upstream or downstream of the gene it regulates. Furthermore, an enhancer doesn't need to be located near the transcription initiation site to affect transcription, as some have been found located in several hundred thousand base pairs upstream or downstream of the start site. Enhancers do not act on the promoter region itself, but are bound by activator proteins. These activator proteins interact with the mediator complex, which recruits polymerase II and the general transcription factors which then begin transcribing the genes. Enhancers can also be found within introns. An enhancer's orientation may even be reversed without affecting its function. Additionally, an enhancer may be excised and inserted elsewhere in the chromosome, and still affect gene transcription. That is one reason that introns polymorphisms may have effects although they are not translated. Enhancers can also be found at the exonic region of an unrelated gene and they may act on genes on another chromosome.
Enhancers are bound by p300-CBP and their location can be predicted by ChIP-seq against this family of coactivators.
Enhancers, transcription factors, Mediator complex and DNA loops in mammalian transcription.
Gene expression in mammals is regulated by many cis-regulatory elements, including core promoters and promoter-proximal elements that are located near the transcription start sites of genes. Core promoters are sufficient to direct transcription
initiation, but generally have low basal activity. Other important cis-regulatory modules are localized in DNA regions that are distant from the transcription start sites. These include enhancers, silencers, insulators and tethering elements. Among this constellation of elements, enhancers and their associated transcription factors have a leading role in the regulation of gene expression. An enhancer localized in a DNA region distant from the promoter of a gene can have a very large effect on gene expression, with some genes undergoing up to 100-fold increased expression due to an activated enhancer.
Enhancers are regions of the genome that are major gene-regulatory elements. Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes. While there are hundreds of thousands of enhancer DNA regions, for a particular type of tissue only specific enhancers are brought into proximity with the promoters that they regulate. In a study of brain cortical neurons, 24,937 loops were found, bringing enhancers to their target promoters. Multiple enhancers, each often at tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and can coordinate with each other to control expression of their common target gene.
The schematic illustration in this section shows an enhancer looping around to come into close physical proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of CTCF or YY1), with one member of the dimer anchored to its binding motif on the enhancer and the other member anchored to its binding motif on the promoter (represented by the red zigzags in the illustration). Several cell function specific transcription factors (there are about 1,600 transcription factors in a human cell) generally bind to specific motifs on an enhancer and a small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern level of transcription of the target gene. Mediator (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (pol II) enzyme bound to the promoter.
Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two Enhancer RNAs (eRNAs) as illustrated in the Figure. An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of transcription factor bound to enhancer in the illustration). An activated enhancer begins transcription of its RNA before activating transcription of messenger RNA from its target gene.
Theories.
, there are two different theories on the information processing that occurs on enhancers:
Examples in the human genome.
HACNS1.
HACNS1 (also known as CENTG2 and located in the Human Accelerated Region 2) is a gene enhancer "that may have contributed to the evolution of the uniquely opposable human thumb, and possibly also modifications in the ankle or foot that allow humans to walk on two legs". Evidence to date shows that of the 110,000 gene enhancer sequences identified in the human genome, HACNS1 has undergone the most change during the evolution of humans following the split with the ancestors of chimpanzees.
GADD45G.
An enhancer near the gene GADD45g has been described that may regulate brain growth in chimpanzees and other mammals, but not in humans. The GADD45G regulator in mice and chimps is active in regions of the brain where cells that form the cortex, ventral forebrain, and thalamus are located and may suppress further neurogenesis. Loss of the GADD45G enhancer in humans may contribute to an increase of certain neuronal populations and to forebrain expansion in humans.
In developmental biology.
The development, differentiation and growth of cells and tissues require precisely regulated patterns of gene expression. Enhancers work as cis-regulatory elements to mediate both spatial and temporal control of development by turning on transcription in specific cells and/or repressing it in other cells. Thus, the particular combination of transcription factors and other DNA-binding proteins in a developing tissue controls which genes will be expressed in that tissue. Enhancers allow the same gene to be used in diverse processes in space and time.
Identification and characterization.
Traditionally, enhancers were identified by enhancer trap techniques using a reporter gene or by comparative sequence analysis and computational genomics. In genetically tractable models such as the fruit fly "Drosophila melanogaster," for example, a reporter construct such as the "lacZ" gene can be randomly integrated into the genome using a P element transposon. If the reporter gene integrates near an enhancer, its expression will reflect the expression pattern driven by that enhancer. Thus, staining the flies for LacZ expression or activity and cloning the sequence surrounding the integration site allows the identification of the enhancer sequence.
The development of genomic and epigenomic technologies, however, has dramatically changed the outlook for cis-regulatory modules (CRM) discovery. Next-generation sequencing (NGS) methods now enable high-throughput functional CRM discovery assays, and the vastly increasing amounts of available data, including large-scale libraries of transcription factor-binding site (TFBS) motifs, collections of annotated, validated CRMs, and extensive epigenetic data across many cell types, are making accurate computational CRM discovery an attainable goal. An example of NGS-based approach called DNase-seq have enabled identification of nucleosome-depleted, or open chromatin regions, which can contain CRM. More recently techniques such as ATAC-seq have been developed which require less starting material. Nucelosome depleted regions can be identified in vivo through expression of Dam methylase, allowing for greater control of cell-type specific enhancer identification.
Computational methods include comparative genomics, clustering of known or predicted TF-binding sites, and supervised machine-learning approaches trained on known CRMs.
All of these methods have proven effective for CRM discovery, but each has its own considerations and limitations, and each is subject to a greater or lesser number of false-positive identifications.
In the comparative genomics approach, sequence conservation of non-coding regions can be indicative of enhancers. Sequences from multiple species are aligned, and conserved regions are identified computationally. Identified sequences can then be attached to a reporter gene such as green fluorescent protein or lacZ to determine the "in vivo" pattern of gene expression produced by the enhancer when injected into an embryo. mRNA expression of the reporter can be visualized by "in situ" hybridization, which provides a more direct measure of enhancer activity, since it is not subjected to the complexities of translation and protein folding. Although much evidence has pointed to sequence conservation for critical developmental enhancers, other work has shown that the function of enhancers can be conserved with little or no primary sequence conservation. For example, the "RET" enhancers in humans have very little sequence conservation to those in zebrafish, yet both species' sequences produce nearly identical patterns of reporter gene expression in zebrafish. Similarly, in highly diverged insects (separated by around 350 million years), similar gene expression patterns of several key genes was found to be regulated through similarly constituted CRMs although these CRMs do not show any appreciable sequence conservation detectable by standard sequence alignment methods such as BLAST.
In segmentation of insects.
The enhancers determining early segmentation in "Drosophila melanogaster" embryos are among the best characterized developmental enhancers. In the early fly embryo, the gap gene transcription factors are responsible for activating and repressing a number of segmentation genes, such as the pair rule genes. The gap genes are expressed in blocks along the anterior-posterior axis of the fly along with other maternal effect transcription factors, thus creating zones within which different combinations of transcription factors are expressed. The pair-rule genes are separated from one another by non-expressing cells. Moreover, the stripes of expression for different pair-rule genes are offset by a few cell diameters from one another. Thus, unique combinations of pair-rule gene expression create spatial domains along the anterior-posterior axis to set up each of the 14 individual segments. The 480 bp enhancer responsible for driving the sharp stripe two of the pair-rule gene "even-skipped" ("eve") has been well-characterized. The enhancer contains 12 different binding sites for maternal and gap gene transcription factors. Activating and repressing sites overlap in sequence. "Eve" is only expressed in a narrow stripe of cells that contain high concentrations of the activators and low concentration of the repressors for this enhancer sequence. Other enhancer regions drive "eve" expression in 6 other stripes in the embryo.
In vertebrate patterning.
Establishing body axes is a critical step in animal development. During mouse embryonic development, Nodal, a transforming growth factor-beta superfamily ligand, is a key gene involved in patterning both the anterior-posterior axis and the left-right axis of the early embryo. The "Nodal" gene contains two enhancers: the Proximal Epiblast Enhancer (PEE) and the Asymmetric Enhancer (ASE). The PEE is upstream of the Nodal gene and drives "Nodal" expression in the portion of the primitive streak that will differentiate into the node (also referred to as the primitive node). The PEE turns on Nodal expression in response to a combination of Wnt signaling plus a second, unknown signal; thus, a member of the LEF/TCF transcription factor family likely binds to a TCF binding site in the cells in the node. Diffusion of Nodal away from the node forms a gradient which then patterns the extending anterior-posterior axis of the embryo. The ASE is an intronic enhancer bound by the fork head domain transcription factor Fox1. Early in development, Fox1-driven Nodal expression establishes the visceral endoderm. Later in development, Fox1 binding to the ASE drives "Nodal" expression on the left side of the lateral plate mesoderm, thus establishing left-right asymmetry necessary for asymmetric organ development in the mesoderm.
Establishing three germ layers during gastrulation is another critical step in animal development. Each of the three germ layers has unique patterns of gene expression that promote their differentiation and development. The endoderm is specified early in development by "Gata4" expression, and Gata4 goes on to direct gut morphogenesis later. "Gata4" expression is controlled in the early embryo by an intronic enhancer that binds another forkhead domain transcription factor, FoxA2. Initially the enhancer drives broad gene expression throughout the embryo, but the expression quickly becomes restricted to the endoderm, suggesting that other repressors may be involved in its restriction. Late in development, the same enhancer restricts expression to the tissues that will become the stomach and pancreas. An additional enhancer is responsible for maintaining "Gata4" expression in the endoderm during the intermediate stages of gut development.
Multiple enhancers promote developmental robustness.
Some genes involved in critical developmental processes contain multiple enhancers of overlapping function. Secondary enhancers, or "shadow enhancers", may be found many kilobases away from the primary enhancer ("primary" usually refers to the first enhancer discovered, which is often closer to the gene it regulates). On its own, each enhancer drives nearly identical patterns of gene expression. Are the two enhancers truly redundant? Recent work has shown that multiple enhancers allow fruit flies to survive environmental perturbations, such as an increase in temperature. When raised at an elevated temperature, a single enhancer sometimes fails to drive the complete pattern of expression, whereas the presence of both enhancers permits normal gene expression.
Evolution of developmental mechanisms.
One theme of research in evolutionary developmental biology ("evo-devo") is investigating the role of enhancers and other cis-regulatory elements in producing morphological changes via developmental differences between species.
Stickleback "Pitx1".
Recent work has investigated the role of enhancers in morphological changes in threespine stickleback fish. Sticklebacks exist in both marine and freshwater environments, but sticklebacks in many freshwater populations have completely lost their pelvic fins (appendages homologous to the posterior limb of tetrapods).<br> "Pitx1" is a homeobox gene involved in posterior limb development in vertebrates. Preliminary genetic analyses indicated that changes in the expression of this gene were responsible for pelvic reduction in sticklebacks. Fish expressing only the freshwater allele of "Pitx1" do not have pelvic spines, whereas fish expressing a marine allele retain pelvic spines. A more thorough characterization showed that a 500 base pair enhancer sequence is responsible for turning on "Pitx1" expression in the posterior fin bud. This enhancer is located near a chromosomal fragile site—a sequence of DNA that is likely to be broken and thus more likely to be mutated as a result of imprecise DNA repair. This fragile site has caused repeated, independent losses of the enhancer responsible for driving "Pitx1" expression in the pelvic spines in isolated freshwater population, and without this enhancer, freshwater fish fail to develop pelvic spines.
In "Drosophila" wing pattern evolution.
Pigmentation patterns provide one of the most striking and easily scored differences between different species of animals. Pigmentation of the "Drosophila" wing has proven to be a particularly amenable system for studying the development of complex pigmentation phenotypes. The "Drosophila guttifera" wing has 12 dark pigmentation spots and 4 lighter gray intervein patches. Pigment spots arise from expression of the "yellow" gene, whose product produces black melanin. Recent work has shown that two enhancers in the "yellow" gene produce gene expression in precisely this pattern – the vein spot enhancer drives reporter gene expression in the 12 spots, and the intervein shade enhancer drives reporter expression in the 4 distinct patches. These two enhancers are responsive to the Wnt signaling pathway, which is activated by "wingless" expression at all of the pigmented locations. Thus, in the evolution of the complex pigmentation phenotype, the "yellow" pigment gene evolved enhancers responsive to the wingless signal and "wingless" expression evolved at new locations to produce novel wing patterns.
In inflammation and cancer.
Each cell typically contains several hundred of a special class of enhancers that stretch over many kilobases long DNA sequences, called "super-enhancers". These enhancers contain a large number of binding sites for sequence-specific, inducible transcription factors, and regulate expression of genes involved in cell differentiation. During inflammation, the transcription factor NF-κB facilitates remodeling of chromatin in a manner that selectively redistributes cofactors from high-occupancy enhancers, thereby repressing genes involved in maintaining cellular identify whose expression they enhance; at the same time, this F-κB-driven remodeling and redistribution activates other enhancers that guide changes in cellular function through inflammation. As a result, inflammation reprograms cells, altering their interactions with the rest of tissue and with the immune system. In cancer, proteins that control NF-κB activity are dysregulated, permitting malignant cells to decrease their dependence on interactions with local tissue, and hindering their surveillance by the immune system.


Masahide Sasaki

Masahide Sasaki was a Japanese chemist. He developed the first fully-automated laboratory, and he popularized this innovation internationally.
Personal life.
Masahide was born in Yamaguchi Prefecture of Japan on August 27, 1933. He married his wife, Tokyo, and had three children, Mika, Kyoko, and Masanori. He died of cancer on September 23, 2005.
Career.
As noted in his obituary in "Clinical Chemistry", Masahide "graduated from Yamaguchi Medical School in 1961. During 1965, he served as an internist for the Hiroshima Atomic Bomb Casualty Committee. Several years later, in 1967, he was appointed the Chief of the Clinical Chemistry Department at Kawasaki Hospital. In 1970, he did a fellowship in the United States at the Michael Reese Hospital in Chicago, IL, which gave him exposure to the US medical system. Two years later he became an Assistant Professor of Internal Medicine at Kawasaki Medical School and rose quickly in the academic ranks to become a Full Professor of Laboratory Diagnosis in 1976 and, ultimately, Vice President of Kawasaki Paramedical College." He was appointed Professor and Director of the Department of the Clinical Laboratory at Kochi Medical School, Kochi, Japan in 1981. There, he developed his automation system.
Masahide published many papers between 1981 and 1999, the most notable of which was a monograph on laboratory automation sponsored by the A&T Corporation.
Automation development.
Masahide provided the first and most prominent example of a totally automated laboratory.


Indopanolol

Indopanolol is a beta blocker.


AG 489

AG 489 (or agatoxin 489) is a component of the venom produced by Agelenopsis aperta, a North American funnel web spider. It inhibits the ligand gated ion channel TRPV1 through a pore blocking mechanism.
To identify new inhibitors, capsaicin receptor channels (TRPV1) were screened from a venom library for activity against these channels. In result, the robust inhibitory activity was found in the venom. Venom fractionation utilizing a reversed phase HPLC which led to the purification of the two acylpolyamine toxins, AG489 and AG505. Both of these inhibit the TRPV1 channels from the extracellular membrane side. From the pore blocking mechanism, the pore mutations that change toxic affinity were identified. As a result, the four mutants decreased toxic affinity and several mutants increased it. Therefore, this was consistent with the scanned TM5-TM6 linker region being the outer vestibule of the channels and further confirming that AG489 is a pore blocker.


Christie G. Enke

Christie G. Enke is a United States academic chemist who made pioneering contributions to the field of analytical chemistry.
Life and career.
Chris Enke was born in Minneapolis, Minnesota on July 8, 1933. His parents were Alvin Enke and Mae Nichols. He graduated from Central High School in Minneapolis in 1951. He received a BA degree from Principia College in 1955 and a Ph.D. from the University of Illinois in 1959. His thesis, concerning the anodic formation of surface oxide films on platinum electrodes, was performed under the guidance of Herbert Laitinen. While at Illinois, he also worked with Howard Malmstadt to introduce a graduate lab and lecture course in the electronics of laboratory instrumentation. He is now Professor Emeriti of Chemistry at the University of New Mexico and Michigan State University. Prior to his move to the University of New Mexico in 1994, he was an instructor and assistant professor at Princeton (1959 –1966), then an associate professor and professor at Michigan State University.


CopA-like RNA

CopA-like RNA is a family of non-coding RNAs found on the R1 plasmid.
In several groups of bacterial plasmids, antisense RNAs regulate copy number through inhibition of replication initiator protein synthesis. These RNAs are characterised by a long hairpin structure interrupted by several unpaired nucleotides or bulged loops. In plasmid R1, the inhibitory complex between the antisense RNA (CopA) and its target mRNA (CopT) is characterised by a four-way junction structure and a side-by-side helical alignment.
See also.
Plasmid-mediated resistance (sRNA section)


N-Terminal peptide of proopiomelanocortin

The N"-terminal peptide/fragment of proopiomelanocortin (NPP; N"-POMC), also known as pro-γ-MSH, is a naturally occurring, endogenous metabolite of the polypeptide proopiomelanocortin (POMC).
"N"-POMC is also a precursor for γ1-MSH, γ2-MSH, and γ3-MSH, and can form them through proteolytic cleavage.
"N"-POMC is an adrenal growth factor.


Streptococcus sRNA

In molecular biology, "Streptococcus" sRNAs are small RNAs produced by species of "Streptococcus" bacteria. Several screens (both computational and experimental) have identified numerous sRNAs in different species and strains of "Streptococcus" including "S. pneumoniae", "S. pyogenes", "S. agalactiae" and "S.mutans". The function of most of these is currently unknown, however a few have been characterised including FasX small RNA. Many sRNAs have roles in pathogenesis.


Serine 2-dehydrogenase

In enzymology, a serine 2-dehydrogenase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are L-serine, H2O, and NAD+, whereas its 4 products are 3-hydroxypyruvate, NH3, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH2 group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is L-serine:NAD+ 2-oxidoreductase (deaminating). Other names in common use include L-serine:NAD+ oxidoreductase (deaminating), and serine dehydrogenase.


The Masterpiece Society

"The Masterpiece Society" is the 113th episode of the American science fiction television series "", the 13th episode of the .
Set in the 24th century, the series follows the adventures of the Starfleet crew of the Federation starship Enterprise-D. In this episode, while the crew of the USS "Enterprise" saves an isolated genetically engineered society from immediate destruction, the cultural contamination resulting from their interaction may still ultimately doom the colony.
Plot.
The "Enterprise" has been assigned to the Moab sector to track a stellar core fragment from a disintegrated Neutron star. They find the fragment is due to pass near Moab IV, threatening a human colony on the planet. On contacting the colony to arrange for evacuation, its leader Aaron Conor (John Snyder) refuses, though allows an away team down to discuss the matter. Conor explains that the colony was formed 200 years prior to create a perfect society using genetic engineering and selective breeding, and he and the other leaders feel that evacuation would destroy the perfect order they have achieved. They discuss other alternatives and "Enterprise" Chief Engineer Geordi La Forge is introduced to Hannah Bates (Dey Young), a scientist. Bates proposes using a multi-phase tractor beam, powered by the "Enterprise"s warp core, to push the fragment from its path, which La Forge agrees would be a possible solution. After some deliberation, Bates is allowed to leave the colony to the "Enterprise" to oversee the process. Meanwhile, Deanna Troi and Conor start to develop a romantic attraction as they try to convince the other leaders that evacuation is the best option.
Aboard the "Enterprise", Bates' solution is found to be effective, but the equipment required is damaged too quickly to be used. La Forge recognizes her solution could be augmented with similar technology that enables his VISOR to operate, allowing the equipment to last long enough to manipulate the fragment safely away from Moab IV. La Forge comments that this solution wouldn't be possible in the current colony's manner of perfection as imperfections like blindness would have been outright eliminated. As they continue simulations, they find that the solution is not perfect, but La Forge suggests that they reinforce the colony's shielding during the fragment's passing, allowing the colony to survive the fragment's passage. Conor initially refuses as this would require more "Enterprise" personnel to transport to the colony, and he fears cultural contamination, but relents when Troi convinces him this is the only solution. The "Enterprise" is able to push the fragment far enough that the colony appears to be safe.
As the other "Enterprise" crew return to the ship, La Forge and Bates check on the status of the colony shielding. Bates reports there are microfractures that will soon fail, and recommends full evacuation. La Forge, having not seen these on his VISOR, recognizes that Bates falsified the readings, as she wishes to leave with the "Enterprise", recognizing that the colony has languished behind the technological improvements of the Federation. Admitting her lie, she requests asylum aboard the "Enterprise". Several other colonists express their desire to leave. Troi brings Captain Picard to the colony to discuss the matter with Conor. Though Picard recognizes that the colony's society will be altered by agreeing to asylum, he cannot refuse this request as a fundamental right of human free will. Conor reluctantly agrees, and allows Bates and 22 other colonists to leave with the ship. As they leave orbit, Picard comments how this affair is a clear example of the necessity of the Prime Directive; the intervention of the Federation to save the colonists may have, in the end, proved just as dangerous to the colony as any core fragment could ever have been.
Reception.
In 2011, this episode was mentioned by Forbes in a review of "Star Trek" episodes that explore the implications of advanced technology, and this episode was noted for a depiction of a "genetically engineered society".


Merozygote

Merozygote is a state when a cell, usually bacterial, is temporarily partial diploid as result of DNA transfer processes like conjugation.
One example of how merozygotes can be formed is the transfer of genetic material
of an Hfr cell to an F- cell through conjugation. When an Hfr cell mates with an F- cell, the chromosome acts as a rolling circle transferring a part of its genomic chromosome across a conjugation bridge. The origin is the first bit of the DNA to be injected, while the F-factor is the last. Very rarely the whole portion of the DNA (from the origin through the F-factor) will be transferred, resulting in a very low chance of passing on the F factor to the F- cell. After conjugation, the F- cell will contain a part of the Hfr chromosome, the exogenote, as well as its own genomic chromosome, the endogenote. At this stage the cell is called a merozygote. This temporary partial diploid state may lead to recombination between the corresponding portions of the DNA, so that the genetic material of the donor may be incorporated into the chromosome of the recipient, thereby altering the genotype of the recipient. However, if no recombination occurs, the linear fragment of donor DNA in the recipient cytoplasm will be lost after one cycle. These merozygotes help to study dominance variation and mutation can be known.


Drofenine

Drofenine is an antimuscarinic antispasmodic drug used for relaxing smooth muscle, thereby treating conditions, such as: dysmenorrhea, and pain in the gastrointestinal tract, biliary passages, and urogenital tract. Drofenine is assumed to work by increasing the levels of the protein TRPV3.


Bulk movement

In cell biology, bulk flow is the process by which proteins with a sorting signal travel to and from different cellular compartments. In other words, bulk transport is a type of transport which involves the transport of large amount of substance like lipid droplets and solid food particles across plasma membrane by utilising energy. Special processes are involved in the transport of such large quantities of materials, which include endocytosis and exocytosis.
It is thought that cargo travels through the Golgi cisternae (from cis- to trans- Golgi) via bulk flow.
References.
1. Rothman J.E. and Weiland F.T. Protein sorting by transport vesicles. Science 272. 227-234. 1996.


Halomonas

Halomonas is a genus of halophilic (salt-tolerating) proteobacteria. It grows over the range of 5 to 25% NaCl.
The type species of this genus is "Halomonas elongata".
Description.
Members of "Halomonas" are Gram-negative, rod-shaped bacteria, generally 0.6-0.8 μm by 1.6-1.9 μm. They move by using flagella. They grow in the presence of oxygen, although some have been reported to be able to grow without oxygen. When grown on an agar plate, they form white/yellow colonies that turn light brown over time.
Ecology.
"Halomonas" species have been found in a broad variety of saline environments, including estuaries, the ocean, and saline lakes.
Species.
Many species of "Halomonas" have been described:
"H. alimentaria"

"H. alkaliantarctica"

"H. alkaliphila"

"H. almeriensis"

"H. andesensis"

"H. anticariensis"

"H. aquamarina"

"H. arcis"

"H. axialensis"

"H. beimenensis"

"H. boliviensis"

"H. campaniensis"

"H. campisalis"

"H. caseinilytica"

"H. cerina"

"H. cibimaris"

"H. cupida"

"H. daqiaonensis"

"H. daqingensis"

"H. denitrificans"

"H. desiderata"

"H. elongata"

"H. eurihalina"

"H. flava"

"H. fontilapidosi"

"H. garicola"

"H. gomseomensis"

"H. gudaonensis"

"H. halmophila"

"H. halocynthiae"

"H. halodenitrificans"

"H. halophila"

"H. hamiltonii"

"H. heilongjiangensis"

"H. huangheensis"

"H. hydrothermalis"

"H. ilicicola"

"H. janggokensis"

"H. jeotgali"

"H. johnsoniae"

"H. kenyensis"

"H. koreensis"

"H. korlensis"

"H. kribbensis"

"H. lutea"

"H. lutescence"

"H. magadiensis"

"H. maura"

"H. meridiana"

"H. mongoliensis"

"H. muralis"

"H. nanhaiensis"

"H. neptunia"

"H. nitroreducens"

"H. olivaria"

"H. organivorans"

"H. pacifica"

"H. pantelleriensis"

"H. qiaohouensis"

"H. qijiaojingensis"

"H. ramblicola"

"H. rifensis"

"H. sabkhae"

"H. saccharevitans"

"H. salicampi"

"H. salifodinae"

"H. salina"

"H. sediminicola"

"H. shengliensis"

"H. sinaiensis"

"H. smyrnensis"

"H. songnenensis"

"H. stenophila"

"H. stevensii"

"H. subglaciescola"

"H. subterranea"

"H. sulfidaeris"

"H. taeanensis"

"H. titanicae"

"H. urumqiensis"

"H. variabilis"

"H. ventosae"

"H. venusta"

"H. vilamensis"

"H. xianhensis"

"H. xinjiangensis"

"H. zhangjiangensis"

"H. zincidurans"
Pathogenic potential.
Certain species of "Halomonas "may display pathogenic potential in humans. In one study, three species were isolated from two patients suffering bacteremia in a dialysis center. The study hypothesized that the bicarbonate used in the dialysis fluid may have been contaminated by the bacteria.
Etymology.
The name "Halomonas" derives from: Greek noun "hals, halos" (ἅλς, ἁλός), salt; and "monas" (μονάς), nominally meaning "a unit", but in effect meaning a bacterium; thus, salt (-tolerant) monad.
Members of the genus "Halomonas" can be referred to as halomonads (see Trivialisation of names).


Nucleotide diversity

Nucleotide diversity is a concept in molecular genetics which is used to measure the degree of polymorphism within a population.
One commonly used measure of nucleotide diversity was first introduced by Nei and Li in 1979. This measure is defined as the average number of nucleotide differences per site between two DNA sequences in all possible pairs in the sample population, and is denoted by formula_1.
It is given by the formula:
where formula_3 and formula_4 are the respective frequencies of the formula_5 th and formula_6 th sequences, formula_7 is the number of nucleotide differences per nucleotide site between the formula_5 th and formula_6 th sequences, and formula_10 is the number of sequences in the sample.
Nucleotide diversity is a measure of genetic variation. It is usually associated with other statistical measures of population diversity, and is similar to expected heterozygosity. This statistic may be used to monitor diversity within or between ecological populations, to examine the genetic variation in crops and related species, or to determine evolutionary relationships.
Nucleotide diversity can be calculated by examining the DNA sequences directly, or may be estimated from molecular marker data, such as Random Amplified Polymorphic DNA (RAPD) data and Amplified Fragment Length Polymorphism (AFLP) data.


Perchloromethyl mercaptan

Perchloromethyl mercaptan is the organosulfur compound with the formula CCl3SCl. It is mainly used as an intermediate for the synthesis of dyes and fungicides (captan, folpet). It is a colorless oil, although commercial samples are yellowish. It is insoluble in water but soluble in organic solvents. It has a foul, unbearable, acrid odor. Perchloromethyl mercaptan is the original name. The systematic name is trichloromethanesulfenyl chloride, because the compound is a sulfenyl chloride, not a mercaptan.
History.
It was used as a chemical warfare agent by the French in the 1915 battle of Champagne. Shortly thereafter, wartime use was abandoned due to the clear warning properties, the decomposition in the presence of iron and steel, and the easy removal of the vapor by charcoal.
Preparation.
The method to prepare perchloromethyl mercaptan was first described by Rathke in 1873 and is still used. Carbon disulfide is chlorinated using an iodine catalyst. The following equations operate most efficiently at temperatures below about 30 °C:
At higher temperatures, the chlorination gives carbon tetrachloride and additional sulfur chlorides. The formation of byproducts can be suppressed by performing the reaction in the presence of diketones. Another byproduct is thiophosgene. The more volatile byproducts such as carbon tetrachloride and sulfur dichloride can be removed by distillation. The separation of perchloromethyl mercaptan from S2Cl2 by distillation is challenging since their boiling points are very close. Another byproduct that forms is hexachloroethane. Innovations in the basic Rathke method have been reported.
Reactivity.
The compound slowly hydrolyzes:
The compound is corrosive to most metals. It reacts with iron, evolving carbon tetrachloride. Perchloromethyl mercaptan is oxidized by nitric acid to trichloromethanesulfonyl chloride (Cl3CSO2Cl), a white solid.
Toxicity.
When it is heated or in a fire, it will emit toxic and corrosive gases. It is also very toxic by inhalation or skin absorption.
At least two mechanisms could account for the toxicity of perchloromethyl mercaptan, as hypothesized by Althoff (1973). The first mechanism is a reaction between perchloromethyl mercaptan and biological functional groups such as hydroxyl, sulfhydryl, amino and carboxyl groups. This results in an inactivation of key enzymes. A second general pathway reaction is the hydrolysis to give hydrochloric acid.


Terazosin

Terazosin, sold under the brand name Hytrin among others, is a medication used to treat symptoms of an enlarged prostate and high blood pressure. For high blood pressure, it is a less preferred option. It is taken by mouth.
Common side effects include dizziness, headache, tiredness, swelling, nausea, and low blood pressure with standing. Severe side effects may include priapism and low blood pressure. Prostate cancer should be ruled out before starting treatment. It is an alpha-1 blocker and works by relaxing blood vessels and the opening of the bladder.
Terazosin was patented in 1975 and came into medical use in 1985. It is available as a generic medication. In 2017, it was the 194th most commonly prescribed medication in the United States, with more than two million prescriptions.
Formulations.
It is available in 1 mg, 2 mg, 5 mg or 10 mg doses.
Synthesis.
Reaction of piperazine with 2-furoyl chloride followed by catalytic hydrogenation of the furan ring leads to 2. This, when heated in the presence of 2-chloro-6,7-dimethoxyquinazolin-4-amine (1) undergoes direct alkylation to terazosin (3).


Chromophil

A chromophil biological cell is a cell which is easily stainable by absorbing chromium salts used in histology to increase the visual contrast of samples for microscopy.
Function.
Chromophil cells are mostly hormone-producing cells containing so-called chromaffin granules. In these subcellular structures, amino acid precursors to certain hormones are accumulated and subsequently decarboxylated to the corresponding amines, for example epinephrine, norepinephrine, dopamine or serotonin. Chromophil cells therefore belong to the group of APUD (amine precursor uptake and decarboxylation) cells.
Location.
These cells are scattered throughout the whole body, but particularly in glands such as the hypothalamus, hypophysis, thyroid, parathyroid and pancreas.


Mycena asterina

Mycena asterina is a species of agaric fungus in the family Mycenaceae. It is found in São Paulo state, Brazil, where it grows singly or scattered on fallen leaves in Atlantic forests. The fruit bodies of the fungus are bioluminescent.


Glucose cycle

The glucose cycle (also known as the hepatic futile cycle) occurs primarily in the liver and is the dynamic balance between glucose and glucose 6-phosphate. This is important for maintaining a constant concentration of glucose in the blood stream.
Function.
The glucose cycle is required for one of the liver functions; the homeostasis of glucose in the blood stream. When the blood glucose level is too high, glucose can be stored in the liver as glycogen. When the level is too low, the glycogen can be catabolised and glucose may re-enter the blood stream.
The catabolic process occurs at the nonreducing end of glycogen. A phosphate group breaks the bond between C 1 of a glucose ring and the O that connects it to the next(phosphorolysis). One glucose unit is thus split off. Glycogen (with n glucose units) is converted into G-1-P(a PO4 group now attaches to C1 where O used to ) and glycogen (with n-1 glucose units) by enzyme glycogen phosphorylase. G-1-P is then converted into G-6-P by enzyme phosphoglucomutase. A water molecule hydrolyses G-6-P to glucose, the enzyme is glucose-6-phosphatase.
Cell specificity.
When glucose enters a cell it is rapidly changed to glucose 6-phosphate, by hexokinase or glucokinase. The glucose cycle can occur in liver cells due to a liver specific enzyme glucose-6-phosphatase, which catalyse the dephosphorylation of glucose 6-phosphate back to glucose.
Glucose-6-phosphate is the product of glycogenolysis or gluconeogenesis, where the goal is to increase free glucose in the blood due body being in catabolic state. Other cells such as muscle and brain cells do not contain glucose 6-phosphatase. As a result, any glucose 6-phosphate produced in those cells is committed to cellular metabolic pathways, primarily pentose phosphate pathway or glycolysis.
Regulation of glucose cycle.
Flux through the glucose cycle is regulated by several hormones including insulin and glucagon as well as allosteric regulation of both hexokinase and glucose 6-phosphatase.
Diseases associated with glucose cycle.
A deficiency in glucose 6-phosphatase that disrupts the liver glucose cycle, can lead to von Gierke's disease.


Clicked peptide polymer

Clicked peptide polymers are poly-triazole-poly-peptide hybrid polymers. They are made of repeating units of a 1,2,3-triazole and an oligopeptide. They can be visualized as an oligopeptide that is flanked at both the C-terminus and N-terminus by a triazole molecule.
Synthesis.
Clicked peptide polymers are prepared by the azide-alkyne Huisgen cycloaddition also called the click reaction; which is commonly used in bioconjugation reactions to link molecules together with a stable triazole bridge. Peptide based polymers are produced from a cycloaddition variant of step-growth polymerization. The monomers used in this polymerization are oligopeptides with terminal azide and terminal alkyne groups
Monomer preparation.
To prepare and oligopeptide with both a terminal azide and terminal alkyne two modifications must be carried out. The first is the amidation of the oligopeptide's C-terminus by propargylamine. This would done with all other reaction groups protected and with the C-terminus activated.
The second modification required is the addition of an azide to the N-terminus. Unlike the addition of the alkyne this can be done on the whole peptide, or solely on the N-terminal residue which is added to the rest of the oligopeptide by solid-phase peptide synthesis. The addition of the azide occurs by Cu(II)-catalyzed diazo transfer.
Degradation.
The molecules linked to one another by the azide-alkyne Huisgen cycloaddition are connected by an aromatic triazole which is extremely stable, and can withstand high temperatures and extremes of pH. The oligopeptide units of a clicked peptide polymer are a different story. The triazole bridges do not confer any stability to oligopeptide. Degradation of the polymer occurs at the peptide bonds linking individual amino acids. The amide bonds can be attacked non-specifically by acid or base catalyzed hydrolysis.
The polymer's peptide bonds can also be attacked by endopeptidases which will cleave at a specific side of a specific peptide bond based upon the residues which make up that bond.
For example, if the first residue is a phenylalanine then the enzyme chymotrypsin will cleave at site 1, and if the third residue of the tripeptide is a lysine then trypsin would cleave at the third cleavage site.


Peroxisome proliferator-activated receptor

In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms.
Nomenclature and tissue distribution.
Three types of PPARs have been identified: alpha, gamma, and delta (beta):
History.
PPARs were originally identified in "Xenopus" frogs as receptors that induce the proliferation of peroxisomes in cells.
The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as "peroxisome proliferators", as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity. These agents, pharmacologically related to the fibrates were discovered in the early 1980s. When it turned out that PPARs played a much more versatile role in biology, the agents were in turn termed "PPAR ligands". The best-known PPAR ligands are the thiazolidinediones; see below for more details.
After PPARδ (delta) was identified in humans in 1992, it turned out to be closely related to the PPARβ (beta) previously described during the same year in other animals ("Xenopus"). The name PPARδ is generally used in the US, whereas the use of the PPARβ denomination has remained in Europe where this receptor was initially discovered in "Xenopus".
Physiological function.
All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. These DNA sequences are termed PPREs (peroxisome proliferator hormone response elements). The DNA consensus sequence is AGGTCANAGGTCA, with N being any nucleotide. In general, this sequence occurs in the promoter region of a gene, and, when the "PPAR" binds its ligand, transcription of target genes is increased or decreased, depending on the gene. The RXR also forms a heterodimer with a number of other receptors (e.g., vitamin D and thyroid hormone).
The function of PPARs is modified by the precise shape of their ligand-binding domain (see below) induced by ligand binding and by a number of coactivator and corepressor proteins, the presence of which can stimulate or inhibit receptor function, respectively.
Endogenous ligands for the PPARs include free fatty acids, eicosanoids and Vitamin B3. PPARγ is activated by PGJ2 (a prostaglandin) and certain members of the 5-HETE family of arachidonic acid metabolites including 5-oxo-15(S)-HETE and 5-oxo-ETE. In contrast, PPARα is activated by leukotriene B4. Certain members of the 15-hydroxyeicosatetraenoic acid family of arachidonic acid metabolites, including 15(S)-HETE, 15(R)-HETE, and 15-HpETE activate to varying degrees PPAR alpha, beta/delta, and gamma. PPARγ activation by agonist RS5444 may inhibit anaplastic thyroid cancer growth. See for a review and critique of the roles of PPAR gamma in cancer.
Genetics.
The three main forms are transcribed from different genes:
Hereditary disorders of all PPARs have been described, generally leading to a loss in function and concomitant lipodystrophy, insulin resistance, and/or acanthosis nigricans. Of PPARγ, a gain-of-function mutation has been described and studied (Pro12Ala) which decreased the risk of insulin resistance; it is quite prevalent (allele frequency 0.03 - 0.12 in some populations). In contrast, pro115gln is associated with obesity. Some other polymorphisms have high incidence in populations with elevated body mass indexes.
Structure.
Like other nuclear receptors, PPARs are modular in structure and contain the following functional domains:
The DBD contains two zinc finger motifs, which bind to specific sequences of DNA known as hormone response elements when the receptor is activated. The LBD has an extensive secondary structure consisting of 13 alpha helices and a beta sheet. Natural and synthetic ligands bind to the LBD, either activating or repressing the receptor.
Pharmacology and PPAR modulators.
PPARα and PPARγ are the molecular targets of a number of marketed drugs. For instance the hypolipidemic fibrates activate PPARα, and the anti diabetic thiazolidinediones activate PPARγ. The synthetic chemical perfluorooctanoic acid activates PPARα while the synthetic perfluorononanoic acid activates both PPARα and PPARγ. Berberine activates PPARγ, as well as other natural compounds from different chemical classes.


Spermidine dehydrogenase

In enzymology, a spermidine dehydrogenase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are spermidine, acceptor, and H2O, whereas its 3 products are propane-1,3-diamine, 4-aminobutanal, and reduced acceptor.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donor with other acceptors. The systematic name of this enzyme class is spermidine:acceptor oxidoreductase. This enzyme is also called spermidine:(acceptor) oxidoreductase. This enzyme participates in urea cycle and metabolism of amino groups and beta-alanine metabolism. It has 2 cofactors: FAD, and Heme.


Cytochrophin-4

Cytochrophin-4 is an opioid peptide.


Iron Cross (Marvel Comics)

Iron Cross is the name of two fictional characters appearing in American comic books published by Marvel Comics.
Publication history.
The Helmut Gruler version of Iron Cross first appears in "Invaders" #36 (Jan. 1979) and was created by Roy Thomas and Frank Robbins.
The Clare Gruler version of Iron Cross first appeared in "All-New Invaders" #9 (Aug. 2014) and was created by James Robinson and Steve Pugh.
Fictional character biography.
Helmut Gruler.
Helmut Gruler is a World War II German soldier that first appears in the title "Invaders". Gruler volunteers to wear armor created by Professor Franz Schneider for use against the Allied forces. Using the alias "Iron Cross", the character creates havoc until apparently killed during a battle with superhero team the "Invaders".
Iron Cross reappears in the modern Marvel universe in the title "Midnight Sons Unlimited", having apparently been saved and sustained by his armor.
Iron Cross is revealed in the limited series to be a founding member of the modern version of the "V-Battalion", a secret group dedicated to hunting down war criminals. Iron Cross apparently dies preventing the spread of nanotechnology throughout the world by terrorist organization HYDRA.
Clare Gruler.
Clare Gruler is the daughter of Helmut Gruler who took on her father's legacy and became a hero in Germany.
As part of the "All-New, All-Different Marvel" event, Clare Gruler's Inhuman gene activated when she was inside the Iron Cross armor which caused her to have powers that molecular-bonded her to the Iron Cross armor transforming her into a cyborg. Iron Cross was later kidnapped by Kurt Dagmar due to her new nature alongside the other robots and AIs. Iron Cross managed to send a signal for help which was received by Winter Soldier. The control Dagmar had over Iron Cross was interrupted when he was killed by one of his Deathloks. She thanks Namor for absolving her father of any war crimes during the Nuremberg Trials.
She later battles Neo-Nazis in Germany and requests help from the All-New Invaders. They are interrupted by the Inhuman Lash, who is attempting to recruit Iron Cross, Toro, and the Neo-Nazis leader, who had no idea he was an Nuhuman. Medusa and the Inhuman Royal Court appear, so Lash leaves with the Neo-Nazi, who abandons the Nazi cause since he doesn't have pure Aryan blood. The Invaders later disband and Iron Cross returns to Germany to protect it from evil.
Powers and abilities.
Helmut Gruler wears an advanced suit of armor that provides superhuman strength and durability, and flight via boot jets. The armor also has several offensive features, and is capable of releasing electric current, sleeping gas and an inky fluid similar to that discharged by an octopus. The suit provides some longevity by sustaining Gruler's body.
Clare Gruler's Iron Cross armor grants her flight and energy discharge. Her molecular bonding appears to have only worked once when her Inhuman gene activated.
In other media.
The Helmut Gruler version of Iron Cross appears in the video game "", voiced by Michael Donovan. This version works for Hydra under the Red Skull and Arnim Zola. He is assigned to capture Captain America and obtain his blood so Hydra can recreate Abraham Erskine's super-soldier serum. However, Captain America defeats Iron Cross.


Creative Biolabs

Creative Biolabs, Inc. is a life-science company which produces and supplies biotech products and services for early drug discovery and development, including various phage display libraries such as pre-made libraries, phage display services, antibody sequencing, and antibody humanization. Customers include pharmaceutical companies, academic institutions, government agencies, clinical research organizations and biotechnology companies.
History.
Creative Biolabs Inc. was founded in 2005 by a group of scientists researching on the treatment and prevention of intractable diseases like cancer. The company has distributors in Australia, New Zealand, Japan and other countries in Europe, Asia, and America. Its headquarter is in Shirley, New York. In June 2017, Creative Biolabs set up its first scholarship program.
Services.
Fab construction is a complex technique as Fab fragments contain both variable domains and constant regions. The same heavy and light variable chains used for scFv construction can be used in the construction of Fab.
Construction of pre-made phage display libraries. Pre-made phage display library is a laboratory technique for the study of protein–protein, protein–peptide, and protein–DNA interactions that uses bacteriophages (viruses that infect bacteria) to connect proteins with the genetic information that encodes them.
Sequencing services such as Database Assisted Shotgun Sequencing (DASS) technology
Analysis of microarray hybridization data
Yeast two-hybrid screen
Products.
Monoclonal antibodies such as mouse anti-human Duox2 monoclonal antibody S-40
Immunoglobulin Y (IgY) such as Anti-ADP3 chicken IgY
Antibody libraries such as HuSdLTM phage display human single domain antibody library
Response to COVID-19.
Creative Biolabs offers SARS-CoV-2 S antibodies that come from common hosts like human, mouse, and rabbit, and apply to various lab tests, like ELISA, FC, ICC/IF, "etc". Apart from S protein antibodies, Creative Biolabs also provides a comprehensive list of anti-SARS-CoV-2 antibodies to assist with the research and development of drug and vaccine candidates, including but not limited to antibodies targeting genes like N, S1/S2, and ORF7a.
Creative Biolabs Scholarship Program.
Since the first scholarship program in 2017, Creative Biolabs has released scholarship every year. The scholarship award of $1,000 is given to one student of freshman, undergraduate, graduate or Ph.D. level majoring in science-related fields such as Biology, Biochemistry, Chemistry and Molecular Biology.


WALP peptide

WALP peptides are a class of synthesized, membrane-spanning α-helices composed of tryptophan (W), alanine (A), and leucine (L) amino acids. They are designed to study properties of proteins in lipid membranes such as orientation, extent of insertion, and hydrophobic mismatch.
Significance.
The transmembrane region of many integral membrane proteins consists of one or more alpha helices. The orientations and interactions of these helices directly affect cell signaling and molecular transport across the bilayer. The hydrophobic environment of the phospholipid tails in turn modulates the position and structure of such domains and thus may influence protein function. Conversely, the bilayer itself can (locally) change the thickness of its hydrocarbon region to interact optimally with hydrophobic regions of a transmembrane protein (a.k.a. hydrophobic matching). WALPs provide an effective model for studying such interactions because of their systematic design of a core of hydrophobic, alternating alanine and leucine regions. This core is readily manipulated by extending or decreasing the number of amino acids. Another key feature is the presence of "anchoring" residues at the ends of the helix, which are tryptophan residues in the WALP versions. Substituting the anchoring tryptophan residues for charged residues, such as lysine, yields "KALP" peptides. This class of model peptides has proved useful for studying the impact of changes in lipid composition on peptide insertion. Following detailed experimental studies by various techniques, the WALP and related peptides have become commonly used model systems in computational biology.
Responses to lipid environment.
When hydrophobic mismatch occurs, WALPs are known to tilt in the bilayer. The extent of this tilt is affected up to a certain point by an entropy contribution that arises from the helix's presence in the bilayer and then by more specific helix-lipid interactions. When charged residues are substituted for the anchoring residues, these charged amino acids prefer a higher position, farther from the interior of the lipid bilayer, in order to maintain their energetically favorable interaction with water. This interaction thus promotes a smaller angle of tilt.


Long terminal repeat

A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus or a retroviral provirus. All retroviral genomes are flanked by LTRs, while there are some retrotransposons without LTRs. Typically, an element flanked by a pair of LTRs will encode a reverse transcriptase and an integrase, allowing the element to be copied and inserted at a different location of the genome. Copies of such an LTR-flanked element can often be found hundreds or thousands of times in a genome. LTR retrotransposons comprise about 8% of the human genome.
The first LTR sequences were found by A.P. Czernilofsky and J. Shine in 1977 and 1980.
Transcription.
The LTR-flanked sequences are partially transcribed into an RNA intermediate, followed by reverse transcription into complementary DNA (cDNA) and ultimately dsDNA (double-stranded DNA) with full LTRs. The LTRs then mediate integration of the DNA via an LTR specific integrase into another region of the host chromosome.
Retroviruses such as human immunodeficiency virus (HIV) use this basic mechanism.
Dating retroviral insertions.
As 5' and 3' LTRs are identical upon insertion, the difference between paired LTRs can be used to estimate the age of ancient retroviral insertions. This method of dating is used by paleovirologists, though it fails to take into account confounding factors such as gene conversion and homologous recombination.
HIV-1.
The HIV-1 LTR is 634 bp in length and, like other retroviral LTRs, is segmented into the U3, R, and U5 regions. U3 and U5 has been further subdivided according to transcription factor sites and their impact on LTR activity and viral gene expression. The multi-step process of reverse transcription results in the placement of two identical LTRs, each consisting of a U3, R, and U5 region, at either end of the proviral DNA. The ends of the LTRs subsequently participate in integration of the provirus into the host genome. Once the provirus has been integrated, the LTR on the 5′ end serves as the promoter for the entire retroviral genome, while the LTR at the 3′ end provides for nascent viral RNA polyadenylation and, in HIV-1, HIV-2, and SIV, encodes the accessory protein, Nef.
All of the required signals for gene expression are found in the LTRs: Enhancer, promoter (can have both transcriptional enhancers or regulatory elements), transcription initiation (such as capping), transcription terminator and polyadenylation signal.
In HIV-1, the 5'UTR region has been characterized according to functional and structural differences into several sub-regions:
The transcript begins, at the beginning of R, is capped, and proceeds through U5 and the rest of the provirus, usually terminating by the addition of a poly A tract just after the R sequence in the 3' LTR.
The finding that both HIV LTRs can function as transcriptional promoters is not surprising since both elements are apparently identical in nucleotide sequence. Instead, the 3' LTR acts in transcription termination and polyadenylation. However, it has been suggested that the transcriptional activity of the 5' LTR is far greater than that of the 3' LTR, a situation that is very similar to that of other retroviruses.
During transcription of the human immunodeficiency virus type 1 provirus, polyadenylation signals present in the 5' long terminal repeat (LTR) are disregarded while the identical polyadenylation signals present in the 3'LTR are utilized efficiently. It has been suggested that transcribed sequences present within the HIV-1 LTR U3 region act in cis to enhance polyadenylation within the 3' LTR.


Wyss Center for Bio and Neuroengineering

The Wyss Center is a not-for-profit neurotechnology research foundation in Geneva, Switzerland.
The Center is based at Campus Biotech (in the former Merck Serono building) located in Geneva, Switzerland. The Director of the Wyss Center is Dr Mary Tolikas who assumed responsibility on 1 June 2019. Dr Tolikas was previously a member of the leadership team at the Wyss Institute for Biologically Inspired Engineering at Harvard University during its launching and growth.
The founding director of the Wyss Center was neuroscientist Professor John P. Donoghue, who is best known for his work on human brain computer interfaces, brain function and plasticity.
The Center was founded by Hansjörg Wyss, who previously created the Wyss Institute for Biologically Inspired Engineering in the United States.
The mission of the Wyss Center is to advance understanding of the brain to realize therapies and improve lives.
The Wyss Center works in the areas of neurobiology, neuroimaging and neurotechnology to develop clinical solutions from neuroscience research.


Bin He

Bin He is an American biomedical engineering scientist. He is the Trustee Professor and Head of the Department of Biomedical Engineering, and Professor by courtesy in the Department of Electrical and Computer Engineering, and Professor of the Neuroscience Institute at Carnegie Mellon University. Prior, he was Distinguished McKnight University Professor of Biomedical Engineering and Medtronic-Bakken Endowed Chair for Engineering in Medicine at the University of Minnesota. He previously served as the director of the Institute for Engineering in Medicine and the Center for Neuroengineering at the University of Minnesota. He is the Editor in Chief of the IEEE Transactions on Biomedical Engineering. He was the president of the IEEE Engineering in Medicine & Biology Society (EMBS) from 2009 to 2010.
Biography.
Bin He received his BS in 1982 in electrical engineering, from Zhejiang University, Hangzhou, China. He later went to study in Japan and obtained his M.S. in electrical engineering and PhD (highest honors) in bioelectrical engineering from the Tokyo Institute of Technology.
Bin He completed his postdoctoral fellowship at Harvard-MIT Division of Health Sciences and Technology in the United States. After working as a Research Scientist at MIT, he later joined the faculty of Electrical Engineering and Bioengineering at the University of Illinois at Chicago, where Bin He was named a University Scholar by the university president.
In January 2004, Bin He became the Professor of Biomedical Engineering, Electrical Engineering, and Neuroscience at the University of Minnesota, Minneapolis. He also served as the founding director of Center for Neuroengineering at Minnesota. Since 2011, Bin He has served as the director of the NSF IGERT Training Program on Systems Neuroengineering. In August 2012, Bin He was named the director of the Institute for Engineering in Medicine, a campus-wide research institute aimed at advancing innovative engineering solutions for tomorrow's medicine, by fostering collaborations between biomedical colleges and College of Science and Engineering at the University of Minnesota. In February 2018, Bin He became the Department Head of the Department of Biomedical Engineering at Carnegie Mellon University. He leads the Biomedical Functional Imaging and Neuroengineering Laboratory, which was founded at the University of Minnesota and relocated to Carnegie Mellon University in 2018.
Awards.
Bin He has been recognized by a number of prestigious awards, including the IEEE EMBS Academic Career Achievements Award in 2015, IEEE Biomedical Engineering Award in 2017, IEEE EMBS Willian J Morlock Award in 2019, among others.
Research.
Bin He has made significant research and education contributions to the field of neuroengineering and biomedical imaging, including functional biomedical imaging, multimodal neuroimaging, and noninvasive brain-computer interface (BCI). His pioneering research has helped transforming electroencephalography from a 1-dimensional detection technique to 3-dimensional neuroimaging modality.


Zolertine

Zolertine is an alpha-adrenoceptor antagonist.


Sarcosine oxidase

Sarcosine oxidase is an enzyme () that catalyzes the oxidative demethylation of sarcosine to yield glycine, H2O2, 5,10-CH2-tetrahydrofolate in a reaction requiring H4-tetrahydrofolate and oxygen. Corynebacterial sarcosine oxidase is a heterotetramer and is produced as an inducible enzyme when "Corynebacterium sp."is grown with sarcosine as source of carbon and energy.


Hugo Van Heuverswyn

Hugo Van Heuverswyn (born 1948) is a Belgian molecular biologist, biotech pioneer, entrepreneur and businessman. He has been the chairman of the VIB, Flanders Institute for Biotechnology, since its inception in 1995.
Education.
He obtained a chemistry degree at University of Ghent in 1971, and he obtained a PhD at the Department of Molecular Biology, under Prof. Walter Fiers, where together with his colleagues, he determined for the first time the structure and regulatory mechanisms of a complete viral DNA genome: the virus SV40.
Career.
In 1979 he created, together with Dr. Carlos Morel, the first molecular biology laboratory in Brazil, at the Oswaldo Cruz Foundation in Rio de Janeiro. After his return to Belgium in 1981, he continued to apply recombinant DNA research in the field of immunology at the university of Ghent.
In 1982 he founded the biotech company Biogent and managed it during the first years of its existence, after which he founded Innogenetics NV in 1985 together with Erik Tambuyzer and Rudy Marien, who became the major private investor. In 2001 he founded BioMaric, a Belgian biotech start-up, together with Dr. Maan Zrein and Eric Saman, and in 2002 he founded Biotech Incubation Partners. In 2003 he initiated together with Rudy Dekeyser the creation of FlandersBio, the association of biotechnology companies in Flanders.


Nucleic acid structure determination

Experimental approaches of determining the structure of nucleic acids, such as RNA and DNA, can be largely classified into biophysical and biochemical methods. Biophysical methods use the fundamental physical properties of molecules for structure determination, including X-ray crystallography, NMR and cryo-EM. Biochemical methods exploit the chemical properties of nucleic acids using specific reagents and conditions to assay the structure of nucleic acids. Such methods may involve chemical probing with specific reagents, or rely on native or analogue chemistry. Different experimental approaches have unique merits and are suitable for different experimental purposes.
Biophysical methods.
X-ray crystallography.
X-ray crystallography is not common for nucleic acids alone, since neither DNA nor RNA readily form crystals. This is due to the greater degree of intrinsic disorder and dynamism in nucleic acid structures and the negatively charged (deoxy)ribose-phosphate backbones, which repel each other in close proximity. Therefore, crystallized nucleic acids tend to be complexed with a protein of interest to provide structural order and neutralize the negative charge.
Nuclear magnetic resonance spectroscopy (NMR).
Nucleic acid NMR is the use of NMR spectroscopy to obtain information about the structure and dynamics of nucleic acid molecules, such as DNA or RNA. As of 2003, nearly half of all known RNA structures had been determined by NMR spectroscopy.
Nucleic acid NMR uses similar techniques as protein NMR, but has several differences. Nucleic acids have a smaller percentage of hydrogen atoms, which are the atoms usually observed in NMR, and because nucleic acid double helices are stiff and roughly linear, they do not fold back on themselves to give "long-range" correlations. The types of NMR usually done with nucleic acids are 1H or proton NMR, 13C NMR, 15N NMR, and 31P NMR. Two-dimensional NMR methods are almost always used, such as correlation spectroscopy (COSY) and total coherence transfer spectroscopy (TOCSY) to detect through-bond nuclear couplings, and nuclear Overhauser effect spectroscopy (NOESY) to detect couplings between nuclei that are close to each other in space.
Parameters taken from the spectrum, mainly NOESY cross-peaks and coupling constants, can be used to determine local structural features such as glycosidic bond angles, dihedral angles (using the Karplus equation), and sugar pucker conformations. For large-scale structure, these local parameters must be supplemented with other structural assumptions or models, because errors add up as the double helix is traversed, and unlike with proteins, the double helix does not have a compact interior and does not fold back upon itself. NMR is also useful for investigating nonstandard geometries such as bent helices, non-Watson–Crick basepairing, and coaxial stacking. It has been especially useful in probing the structure of natural RNA oligonucleotides, which tend to adopt complex conformations such as stem-loops and pseudoknots. NMR is also useful for probing the binding of nucleic acid molecules to other molecules, such as proteins or drugs, by seeing which resonances are shifted upon binding of the other molecule.
Cryogenic electron microscopy (cryo-EM).
Cryogenic electron microscopy (cryo-EM) is a technique that uses an electron beam to image samples that have been cryogenically preserved in an aqueous solution. Liquid samples are pipetted on small metallic grids and plunged into a liquid ethane/propane solution which is kept extremely cold by a liquid nitrogen bath. Upon this freezing process, water molecules in the sample do not have enough time to form hexagonal lattices as found in ice, and therefore the sample is preserved in a glassy water-like state (also referred to as a vitrified ice), making these samples easier to image using the electron beam. An advantage of cryo-EM over x-ray crystallography is that the samples are preserved in their aqueous solution state and not perturbed by forming a crystal of the sample. One disadvantage, is that it is difficult to resolve nucleic acid or protein structures that are smaller than ~75 kilodaltons, partly due to the difficulty of having enough contrast to locate particles in this vitrified aqueous solution. Another disadvantage is that to attain atomic-level structure information about a sample requires taking many images (often referred to as electron micrographs) and averaging over those images in a process called single-particle reconstruction. This is a computationally intensive process.
Cryo-EM is a newer, less perturbative version of transmission electron microscopy (TEM). It is less perturbative because the sample is not dried onto a surface, this drying process is often done in negative-stain TEM, and because Cryo-EM does not require contrast agent like heavy metal salts (e.g. uranyl acetate or phoshotungstic acid) which also may affect the structure of the biomolecule. Transmission electron microscopy, as a technique, utilizes the fact that samples interact with a beam of electrons and only parts of the sample that do not interact with the electron beam are allowed to 'transmit' onto the electron detection system. TEM, in general, has been a useful technique in determining nucleic acid structure since the 1960s. While double-stranded DNA (dsDNA) structure may not traditionally be considered structure, in the typical sense of alternating segments of single- and double-stranded regions, in reality, dsDNA is not simply a perfectly ordered double helix at every location of its length due to thermal fluctuations in the DNA and alternative structures that can form like g-quadruplexes. CryoEM of nucleic acid has been done on ribosomes, viral RNA, and single-stranded RNA structures within viruses. These studies have resolved structural features at different resolutions from the nucleobase level (2-3 angstroms) up to tertiary structure motifs (greater than a nanometer).
Chemical probing.
RNA chemical probing uses chemicals that react with RNAs. Importantly, their reactivity depends on local RNA structure e.g. base-pairing or accessibility. Differences in reactivity can therefore serve as a footprint of structure along the sequence. Different reagents react at different positions on the RNA structure, and have different spectra of reactivity. Recent advances allow the simultaneous study of the structure of many RNAs (transcriptome-wide probing) and the direct assay of RNA molecules in their cellular environment (in-cell probing).
Structured RNA is first reacted with the probing reagents for a given incubation time. These reagents would form a covalent adduct on the RNA at the site of reaction. When the RNA is reverse transcribed using a reverse transcriptase into a DNA copy, the DNA generated is truncated at the positions of reaction because the enzyme is blocked by the adducts. The collection of DNA molecules of various truncated lengths therefore informs the frequency of reaction at every base position, which reflects the structure profile along the RNA. This is traditionally assayed by running the DNA on a gel, and the intensity of bands inform the frequency of observing a truncation at each position. Recent approaches use high-throughput sequencing to achieve the same purpose with greater throughput and sensitivity.
The reactivity profile can be used to study the degree of structure at particular positions for specific hypotheses, or used in conjunction with computational algorithms to produce a complete experimentally supported structure model.
Depending on the chemical reagent used, some reagents, e.g. hydroxyl radicals, would cleave the RNA molecule instead. The result in the truncated DNA is the same. Some reagents, e.g. DMS, sometimes do not block the reverse transcriptase, but trigger a mistake at the site in the DNA copy instead. These can be detected when using high-throughput sequencing methods, and is sometimes employed for improved results of probing as mutational profiling (MaP).
Positions on the RNA can be protected from the reagents not only by local structure but also by a binding protein over that position. This has led some work to use chemical probing to also assay protein-binding.
Hydroxyl radical probing.
As hydroxyl radicals are short-lived in solution, they need to be generated upon experiment. This can be done using H2O2, ascorbic acid, and Fe(II)-EDTA complex. These reagents form a system that generates hydroxyl radicals through Fenton chemistry. The hydroxyl radicals can then react with the nucleic acid molecules. Hydroxyl radicals attack the ribose/deoxyribose ring and this results in breaking of the sugar-phosphate backbone. Sites under protection from binding proteins or RNA tertiary structure would be cleaved by hydroxyl radical at a lower rate. These positions would therefore show up as absence of bands on the gel, or low signal through sequencing.
DMS.
Dimethyl sulfate, known as DMS, is a chemical that can be used to modify nucleic acids in order to determine secondary structure. Reaction with DMS adds a methyl adduct at the site, known as methylation. In particular, DMS methylates N1 of adenine (A) and N3 of cytosine (C), both located at the site of natural hydrogen bonds upon base-pairing. Therefore, modification can only occur at A and C nucleobases that are single-stranded, base paired at the end of a helix, or in a base pair at or next to a GU wobble pair, the latter two being positions where the base-pairing can occasionally open up. Moreover, since modified sites cannot be base-paired, modification sites can be detected by RT-PCR, where the reverse transcriptase falls off at methylated bases and produces different truncated cDNAs. These truncated cDNAs can be identified through gel electrophoresis or high-throughput sequencing.
Improving upon truncation-based methods, DMS mutational profiling with sequencing (DMS-MaPseq) can detect multiple DMS modifications in a single RNA molecule, which enables one to obtain more information per read (for a read of 150 nt, typically two to three mutation sites, rather than zero to one truncation sites), determine structures of low-abundance RNAs, and identify subpopulations of RNAs with alternative secondary structures. DMS-MaPseq uses a thermostable group II intron reverse transcriptase (TGIRT) that creates a mutation (rather than a truncation) in the cDNA when it encounters a base methylated by DMS, but otherwise it reverse transcribes with high fidelity. Sequencing the resulting cDNA identifies which bases were mutated during reverse transcription; these bases cannot have been base-paired in the original RNA.
DMS modification can also be used for DNA, for example in footprinting DNA-protein interactions.
SHAPE.
Selective 2′-hydroxyl acylation analyzed by primer extension, or SHAPE, takes advantage of reagents that preferentially modify the backbone of RNA in structurally flexible regions. Reagents such as N-methylisatoic anhydride (NMIA) and 1-methyl-7-nitroisatoic anhydride (1M7) react with the 2'-hydroxyl group to form adducts on the 2'-hydroxyl of the RNA backbone. Compared to the chemicals used in other RNA probing techniques, these reagents have the advantage of being largely unbiased to base identity, while remaining very sensitive to conformational dynamics. Nucleotides which are constrained (usually by base-pairing) show less adduct formation than nucleotides which are unpaired. Adduct formation is quantified for each nucleotide in a given RNA by extension of a complementary DNA primer with reverse transcriptase and comparison of the resulting fragments with those from an unmodified control. SHAPE therefore reports on RNA structure at the individual nucleotide level. This data can be used as input to generate highly accurate secondary structure models. SHAPE has been used to analyze diverse RNA structures, including that of an entire HIV-1 genome. The best approach is to use a combination of chemical probing reagents and experimental data. In SHAPE-Seq SHAPE is extended by bar-code based multiplexing combined with RNA-Seq and can be performed in a high-throughput fashion.
Carbodiimides.
The carbodiimide moiety can also form covalent adducts at exposed nucleobases, which are uracil, and to a smaller extent guanine, upon nucleophilic attack by a deprotonated N. They react primarily with N3 of uracil and N1 of guanine modifying two sites responsible for hydrogen bonding on the bases.
1-cyclohexyl-(2-morpholinoethyl)carbodiimide metho-"p"-toluene sulfonate, also known as CMCT or CMC, is the most commonly used carbodiimide for RNA structure probing. Similar to DMS, it can be detected by reverse transcription followed by gel electrophoresis or high-throughput sequencing. As it is reactive towards G and U, it can be used to complement the data from DMS probing experiments, which inform A and C.
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, also known as EDC, is a water-soluble carbodiimide that exhibits similar reactivity as CMC, and is also used for the chemical probing of RNA structure. EDC is able to permeate into cells and is thus used for direct in-cell probing of RNA in their native environments.
Kethoxal, glyoxal and derivatives.
Some 1,2-dicarbonyl compounds are able to react with single-stranded guanine (G) at N1 and N2, forming a five-membered ring adduct at the Watson-Crick face.
1,1-Dihydroxy-3-ethoxy-2-butanone, also known as kethoxal, has a structure related to 1,2-dicarbonyls, and was the first in this category used extensively for the chemical probing of RNA. Kethoxal causes the modification of guanine, specifically altering the N1 and the exocyclic amino group (N2) simultaneously by covalent interaction.
Glyoxal, methylglyoxal, and phenylglyoxal, which all carry the key 1,2-dicarbonyl moiety, all react with free guanines similar to kethoxal, and can be used to probe unpaired guanine bases in structured RNA. Due to their chemical properties, these reagents can permeate readily into cells and can therefore be used to assay RNAs in their native cellular environments.
LASER or NAz Probing.
Light-Activated Structural Examination of RNA (LASER) probing utilizes UV light to activate nicotinoyl azide (NAz), generating highly reactive nitrenium cation in water, which reacts with solvent accessible guanosine and adenosine of RNA at C-8 position through a barrierless Friedel-Crafts reaction. LASER probing targets both single-stranded and double-stranded residues as long as they are solvent accessible. Because hydroxyl radical probing requires synchrotron radiation to measure solvent accessibility of RNA "in vivo", it is hard to apply hydroxyl radical probing to footprint RNA in cells for many laboratories. In contrast, LASER probing utilizes a hand-held UV lamp (20 W) for excitation, it is much easier to apply LASER probing for "in vivo" studying RNA solvent accessibility. This chemical probing method is light-controllable, and probes solvent accessibility of nucleobase, which has been shown to footprint RNA binding proteins inside cells.
In-line probing.
In-line probing does not involve treatment with any type of chemical or reagent to modify RNA structures. This type of probing assay uses the structure dependent cleavage of RNA; single stranded regions are more flexible and unstable and will degrade over time. The process of in-line probing is often used to determine changes in structure due to ligand binding. Binding of a ligand can result in different cleavage patterns. The process of in-line probing involves incubation of structural or functional RNAs over a long period of time. This period can be several days, but varies in each experiment. The incubated products are then run on a gel to visualize the bands. This experiment is often done using two different conditions: 1) with ligand and 2) in the absence of ligand. Cleavage results in shorter band lengths and is indicative of areas that are not basepaired, as basepaired regions tend to be less sensitive to spontaneous cleavage. In-line probing is a functional assay that can be used to determine structural changes in RNA in response to ligand binding. It can directly show the change in flexibility and binding of regions of RNA in response to a ligand, as well as compare that response to analogous ligands. This assay is commonly used in dynamic studies, specifically when examining riboswitches.
Nucleotide analog interference mapping (NAIM).
Nucleotide analog interference mapping (NAIM) is the process of using nucleotide analogs, molecules that are similar in some ways to nucleotides but lack function, to determine the importance of a functional group at each location of an RNA molecule. The process of NAIM is to insert a single nucleotide analog into a unique site. This can be done by transcribing a short RNA using T7 RNA polymerase, then synthesizing a short oligonucleotide containing the analog in a specific position, then ligating them together on the DNA template using a ligase. The nucleotide analogs are tagged with a phosphorothioate, the active members of the RNA population are then distinguished from the inactive members, the inactive members then have the phosphorothioate tag removed and the analog sites are identified using gel electrophoresis and autoradiography. This indicates a functionally important nucleotide, as cleavage of the phosphorothioate by iodine results in an RNA that is cleaved at the site of the nucleotide analog insert. By running these truncated RNA molecules on a gel, the nucleotide of interest can be identified against a sequencing experiment Site directed incorporation results indicate positions of importance where when running on a gel, functional RNAs that have the analog incorporated at that position will have a band present, but if the analog results in non-functionality, when the functional RNA molecules are run on a gel there will be no band corresponding to that position on the gel. This process can be used to evaluate an entire area, where analogs are placed in site specific locations, differing by a single nucleotide, then when functional RNAs are isolated and run on a gel, all areas where bands are produced indicate non-essential nucleotides, but areas where bands are absent from the functional RNA indicate that inserting a nucleotide analog in that position caused the RNA molecule to become non-functional


Citrus tristeza virus replication signal

The Citrus tristeza virus replication signal is a regulatory element involved in a viral replication signal which is highly conserved in citrus tristeza viruses. Replication signals are required for viral replication and are usually found near the 5' and 3' termini of protein coding genes. This element is predicted to form ten stem loop structures some of which are essential for functions that provide for efficient viral replication.


Mineralocorticoid receptor

The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the "NR3C2" gene that is located on chromosome 4q31.1-31.2.
MR is a receptor with equal affinity for mineralocorticoids and glucocorticoids. It belongs to the nuclear receptor family where the ligand diffuses into cells, interacts with the receptor and results in a signal transduction affecting specific gene expression in the nucleus. The selective responsive of some tissues and organs to mineralocorticoids over glucocorticoids occurs because mineralocorticoid-responsive cells express Corticosteroid 11-beta-dehydrogenase isozyme 2, an enzyme which selectively inactivates glucocorticoids more readily than mineralocorticoids.
Function.
MR is expressed in many tissues, such as the kidney, colon, heart, central nervous system (hippocampus), brown adipose tissue and sweat glands. In epithelial tissues, its activation leads to the expression of proteins regulating ionic and water transports (mainly the epithelial sodium channel or ENaC, Na+/K+ pump, serum and glucocorticoid induced kinase or SGK1) resulting in the reabsorption of sodium, and as a consequence an increase in extracellular volume, increase in blood pressure, and an excretion of potassium to maintain a normal salt concentration in the body.
The receptor is activated by mineralocorticoids such as aldosterone and its precursor deoxycorticosterone as well as glucocorticoids like cortisol. In intact animals, the mineralocorticoid receptor is "protected" from glucocorticoids by co-localization of an enzyme, corticosteroid 11-beta-dehydrogenase isozyme 2 (a.k.a. 11β-hydroxysteroid dehydrogenase 2; 11β-HSD2), that converts cortisol to inactive cortisone.
Activation of the mineralocorticoid receptor, upon the binding of its ligand aldosterone, results in its translocation to the cell nucleus, homodimerization and binding to hormone response elements present in the promoter of some genes. This results in the complex recruitment of the transcriptional machinery and the transcription into mRNA of the DNA sequence of the activated genes.
An activating mutation in the NR3C2 gene (S810L) results in constitutive activity of the mineralocorticoid receptor, leading to severe early-onset hypertension that is exacerbated by pregnancy. In a family known to harbor the S810L mutation, 3 individuals carrying the mutation died of chronic heart failure before age 50. Additional studies have shown that this activated version of MR can positively respond to ligands that are traditionally antagonists, such as endogenous hormones like progesterone, and the diuretic drugs spironolactone and eplerenone.
Ligands.
Aldosterone, 11-deoxycorticosterone, and cortisol are endogenous agonists of the MR. Fludrocortisone is a synthetic agonist of the MR which is used clinically. Progesterone is a potent endogenous antagonist of the MR. Synthetic antagonists of the MR include the steroidal compounds spironolactone, canrenone, eplerenone, and drospirenone and the nonsteroidal compounds apararenone, esaxerenone, and finerenone.
Interactions.
Mineralocorticoid receptor has been shown to interact with:


Operation Dew

Operation Dew refers to two separate field trials conducted by the United States in the 1950s. The tests were designed to study the behavior of aerosol-released biological agents.
General description.
Operation Dew took place from 1951-1952 off the southeast coast of the United States, including near Georgia, and North and South Carolina. Operation Dew consisted of two sets of trials, Dew I and Dew II. The tests involved the release of 250 pounds (110 kg) of fluorescent particles from a minesweeper off the coast. Operation Dew I was described in a U.S. Army report known as "Dugway Special Report 162", dated August 1, 1952. The purpose of Operation Dew was to study the behavior of aerosol-released biological agents.
Dew I.
Operation Dew I consisted of five separate trials from March 26, 1952 until April 21, 1952 that were designed to test the feasibility of maintaining a large aerosol cloud released offshore until it drifted over land, achieving a large area coverage. The tests released zinc cadmium sulfide along a line approximately off the coast of Georgia, North Carolina and South Carolina. Two of the trials dispersed clouds of zinc cadmium sulfide over large areas of all three U.S. states. The tests affected over 60,000 square miles (150,000 km²) of populated coastal region in the U.S. southeast. The Dew I releases were from a Navy minesweeper, the .
Dew II.
Dew II involved the release of fluorescent particles (zinc cadmium sulfide) and plant spores ("Lycopodium") from an aircraft. Dew II was described in a 1953 Army report which remained classified at the time of a 1997 report by the U.S. National Research Council concerning the U.S. Army's zinc cadmium sulfide dispersion program of the 1950s.


Dyadobacter psychrophilus

Dyadobacter psychrophilus is a Gram-negative, aerobic and psychrophilic bacterium from the genus of Dyadobacter which has been from soil which was contaminated with hydrocarbon in Bozen in Italy.


George Weinstock

George M. Weinstock (born February 6, 1949) is an American geneticist and microbiologist on the faculty of The Jackson Laboratory for Genomic Medicine, where he is a professor and the associate director for microbial genomics. Before joining The Jackson Laboratory, he taught at Washington University in St. Louis and served as associate director of The Genome Institute. Previously, Dr. Weinstock was Co-Director of the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine in Houston, Texas, and Professor of Molecular and Human Genetics there.[1] He received his B.S. degree from the University of Michigan in 1970 and his Ph.D. from the Massachusetts Institute of Technology in 1977. He has spent most of his career taking genomic approaches to study fundamental biological processes.
Weinstock's parents met during the Manhattan Project in Los Alamos, New Mexico, and he grew up meeting many of the participants in the atomic bomb project and their colleagues. He performed his PhD thesis under David Botstein at MIT, studying the structure of phage P22 chromosome.
As a postdoctoral fellow with Dr. I. R. Lehman at Stanford University School of Medicine, Dr. Weinstock and Kevin McEntee discovered that the RecA protein of "E. coli" catalyzed strand transfer in genetic recombination. Later, as a faculty member at the University of Texas Health Science Center at Houston (UTHealth), he led one of the first bacterial genome projects, collaborating with The Institute for Genomic Research to sequence the entire genome of a bacterium, "Treponema pallidum", the organism that causes syphilis. In 1999 he joined Richard Gibbs at the HGSC as one of the five main centers to work on the Human Genome Project. The HGSC produced sequences of human chromosomes 3, 12 and X. Dr. Weinstock was a principal investigator in projects producing genome sequences for rat, mouse, macaque, bovine, sea urchin, honey bee, fruit fly and many microbial genomes, as well as one of the first personal genome projects, sequencing Dr. James Watson’s genome using next-generation sequencing technology.
He was a leader of the Human Microbiome Project, studying the collection of microbes that colonize the human body.