Euchromatin

Euchromatin is a lightly packed form of chromatin (DNA, RNA, and protein) that is enriched in genes, and is often (but not always) under active transcription. Euchromatin comprises the most active portion of the genome within the cell nucleus. 92% of the human genome is euchromatic.
Structure.
The structure of euchromatin is reminiscent of an unfolded set of beads on a string, wherein those beads represent nucleosomes. Nucleosomes consist of eight proteins known as histones, with approximately 147 base pairs of DNA wound around them; in euchromatin, this wrapping is loose so that the raw DNA may be accessed. Each core histone possesses a 'tail' structure, which can vary in several ways; it is thought that these variations act as "master control switches", which determine the overall arrangement of the chromatin. In particular, it is believed that the presence of methylated lysine 4 on the histone tails acts as a general marker.
Appearance.
In general, euchromatin appears as light-colored bands when stained in G banding and observed under an optical microscope, in contrast to heterochromatin, which stains darkly. This lighter staining is due to the less compact structure of euchromatin. The basic structure of euchromatin is an elongated, open, 10 nm microfibril, as noted by electron microscopy. In prokaryotes, euchromatin is the "only" form of chromatin present; this indicates that the heterochromatin structure evolved later along with the nucleus, possibly as a mechanism to handle increasing genome size.
Function.
Euchromatin participates in the active transcription of DNA to mRNA products. The unfolded structure allows gene regulatory proteins and RNA polymerase complexes to bind to the DNA sequence, which can then initiate the transcription process. Not all euchromatin is necessarily transcribed, but in general that which is not is transformed into heterochromatin to protect the genes while they are not in use. There is therefore a direct link to how actively productive a cell is and the amount of euchromatin that can be found in its nucleus.
It is thought that the cell uses transformation from euchromatin into heterochromatin as a method of controlling gene expression and replication, since such processes behave differently on densely compacted chromatin, known as the 'accessibility hypothesis'. One example of constitutive euchromatin that is 'always turned on' is housekeeping genes, which code for the proteins needed for basic functions of cell survival.


Recombination hotspot

Recombination hotspots are regions in a genome that exhibit elevated rates of recombination relative to a neutral expectation. The recombination rate within hotspots can be hundreds of times that of the surrounding region. Recombination hotspots result from higher DNA break formation in these regions, and apply to both mitotic and meiotic cells. This appellation can refer to recombination events resulting from the uneven distribution of programmed meiotic double-strand breaks.
Meiotic recombination.
Meiotic recombination through crossing over is thought to be a mechanism by which a cell promotes correct segregation of homologous chromosomes and repair of DNA damages. Crossing over requires a DNA double-stranded break followed by strand invasion of the homolog and subsequent repair. Initiation sites for recombination are usually identified by mapping crossing over events through pedigree analysis or through analysis of linkage disequilibrium. Linkage disequilibrium has identified more than 30,000 hotspots within the human genome. In humans, the average number of crossover recombination events per hotspot is one crossover per 1,300 meioses, and the most extreme hotspot has a crossover frequency of one per 110 meioses.
Genomic rearrangements.
Recombination can also occur due to errors in DNA replication that lead to genomic rearrangements. These events are often associated with pathology. However, genomic rearrangement is also thought to be a driving force in evolutionary development as it gives rise to novel gene combinations.
Recombination hotspots may arise from the interaction of the following selective forces: the benefit of driving genetic diversity through genomic rearrangement coupled with selection acting to maintain favorable gene combinations.
Initiation sites.
DNA contains "fragile sites" within the sequence that are more prone to recombination. These fragile sites are associated with the following trinucleotide repeats: CGG-CCG, GAG-CTG, GAA-TTC, and GCN-NGC. These fragile sites are conserved in mammals and in yeast, suggesting that the instability is caused by something inherent to the molecular structure of DNA and is associated with DNA-repeat instability. These fragile sites are thought to form hairpin structures on the lagging strand during replication from single-stranded DNA base-pairing with itself in the trinucleotide repeat region. These hairpin structures cause DNA breaks that lead to a higher frequency of recombination at these sites.
Recombination hotspots are also thought to arise due to higher-order chromosome structure that make some areas of the chromosome more accessible to recombination than others. A double stranded-break initiation site was identified in mice and yeast, located at a common chromatin feature: the trimethylation of lysine 4 of histone H3 (H3K4me3).
Recombination hotspots do not seem to be solely caused by DNA sequence arrangements or chromosome structure. Alternatively, initiation sites of recombination hotspots can be coded for in the genome. Through the comparison of recombination between different mouse strains, locus Dsbc1 was identified as a locus that contributes to the specification of initiation sites in the genome in at least two recombination hotspot locations. Additional crossing over mapping located the Dsbc1 locus to the 12.2 to 16.7-Mb region of mouse chromosome 17, which contains the PRDM9 gene. The PRDM9 gene encodes a histone methyltransferase in the Dsbc1 region, providing evidence of a non-random, genetic basis for recombination initiation sites in mice. Rapid evolution of the PRDM9 gene explains the observation that human and chimpanzees share few recombination hotspots, despite a high level of sequence identity.
Transcription associated recombination.
Homologous recombination in functional regions of DNA is strongly stimulated by transcription, as observed in a range of different organisms. Transcription associated recombination appears to be due, at least in part, to the ability of transcription to open the DNA structure and enhance accessibility of DNA to exogenous chemicals and internal metabolites that cause recombinogenic DNA damages. These findings suggest that transcription-associated recombination may contribute significantly to recombination hotspot formation.


Frank H. Field

Frank Henry Field (February 27, 1922 – April 12, 2013) was an American chemist and mass spectrometrist known for his work in the development of chemical ionization.
Early life and education.
Frank field was born in Keansburg, New Jersey, on February 27, 1922. His father died two months after he was born and his mother died in 1933, after which he was raised by his aunt in Cliffside Park, New Jersey. He attended Duke University, where he studied chemistry, receiving his B.S. degree in chemistry in 1943, M.S. in 1944, and Ph.D. in 1948.
Professional career.
Field took a position as instructor at the University of Texas at Austin in 1947 and became an assistant professor in 1949. In 1952, he took a position as a research chemist at Humble Oil in Baytown, Texas, where he, along with Burnaby Munson, discovered chemical ionization.
In 1966, he moved to Esso Research and Development Company in Linden, New Jersey, where he rose through the ranks to become a senior research associate. In 1970 he took a position as a professor at the Rockefeller University and became emeritus in 1989.
Awards and honors.
Field was a Guggenheim Fellow in 1963–1964 and was president of the American Society for Mass Spectrometry from 1972 to 1974. In 1987 he became a fellow of the American Association for the Advancement of Science. The Frank H. Field and Joe L. Franklin Award for Outstanding Achievement in Mass Spectrometry, given by the American Chemical Society, was created in 1983. Field received the award in 1988.


Selenate reductase

In enzymology, a selenate reductase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are selenite, H2O, and acceptor, whereas its two products are selenate and reduced acceptor.
This enzyme belongs to the family of oxidoreductases. The systematic name of this enzyme class is selenite:reduced acceptor oxidoreductase.


Microgale grandidieri

Microgale grandidieri, also known as Grandidier's shrew tenrec, is a species of shrew tenrec occurring in the dry forests of western and southwestern Madagascar. Populations of this species were formerly included in "Microgale brevicaudata"; "M. grandidieri" was described as a separate species in 2009 based on differences in morphology and DNA sequences.


Open reading frame

In molecular genetics, an open reading frame (ORF) is the part of a reading frame that has the ability to be translated. An ORF is a continuous stretch of codons that may begin with a start codon (usually AUG) and ends at a stop codon (usually UAA, UAG or UGA). An ATG codon (AUG in terms of RNA) within the ORF (not necessarily the first) may indicate where translation starts. The transcription termination site is located after the ORF, beyond the translation stop codon. If transcription were to cease before the stop codon, an incomplete protein would be made during translation. In eukaryotic genes with multiple exons, introns are removed and exons are then joined together after transcription to yield the final mRNA for protein translation. In the context of gene finding, the start-stop definition of an ORF therefore only applies to spliced mRNAs, not genomic DNA, since introns may contain stop codons and/or cause shifts between reading frames. An alternative definition says that an ORF is a sequence that has a length divisible by three and is bounded by stop codons. This more general definition can also be useful in the context of transcriptomics and/or metagenomics, where start and/or stop codon may not be present in the obtained sequences. Such an ORF corresponds to parts of a gene rather than the complete gene.
Biological significance.
One common use of open reading frames (ORFs) is as one piece of evidence to assist in gene prediction. Long ORFs are often used, along with other evidence, to initially identify candidate protein-coding regions or functional RNA-coding regions in a DNA sequence. The presence of an ORF does not necessarily mean that the region is always translated. For example, in a randomly generated DNA sequence with an equal percentage of each nucleotide, a stop-codon would be expected once every 21 codons. A simple gene prediction algorithm for prokaryotes might look for a start codon followed by an open reading frame that is long enough to encode a typical protein, where the codon usage of that region matches the frequency characteristic for the given organism's coding regions. Therefore, some authors say that an ORF should have a minimal length, e.g. 100 codons or 150 codons. By itself even a long open reading frame is not conclusive evidence for the presence of a gene. On the other hand, it has been proven that some short ORFs (sORFs) that lack the classical hallmarks of protein-coding genes (both from ncRNAs and mRNAs) can produce functional peptides. 5’-UTR of about 50% of mammal mRNAs are known to contain one or several sORFs. 64–75% of experimentally found translation initiation sites of sORFs are conserved in the genomes of human and mouse and may indicate that these elements have function. However, sORFs can often be found only in the minor forms of mRNAs and avoid the selection; the high conservatism of initiation sites may be connected with their location inside promoters of the relevant genes. This is characteristic of SLAMF1 gene, for example.
Six-frame translation.
Since DNA is interpreted in groups of three nucleotides (codons), a DNA strand has three distinct reading frames. The double helix of a DNA molecule has two anti-parallel strands; with the two strands having three reading frames each, there are six possible frame translations.
ORF finding tools.
ORF Finder.
The ORF Finder (Open Reading Frame Finder) is a graphical analysis tool which finds all open reading frames of a selectable minimum size in a user's sequence or in a sequence already in the database. This tool identifies all open reading frames using the standard or alternative genetic codes. The deduced amino acid sequence can be saved in various formats and searched against the sequence database using the basic local alignment search tool (BLAST) server. The ORF Finder should be helpful in preparing complete and accurate sequence submissions. It is also packaged with the Sequin sequence submission software (sequence analyser).
ORF Investigator.
ORF Investigator is a program which not only gives information about the coding and non coding sequences but also can perform pairwise global alignment of different gene/DNA regions sequences. The tool efficiently finds the ORFs for corresponding amino acid sequences and converts them into their single letter amino acid code, and provides their locations in the sequence. The pairwise global alignment between the sequences makes it convenient to detect the different mutations, including single nucleotide polymorphism. Needleman–Wunsch algorithms are used for the gene alignment. The ORF Investigator is written in the portable Perl programming language, and is therefore available to users of all common operating systems.
ORF Predictor.
OrfPredictor is a web server designed for identifying protein-coding regions in expressed sequence tag (EST)-derived sequences. For query sequences with a hit in BLASTX, the program predicts the coding regions based on the translation reading frames identified in BLASTX alignments, otherwise, it predicts the most probable coding region based on the intrinsic signals of the query sequences. The output is the predicted peptide sequences in the FASTA format, and a definition line that includes the query ID, the translation reading frame and the nucleotide positions where the coding region begins and ends. OrfPredictor facilitates the annotation of EST-derived sequences, particularly, for large-scale EST projects.
ORF Predictor uses a combination of the two different ORF definitions mentioned above. It searches stretches starting with a start codon and ending at a stop codon. As an additional criterion, it searches for a stop codon in the 5' untranslated region (UTR or NTR, "nontranslated region").
ORFik.
ORFik is a R-package in Bioconductor for finding open reading frames and using Next generation sequencing technologies for justification of ORFs.
orfipy.
orfipy is a tool written in Python/Cython to extract ORFs in an extremely and fast and flexible manner. orfipy can work with plain or gzipped FASTA and FASTQ sequences, and provides several options to fine-tune ORF searches; these include specifying the start and stop codons, reporting partial ORFs, and using custom translation tables. The results could be saved in multiple formats, including the space-efficient BED format. orfipy is particularly faster for data containing multiple smaller FASTA sequences such as de-novo transcriptome assemblies.


Leela and the Genestalk

"Leela and the Genestalk" is the twenty-second episode of the seventh season of the animated sitcom "Futurama". It originally aired on Comedy Central on August 7, 2013. The episode was written by Eric Horsted and directed by Lance Kramer. Leela develops a mutation which causes her to sprout tentacles all over her body, and ends up at a genetic engineering facility owned by Mom's Friendly Robot Company. The episode parodies many well-known fairy tales including "Rapunzel", "Chicken Little", and especially "Jack and the Beanstalk" among other references.
Plot.
While riding a mechanical buggalo at Tex 1138's, Leela finds that she is breaking out in suction cups. Dr. Tenderman explains that due to a genetic condition, her body has begun a process called squidification, in which her limbs "will be gradually transformed into a slithering mass of tentacles." There is no cure and a very expensive surgery can only delay the symptoms for a few months. In spite of these drawbacks, the crew send Fry to sell the company ship to pay for the operation. At the market, a con artist buys the ship for two gigantic, magic beans that are supposedly a miracle cure for Leela's ailment. Back at headquarters, Farnsworth is so angry that he knocks the beans out of Fry's hands, causing them to fly out the window. The beans fall onto fertile soil, watered by a leaking pipe, and rapidly grow into a beanstalk that reaches to the clouds. Leela, not wanting to share her misery with her friends, decides to cut off contact with them and live in the sewer. As she opens the manhole leading to the sewer, she sees the new beanstalk and chooses to climb it instead.
At the top of the beanstalk, Leela finds a flying castle grounds occupied by colorful flying fish and a unicorn that eats them. She is captured by Mom's three sons and taken to Mom who explains that the castle is her genetic engineering facility, where she conducts experiments such as creating gigantic beanstalks for feeding the hungry. In spite of the arguably philanthropic nature of Mom's experiments, Leela is offended, considering the experiments to be crimes.
After the Planet Express crew realize that Leela is gone, Fry and Bender fly to Mom's facility to rescue Leela. They find Leela in the lab, where Fry is horrified to see Leela's entire body has been transformed into the mass of tentacles that Dr. Tenderman predicted. While trying to escape from the lab, Fry, Leela, and Bender encounter a giant bound to an operating table connected to medical machinery. Believing that he is suffering from Mom's genetic experiments, Leela frees the giant, who chases the escapees until they flee down the drain of the giant's bathroom sink. The drain carries the three back to the bridge of the facility, where Leela confronts Mom. In order to put a stop to the experiments, Leela causes the facility to fly out of control. As it nears the ground, it passes close by the Planet Express headquarters, to which Fry, Leela, and Bender jump to safety.
Back at Planet Express, Leela attempts to end her and Fry's relationship, believing there's no possibility that he wants to be with her after what she's become. Fry refuses, promising her that he doesn't care how she looks, she'll always be the woman he loves. Touched, she thanks him and they share a loving kiss.
Later, Mom drops by to thank Leela for helping her to "engineer the perfect bean", incorporating suction cups which prevent the stalks from collapsing under their own weight. Leela is still opposed to genetic engineering in principle. Mom attempts to sway her by re-introducing her to the giant, whom she has cured of hereditary gigantism and reduced back to a normal-sized man. Leela is still not impressed, but changes her mind when Mom announces that she can cure Leela herself. The episode ends with Fry and a cured Leela walking hand-in-hand through New New York City, which has been transformed into a jungle of giant beanstalks.
Reception.
"The A.V. Club" gave this episode a B-. Max Nicholson of IGN gave the episode a 7.7/10 "Good" rating, saying "This week's "Futurama" put a unique twist on the classic "Jack and the Beanstalk" fairytale." Sean Gandert wrote for "Paste" that this was a "fun, surprising episode" even though it wasn't as funny as most episodes.


Pleurotus

Pleurotus is a genus of gilled mushrooms which includes one of the most widely eaten mushrooms, "P. ostreatus". Species of "Pleurotus" may be called oyster, abalone, or tree mushrooms, and are some of the most commonly cultivated edible mushrooms in the world. "Pleurotus" fungi have also been used in mycoremediation of pollutants, such as petroleum and polycyclic aromatic hydrocarbons.
Etymology.
The genus name "Pleurotus" literally means "side ear" in reference to the mushroom caps being laterally attached to the substrate. It is a composite of the Ancient Greek words : pleurá - "side", and the stem "-oto" referring to ears (from , ὠτός : "ear").
Description.
The caps may be laterally attached (with no stipe). If there is a stipe, it is normally eccentric and the gills are decurrent along it. The term "pleurotoid" is used for any mushroom with this general shape.
The spores are smooth and elongated (described as "cylindrical"). Where hyphae meet, they are joined by clamp connections. "Pleurotus" is not considered to be a bracket fungus, and most of the species are monomitic (with a soft consistency). However, remarkably, "Pleurotus dryinus" can sometimes be dimitic, meaning that it has additional skeletal hyphae, which give it a tougher consistency like bracket fungi.
Ecology.
"Pleurotus" fungi are found in both tropical and temperate climates throughout the world. Most species of "Pleurotus" are white-rot fungi on hardwood trees, although some also decay conifer wood. "Pleurotus eryngii" is unusual in being a weak parasite of herbaceous plants, and "P. tuber-regium" produces underground sclerotia. In addition to being saprotrophic, all species of "Pleurotus" are also nematophagous, catching nematodes by paralyzing them with a toxin.
Cuisine.
Oyster mushrooms are popular for cooking, torn up instead of sliced, especially in stir fry or sauté, because they are consistently thin, and so will cook more evenly than uncut mushrooms of other types. They are often used in vegetarian cuisine.
Taxonomy.
The classification of species within the genus "Pleurotus" is difficult due to high phenotypic variability across wide geographic ranges, geographic overlap of species, and on going evolution and speciation. Early taxonomic efforts placed the oyster mushrooms within a very broad "Agaricus" as "Agaricus ostreatus" (Jacq. 1774). Paul Kummer defined the genus "Pleurotus" in 1871; since then, the genus has been narrowed with species moving to other genera such as "Favolaschia", "Hohenbuehelia", "Lentinus", "Marasmiellus", "Omphalotus", "Panellus", "Pleurocybella", and "Resupinatus". See Singer (1986) for an example of "Pleurotus" taxonomy based on morphological characteristics.
Phylogeny.
More recently, molecular phylogenetics has been utilized to determine genetic and evolutionary relationships between groups within the genus, delineating discrete clades. "Pleurotus", along with the closely related genus "Hohenbuehelia", has been shown to be monophyletic. Tests of cross-breeding viability between groups have been used to further define which groups are deserving of species rank, as opposed to subspecies, variety, or synonymy. If two groups of morphologically distinct "Pleurotus" fungi are able to cross-breed and produce fertile offspring, they meet one definition of species. These reproductively discrete groups, referred to as intersterility groups, have begun to be defined in "Pleurotus". Many binomial names used in literature are now being grouped together as species complexes using this technique, and may change.
Phylogenetic species.
The following species list is organized according to 1. phylogenetic clade, 2. intersterility group (group number in Roman numerals) or sub-clade, and then 3. any older binomial names that have been found to be closely related, reproductively compatible, or synonymous, although they may no longer be taxonomically valid. This list is likely to be incomplete.


TFMFly

TFMFly is a compound related to psychedelic phenethylamines such as 2C-B-FLY and 2C-TFM. It was first reported in 2005 by a team at Purdue University led by David Nichols. It acts as a potent agonist at the 5HT2A serotonin receptor subtype, and is a chiral compound with the more active (R) enantiomer having a Ki of 0.12nM at the human 5HT2A receptor. While the fully aromatic benzodifurans such as bromodragonfly generally have higher binding affinity than saturated compounds like 2C-B-FLY, the saturated compounds have higher efficacy as agonists.
Legal Status.
TFMFly is illegal in Latvia.


Phospholipid-hydroperoxide glutathione peroxidase

In enzymology, a phospholipid-hydroperoxide glutathione peroxidase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are glutathione and lipid hydroperoxide, whereas its 3 products are glutathione disulfide, lipid, and H2O.
This enzyme belongs to the family of oxidoreductases, to be specific those acting on a peroxide as acceptor (peroxidases). The systematic name of this enzyme class is glutathione:lipid-hydroperoxide oxidoreductase. Other names in common use include peroxidation-inhibiting protein, PHGPX, peroxidation-inhibiting protein: peroxidase, glutathione, (phospholipid hydroperoxide-reducing), phospholipid hydroperoxide glutathione peroxidase, hydroperoxide glutathione peroxidase, or glutathione peroxidase 4 (GPX4). This enzyme participates in glutathione metabolism.
Structural studies.
As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes and .


D-proline reductase (dithiol)

In enzymology, a D-proline reductase (dithiol) () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 5-aminopentanoate and lipoate, whereas its two products are D-proline and dihydrolipoate.
This enzyme belongs to the family of oxidoreductases, specifically those acting on X-H and Y-H to form an X-Y bond with a disulfide as acceptor. The systematic name of this enzyme class is 5-aminopentanoate:lipoate oxidoreductase (cyclizing). This enzyme participates in arginine and proline metabolism. It employs one cofactor, pyruvate.


SR-57227

SR-57227 is a potent and selective agonist at the 5HT3 receptor, with high selectivity over other serotonin receptor subtypes and good blood-brain barrier penetration.


Exaprolol

Exaprolol is a beta-adrenoceptor antagonist.


Ethanol metabolism

Ethanol, an alcohol found in nature and in alcoholic drinks, is metabolized through a complex catabolic metabolic pathway. In humans, several enzymes are involved in processing ethanol first into acetaldehyde and further into acetic acid and acetyl-CoA. Once acetyl-CoA is formed, it becomes a substrate for the citric acid cycle ultimately producing cellular energy and releasing water and carbon dioxide. Due to differences in enzyme presence and availability, human adults and fetuses process ethanol through different pathways. Gene variation in these enzymes can lead to variation in catalytic efficiency between individuals. The liver is the major organ that metabolizes ethanol due to its high concentration of these enzymes.
Human metabolic physiology.
Ethanol and evolution.
The average human digestive system produces approximately 3g of ethanol per day through fermentation of its contents. Catabolic degradation of ethanol is thus essential to life, not only of humans, but of all known organisms. Certain amino acid sequences in the enzymes used to oxidize ethanol are conserved (unchanged) going back to the last common ancestor over 3.5bya. Such a function is necessary because all organisms produce alcohol in small amounts by several pathways, primarily through fatty acid synthesis, glycerolipid metabolism, and bile acid biosynthesis pathways. If the body had no mechanism for catabolizing the alcohols, they would build up in the body and become toxic. This could be an evolutionary rationale for alcohol catabolism also by sulfotransferase.
Physiologic structures.
A basic organizing theme in biological systems is that increasing complexity in specialized tissues and organs, allows for greater specificity of function. This occurs for the processing of ethanol in the human body. The enzymes required for the oxidation reactions are confined to certain tissues. In particular, much higher concentration of such enzymes are found in the liver, which is the primary site for alcohol catabolism. Variations in genes influence alcohol metabolism and drinking behavior.
Thermodynamic considerations.
Energy thermodynamics.
Energy calculations.
The reaction from ethanol to carbon dioxide and water is a complex one that proceeds in three steps. Below, the Gibbs free energy of formation for each step is shown with ΔGf values given in the CRC.
Complete reaction:
C2H6O(ethanol) → C2H4O(acetaldehyde) → C2H4O2(acetic acid) → acetyl-CoA → 3H2O + 2CO2.
ΔGf = Σ ΔGfp − ΔGfo
Step one.
C2H6O(ethanol) + NAD+ → C2H4O(acetaldehyde) + NADH + H+

Ethanol:

Acetaldehyde:

ΔGf1 = + = (endergonic)

ΣΔGf = (endergonic, but this does not take into consideration the simultaneous reduction of NAD+.)
Step two.
C2H4O(acetaldehyde) + NAD+ + H2O → C2H4O2(acetic acid) + NADH + H+

Acetaldehyde:

Acetic acid:

ΔGf2 = + = (exergonic)

ΣΔGf = + = (exergonic, but again this does not take into consideration the reduction of NAD+.)
Step three.
C2H4O2(acetic acid) + CoA + ATP → Acetyl-CoA + AMP + PPi
For the oxidation of acetic acid we have:

Acetic acid:

3H2O + 2CO2:

ΔGf4 = + = (exergonic)

ΣΔGf = − = (exergonic)
Discussion of calculations.
If catabolism of alcohol goes all the way to completion, then, we have a very exothermic event yielding some of energy. If the reaction stops part way through the metabolic pathways, which happens because acetic acid is excreted in the urine after drinking, then not nearly as much energy can be derived from alcohol, indeed, only . At the very least, the theoretical limits on energy yield are determined to be to . It is also important to note that step 1 on this reaction is endothermic, requiring of alcohol, or about 3 molecules of adenosine triphosphate (ATP) per molecule of ethanol.
Organic reaction scheme.
Steps of the reaction.
The first three steps of the reaction pathways lead from ethanol to acetaldehyde to acetic acid to acetyl-CoA. Once acetyl-CoA is formed, it is free to enter directly into the citric acid cycle. However, under alcoholic conditions, the citric acid cycle has been stalled by the oversupply of NADH derived from ethanol oxidation. The resulting backup of acetate shifts the reaction equilibrium for acetaldehyde dehydrogenase back towards acetaldehyde. Acetaldehyde subsequently accumulates and begins to form covalent bonds with cellular macromolecules, forming toxic adducts that, eventually, lead to death of the cell.
This same excess of NADH from ethanol oxidation causes the liver to move away from fatty acid oxidation, which produces NADH, towards fatty acid synthesis, which consumes NADH. This consequent lipogenesis is believed to at least largely underlie the pathogenesis of alcoholic fatty liver disease.
Gene expression and ethanol metabolism.
Ethanol to acetaldehyde in human adults.
In human adults, ethanol is oxidized to acetaldehyde using NAD+, mainly via the hepatic enzyme alcohol dehydrogenase IB (class I), beta polypeptide (ADH1B, EC 1.1.1.1). The gene coding for this enzyme is located on chromosome 4, locus. The enzyme encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster.
Ethanol to acetaldehyde in human fetuses.
In human embryos and fetuses, ethanol is not metabolized via this mechanism as ADH enzymes are not yet expressed to any significant quantity in human fetal liver (the induction of ADH only starts after birth, and requires years to reach adult levels). Accordingly, the fetal liver cannot metabolize ethanol or other low molecular weight xenobiotics. In fetuses, ethanol is instead metabolized at much slower rates by different enzymes from the cytochrome P-450 superfamily (CYP), in particular by CYP2E1. The low fetal rate of ethanol clearance is responsible for the important observation that the fetal compartment retains high levels of ethanol long after ethanol has been cleared from the maternal circulation by the adult ADH activity in the maternal liver. CYP2E1 expression and activity have been detected in various human fetal tissues after the onset of organogenesis (ca 50 days of gestation). Exposure to ethanol is known to promote further induction of this enzyme in fetal and adult tissues. CYP2E1 is a major contributor to the so-called Microsomal Ethanol Oxidizing System (MEOS) and its activity in fetal tissues is thought to contribute significantly to the toxicity of maternal ethanol consumption. In presence of ethanol and oxygen, CYP2E1 is known to release superoxide radicals and induce the oxidation of polyunsaturated fatty acids to toxic aldehyde products like 4-hydroxynonenal (HNE).
Acetaldehyde to acetic acid.
At this point in the metabolic process, the ACS alcohol point system is utilized. It standardizes ethanol concentration regardless of volume, based on fermentation and reaction coordinates, cascading through the β-1,6 linkage. Acetaldehyde is a highly unstable compound and quickly forms free radical structures which are highly toxic if not quenched by antioxidants such as ascorbic acid (vitamin C) or thiamine (vitamin B1). These free radicals can result in damage to embryonic neural crest cells and can lead to severe birth defects. Prolonged exposure of the kidney and liver to these compounds in chronic alcoholics can lead to severe damage. The literature also suggests that these toxins may have a hand in causing some of the ill effects associated with hang-overs.
The enzyme associated with the chemical transformation from acetaldehyde to acetic acid is aldehyde dehydrogenase 2 family (ALDH2, EC 1.2.1.3). In humans, the gene coding for this enzyme is found on chromosome 12, locus q24.2. There is variation in this gene leading to observable differences in catalytic efficiency between people.
Acetic acid to acetyl-CoA.
Two enzymes are associated with the conversion of acetic acid to acetyl-CoA. The first is acyl-CoA synthetase short-chain family member 2 ACSS2 (EC 6.2.1.1). The second enzyme is acetyl-CoA synthase 2 (confusingly also called ACSS1) which is localized in mitochondria.
Acetyl-CoA to water and carbon dioxide.
Once acetyl-CoA is formed, it enters the normal citric acid cycle.


Gerald M. Rubin

Gerald Mayer Rubin (born 1950) is an American biologist, notable for pioneering the use of transposable P elements in genetics, and for leading the public project to sequence the "Drosophila melanogaster" genome. Related to his genomics work, Rubin's lab is notable for development of genetic and genomics tools and studies of signal transduction and gene regulation. Rubin also serves as a Vice President of the Howard Hughes Medical Institute and Executive Director of the Janelia Research Campus.
Education and early life.
Rubin was born in Boston, Massachusetts, in 1950, attending the Boston Latin School. Rubin completed his undergraduate degree in biology at MIT, working at Cold Spring Harbor Laboratory during the summer. He completed his Ph.D. at the University of Cambridge, working at the Laboratory of Molecular Biology in 1974, for studies on 5.8S ribosomal RNA supervised by Sydney Brenner.
Career and research.
Following his PhD, Rubin did postdoctoral research at Stanford University with David Hogness.
Rubin's first faculty position was at Harvard Medical School, followed by the Carnegie Institution of Washington; in 1983 he accepted an appointment as the John D. MacArthur Professor of Genetics at the University of California, Berkeley. He was appointed a Howard Hughes Medical Investigator in 1987. He is currently the MacArthur Professor of Genetics emeritus, Genomics and Development, in Berkeley's Department of Molecular and Cell Biology.
Rubin has taken a leading role in a number of high-profile scientific research projects. As the director of the Berkeley Drosophila Genome Project, he led the public effort to sequence "Drosophila melanogaster". As Vice President of the Howard Hughes Medical Institute, Rubin led the development of HHMI's Janelia Research Campus, an independent biomedical research institute in Virginia.
His lab is particularly known for its development of genomics tools, studies of gene regulation, and other genome-wide research.
He was one of the three scientific founders of Exelixis in 1994; the company's original business plan was to exploit genomic research in "Drosophila" and other model organism to discover biological targets that could be used in drug discovery.
Awards and honours.
Rubin has won numerous awards including:


Pyrogallol hydroxytransferase

In enzymology, a pyrogallol hydroxytransferase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 1,2,3,5-tetrahydroxybenzene and 1,2,3-trihydroxybenzene (pyrogallol), whereas its two products are 1,3,5-trihydroxybenzene (phloroglucinol) and 1,2,3,5-tetrahydroxybenzene.
This enzyme participates in benzoic acid degradation via CoA ligation.
Nomenclature.
This enzyme belongs to the family of oxidoreductases. The systematic name of this enzyme class is 1,2,3,5-tetrahydroxybenzene:1,2,3-trihydroxybenzene hydroxytransferase. Other names in common use include 1,2,3,5-tetrahydroxybenzene hydroxyltransferase, 1,2,3,5-tetrahydroxybenzene:pyrogallol transhydroxylase, 1,2,3,5-tetrahydroxybenzene-pyrogallol hydroxyltransferase (transhydroxylase), pyrogallol hydroxyltransferase, 1,2,3,5-tetrahydroxybenzene:1,2,3-trihydroxybenzene hydroxyltransferase.


List of genetic codes

While there is much commonality, different parts of the tree of life use slightly different genetic codes.
Notably the mitochondrial codes vary.
When translating from genome to protein, the use of the correct genetic code is essential.
The alternative translation tables (2 to 33) involve codon reassignments that are recapitulated in the list of all known alternative codons.
Comparison of alternative translation tables for all codons (using IUPAC amino acid codes):
Notes.
Three translation tables have a peculiar status:
Other mechanisms also play a part in protein biosynthesis, such as post-transcriptional modification.


Applied DNA Sciences

Applied DNA Sciences, Inc. (NASDAQ: APDN) is a provider of molecular technologies that enable supply chain security, anti-counterfeiting and anti-theft technology, product genotyping and pre-clinical nucleic acid-based therapeutic drug candidates.
The company's DNA-based technology is utilized in a variety of industries including: textiles/fashion, wine, musical instruments, and electronics. Luxury goods manufacturers use these products to identify counterfeit consumer goods and to ensure their products' authenticity, helping, in part, to stem the flow of counterfeit goods and eliminate the slavery that is often implicit in the production of fake goods.
From a cybersecurity perspective, counterfeit microchips have become a national security concern for the United States, and this development is creating a sense of urgency around the topic of counterfeit prevention. As recently as July 7, 2011, The House Committee on Oversight and Government Reform held a hearing, entitled, "Cybersecurity: Assessing the Nation's Ability to Address the Growing Cyber Threat".
Just prior to these hearings, Applied DNA Sciences' products were vetted in a pilot program by the Defense Logistics Agency of the Department of Defense, where their technology succeeded in distinguishing between counterfeit and authentic microchips 100% of the time.


AsrC small RNA

AsrC (Antisense RNA of rseC) is a "cis-"encoded antisense RNA of rseC (an activator gene of sigma factor RpoE) described in "Salmonella enterica" serovar Typhi. It was discovered by deep sequencing and its transcription was confirmed by Northern blot. AsrC  is an 893 bp sequence that covers all of the rseC coding region in the reverse direction of transcription. It increases the level of rseC mRNA and protein, indirectly activating RpoE. RpoE can promote flagellar gene expression and motility. Coincidentally, expression of AsrC increased bacterial swimming motility. it is possible that it is because AsrC is promoting the expression of genes related to motility.


2,5-Diketopiperazine

2,5-Diketopiperazine, also known as piperazine-2,5-dione and as the cyclodipeptide cyclo(Gly-Gly), is an organic compound and the smallest cyclic dipeptide that consists of a six-membered ring containing two amide linkages where the two nitrogen atoms and the two carbonyls are at opposite positions in the ring. It was first synthesized by Curtius and Gloebel in 1888 and was the first compound containing a peptide bond to be studied by X-ray crystallography in 1938. It occurs in cocoa and bread and has a metallic and bitter taste.
2,5-Diketopiperazines (2,5-DKPs) which include mono- and disubstituted 2,5-diketopiperazines, their annulated, spiro-annulated and bridged derivatives are amongst the most ubiquitous peptide derivatives found in nature. They are found in fermentation broths and yeast cultures and this subunit is often found alone or embedded in larger more complex architectures in a variety of natural products isolated from fungi, bacteria, plants, and mammals, and their core structure occurs in several drugs. In addition, they are often produced as degradation products of polypeptides, especially in processed food and beverages, and have been identified in the contents of comets.
Occurrence as natural products.
There is a widespread occurrence of the 2,5-diketopiperazine core in biologically active natural products. The most structurally diverse 2,5-diketopiperazine natural products are based on tryptophan and proline modified by heterocyclisation and isoprenyl addition. These range from the hepatoxic brevianamide F (cyclo(-Trp--Pro)) to the annulated tremorogenic verruculogen and the spiro-annulated spirotryprostatin B which represent a promising class of antimitotic arrest agents, to the structurally complex (+)-stephacidin A, a bridged 2,5-diketopiperazine that possess a unique bicyclo[2.2.2]diazaoctane core ring system and is active against the human colon HCT-116 cell line.
Other bridged 2,5-diketopiperazines include bicyclomycin, an antibacterial agent used as food additives to prevent diarrhea in animals while the thio derivatives such as the cytotoxic bridged epipolythiodioxopiperazine are represented by gliotoxin. The unsaturated derivatives are illustrated by phenylahistin the anti-cancer microtubule binding agent, and the mycotoxin roquefortine C found in blue cheeses.
Occurrence in foods and beverages.
2,5-Diketopiperazines are often formed during chemical and thermal processing of food and beverages as the degradation products of polypeptides. They have been detected in stewed beef, beer, bread, Awamori spirits, cocoa, chicken essence, roasted coffee, Comte cheese, dried squid, aged saki and yeast extract. In food systems, 2,5-diketopiperazines have been shown to be important sensory compounds contributing to the taste of the final products and being perceived as astringent, salty, grainy, metallic or bitter. Although these range from proline, aromatic, aliphatic to polar 2,5-diketopiperazines, the proline 2,5-diketopiperazines are the most abundant and structurally diverse 2,5-diketopiperazines found in food.
The valine derivative cyclo(-Val--Pro) at a concentration of 1742 ppm, was identified as the most important bitter 2,5-diketopiperazine contributing to the bitter taste of roasted cocoa. It has also been found as one of the major 2,5-diketopiperazines in autolyzed yeast extract and stewed beef and is also present in chicken essence and coffee. It has also been isolated from a variety of marine microorganisms and has been identified as an active LasI quorum-sensing signal molecule important for the plant growth promotion by "Pseudomonas aeruginosa".
The most studied of all the simple 2,5-diketopiperazines is the histidyl-proline 2,5-diketopiperazine cyclo(-His--Pro) which is found in a variety of foods, with particularly high concentrations in fish and fish products. It is well absorbed orally, and crosses the blood–brain barrier via a non-saturable mechanism. It also occurs in humans as a metabolite from the thyrotropin-releasing hormone (TRH) and exhibits a wide variety of central nervous system, endocrine, electrophysiological, and cardiovascular effects. Derivatives of cyclo(L-His-L-Pro) have been studied extensively to develop therapeutic agents for neurodegeneration.
Structure and conformation.
The 2,5-diketopiperazines (2,5-DKPs) are the smallest possible cyclic peptides, which are peptidomimetic in nature and bear resemblance with a constrained protein beta turn. These cyclic dipeptides incorporate both donor and acceptor groups for hydrogen bonding and are small, conformationally constrained heterocyclic scaffolds in which diversity can be introduced at up to six positions and stereochemistry controlled at up to four positions, and they are stable to proteolysis. These characteristics enable them to bind to a wide range of receptors which result in a widespread class of biologically active natural compounds. They have a rigid backbone, which can mimic a preferential peptide conformation and contain constrained amino acids embedded within their structures without the unwanted physical and metabolite properties of peptides. This improves their bioavailability and resistance to enzymatic degradation in comparison to their linear analogues.
These conformationally constrained heterocycles are flexible because the six-membered ring can exist in an essentially flat conformation 1 or a slightly puckered boat form 2, with only a few kcal/mol difference in energy between the boat and planar forms.
In addition, the 2,5-DKPs can be configured as both "cis" and "trans" isomers. As a consequence of their predominant biosynthetic origin from -α-amino acids most naturally occurring 2,5-DKPs are "cis" configured as the cyclo(-Xaa--Yaa) isomers. However, 2,5-DKPs epimerize under basic, acidic and thermal conditions. The composition of the "cis" and "trans" isomers in the equilibrium state varies widely depending on the bulk of the side chains, if a ring (e.g. proline) is present, or if the nitrogen atoms are alkylated . Although epimerization was historically an issue in the synthesis of 2,5-DKPs, several mild methods have been developed recently that avoid epimerization.
Synthesis.
In the synthesis of 2,5-diketopiperazines there are essentially three methods of ring closure: amide bond formation, "N"-alkylation and "C"-acylation.
Amide bond formation.
The most commonly used synthesis of 2,5-diketopiperazines 3 is amide bond formation by cyclisation of dipeptide 1 or 2. These dipeptides can be formed by coupling two amino acids together by the many methods of peptide synthesis or by using the Ugi reaction of an isonitrile, amino acid, aldehyde and amine, followed by deprotection.
Dipeptides substituted with an amine at one terminus and an ester at the other 1 can spontaneously cyclize to form a 2,5-diketopiperazine at a range of pHs. However, careful selection of reaction conditions is required to limit racemization. This has been achieved in a general, efficient, and environmentally benign solution-phase synthesis of 2,5-diketopiperazines using microwave-assisted heating in water, which in contrast to other published methods is independent of the amino acid sequence, and no epimerization was seen.
The Ugi reaction using an isonitrile, amino acid, aldehyde and amine, can produce a dipeptide in equally high yield and optical purity, to that formed by standard peptide couplings. Commonly, an isonitrile is chosen to give a labile terminal amide to enable cyclization. For example, the direct 2,5-DKP ring formation via such an activated leaving group using the stable, easily accessible and versatile convertible isonitrile 1-isocyano-2-(2,2-dimethoxyethyl)-benzene 4 gave a one-pot synthesis of N-substituted 2,5-diketopiperazine's 7.
The mild acidic and chemoselective post Ugi activation of 5 involving simultaneous indolamide formation and tert-butoxycarbonyl (Boc) removal gives the active amide 6 which allows cyclization to 7 without affecting other peptidic or even ester moieties and with stereochemical retention of the chiral centers.
"N"-Alkylation.
Intramolecular amide "N"-alkylation of "alpha"-haloacetamide amides 8 with ethanolic potassium hydroxide using ultrasonication gave the 2,5-diketopiperazines 9, where 8 was obtained by an Ugi reaction between amines, aldehydes, isocyanides, and chloroacetic acid. However this route is limited by epimerization at the stereogenic centre and failure to obtain the 2,5-diketopiperazine ring if R1 = Alkyl.
"C"-Acylation.
Formation of the 2,5-diketopiperazine ring by enolate acylation was used in the construction of the 2,5-diketopiperazine ring in 11 by intramolecular cyclization of the enolate of 10 onto the carbonyl of the phenyl carbamate to give 11 in 90% yield.
Reactions.
Reactivity at carbon (C-3 and C-6).
Regio- and sterocontrolled C-functionalization of 2,5-diketopiperazines at C-3 and C-6 involve enolate, radical and cationic precursors (and "N"-acyliminium ion) and are sensitive to polar and steric effects.
Alkylation of enolates.
Alkylation of the bis-"para"methoxybenzyl ("pMB") protected 2,5-DKP 1 using the base LHMDS and an alkyl bromide R1Br, gave the mono-alkylated derivative 2, which on further alkylation gave the symmetrical "trans"-disubstituted derivative 3
Halogenation and displacement.
The 3-monobromides 6 and the 3,6-dibromides 5 are prepared from the benzyl protected 2,5-DKP 4 by radical halogenation with N-bromosuccinimide in carbon tetrachloride. Displacement of these labile bromides readily occurs with a range of nucleophiles SR, OR, NR2, alkyl and aryl to give 7 .
Aldol addition.
A one- or two-fold aldol condensation of "N"-acetylated 2,5-DKP 8 gives access to 3-dehydro-2,5-diketopiperazines 9 and 3,6-didehydro-2,5-diketopiperazines 10 and the condensation of 8 can controlled in a stepwise fashion using triethylamine in dimethylformamide to give the unsymmetrical 3,6-didehydro-2,5-diketopiperazines 10 (R1 = Ar1, R2 = Ar2).
Reactivity at nitrogen.
Alkylation.
The most common method for alkylation of the lactam nitrogen of 2,5-diketopiperazines is based on the use of sodium hydride as base. However epimerisation can occur especially with proline-fused 2,5-diketopiperazines, even with milder methods such as under phase-transfer catalyst conditions for example 1 to 2.
Reactivity at carbonyl carbons (C-2 and C-5).
Reduction.
Reduction of the carbonyl groups of chiral 2,5-diketopiperazine with lithium aluminium hydride (LiAlH4) cleanly gives the corresponding chiral piperazines. For example, cyclo(-Phe--Phe) 1 gives the chiral piperazine (2"S",5"S")-dibenzylpiperazine 2.
Dihydropyrazine and pyrazine synthesis.
Reaction of the lactam-derived enol phosphates 4 of 2,5-diketopiperazines with palladium catalyzed reactions (reduction, Suzuki and Stille cross-coupling reactions) enables the synthesis of a range of functionalised 1,4-dihydropyrazines 5 which can be aromatized to 1,4-pyrazines 6 in the presence of acid.
Applications.
Therapeutics.
There are numerous bioactive molecules containing the 2,5-DKP core template in the literature arising from natural products and available from combinatorial libraries. These small, conformationally rigid, chiral templates have multiple H-bond acceptor and donor functionality and have multiple sites for structural elaboration of diverse functional groups with defined stereochemistry. These characteristics not only enable them to bind with high affinity to a large variety of receptors, showing a broad range of biological activities, but also allow the development of the drug-like physicochemical properties required for the multiobjective optimization process of transforming a lead to a drug product. The structure–activity relationship (SAR) has been explored for many of these 2,5-DKP templates, and several have been developed into clinical drugs. These include tadalafil (a PDE5 inhibitor for erectile dysfunction), retosiban (an oxytocin antagonist for preterm labor), aplaviroc (a CCR5 antagonists for HIV), epelsiban (an oxytocin antagonist for premature ejaculation) and the experimental cancer drug plinabulin (NPI-2358/KPU-2) that is active in multidrug-resistant (MDR) tumor cell lines.
Reagents.
The diketopiperazine obtains from glycylserine is a reagent for the preparation of C-alkylated derivatives of glycine. This approach is useful for the production of unnatural amino acids with stereochemical control. The diketopiperazine skeleton protects both the N and O termini of the glycine. For this application, the diketopiperazine is O-alkylated with concomitant "N"-deprotonation to give what is called the Schöllkopf reagent.


Wriothesley Russell, 2nd Duke of Bedford

Wriothesley Russell, 2nd Duke of Bedford KG (1 November 1680 – 26 May 1711) was an English nobleman and politician. He was the son of William Russell, Lord Russell, and his wife Lady Rachel Wriothesley. From 1683 until 1694, he was styled Lord Russell, and from 1695 until his accession in 1700, Marquess of Tavistock.
Russell married the rich heiress Elizabeth Howland, daughter of John Howland of Streatham, on 23 May 1695. Shortly thereafter (13 June 1695), his grandfather, the Duke of Bedford, was created Baron Howland of Streatham to commemorate the marriage. The couple had six children:
On 13 May 1696, Tavistock, as he then was, matriculated at Magdalen College, Oxford. Around 1698, he began the construction of the Howland Great Wet Dock on the Thames, on some of his wife's dowry lands in Rotherhithe.
Russell held the offices of Lord Lieutenant of Cambridgeshire, Bedfordshire and Middlesex between 1701 and 1711. He was also a Gentleman of the Bedchamber to William III from 1701 to 1702. After William's death, he was invested as a Knight of the Garter on 14 March 1702 and served as Lord High Constable of England for the coronation of Queen Anne.
Russell died in 1711, aged 30, from smallpox and was buried on 30 May 1711 in the 'Bedford Chapel' at St. Michael's Church at Chenies, Buckinghamshire.


Nitroalkane oxidase

In enzymology, a nitroalkane oxidase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are nitroalkane, H2O, and O2, whereas its 4 products are aldehyde, ketone, nitrite, and H2O2.
This enzyme belongs to the family of oxidoreductases, specifically those acting on other nitrogenous compounds as donors with oxygen as acceptor. The systematic name of this enzyme class is nitroalkane:oxygen oxidoreductase. Other names in common use include nitroethane oxidase, NAO, and nitroethane:oxygen oxidoreductase. This enzyme participates in nitrogen metabolism.


Mycena galopus

Mycena galopus, commonly known as the milking bonnet or the milk-drop mycena, is an inedible species of fungus in the family Mycenaceae of the order Agaricales. It produces small mushrooms that have grayish-brown, bell-shaped, radially-grooved caps up to wide. The gills are whitish to gray, widely spaced, and squarely attached to the stem. The slender stems are up to long, and pale gray at the top, becoming almost black at the hairy base. The stem will ooze a whitish latex if it is injured or broken. The variety "nigra" has a dark gray cap, while the variety "candida" is white. All varieties of the mushroom occur during summer and autumn on leaf litter in coniferous and deciduous woodland.
"Mycena galopus" is found in North America and Europe. The saprobic fungus is an important leaf litter decomposer, and able to utilize all the major constituents of plant litter. It is especially adept at attacking cellulose and lignin, the latter of which is the second most abundant renewable organic compound in the biosphere. The mushroom latex contains chemicals called benzoxepines, which are thought to play a role in a wound-activated chemical defense mechanism against yeasts and parasitic fungi.
Taxonomy.
The mushroom was first described as "Agaricus galopus" by Christian Hendrik Persoon in 1800, and later transferred to the genus "Mycena" by Paul Kummer in 1871. An Australian taxon formerly considered a variety, "Mycena galopus" var. "mellea", was raised to species level and renamed "M. thunderboltensis" in 1998. The variety "candida" was described by Jakob Emanuel Lange in 1914 based on specimens he found in Denmark; variety "nigra" was named by Carleton Rea in 1922. "Mycena galopoda" is an orthographical variant spelling.
The specific epithet "galopus" is derived from the Greek γαλα "milk", and πονς "foot". The mushroom is commonly known as the "milking bonnet", or the "milk-drop Mycena". The varieties "candida" and "nigra" are the white and black milking bonnets, respectively.
Description.
The cap of "M. galopus" is egg-shaped when young, later becoming conic to somewhat bell-shaped, and eventually reaching a diameter of . In age it often has a margin curved inward, and a prominent umbo. The cap surface has a hoary sheen (remnants of the universal veil that once covered the immature fruit body) that soon sloughs off, leaving it naked and smooth. The cap margin, which is initially pressed against the stem, is translucent when moist, so that the outline of the gills underneath the cap may be seen, and has deep narrow grooves when dry. The color is largely fuscous-black except for the whitish margin that fades to pale gray; the umbo remains blackish or becomes dark gray, sometimes with a very pale ashy gray over all when moist, and opaque and ashy gray after drying. The flesh is thin, soft, and fragile, without any distinctive odor and taste.
The gills are subdistantly spaced, narrow, ascending-adnate, whitish to gray, usually darker in age, with edges that are pallid or grayish. The stem is (rarely up to 12 cm) long, 1–2 mm thick, equal in length throughout, smooth, and fragile. The lower portion of the stem is dark blackish-brown to a dark ashy color. The apex of the stem is pallid, and the whitish base covered with coarse, stiff hairs. When broken it exudes a white milk-like liquid. The variety "candida" is similar in appearance to the main variety, except its fruit body is completely white. Variety "nigra" has a dark or blackish-gray cap, and gills that are initially whitish before turning gray.
Although not poisonous, "M. galopus" and the varieties "candida" and "nigra" are inedible.
Microscopic characteristics.
The spores are 9–13 by 5–6.5 μm, smooth, ellipsoid, occasionally somewhat pear-shaped, and very weakly amyloid. The basidia are four-spored. The pleurocystidia and cheilocystidia are similar and very abundant, and measure 70–90 by 9–15 μm. They are narrowly fusoid-ventricose and usually have abruptly pointed tips, sometimes forked or branched near the apex, hyaline, and smooth. The flesh of the gill is homogenous, and stains dark vinaceous-brown in iodine. The flesh of the cap has a thin but clearly differentiated pellicle, a well-developed hypoderm (the tissue layer immediately underneath the pellicle), and the remainder is filamentous. All but the pellicle stain vinaceous-brown in iodine.
Similar species.
The "red edge bonnet", "Mycena rubromarginata", is also grayish-brown, but it has gill edges that are red, and it does not ooze latex when broken. It has amyloid, pip-shaped to roughly spherical spores that measure 9.2–13.4 by 6.5–9.4 µm.
Ecology, habitat, and distribution.
"Mycena galopus" is a saprobic fungus, and plays an important role in forest ecosystems as a decomposer of leaf litter. It has been estimated in the UK to account for a large portion of the decomposition of the autumn leaf litter in British woodlands. It is able to break down the lignin and cellulose components of leaf litter. Grown in axenic culture in the laboratory, the fungus mycelium has been shown to degrade (in addition to lignin and cellulose) hemicelluloses, protein, soluble carbohydrates, and purified xylan and pectin using enzymes such as polyphenol oxidases, cellulases, and catalase. It is particularly adept at breaking down lignin, which is the second most abundant renewable organic compound in the biosphere, after cellulose. Research also suggests that the fungus weathers soil minerals, making them more available to mycorrhizal plants. Phosphorus, an important macronutrient influencing plant growth, typically occurs in primary minerals like apatite, or other organic complexes, and its low solubility often results in low phosphorus availability in soil. The biological activity of "M. galopus" mycelium can increase the availability of phosphorus and other nutrients, both as a result of soil acidification due to cation uptake and via the release of weathering agents such low molecular mass organic acids. Studies have shown that the fungus is sensitive to low concentrations of sulphite (SO32−), a byproduct of sulphur dioxide pollution, suggesting that this pollution can be toxic to the growth of the fungus (and the subsequent decomposition of leaf litter) at environmentally relevant concentrations.
The fruit bodies of "Mycena galopus" grow in groups to scattered on humus under hardwoods or conifers. In the United States, it is very abundant along the Pacific Coast from Washington to California, and also in Tennessee and North Carolina; its northern distribution extends to Canada (Nova Scotia). In Europe, it has been collected from Britain, Germany, Ireland, and Norway.
Chemistry.
In 1999, Wijnberg and colleagues reported the presence of several structurally related antifungal compounds called benzoxepines in the latex of "Mycena galopus". One of these compounds, 6-hydroxypterulone, is a derivative of pterulone, a potent antifungal metabolite first isolated from submerged cultures of "Pterula" species in 1997. The antifungal activity of pterulone is based on selective inhibition of the NADH dehydrogenase enzyme of the electron transport chain. A 2008 publication reported that fatty acid esters of benzoxepine serve as precursors to wound-activated chemical defense. When the fruit body is injured and the latex is exposed, an esterase enzyme (an enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis) presumably cleaves the inactive esterified benzoxepines into their active forms, where they can help defend the mushroom against yeasts and parasitic fungi. In nature, the mushroom is rarely attacked by parasitic fungi, however, it is prone to infection by the "bonnet mold" "Spinellus fusiger", which is insensitive to the benzoxepines of "M. galopus". In an English field study, where the two fungi "M. galopus" and "Marasmius androsaceus" made up over 99% of the fruit bodies in a site under Sitka spruce, the fungivorous collembolan arthropod "Onychiurus latus" preferred to graze on the mycelium of "M. androsaceus". This selective grazing influences the vertical distribution of the two fungi in the field.


Valorphin

Valorphin, also known as VV-hemorphin-5, is a naturally occurring, endogenous opioid heptapeptide of the hemorphin family with the amino acid sequence H-Val-Val-Tyr-Pro-Trp-Thr-Gln-OH. It is produced in the body via proteolyic cleavage of residues 33-39 of the β-chain of hemoglobin. Valorphin binds preferentially to the μ-opioid receptor and produces effects such as analgesia and self-administration in animals. It also possesses cytotoxic and antiproliferative properties against tumor cells, the mediation of which, because they are reversed by naloxone, appears to be dependent on the opioid receptors.


Fred Winston

Fred Marshall Winston (born 1952) is the John Emory Andrus Professor of Genetics in the Harvard Medical School Genetics Department, where he has been a member of the faculty since 1983. Research in his laboratory has focused on mechanisms of transcription and the regulation of chromatin structure in the budding yeast "Saccharomyces cerevisiae" and the fission yeast "Schizosaccharomyces pombe". Dr. Winston served as the President of the Genetics Society of America in 2009 and has been elected to both the American Academy of Arts and Sciences (2009) and the National Academy of Sciences (2013).
Dr. Winston has served as a Senior Editor for the Genetics Society of America journal "Genetics" and is Chair of the GSA Publications Committee.
Dr. Winston received a BA in Biology from the University of Chicago in 1974 and a PhD from the Massachusetts Institute of Technology in 1980, where he conducted research with Dr. David Botstein on phage P22 lysogenization. He went on to conduct postdoctoral studies on "S. cerevisiae" transcription with Dr. Gerald Fink at Cornell University and the Whitehead Institute for Biomedical Research.


5-Aminoimidazole ribotide

5'-Phosphoribosyl-5-aminoimidazole (or aminoimidazole ribotide) is an intermediate in the formation of purines. Thus, it is an intermediate in the adenine pathway, and is synthesized from 5'-phosphoribosylformylglycinamidine by AIR synthetase.


GRIA4

Glutamate receptor 4 is a protein that in humans is encoded by the "GRIA4" gene.
This gene is a member of a family of L-glutamate-gated ion channels that mediate fast synaptic excitatory neurotransmission. These channels are also responsive to the glutamate agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA). Some haplotypes of this gene show a positive association with schizophrenia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.
Interactions.
GRIA4 has been shown to interact with CACNG2, GRIP1, PICK1 and PRKCG.
RNA editing.
Several ion channels and neurotransmitters receptors pre-mRNa are substrates for ADARs. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and Kainate receptor subunits (Glur5, Glur6). Glutamate-gated ion channels are made up of four subunits per channel. Their function is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as RNA splicing, by RNA editing events of the individual subunits. This give rise to the necessary diversity of the receptors. GluR4 is a gene product of the GRIA4 gene, and its pre-mRNA is subject to RNA editing.
Type.
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 are widely expressed in tissues, while ADAR 3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).
Location.
The pre-mRNA of this subunit is edited at one position.
The R/G editing site is located in exon 13 between the M3 to M4 region. Editing results in a codon change from an Arginine (AGA) to a Glycine (GGA). The location of editing corresponds to a bipartite ligand interaction domain of the receptor.((((((37))))))The R/G site is found at amino acid 769 immediately before the 3-amino-acid-long flip and flop modules introduced by alternative splicing. Flip and Flop forms are present in both edited and nonedited versions of this protein.
The editing complementary sequence (ECS) is found in an intronic sequence close to the exon. The intronic sequence includes a 5' splice site, and the predicted double-stranded region is 30 base pairs in length. The adenosine residue is mismatched in genomically encoded transcript, however this is not the case following editing. Despite similar sequences to the Q/R site of GluR-B, editing this site does not occur in GluR-3 pre-mRNA. Editing results in the targeted adenosine, which is mismatched prior to editing in the double-stranded RNA structure to become matched after editing. The intronic sequence involved contains a 5' donor splice site.
Conservation.
Editing also occurs in rat.
Regulation.
Editing of GluR-3 is regulated in rat brain from low levels in embryonic stage to a large increase in editing levels at birth. In humans, 80-90% of GRIA3 transcripts are edited. The absence of the Q/R site editing in this glutamate receptor subunit is due to the absence of necessary intronic sequence required to form a duplex.
Consequences.
Structure.
Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.
Function.
Editing at R/G site allows for faster recovery from desensitisation. Unedited Glu-R at this site have slower recovery rates. Editing, therefore, allows sustained response to rapid stimuli. A crosstalk between editing and splicing is likely to occur here. Editing takes place before splicing. All AMPA receptors occur in flip and flop alternatively spliced variants. AMPA receptors that occur in the Flop form desenstise faster than the flip form.
Editing is also thought to affect splicing at this site


Ancestor (novel)

Ancestor is a science fiction thriller novel by American writer Scott Sigler. The novel was released in podcast format in 2006, with it also being released in print via Dragon Moon Press in 2007. Ancestor was later re-released by Crown Publishing in 2010.
Plot.
"Ancestor" follows PJ Colding as he and his crew are tasked with transporting a team of scientists to a remote snow-covered landscape to finish their project: to recreate the ancestor of all humanity in order to provide life-saving organs that would be compatible with all people. As a snow storm threatens to trap them on the island, the scientists succeed beyond their wildest expectations. The result, however, might just bring humanity to extinction.
Reception.
Critical reception for the 2010 re-release of "Ancestor" has been positive, with Nerdist writing "It’s like Michael Crichton and Stephen King had a fabulous, bouncing baby". The Guardian criticized the prose and characterisation as "rudimentary" but praised the pacing and denouement. BookReporter also praised the novel, citing its characters as a highlight.
Of the 2009 print release, HorrorNews.net wrote "I can see how this format was appealing for the more imaginative podcast format – but avid readers who enjoy fast-paced and exciting sci-fi thrillers will be disappointed by the print version of this effort."


Lnt RNA motif

The Lnt RNA motif refers to a conserved RNA structure found in certain bacteria. Specifically, Lnt RNAs are known only in species within the phylum Chlorobi, and are located in the possible 5' untranslated regions (5' UTRs) of genes that are annotated as encoding apolipoprotein N-acyltransferase enzymes. There is some doubt as to whether the indicated motif is transcribed as RNA, or whether its reverse complement is transcribed. If the reverse complement is transcribed it would potentially in 5' UTRs of genes encoding bacteriochlorophyll A, and would be close to the start codon of those genes.


CCR5

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.
In humans, the "CCR5" gene that encodes the CCR5 protein is located on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the "Delta 32" mutation, resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains of HIV-1 infection.
Function.
The CCR5 protein belongs to the beta chemokine receptors family of integral membrane proteins. It is a G protein–coupled receptor which functions as a chemokine receptor in the CC chemokine group.
CCR5's cognate ligands include CCL3, CCL4 (also known as MIP 1"α" and 1"β", respectively), and CCL3L1. CCR5 furthermore interacts with CCL5 (a chemotactic cytokine protein also known as RANTES).
CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, eosinophils, microglia and a subpopulation of either breast or prostate cancer cells. The expression of CCR5 is selectively induced during the cancer transformation process and is not expressed in normal breast or prostate epithelial cells. Approximately 50% of human breast cancer expressed CCR5, primarily in triple negative breast cancer. CCR5 inhibitors blocked the migration and metastasis of breast and prostate cancer cells that expressed CCR5, suggesting that CCR5 may function as a new therapeutic target. Recent studies suggest that CCR5 is expressed in a subset of cancer cells with characteristics of cancer stem cells, which are known to drive therapy resistance, and that CCR5 inhibitors enhanced the number of cells killed by current chemotherapy. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. Regions of this protein are also crucial for chemokine ligand binding, the functional response of the receptor, and HIV co-receptor activity.
HIV.
HIV-1 most commonly uses the chemokine receptors CCR5 and/or CXCR4 as co-receptors to enter target immunological cells. These receptors are located on the surface of host immune cells whereby they provide a method of entry for the HIV-1 virus to infect the cell. The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell. The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 "env" gene: the Gp120 external subunit and the Gp41 transmembrane subunit. This envelope glycoprotein structure is arranged into a spike-like structure located on the surface of the virion and consists of a trimer of Gp120-Gp41 hetero-dimers. The Gp120 envelope protein is a chemokine mimic. Though it lacks the unique structure of a chemokine, it is still capable of binding to the CCR5 and CXCR4 chemokine receptors. During HIV-1 infection, the Gp120 envelope glycoprotein subunit binds to a CD4 glycoprotein and a HIV-1 co-receptor expressed on a target cell, forming a heterotrimeric complex. The formation of this complex stimulates the release of a fusogenic peptide, causing the viral membrane to fuse with the membrane of the target host cell. Because binding to CD4 alone can sometimes result in gp120 shedding, gp120 must next bind to co-receptor CCR5 in order for fusion to proceed. The tyrosine-sulfated amino terminus of this co-receptor is the "essential determinant" of binding to the gp120 glycoprotein. The co-receptor also recognizes the V1-V2 region of gp120 and the bridging sheet (an antiparallel, 4-stranded β sheet that connects the inner and outer domains of gp120). The V1-V2 stem can influence "co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation." Unlike V1-V2 however, the V3 loop is highly variable and thus is the most important determinant of co-receptor specificity. The normal ligands for this receptor, RANTES, MIP-1β, and MIP-1α, are able to suppress HIV-1 infection "in vitro". In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection, suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.
CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This bind results in gp41, the other protein product of gp160, to be released from its metastable conformation and insert itself into the membrane of the host cell. Although it has not been confirmed, binding of gp120-CCR5 involves two crucial steps: 1) The tyrosine-sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp120 (as stated previously) 2) Following step 1., there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains.
CCR5 is essential for the spread of the R5-strain of the HIV-1 virus. Knowledge of the mechanism by which this strain of HIV-1 mediates infection has prompted research into the development of therapeutic interventions to block CCR5 function. A number of new experimental HIV drugs, called CCR5 receptor antagonists, have been designed to interfere with binding between the Gp120 envelope protein and the HIV co-receptor CCR5. These experimental drugs include PRO140 (CytoDyn), Vicriviroc (Phase III trials were cancelled in July 2010) (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). Maraviroc was approved for use by the FDA in August 2007. It is the only one thus far approved by the FDA for clinical use, thus becoming the first CCR5 inhibitor. A problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another co-receptor (CXCR4), but persisted in using CCR5: they either bound to alternative domains of CCR5 or to the receptor at a higher affinity. However, because there is still another co-receptor available, it is probable that lacking the CCR5 gene does not make one immune to the virus; it would simply be more challenging for the individual to contract it. Also, the virus still has access to CD4. Unlike CCR5, which is not required (as evidenced by those living healthy lives even when lacking the gene as a result of the delta32 mutation), CD4 is critical in the body's immune defense system. Even without the availability of either co-receptor (even CCR5), the virus can still invade cells if gp41 were to go through an alteration (including its cytoplasmic tail) that resulted in the independence of CD4 without the need of CCR5 and/or CXCR4 as a doorway.
Cancer.
Expression of CCR5 is induced in breast and prostate epithelial cells upon transformation. The induction of CCR5 expression promotes cellular invasion, migration, and metastasis. The induction of metastasis involves homing to the metastatic site. CCR5 inhibitors including maraviroc and leronlimab have been shown to block lung metastasis of human breast cancer cell lines. In preclinical studies of immune competent mice CCR5 inhibitors blocked metastasis to the bones and brain. CCR5 inhibitors also reduce the infiltration of tumor associated macrophages. A Phase 1 clinical study of a CCR5 inhibitor in heavily-pretreated patients with metastatic colon cancer demonstrated an objective clinical response and reduction in metastatic tumor burden.
Brain.
Increased levels of CCR5 are part of the inflammatory response to stroke. Blocking CCR5 with Maraviroc (a drug approved for HIV) may enhance recovery after stroke.
In the developing brain, chemokines such as CCR5 influence neuronal migration and connection. After stroke, they seem to decrease the number of connection sites on neurons near the damage.
CCR5-Δ32.
CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is an allele of CCR5.
CCR5 Δ32 is a 32-base-pair deletion that introduces a premature stop codon into the CCR5 receptor locus, resulting in a nonfunctional receptor. CCR5 is required for M-tropic HIV-1 virus entry. Individuals homozygous (denoted Δ32/Δ32) for CCR5 Δ32 do not express functional CCR5 receptors on their cell surfaces and are resistant to HIV-1 infection, despite multiple high-risk exposures. Individuals heterozygous (+/Δ32) for the mutant allele have a greater than 50% reduction in functional CCR5 receptors on their cell surfaces due to dimerization between mutant and wild-type receptors that interferes with transport of CCR5 to the cell surface. Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reduced viral loads and a 2-3-year-slower progression to AIDS relative to wild types. Heterozygosity for this mutant allele also has shown to improve one's virological response to anti-retroviral treatment. CCR5 Δ32 has an (heterozygote) allele frequency of 10% in Europe, and a homozygote frequency of 1%.
Recent research indicates that CCR5 Δ32 enhances cognition and memory. In 2016, researchers showed that removing the CCR5 gene from mice significantly improved their memory. CCR5 is a powerful suppressor for neuronal plasticity, learning, and memory; CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits.
Evolutionary history and age of the allele.
The CCR5 Δ32 allele is notable for its recent origin, unexpectedly high frequency, and distinct geographic distribution, which together suggest that (a) it arose from a single mutation, and (b) it was historically subject to positive selection.
Two studies have used linkage analysis to estimate the age of the CCR5 Δ32 deletion, assuming that the amount of recombination and mutation observed on genomic regions surrounding the CCR5 Δ32 deletion would be proportional to the age of the deletion. Using a sample of 4000 individuals from 38 ethnic populations, Stephens et al. estimated that the CCR5-Δ32 deletion occurred 700 years ago (275-1875, 95% confidence interval). Another group, Libert et al. (1998), used microsatellite mutations to estimate the age of the CCR5 Δ32 mutation to be 2100 years (700-4800, 95% confidence interval). On the basis of observed recombination events, they estimated the age of the mutation to be 2250 years (900-4700, 95% confidence interval). A third hypothesis relies on the north-to-south gradient of allele frequency in Europe, which shows that the highest allele frequency occurred in the Nordic countries and lowest allele frequency in southern Europe. Because the Vikings historically occupied these countries, it may be possible that the allele spread throughout Europe due to the Viking dispersal in the 8th to 10th centuries. Vikings were later replaced by the Varangians in Russia, which may have contributed to the observed east-to-west cline of allele frequency.
HIV-1 was initially transmitted from chimpanzees ("Pan troglodytes") to humans in the early 1900s in Southeast Cameroon, Africa, through exposure to infected blood and body fluids while butchering bushmeat. However, HIV-1 was effectively absent from Europe until the 1980s. Therefore, given the average age of roughly 1000 years for the CCR5-Δ32 allele, it can be established that HIV-1 did not exert selection pressure on the human population for long enough to achieve the current frequencies. Hence, other pathogens have been suggested as agents of positive selection for CCR5 Δ32, including bubonic plague ("Yersinia pestis") and smallpox ("Variola" major).
Other data suggest that the allele frequency experienced negative selection pressure as a result of pathogens that became more widespread during Roman expansion. The idea that negative selection played a role in the allele's low frequency is also supported by experiments using knockout mice and Influenza A, which demonstrated that the presence of the CCR5 receptor is important for efficient response to a pathogen.
Evidence for a single mutation.
Several lines of evidence suggest that the CCR5 Δ32 allele evolved only once. First, CCR5 Δ32 has a relatively high frequency in several different European populations but is comparatively absent in Asian, Middle Eastern and American Indian populations, suggesting that a single mutation occurred after divergence of Europeans from their African ancestor. Second, genetic linkage analysis indicates that the mutation occurs on a homogenous genetic background, implying that inheritance of the mutation occurred from a common ancestor. This was demonstrated by showing that the CCR5 Δ32 allele is in strong linkage disequilibrium with highly polymorphic microsatellites. More than 95% of CCR5 Δ32 chromosomes also carried the IRI3.1-0 allele, while 88% carried the IRI3.2 allele. By contrast, the microsatellite markers IRI3.1-0 and IRI3.2-0 were found in only 2 or 1.5% of chromosomes carrying a wild-type CCR5 allele. This evidence of linkage disequilibrium supports the hypothesis that most, if not all, CCR5 Δ32 alleles arose from a single mutational event. Finally, the CCR5 Δ32 allele has a unique geographical distribution indicating a single Northern origin followed by migration. A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%).
Positive selection.
In the absence of selection, a single mutation would take an estimated 127,500 years to rise to a population frequency of 10%. Estimates based on genetic recombination and mutation rates place the age of the allele between 1000 and 2000 years. This discrepancy is a signature of positive selection.
It is estimated that HIV-1 entered the human population in Africa in the early 1900s; however symptomatic infections were not reported until the 1980s. The HIV-1 epidemic is therefore far too young to be the source of positive selection that drove the frequency of CCR5 Δ32 from zero to 10% in 2000 years. Stephens, et al. (1998), suggest that bubonic plague ("Yersinia pestis") had exerted positive selective pressure on CCR5 Δ32. This hypothesis was based on the timing and severity of the Black Death pandemic, which killed 30% of the European population of all ages between 1346 and 1352. After the Black Death, there were less severe, intermittent epidemics. Individual cities experienced high mortality, but overall mortality in Europe was only a few percent. In 1655-1656 a second pandemic called the "Great Plague" killed 15-20% of Europe's population. Importantly, the plague epidemics were intermittent. Bubonic plague is a zoonotic disease, primarily infecting rodents, spread by fleas, and only occasionally infecting humans. Human-to-human infection of bubonic plague does not occur, though it can occur in pneumonic plague, which infects the lungs. Only when the density of rodents is low are infected fleas forced to feed on alternative hosts such as humans, and under these circumstances a human epidemic may occur. Based on population genetic models, Galvani and Slatkin (2003) argue that the intermittent nature of plague epidemics did not generate a sufficiently strong selective force to drive the allele frequency of CCR5 Δ32 to 10% in Europe.
To test this hypothesis, Galvani and Slatkin (2003) modeled the historical selection pressures produced by plague and smallpox. Plague was modeled according to historical accounts, while age-specific smallpox mortality was gleaned from the age distribution of smallpox burials in York (England) between 1770 and 1812. Smallpox preferentially infects young, pre-reproductive members of the population since they are the only individuals who are not immunized or dead from past infection. Because smallpox preferentially kills pre-reproductive members of a population, it generates stronger selective pressure than plague. Unlike plague, smallpox does not have an animal reservoir and is only transmitted from human to human. The authors calculated that if plague were selecting for CCR5 Δ32, the frequency of the allele would still be less than 1%, while smallpox has exerted a selective force sufficient to reach 10%.
The hypothesis that smallpox exerted positive selection for CCR5 Δ32 is also biologically plausible, since poxviruses, like HIV, enter white blood cells using chemokine receptors. By contrast, "Yersinia pestis" is a bacterium with a very different biology.
Although Europeans are the only group to have subpopulations with a high frequency of CCR5 Δ32, they are not the only population that has been subject to selection by smallpox, which had a worldwide distribution before it was declared eradicated in 1980. The earliest unmistakable descriptions of smallpox appear in the 5th century A.D. in China, the 7th century A.D. in India and the Mediterranean, and the 10th century A.D. in southwestern Asia. By contrast, the "CCR5 Δ"32 mutation is found only in European, West Asian, and North African populations. The anomalously high frequency of CCR5 Δ32 in these populations appears to require both a unique origin in Northern Europe and subsequent selection by smallpox.
Potential costs.
CCR5 Δ32 can be beneficial to the host in some infections (e.g., HIV-1, possibly smallpox), but detrimental in others (e.g., tick-borne encephalitis, West Nile virus). Whether CCR5 function is helpful or harmful in the context of a given infection depends on a complex interplay between the immune system and the pathogen.
In general, research suggests that the CCR5 Δ32 mutation may play a deleterious role in post-infection inflammatory processes, which can injure tissue and create further pathology. The best evidence for this proposed antagonistic pleiotropy is found in flavivirus infections. In general many viral infections are asymptomatic or produce only mild symptoms in the vast majority of the population. However, certain unlucky individuals experience a particularly destructive clinical course, which is otherwise unexplained but appears to be genetically mediated. Patients homozygous for CCR5 Δ32 were found to be at higher risk for a neuroinvasive form of tick-borne encephalitis (a flavivirus). In addition, functional CCR5 may be required to prevent symptomatic disease after infection with West Nile virus, another flavivirus; CCR5 Δ32 was associated with early symptom development and more pronounced clinical manifestations after infection with West Nile virus.
This finding in humans confirmed a previously observed experiment in an animal model of CCR5 Δ32 homozygosity. After infection with West Nile Virus, CCR5 Δ32 mice had markedly increased viral titers in the central nervous system and had increased mortality compared with that of wild-type mice, thus suggesting that CCR5 expression was necessary to mount a strong host defense against West Nile virus.
Medical applications.
A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for HIV-1 infected individuals. When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 eventually take over the culture, as HIV-1 kills the non-modified T-cells. This same method might be used in vivo to establish a virus-resistant cell pool in infected individuals.
This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia, and was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However, the transplant was performed from a donor with 2 copies of CCR5-Δ32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues. Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either. However, this outcome is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIVX4. After over six years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.
Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified with a zinc finger nuclease to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment. Results reported in 2014 were promising.
Inspired by the first person ever to be cured of HIV, The Berlin Patient, StemCyte began collaborations with Cord blood banks worldwide to systematically screen Umbilical cord blood samples for the CCR5 mutation beginning in 2011.<ref name="CCR5Δ32/Δ32 HIV-resistant cord blood"></ref>
In November 2018, Jiankui He announced that he had edited two human embryos, to attempt to disable the gene for CCR5, which codes for a receptor that HIV uses to enter cells. He said that twin girls, Lulu and Nana, had been born a few weeks earlier, and that the girls still carried functional copies of CCR5 along with disabled CCR5 (mosaicism), hence being still vulnerable to HIV. The work was widely condemned as unethical, dangerous, and premature.


Joint replacement registry

A joint replacement registry is a system of collecting information of arthroplasty outcomes at a population (often national) level, in order to provide an evidence-base for safe and effective treatment options.
Background.
The UK registry, the NJR, was set up as recommendation of a Royal College of Surgeons of England review into the high-profile failure of the 3M Capital Hip.
Information collected.
Registers collect information on a combination of hip replacements, knee replacements (both total and unicompartmental), shoulder replacements, ankle replacements and elbow replacements. Some countries exclude hemiarthroplasties done for traumatic hip fractures.
Initially designed only to record surgeon and implant performance, the main outcome collected was implant failure, however recently patient-reported outcome measures are being added.
Research.
Given the amount of information stored, the data from many of the registries is used as the basis of scientific papers, for example on the metal-on-metal hip controversy.
Worldwide registries.
There are currently 31 national members of the International Society of Arthroplasty Registers (ISAR). In addition, in the United States, there are 10 regional or private registries collecting data.


London Smallpox Hospital

The London Smallpox Hospital, sometimes known as the Middlesex County Hospital for Smallpox and Inoculation, was established in 1745–6 and was said to be the first establishment of its type in Europe. The earliest buildings were in the West End of London, Finsbury and Bethnal Green, but in 1752 it moved to the house formerly occupied by Sir John Oldcastle in Coldbath Fields, admitting patients from 1753.
A new hospital in St Pancras was opened in 1793–4 and the Coldbath Fields building demolished in the 1860s. The Hospital in Saint Pancras near Battle Bridge, was demolished to make way for St Pancras railway station. The Hospital was replaced by the Highgate Smallpox and Vaccination Hospital, erected in 1848–1850.


Chryseobacterium oranimense

Chryseobacterium oranimense is a Gram-negative psychrotolerant, proteolytic, lipolytic, rod-shaped and non-motile bacteria from the genus of Chryseobacterium which has been isolated from raw cow milk in Israel.


Asd RNA motif

The "asd" RNA motif is a conserved RNA structure found is certain lactic acid bacteria. The "asd" motif was detected by bioinformatics and an individual "asd" RNA in "Streptococcus pyogenes" was detected by microarray and northern hybridization experiments as a 170-nucleotide molecule called "SR914400". The transcription start site determined for SR914400 corresponds to the 5′-end of the molecule shown in the consensus diagram.
Some "asd" RNAs are associated with genes, such as "asd", that are suggestive of a cis-regulatory function. However, several lines of evidence suggest that this is not the biological role of "asd" RNAs. First, in some cases, the "asd" RNA is not in the 5' untranslated region of any annotated gene. Second, in "Streptococcus mutans", there is a strong promoter immediately downstream of the transcription terminator that follows the "asd" RNA, and this promoter precedes the downstream gene. This arrangement suggests that "asd" RNA transcription is terminated, and the gene is transcribed from the downstream promoter. Finally, although the "asd" gene encodes an enzyme, aspartate-semialdehyde dehydrogenase, that participates in the synthesis of methionine, lysine and threonine, transcription levels of the "asd" gene remain constant even when the concentrations of these amino acids are varied.
The sRNA was shown to interact with the 5'UTR of the "mga" transcript (the multiple virulence gene regulator gene) and was renamed MarS for mag-activating regulatory sRNA. In MarS deletion strains expression of "mga" and several Mga-activated genes is reduced. This down-regulation of virulence factors leads to increased susceptibility of the deletion strain to phagocytosis, reduced adherence to human keratinocytes. However, the lack of MarS increased bacterial dissemination and tolerance towards oxidative stress.


Arthrobacter livingstonensis

Arthrobacter livingstonensis is a species of bacteria. It is psychrotolerant, halotolerant, Gram-positive, motile and facultatively anaerobic. It possesses a rod–coccus cycle. Its type strain is LI2T (=DSM 22825T =NCCB 100314T).