MicroRNA

A microRNA (abbreviated miRNA) is a small single-stranded non-coding RNA molecule (containing about 22 nucleotides) found in plants, animals and some viruses, that functions in RNA silencing and post-transcriptional regulation of gene expression. miRNAs function via base-pairing with complementary sequences within mRNA molecules. As a result, these mRNA molecules are silenced, by one or more of the following processes: (1) Cleavage of the mRNA strand into two pieces, (2) Destabilization of the mRNA through shortening of its poly(A) tail, and (3) Less efficient translation of the mRNA into proteins by ribosomes.
miRNAs resemble the small interfering RNAs (siRNAs) of the RNA interference (RNAi) pathway, except miRNAs derive from regions of RNA transcripts that fold back on themselves to form short hairpins, whereas siRNAs derive from longer regions of double-stranded RNA. The human genome may encode over 1900 miRNAs, although more recent analysis indicates that the number is closer to 600.
miRNAs are abundant in many mammalian cell types and as extracellular circulating miRNAs. Circulating miRNAs are released into body fluids including blood and cerebrospinal fluid and have the potential to be available as biomarkers in a number of diseases. MiRNAs appear to target about 60% of the genes of humans and other mammals. Many miRNAs are evolutionarily conserved, which implies that they have important biological functions. For example, 90 families of miRNAs have been conserved since at least the common ancestor of mammals and fish, and most of these conserved miRNAs have important functions, as shown by studies in which genes for one or more members of a family have been knocked out in mice.
History.
The first miRNA was discovered in the early 1990s. However, miRNAs were not recognized as a distinct class of biological regulators until the early 2000s. miRNA research revealed different sets of miRNAs expressed in different cell types and tissues and multiple roles for miRNAs in plant and animal development and in many other biological processes. Aberrant miRNA expression are implicated in disease states. MiRNA-based therapies are under investigation.
The first miRNA was discovered in 1993 by a group led by Ambros and including Lee and Feinbaum. However, additional insight into its mode of action required simultaneously published work by Ruvkun's team, including Wightman and Ha. These groups published back-to-back papers on the "lin-4" gene, which was known to control the timing of "C. elegans" larval development by repressing the "lin-14" gene. When Lee et al. isolated the "lin-4" miRNA, they found that instead of producing an mRNA encoding a protein, it produced short non-coding RNAs, one of which was a ~22-nucleotide RNA that contained sequences partially complementary to multiple sequences in the 3' UTR of the "lin-14" mRNA. This complementarity was proposed to inhibit the translation of the "lin-14" mRNA into the LIN-14 protein. At the time, the "lin-4" small RNA was thought to be a nematode idiosyncrasy.
In 2000, a second small RNA was characterized: "let-7" RNA, which represses "lin-41" to promote a later developmental transition in "C. elegans". The "let-7" RNA was found to be conserved in many species, leading to the suggestion that "let-7" RNA and additional "small temporal RNAs" might regulate the timing of development in diverse animals, including humans.
A year later, the "lin-4" and "let-7" RNAs were found to be part of a large class of small RNAs present in "C. elegans", "Drosophila" and human cells. The many RNAs of this class resembled the "lin-4" and "let-7" RNAs, except their expression patterns were usually inconsistent with a role in regulating the timing of development. This suggested that most might function in other types of regulatory pathways. At this point, researchers started using the term "microRNA" to refer to this class of small regulatory RNAs.
The first human disease associated with deregulation of miRNAs was chronic lymphocytic leukemia. In this disorder, the miRNAs have a dual role working as both tumor suppressors and oncogenes.
Nomenclature.
Under a standard nomenclature system, names are assigned to experimentally confirmed miRNAs before publication. The prefix "miR" is followed by a dash and a number, the latter often indicating order of naming. For example, miR-124 was named and likely discovered prior to miR-456. A capitalized "miR-" refers to the mature form of the miRNA, while the uncapitalized "mir-" refers to the pre-miRNA and the -miRNA. The miRNAs encoding genes are also named using the same three-letter prefix according to the conventions of the organism gene nomenclature. For examples, the official miRNAs gene names in some organisms are “"mir-1" in "C. elegans" and "Drosophila," "Mir-1" in "Rattus norvegicus and MIR-25" in human.
miRNAs with nearly identical sequences except for one or two nucleotides are annotated with an additional lower case letter. For example, miR-124a is closely related to miR-124b. For example:
Pre-miRNAs, -miRNAs and genes that lead to 100% identical mature miRNAs but that are located at different places in the genome are indicated with an additional dash-number suffix. For example, the pre-miRNAs -mir-194-1 and -mir-194-2 lead to an identical mature miRNA (-miR-194) but are from genes located in different genome regions.
Species of origin is designated with a three-letter prefix, e.g., -miR-124 is a human ("Homo sapiens") miRNA and oar-miR-124 is a sheep ("Ovis aries") miRNA. Other common prefixes include "v" for viral (miRNA encoded by a viral genome) and "d" for "Drosophila" miRNA (a fruit fly commonly studied in genetic research).
When two mature microRNAs originate from opposite arms of the same pre-miRNA and are found in roughly similar amounts, they are denoted with a -3p or -5p suffix. (In the past, this distinction was also made with "s" (sense) and "as" (antisense)). However, the mature microRNA found from one arm of the hairpin is usually much more abundant than that found from the other arm, in which case, an asterisk following the name indicates the mature species found at low levels from the opposite arm of a hairpin. For example, miR-124 and miR-124* share a pre-miRNA hairpin, but much more miR-124 is found in the cell.
Targets.
Plant miRNAs usually have near-perfect pairing with their mRNA targets, which induces gene repression through cleavage of the target transcripts. In contrast, animal miRNAs are able to recognize their target mRNAs by using as few as 6–8 nucleotides (the seed region) at the 5' end of the miRNA, which is not enough pairing to induce cleavage of the target mRNAs. Combinatorial regulation is a feature of miRNA regulation in animals. A given miRNA may have hundreds of different mRNA targets, and a given target might be regulated by multiple miRNAs.
Estimates of the average number of unique messenger RNAs that are targets for repression by a typical miRNA vary, depending on the estimation method, but multiple approaches show that mammalian miRNAs can have many unique targets. For example, an analysis of the miRNAs highly conserved in vertebrates shows that each has, on average, roughly 400 conserved targets. Likewise, experiments show that a single miRNA species can reduce the stability of hundreds of unique messenger RNAs. Other experiments show that a single miRNA species may repress the production of hundreds of proteins, but that this repression often is relatively mild (much less than 2-fold). The first human disease discovered to be associated with deregulation of miRNAs was chronic lymphocytic leukemia. Other B cell malignancies followed.
Biogenesis.
As many as 40% of miRNA genes may lie in the introns or even exons of other genes. These are usually, though not exclusively, found in a sense orientation, and thus usually are regulated together with their host genes.
The DNA template is not the final word on mature miRNA production: 6% of human miRNAs show RNA editing (IsomiRs), the site-specific modification of RNA sequences to yield products different from those encoded by their DNA. This increases the diversity and scope of miRNA action beyond that implicated from the genome alone.
Transcription.
miRNA genes are usually transcribed by RNA polymerase II (Pol II). The polymerase often binds to a promoter found near the DNA sequence, encoding what will become the hairpin loop of the pre-miRNA. The resulting transcript is capped with a specially modified nucleotide at the 5' end, polyadenylated with multiple adenosines (a poly(A) tail), and spliced. Animal miRNAs are initially transcribed as part of one arm of an ∼80 nucleotide RNA stem-loop that in turn forms part of a several hundred nucleotide-long miRNA precursor termed a pri-miRNA. When a stem-loop precursor is found in the 3' UTR, a transcript may serve as a pri-miRNA and a mRNA. RNA polymerase III (Pol III) transcribes some miRNAs, especially those with upstream Alu sequences, transfer RNAs (tRNAs), and mammalian wide interspersed repeat (MWIR) promoter units.
Nuclear processing.
A single pri-miRNA may contain from one to six miRNA precursors. These hairpin loop structures are composed of about 70 nucleotides each. Each hairpin is flanked by sequences necessary for efficient processing.
The double-stranded RNA (dsRNA) structure of the hairpins in a pri-miRNA is recognized by a nuclear protein known as DiGeorge Syndrome Critical Region 8 (DGCR8 or "Pasha" in invertebrates), named for its association with DiGeorge Syndrome. DGCR8 associates with the enzyme Drosha, a protein that cuts RNA, to form the Microprocessor complex. In this complex, DGCR8 orients the catalytic RNase III domain of Drosha to liberate hairpins from pri-miRNAs by cleaving RNA about eleven nucleotides from the hairpin base (one helical dsRNA turn into the stem). The product resulting has a two-nucleotide overhang at its 3' end; it has 3' hydroxyl and 5' phosphate groups. It is often termed as a pre-miRNA (precursor-miRNA). Sequence motifs downstream of the pre-miRNA that are important for efficient processing have been identified.
Pre-miRNAs that are spliced directly out of introns, bypassing the Microprocessor complex, are known as "Mirtrons." Originally thought to exist only in "Drosophila" and "C. elegans", mirtrons have now been found in mammals.
As many as 16% of pre-miRNAs may be altered through nuclear RNA editing. Most commonly, enzymes known as adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine (A to I) transitions. RNA editing can halt nuclear processing (for example, of pri-miR-142, leading to degradation by the ribonuclease Tudor-SN) and alter downstream processes including cytoplasmic miRNA processing and target specificity (e.g., by changing the seed region of miR-376 in the central nervous system).
Nuclear export.
Pre-miRNA hairpins are exported from the nucleus in a process involving the nucleocytoplasmic shuttler Exportin-5. This protein, a member of the karyopherin family, recognizes a two-nucleotide overhang left by the RNase III enzyme Drosha at the 3' end of the pre-miRNA hairpin. Exportin-5-mediated transport to the cytoplasm is energy-dependent, using guanosine triphosphate (GTP) bound to the Ran protein.
Cytoplasmic processing.
In the cytoplasm, the pre-miRNA hairpin is cleaved by the RNase III enzyme Dicer. This endoribonuclease interacts with 5' and 3' ends of the hairpin and cuts away the loop joining the 3' and 5' arms, yielding an imperfect miRNA:miRNA* duplex about 22 nucleotides in length. Overall hairpin length and loop size influence the efficiency of Dicer processing. The imperfect nature of the miRNA:miRNA* pairing also affects cleavage. Some of the G-rich pre-miRNAs can potentially adopt the G-quadruplex structure as an alternative to the canonical stem-loop structure. For example, human pre-miRNA 92b adopts a G-quadruplex structure which is resistant to the Dicer mediated cleavage in the cytoplasm. Although either strand of the duplex may potentially act as a functional miRNA, only one strand is usually incorporated into the RNA-induced silencing complex (RISC) where the miRNA and its mRNA target interact.
While the majority of miRNAs are located within the cell, some miRNAs, commonly known as circulating miRNAs or extracellular miRNAs, have also been found in extracellular environment, including various biological fluids and cell culture media.
Biogenesis in plants.
miRNA biogenesis in plants differs from animal biogenesis mainly in the steps of nuclear processing and export. Instead of being cleaved by two different enzymes, once inside and once outside the nucleus, both cleavages of the plant miRNA are performed by a Dicer homolog, called Dicer-like1 (DL1). DL1 is expressed only in the nucleus of plant cells, which indicates that both reactions take place inside the nucleus. Before plant miRNA:miRNA* duplexes are transported out of the nucleus, its 3' overhangs are methylated by a RNA methyltransferaseprotein called Hua-Enhancer1 (HEN1). The duplex is then transported out of the nucleus to the cytoplasm by a protein called Hasty (HST), an Exportin 5 homolog, where they disassemble and the mature miRNA is incorporated into the RISC.
RNA-induced silencing complex.
The mature miRNA is part of an active RNA-induced silencing complex (RISC) containing Dicer and many associated proteins. RISC is also known as a microRNA ribonucleoprotein complex (miRNP); A RISC with incorporated miRNA is sometimes referred to as a "miRISC."
Dicer processing of the pre-miRNA is thought to be coupled with unwinding of the duplex. Generally, only one strand is incorporated into the miRISC, selected on the basis of its thermodynamic instability and weaker base-pairing on the 5' end relative to the other strand. The position of the stem-loop may also influence strand choice. The other strand, called the passenger strand due to its lower levels in the steady state, is denoted with an asterisk (*) and is normally degraded. In some cases, both strands of the duplex are viable and become functional miRNA that target different mRNA populations.
Members of the Argonaute (Ago) protein family are central to RISC function. Argonautes are needed for miRNA-induced silencing and contain two conserved RNA binding domains: a PAZ domain that can bind the single stranded 3' end of the mature miRNA and a PIWI domain that structurally resembles ribonuclease-H and functions to interact with the 5' end of the guide strand. They bind the mature miRNA and orient it for interaction with a target mRNA. Some argonautes, for example human Ago2, cleave target transcripts directly; argonautes may also recruit additional proteins to achieve translational repression. The human genome encodes eight argonaute proteins divided by sequence similarities into two families: AGO (with four members present in all mammalian cells and called E1F2C/hAgo in humans), and PIWI (found in the germ line and hematopoietic stem cells).
Additional RISC components include TRBP [human immunodeficiency virus (HIV) transactivating response RNA (TAR) binding protein], PACT (protein activator of the interferon-induced protein kinase), the SMN complex, fragile X mental retardation protein (FMRP), Tudor staphylococcal nuclease-domain-containing protein (Tudor-SN), the putative DNA helicase MOV10, and the RNA recognition motif containing protein TNRC6B.
Mode of silencing and regulatory loops.
Gene silencing may occur either via mRNA degradation or preventing mRNA from being translated. For example, miR16 contains a sequence complementary to the AU-rich element found in the 3'UTR of many unstable mRNAs, such as TNF alpha or GM-CSF. It has been demonstrated that given complete complementarity between the miRNA and target mRNA sequence, Ago2 can cleave the mRNA and lead to direct mRNA degradation. In the absence of complementarity, silencing is achieved by preventing translation. The relation of miRNA and its target mRNA can be based on the simple negative regulation of a target mRNA, but it seems that a common scenario is the use of a "coherent feed-forward loop", "mutual negative feedback loop" (also termed double negative loop) and "positive feedback/feed-forward loop". Some miRNAs work as buffers of random gene expression changes arising due to stochastic events in transcription, translation and protein stability. Such regulation is typically achieved by the virtue of negative feedback loops or incoherent feed-forward loop uncoupling protein output from mRNA transcription.
Turnover.
Turnover of mature miRNA is needed for rapid changes in miRNA expression profiles. During miRNA maturation in the cytoplasm, uptake by the Argonaute protein is thought to stabilize the guide strand, while the opposite (* or "passenger") strand is preferentially destroyed. In what has been called a "Use it or lose it" strategy, Argonaute may preferentially retain miRNAs with many targets over miRNAs with few or no targets, leading to degradation of the non-targeting molecules.
Decay of mature miRNAs in "Caenorhabditis elegans" is mediated by the 5'-to-3' exoribonuclease XRN2, also known as Rat1p. In plants, SDN (small RNA degrading nuclease) family members degrade miRNAs in the opposite (3'-to-5') direction. Similar enzymes are encoded in animal genomes, but their roles have not been described.
Several miRNA modifications affect miRNA stability. As indicated by work in the model organism "Arabidopsis thaliana" (thale cress), mature plant miRNAs appear to be stabilized by the addition of methyl moieties at the 3' end. The 2'-O-conjugated methyl groups block the addition of uracil (U) residues by uridyltransferase enzymes, a modification that may be associated with miRNA degradation. However, uridylation may also protect some miRNAs; the consequences of this modification are incompletely understood. Uridylation of some animal miRNAs has been reported. Both plant and animal miRNAs may be altered by addition of adenine (A) residues to the 3' end of the miRNA. An extra A added to the end of mammalian miR-122, a liver-enriched miRNA important in hepatitis C, stabilizes the molecule and plant miRNAs ending with an adenine residue have slower decay rates.
Cellular functions.
The function of miRNAs appears to be in gene regulation. For that purpose, a miRNA is complementary to a part of one or more messenger RNAs (mRNAs). Animal miRNAs are usually complementary to a site in the 3' UTR whereas plant miRNAs are usually complementary to coding regions of mRNAs. Perfect or near perfect base pairing with the target RNA promotes cleavage of the RNA. This is the primary mode of plant miRNAs. In animals the match-ups are imperfect.
For partially complementary microRNAs to recognise their targets, nucleotides 2–7 of the miRNA (its 'seed region') must be perfectly complementary. Animal miRNAs inhibit protein translation of the target mRNA (this is present but less common in plants). Partially complementary microRNAs can also speed up deadenylation, causing mRNAs to be degraded sooner. While degradation of miRNA-targeted mRNA is well documented, whether or not translational repression is accomplished through mRNA degradation, translational inhibition, or a combination of the two is hotly debated. Recent work on miR-430 in zebrafish, as well as on bantam-miRNA and miR-9 in "Drosophila" cultured cells, shows that translational repression is caused by the disruption of translation initiation, independent of mRNA deadenylation.
miRNAs occasionally also cause histone modification and DNA methylation of promoter sites, which affects the expression of target genes.
Nine mechanisms of miRNA action are described and assembled in a unified mathematical model:
It is often impossible to discern these mechanisms using experimental data about stationary reaction rates. Nevertheless, they are differentiated in dynamics and have different "kinetic signatures".
Unlike plant microRNAs, the animal microRNAs target diverse genes. However, genes involved in functions common to all cells, such as gene expression, have relatively fewer microRNA target sites and seem to be under selection to avoid targeting by microRNAs.
dsRNA can also activate gene expression, a mechanism that has been termed "small RNA-induced gene activation" or RNAa. dsRNAs targeting gene promoters can induce potent transcriptional activation of associated genes. This was demonstrated in human cells using synthetic dsRNAs termed small activating RNAs (saRNAs), but has also been demonstrated for endogenous microRNA.
Interactions between microRNAs and complementary sequences on genes and even pseudogenes that share sequence homology are thought to be a back channel of communication regulating expression levels between paralogous genes. Given the name "competing endogenous RNAs" (ceRNAs), these microRNAs bind to "microRNA response elements" on genes and pseudogenes and may provide another explanation for the persistence of non-coding DNA.
Some researches show that mRNA cargo of exosomes may have a role in implantation, they can savage an adhesion between trophoblast and endometrium or support the adhesion by down regulating or up regulating expression of genes involved in adhesion/invasion.
Moreover, miRNA as miR-183/96/182 seems to play a key role in circadian rhythm.
Evolution.
miRNAs are well conserved in both plants and animals, and are thought to be a vital and evolutionarily ancient component of gene regulation. While core components of the microRNA pathway are conserved between plants and animals, miRNA repertoires in the two kingdoms appear to have emerged independently with different primary modes of action.
microRNAs are useful phylogenetic markers because of their apparently low rate of evolution. microRNAs' origin as a regulatory mechanism developed from previous RNAi machinery that was initially used as a defense against exogenous genetic material such as viruses. Their origin may have permitted the development of morphological innovation, and by making gene expression more specific and 'fine-tunable', permitted the genesis of complex organs and perhaps, ultimately, complex life. Rapid bursts of morphological innovation are generally associated with a high rate of microRNA accumulation.
New microRNAs are created in multiple ways. Novel microRNAs can originate from the random formation of hairpins in "non-coding" sections of DNA (i.e. introns or intergene regions), but also by the duplication and modification of existing microRNAs. microRNAs can also form from inverted duplications of protein-coding sequences, which allows for the creation of a foldback hairpin structure. The rate of evolution (i.e. nucleotide substitution) in recently originated microRNAs is comparable to that elsewhere in the non-coding DNA, implying evolution by neutral drift; however, older microRNAs have a much lower rate of change (often less than one substitution per hundred million years), suggesting that once a microRNA gains a function, it undergoes purifying selection. Individual regions within an miRNA gene face different evolutionary pressures, where regions that are vital for processing and function have higher levels of conservation. At this point, a microRNA is rarely lost from an animal's genome, although newer microRNAs (thus presumably non-functional) are frequently lost. In "Arabidopsis thaliana", the net flux of miRNA genes has been predicted to be between 1.2 and 3.3 genes per million years. This makes them a valuable phylogenetic marker, and they are being looked upon as a possible solution to outstanding phylogenetic problems such as the relationships of arthropods. On the other hand, in multiple cases microRNAs correlate poorly with phylogeny, and it is possible that their phylogenetic concordance largely reflects a limited sampling of microRNAs.
microRNAs feature in the genomes of most eukaryotic organisms, from the brown algae to the animals. However, the difference in how these microRNAs function and the way they are processed suggests that microRNAs arose independently in plants and animals.
Focusing on the animals, the genome of "Mnemiopsis leidyi" appears to lack recognizable microRNAs, as well as the nuclear proteins Drosha and Pasha, which are critical to canonical microRNA biogenesis. It is the only animal thus far reported to be missing Drosha. MicroRNAs play a vital role in the regulation of gene expression in all non-ctenophore animals investigated thus far except for "Trichoplax adhaerens", the only known member of the phylum Placozoa.
Across all species, in excess of 5000 different miRNAs had been identified by March 2010. Whilst short RNA sequences (50 – hundreds of base pairs) of a broadly comparable function occur in bacteria, bacteria lack true microRNAs.
Experimental detection and manipulation.
While researchers focused on miRNA expression in physiological and pathological processes, various technical variables related to microRNA isolation emerged. The stability of stored miRNA samples has been questioned. microRNAs degrade much more easily than mRNAs, partly due to their length, but also because of ubiquitously present RNases. This makes it necessary to cool samples on ice and use RNase-free equipment.
microRNA expression can be quantified in a two-step polymerase chain reaction process of modified RT-PCR followed by quantitative PCR. Variations of this method achieve absolute or relative quantification. miRNAs can also be hybridized to microarrays, slides or chips with probes to hundreds or thousands of miRNA targets, so that relative levels of miRNAs can be determined in different samples. microRNAs can be both discovered and profiled by high-throughput sequencing methods (microRNA sequencing). The activity of an miRNA can be experimentally inhibited using a locked nucleic acid (LNA) oligo, a Morpholino oligo or a 2'-O-methyl RNA oligo. A specific miRNA can be silenced by a complementary antagomir. microRNA maturation can be inhibited at several points by steric-blocking oligos. The miRNA target site of an mRNA transcript can also be blocked by a steric-blocking oligo. For the "in situ" detection of miRNA, LNA or Morpholino probes can be used. The locked conformation of LNA results in enhanced hybridization properties and increases sensitivity and selectivity, making it ideal for detection of short miRNA.
High-throughput quantification of miRNAs is error prone, for the larger variance (compared to mRNAs) that comes with methodological problems. mRNA-expression is therefore often analyzed to check for miRNA-effects in their levels (e.g. in). Databases can be used to pair mRNA- and miRNA-data that predict miRNA-targets based on their base sequence. While this is usually done after miRNAs of interest have been detected (e. g. because of high expression levels), ideas for analysis tools that integrate mRNA- and miRNA-expression information have been proposed.
Disease.
Just as miRNA is involved in the normal functioning of eukaryotic cells, so has dysregulation of miRNA been associated with disease. A manually curated, publicly available database, miR2Disease, documents known relationships between miRNA dysregulation and human disease.
Inherited diseases.
A mutation in the seed region of miR-96 causes hereditary progressive hearing loss.
A mutation in the seed region of miR-184 causes hereditary keratoconus with anterior polar cataract.
Deletion of the miR-17~92 cluster causes skeletal and growth defects.
Cancer.
The first human disease known to be associated with miRNA deregulation was chronic lymphocytic leukemia. Many other miRNAs also have links with cancer and accordingly are sometimes referred to as "oncomirs". In malignant B cells miRNAs participate in pathways fundamental to B cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches and the production and class-switching of immunoglobulins. MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells.
Another role for miRNA in cancers is to use their expression level for prognosis. In NSCLC samples, low miR-324a levels may serve as an indicator of poor survival. Either high miR-185 or low miR-133b levels may correlate with metastasis and poor survival in colorectal cancer.
Furthermore, specific miRNAs may be associated with certain histological subtypes of colorectal cancer. For instance, expression levels of miR-205 and miR-373 have been shown to be increased in mucinous colorectal cancers and mucin-producing Ulcerative Colitis-associated colon cancers, but not in sporadic colonic adenocarcinoma that lack mucinous components. In-vitro studies suggested that miR-205 and miR-373 may functionally induce different features of mucinous-associated neoplastic progression in intestinal epithelial cells.
Hepatocellular carcinoma cell proliferation may arise from miR-21 interaction with MAP2K3, a tumor repressor gene. Optimal treatment for cancer involves accurately identifying patients for risk-stratified therapy. Those with a rapid response to initial treatment may benefit from truncated treatment regimens, showing the value of accurate disease response measures. Cell-free circulating miRNAs (cimiRNAs) are highly stable in blood, are overexpressed in cancer and are quantifiable within the diagnostic laboratory. In classical Hodgkin lymphoma, plasma miR-21, miR-494, and miR-1973 are promising disease response biomarkers. Circulating miRNAs have the potential to assist clinical decision making and aid interpretation of positron emission tomography combined with computerized tomography. They can be performed at each consultation to assess disease response and detect relapse.
MicroRNAs have the potential to be used as tools or targets for treatment of different cancers. The specific microRNA, miR-506 has been found to work as a tumor antagonist in several studies. A significant number of cervical cancer samples were found to have downregulated expression of miR-506. Additionally, miR-506 works to promote apoptosis of cervical cancer cells, through its direct target hedgehog pathway transcription factor, Gli3.
DNA repair and cancer.
Cancer is caused by the accumulation of mutations from either DNA damage or uncorrected errors in DNA replication. Defects in DNA repair cause the accumulation of mutations, which can lead to cancer. Several genes involved in DNA repair are regulated by microRNAs.
Germ line mutations in DNA repair genes cause only 2–5% of colon cancer cases. However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important causal factor. Among 68 sporadic colon cancers with reduced expression of the DNA mismatch repair protein MLH1, most were found to be deficient due to epigenetic methylation of the CpG island of the MLH1 gene. However, up to 15% of MLH1-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA miR-155, which represses MLH1 expression.
In 29–66% of glioblastomas, DNA repair is deficient due to epigenetic methylation of the MGMT gene, which reduces protein expression of MGMT. However, for 28% of glioblastomas, the MGMT protein is deficient, but the MGMT promoter is not methylated. In glioblastomas without methylated MGMT promoters, the level of microRNA miR-181d is inversely correlated with protein expression of MGMT and the direct target of miR-181d is the MGMT mRNA 3'UTR (the three prime untranslated region of MGMT mRNA). Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor.
HMGA proteins (HMGA1a, HMGA1b and HMGA2) are implicated in cancer, and expression of these proteins is regulated by microRNAs. HMGA expression is almost undetectable in differentiated adult tissues, but is elevated in many cancers. HMGA proteins are polypeptides of ~100 amino acid residues characterized by a modular sequence organization. These proteins have three highly positively charged regions, termed AT hooks, that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Human neoplasias, including thyroid, prostatic, cervical, colorectal, pancreatic and ovarian carcinomas, show a strong increase of HMGA1a and HMGA1b proteins. Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is associated with cancers and that HMGA1 can act as an oncogene. HMGA2 protein specifically targets the promoter of ERCC1, thus reducing expression of this DNA repair gene. ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is not known).
Single Nucleotide polymorphisms (SNPs) can alter the binding of miRNAs on 3'UTRs for example the case of hsa-mir181a and hsa-mir181b on the CDON tumor suppressor gene.
Heart disease.
The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the murine heart. This revealed that miRNAs play an essential role during its development. miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies. Furthermore, animal studies on specific miRNAs identified distinct roles for miRNAs both during heart development and under pathological conditions, including the regulation of key factors important for cardiogenesis, the hypertrophic growth response and cardiac conductance. Another role for miRNA in cardiovascular diseases is to use their expression levels for diagnosis, prognosis or risk stratification. miRNA's in animal models have also been linked to cholesterol metabolism and regulation.
miRNA-712.
Murine microRNA-712 is a potential biomarker (i.e. predictor) for atherosclerosis, a cardiovascular disease of the arterial wall associated with lipid retention and inflammation. Non-laminar blood flow also correlates with development of atherosclerosis as mechanosenors of endothelial cells respond to the shear force of disturbed flow (d-flow). A number of pro-atherogenic genes including matrix metalloproteinases (MMPs) are upregulated by d-flow, mediating pro-inflammatory and pro-angiogenic signals. These findings were observed in ligated carotid arteries of mice to mimic the effects of d-flow. Within 24 hours, pre-existing immature miR-712 formed mature miR-712 suggesting that miR-712 is flow-sensitive. Coinciding with these results, miR-712 is also upregulated in endothelial cells exposed to naturally occurring d-flow in the greater curvature of the aortic arch.
Origin.
Pre-mRNA sequence of miR-712 is generated from the murine ribosomal RN45s gene at the internal transcribed spacer region 2 (ITS2). XRN1 is an exonuclease that degrades the ITS2 region during processing of RN45s. Reduction of XRN1 under d-flow" "conditions therefore leads to the accumulation of miR-712.
Mechanism.
MiR-712 targets tissue inhibitor of metalloproteinases 3 (TIMP3). TIMPs normally regulate activity of matrix metalloproteinases (MMPs) which degrade the extracellular matrix (ECM). Arterial ECM is mainly composed of collagen and elastin fibers, providing the structural support and recoil properties of arteries. These fibers play a critical role in regulation of vascular inflammation and permeability, which are important in the development of atherosclerosis. Expressed by endothelial cells, TIMP3 is the only ECM-bound TIMP. A decrease in TIMP3 expression results in an increase of ECM degradation in the presence of d-flow. Consistent with these findings, inhibition of pre-miR712 increases expression of TIMP3 in cells, even when exposed to turbulent flow.
TIMP3 also decreases the expression of TNFα (a pro-inflammatory regulator) during turbulent flow.  Activity of TNFα in turbulent flow was measured by the expression of TNFα-converting enzyme (TACE) in blood. TNFα decreased if miR-712 was inhibited or TIMP3 overexpressed, suggesting that miR-712 and TIMP3 regulate TACE activity in turbulent flow conditions.
Anti-miR-712 effectively suppresses d-flow-induced miR-712 expression and increases TIMP3 expression. Anti-miR-712 also inhibits vascular hyperpermeability, thereby significantly reducing atherosclerosis lesion development and immune cell infiltration.
Human homolog microRNA-205.
The human homolog of miR-712 was found on the RN45s homolog gene, which maintains similar miRNAs to mice. MiR-205 of humans share similar sequences with miR-712 of mice and is conserved across most vertebrates. MiR-205 and miR-712 also share more than 50% of the cell signaling targets, including TIMP3.
When tested, d-flow decreased the expression of XRN1 in humans as it did in mice endothelial cells, indicating a potentially common role of XRN1 in humans.
Kidney disease.
Targeted deletion of Dicer in the FoxD1-derived renal progenitor cells in a murine model resulted in a complex renal phenotype including expansion of nephron progenitors, fewer renin cells, smooth muscle arterioles, progressive mesangial loss and glomerular aneurysms. High throughput whole transcriptome profiling of the FoxD1-Dicer knockout mouse model revealed ectopic upregulation of pro-apoptotic gene, Bcl2L11 (Bim) and dysregulation of the p53 pathway with increase in p53 effector genes including Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a. p53 protein levels remained unchanged, suggesting that FoxD1 stromal miRNAs directly repress p53-effector genes. Using a lineage tracing approach followed by Fluorescent-activated cell sorting, miRNA profiling of the FoxD1-derived cells not only comprehensively defined the transcriptional landscape of miRNAs that are critical for vascular development, but also identified key miRNAs that are likely to modulate the renal phenotype in its absence. These miRNAs include miRs‐10a, 18a, 19b, 24, 30c, 92a, 106a, 130a, 152, 181a, 214, 222, 302a, 370, and 381 that regulate Bcl2L11 (Bim) and miRs‐15b, 18a, 21, 30c, 92a, 106a, 125b‐5p, 145, 214, 222, 296‐5p and 302a that regulate p53-effector genes. Consistent with the profiling results, ectopic apoptosis was observed in the cellular derivatives of the FoxD1 derived progenitor lineage and reiterates the importance of renal stromal miRNAs in cellular homeostasis.
Nervous system.
miRNAs appear to regulate the development and function of the nervous system. Neural miRNAs are involved at various stages of synaptic development, including dendritogenesis (involving miR-132, miR-134 and miR-124), synapse formation and synapse maturation (where miR-134 and miR-138 are thought to be involved). Some studies find altered miRNA expression in Alzheimer's disease, as well as schizophrenia, bipolar disorder, major depression and anxiety disorders.
Stroke.
According to the Center for Disease Control and Prevention, Stroke is one of the leading causes of death and long-term disability in America. 87% of the cases are ischemic strokes, which results from blockage in the artery of the brain that carries oxygen-rich blood. The obstruction of the blood flow means the brain cannot receive necessary nutrients, such as oxygen and glucose, and remove wastes, such as carbon dioxide. miRNAs plays a role in posttranslational gene silencing by targeting genes in the pathogenesis of cerebral ischemia, such as the inflammatory, angiogenesis, and apoptotic pathway.
Alcoholism.
The vital role of miRNAs in gene expression is significant to addiction, specifically alcoholism. Chronic alcohol abuse results in persistent changes in brain function mediated in part by alterations in gene expression. miRNA global regulation of many downstream genes deems significant regarding the reorganization or synaptic connections or long term neural adaptations involving the behavioral change from alcohol consumption to withdrawal and/or dependence. Up to 35 different miRNAs have been found to be altered in the alcoholic post-mortem brain, all of which target genes that include the regulation of the cell cycle, apoptosis, cell adhesion, nervous system development and cell signaling. Altered miRNA levels were found in the medial prefrontal cortex of alcohol-dependent mice, suggesting the role of miRNA in orchestrating translational imbalances and the creation of differentially expressed proteins within an area of the brain where complex cognitive behavior and decision making likely originate.
miRNAs can be either upregulated or downregulated in response to chronic alcohol use. miR-206 expression increased in the prefrontal cortex of alcohol-dependent rats, targeting the transcription factor brain-derived neurotrophic factor (BDNF) and ultimately reducing its expression. BDNF plays a critical role in the formation and maturation of new neurons and synapses, suggesting a possible implication in synapse growth/synaptic plasticity in alcohol abusers. miR-155, important in regulating alcohol-induced neuroinflammation responses, was found to be upregulated, suggesting the role of microglia and inflammatory cytokines in alcohol pathophysiology. Downregulation of miR-382 was found in the nucleus accumbens, a structure in the basal forebrain significant in regulating feelings of reward that power motivational habits. miR-382 is the target for the dopamine receptor D1 (DRD1), and its overexpression results in the upregulation of DRD1 and delta fosB, a transcription factor that activates a series of transcription events in the nucleus accumbens that ultimately result in addictive behaviors. Alternatively, overexpressing miR-382 resulted in attenuated drinking and the inhibition of DRD1 and delta fosB upregulation in rat models of alcoholism, demonstrating the possibility of using miRNA-targeted pharmaceuticals in treatments.
Obesity.
miRNAs play crucial roles in the regulation of stem cell progenitors differentiating into adipocytes. Studies to determine what role pluripotent stem cells play in adipogenesis, were examined in the immortalized human bone marrow-derived stromal cell line hMSC-Tert20. Decreased expression of miR-155, miR-221, and miR-222, have been found during the adipogenic programming of both immortalized and primary hMSCs, suggesting that they act as negative regulators of differentiation. Conversely, ectopic expression of the miRNAs 155, 221, and 222 significantly inhibited adipogenesis and repressed induction of the master regulators PPARγ and CCAAT/enhancer-binding protein alpha (CEBPA). This paves the way for possible genetic obesity treatments.
Another class of miRNAs that regulate insulin resistance, obesity, and diabetes, is the let-7 family. Let-7 accumulates in human tissues during the course of aging. When let-7 was ectopically overexpressed to mimic accelerated aging, mice became insulin-resistant, and thus more prone to high fat diet-induced obesity and diabetes. In contrast when let-7 was inhibited by injections of let-7-specific antagomirs, mice become more insulin-sensitive and remarkably resistant to high fat diet-induced obesity and diabetes. Not only could let-7 inhibition prevent obesity and diabetes, it could also reverse and cure the condition. These experimental findings suggest that let-7 inhibition could represent a new therapy for obesity and type 2 diabetes.
Hemostasis.
miRNAs also play crucial roles in the regulation of complex enzymatic cascades including the hemostatic blood coagulation system. Large scale studies of functional miRNA targeting have recently uncovered rationale therapeutic targets in the hemostatic system.
Non-coding RNAs.
When the human genome project mapped its first chromosome in 1999, it was predicted the genome would contain over 100,000 protein coding genes. However, only around 20,000 were eventually identified. Since then, the advent of bioinformatics approaches combined with genome tiling studies examining the transcriptome, systematic sequencing of full length cDNA libraries and experimental validation (including the creation of miRNA derived antisense oligonucleotides called antagomirs) have revealed that many transcripts are non-protein-coding RNA, including several snoRNAs and miRNAs.
Viruses.
Viral microRNAs play an important role in the regulation of gene expression of viral and/or host genes to benefit the virus. Hence, miRNAs play a key role in host–virus interactions and pathogenesis of viral diseases. The expression of transcription activators by "human herpesvirus-6" DNA is believed to be regulated by viral miRNA.
Target prediction.
miRNAs can bind to target messenger RNA (mRNA) transcripts of protein-coding genes and negatively control their translation or cause mRNA degradation. It is of key importance to identify the miRNA targets accurately. A comparison of the predictive performance of eighteen "in silico" algorithms is available. Large scale studies of functional miRNA targeting suggest that many functional miRNAs can be missed by target prediction algorithms.


Microbacterium sediminis

Microbacterium sediminis is a Gram-positive, rod-shaped, aerobic, psychrotolerant, thermotolerant, halotolerant, alkalitolerant bacterium from the genus of Microbacterium which has been isolated from deep-sea sediments from the Indian Ocean.


List of Crash Bandicoot video games

"Crash Bandicoot" is a video game series created by Andy Gavin and Jason Rubin. It is published by Activision, Sierra Entertainment, Vivendi Universal Games, Konami, Universal Interactive Studios, King, and Sony Computer Entertainment, with entries developed by Polarbit, Toys for Bob, Beenox, Radical Entertainment, Vicarious Visions, Traveller's Tales, Eurocom, King and Naughty Dog. The series debuted in 1996 with the Sony PlayStation video game "Crash Bandicoot", premiered in North America on September 9, 1996. Most "Crash Bandicoot" games have either been platform games or released for Sony consoles and handhelds.
Most of the games in the franchise are platform games, although the series also includes other genres such as racing video games, party games and endless runners. Each game focuses on the titular protagonist Crash Bandicoot, an anthropomorphic orange bandicoot. It also features a large cast of other characters such as Doctor Neo Cortex, Aku Aku, Coco Bandicoot, Crunch Bandicoot, Doctor N. Gin, and Uka Uka. The latest game in the series is "", released on March 2021 for Android and iOS.


Robert Tranquillo

Robert T. Tranquillo is an American bioengineer, focusing in cardiovascular tissue engineering, currently the Distinguished McKnight University Professor at the University of Minnesota and at the University of Illinois at Urbana–Champaign, formerly the Shell Land Grant Chair, and is an Elected Fellow of the American Institute for Medical and Biological Engineering, International Academy of Medical and Biological Engineering and the Biomedical Engineering Society.
Early life and career.
Bob Tranquillo had obtained his Bachelor's degree from Pennsylvania State University in chemical engineering in 1979 and next year got his Master's from Stanford University in the same field. Four years later he completed his Ph.D. in chemical engineering at the University of Pennsylvania in 1986 and immediately became NATO Postdoctoral Fellow at the Center for Mathematical Biology at Oxford University. In 1987 he worked at the Department of Chemical Engineering and Materials Science at the University of Minnesota and in 2000 was the head of the Department of Biomedical Engineering at the same place.


D-glutamate oxidase

In enzymology, a D-glutamate oxidase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are D-glutamate, H2O, and O2, whereas its 3 products are 2-oxoglutarate, NH3, and H2O2.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH2 group of donors with oxygen as acceptor. The systematic name of this enzyme class is D-glutamate:oxygen oxidoreductase (deaminating). Other names in common use include D-glutamic oxidase, and D-glutamic acid oxidase. This enzyme participates in d-glutamine and d-glutamate metabolism.


SmeT

SmeT is a transcriptional repressor protein of 24.6 kDa found in the pathogen bacteria "Stenotrophomonas maltophilia". It is responsible for the regulation of the Multidrug Resistance system (MDR) SmeDEF and can increase or decrease the resistance of the bacteria to several antibiotics such as tetracycline, chloramphenicol, quinolones or erythromycin through binding to a specific region of the bacterial chromosome. Structurally SmeT forms 9 helices:α1, α2 and α3 are responsible for the DNA binding, α4, α5, α6 and α7 form the effector binding pocket and α8 and α9 allow the dimerization of the protein. SmeT is a member of the TetR family of Tetracycline repressors and its mechanism of repression is based in the binding of two dimmers to its cognate DNA.


Reticulocyte binding protein homologs

Reticulocyte binding protein homologs (RHs) are a superfamily of proteins found in "Plasmodium" responsible for cell invasion. Together with the family of erythrocyte binding-like proteins (EBLs) they make up the two families of invasion proteins universal to "Plasmodium". The two families function cooperatively.
This family is named after the reticulocyte binding proteins in "P. vivax", a parasite that only infects reticulocytes (immature red blood cells) expressing the Duffy antigen. Homologs have since been identified in "P. yoelii" and "P. reichenowi".
A "P. falciparum" protein complex called PfRH5-PfCyRPA-PfRipr (RCR) is known to bind basigin via the tip of RH5. The trimeric complex forms an elongated structure with RH5 and Ripr on distal ends and CyRPA in the middle. The RCR complex has been identified as a promising malaria vaccine target with each individual component capable of inducing strain transcending immunity in "in vitro" assays of parasite growth. Of the entire family of RHs, only RH5 appears to be essential for invasion and functions downstream of the other RHs during invasion.
PfRH4 is known to bind complement receptor 1.
RHs do not express any significant sequence feature for specific domains, except for a set of transmembrane helices at the C-terminal. From experimentation on partial proteins, RHs are known to contain enterocyte-binding and nucleotide-sensing domains (EBD and NBD) that may partially overlap. The structure of the EBD has been experimentally observed in 2011 by small angle X-ray scattering. A much better crystal structure for an N-terminal receptor-binding domain (presumably the same as EBD) was published in 2014.


Microsomal ethanol oxidizing system

The microsomal ethanol oxidizing system (MEOS) is an alternate pathway of ethanol metabolism that occurs in the smooth endoplasmic reticulum in the oxidation of ethanol to acetaldehyde. While playing only a minor role in ethanol metabolism in average individuals, MEOS activity increases after chronic alcohol consumption. The MEOS pathway requires the CYP2E1 enzyme, part of the cytochrome P450 family of enzymes, to convert ethanol to acetaldehyde. Ethanol’s affinity for CYP2E1 is lower than its affinity for alcohol dehydrogenase. It has delayed activity in non-chronic alcohol consumption states as increase in MEOS activity is correlated with an increase in production of CYP2E1, seen most conclusively in alcohol dehydrogenase negative deer mice.
The MEOS pathway converts ethanol to acetaldehyde by way of a redox reaction. In this reaction, ethanol is oxidized (losing two hydrogens) and O2 is reduced (by accepting hydrogen) to form H2O. NADPH is used as donor of hydrogen, forming NADP+. This process consumes ATP and dissipates heat, thus leading to the hypothesis that long term drinkers see an increase in resting energy expenditure.
The increase in rest energy expenditure has, according to some studies, been explained by indicating that the MEOS "expends" nine calories per gram of ethanol to metabolize versus 7 calories per gram of ethanol ingested. This results in a net loss of 2 calories per gram of ethanol ingested.


Checkered elephant shrew

The checkered elephant shrew or checkered sengi ("Rhynchocyon cirnei") is a species of elephant shrew in the family Macroscelididae.
Description.
Checked elephant shrews will grow to be around 25 - 30 centimeters long, excluding their tail, making them one of the longest elephant shrews. Their average tail length is slightly over 25 centimeters, which is slightly shorter than their body length. They commonly weigh around half a kilogram (1.1 pounds), but will sometimes grow to be about 0.7 kilogram (1.5 pounds). Their coat is usually a light to medium brown, but it can range from beige to dark brown. Their back contains alternating chestnut and lighter colors, creating a "checkered" pattern. Checkered elephant shrews also contain stripes on the sides of their body, which have a darker color than most of their body.
Range and habitat.
It is found in Democratic Republic of the Congo, Malawi, Mozambique, Tanzania, Uganda, Zambia, and possibly Central African Republic. Its natural habitats are subtropical or tropical dry forest, subtropical or tropical moist lowland forest, subtropical or tropical moist montane forest, and subtropical or tropical dry shrubland. It is threatened by habitat loss.
Behavior.
Checkered elephant shrews will mate for life. The pair of them will defend a territory of a few acres.
Diet.
The checkered elephant shrew is primarily an insectivore, eating termites, ants, beetles and centipedes. It also will eat mollusks, eggs and small mammals, amphibians and birds.


Retrogenix

Retrogenix is a UK biotechnology company that uses a human cell microarray system to identify cell surface receptors for antibodies and natural ligands as well as targets for small molecules in drug discovery. This protein expression technology is also used for off-target profiling of biologics during safety assessment in drug development.
Research and development.
The human cell microarray tool developed by Retrogenix utilises a library of expression vectors containing open reading frames (ORFs) encoding full-length human plasma membrane proteins, as well as a green fluorescent protein (GFP). Each vector is combined with a lipid and the complexes are spotted in precise locations on specialized slides. Reverse transfection of human cells which are grown on the microarray slides results in over-expression of each membrane protein located over its respective vector spot. Expression of GFP acts as a control to ensure transfection efficiency as well as confirming positioning of the spot co-ordinates. Putative receptor targets are identified by assessing gain-of-binding when a test ligand is applied to the cell microarrays. Further tests determine whether the receptor ‘hit’ is reproducible and to confirm specificity to the test ligand.
Currently, more than 4,500 proteins are simultaneously expressed in the cell microarray system for individual screening. The human expression system allows for correct folding and localisation at the surface of the cell and there are documented cases of biological interactions that are mediated by post-translational modifications being detected using the technology.
Applications in medical research.
The cell microarray technology identifies targets and receptors that are important in the understanding of normal biological and disease processes. Diverse ligands can be screened using the technology which has led to the discovery of key receptors for malaria proteins and targets that mediate virus binding to human cells.
Target deconvolution.
Cell microarray screening identifies the receptors for biologic molecules that have been selected through phenotypic screening. Notably, in studies led by Medimmune, the technology identified disease-relevant cell surface antigens of promising phenotypic molecules including the identification of TNFR2 as a potential target for cancer immunotherapy.
Off-target profiling.
Cell microarray off-target profiling assesses the specificity of ligands, either prior to clinical testing or to uncover the mechanism of action for an observed adverse event or an unexpected pharmacokinetic profile.
Awards.
Retrogenix has twice won the Queen's Awards for Enterprise. The first award was granted for innovation in 2015. This was followed by an award for international trade in 2017.


Ub-AMC

Ubiquitin-AMC is a fluorogenic substrate for a wide range of deubiquitinating enzymes (DUBs), including ubiquitin C-terminal hydrolases (UCHs) and ubiquitin specific proteases (USPs). It is a particularly useful reagent for the study of deubiquitinating activity where detection sensitivity or continuous monitoring of activity is essential.
Background.
Ubiquitin-AMC is prepared by the C-terminal derivatization of ubiquitin with 7-amino-4-methylcoumarin and has been shown to be a useful and sensitive fluorogenic substrate for wide range of deubiquitinylating enzymes (DUBs), including ubiquitin C-terminal hydrolases (UCHs) and ubiquitin specific proteases (USPs).
Ubiquitin-AMC has been shown to be a sensitive substrate for UCH-L3 (Km = 0.039µM) and for Isopeptidase-T (Km = 0.17-1.4µM), and is particularly useful for studying deubiquitinylating activity where detection sensitivity or continuous monitoring of activity is essential.
Typical assay set-up: Assay substrate concentration: 0.01-1.0µM. Enzyme concentrations, UCH-L3: 10-100pM, isopeptidase-T: 10-100nM. Release of AMC fluorescence by DUB enzymes can be monitored using 380 nm excitation and 460 nm emission wavelengths.


Universal Inhumans


J. Heinrich Matthaei

J. Heinrich Matthaei (born 4 May 1929) is a German biochemist. He is best known for his unique contribution to solving the genetic code on 15 May 1961. Whilst a post-doctoral visitor in the laboratory of Marshall Warren Nirenberg at the NIH in Bethesda, Maryland, he discovered that a synthetic RNA polynucleotide, composed of a repeating uridylic acid residue, coded for a polypeptide chain encoding just one kind of amino acid, phenylalanine. In scientific terms, he discovered that polyU codes for polyphenylalanine and hence the coding unit for this amino acid is composed of a series of Us or, as we now know the genetic code is read in triplets, the codon for phenylalanine is UUU. This single experiment opened the way to the solution of the genetic code. It was for this and later work on the genetic code for which Nirenberg shared the Nobel Prize for Medicine and Physiology. In addition, Matthaei and his co-workers in the following years published a multitude of results concerning the early understanding of the form and function of the genetic code.
Why Matthaei, who personally deciphered the genetic code, was excluded from this scientific prize is one of the Nobel Prize controversies.
Later, Matthaei was a member of the Max Planck Society in Göttingen.


Smallpox Hospital

The Smallpox Hospital, sometimes referred to as the Renwick Smallpox Hospital and later the Maternity and Charity Hospital Training School, was a
hospital located on Roosevelt Island in Manhattan, New York City. Originally designed by architect James Renwick Jr., the 100-bed hospital opened in 1856, when the area was known as Blackwell's Island.
A century after it opened, the hospital was closed, and the building eventually fell into disrepair. It was listed on the National Register of Historic Places in 1972 and designated a New York City Landmark four years later, the only ruin in the city with that designation. After the completion of an ongoing $4.5 million stabilization project, the Smallpox Hospital ruins will be open to the public.
Building.
The hospital is situated at the southern tip of the island, adjacent to Franklin D. Roosevelt Four Freedoms Park. Renwick designed the main building. The south wing, built in 1903-04, was designed by York & Sawyer, while the north wing (1904–05) was designed by Renwick, Aspinwall & Owen. When completed, it was a three-story, nine-bay U-shaped structure faced in granite veneer in a random ashlar pattern over load-bearing rubble masonry. The central block has a hipped roof, with corbeled crenelated parapets on the projecting sections, with a simple cornice on the non-projecting sections. Crenelated polygonal chimneys rise from the southeast side of the main block. The two wings, which project from the ends of the northwest (front) facade, had mansard roofs.
At the center of the front facade is the main entrance. It has a porch open on three sides, oriel window above and projecting corbeled feature above the roofline. A wide pointed arch holds the main entrance. Though designed in the Gothic Revival style, all of the windows on the third floor have pointed arches rather than curves, unusual for that architectural style.
History.
Hospital and school.
Despite the availability of the smallpox vaccine, New York City still had large outbreaks of the disease, in part because of the arrival of infected immigrants. Located on the isolated southern tip of the island in an attempt to quarantine patients, the hospital contained a large charity ward in addition to private rooms on the upper floors. In 1875, the hospital closed and became a training center for nurses attached to City Hospital, later renamed Charity Hospital. Renwick designed the building in the Gothic Revival style, and in 1903-1905, two wings with the same architectural theme were added to the school, named the Home for the Nurses and the Maternity and Charity Hospital Training School, to accommodate the growing student base. In deference to the changing use of the island, in 1921 Blackwell's Island was renamed Welfare Island, and many of the structures there fell into disrepair as they became obsolete. In the 1950s, both Charity Hospital and the nurses school were closed, and their operations moved to new buildings in Queens.
"Renwick Ruin".
Both buildings fell into disrepair, eventually becoming ruins. In the 1970s, architect Giorgio Cavaglieri inspected them both, making plans to reinforce the walls of the Smallpox Hospital. In 1972, the hospital was added to the National Register of Historic Places, making it New York City's "only landmarked ruin." In 1973, Welfare Island was renamed as Roosevelt Island after former President Franklin D. Roosevelt. Often referred to as the Renwick Ruin, the Neo-Gothic ruins have been illuminated nightly since 1995, in a somewhat successful effort to raise funds for stabilizing the structure. However, on December 26, 2007, a section of the north wing collapsed, adding an urgency to preservation plans. On May 28, 2009, ground was broken on the Franklin D. Roosevelt Four Freedoms Park, which includes plans to stabilize the Smallpox Hospital, a memorial to Franklin D. Roosevelt, and a public area. After a $4.5 million stabilization project, the Smallpox Hospital ruins will be open to the public.
According to the "AIA Guide to New York City", the remains of the Smallpox Hospital have the quality that architectural historian Paul Zucker, in his 1968 book "Fascination of Decay", ascribed to ruins in general: "[A]n expression of an eerie romantic mood ... a palpable documentation of a period in the past ... something which recalls a specific concept of architectural space and proportion." The New York City Landmarks Preservation Commission, in its 1976 report designating the ruins a New York City landmark, speculated that "The Smallpox Hospital could easily become the American equivalent of the great Gothic ruins of England, such as the late 13th century Tintern Abbey in Monmouthshire, which has been admired and cherished since the 18th century as a romantic ruin," and described the building as "a picturesque ruin, one that could readily serve as the setting for a 19th century Gothic romance."
In popular culture.
In "City of Bones", Renwick Smallpox Hospital was used by Valentine Morgenstern and other members of The Circle as a hideout. The hospital contained one of only two portals in New York City, which were both later destroyed.
Ruins of a similar hospital feature prominently in the video game "Grand Theft Auto IV", set in a fictional city called Liberty City, which is based on New York City.
The hospital was taken over by an evil witch and her minions in issues three through five of the Marvel Comics series "Patsy Walker A.K.A. Hellcat".
The hospital was depicted in the 2002 Marvel Comics movie "Spider-Man" in the film's climactic scene.
The hospital was featured in the 1993 movie, "For Love or Money" starring Michael J. Fox. The main character, "Doug" wanted to turn it into the "River House Hotel".
References.
Notes


Yellow golden mole

The yellow golden mole ("Calcochloris obtusirostris") is a species of mammal in the family Chrysochloridae. It is found in Mozambique, South Africa, and Zimbabwe. Its natural habitats are subtropical or tropical dry forest, subtropical or tropical moist lowland forest, dry savanna, moist savanna, arable land, pastureland, plantations, and rural gardens.
Yellow golden moles are likely to dig at the base of trees and create underground "nest" in which they forage for food. Its diet mainly consists of insects, bugs, small lizards, flies, and other tiny animals found underground.
Conservation Status.
This species has been classified as NT(Near Threatened).


Shantha Biotechnics

Shantha Biotechnics Limited is an Indian biotechnology company headquartered in Hyderabad, India. It is the first Indian company to develop, manufacture and market recombinant human healthcare products in India. The company is a wholly owned subsidiary of Sanofi group.
Shantha Biotechnics caters to major international markets including Asia-Pacific, Africa, Commonwealth of Independent States, and Latin America in addition to international organisations UNICEF and PAHO.
History.
Shantha Biotechnics, Ltd. began with the initiatives of Dr. K. I. Varaprasad Reddy and Khalil Ahmed. Varaprasad and Ahmed established the company in 1993 to produce affordable drugs for the general population, while maintaining international standards in quality. The project originated as an R&D project at Osmania University under the industry-university interactive programme in 1993, and later operated from the Center for Cellular and Molecular Biology until an independent research and development facility was built.
In 2006 the European biotech major Mérieux Alliance bought a 60% stake in Shantha Biotechnics at a valuation of $175 million.
In 2009, the vaccine division of French pharmacological company Sanofi Pasteur acquired the stake held by Mérieux Alliance, valuing Shantha Biotech at Euro 550 million (over Rs 3,770 crore).
Over time, Sanofi acquired a further stake in Shantha Biotechnics and in 2013 acquired 100% of the company.
Products.
Drugs developed by Shantha include SHANVAC-B, SHANFERON, SHANKINASE, SHANPOIETIN, pediatric combination vaccines Shantetra and Shan5, SHAN HIB-DPT, SHAN HIB and SHANTT.
Insuman cartridges project.
The main object of the Insuman Cartridges Project is to produce insulin at a lower cost. It is in Medak district, Telangana. The project cost is 460 crore.


Symbescaline

Symbescaline, or 3,5-diethoxy-4-methoxyphenethylamine, is a lesser-known psychedelic drug. It is an isomer of asymbescaline. Symbescaline was first synthesized by Alexander Shulgin. In his book "PiHKAL (Phenethylamines i Have Known And Loved)", the dosage is listed as 240 mg, and the duration listed as unknown. Symbescaline causes few effects, which include alertness and a threshold. Very little data exists about the pharmacological properties, metabolism, and toxicity of symbescaline.


Flg-Rhizobiales RNA motif

The "flg"-Rhizobiales RNA motif is an RNA structure that is conserved in certain bacteria. All known "flg"-Rhizobiales RNAs are located in the presumptive 5' untranslated regions of operons that contain genes whose functions relate to the creation of flagellar basal bodies. The "flg"-Rhizobiales RNAs are restricted to the Rhizobiales, an order of alphaproteobacteria, although only some Rhizobiales bacterial are predicted to use "flg"-Rhizobiales RNAs. The exact function of these RNAs is unknown, although it is hypothesized that they have a "cis"-regulatory function in controlling expression of the downstream operons.


Thioproscaline

Thioproscaline, or 3,5-dimethoxy-4-propylthiophenethylamine, is a lesser-known psychedelic drug. It is the 4-propylthio analog of mescaline. Thioproscaline was first synthesized by Alexander Shulgin. In his book "PiHKAL (Phenethylamines i Have Known And Loved)", the dosage range is listed as 20–25 mg, and the duration listed as 10–15 hours. Thioproscaline causes closed-eye visuals, slight open-eye visuals, and a body load. Very little data exists about the pharmacological properties, metabolism, and toxicity of thioproscaline.


Membrane vesicle trafficking

Membrane vesicle trafficking in "eukaryotic" animal cells involves movement of important biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific 'release' locations on the inside of the plasma membrane of the secretory cell, in the form of Golgi membrane-bound micro-sized vesicles, termed "membrane vesicles" (MVs). In this process, the 'packed' cellular products are released/secreted outside the cell across its plasma membrane. However, this vesicular membrane is retained and recycled by the secretory cells. This phenomenon has a key role in synaptic neurotransmission, endocrine secretion, mucous secretion, granular-product secretion by neutrophils, etc. The scientists behind this discovery were awarded Nobel prize for the year 2013.
In the "prokaryotic" gram-negative bacterial cells, membrane vesicle trafficking is mediated via bacterial outer membrane bounded nano-sized vesicles, called bacterial outer membrane vesicles (OMVs). In this case, however, the OMV membrane is secreted as well, along with OMV-contents to outside the secretion-active bacterium. This phenomenon has a key role in host-pathogen interactions, endotoxic shock in patients, invasion and infection of animals/plants, inter-species bacterial competition, quorum sensing, exocytosis, etc.
Movement within eukaryotic cells.
Once vesicles are produced in the endoplasmic reticulum and modified in the golgi body they make their way to a variety of destinations within the cell. Vesicles first leave the golgi body and are released into the cytoplasm in a process called budding. Vesicles are then moved towards their destination by motor proteins. Once the vesicle arrives at its destination it joins with the bi-lipid layer in a process called fusion, and then releases its contents.
Budding.
Receptors embedded in the membrane of the golgi body bind specific cargo (such as dopamine) on the lumenal side of the vesicle. These cargo receptors then recruit a variety of proteins including other cargo receptors and coat proteins such as clathrin, COPI and COPII. As more and more of these coating proteins come together, they cause the vesicle to bud outward and eventually break free into the cytoplasm. The coating proteins are then shed into the cytoplasm to be recycled and reused.
Motility between cell compartments.
For movement between different compartments within the cell, vesicles rely on the motor proteins myosin, kinesin (primarily anterograde transport) and dynein (primarily retrograde transport). One end of the motor proteins attaches to the vesicle while the other end attaches to either microtubules or microfilaments. The motor proteins then move by hydrolyzing ATP, which propels the vesicle towards its destination.
Docking and Fusion.
As a vesicle nears its intended location, RAB proteins in the vesicle membrane interact with docking proteins at the destination site. These docking proteins bring the vesicle in closer to interact with the SNARE Complex found in the target membrane. The SNARE complex reacts with synaptobrevin found on the vesicle membrane. This forces the vesicle membrane against the membrane of the target complex (or the outer membrane of the cell) and causes the two membranes to fuse. Depending on whether the vesicle fuses with a target complex or the outer membrane, the contents of the vesicle are then released either into the target complex or outside the cell.
Examples In eukaryotes.
All these types (1-4) of modes of membrane vesicle trafficking, taking place in eukaryotic cells have been explained diagrammatically.
In prokaryotes.
Unlike in eukaryotes, membrane vesicular trafficking in prokaryotes is an emerging area in interactive biology for intra-species (quorum sensing) and inter-species signaling at host-pathogen interface, as prokaryotes lack internal membrane-compartmentalization of their cytoplasm.
For more than four decades, cultures of gram negative microbes revealed the presence of nanoscale membrane vesicles. A role for membrane vesicles in pathogenic processes has been suspected since the 1970s, when they were observed in gingival plaque by electron microscopy. These vesicles were suspected to promote bacterial adhesion to the host epithelial cell surface. Their role in invasion of animal host cells "in vivo" was then demonstrated. In inter-bacterial interactions, OMVs released by "Pseudomonas aeruginosa" microbes were shown to fuse with outer membrane of other gram negative microbes causing their bacteriolysis; these OMVs could lyse gram-positive microbes as well. Role of OMVs in "Helicobacter pylori" infection of "human" primary antral epithelial cells, as model that closely resembles human stomach, has also been confirmed VacA-containing OMVs could also be detected in human gastric mucosa, infected with "H. pylori.". "Salmonella" OMVs were also shown to have direct role in invasion of chicken ileal epithelial cells "in vivo" in the year, 1993 (ref 4) and later, in hijacking of defense macrophages into sub-service for pathogen replication and consequent apoptosis of infected macrophages in typhoid-like animal infection. These studies brought the focus on OMVs into "membrane vesicle trafficking" and showed this phenomenon as involved in multifarious processes like genetic transformation, quorum sensing, competition arsenal among microbes, etc., and invasion, infection, immuno-modulation, etc., of animal hosts. A mechanism has already been proposed for generation of OMVs by gram negative microbes involving, expansion of pockets of periplasm (named, "periplasmic organelles") due to accumulation of bacterial cell secretions and their pinching off as outer membrane bounded vesicles (OMVs) on the lines of a 'soap bubble' formation with a bubble tube, and further fusion or uptake of diffusing OMVs by host/target cells (Fig. 2).
In conclusion, "membrane vesicle trafficking" via OMVs of Gram-negative organisms, cuts across species and kingdoms - including plant kingdom - in the realm of cell-to-cell signaling.


Katherine Philips

Katherine or Catherine Philips (1 January 1631/2 – 22 June 1664), also known as "The Matchless Orinda", was an Anglo-Welsh royalist poet, translator, and woman of letters. She achieved renown as a translator of Pierre Corneille's "Pompée" and "Horace", and for her editions of poetry after her death. She was highly regarded by many notable later writers, including John Dryden and John Keats, as being influential.
Early years.
Born in London, Katherine Philips was daughter of John Fowler, a Presbyterian cloth merchant of Bucklersbury, near the river in the City of London, and of Katherine Oxenbridge, whose father worked in the medical profession. Philips, it seems, had a strong memory and was intellectually advanced, and was, according to a cousin of hers, able to read the Bible before the age of four. Additionally, she acquired remarkable fluency in several languages. After her father's death, she moved to Wales with her newly married mother.  She attended boarding school from 1640 to 1645 where she began to write verse within a circle of friends and to appreciate French romances and Cavalier plays from which she would later choose many of the pet names she gave to members of her Society of Friendship. This school, run by a Mrs Salmon, was in Hackney, a hotbed of female education at the time.
Philips also broke with Presbyterian traditions, in both religion and politics, by becoming a member of the Church of England, as well as an ardent admirer of the king and his policy.
In 1647, when she was sixteen, Katherine Fowler married Welsh Parliamentarian James Philipps. James Philips' age has been the subject of some dispute, as he was long thought to be 54 years old on their wedding day, thus making him 38 years Katherine's senior. However, it seems their recovered marriage certificate has since shown that James Philips was actually only 24 years old at the time of their union. The couple had two children, including a son named Hector who did not live past infancy. He was buried in London in 1655. Hector's death was the subject of some of Philips' later poems, such as "Epitaph on Hector Philips" and "On the Death of my First and Dearest Childe."
Life and career.
The Society of Friendship had its origins in the cult of Neoplatonic love imported from the continent in the 1630s by Charles I's French wife, Henrietta Maria. Members adopted pseudonyms drawn from French pastoral romances of Cavalier dramas. Philips dramatised in her Society of Friendship the ideals, as well as the realities and tribulations, of Platonic love. Thus the Society helped establish a literary standard for her generation and Orinda herself as a model for the female writers who followed her. Her home at the Priory, Cardigan, Wales became the centre of the Society of Friendship, the members of which were known to one another by pastoral names: Philips was "Orinda", her husband "Antenor", and Sir Charles Cotterel "Poliarchus". "The Matchless Orinda", as her admirers called her, was regarded as the apostle of female friendship, and inspired great respect. She was widely considered an exemplar of the ideal woman writer: virtuous, proper, and chaste. She was frequently contrasted to the more daring Aphra Behn, to the latter's detriment. Her poems, frequently occasional, typically celebrate the refined pleasures of platonic love. Jeremy Taylor in 1659 dedicated to her his "Discourse on the Nature, Offices and Measures of Friendship", and Cowley, Henry Vaughan the Silurist, the Earl of Roscommon and the Earl of Cork and Orrery all celebrated her talent.
In 1662 she went to Dublin to pursue her husband's claim to certain Irish estates, which, due to her late father's past monetary investments in the British military, they were in danger of losing. There she completed a translation of Pierre Corneille's "Pompée", produced with great success in 1663 in the Smock Alley Theatre, and printed in the same year both in Dublin and London, under the title "Pompey". Although other women had translated or written dramas, her translation of "Pompée" broke new ground as the first rhymed version of a French tragedy in English and the first English play written by a woman to be performed on the professional stage. In 1664, an edition of her poetry entitled "Poems by the Incomparable Mrs. K.P." was published; this was an unauthorised edition that made several grievous errors. In March 1664, Philips travelled to London with a nearly completed translation of Corneille's "Horace", but died of smallpox. She was buried in the church of St Benet Sherehog, later destroyed in the Great Fire of London.
Reception and legacy.
After her death, in 1667 an authorised edition of her poetry was printed entitled "Poems by the Most Deservedly Admired Mrs. Katherine Philips, the Matchless Orinda". The edition included her translations of "Pompée" and "Horace".
Edward Phillips, nephew of John Milton, placed Katherine Philips high above Aphra Behn, writing in "Theatrum poetarum" (1675), a list of the chief poets of all ages and countries, that she was "the most applauded...Poetess of our Nation".
The literary atmosphere of her circle is preserved in the excellent "Letters of Orinda to Poliarchus", published by Bernard Lintot in 1705 and 1709. Poliarchus (Sir Charles Cotterell) was master of the ceremonies at the court of the Restoration, and afterwards translated the romances of La Calprenède. Philips had two children, one of whom, Katharine, became the wife of a "Lewis Wogan" of Boulston, Pembrokeshire. According to Gosse, Philips may have been the author of a volume of "Female Poems ... written by Ephelia", which are in the style of Orinda, though other scholars have not embraced this attribution.
Philips's translations and poems consider questions of political authority and express her royalist beliefs. Her work also considers the nature and value of friendship between women. There has been speculation over whether her work could be described as lesbian. Certainly her representations of female friendship are intense, even passionate. She herself always insisted on their platonic nature and characterises her relationships as the "meeting of souls," as in these lines from "To my Excellent Lucasia, on our Friendship":
<poem>
For as a watch by art is wound
To motion, such was mine;
But never had Orinda found
A soul till she found thine;
Which now inspires, cures, and supplies,
And guides my darkened breast;
For thou art all that I can prize,
My joy, my life, my rest. (9–16)
</poem>
Harriette Andreadis has argued that 'her manipulations of the conventions of male poetic discourse constitute a form of lesbian writing.' However, there are many critics who do not believe Philips's poetry is indicative of her sexuality. For example, in discussing "To the Excellent Lucasia" Mark Llewellyn argues that the image portrayed by the speaker is "stripped of all sensual appetite, could become the pathway to apprehension of, and eventually mystic union with, divine love and beauty" (447). Andreadis says, "friendship here is no less than the mingling of souls, the intimacy of hearts joined in secret and holding each other's secrets, sublimely elevating the friends to such ecstasies that they pity the mundane pleasures and powers of worldly rulers" (529).
"Upon the Double Murder of King Charles" is a more politically minded piece than many of her others from this time period, although she is often associated with a class of poets termed Royalist or Cavalier poets, noting their political sympathy to the Royalist cause, those who supported the monarchy of King Charles I of England during the English Civil War and the following English Interregnum.
Influences.
She inspired the figure of "Orinda", elderly widow, hypersensitive to matters of love, and she herself a victim of love (albeit platonic) for a woman, in the Italian tragedy of 1671 "Il Cromuele" (Cromwell) written by Girolamo Graziani, set in England during the Civil War.
Premiere of "Pompey".
On 10 February 1663 Philips premiered her adaptation of the French verse tragedy, Pierre Corneille's, "Pompée" at Smock Alley. The opening night was notable for its political undertones, as well as having the Lord Lieutenant of Ireland in the audience. It also had theatre goers of all classes in attendance. Some Catholic, loyal to the monarchy after the war and desiring to acquire their lands back for their families. Others in the audience were Protestant and felt entitled to these same lands based on the promises made to them. Due to Ireland's tense political climate, the theatre was a welcomed escape from these politically complicated Catholic/Protestant relations, following the English Civil War and the Cromwellian conquest of Ireland. The play opened with a direct heroic couplet suggesting the idea of two rivals finding a successful compromise:"The "mighty Rivals, whose destructive Rage"
"Did the whole World in Civil Arms engage,"
"Are now agreed, and make it both their Choice,"
"To have their Fates determin'd by your Voice.""
The original speaker on opening night failed to mention specific details to the play which are in the script in this opening, allowing the audience to assume the text could be directed at the current political affairs. There are rumours that Phillips was either in the audience, or could have even been an actress in the play herself.
Sexuality.
There has been speculation among critics over Katherine Philips' sexuality, specifically in regards to the relationships she shared with some of her female friends. Literary critics have often highlighted suggestions of female intimacy and eroticism within Philips' work. In fact, many of her poems were written for or about fellow Society of Friendship members Anne Owen and Mary Aubrey, who went by the names of Lucasia and Rosania, respectively. A series of letters exchanged by Philips and her friend Sir Charles Cotterell between 6 December 1661 and 17 May 1664 were recovered and published in 1705,  under the title "Letters from Orinda to Poliarchus."  Hints of Philips' affection for Owen can be found throughout this correspondence, notably within an exchange referring to Philips' attempt to convince Owen to marry Sir Charles in order to keep her nearby, as Owen was engaged at the time and planned to move to Dublin with one Marcus Trevor. This attempt would ultimately prove unsuccessful.


Frederick Lossing

Frederick Pettit Lossing was a Canadian chemist at the National Research Council in Ottawa. He was a prolific scientist and is mainly known for his contributions to mass spectrometry, the Fred P. Lossing Award awarded by the Canadian Society for Mass Spectrometry is named after him.
Lossing was born in Norwich and studied at the University of Western Ontario and obtained a PhD from McGill University in 1942. In 1946 he joined the National Research Council in Ottawa where he worked until his retirement in 1980. His work included measurements of the ionization energies of free radicals and thermochemistry.


Boris Kovatchev

Boris P. Kovatchev is a scientist at the University of Virginia, director of the UVA Center for Diabetes Technology, and a principal investigator of the JDRF Artificial Pancreas Project.
He and his team of more than 25 investigators at UVA have been working on the integration of continuous glucose monitors and insulin pumps to create a closed-loop system requiring little or no intervention by the user. He holds 38 patents for technology related to diabetes and blood glucose monitoring.
In 2008, he became the first mathematician to be awarded the international Diabetes Technology Leadership Award, presented by the Diabetes Technology Society, and in 2013, he was awarded the prestigious Gerold & Kayla Grodsky Basic Research Scientist Award for leadership and innovation in type 1 diabetes.
He received his Ph.D. in Mathematics from Sofia University, Bulgaria in 1989.


P-benzoquinone reductase (NADPH)

In enzymology, a p-benzoquinone reductase (NADPH) () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are NADPH, H+, and p-benzoquinone, whereas its two products are NADP+ and hydroquinone.
This enzyme belongs to the family of oxidoreductases, specifically those acting on NADH or NADPH with a quinone or similar compound as acceptor. The systematic name of this enzyme class is NADPH:p-benzoquinone oxidoreductase. This enzyme participates in gamma-hexachlorocyclohexane degradation.


Josias Lyndon

Josias Lyndon (March 10, 1704 – March 30, 1778) was a governor of the Colony of Rhode Island and Providence Plantations, serving for a single one-year term.
Biography.
Lyndon was the son of Samuel and Priscilla (Tompkins) Lyndon of Newport, the grandson of Josias Lyndon of Newport, and the great grandson of Augustin Lyndon, a shipwright in Boston in the Massachusetts Bay Colony. Lyndon married in 1727 Mary Carr, the daughter of Edward and Hannah (Stanton) Carr, and granddaughter of Governor Caleb Carr. The couple had no children.
In 1728 Lyndon was made a freeman of Newport, and having been educated in the Newport Grammar School, he became a scrivener (scribe) and went to work the same year as the Clerk of the Assembly, which he continued uninterrupted for nearly four decades until 1767. After serving a term as governor, he resumed this position again from 1770 until 1777, just before his death. As the recorder of colonial affairs, he became familiar with virtually every piece of legislation and every official manuscript written over a period of nearly half a century. At the time of Lyndon's election to governor in 1768, there was a lot of bitter acrimony between one camp led by Samuel Ward and the other camp led by Stephen Hopkins, both of whom had already served multiple terms as governor. Lyndon was elected almost unanimously as a peace and compromise candidate.
Most of Lyndon's year as governor was spent in correspondence with a representative of the King of England, expressing concerns of the colony over the unjust taxation brought about by the Stamp Act. Fifteen letters from the Colonial Secretary, Hillsborough, in London, and as many replies by Lyndon concerning the constitutional rights of the colony were the main business of this administration. The only act of importance during Lyndon's term was the valuation of the Rhode Island colony, an amount that came to a little more than two million pounds.
When war with Britain came to the colonies and Newport was occupied, Lyndon found safety in Warren, Rhode Island where he died of smallpox in 1778. He was buried in a cemetery on Serpentine Road, along the bank of the Kickamuit River in Warren.


Phycocyanobilin

Phycocyanobilin is a blue phycobilin, i.e., a tetrapyrrole chromophore found in cyanobacteria and in the chloroplasts of red algae, glaucophytes, and some cryptomonads. Phycocyanobilin is present only in the phycobiliproteins allophycocyanin and phycocyanin, of which it is the terminal acceptor of energy. It is covalently linked to these phycobiliproteins by a thioether bond.
Phycocyanobilin, PCB, has the ability to bind to human serum albumin, HSA, protein found mainly in the blood of humans. This PCB-HCA complex benefits the structure of HSA, increasing the thermal stability of HSA, as well as increasing its ability to prevent against proteolytic activity of other proteins.


John H. Hoffman

John Hoffman was a space scientist who developed instruments for Apollo 15, Apollo 16, Apollo 17, the Pioneer Venus project, and Giotto mission. He also designed the mass spectrometer for the Phoenix Mars Lander mission in May 2008. He was a professor of physics at the University of Texas at Dallas.
Education.
Hoffman received his bachelor's degree from St. Mary's College in Winona, Minnesota and continued his education at the University of Minnesota under the mentorship of Professor A. O. C. Nier who pioneered the field of mass spectrometry. His PhD dissertation was on the helium isotopic distribution in large iron meteorites.
Career.
Hoffman spent 7 years at the U. S. Naval Research Laboratory, Washington, D. C., developing miniaturized mass spectrometers for space flight. These were flown on Aerobee and Javelin rockets.
He joined the Graduate Research Center of the Southwest in 1966. His main interest was in the study of atmospheric/ionospheric composition and isotopic ratios for which he has developed instrument packages that have flown on many rockets and satellites.
Missions.
He developed instruments for the Apollos 15, 16, and 17 lunar missions, the latter being part of the ALSEP surface package. The goal was to detect and determine the composition of the lunar atmosphere. There is an atmosphere on the moon composed mainly of noble gases and hydrogen, but the pressure is lower than that in the best vacuum systems on earth. His instrument flew on the Pioneer Venus Multiprobe mission to Venus in 1978. Data was received throughout the descent of the probe to the surface. Carbon dioxide is the dominant gas in the atmosphere. A surprise discovery showed that for the two "sister" planets there is a two order of magnitude difference in the isotopic ratios (the ratio of the heavier to lighter forms of these gases) for hydrogen and argon than for those gases on earth. These isotopic ratio differences have had large implications on models of the nature of the solar nebula and the formation of the present (secondary) atmospheres of the terrestrial planets.
Hoffman was a member of the team who flew a mass spectrometer on the European Space Agency's Giotto mission to Halley's Comet in 1986. This instrument was developed by laboratories in four countries, three European and at UT Dallas. It measured both the neutral and ionized constituents of the comet's coma. The coma contains, besides water vapor and H30 ions, an extended source of carbon monoxide. The atmosphere forms around a comet as it comes near the sun and is heated by radiation from the sun.
Hoffman has also flown mass spectrometers on earth orbiting satellites, Explorer 31, ISIS-II, AE-C, D, and E, and Wake Shield, plus numerous sounding rockets and stratospheric balloon flights. The first observations of the polar wind, ions flowing out from the atmosphere, were made by his ion mass spectrometer flown on the ISIS spacecraft in 1971.
Hoffman was a co-investigator for the TEGA experiment that flew on the Mars Scout Phoenix mission that descended on Mars on May 25, 2008. The spacecraft will land in the far northern region of Mars, above the Arctic Circle in the area that the Mars Odyssey spacecraft has found evidence for water. An arm on the lander will dig a trench a meter deep in the surface of Mars to look for water ice and other water related substances (minerals). These will be scooped up and analyzed in a series of small furnaces. The effluents from the furnaces will be analyzed by the UT Dallas mass spectrometer to determine the presence of water and the mineralogical composition of soil samples. Isotopic ratios of the principal elements in the samples will be determined and compared to the isotopic ratios of the atmospheric gases that will be measured by the mass spectrometer when it is not analyzing samples from the TEGA furnaces.