Microphthalmia-associated transcription factor

Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the "MITF" gene.
MITF is a basic helix-loop-helix leucine zipper transcription factor involved in lineage-specific pathway regulation of many types of cells including melanocytes, osteoclasts, and mast cells. The term "lineage-specific", since it relates to MITF, means genes or traits that are only found in a certain cell type. Therefore, MITF may be involved in the rewiring of signaling cascades that are specifically required for the survival and physiological function of their normal cell precursors.
MITF, together with transcription factor EB (TFEB), TFE3 and TFEC, belong to a subfamily of related bHLHZip proteins, termed the MiT-TFE family of transcription factors. The factors are able to form stable DNA-binding homo- and heterodimers. The gene that encodes for MITF resides at the "mi" locus in mice, and its protumorogenic targets include factors involved in cell death, DNA replication, repair, mitosis, microRNA production, membrane trafficking, mitochondrial metabolism, and much more. Mutation of this gene results in deafness, bone loss, small eyes, and poorly pigmented eyes and skin. In human subjects, because it is known that MITF controls the expression of various genes that are essential for normal melanin synthesis in melanocytes, mutations of MITF can lead to diseases such as melanoma, Waardenburg syndrome, and Tietz syndrome. Its function is conserved across vertebrates, including in fishes such as zebrafish and "Xiphophorus".
An understanding of MITF is necessary to understand how certain lineage-specific cancers and other diseases progress. In addition, current and future research can lead to potential avenues to target this transcription factor mechanism for cancer prevention .
Clinical significance.
Mutations.
As mentioned above, changes in MITF can result in serious health conditions. For example, mutations of MITF have been implicated in both Waardenburg syndrome and Tietz syndrome.
Waardenburg syndrome is a rare genetic disorder. Its symptoms include deafness, minor defects, and abnormalities in pigmentation. Mutations in the MITF gene have been found in certain patients with Waardenburg syndrome, type II. Mutations that change the amino acid sequence of that result in an abnormally small MITF are found. These mutations disrupt dimer formation, and as a result cause insufficient development of melanocytes. The shortage of melanocytes causes some of the characteristic features of Waardenburg syndrome.
Tietz syndrome, first described in 1923, is a congenital disorder often characterized by deafness and leucism. Tietz is caused by a mutation in the MITF gene. The mutation in MITF deletes or changes a single amino acid base pair specifically in the base motif region of the MITF protein. The new MITF protein is unable to bind to DNA and melanocyte development and subsequently melanin production is altered. A reduced number of melanocytes can lead to hearing loss, and decreased melanin production can account for the light skin and hair color that make Tietz syndrome so noticeable.
Melanoma.
Melanocytes are commonly known as cells that are responsible for producing the pigment melanin which gives coloration to the hair, skin, and nails. The exact mechanisms of how exactly melanocytes become cancerous are relatively unclear, but there is ongoing research to gain more information about the process. For example, it has been uncovered that the DNA of certain genes is often damaged in melanoma cells, most likely as a result of damage from UV radiation, and in turn increases the likelihood of developing melanoma. Specifically, it has been found that a large percentage of melanomas have mutations in the B-RAF gene which leads to melanoma by causing an MEK-ERK kinase cascade when activated. In addition to B-RAF, MITF is also known to play a crucial role in melanoma progression. Since it is a transcription factor that is involved in the regulation of genes related to invasiveness, migration, and metastasis, it can play a role in the progression of melanoma. Figure 1 shows the specific activators and targets of MITF that are related to the survival, migration, proliferation, invasion and metastasis of melanoma cells.
Target genes.
MITF recognizes E-box (CAYRTG) and M-box (TCAYRTG or CAYRTGA) sequences in the promoter regions of target genes. Known target genes (confirmed by at least two independent sources) of this transcription factor include,
Additional genes identified by a microarray study (which confirmed the above targets) include the following,
The LysRS-Ap4A-MITF signaling pathway.
The LysRS-Ap4A-MITF signaling pathway was first discovered in mast cells, in which, the A mitogen-activated protein kinase (MAPK) pathway is activated upon allergen stimulation. The binding of immunoglobulin E to the high-affinity IgE receptor (FcεRI) provides the stimulus that starts the cascade.
Lysyl-tRNA synthetase (LysRS) normally resides in the multisynthetase complex. This complex consists of nine different aminoacyl-tRNA synthetases and three scaffold proteins and has been termed the "signalosome" due to its non-catalytic signalling functions. After activation, LysRS is phosphorylated on Serine 207 in a MAPK-dependent manner. This phosphorylation causes LysRS to change its conformation, detach from the complex and translocate into the nucleus, where it associates with the encoding histidine triad nucleotide–binding protein 1 (HINT1) thus forming the MITF-HINT1 inhibitory complex. The conformational change also switches LysRS activity from aminoacylation of Lysine tRNA to diadenosine tetraphosphate (Ap4A) production. Ap4A, which is an adenosine joined to another adenosine through a 5‘-5’tetraphosphate bridge, binds to HINT1 and this releases MITF from the inhibitory complex, allowing it to transcribe its target genes. Specifically, Ap4A causes a polymerization of the HINT1 molecule into filaments. The polymerization blocks the interface for MITF and thus prevents the binding of the two proteins. This mechanism is dependent on the precise length of the phosphate bridge in the Ap4A molecule so other nucleotides such as ATP or AMP will not affect it.
MITF is also an integral part of melanocytes, where it regulates the expression of a number of proteins with melanogenic potential. Continuous expression of MITF at a certain level is one of the necessary factors for melanoma cells to proliferate, survive and avoid detection by host immune cells through the T-cell recognition of the melanoma-associated antigen (melan-A). Post-translational modifications of the HINT1 molecules have been shown to affect MITF gene expression as well as the binding of Ap4A. Mutations in HINT1 itself have been shown to be the cause of axonal neuropathies.  The regulatory mechanism relies on the enzyme diadenosine tetraphosphate hydrolase, a member of the Nudix type 2 enzymatic family (NUDT2), to cleave Ap4A, allow the binding of HINT1 to MITF and thus suppress the expression of the MITF transcribed genes. NUDT2 itself has also been shown to be associated with human breast carcinoma, where it promotes cellular proliferation. The enzyme is 17 kDa large and can freely diffuse between the nucleus and cytosol explaining its presence in the nucleus. It has also been shown to be actively transported into the nucleus by directly interacting with the N-terminal domain of importin-β upon immunological stimulation of the mast cells. Growing evidence is pointing to the fact that the LysRS-Ap4A-MITF signalling pathway is in fact an integral aspect of controlling MITF transcriptional activity.
Activation of the LysRS-Ap4A-MITF signalling pathway by isoproterenol has been confirmed in cardiomyocytes. A heart specific isoform of MITF is a major regulator of cardiac growth and hypertrophy responsible for heart growth and for the physiological response of the cardiomyocytes to beta-adrenergic stimulation.
Phosphorylation.
MITF is phosphorylated on several serine and tyrosine residues. Serine phosphorylation is regulated by several signaling pathways including MAPK/BRAF/ERK, receptor tyrosine kinase KIT, GSK-3 and mTOR. In addition, several kinases including PI3K, AKT, SRC and P38 are also critical activators of MITF phosphorylation. In contrast, tyrosine phosphorylation is induced by the presence of the KIT oncogenic mutation D816V. This KITD816V pathway is dependent on SRC protein family activation signaling. The induction of serine phosphorylation by the frequently altered MAPK/BRAF pathway and the GSK-3 pathway in melanoma regulates MITF nuclear export and thereby decreasing MITF activity in the nucleus. Similarly, tyrosine phosphorylation mediated by the presence of the KIT oncogenic mutation D816V also increases the presence of MITF in the cytoplasm.
Interactions.
Most transcription factors function in cooperation with other factors by protein–protein interactions. Association of MITF with other proteins is a critical step in the regulation of MITF-mediated transcriptional activity. Some commonly studied MITF interactions include those with MAZR, PIAS3, Tfe3, hUBC9, PKC1, and LEF1. Looking at the variety of structures gives insight into MITF's varied roles in the cell.
The Myc-associated zinc-finger protein related factor (MAZR) interacts with the Zip domain of MITF. When expressed together, both MAZR and MITF increase promoter activity of the mMCP-6 gene. MAZR and MITF together transactivate the mMCP-6 gene. MAZR also plays a role in the phenotypic expression of mast cells in association with MITF.
PIAS3 is a transcriptional inhibiter that acts by inhibiting STAT3's DNA binding activity. PIAS3 directly interacts with MITF, and STAT3 does not interfere with the interaction between PIAS3 and MITF. PIAS3 functions as a key molecule in suppressing the transcriptional activity of MITF. This is important when considering mast cell and melanocyte development.
MITF, TFE3 and TFEB are part of the basic helix-loop-helix-leucine zipper family of transcription factors. Each protein encoded by the family of transcription factors can bind DNA. MITF is necessary for melanocyte and eye development and new research suggests that TFE3 is also required for osteoclast development, a function redundant of MITF. The combined loss of both genes results in severe osteopetrosis, pointing to an interaction between MITF and other members of its transcription factor family. In turn, TFEB has been termed as the master regulator of lysosome biogenesis and autophagy. Interestingly, MITF, TFEB and TFE3 separate roles in modulating starvation-induced autophagy have been described in melanoma. Moreover, MITF and TFEB proteins, directly regulate each other’s mRNA and protein expression while their subcellular localization and transcriptional activity are subject to similar modulation, such as the mTOR signaling pathway.
UBC9 is a ubiquitin conjugating enzyme whose proteins associates with MITF. Although hUBC9 is known to act preferentially with SENTRIN/SUMO1, an in vitro analysis demonstrated greater actual association with MITF. hUBC9 is a critical regulator of melanocyte differentiation. To do this, it targets MITF for proteasome degradation.
Protein kinase C-interacting protein 1 (PKC1) associates with MITF. Their association is reduced upon cell activation. When this happens MITF disengages from PKC1. PKC1 by itself, found in the cytosol and nucleus, has no known physiological function. It does, however, have the ability to suppress MITF transcriptional activity and can function as an in vivo negative regulator of MITF induced transcriptional activity.
The functional cooperation between MITF and the lymphoid enhancing factor (LEF-1) results in a synergistic transactivation of the dopachrome tautomerase gene promoter, which is an early melanoblast marker. LEF-1 is involved in the process of regulation by Wnt signaling. LEF-1 also cooperates with MITF-related proteins like TFE3. MITF is a modulator of LEF-1, and this regulation ensures efficient propagation of Wnt signals in many cells.
Translational regulation.
Translational regulation of MITF is still an unexplored area with only two peer-reviewed papers (as of 2019) highlighting the importance. During glutamine starvation of melanoma cells ATF4 transcripts increases as well as the translation of the mRNA due to eIF2α phosphorylation. This chain of molecular events leads to two levels of MITF suppression: first, ATF4 protein binds and suppresses MITF transcription and second, eIF2α blocks MITF translation possibly through the inhibition of eIF2B by eIF2α.
MITF can also be directly translationally modified by the RNA helicase DDX3X. The 5' UTR of MITF contains important regulatory elements (IRES) that is recognized, bound and activated by DDX3X. Although, the 5' UTR of MITF only consists of a nucleotide stretch of 123-nt, this region is predicted to fold into energetically favorable RNA secondary structures including multibranched loops and asymmetric bulges that is characteristics of IRES elements. Activation of this cis-regulatory sequences by DDX3X promotes MITF expression in melanoma cells.


Helix (genomics company)

Helix is an American population genomics company.
History.
Helix focuses on personal genomics and citizen science. Helix has a marketplace that offers applications created by approved partners. Helix handles sample collection, DNA sequencing, and secure data storage and partners develop on-demand products. Helix is headquartered in the San Francisco Bay Area and operates a sequencing laboratory in San Diego.
In 2016, Helix partnered with the National Geographic Society to sequence DNA for the Genographic Project.
In 2018, Helix partnered with the Desert Research Institute and Renown Institute of Health Innovation in support of the Healthy Nevada project, which offers free access to genomic sequencing to 40,000 residents of northern Nevada for health research.
Sequencing methodology.
Helix uses NGS to sequence a proprietary assay called Exome+, a version of Exome sequencing the company claims to provide 100 times more data than was previously available. Exome+ includes all 22,000 protein-coding genes as well as additional regions known to be of interest. All samples are processed in Helix’s CLIA- and CAP-accredited sequencing lab powered by Illumina NGS technology, using the Exome+ assay.


4-MeO-DMT

4-MeO-DMT (4-methoxy-"N","N"-dimethyltryptamine) is a tryptamine derivative which has some central activity in animal tests similar to that of related psychedelic tryptamine drugs, although with significantly lower potency than either 5-MeO-DMT or 4-hydroxy-DMT (psilocin).


Chen Yu-chie

Chen Yu-chie () is a Taiwanese chemist and is a Professor of Chemistry in the National Chiao Tung University, Hsinchu, Taiwan.  She received her Ph.D. from Montana State University (United States).
Research.
Chen's research interests include biological mass spectrometry, analytical nanotechnology, and nanobiotechnology.
Achievements.
Chen is the inventor of Ultrasonication-Assisted Spray Ionization (UASI),  as well as Contactless Atmospheric Pressure Ionization (Contactless API), and one of the inventors of the surface-assisted laser desorption/ionization (SALDI) techniques for mass spectrometric analysis of chemical molecules.


Yuichi Motai

Yuichi Motai is a Japanese researcher, professor, and book author. He serves as director of the Sensory Intelligence Laboratory at Virginia Commonwealth University (VCU) and as an associate professor of Electrical and Computer Engineering. Motai is a past professor at University of Vermont; He was a visiting faculty of Air Force Research Lab at Hanscom MA, and Harvard Medical School, Boston, MA.
Motai received his Ph.D at Purdue University, West Lafayette, Indiana, after completing his MS and BS education in Japan. He is a leader in the fields of Engineering Data. He published four books including "Data-variant kernel analysis", published in 2015 by John Wiley & Sons.
Research.
Motai's papers address fundamental and applied problems of sensory intelligence, which relate to specific application domains such as medical imaging, pattern recognition, computer vision, sensory-based robotic and biomedical applications. The majority of his 39 papers were published in "IEEE Transactions", in 1) sensory Intelligence, focused on 2) adaptive prediction and 3) online classification methodologies:
Specific applications such as Radiation Oncology and Radiology were chosen based on his collaborator's expertise.
Teaching.
Motai has offered more than 10 different courses. The 4 fields he teaches in are Pattern Recognition, Automatic Control, Dynamic and Multivariable Systems, Signals and Systems I
Motai also taught at the University of Vermont, offering classes in the fields of Sensory-based robotics, Computer vision, and Ubiquitous computing.


Rotigotine

Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS). It is formulated as a once-daily transdermal patch which provides a slow and constant supply of the drug over the course of 24 hours.
Like other dopamine agonists, rotigotine has been shown to possess antidepressant effects and may be useful in the treatment of depression as well.
History.
Rotigotine was first developed in 1985 as N-0437 by a team from the University of Groningen. Development was then continued by Aderis Pharmaceuticals. In 1998, Aderis licensed worldwide development and commercialization rights for rotigotine to the German pharmaceutical company Schwarz Pharma (today a subsidiary of the Belgian company UCB S.A.).
The drug was approved by the European Medicines Agency (EMA) for use in Europe in 2006. In 2007, the Neupro patch was approved by the Food and Drug Administration (FDA) as the first transdermal treatment of Parkinson's disease in the United States. In 2008, Schwarz Pharma recalled all Neupro patches in the United States and some in Europe because of problems with the delivery mechanism. The patch was reformulated, and was reintroduced in the United States in 2012.
Rotigotine was authorized as a treatment for restless legs syndrome in August 2008.
Side effects.
General side effects for rotigotine may include constipation, dyskinesia, nausea, vomiting, dizziness, fatigue, insomnia, somnolence, confusion, and hallucinations. More serious complications can include psychosis and impulse control disorders like hypersexuality, punding, and pathological gambling. Mild adverse skin reactions at the patch application site may also occur.
Pharmacology.
Rotigotine acts as a non-selective agonist of the dopamine D1, D2, D3, and, to a lesser extent, D4 and D5 receptors, with highest affinity for the D3 receptor. In terms of affinity, rotigotine has 10-fold selectivity for the D3 receptor over the D2, D4, and D5 receptors and 100-fold selectivity for the D3 receptor over the D1 receptor. In functional studies however, rotigotine behaves as a full agonist of D1, D2, and D3 with similar potencies (EC50). Its ability to activate both D1-like and D2-like receptors is similar to the case of apomorphine (which notably has greater efficacy in the treatment of Parkinson's disease than D2-like-selective agonists but has suboptimal pharmacokinetic properties) and pergolide but unlike pramipexole and ropinirole.
Rotigotine possesses the following "in vitro" receptor binding profile:
All affinities listed were assayed using human materials except that for α2B-adrenergic which was done with NG 108–15 cells. Rotigotine behaves as a partial or full agonist (depending on the assay) at all dopamine receptors listed, as an antagonist at the α2B-adrenergic receptor, and as a partial agonist at the 5-HT1A receptor. Though it has affinity for a large number of sites as shown above, at clinical doses rotigotine behaves mostly as a selective D1-like (D1, D5) and D2-like (D2, D3, D4) receptor agonist, with its α2B-adrenergic and 5-HT1A activity also possibly having some minor relevance.


Coenzyme F420 hydrogenase

In enzymology, a coenzyme F420 hydrogenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are H2 and coenzyme F420, whereas its product is reduced coenzyme F420.
This enzyme belongs to the family of oxidoreductases, specifically those acting on hydrogen as donor with other, known, acceptors. The systematic name of this enzyme class is hydrogen:coenzyme F420 oxidoreductase. Other names in common use include 8-hydroxy-5-deazaflavin-reducing hydrogenase, F420-reducing hydrogenase, and coenzyme F420-dependent hydrogenase. This enzyme participates in folate biosynthesis and is a critical part of energy conservation in some methanogens such as Methanosarcina barkeri. It has 3 cofactors: iron, nickel, and deazaflavin.


Prodigal Son (novel)

Prodigal Son is a novel by the best-selling author Dean Koontz, released in 2005. The book is the first book released by Koontz in a series of five, entitled "Dean Koontz's Frankenstein". The book was co-authored by Kevin J. Anderson.
Plot.
The basic plot follows New Orleans detective Carson and her partner Michael on the hunt for a serial killer dubbed "The Surgeon". Reports of this killer catch the attention of Deucalion, formerly known as The Monster, who believes his former master and maker, Dr. Victor Frankenstein, has returned. As the body count grows, the case takes a darker turn when Carson encounters Deucalion, pushing Carson and Michael on to the path of a 200-year-old mystery and evil that threatens more than just New Orleans.
Development.
The concept for the series was adapted from a treatment written by Koontz and Anderson for the 2004 TV movie "Frankenstein", which was produced for the USA Network. Koontz withdrew from the project over creative differences with the network, and the production continued in a different direction with similar characters and a modified plot while Koontz was allowed to publish his own series.
TV series.
In October 2012, the production company 1019 Entertainment announced they had purchased the rights to the entire Koontz Frankenstein book series. Plans were announced to develop it as a television series for TNT with writer James V. Hart and his son Jake Hart scripting the project.


Kurt Henseleit

Kurt Henseleit (1908–1973) was a student of and assistant to Hans Krebs. Between them they discovered the urea cycle (known also as the "Krebs-Henseleit cycle"), and developed the Krebs-Henseleit solution.


TRNA nucleotidyltransferase

In enzymology, a tRNA nucleotidyltransferase () is an enzyme that catalyzes the chemical reaction
where tRNA-N is a product of transcription, and tRNA Nucleotidyltransferase catalyzes this cytidine-cytidine-adenosine (CCA) addition to form the tRNA-NCCA product.
Function.
Protein synthesis takes place in cytosolic ribosomes, mitochondria (mitoribosomes), and in plants, the plastids (chloroplast ribosomes). Each of these compartments requires a complete set of functional tRNAs to carry out protein synthesis. The production of mature tRNAs requires processing and modification steps such as the addition of a 3’-terminal cytidine-cytidine-adenosine (CCA). Since no plant tRNA genes encode this particular sequence, a tRNA nucleotidyltransferase must add this sequence post-transcriptionally and therefore is present in all three compartments.
In eukaryotes, multiple forms of tRNA nucleotidyltransferases are synthesized from a single gene and are distributed to different subcellular compartments in the cell. There are multiple in-frame start codons which allow for the production of variant forms of the enzyme containing different targeting information predominantly found in the N-terminal sequence of the protein (reference). In vivo experiments show that the N-terminal sequences are used as transit peptides for import into the mitochondria and plastids. Comparison studies using available tRNA nucleotidyltransferase sequences have identified a single gene coding for this enzyme in plants. Complementation studies in yeast using cDNA derived from "Arabidopsis thaliana" or "Lupinus albus" genes demonstrate the biological activity of these enzymes. The enzyme has also been shown to repair damaged or incomplete CCA sequences in yeast.
This enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing nucleotide groups (nucleotidyltransferases).


Ethanolamine oxidase

In enzymology, an ethanolamine oxidase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are ethanolamine, H2O, and O2, whereas its 3 products are glycolaldehyde, 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 ethanolamine:oxygen oxidoreductase (deaminating). It has 2 cofactors: cobalt, and Cobamide.


Administrative Controlled Substances Code Number

Administrative Controlled Substances Code Number (ACSCN) is a number assigned to drugs listed on the schedules created by the Controlled Substances Act (CSA). The ACSCN is defined in 21 CFR § 1308.03(a).
Each chemical/drug on one of the schedules is assigned an ACSCN (for example, heroin is assigned 9200). The code number is used on various documents used in administration of the system mandated by the CSA.
ACSCN tables include the CSA schedule, common alternative chemical and trade names, and the free base conversion ratio (the molecular mass of the substance in question divided by the molecular mass of the free base). This is used to make meaningful qualitative comparisons between substances, and labeling of the end product may, as is required in many European countries, list the active substance using both (e.g. "each tablet contains 120 mg dihydrocodeine bitartrate, representing 80 mg dihydrocodeine base"). This method of citation is in theory compulsory worldwide for substances in Schedule I of the Single Convention on Narcotic Drugs 1961, a classification corresponding to opioids in US Schedule II with Narcotic classification plus cocaine (which inherited a narcotic designation from the 1931 Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs and preceding treaties and national laws including the 1914 Harrison Narcotics Tax Act) and German Betäubungsmittelgesetz (BtMG) Schedule I and so on. This is also the case for Single Convention Schedule IV, which roughly corresponds to the United States' CSA Schedule I. and CSU Schedule
List of schedules.
For a complete list, see the list of schedules:


Mosapride

Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist. The major active metabolite of mosapride, known as M1, additionally acts as a 5HT3 antagonist, which accelerates gastric emptying throughout the whole of the gastrointestinal tract in humans, and is used for the treatment of gastritis, gastroesophageal reflux disease, functional dyspepsia and irritable bowel syndrome. It is recommended to be taken on an empty stomach (i.e. at least one hour before food or two hours after food).
In addition to its prokinetic properties, mosapride also exerts anti-inflammatory effects on the gastrointestinal tract which may contribute to some of its therapeutic effects. Mosapride also promotes neurogenesis in the gastrointestinal tract which may prove useful in certain bowel disorders. The neurogenesis is due to mosapride's effect on the 5-HT4 receptor where it acts as an agonist.
Its common side effects include dry mouth, abdominal pain, dizziness, headache, insomnia, malaise, nausea, diarrhea and sometimes constipation. Unlike some other prokinetic agents, mosapride has little effect on potassium channels, no effect on hERG transfected cells, and no effect on cardiovascular function that could be detected in tests on humans. Due to the pharmacokinetics of mosapride, it would take 1,000–3,000 times the therapeutic dose to elicit cardiovascular effects.


Variolation

Variolation was the method of inoculation first used to immunize individuals against smallpox ("Variola") with material taken from a patient or a recently variolated individual, in the hope that a mild, but protective, infection would result.
The procedure was most commonly carried out by inserting/rubbing powdered smallpox scabs or fluid from pustules into superficial scratches made in the skin. The virus was normally spread through the air, infecting first the mouth, nose, or respiratory tract, before spreading throughout the body via the lymphatic system. In contrast, infection of the skin usually led to a —but, crucially, still induced immunity to the virus. The patient would develop pustules like those caused by naturally acquired smallpox. Eventually, after about two to four weeks, these symptoms would subside, indicating successful recovery and immunity.
The method was first used in China, India, parts of Africa and the Middle East before it was introduced into England and North America in the 1720s in the face of some opposition. The method is no longer used today. It was replaced by smallpox vaccine, a safer alternative. This in turn led to the development of the many vaccines now available against other diseases.
Terminology.
The terminology used to describe the prevention of smallpox can cause confusion. In 18th-century medical terminology, "inoculation" refers to "smallpox inoculation". Confusion is caused by writers who interchange "variolation" and "vaccination" through either mistranslation or misinterpretation. The term "variolation" refers solely to inoculation with smallpox virus and is not interchangeable with "vaccination". The latter term was first used in 1800 soon after Edward Jenner introduced smallpox vaccine derived from cowpox, an animal disease distinct from smallpox. The term "variolation" was then used from the 19th century to avoid confusion with vaccination. Most modern writers tend to refer to smallpox inoculation as variolation throughout without regard for chronology, as is used here. Further confusion was caused when, in 1891, Louis Pasteur honoured Jenner by widening the terms "vaccine/vaccination" to refer to the artificial induction of immunity against any infectious disease. "Inoculation" refers to intentionally exposing an individual to a virus, bacterium, other pathogen, or artificial vaccine that may induce active immunity, and inoculation can be done by any suitable route of administration. Many familiar vaccines are injected intramuscularly or swallowed. The word "inoculation" actually derives from Latin roots meaning "into the eye". Some viruses can cause infection if introduced into the eyes.
Origins.
China.
The Chinese practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of "nasal insufflation" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China. According to such documentation, mild smallpox cases were selected as donors in order to prevent serious attack. The technique used scabs that had been left to dry out for some time. Fresh scabs were more likely to lead to a full-blown infection. Three or four scabs were ground into powder or mixed with a grain of musk and bound in cotton. Infected material was then packed into a pipe and puffed up the patient's nostril. The practice of variolation is believed to have been ritualized by the Chinese. The blowpipe used during the procedure was made of silver. The right nostril was used for boys and the left for girls. Variolated cases were treated as if they were as infectious as those who had acquired the disease naturally. These patients were subsequently kept apart from others until the rash had cleared. Two reports on the Chinese practice were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China, and another by the physician Clopton Havers. But no action was taken.
India.
India has been suggested as another possible origin for the spread of variolation into Europe, particularly the Ottoman Empire and Wales. There are two accounts from the 18th century of inoculations being performed by itinerant Brahmins: Oliver Coult in 1731 wrote that it had been "first performed by Dununtary a physician of Champanagar" about 150 years before that time (Dhanvantari being the name of the Hindu God of medicine, and a common name among physicians), and John Zephaniah Holwell in 1768 wrote of its being practiced for many hundreds of years. Aspects of these accounts have been called into question, but reportedly, by 1768 inoculation was being practiced in Bengal. The doctors who performed this procedure were known as "Tikadars". The term 'tika' is still in use now to mean "vaccination" in many Indian languages.
Sudan.
Similar methods were seen through the Middle East and Africa. Two similar methods were described in Sudan during the late eighteenth and early nineteenth centuries. Both had been long established and stemmed from Arabic practices. "Tishteree el Jidderi" ("buying the smallpox") was a practice seen within the women of Sennar in Central Sudan. A mother of an unprotected child would visit the house of a newly infected child and tie a cotton cloth around the ailing child's arm. She would then haggle with the child's mother over the cost of each pustule. When a bargain was struck, the woman would return home and tie the cloth around her own child's arm. Variations of this practice included bringing gifts to the donor. The second method was known as "Dak el Jedri" ("hitting the smallpox"), a method similar to that used in the Ottoman Empire and eventually transported into England. Fluid was collected from a smallpox pustule and rubbed into a cut made into the patient's skin. This practice spread more widely through Africa. It may have also traveled with merchants and pilgrims along the middle-eastern caravan routes into Turkey and Greece.
Spread into Western Europe.
Introduction.
Letters from physicians in Wales published in 1722 indicated the local use of variolation from as early as 1600 near the Welsh port of Haverfordwest. Another reference to variolation is by Thomas Bartholin in 1675. After coming across the practice in Istanbul, Italian physician Emmanuel Timoni of Constantinople wrote a letter describing the method in detail which was later published in the "Philosophical Transactions" in early 1714. His account would become the first medical account of variolation to appear in Europe. Although the article did not gain widespread notoriety, it caught the attention of two important figures in the variolation movement, Bostonian preacher Cotton Mather and the wife of the British Ambassador to the Ottoman Empire, Lady Mary Wortley Montagu.
Lady Mary Wortley Montagu.
Lady Mary Wortley Montagu had lost her brother to smallpox in 1713. In 1715 she contracted the disease herself. Although she survived, she was left with severe facial scarring. While in Turkey she came across the process of variolation as it was introduced and published in Istanbul by two doctors, Emmanuel Timoni and Iacob Pylarino. She first mentioned variolation in the famous letter to her friend, Sarah Chiswell, in April 1717. in which she enthusiastically recounted the process, which in Istanbul was most commonly administered by experienced elderly women. In 1718, she had the procedure conducted on her five-year-old son, Edward Montagu. The procedure was supervised by the embassy doctor Charles Maitland. On her return to England, she had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721. Both variolations proved successful. Later on that year Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London. In the experiment, six condemned prisoners were variolated and later exposed to smallpox with the promise of freedom if they survived. The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure throughout England. However, variolation caused the death of Prince Octavius of Great Britain, eighth son and thirteenth child of King George III in 1783.
Despite opposition, variolation established itself as a mainstream medical treatment in England. Part of its success was founded on statistical observation, which confirmed that variolation was a safer alternative to contracting smallpox naturally, strengthened by the assumption that it protected against the disease for life. The major faults of variolation lay in its simplicity. Doctors sought to monopolize the simple treatment by convincing the public that the procedure could only be done by a trained professional. The procedure was now preceded by a severe bloodletting, in which the patient was bled, often to faintness, in order to 'purify' the blood and prevent fever. Doctors also began to favour deep incisions, which also discouraged amateurs.
The Suttonian Method.
The main proponents of the English variolation movement were the Suttons, a family of physicians who would revolutionize the practice. The patriarch, Robert Sutton, was a surgeon from Suffolk. In 1757 the procedure failed on one of his sons. He sought a new method in which the procedure would become as mild as possible. By 1762 he began advertising "A New Method of Inoculating for Small-Pox." Sutton kept his method a secret and shared it only with his three sons. The mystique and effectiveness behind this new method helped to promote their business, which soon became very successful. They established a network of variolation houses and clinics and offered franchises to other variolators for a share of the profits, on condition that the secret would not be revealed. By 1770, the Suttons had treated over 300,000 satisfied customers. Daniel, the eldest of the Sutton sons, eventually revealed the family secret in his book "The Inoculator", published in 1796. The success of their method lay in a shallow scratch, careful selection of only mildly affected donors, and no bleeding or extreme purging. Although the renown of the Suttons gradually faded after this revelation, the family's lasting impression would remain for generations.
Thomas Nettleton (1683–1748) was a precursor of the Suttons around 1722.
Other prominent English variolators included Thomas Dimsdale, who published accounts of his method in 1769 and 1781; William Woodville, appointed Director of the London Smallpox and Inoculation Hospital in 1791, who published a history of variolation in 1796; and John Haygarth, who published an ambitious plan to "exterminate" smallpox in 1783.
Johnnie Notions.
John Williamson, more commonly known by the nickname Johnnie Notions, was a self-taught physician from Shetland, Scotland, who independently developed and successfully administered a variolation for smallpox to thousands of patients in Shetland during the late 18th century. Despite having only an elementary education and no formal medical background, the effectiveness of the treatment he devised yielded an extremely high success rate, resulting in the immunisation of approximately 3,000 people and the saving of many lives, which had a significant effect on the demographics of the Shetland population at the time. He is reputed to have not lost a single patient.
Notions would first collect small pox pus. He would then dry it using peat smoke (which was believed to lessen the virus's virulence), and bury it in the ground with camphor (which has anti-bacterial properties, preventing the matter from decomposing). Oral history indicates the matter was spread between sheets of glass before burial. It would be kept in this state for up to 7 or 8 years to reduce its virulence before being administered to a patient. By using a knife (which Notions made himself) he would incise into the patient's arm intradermally (without drawing blood), insert a small amount of the matter, and immediately cover the incision with the patient's skin, before using a cabbage leaf as a plaster. In contrast to contemporaneous quack doctors, Notions would not stipulate any particular resting conditions (such as "hot-treatment" – heating the ill patient in front of a fire, covering them with blankets and allowing them no fresh-air), nor would he administer any other medicines during the period of infection and recovery.
Notions' variolation bears a strong similarity to the Suttonian method. How Notions became aware of this method of variolation is unclear – it may have been through written account, or through discussion with someone else aware of the technique, such as another physician or a member of the clergy.
Widespread recognition.
In 1738, variolation was added to the second edition of "Chambers' Cyclopædia", which in its time was an authority of knowledge for the literary class. Later in 1754, variolation received the sanction of the Royal College of Physicians. All of this made England the international center of variolation, attracting visitors from all over the world to explore this "new" method of prevention. The nation also acted as a magnet for those who sought to introduce the benefits of variolation to their own countries. A remarkable example of this is the introduction of variolation into Russia. Thomas Dimsdale, a prominent banker, politician, and physician, was invited to visit St Petersburg to variolate Catherine the Great. In 1769, he variolated Catherine, her 14-year-old son Grand Duke Paul, and over 140 prominent members of the Court. The results were successful. Dimsdale was created a baron of the Russian Empire, and awarded £10,000, with £2000 for expenses and an annuity of £500. His son, who accompanied him, was also rewarded. In case Dimsdale's variolations had ended badly, Catherine had arranged a relay of horses to carry them safely out of the country.
France was the last European country to embrace variolation. It was not until an outbreak of smallpox in Paris in 1752 nearly killed the heir to the French throne that the public embraced the practice after seeing the prince variolated. Similarly in Japan, Chinese merchant Li Jen-Shan proposed the method of traditional Chinese intranasal variolation after a severe smallpox outbreak in Nagasaki in 1744. This led Japanese physician to variolate children using a human smallpox vaccination method during an outbreak in Chikuzen Province from 1789 to 1790. There were no deaths among the children, and they all appeared to be protected.
By the end of the eighteenth century, variolation had gained widespread global respect and was thought to be one of the greatest medical successes of its time. It had become the subject of serious medical study, leading physicians like John Haygarth from Chester, England, to explore its application on a larger scale. In 1793 he published "A Sketch of a Plan to Exterminate the Small-Pox from Great Britain". This relied on rules summarised by Donald Hopkins; Systematic inoculation throughout the country, isolation of patients, decontamination of potentially contaminated fomites, supervised inspectors responsible for specific districts, rewards for observation of rules for isolation by poor persons, fines for transgression of those rules, inspection of vessels at ports, and prayers every Sunday. Its implementation at the time was impractical for logistical reasons and the risk that variolation would spread smallpox. However, with suitable modifications, such as the substitution of vaccination for variolation, it was remarkably similar to the strategy adopted during the World Health Organization's smallpox eradication campaign.
Spread into America.
Documentation of variolation in the Americas may be traced back to 1706 in Boston, where Puritan minister Cotton Mather learned of the technique from his West African slave Onesimus. Further research into the matter revealed to Mather that several other slaves had too been variolated. In 1714, he came across Timoni's article in "Philosophical Transactions", in which he described methods of variolation found in Turkey. Mather was able to implement this new method in 1721 when Boston suffered a smallpox outbreak, although others such as William Douglass strongly opposed the idea.
The main arguments against variolation were on religious grounds. Because religion was never far from any aspect of life in eighteenth-century Boston, several wondered how this new method would coincide with religious teachings. The simplest debate argued that variolation was ungodly because it was not mentioned specifically in the Bible. Inoculation was also viewed by some as a direct affront to God's innate right to determine who was to die, and how and when death would occur. Several believed smallpox outbreaks were well-merited punishments for the sins of those who contracted the disease. Those who were empirically minded saw the notion of using the products of such a deadly disease to prevent said disease as being an insult to logic.
Despite these persistent arguments, Mather also gained several supporters. Among this group of followers was surgeon Zabdiel Boylston, who urged Mather to further promote the procedure. With the support of Mather, Boylston went on to successfully variolate 300 patients, with only six of them dying. By contrast, 1,000 of the 6,000 people who acquired smallpox naturally died during the same period. Boylston traveled to London in 1724. There he published his results and was elected to the Royal Society in 1726.
From Boston, the practice spread throughout the colonies. In 1775, George Washington ordered that the Continental Army be variolated. By the end of the American Revolutionary War, variolation had gained widespread acceptance in the larger cities and towns of the United States.
Transition into vaccination.
The success of variolation led many, including medical professionals, to overlook its drawbacks. Variolation was practiced on the basis that it protected against smallpox for life, and was far less likely to kill than natural infection. In some cases however, natural smallpox or variolation failed to protect from a second attack. These cases were a result of a lapse of immune "memory", while others may have been misdiagnosed (experts often confused smallpox with chickenpox). Variolation also required a level of skill and attention to detail which some physicians lacked. Many physicians failed to take note of local redness and discharge to assure the variolation had taken, resulting in inadequate treatment. However, it was its great risk to others that led to the end of the practice. The collateral smallpox cases spread by variolated subjects shortly after variolation began to outweigh the benefits of the procedure.
From the 1760s, a number of individuals, including John Fewster, Peter Plett, Benjamin Jesty, and particularly Edward Jenner, were interested in the use of material from cowpox, an animal infection, to protect against smallpox. In 1796, Jenner vaccinated James Phipps, did more vaccinations in 1798, and was the first to publish evidence that cowpox protected against smallpox, was safer than variolation, and that his vaccine could be maintained by arm-to-arm transfer. The use of variolation soon began to decline as the smallpox vaccine became widely used and its benefits appreciated. Various countries made variolation illegal, starting with Russia in 1805.
Variolation served as a natural precursor to the discovery of vaccination. The major differences between the two were that in vaccination, material from cowpox, an animal disease, was used, but particularly that it was far safer to those vaccinated and was far more rarely transmitted to their contacts. Vaccination offered the public a less-harmful method of preventing smallpox. Vaccination would revolutionize the control of smallpox, leading to its eventual eradication. The extension of the principle of vaccination by Pasteur and his successors would lead to the development of vaccines for diseases such as diphtheria, measles, mumps, rubella, and influenza, and make the eradication of infectious diseases, particularly poliomyelitis, a realistic prospect.
Decline.
Although variolation eventually declined or was banned in some countries, it was still practiced in others. "Buying the smallpox" was still practiced in Sudan until the late nineteenth century. However, variolation survived longer elsewhere. During the World Health Organization's Smallpox Eradication Campaign, vaccination teams came across variolators in remote areas of Pakistan and Afghanistan and their samples were confiscated. In the early stages of the campaign, live virus was detected in some, but as the campaign progressed variolators could not replenish their stocks, and although virus particles were detected in some samples, very few contained live virus. Our knowledge about the survival of smallpox virus suggests that passage of time makes it extremely unlikely that any infectious samples have survived.
Other diseases.
Although variolation has ceased, it has influenced the concept of other traditional practices, such as "pox parties", in which children are intentionally exposed to diseases like chickenpox, measles and rubella, in an attempt to gain immunity. Although strongly discouraged by public health officials, the practice persists.
While intentional exposure has been rejected as a strategy to combat COVID-19 because of the risks involved, there is also a hypothesis that widespread to universal use of face coverings, which tend to be less than perfect, is associated with a higher proportion of asymptomatic or relatively mild infections because of the decreased dose of viral particles expelled or received by the wearer, as a welcome addition to their primary purpose of significantly reducing transmission by asymptomatic wearers.


Serono

Serono was a biotechnology company headquartered in Geneva, Switzerland. It was acquired by the German pharmaceutical company Merck in 2006. The company was founded as the Serono Pharmacological Institute by Cesare Serono in 1906 in Italy. A key step in its development was the discovery of a method of extracting urinary gonadotropins by Dr. Piero Donini. Serono was incorporated in 1987 and the holding company, Ares-Serono S.A., changed its name to Serono S.A. in May 2000.
Serono develops and markets pharmaceuticals in the fields of reproductive health, multiple sclerosis, growth & metabolism and dermatology.
The eight biotechnology products are available in four core therapeutic areas: neurology for the treatment of relapsing forms of multiple sclerosis, reproductive health for treatments of infertility, dermatology, where Serono has launched biologics in Europe for moderate-to-severe psoriasis, and
growth and metabolism for treatments for HIV-associated wasting and growth deficiencies.
The company also conducts research in oncology and autoimmune diseases. Through the acquisition in 1997 of GBRI from GlaxoWelcome, becoming its Geneva based research institute named SPRI, and the Manteia Predictive Medicine spin-off, Serono also nursed the emergence of now a commercial leading massive parallel sequencing technology.
Sale to Merck KGaA.
36% of Serono was sold to Merck KGaA in Sept. 2006 for €10.6 billion; Merck KGaA paid CHF 1,100 for each share. The new entity, which merges Serono with Merck's Ethicals division, is called Merck Serono. Its headquarters was in Geneva, within the new Serono facilities. The US operations remain near Boston and was renamed here "EMD Serono" due to trademark issues with Merck & Co./MSD. The process of merging started in January 2007 after various business regulatory reviews and phases were complete. Until that time, Serono and Merck KGaA operated as separate entities. The new, combined entity, Merck Serono is the size of other large biotechs. In 2011, a decision was made to close the Geneva headquarters and move the headquarters to Darmstadt, Germany resulting in job losses to most of the employees in Geneva.
Facilities.
Serono operated in 44 countries, with manufacturing facilities in eight countries and sales in over 90 countries. Main manufacturing sites were in Switzerland, Italy, Spain and France; a fifth facility in Israel was closed in 2004 owing to its obsolescence. Research and development facilities were maintained in Geneva, Switzerland, Boston, USA, and Ivrea, Italy. It employed over 4,750 people with worldwide revenues of USD 2,586.4 million (2005). It had eight biotechnology products on the market, and more than 25 ongoing preclinical and clinical development projects at the end of 2005.
Serono Headquarters and the Geneva research site moved to a brand new campus (Horizon Secheron) in the heart of Geneva in 2006. This facility and the headquarters were closed by Merck KGaA in 2013. The building was sold back to Berterelli family.
Lawsuit.
In 2005, Serono agreed to a $704 million settlement with the Department of Justice to resolve civil and criminal allegations that the company engaged in a fraudulent scheme to promote the drug Serostim for off-label uses and paid out illegal kickbacks for prescribing the drug in violation of the False Claims Act. The settlement is, to date, the ninth largest pharmaceutical settlement in U.S. history.
Fertility LifeLines.
Serono provides Fertility LifeLines as a free and confidential source of information to infertility patients.


Malonyl-CoA

Malonyl-CoA is a coenzyme A derivative of malonic acid.
Functions.
It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis.
Fatty acid biosynthesis.
In the former, it provides 2-carbon units to fatty acids and commits them to fatty acid chain synthesis.
Malonyl-CoA is formed by carboxylating acetyl-CoA using the enzyme acetyl-CoA carboxylase. One molecule of acetyl-CoA joins with a molecule of bicarbonate, requiring energy rendered from ATP.
Malonyl-CoA is utilised in fatty acid biosynthesis by the enzyme malonyl coenzyme A:acyl carrier protein transacylase (MCAT). MCAT serves to transfer malonate from malonyl-CoA to the terminal thiol of "holo"-acyl carrier protein (ACP).
Polyketide biosynthesis.
MCAT is also involved in bacterial polyketide biosynthesis. The enzyme MCAT together with an acyl carrier protein (ACP), and a polyketide synthase (PKS) and chain-length factor heterodimer, constitutes the minimal PKS of type II polyketides.
Regulation.
Malonyl-CoA is a highly regulated molecule in fatty acid synthesis; as such, it inhibits the rate-limiting step in beta-oxidation of fatty acids. Malonyl-CoA inhibits fatty acids from associating with carnitine by regulating the enzyme carnitine acyltransferase, thereby preventing them from entering the mitochondria, where fatty acid oxidation and degradation occur.


Methyl-DMA

Methyl-DMA (2,5-dimethoxy-"N"-methylamphetamine) is a lesser-known psychedelic drug and substituted methamphetamine. It was first synthesized by Alexander Shulgin. In his book "PiHKAL", the minimum dosage is listed as 250 mg, and the duration unknown. Methyl-DMA produces slight paresthesia. Very little data exists about the pharmacological properties, metabolism, and toxicity of Methyl-DMA.


HgcC family RNA

HgcC is a small non coding RNA (ncRNA). It is the functional product of a gene which is not translated into protein.
This ncRNA gene was originally identified by computationally searching the genome of the thermophilic archea "Methanococcus jannaschii" for non-coding regions of high guanine-cytosine (GC) content. The original rational for this search was based on the observation that the genomes of these bacteria are adenosine-thiamine (AT) rich and consequently have a low GC content. However, the GC content of ribosomal RNA (rRNA) and transfer RNA (tRNA) genes in hyperthermophiles shows a strong correlation with optimal growth temperature. It was proposed that non coding regions of high GC-content might encode functional RNA products. The computational screen identified a number of novel ncRNA genes in the genome of "M.jannaschii". These were named hgc- ("high GC") A, B, C, D, E, F and G. Two other homologues were detected called HhcA and HhcB after "homologue of hgcC". A further RNA element, SscA RNA, was also identified.
The HgcC gene product was experimentally validated by Northern blot and RACE-PCR analysis. The function of this ncRNA is unknown.


Cheng Fong Chemical

Cheng Fong Chemical Co. Ltd is a Chinese active pharmaceutical ingredient (API) company that exports to the United States of America. In September 2016, the US FDA issued a warning letter "following a five-day inspection in April 2016 that found the company failed to appropriately maintain its facilities and investigate reports of foreign particles in finished batches."<ref name="Cheng Fong Chemical Co., Ltd. 9/15/16"></ref> According to the FDA, Cheng Fong officials told investigators "that the rooms had never been cleaned.".


Streptogramin B

Streptogramin B is a subgroup of the streptogramin antibiotics family. These natural products are cyclic hexa- or hepta depsipeptides produced by various members of the genus of bacteria "Streptomyces". Many of the members of the streptogramins reported in the literature have the same structure and different names; for example, pristinamycin IA = vernamycin Bα = mikamycin B = osteogrycin B.
Biosynthesis.
The biosynthesis of streptogramin B is carried out by large multifunctional enzymes called non-ribosomal peptide synthetases (NRPS). In the NRPS system, each amino acid is activated as an aminoacyladenylate and is linked to the enzyme as a thioester with a phosphopantetheinyl group. An elongation reaction then occurs by transferring the activated carboxyl to the amino group in the next amino acid, thus executing the N-to-C stepwise condensation.
NRPSs contain several modules on a single polypeptide. Each of these modules can catalyze activation, condensation and a modification reaction specific to one kind of amino acid. A typical elongation module consists of an adenylation domain (A), a peptidyl carrier protein domain (PCP) and a condensation domain (C). Some other domains may be present that are responsible for modifications to the residues, such as epimerization domain (E) and N-methyltransferase domain (MT). The domain responsible for the termination is the thioesterase domain (TE) located in the final module.
Amino acid composition.
The general amino acid composition of streptogramin B consists of: 3-hydroxypicolinic acid, L-threonine, D-aminobutyric acid, L-proline, 4-N,N-(dimethylamino)-L-phenylalanine, 4-oxo-L-pipecolic acid and phenylglycine.
Mechanism of Action.
Streptogramins A and B synergically inhibit cell growth of gram positive, less so gram negative bacteria by inhibiting protein synthesis, but separately they are bacteriostatic. The molecular target of streptogramins is the 23S rRNA. Both streptogramin A and B bind to the P binding site of the 50S ribosome subunit. The type A streptogramin binding causes a conformational change to the 50S subunit, which increases the activity of the type B streptogramin by a 100-fold. Streptogramin B prevents the elongation of protein chains and causes the release of incomplete peptides.
Clinical use.
The streptogramin antibiotics were identified almost 50 years ago, but have only recently found clinical use as a consequence of the increase in multidrug-resistant bacteria. They present poor solubility in aqueous solution, and this has limited their clinical use; however, the natural products still find use as feed additives in agriculture.
Medicinal chemists at Rhône-Poulenc worked in the preparation of semi-synthetic, water-soluble, derivatives of pristinamycin IA (B type streptogramin) and pristinamycin IIA (A type streptogramin) giving rise to quinupristin and dalfopristin, respectively, which, when administered in a 3:7 ratio, comprise the 1999 FDA approved drug Synercid.


Chlamydia psittaci

Chlamydia psittaci is a lethal intracellular bacterial species that may cause endemic avian chlamydiosis, epizootic outbreaks in mammals, and respiratory psittacosis in humans. Potential hosts include feral birds and domesticated poultry, as well as cattle, pigs, sheep, and horses. "C. psittaci" is transmitted by inhalation, contact, or ingestion among birds and to mammals. Psittacosis in birds and in humans often starts with flu-like symptoms and becomes a life-threatening pneumonia. Many strains remain quiescent in birds until activated by stress. Birds are excellent, highly mobile vectors for the distribution of chlamydia infection, because they feed on, and have access to, the detritus of infected animals of all sorts.
"C. psittaci" in birds is often systemic, and infections can be inapparent, severe, acute, or chronic with intermittent shedding. "C. psittaci" strains in birds infect mucosal epithelial cells and macrophages of the respiratory tract. Septicaemia eventually develops and the bacteria become localized in epithelial cells and macrophages of most organs, conjunctiva, and gastrointestinal tracts. It can also be passed in the eggs. Stress will commonly trigger onset of severe symptoms, resulting in rapid deterioration and death. "C. psittaci" strains are similar in virulence, grow readily in cell culture, have 16S rRNA genes that differ by <0.8%, and belong to eight known serotypes. All should be considered to be readily transmissible to humans.
"C. psittaci" serovar A is endemic among psittacine birds and has caused sporadic zoonotic disease in humans, other mammals, and tortoises. Serovar B is endemic among pigeons, has been isolated from turkeys, and has also been identified as the cause of abortion in herds of dairy cattle. Serovars C and D are occupational hazards for slaughterhouse workers and for people in contact with birds. Serovar E isolates (known as Cal-10, MP or MN) have been obtained from a variety of avian hosts worldwide and, although they were associated with the 1920s–1930s outbreak in humans, a specific reservoir for serovar E has not been identified. The M56 and WC serovars were isolated during outbreaks in mammals. Many "C. psittaci" strains are susceptible to bacteriophages.
Life cycle and method of infection.
"Chlamydia psittaci" is a small bacterium (0.5μm) that undergoes several transformations during its lifecycle. It exists as an elementary body (EB) between hosts. The EB is not biologically active, but is resistant to environmental stresses and can survive outside a host. The EB travels from an infected bird to the lungs of an uninfected bird or person in small droplets, and is responsible for infection. Once in the lungs, the EB is taken up by cells in a pouch called an endosome by phagocytosis. However, the EB is not destroyed by fusion with lysosomes, as is typical for phagocytosed material. Instead, it transforms into a reticulate body and begins to replicate within the endosome. The reticulate bodies must use some of the host's cellular machinery to complete their replication. The reticulate bodies then convert back to elementary bodies, and are released back into the lung, often after causing the death of the host cell. The EBs are thereafter able to infect new cells, either in the same organism or in a new host. Thus, the lifecycle of "C. psittaci" is divided between the elementary body which is able to infect new hosts, but can not replicate, and the reticulate body, which replicates, but is not able to cause new infection.
History.
The disease caused by "C. psittaci", psittacosis, was first characterized in 1879 when seven individuals in Switzerland were found to experience pneumonia after exposure to tropical pet birds. The causative pathogen was not known. The related bacterial species "Chlamydia trachomatis" was described in 1907, but was assumed to be a virus, as it could not be grown on artificial media. In the winter of 1929–1930, a psittacosis pandemic spread across the United States and Europe. Its mortality rate was 20% and as high as 80% for pregnant women. The disease's spread was eventually attributed to exposure to Amazon parrots imported from Argentina. Though "C. psittaci" was identified in 1930 as the agent responsible for psittacosis, it was not found to be a bacterium until examination by electron microscopy in the 1960s.
Taxonomy.
For several decades, the family Chlamydiaceae contained a sole genus, "Chlamydia". "C. psittaci" was originally classified from the 1960s to 1999 as a species of this sole genus. In 1999, the order Chlamydiales was assigned two new families (Parachlamydiaceae and Simkaniaceae), and within the family Chlamydiaceae, the genus "Chlamydia" was divided into two genera, "Chlamydia" and the newly designated genus "Chlamydophila", with "C. psittaci" becoming "Chlamydophila psittaci". However, this reclassification "was not wholly accepted or adopted" among microbiologists, which "resulted in a reversion to the single, original genus "Chlamydia", which now encompasses all 9 species including "C. psittaci"." A new species was added to the reunited genus "Chlamydia" in 2013, two more were added in 2014.
What were once classified as the mammal-endemic strains "C. psittaci" abortion, "'C. psittaci" feline, and "C. psittaci" guinea pig are today three separate species, "C. abortus", "C. felis", and "C. caviae".
Diseases.
"C. psittaci" infection is also associated with schizophrenia. Many other kinds of infections have been associated with schizophrenia.
Genomics.
Like other Chlamydia, "C. psittaci" is an intracellular pathogen and has thus undergone significant genome reduction. Most "C. psittaci" genomes encode between 1,000 and 1,400 proteins. A total of 911 core genes were found to be present in all 20 strains sequenced by Read et al., corresponding to 90% of the genes present in each genome.
Confirmation of diagnosis.
In addition to symptoms and CHX, complement fixation, microimmunofluorescence, and polymerase chain reaction tests can be used to confirm the diagnosis.
Treatment.
Tetracycline or macrolides can be used to treat this condition. The drugs are given intravenously or orally, depending on drug choice. Treatment should continue for 10–14 days after the fever subsides. In children or pregnant women, though, tetracycline should not be used. Ibuprofen or acetominophen, and fluids are also administered. Cigarette or tobacco smoke should be avoided. While taking tetracycline, dairy products should be avoided.


Wayne Quinton

Wayne Everett Quinton (January 4, 1921 – January 22, 2015) was a developer of over 30 biomedical devices, including the Quinton catheter. He also invented a lightweight treadmill, for cardiac stress testing - the prototype of those used in fitness centers.
Quinton was raised in Rigby, Idaho. He received a degree in mechanical engineering from the University of Washington in 1959. He previously attended Ricks College (now BYU-Idaho) and Montana State University. A week after Pearl Harbor, he arrived in Seattle and began working for Boeing to work on the B-29 bomber.
He was hired by the University of Washington for an Arctic Acclimatization study and subsequently as the sole member of the instrument shop.
Among Quinton's inventions was a shunt with Belding Scribner and David Dillard that allowed for repeated kidney dialysis procedures on an individual, making the process one that truly extended the patient's life expectancy. He was also involved with the following inventions: structure to allow polio patients to get into a sitting position; movable camera boom and cart to reduce time taking autopsy photos; uniform bubble oxygenator for use during open-heart surgery; hydraulic gastrointestinal biopsy instrument; Mitral valve finger knife for use during open-heart surgery; small aortic valve dilator for use during open-heart surgery; high-speed machine to test fatigue in artificial heart valves; Teflon tracheotomy plug to aid patients with paralytic polio.
Although Quinton was raised in a rural Mormon community, it wasn't until age 35 that he was baptized a member of The Church of Jesus Christ of Latter-day Saints.
Wayne Quinton died of congestive heart failure, age 94, at his home in the Highlands area of Seattle, Washington.


Penicillin-binding proteins

Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics (except for tabtoxinine-β-lactam, which inhibits glutamine synthetase) bind to PBPs, which are essential for bacterial cell wall synthesis. PBPs are members of a subgroup of enzymes called transpeptidases. Specifically, PBPs are DD-transpeptidases.
Diversity.
There are a large number of PBPs, usually several in each organism, and they are found as both membrane-bound and cytoplasmic proteins. For example, Spratt (1977) reports that six different PBPs are routinely detected in all strains of "E. coli" ranging in molecular weight from 40,000 to 91,000. The different PBPs occur in different numbers per cell and have varied affinities for penicillin. The PBPs are usually broadly classified into high-molecular-weight (HMW) and low-molecular-weight (LMW) categories. Proteins that have evolved from PBPs occur in many higher organisms and include the mammalian LACTB protein.
Function.
PBPs are all involved in the final stages of the synthesis of peptidoglycan, which is the major component of bacterial cell walls. Bacterial cell wall synthesis is essential to growth, cell division (thus reproduction) and maintaining the cellular structure in bacteria. Inhibition of PBPs leads to defects in cell wall structure and irregularities in cell shape, for example filamentation, pseudomulticellular forms, lesions leading to spheroplast formation, and eventual cell death and lysis.
PBPs have been shown to catalyze a number of reactions involved in the process of synthesizing cross-linked peptidoglycan from lipid intermediates and mediating the removal of -alanine from the precursor of peptidoglycan. Purified enzymes have been shown to catalyze the following reactions: -alanine carboxypeptidase, peptidoglycan transpeptidase, and peptidoglycan endopeptidase. In all bacteria that have been studied, enzymes have been shown to catalyze more than one of the above reactions. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (involved in formation of linear glycan strands) and a penicillin-sensitive transpeptidase C-terminal domain (involved in cross-linking of the peptide subunits) and the serine at the active site is conserved in all members of the PBP family.
Some low-molecular-weight PBPs associate with the MreB cytoskeleton and follow its rotation around the cell, inserting petipdoglycan in an oriented manner during cell growth. In contrast, high-molecular-weight PBPs are independent from MreB and maintain cell wall integrity by detecting and repairing defects in the peptidoglycan.
Antibiotics.
PBPs bind to β-lactam antibiotics because they are similar in chemical structure to the modular pieces that form the peptidoglycan. When they bind to penicillin, the β-lactam amide bond is ruptured to form a covalent bond with the catalytic serine residue at the PBPs active site. This is an irreversible reaction and inactivates the enzyme.
There has been a great deal of research into PBPs because of their role in antibiotics and resistance. Bacterial cell wall synthesis and the role of PBPs in its synthesis is a very good target for drugs of selective toxicity because the metabolic pathways and enzymes are unique to bacteria. Resistance to antibiotics has come about through overproduction of PBPs and formation of PBPs that have low affinity for penicillins (among other mechanisms such as lactamase production). These experiments change the structure of PBP by adding different amino acids into the protein, allowing for new discovery of how the drug interacts with the protein. Research on PBPs has led to the discovery of new semi-synthetic β-lactams, wherein altering the side-chains on the original penicillin molecule has increased the affinity of PBPs for penicillin, and, thus, increased effectiveness in bacteria with developing resistance.
Presence of the protein penicillin binding protein 2A (PBP2A) is responsible for the antibiotic resistance seen in methicillin-resistant "Staphylococcus aureus" (MRSA).
The β-lactam ring is a structure common to all β-lactam antibiotics.
See also.
PASTA domain


Methylisopropyltryptamine

"N"-Methyl-"N"-isopropyltryptamine (MiPT) is a psychedelic tryptamine, closely related to DMT, DiPT and Miprocin.
Chemistry.
MiPT base, unlike many other tryptamines in their freebase form, does not decompose rapidly in the presence of light or oxygen.
In August 2019, Chadeayne et al. solved the crystal structure of MiPT fumarate. Its systematic name is [2-(1H-indol-3-yl)ethyl](methyl)propan-2-ylazanium 3-carboxyprop-2-enoate. The salt consists of a protonated tryptammonium cation and a 3-carboxyacrylate (hydrogen fumarate) anion in the asymmetric unit.
Dosage.
10-25 mg is usually taken , with effects lasting 4–6 hours.
Effects.
MiPT is said to emphasize psychedelic/entheogenic effects over sensory/hallucinogenic activity. Users report strong mental effects, but few perceptual alterations.
Hyper sensitivity to sound as well
Legality.
Sweden's public health agency suggested classifying MiPT as a hazardous substance, on May 15, 2019.
MiPT is unscheduled in the United States. It may be considered controlled as an analog of another stimulant, alpha-methyl-tryptamine, but this has not been tested in court.


Raphael Carl Lee

Raphael Carl Lee (born October 29, 1949 in Sumter, South Carolina) is an American surgeon, medical researcher, biomedical engineer, and entrepreneur.
Life.
Lee spent his childhood and adolescence in South Carolina. During medical school and graduate school he lived in Philadelphia, Chicago and Boston. Today, he practices reconstructive plastic surgery at the University of Chicago. Mostly his research has focused on advancing the care of trauma victims. Lee is recognized for the application of block copolymer surfactants to mimic some basic cellular protective processes of natural stress proteins to augment cellular self-repair capability following injury. He has also advanced understanding the biophysical mechanisms of tissue injury and neuromuscular disorders in survivors of electrical shock .
He is the Paul S. and Ailene T. Russell Professor of Surgery at the University of Chicago, and holds appointments in the departments of Medicine (Dermatology), Molecular Medicine, and Organismal Biology and Anatomy. Dr. Lee is the Director of the University of Chicago's Laboratory for Molecular Regeneration.
Lee graduated from Bishop England High School in Charleston, South Carolina and then studied engineering at the University of South Carolina in Columbia, South Carolina. He completed the electrical engineering curriculum in 1971 with an interest in medical applications. He then enrolled in the combined medicine and engineering curriculum established by Temple University School of Medicine and Drexel University College of Engineering in central Philadelphia. Dr. Lee was elected to the Alpha Omega Alpha honor medical society and the Tau Beta Pi engineering honor society. He completed both M.D. and M.S. degrees in 1975. This was followed by general surgery residency training at the University of Chicago Hospitals in Chicago and then plastic surgery residency training at the Massachusetts General Hospital. While a resident at the University of Chicago, he enrolled in graduate studies at M.I.T. and in Harvard-MIT Division of Health Sciences and Technology doctoral program. He received a Sc.D. in bioelectrical engineering from the Massachusetts Institute of Technology in 1979. He received several significant awards for his research during his surgical residency training including the Schering Scholar Award in 1978 from the American College of Surgeons and MacArthur Prize Fellows Award in 1981 from the John D and Catherine T. MacArthur Foundation in Chicago.
While on the faculty at Harvard Medical School he receive the James Barrett Brown Award from the American Association of Plastic Surgeons for advancing the understand of electrical injuries. He returned to the University of Chicago in 1990 where he practices plastic surgery and teaches graduate courses in molecular pathogenesis of disease. Dr. Lee has served as President of the American Institute for Medical and Biological Engineering, the Midwestern Association of Plastic Surgeons, the Drexel 100 Society, and the Society for Physical Regulation of Biology and Medicine. He a clinical investigator at the University of Chicago who was elected to the Institute of Medicine of Chicago and the International Academy of Medical and Biological Engineering.
He is founder and chairman of RenaCyte BioMolecular Technologies (2005) and Avocet Polymer Technologies,Inc (1997). He is affiliated with the Chicago Electrical Trauma Rehabilitation Institute.
Works.
Author or coauthor of more than 200 journal publications and book chapters


Anti-hemB RNA motif

The anti-hemB RNA motif is a conserved RNA structure that was found in all known bacteria in the genus "Burkholderia", and in a variety of other betaproteobacteria. The anti-hemB RNA motif consists primarily of two stem-loops, followed by a predicted rho-independent transcription termination stem-loop. As anti-hemB RNAs are generally not located in a 5' UTR, the RNAs are presumed to be non-coding RNAs. The terminator stem-loop implies that anti-hemB RNAs are transcribed as independent molecules.
The name "anti-hemB" is to distinguish the motif from its reverse complement, which was called the "hemB" motif, a motif that is often in the apparent 5' UTRs of "hemB" genes. It was considered ambiguous as to which of these orientations is correct, as both directions exhibit covariation (see secondary structure prediction), and both fold into plausible RNA structures. However, the anti-hemB was judged the more likely orientation, because it had fewer A-C base pairs, which do not contribute to RNA stability. In reverse complement, an A-C pair becomes the stable G-U wobble pair.


SOD3

Extracellular superoxide dismutase [Cu-Zn] is an enzyme that in humans is encoded by the "SOD3" gene.
This gene encodes a member of the superoxide dismutase (SOD) protein family. SODs are antioxidant enzymes that catalyze the dismutation of two superoxide radicals into hydrogen peroxide and oxygen. The product of this gene is thought to protect the brain, lungs, and other tissues from oxidative stress. The protein is secreted into the extracellular space and forms a glycosylated homotetramer that is anchored to the extracellular matrix (ECM) and cell surfaces through an interaction with heparan sulfate proteoglycan and collagen. A fraction of the protein is cleaved near the C-terminus before secretion to generate circulating tetramers that do not interact with the ECM.
Among black garden ants ("Lasius niger"), the lifespan of queens is an order of magnitude greater than of workers despite no systematic nucleotide sequence difference between them. The "SOD3" gene was found to be the most differentially over-expressed gene in the brains of queen vs worker ants. This finding raises the possibility that SOD3 antioxidant activity plays a key role in the striking longevity of social insect queens.


Andrew Zydney

Andrew L. Zydney (born October 2, 1958) is an American chemical engineer, currently a Distinguished Professor of Chemical Engineering at Pennsylvania State University and an Elected Fellow of the American Association for the Advancement of Science, American Institute for Medical and Biological Engineering and American Institute of Chemical Engineers.


John Kenneth MacKenzie

John Kenneth MacKenzie (25 August 1850 – 1 April 1888) was an English medical missionary to China. He initially started his work through the London Missionary Society in Hankow in 1875. In Hankow, he treated patients in the London Missionary Society hospital, learned Chinese, and engaged in evangelism. The majority of the cases he treated were eye disease, opium addiction, and cases involving surgery. In 1878, MacKenzie transferred to Tientsin due to the failing health of his wife. In Tientsin, MacKenzie constructed and ran a hospital with the help of the Viceroy's patronage and also established the Tientsin Medical School. MacKenzie also helped in the organisation of the Medical Missionary Association in China and the editing of the "Medical Missionary Journal". He employed evangelism in many parts of his work but died an early death in 1888 due to smallpox.
Early life.
John Kenneth MacKenzie, an English medical missionary to China, was born in Yarmouth, England on 25 August 1850. His father, Alexander Mackenzie, was a Scotsman from Ross-shire and his Welsh mother, Margaret Mackenzie, was from Breconshire. Both sets of grandparents were extremely religious. After moving to Bristol when he was an infant, John MacKenzie's father became deeply attached to Reverend Matthew Dickie at the Presbyterian Church. This created a very religious environment at the MacKenzie household. John was described to be reserved but easily provoked as a child, as well as having a sympathising heart. After attending a private school in Bristol, he wasn't fond of studying so he left school at age fifteen and became a clerk in a merchant's office. MacKenzie started to regularly attend the meetings of the Young Men's Christian Association in Bristol. Even though he stopped attending the meetings, Christianity was still a very strong influence in his life. MacKenzie spoke to his friend Colonel Duncan about how he had an urge to engage in the Lord's work in foreign fields so Colonel Duncan recommended that MacKenzie read a book entitled, "The Double Cure; or, What is a Medical Mission?" After reading his book, MacKenzie decided to ask his parents if he could quit his job and begin to study medicine with the goal of going to China as a medical missionary. MacKenzie's parents agreed and he quickly enrolled into medical school.
Education.
In October 1870, John Kenneth MacKenzie enrolled in the Bristol Medical School and received his M.R.C.S. London and L.R.C.P. Edinburgh diplomas in four short years. While in Edinburgh, MacKenzie met Dr. Lowe, a member of the Edinburgh Medical Missionary Society. MacKenzie had already expressed interest in travelling to China from reading memoirs of Burns and Henderson, but Dr. Lowe strengthened his desire by explaining China's great need of a medical missionary to take charge of a hospital in Hankow. Thus, MacKenzie decided to offer his services to the London Missionary Society for medical missionary work in Hankow. He set off to China on the S.S. Glenlyon on 8 April 1875.
Medical missionary work in China.
Hankow.
On 8 June 1875, MacKenzie was welcomed to Hankow by Mr. and Mrs. Griffith John as well as Mr. Foster, his future colleagues. Hankow, previously known as the "Heart of the Empire", is large and situated in the middle of the central province of Hupeh where the Yang-tse River and the Han River meet. In Hankow, MacKenzie assisted Dr. Reid at the local missionary hospital and dispensary. In addition, MacKenzie also took daily Chinese lessons after work in the hospital. He faced tremendous prejudice because many of the Chinese did not trust the medicine of the foreign on the part of the Christians living in Hankow. But after MacKenzie successfully attended the chief deacon of the Hankow Church, the distrust was alleviated. In August, MacKenzie suffered heavily from Malaria, but recovered in a month and he soon became head doctor at the hospital. Although he was very busy in the hospital, MacKenzie felt the urge to help the surrounding villages in the country-side surrounding Hankow. He and Mr. Joh, a colleague, visited a number of villages where eye disease was the most prevalent cases. At some of the villages they met physical hostility toward foreign Christians, but after meeting with the chief magistrate of the district, the magistrate issued a proclamation through the district and the villagers were much more welcoming the second time around.
 Word of the foreign doctor soon spread all across the province of Hupeh. John MacKenzie cured hundreds of opium smoking patients and thousands of other patients. He discovered that many Chinese doctors were coming to him with questions and he realised that they had little to no knowledge of anatomy of physiology. He began his plans to construct a medical school with the hopes of teaching the Chinese how to perform surgery.
 In December 1876, Dr. MacKenzie travelled to Shanghai to marry Miss Travers, the woman he met while doing Christian work in Bristol. They returned to Hankow and continued their daily work; MacKenzie worked at the hospital and cured an average of 100 patients each day and Miss Travers began to learn Chinese. There was a cholera outbreak that MacKenzie treated and there was also an increase in surgeries, indicating the building trust of the Chinese to western medicine.
Tientsin.
In March 1879, Dr. MacKenzie and his family moved stations from Hankow to Tientsin. This move was due to family matters for the health of his wife was failing and he believed a change in environment would be best. At this time, Dr. MacKenzie also had a daughter named Maggie. Tientsin is located in the North very close to the capital, Beijing. It was the port of the capital at that time. Upon his arrival at Tientsin, the city had no hospital or foreign drugs, only a small dispensary ran by Mr. Pai. MacKenzie used his own money to buy foreign drugs to dispense to people in need but only a few showed up each day. After curing a general one day, he discussed with him his plans of building a new hospital. This information was passed onto the Viceroy of the province who decided to help fund the construction and running of the new hospital. After the completion of the hospital, residents of Tientsin and the surrounding areas came in great numbers to be treated. MacKenzie treated many cases of eye disease, performed many surgeries, and gave out thousands of vaccines. He was assisted in 1887 and 1888 by Dr. Fred Charles Roberts, who would end up succeeding Mackenzie after his death.
Chinese Medical School.
Even though MacKenzie was struggling to keep up with the hospital, he still had the goal of creating a medical school in China to teach the Chinese of western medicine. His proposition was accepted by the government and thus, he received eight students who were to be used as medical officers by the government after their education with MacKenzie. His small medical school was officially opened in December 1881. The structure of the school mirrored that of western schools, with textbooks, exams, and papers. MacKenzie took a break from China in 1883 for five months to return to England to visit his wife and daughter who had moved back after Ms. MacKenzie's health continued to decline. When he returned, six students graduated from the Tientsin Medical School in 1884 after three years of study. MacKenzie withdrew from being involved in the medical school because he didn't want to spend his time raising pupils up to be Government workers.
Late life.
In the autumn of 1886, it was decided that all of the medical missionaries in China should come together and form a society called the Medical Missionary Association of China. MacKenzie was a prominent part in organising this society and also helped edit the society's journal entitled, Medical Missionary Journal. He contributed to the journal a few times. He died on Easter Day, 1888 from smallpox contracted from a patient.


GlobalStem

GlobalStem, Inc. is a biotechnology company based in Rockville, Maryland.
GlobalStem is a provider of laboratory products and services for the stem cell research community. The company is based in Rockville, Maryland and serves an international base of academic, private industry and government customers. The company was founded in 2006 by a team of stem cell researchers who desired to bring to market better quality and more standardized research tools. GlobalStem is engaged in collaborative and strategic partnerships with a number of major companies in the stem cell research field, and is a leading resource center to foster the advancement of human embryonic stem cell research.
Globalstem, Inc. was acquired by Molecular Transfer, Inc. in 2009. In 2015, the newly organized company was rebranded as MTI-GlobalStem.
MTI-GlobalStem was subsequently acquired by Thermo Fisher Scientific in late 2016.


Lacto-rpoB RNA motif

The Lacto-"rpoB" RNA motif is a conserved RNA structure identified by bioinformatics. It has been detected only in lactic acid bacteria, and is always located in the presumed 5' untranslated regions of "rpoB" genes. These genes encode a subunit of RNA polymerase, and it is hypothesized that Lacto-"rpoB" RNA participate in the regulation of these genes.


Thalassicolla

Thalassicolla is a radiolarian genus reported in the Thalassicollidae. The genus contains bioluminescent species. It is a genus of solitary (not colonial) radiolarians.
Species.
The following species are recognized (incomplete list):


Jian Liu (academic)

Jian Liu (born December 20, 1962) is a John & Deborah S. McNeill, Jr. Distinguished Professor at the UNC Eshelman School of Pharmacy, at the University of North Carolina at Chapel Hill. He is also a founder and the chief scientific officer at Glycan Therapeutics.
Academic career.
Education.
Jian Liu received his bachelor degree in chemistry and master degree in biochemistry from Nankai University. He then moved to the University of Iowa in 1988 to obtain his PhD training in medicinal chemistry. After his PhD studies, he joined the Massachusetts Institute of Technology as a postdoctoral fellow in 1993.
Academic Work.
Jian Liu started his independent scientific career as an assistant professor in chemical biology and medicinal chemistry at the University of North Carolina in 2000 and moved to the rank of full professor in 2012. His research interest is in the interface of chemistry and biology of heparin and heparan sulfate. His work covers the understanding of the biosynthetic mechanism of heparan sulfate biosynthesis and the development of heparan sulfate-based medicines. In his work at the Massachusetts Institute of Technology and the early period of his independent career at the University of North Carolina, he isolated the heparan sulfate 3-O-sulfotransferases that are key enzymes responsible for the biosynthesis of heparan sulfate with anticoagulant activity. He then led a research team to discover a chemoenzymatic method to prepare synthetic heparin, a drug to treat blood clotting disorders. He is also engaged in discovering new therapeutic potential of heparan sulfate and chondroitin sulfate through exploiting the anti-inflammatory effects of these molecules. His research team recently announced that a synthetic heparan sulfate 18-mer protects against acute liver injury caused by acetaminophen overdose. The team also discovered that a synthetic chondroitin sulfate E 19-mer attenuates multi-organ damage in endotoxemia mice. Jian Liu also participated in the effort organized by the US FDA and US Pharmacopeia to define the purity standards for heparin drugs. He served as a member of Unfractionated Heparins Ad Hoc Advisory Panel for US Pharmacopeia from 2010 to 2012.


Psirens

"Psirens" is the first episode of science fiction sit-com "Red Dwarf" Series VI and the 31st in the series run. It was first broadcast on the British television channel BBC2 on 7 October 1993. Written by Rob Grant & Doug Naylor and directed by Andy de Emmony. The episode – which involves Psirens who try to lure the crew to them to feast on their brains – had its script published before the episode was broadcast.
Plot.
Dave Lister awakes aboard "Starbug" with amnesia, and encounters Kryten in the ship's dining area. After being helped by him to recover, and bringing both Arnold Rimmer and Cat out of hibernation, the mechanoid explains their situation – for the past 200 years, the crew have been chasing after "Red Dwarf" through its vapour trail, after an unknown party stole it from them following their adventure on the "SSS Esperanto", with Holly having gone offline as a result. Proceeding to continue the pursuit, the group attempt to catch up by taking a shortcut through an asteroid belt, only to discover it is a ship graveyard inhabited by Psirens – shape-changing GELFs who prey on unwary travellers by luring them with psychic visions. Despite their best efforts, the Psirens manage to cause them to crash on an asteroid, forcing Lister to attempt to pry them loose from it.
Once outside, a Psiren begins to overpower him with a powerful illusion, but is killed by a second Psiren disguised as Kryten, whom Lister promptly kills when it calls him "Dave", something the real Kryten would never do. Managing to get back aboard, the others find that a third Psiren has disguised itself as Lister, leaving them unable to determine who is the real one and forced to hold both at gunpoint. To determine which one is false, the crew ask them to play guitar, and shoot the fake when it plays well, knowing the real Lister is terrible despite his belief that he is excellent, determining the Psiren's illusion was based on this belief that his genuine skill set. Wounded, the Psiren disappears, and uses illusions to separate Kryten and put him in the waste compactor, whereupon it proceeds to attack Lister and Cat, after Rimmer's light bee runs out of energy. Kryten, surviving the compactor, manages to kill the Psiren by crushing it with his now cubed-shaped body, allowing the crew to recover and continue pursuing "Red Dwarf".
Production.
This episode features the first appearance of Kochanski since series 2's "Stasis Leak", albeit as a Psiren illusion used to fool Lister. Clare Grogan returned to play Kochanski for the last time. Samantha Robson plays a Psiren that lures him with an illusion of one of his teenage fantasies - Pete Tranter's sister. Jenny Agutter plays another Psiren, this time an illusion of Kryten's creator Professor Mamet. Anita Dobson also appears as Captain Tau, part of the Psiren illusion to fool Lister. The hands of Phil Manzanera appear in the scene in which the fake Lister plays the guitar brilliantly. Zoe Hilson and Elizabeth Anson both appear as Temptresses in a Psiren illusion to tempt the Cat. Race Davies and Janan Kubba had been cast as temptresses but in the end were "not used".
Anita Dobson's guest role came about when Grant and Naylor approached her partner (later husband) Brian May about providing his hands for the sequence where the fake Lister plays guitar. Although May was unavailable, Dobson agreed to play the part of Captain Tau when Grant and Naylor mentioned the possibility to her. The two regretted that—had they known that Dobson was willing and available, they would have written something more substantial for her.
The book "Primordial Soup: The Least Worst Scripts" contained the script for the "Psirens" episode. Edited by Grant Naylor and published by Penguin Books, it was released just a few months before the episode was broadcast.
Cultural references.
The concept of sirens creating illusions to lure unwary travellers to their deaths first appears in Homer's "Odyssey", and this concept is much-repeated in Western film and literature.
Among the derelicts in the asteroid field are models of the Narcissus escape shuttle from "Alien" (1979), the from ' (1975) and a Klingon Vor'cha attack cruiser from '.
Reception.
The episode was first broadcast on the British television channel BBC2 on 7 October 1993 in the 9:00pm time slot. The ratings had yet again increased on the previous series, Sci-Fi.com stated that "though no less funny, the show looks more and more like conventional, plot-driven science fiction." while Sci-Fi Dimensions said "the show was at its best when it was fresh" before adding "these slightly slicker episodes, with their confusing discontinuity, are still some damned funny stuff."


AL-37350A

AL-37350A (4,5-DHP-AMT) is a tryptamine derivative which acts as a potent and selective agonist for the serotonin receptor 5-HT2A, with a Ki of 2.0 nM, and moderate selectivity over the related 5-HT2B and 5-HT2C receptors. It has been shown to have ocular hypotensive activity in animal models, suggesting it may be useful for the treatment of glaucoma.


AtoC RNA motif

The "atoC" RNA motif is a conserved RNA-like structure identified by bioinformatics. It consistently appears upstream of protein-coding gene that are predicted to encode oxidoreductase activity, dihydropteroate synthase (part of folate metabolism) or DNA-binding response regulators.


Glycine reductase

In enzymology, a glycine reductase () is an enzyme that catalyzes the chemical reaction
The 4 substrates of this enzyme are acetyl phosphate, NH3, thioredoxin disulfide, and H2O, whereas its 3 products are glycine, phosphate, and thioredoxin.
This enzyme belongs to the family of oxidoreductases, to be specific, those acting on X-H and Y-H to form an X-Y bond with a disulfide as acceptor. The systematic name of this enzyme class is acetyl-phosphate ammonia:thioredoxin disulfide oxidoreductase (glycine-forming).


N5-(carboxyethyl)ornithine synthase

In enzymology, a N5-(carboxyethyl)ornithine synthase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are N5-(L-1-carboxyethyl)-L-ornithine, NADP+, and H2O, whereas its 4 products are L-ornithine, pyruvate, NADPH, and H+.
Nomenclature.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is N5-(L-1-carboxyethyl)-L-ornithine:NADP+ oxidoreductase (L-ornithine-forming). Other names in common use include 5-N-(L-1-carboxyethyl)-L-ornithine:NADP+ oxidoreductase, and (L-ornithine-forming).