Charles Maitland (physician)

Charles Maitland (–1748) was a Scottish surgeon who inoculated people against smallpox.
Career.
In March 1718, Lady Mary Wortley Montagu had Maitland, who was then serving in the British embassy in Constantinople, Turkey, inoculate her five-year-old son Edward. The process was done by an elderly Greek woman from Pera under Maitland's direction. Montague did not tell her husband until a week after when it proved to be successful.
They returned to London in April 1721, when Montagu requested that her daughter Mary, who was four, be inoculated. Maitland reluctantly agreed if there were other witnesses present, so three physicians from the Royal College of Physicians were there for the procedure, the first professional inoculation in England. One of the witnesses, James Keith, was so pleased by the success that he had Maitland inoculate his six-year-old son; Keith's other children had all died of smallpox. The Montague family promoted inoculation in England, calling it a "useful invention".
On 9 August 1721, Maitland received a Royal Licence that allowed him to test variolation on six prisoners from Newgate Prison. The experiment took place in August 1722, under the direction of Sir Hans Sloane. All prisoners survived, and they were pardoned later that year. One prisoner who was exposed to the disease proved to be immune.
In late 1722, Caroline of Ansbach ordered the inoculation of five orphans of St. James's Parish in London. Following their success, Caroline had Maitland inoculate her eldest son, Frederick and one other child.
The surgeon died in Aberdeen, Scotland in 1748.


Falck-Hillarp method of fluorescence

The Falck-Hillarp method of fluorescence (the F-H method) is a technique that makes it possible to demonstrate and study, with unique precision and susceptibility, certain monoamines, among those the three catecholamines dopamine, noradrenaline, and adrenaline, as well as serotonin and related substances.
The method is based on the important and decisive discovery that these compounds are able to react with formaldehyde – in near complete absence of water – to form fluorophores, i.e. molecules that, when irradiated with light invisible to the eye, will emit visible light. This happens in a “dry” state, without extracting the monoamines from the cells during the entire procedure, a process that starts with separation of a tissue sample and ends with a thin tissue slice that can be examined in a fluorescence microscope.
The F-H method allowed, for the first time, the examiner to watch these monoamines light up in the microscope and to precisely determine in which cells they were present, and thereby understanding their functions. The method was developed by Bengt Falck and Nils-Åke Hillarp in the 1960s at the Department of Histology, University of Lund. For intense neurobiological research it became possible to demonstrate the presence of monoamines in nerve cells belonging to the central and the peripheral nervous system and for the first time comprehend that these substances act as signal substances, i.e. transmitters.
The initial publication, written already in 1961, described a wide-ranging examination of nerves supplying a large number of organs in the body. This work validated the concept of Ulf von Euler, the Nobel prize winner, that noradrenaline is the signal substance in peripheral autonomic nerves. In the same year, this first publication was followed by an explanation of the chemical background of the F–H method.
Very thin membranes, such as the rat iris or mesentery, do not have to be sectioned for microscopic studies but may simply be spread on glass, dried, and then exposed to gaseous formaldehyde for subsequent study with a fluorescence microscope.
The publication on the chemical background was later named among "The 200 Most-Cited Papers of All Time".
In 2012, the Faculty of Medicine at the University of Lund arranged a symposium “From Nerve to Pills” celebrating the 50th anniversary of the initial publication of the F-H method.


Infected (novel)

Infected is a science fiction novel by author Scott Sigler. The novel was initially released in 2006 in podcast format with a print release in 2008 by Crown Publishing, with Sigler continuing to offer the podcast version online. The book was initially titled "Infested", with the name changing in order to distance itself from a movie releasing with a similar title.
Plot.
The book follows several characters as they deal with an alien invasion on the microscopic level. The narration is primarily through the perspectives of Perry Dawsey, an ex-football player with an anger problem, and Margaret Montoya, an epidemiologist with the CDC who is investigating a strange disease that turns seemingly normal people into murderers.
Reception.
Critical reception for "Infected" has been mixed, with Monsters and Critics praising the book's action and pacing. The San Francisco Chronicle panned the book, stating that the book's intensity "might work in a series of cliff-hanging audio episodes, but as a novel to be read in a few sittings, "Infected" can't rise above its overheated prose and rote characterizations. The Guardian also reviewed "Infected", criticizing the book's "portentous cliff-hangers and one-dimensional characters".
The Sacramento News's Bibliolatry praised "Infected", calling it "imaginative, gross, frightening, suspenseful, funny, thought-provoking and sick in the "omigawd-I-wanna-barf" way". BookReporter and Publishers Weekly also positively reviewed the book, with BookReporter citing the character of Perry Dawsey as the "heart" of the book.
Adaptations.
Film.
"Infected" was formerly optioned by Rogue Pictures and Random House Films, with the option having lapsed in 2010.
Graphic novel.
In 2010 work began on a graphic novel adaptation of Sigler's "Infected", with the series to be published by IDW in the summer of 2012. The first issue was released August 1, 2012, but the series was put on hold indefinitely due to delays with subsequent issues.


Department of Chemical Engineering and Biotechnology, University of Cambridge

The Department of Chemical Engineering and Biotechnology (CEB) is one of the teaching and research departments at the University of Cambridge. The department trains undergraduate students and conducts original research at the interfaces between engineering, chemistry, biology and physics. It conducts research in collaboration with industrial partners. Its research programmes encompass sustainable reaction engineering, chemical product and process design, healthcare, measurement, and materials science. It conducts biotechnology research with chemical engineering at the science-engineering interface.
Notable staff.
 notable staff include
Heads of department.
These include heads of the former Department of Chemical Engineering and Institute of Biotechnology which merged to form the current department.
Alumni.
Former staff include:
History.
In 1945, the University received an endowment from Shell for a chemical engineering department and chair. The first Shell Professor was Terence Fox, appointed in 1946. The undergraduate Tripos course began in 1948. Peter Danckwerts was head of department from 1959 to 1975 and then John Davidson became Shell Professor and Head of department in 1975. He held the post until 1993 when he retired.
in 2008, the Department of Chemical Engineering merged with the Institute of Biotechnology to become the Department of Chemical Engineering and Biotechnology.
Until 2017, the department's main centre of activity was the Shell building on Pembroke Street on the New Museums Site, to the south of Cambridge city centre. In 2017, the department moved over to a new building on Philippa Fawcett Drive on the West Cambridge site.
The building was officially opened by the Chancellor of the University, David Sainsbury, Baron Sainsbury of Turville, on 24 April 2018.


Michael Barber (chemist)

Michael (Mickey) Barber, (3 November 1934 – 8 May 1991) was a British chemist and mass spectrometrist, best known for his invention of fast atom bombardment ionisation.
Biography.
On 3 November 1934, Barber was born at his family's home in Manchester at 166 Lodge Lane in Newton. His family were working-class and underprivileged. Barber was one of two boys; his brother Peter, born in 1927, was seven years his elder. His father, Joseph Barber, was a carpenter.
He went to Manchester Grammar School and was then educated at the Queen's College, Oxford, obtaining his B.A. in 1958 and his B.Sc. in 1959. There he worked with Jack Linnett and they designed and built a mass spectrometer for
the analysis of flames. He married Joan Gaskell in 1958, the coupled had three children.
In 1961 he returned to Manchester to work at the Scientific Instruments division of Associated Electrical Industries. There, he and Martin Elliott developed a method to study the fragmentation of ions with a mass spectrometer and started to work on X-ray photoelectron spectroscopy. In 1973 he took up a lectureship position at UMIST and was promoted to Professor in 1985. In the same year, 1985, he was also elected a Fellow of the Royal Society. He remained at Manchester until his death.
Fast atom bombardment.
Fast atom bombardment (FAB) is a method of ionization used in mass spectrometry that uses a beam of high energy atoms strikes a surface to create ions. An energetic beam of atoms or ions will destroy an organic molecule under conditions typically used to create secondary ions. Barber realised that mixing the compound of interest with a vacuum compatible low-volatility liquid such as glycerol effectively protected the organic molecule and allowed it to be ionized and detected. The protecting liquid "matrix" allowed compounds as large as 10,000 Da molecular mass to be detected. The concept of a protecting matrix was later used in matrix-assisted laser desorption ionization. The FAB technique was employed by Barber, Howard Morris (biochemist) and co-workers for early peptide sequencing experiments.
Honours and distinctions.
The Michael Barber Centre for Collaborative Mass Spectrometry, based at the University of Manchester, is named in honour of him.


Stealth Bastard

Stealth Bastard: Tactical Espionage Arsehole is a 2D platform video game developed by Curve Studios and published by Curve Digital. Its mechanics revolve around stealth, and the gameplay has been likened to that of "Metal Gear Solid" and "Super Meat Boy". The player controls a goggle-wearing clone who must make his way through a testing facility filled with hazards and robot sentries by staying in the shadows, risking instant death if he is spotted by an enemy. The game was released on 4 November 2011 as "Stealth Bastard" as a free download for Microsoft Windows. An expanded version, "Stealth Bastard Deluxe", was released for Windows via Steam the following November. It subsequently became available for OS X and Linux in April 2013 along with "The Teleporter Chambers" downloadable content released the previous month. In June 2013, it was released for Android as part of the Humble Bundle with Android 6, including DRM-free versions for Windows, Mac OS and Linux and its soundtrack. Versions for the PlayStation 3 and PlayStation Vita were also released in July 2013 under the name Stealth Inc: A Clone in the Dark. Curve have also announced plans to release the game for iPad and iPhone. In February 2014 a PlayStation 4 version of the game titled the "Ultimate Edition" was announced. It contains two DLC expansions "The Teleporter Chambers" and "The Lost Clones" and was released in March 2014. On 1 May 2014, a sequel, "", was announced for the Wii U. It was released on 30 October 2014. The Microsoft Windows, PlayStation 3, PlayStation 4, PlayStation Vita, and Xbox One version was also announced. The sequel, "Stealth Inc. 2", was released in April 2015 for Xbox One, PlayStation 4 and PC.


Synapse (comics)

Synapse is the name of two different fictional characters appearing in American comic books published by Marvel Comics.
Publication history.
The first Synapse, Max Mullins, first appeared in "Daredevil" #377 (July 1998) and was created by Scott Lobdell and Tom Morgan.
The second Synapse, Emily Guerrero, was introduced as a new member of the Avengers. She first appeared in "Uncanny Avengers" Vol. 3 #1 (December 2015) and was created by Gerry Duggan and Ryan Stegman.
Fictional character biography.
Max Mullins.
Max Mullins has the ability to rewire and alter a person's brainwaves to his liking. Taking on the name Synapse he, along with La Concierge and Stilt-Man, were recruited by the Kingpin to form the third incarnation of the Emissaries of Evil. One of the first things he did was shut down Stilt-Man's brain, albeit temporarily, so that he would not reveal his employer's name to Daredevil, who at the time was acting as an agent for S.H.I.E.L.D. and had his mind wiped to think he was Laurent Levasseur. While La Concierge was battling Laurent, Synapse was holding Dr. Claudia DuBois hostage along with Wilson Fisk. Tired of being pushed around, Synapse planned on using his powers on Fisk, but Fisk, who had a stronger mind, knew of Synapses plot and threatened to kill him if he did not continue to work under him. Eventually, Fisk has Synapse use his powers on Laurent, but it instead reminds him that he is Daredevil and knocks out Synapse with one kick.
Emily Guerrero.
Emily Guerrero lived with her younger brother and grandfather, Ivan, when the Terrigen Cloud affected their area. Emily emerged as an Inhuman while her grandfather also emerged where he took the name Shredded Man. Later, she joined the Avengers Unity Division under Captain America's leadership. Despite being new, Steve Rogers had faith in her even though she and teammate Rogue did not get along very well. She fought Super-Adaptoid by getting a flock of pigeons to take it out.
Powers and abilities.
The Emily Guerrero version of Synapse possesses telepathy, animal control, enhanced speed and super strength.


Lactis-plasmid RNA motif

The "lactis"-plasmid RNA motif is a conserved RNA structure identified by bioinformatics. The RNAs are restricted to lactic acid bacteria, and are especially common in "Lactococcus lactis". They typically lie near to "repB" genes, and are almost found in plasmids. This data suggested that "lactis"-plasmid RNAs participate in the control of plasmid abundance. However, many of the plasmids that carry "lactis"-plasmid RNAs also carry ctRNA-pND324 RNAs, which are involved in plasmid copy count regulation. Therefore "lactis"-plasmid RNAs might have a different function.


LP-44

LP-44 is a drug which acts as a potent and selective agonist at the 5HT7 serotonin receptor. While LP-44 is less selective than the related compound LP-12, it has been more widely used in research and has been used to show the complex role of 5-HT7 receptors in several aspects of brain function, including regulation of the sleep-wake cycle and roles in stress, learning and memory.


Mycena sanguinolenta

Mycena sanguinolenta, commonly known as the bleeding bonnet, the smaller bleeding Mycena, or the terrestrial bleeding Mycena, is a species of mushroom in the family Mycenaceae. It is a common and widely distributed species, and has been found in North America, Europe, Australia, and Asia. The fungus produces reddish-brown to reddish-purple fruit bodies with conic to bell-shaped caps up to wide held by slender stipes up to high. When fresh, the fruit bodies will "bleed" a dark reddish-purple sap. The similar "Mycena haematopus" is larger, and grows on decaying wood, usually in clumps. "M. sanguinolenta" contains alkaloid pigments that are unique to the species, may produce an antifungal compound, and is bioluminescent. The edibility of the mushroom has not been determined.
Taxonomy.
First called "Agaricus sanguinolentus" by Johannes Baptista von Albertini, the species was transferred to the genus "Mycena" in 1871 by German Paul Kummer, when he raised many of Fries' "tribes" to the rank of genus. The specific epithet is derived from the Latin word "sanguinolentus" and means "bloody". It is commonly known as the "bleeding bonnet" the "smaller bleeding Mycena", or the "terrestrial bleeding Mycena".
The fungus is classified in the section "Lactipedes" along with other latex-producing species. A molecular phylogenetic analysis of several dozen European "Mycena" species suggests that "M. sanguinolenta" is closely related to . Other phylogenically related species include and .
Description.
The cap of "M. sanguinolenta" is either convex or conic when young, with its margin pressed against the stipe. As it expands, it becomes broadly convex or bell-shaped, ultimately reaching a diameter of . The surface is initially covered with a dense whitish-grayish coating or powder that is produced by delicate microscopic cells, but these cells soon collapse and disappear, leaving the surface naked and smooth. The surface is moist with an opaque margin that soon developing furrows. The cap color is variable but always some shade of bright or dull reddish brown with a dull grayish-brown margin. The flesh is thin, not very fragile, sordid reddish, and exudes a reddish latex when cut. The odor and taste are not distinctive.
The gills are adnate or slightly toothed, and well-spaced. They are narrow to moderately broad, sordid reddish to grayish, with even edges that are dark reddish brown. The stipe is long, 1–1.5 mm thick, equal in width throughout, and fragile. The base of the stipe is covered with coarse, stiff white hairs, while the remainder is covered with a drab powder that soon sloughs off to leave the stipe polished, and more or less the same color as the cap. It also exudes a bright or dull-red juice when cut or broken. The edibility of the mushroom is unknown—but it is considered too insubstantial to be of culinary interest.
The spores are 8–10 by 4–5 μm, roughly ellipsoid, and only weakly amyloid. The basidia (spore-bearing cells) four-spored (occasionally two- or three-spored). The pleurocystidia (cystidia on the face of a gill) are rare to scattered or sometimes quite abundant, narrowly to broadly ventricose, measuring 36–54 by 8–13 μm. They are filled with a sordid-reddish substance. The cheilocystidia (cystidia on the gill edge) are similar to the pleurocystidia or shorter and more obese, and very abundant. The flesh if the gill is made of broad hyphae the cells of which are often vesiculose (covered with vesicles) in age, and stain pale reddish brown in iodine. The flesh of the cap is covered with a thin pellicle, and the hypoderm (the layer of cells immediately underneath the pellicle) is moderately well-differentiated. The remainder of the cap flesh is floccose and filamentous, and all except the pellicle stain pale vinaceous-brown in iodine. Lactiferous (latex-producing) hyphae are abundant.
Similar species.
The other "bleeding Mycena" () is readily distinguished from "M. sanguinolenta" by its larger size, different color, growth on rotting wood, and presence of a sterile band of tissue on the margin of the cap. Further, "M. sanguinolenta" consistently has red-edged gills, while the gill edges of "M. haematopus" are more variable. The similarly named has red to orange juice, is slightly yellower, and does not have pleurocystidia. has a similar furrowed cap, but also has a tough stipe and does not ooze liquid when injured. "Mycena" specialist Alexander H. Smith has noted a "striking" resemblance to , but this species has different colors (pale vinaceous brown or sordid brown when faded), produces uncolored latex, and does not have differently-colored gill edges.
Distribution and habitat.
"Mycena sanguinolenta" is common and widely distributed. It has been found from Maine to Washington and south to North Carolina and California in the United States, and from Nova Scotia to British Columbia in Canada. In Jamaica, it has been collected at an elevation of . The distribution includes Europe (Britain, Germany, The Netherlands, Norway, Romania and Sweden) and Australia. In Asia, it has been collected from the alpine zone of the Changbai Mountains in Jilin Province, China, and from the provinces of Ōmi and Yamashiro in Japan.
The fruit bodies grow in groups on leaf mold, moss beds, or needle carpets during the spring and fall. It is common in forests of fir and beech, and prefers to grow in soil of high acidity.
Chemistry.
The fruit bodies of "Mycena sanguinolenta" contain the blue alkaloid pigments, sanguinones A and B, unique to this species. It also has the red-colored alkaloid sanguinolentaquinone. The sanguinones are structurally related to mycenarubin A, made by "M. rosea", and the discorhabins, a series of compounds produced by marine sponges. Although the function of the sanguinones is not known, it has been suggested that they may have "an ecological role ... beyond their contribution to the color of the fruiting bodies, ... since predators rarely feed on fruiting bodies". When grown in pure culture in the laboratory, the fungus produces the antifungal compound hydroxystrobilurin-D. "M. sanguinolenta" is one of over 30 "Mycena" species that is bioluminous.


MMP2

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the "MMP2" gene. The "MMP2" gene is located on chromosome 16 at position 12.2.
Function.
Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix (ECM) in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. This gene encodes an enzyme which degrades type IV collagen, the major structural component of basement membranes. The enzyme plays a role in endometrial menstrual breakdown, regulation of vascularization and the inflammatory response. The role of MMP2 in lymphangiogenesis was considered in a modelling and theoretical study; MMP2 degrades collagen I to switch on different patterning mechanisms for VEGFC.
Activation.
Activation of MMP-2 requires proteolytic processing. A complex of membrane type 1 MMP (MT1-MMP/MMP14) and tissue inhibitor of metalloproteinase 2 recruits pro-MMP 2 from the extracellular milieu to the cell surface. Activation then requires an active molecule of MT1-MMP and auto catalytic cleavage. Clustering of integrin chains promotes activation of MMP-2. Another factor that will support the activation of MMP-2 is cell-cell clustering. A wild-type activated leukocyte cell adhesion molecule (ALCAM) is also required to activate MMP-2.
Clinical significance.
Mutations in the MMP2 gene are associated with Torg-Winchester syndrome, multicentric osteolysis, arthritis syndrome, and possibly keloids.
Role of MMP-2 in chronic disease.
Activity of MMP-2 relative to the other gelatinase (MMP-9) has been associated with severity of chronic airway diseases including Idiopathic interstitial pneumonia and Bronchiectasis. In idiopathic interstitial pneumonia, MMP-2 activity was elevated in patients with the less severe disease phenotype which is more responsive and reversible with corticosteroid therapy. In non-cystic fibrosis bronchiectasis, MMP-2 concentration was elevated in patients with Haemophilus influenzae airway infection compared to Pseudomonas aeruginosa airway infection. Bronchiectasis patients with P. aeruginosa infection have a more rapid decline in lung function.
Altered expression and activity levels of MMPs have been strongly implicated in the progression and metastasis of many forms of cancer. Increased MMP-2 activity has also been linked with a poor prognosis in multiple forms of cancer including colorectal, melanoma, breast, lung, ovarian, and prostate. Furthermore, changes in MMP-2 activity can come from alterations in levels of transcription, MMP secretion, MMP activation, or MMP inhibition. MMP production in many cancers may be upregulated in surrounding stromal tissue rather than simply in the tumor lesion. For instance, Mook, et al. showed that MMP-2 mRNA levels are strikingly similar between metastatic and non-metastatic lesions in colorectal cancer, but metastatic cases are correlated with higher levels of MMP-2 mRNA in surrounding healthy tissue. For this reason, it is difficult to fully understand the complex role of MMPs in cancer progression.
Role in cancer cell invasion.
One of the major implications of MMPs in cancer progression is their role in ECM degradation, which allows cancer cells to migrate out of the primary tumor to form metastases. More specifically, MMP-2 (along with MMP-9) is capable of degrading type IV collagen, the most abundant component of the basement membrane. The basement membrane is important for maintaining tissue organization, providing structural support for cells, and influencing cell signaling and polarity. Degradation of the basement membrane is an essential step for the metastatic progression of most cancers.
Cancer cell invasion, ECM degradation, and metastasis are highly linked with the presence of invadopodia, protrusive and adhesive structures on cancer cells. Invadopodia have been shown to concentrate MMPs (including MT1-MMP, MMP-2, and MMP-9) for localized release and activation. Furthermore, degradation products of MMP activity may further promote invadopodia formation and MMP activity. Finally, MMP-2 and several other MMPs have been shown to proteolytically activate TGF-β, which has been shown to promote epithelial mesenchymal transition (EMT), a key process involved in cancer metastasis.
Role in cell signaling.
MMP degradation of the ECM affects cellular behavior through changes in integrin-cell binding, by releasing growth factors harbored by the ECM, by generating ECM degradation products, and by revealing cryptic binding sites in ECM molecules. For instance, MMP-2 degradation of collagen type I can reveal a previously inaccessible cryptic binding site that binds with the αvβ3 integrin expressed by human melanoma cells. Signaling through this integrin is necessary for melanoma cell viability and growth in a collagen matrix and can potentially rescue the cells from apoptosis. As another example, cleavage of laminin-5, a component of the basement membrane, by MMP-2 has been shown to reveal a cryptic site inducing migration of breast epithelial cells.
More generally, by degrading the ECM, MMPs release growth factors that were previously bound to the ECM, allowing them to bind with cell receptors and influence cell signaling. Furthermore, many MMPs also activate other proMMPs along with growth factors. MMP-2 has also been shown to cleave other non-ECM substrates including growth factors such as TGF-β, FGF receptor-1, proTNF, IL-1β and various chemokines. For instance, MMP-2 has been implicated, along with MMP-9 in cleaving latent TGF-β, which has complex interactions with cancer cells. TGF-β generally plays a role in maintaining tissue homeostasis and preventing tumor progression. However, genetically unstable cancer cells can often evade regulation by TGF-β by altering TGF-β receptors in downstream signaling processes. Furthermore, expression of TGF-β is also correlated with immune tolerance and may help shield cancer cells from immune regulation.
Role in neovascularization and lymphangiogenesis.
MMP-2 also plays an important role in the formation of new blood vessels within tumors, a process known as angiogenesis. This process is essential for tumor progression, because as tumors grow they need increasing supplies of oxygen and nutrients. Localized MMP-2 activity plays an important role in endothelial cell migration, a key feature of angiogenesis. Additionally, MMP-9 and other MMPs have been suggested to also play a complex, indirect role in angiogenesis by promoting VEGF mobilization and generating antiangiogenic factors.
For instance, when studying carcinogenesis of pancreatic islets in transgenic mice, Bergers et al. showed that MMP-2 and MMP-9 were upregulated in angiogenic lesions and that the upregulation of these MMPs triggered the release of bioactive VEGF, a potent stimulator of angiogenesis. Additionally, the group determined that MMP-2 knockout mice showed decreased rates of tumor growth relative to tumor growth rates in wild type mice. Furthermore, increased expression and activity of MMP-2 has been tied to increased vascularization of lung carcinoma metastases in the central nervous system, which likely increases survival rate of these metastases.
Finally, MMP-2 has been also shown to drive lymphangiogenesis, which is often excessive in tumor environments and can provide a route of metastasis for cancer cells. Detry, et al. showed that knocking down "mmp2"
in zebrafish prevented the formation of lymphatic vessels without altering angiogenesis, while MMP-2 inhibition slowed the migration of lymphatic endothelial cells and altered the morphology of new vessels. These results suggest that MMP-2 may alter tumor viability and invasion by regulating lymphangiogenesis in addition to angiogenesis.
Inhibition of MMP-2 as cancer therapy.
Clinical trials for cancer therapies using MMP inhibitors have yielded generally unsuccessful results. These poor results are likely due to the fact that MMPs play complex roles in tissue formation and cancer progression, and indeed many MMPs have both pro and anti-tumorogenic properties. Furthermore, most clinical studies involve advanced stages of cancer, where MMP inhibitors are not particularly effective. Finally, there are no reliable biomarkers available for assessing the efficacy of MMP inhibitors and MMPs are not directly cytotoxic (so they do not cause tumor shrinkage), so it is difficult for researchers to determine whether the inhibitors have successfully reached their targets.
However, initial clinical trials using broad spectrum MMP inhibitors did show some positive results. Phase I clinical trials showed that MMP inhibitors are generally safe with minimal adverse side effects. Additionally, trials with marimastat did show a slight increase in survival of patients with gastric or pancreatic cancer.
Various research groups have already suggested many strategies for improving the effectiveness of MMP inhibitors in cancer treatment. First, highly specific MMP inhibitors could be used to target the functions of specific MMPs, which should allow doctors to increase the treatment dosage while minimizing adverse side effects. MMP inhibitors could also be administered along with cytotoxic agents or other proteinase inhibitors. Finally, MMP inhibitors could be used during earlier stages of cancer to prevent invasion and metastasis.
Additionally, tumor overexpression of MMPs can be used to potentially target the release of chemotherapeutic agents specifically to tumor sites. For instance, cytotoxic agents or siRNA could be encapsulated in liposomes or viral vectors that only become activated upon proteolytic cleavage by a target MMP. Finally, the tumor-targeting properties of MMP inhibitors offer a potential strategy for identifying small tumors. Researchers could couple MMP inhibitors to imaging agents to help detect tumors before they spread. Though initial trials yielded disappointing results, MMP inhibitors offer significant potential for improving cancer treatment by slowing the process of cancer cell invasion and metastasis.
Interactions.
MMP2 has been shown to interact with:


HgcG RNA

The HgcG RNA gene is a non-coding RNA that was identified computationally and experimentally verified in AT-rich hyperthermophiles. The genes from this screen were named "hgcA" through "hgcG" ("high GC"). "HgcG" is of unknown function. "hgcG" is significantly similar to a region of the "Archaeoglobus fulgidus" genome. The genes were named hgcA through hgcG ("high GC"). It was later identified as Pab40 H/ACA snoRNA with rRNA targets.


Pyrroline-2-carboxylate reductase

In enzymology, a pyrroline-2-carboxylate reductase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are L-proline, NAD+, and NADP+, whereas its 4 products are 1-pyrroline-2-carboxylate, NADH, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is L-proline:NAD(P)+ 2-oxidoreductase. This enzyme is also called Delta1-pyrroline-2-carboxylate reductase. This enzyme participates in lysine degradation and arginine and proline metabolism.


Trends in Biotechnology


Metkefamide

Metkefamide (INN; LY-127,623), or metkephamid acetate (USAN), but most frequently referred to simply as metkephamid, is a synthetic opioid pentapeptide and derivative of [Met]enkephalin with the amino acid sequence Tyr--Ala-Gly-Phe-("N"-Me)-Met-NH2. It behaves as a potent agonist of the δ- and μ-opioid receptors with roughly equipotent affinity, and also has similarly high affinity as well as subtype-selectivity for the κ3-opioid receptor.
Despite its peptidic nature, upon systemic administration, metkefamide rapidly penetrates the blood-brain-barrier and disperses into the central nervous system where it produces potent, centrally-mediated analgesic effects, of which have been shown to be dependent on activity at both the μ- and δ-opioid receptors. In addition, on account of modifications to the N- and C-terminals, metkefamide is highly stable against proteolytic degradation relative to many other opioid peptides. As an example, while its parent peptide, [Met]enkephalin, has an "in vivo" half-life of merely seconds, metkefamide has a half-life of nearly 60 minutes, and upon intramuscular administration, has been shown to provide pain relief that lasts for hours.
Likely on account of its δ-opioid activity, clinical trials have found metkefamide to possess less of a tendency for producing many of the undesirable side effects usually associated with conventional opioids such as respiratory depression, tolerance, and physical dependence. However, it has been shown to cause some additional side effects that are considered unusual for standard opioid analgesics like sensations of heaviness in the extremities and nasal congestion—though these were not considered to be particularly distressing—and it has also been shown to raise the seizure threshold in animals. In any case, clinical development was not further pursued after phase I clinical studies and metkefamide never reached the pharmaceutical market.


Prince George of Imereti

George () (1778 – 20 November 1807) was a Georgian prince of the Bagrationi house of Imereti and claimant to the crown of Imereti. He was the ancestor of the Bagration-Imeretinsky, princes of the Russian Empire.
George was the only son of Alexander, son of Solomon I of Imereti, of his marriage with Princess Darejan née Tsulukidze, which was not authorized by the church. Alexander had led an abortive revolt against Solomon in 1778, but then reconciled with him. He died before his father and Solomon's death in 1784 left the issue of Imeretian succession open to rivaling claims. George was designed as heir apparent at Solomon's death, but was prevented from being crowned by Solomon's cousin David II, who was in turn overthrown by Solomon's nephew Solomon II. The latter arrested George as a pretender to the throne and imprisoned him at the Mukhuri castle in 1795. George was able to escape on 15 October 1806 and fled to the Russian Empire where he spent his last years, writing memoirs of his life. He died of smallpox at St. Petersburg and was buried there, at the St. Alexander Nevsky Convent.
George was married to Princess Darejan, of the Eristavi of Racha (1779–1816), and fathered two sons – Alexander and Dimitry Bagration-Imeretinsky, both generals of the Russian army. Darejan and her sons were deported from Imereti to Russia proper after the Russian conquest of that kingdom in 1810.


Deoxyadenosine monophosphate

Deoxyadenosine monophosphate (dAMP), also known as deoxyadenylic acid or deoxyadenylate in its conjugate acid and conjugate base forms, respectively, is a derivative of the common nucleic acid AMP, or adenosine monophosphate, in which the -OH (hydroxyl) group on the 2' carbon on the nucleotide's pentose has been reduced to just a hydrogen atom (hence the "deoxy-" part of the name). Deoxyadenosine monophosphate is abbreviated dAMP. It is a monomer used in DNA.


Moprolol

Moprolol is a beta-adrenergic antagonist, or beta blocker. Typically moprolol is prescribed to treat hypertension, high blood pressure, anxiety, and glaucoma. Moprolol was first introduced by SIMS, or S.p.A. Societa Italiana Medicinali e Sintetici, in 1982. SIMS is a private Italian company that has been present in the pharmaceutical industry since 1937. In 1972 SIMS first submitted a Drug Master file to the US FDA and has continued to do so over the years. In addition to formulating moprolol SIMES has also manufactured Omeral and Levotensin, derivatives of moprolol.
Regulation history.
Moprolol was prominent in both literature and clinical trials up until the 1990s. At this point moprolol was pulled from the market. This could have been for a number of reasons, including FDA recalls and ineffective formulations. Through some clinical trials it was seen that moprolol was not as effective for treating blood pressure as originally thought, and this will be covered in the clinical section.
Even though there were no specific FDA recalls issued for moprolol, the FDA has issued warnings to SIMS. In 2000 the FDA and the United States Department of Health and Sciences issued a warning letter to the SIMS facility. In this letter it stated that during a routine inspection of the SIMS facility it was found that there were significant deviations from the US good manufacturing practices when manufacturing active pharmaceutical ingredients. SIMS was then notified that until these deviations were corrected and another FDA inspection was completed the FDA will disapprove any applications for active pharmaceutical ingredients from the SIMS facility.
Then in June 2015 the FDA issued an Import alert including SIMS. This alert stated that some active pharmaceutical ingredients appeared to be misbranded. Therefore, any active pharmaceutical ingredients can be refused admission if the facility they are from is listed in this alert.
Before being pulled from the market moprolol was a prescription drug, meaning it must be prescribed from a doctor, and could not be given over the counter.
Clinical studies.
Moprolol has been the subject for many clinical trials to study the effect moprolol has on both blood pressure and glaucoma.
In many hypertension and blood pressure studies the moprolol is prescribed as a tablet given once a day, typically on a schedule. For glaucoma studies moprolol is typically prescribed as an ophthalmic solution where ½ a drop of 1% moprolol solution was given 2 to 3 times a day. The specific dosages and concentrations can vary depending on the severity of the condition.
One significant clinical study in hypertension ran in 2013 using non-selective beta-blocker to study the effects on lowering blood pressure. In this study 30 participants were given 75 mg of moprolol twice a day. Through this study it was found that moprolol had no significant effect on lowering the heart rate.
Another important clinical trial for the treatment of glaucoma with moprolol was conducted in 1994. This was a double-blind prospective trial to test the efficacy of lowering intraocular pressure when using l-moprolol alone and in combination with dipivefrine. In this study 27 patients that had glaucoma or ocular hypertension were given l-moprolol eye drops twice a day for 4 weeks. After this a combination of l-moprolol and dipivefrin eye drops were given for another 4 weeks. Through this study it was found that l-moprolol was a good treatment for glaucoma but that a treatment consisting of a combination of hypertension medications can have a greater effect at lowering ocular pressure.
Both studies show that moprolol, or its derivatives, has some effect at lowering blood pressure but may not have an effect on the heart rate. This opens a way for future studies, especially in the treatment for glaucoma.
Commercialization.
Moprolol was first patented by SIMS in 1987 under US patent number 4647590. In this patent SIMS states that moprolol can be used to treat glaucoma when administered locally as well as arterial hypertension. Then it goes into the studies conducted that proved the effectiveness of moprolol to treat these conditions without having the side effects of treatments on the market. This led to many other patents over the years, a few of which are listed in the table below:
As previously mentioned moprolol is currently off the market, most likely due to the SIMS facility being in violation of US good manufacturing practices. This means that currently there are no sales being brought in by moprolol.
That being said there is still a huge market for moprolol, both for hypertension and glaucoma treatment. A similar beta-blocker, metoprolol, that is very popular both overseas and in the US brought in an estimated €2.2 million in 2010 in Europe. Metoprolol is also sold for $2.93-$0.76 per pill here in the US. Since moprolol and metoprolol both treat hypertension the market and estimated sales should be the same, all of which is reasonable for this type of non-invasive treatment.


NDPCP

5'-guanosyl-methylene-triphosphate (GDPCP) and 5'-adenosyl-methylene-triphosphate (ADPCP) are analogues of guanosine 5'-triphosphate (GTP) and adenosine 5'-triphosphate (ATP), which store chemical energy from metabolism in the cell. Hydrolysis of nucleoside triphosphates (NTPs) such as ATP and GTP yields energy, inorganic phosphate (Pi or PPi), and either NDP or NMP. GDPCP and ADPCP are not subject to hydrolysis under the same conditions as NTPs; it is this property which makes them useful in experiments in biochemistry and molecular biology.
NTPs can be hydrolyzed at the phosphodiester bonds between phosphates, releasing energy and one or more of the three phosphate groups. Additionally, NTPs are inextricable components of some proteins, where their role may be structural and need not involve hydrolysis. In some cases, the presence of an NTP may be required for association of one protein with another, while hydrolysis is necessary for dissociation. GDPCP and ADPCP could be used in such a case, since association can still occur, but hydrolysis-dependent dissociation cannot.
GDPCP was used to examine the prokaryotic elongation factor EF-Tu. EF-Tu is required for the elongation phase of protein synthesis (translation). EF-Tu requires GTP in order for the ribosome to bind it, necessary for recruiting an aminoacyl-tRNA. The later dissociation of EF-Tu from the ribosome, however, requires that the GTP first be hydrolyzed to GDP and Pi. GDPCP was used in place of GTP to differentiate between these two steps: the elongation factor could associate, but without hydrolysis, it was effectively stuck.


Orly Yadid-Pecht

Orly Yadid-Pecht is a Professor of Electrical and Computer Engineering and Alberta Innovates Technology Futures Strategic Chair of Integrated Intelligent Sensors at the University of Calgary. She develops CMOS based imaging devices for biomedical sensing. She is a Fellow of the Institute of Electrical and Electronics Engineers, SPIE and American Institute for Medical and Biological Engineering. She is an ASTech Award Winner for Technology. Yadid-Pecht holds several patents for new technologies, including sensors, health monitoring devices and drug delivery systems.
Early life and education.
Yadid-Pecht grew up in Israel. She studied electrical engineering at the Technion – Israel Institute of Technology. She earned her Master's degree and doctorate in 1995, before moving to the United States to join the Jet Propulsion Laboratory. Here she worked on advanced wide intarascene image sensors for dynamic range CMOS active pixel sensors. These circuits could generate an intensity reading and simultaneously identify the location of the brightest pixel in a particular photodetector array. These sensors were created for star tracking, or monitoring laser beams in communication systems. The sensors integrate winner-take-all protocols, which would allow for the selection of the brightest pixel in each row. This would be compared with the previous stored intensity readings of other row's brightest pixels, and their data stored if they were the new brightest pixel.
Career and research.
Yadid-Pecht joined Ben-Gurion University of the Negev as a member of the Department of Electro-Optical Engineering. She founded the Ben-Gurion Very Large-Scale Integration (VLSI) Systems Center, where she specialised in CMOS image sensors. Researchers at the VLSI work on sensor design, reconfigurable processor architectures and high speed data channels. In 2009 Yadid-Pecht moved to Canada, where she was appointed the iCORE Professor of Integrated Sensors at the University of Calgary. She founded the I2Sense Laboratory, where she continued her research in advanced sensors. Her work involves sensors that are smart; including silicon photonics and MicroElectroMechanical systems (MEMs).
She is developing a compact-imaging sensor for lab-on-a-chip technology. Yadid-Pecht uses the sensors to image neurons and other biological tissues. She has developed wide dynamic range sensors that can capture information in real-time in environments with extreme variations of light intensity. The wide dynamic range sensors can be used in biology, nutrition and security systems. She worked with the Hotchkiss Brain Institute to monitor neurons that were being treated with various Alzheimer's disease treatments.
In 2015, Yadid-Pecht joined the advisory board of M Pharmaceutical, a Canadian biomedical innovation company. She is a trained coach, and supports students who are bringing their projects to commercialisation. She is the co-founder of Luxmux, a photonics company, and Eat Little, a nutrition start-up.
Selected publications.
Her publications include;


Lactis-leu-phe leader RNA motif

The leu/phe-leader RNA motif (also the "lactis"-leu/phe-leader motif) is a conserved RNA structure identified by bioinformatics. These RNAs function as peptide leaders. They contain a short open reading frame (ORF) that contains many codons for leucine or phenylalanine. Normally, expression of the downstream genes is suppressed. However, when cellular concentrations of the relevant amino acid is low, ribosome stalling leads to an alternate structure that enables downstream gene expression.
Leu/phe leaders of this structure are known only in the species "Lactococcus lactis", and is essentially the same as a previously characterized leucine leader in the same species. Additional homologs were uncovered that contain phenylalanine codons instead of leucine codons, and are upstream of genes involved in the synthesis of phenylalanine, instead of leucine.


New Biotechnology

New Biotechnology is a peer-reviewed scientific journal and the official journal of the European Federation of Biotechnology. It is published bimonthly by Elsevier. The journal covers research, industrial, and commercial aspects of biotechnology, in areas such as: healthcare and pharmaceuticals; food and agriculture; biofuels; genetic engineering and molecular biology; genomics and synthetic biology; nanotechnology; environment and biodiversity; biocatalysis; bioremediation; and process engineering.
History.
The journal was established in 1984 as "Gene Analysis Techniques" (). It changed names in 1991 ("Genetic Analysis: Biomolecular Engineering", ) and 1999 ("Biomolecular Engineering", ), before obtaining its current title in 2007.
Abstracting and indexing.
"New Biotechnology" is abstracted and indexed in:


Cephem

Cephems are a sub-group of β-lactam antibiotics including cephalosporins and cephamycins. It is one of the most common 4-membered ring heterocycle.


EarthCam

EarthCam, Inc., based in Upper Saddle River, New Jersey, United States, provides webcam content, technology and services. It was founded in 1996.
History.
Brian Cury, CEO and founder of EarthCam, Inc., launched EarthCam.com in 1996 to build a network of webcams offering views of destinations throughout the world.
As the company grew, EarthCam expanded beyond building its network of tourism cameras and extended its reach into other industries by developing and delivering technology for many applications in verticals including construction, transportation, and surveillance. With that concept came the creation of EarthCam.net, a site for businesses and organizations to purchase webcams and EarthCam's proprietary software to manage their camera networks.
EarthCam and other live webcam services have resulted in an impact upon entertainment and business, allowing for online "travel," meetings, and easy access to knowledge.
In May 2015, EarthCam announced that it had chosen Davis Brody Bond - Architect of the 9/11 Memorial Museum - to design its new 10-acre campus in Upper Saddle River, New Jersey.
Websites.
Expanding beyond the pages of its main site, EarthCam.com, EarthCam's network of websites has grown to include EarthCam.net, WebCamStore.com, and EarthCamMobile.com, which cater to both consumers and professionals. Mobile applications for accessing EarthCam's live webcams and for clients to control their private cameras are available for Apple Inc. or Android (operating system) Devices.
EarthCam.com is a network of scenic webcams offering a complete searchable database of views of places around the world. In 1999 it was claimed 20 people per day were adding their webcams to the website. In 2006 the website was a Webby Award Winner in the Tourism category. It is viewed by fans in 192 countries and ranks among the top 1% of all websites, according to Alexa.com.
One of the first highly publicized events that EarthCam produced, labeled "Webcast of the Century", featured celebrations from around the world at the turn of the new millennium on New Year's Eve 1999 / New Year's Day 2000. 100 cameras were located across the world, taking pictures every 30 seconds, viewed using an interactive world map on EarthCam.com.
Virtual travel also becomes possible with webcams located at major worldwide tourist attractions such as London's Abbey Road, the Eiffel Tower in Paris, Rio de Janeiro's Copacabana Beach, Hollywood Boulevard in Los Angeles and the "Welcome to Fabulous Las Vegas sign".
By visiting EarthCam, viewers have the capability to see historical places and landmarks around the world, especially in the US. EarthCam cameras located at the Martin Luther King Jr. Memorial in Washington DC, the Flight 93 National Memorial in Shanksville, PA, Seattle's Space Needle, Wall Street's notable Charging Bull and more deliver unique views, both live and archived. The archived images can be edited together to produce time-lapse videos such as the Ground Zero 10 year time-lapse which was created from images captured at the site from September 2001 through September 2011.
In October 2011 EarthCam built and installed the 'TorchCams', custom camera systems that generate live video and widescreen images, giving visitors panoramic views from the Statue of Liberty torch, the location that has been closed to the public since 1916. The five cameras were donated to the National Park Service by EarthCam, Inc.
To ring in the new year in 2017, EarthCam installed 4K live streaming video cameras in Times Square in order to broadcast the first-ever 4K stream of the Times Square celebration live on YouTube. Through the years, EarthCam’s streaming video quality has evolved, from still jpeg images updating once every 60 seconds in 1996 to 4K "ultra-high definition" streaming video today.
EarthCam.net provides live streaming video, megapixel, wireless, and solar-powered camera systems, along with managed services, for corporate clients and government agencies worldwide, including the General Services Administration (GSA). Powered by EarthCam's Control Center 8 webcam management service that is delivered as a user-controllable SaaS (Software as a Service) interface, EarthCam's professional webcam technology is used to view, document, and promote projects. Additional advanced imaging technology services are offered including gigapixel images and most recently, EarthCamAir, aerial photography which combines EarthCam’s webcam technology with Unmanned Aerial Vehicle (UAV) services to produce geospatial images.


Akaryocyte

Akaryocytes, also known as akaryotes or acaryotes, are cells without a nucleus. The most common type of akaryocytes are viruses. The name is derived from the Greek prefix "a-", meaning "without" and the Greek "karyo-", meaning "nut" or "kernel". Akaryocytes also include viruses since they lack a nucleus but have instead, a central core of RNA or DNA. Akaryocytes are not part of the seven main ranks of taxa. Red blood cells are also classified as akaryocytes because they lack a cell nucleus after they have developed.


Coronavirus frameshifting stimulation element

In molecular biology, the coronavirus frameshifting stimulation element is a conserved stem-loop of RNA found in coronaviruses that can promote ribosomal frameshifting. Such RNA molecules interact with a downstream region to form a pseudoknot structure; the region varies according to the virus but pseudoknot formation is known to stimulate frameshifting. In the classical situation, a sequence 32 nucleotides downstream of the stem is complementary to part of the loop. In other coronaviruses, however, another stem-loop structure around 150 nucleotides downstream can interact with members of this family to form kissing stem-loops and stimulate frameshifting.
Other RNA families identified in the coronavirus include the SL-III cis-acting replication element (CRE), the coronavirus 3′ stem-loop II-like motif (s2m), the coronavirus packaging signal and the coronavirus 3′ UTR pseudoknot.
During protein synthesis, rapidly changing conditions in the cell can cause ribosomal pausing. In coronaviruses, this can affect growth rate and trigger translational abandonment. This releases the ribosome from the mRNA and the incomplete polypeptide is targeted for destruction.


Neurokinin A

Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.
Introduction.
Neurokinin A (formally known as substance K) is a member of the tachykinin family of neuropeptide neurotransmitters. Tachykinins are important contributors to nociceptive processing, satiety, and smooth muscle contraction. Tachykinins are known to be highly excitatory neurotransmitters in major central neural systems. Neurokinin A is ubiquitous in both the central and peripheral mammalian nervous systems, and seems to be involved in reactions to pain and the inflammatory responses. It is produced from the same preprotachykinin A gene as the neuropeptide substance P. Both substance P and neurokinin A are encoded by the same mRNA, which when alternatively spliced can be translated into either compound. It has various roles in the body of humans and other animals, specifically stimulation of extravascular smooth muscle, vasodilation, hypertensive action, immune system activation, and pain management. The deduced amino acid sequence of neurokinin A is as follows:
with amidation at the C-terminus.
Mechanism of action.
Modified from: Sun J, Ramnath RD, Tamizhselvi R, Bhatia M."Neurokinin A engages neurokinin-1 receptor to induce NF-kappaB-dependent gene expression in murine macrophages: implications of ERK1/2 and PI 3-kinase/Akt pathways." Am J Physiol Cell Physiol. 2008 Sep;295(3):C679-91
Like Substance P [SP], Neurokinin A is present in excitatory neurons and secretory cells of the hypothalamic–pituitary–adrenal axis. Additionally both SP neurokinin A is found in the neurosensory system and modulates a wide range of inflammatory and tissue repairing processes . In various tissues, such as the skin, the release of bioactive tachykinins by sensory nerve fibers C, that extend from the dorsal root ganglia into the epidermis, directly influence the activity of keratinocytes. Inflammation, tissue healing and cell proliferation have been linked to both SP and neurokinin A release into surrounding tissues.
Nervous system.
The overstimulation of the hypothalamic–pituitary–adrenal axis system and elevated secretion of corticotropin-releasing hormone from the hypothalamus, have been studied in many clinical manifestations of pathological depression. Studies have shown that stress-induced activation of the noradrenergic prefrontal lobe system may be under the control of both endogenously released corticotrophin-releasing hormone and SP and neurokinin A. This study directly links the secretion of neurokinin A and SP to certain forms of depression characterized by the corticoid receptor hypothesis of depression.
Inflammatory responses within the central nervous system (CNS) are often the result of traumatic injury or exposure to infectious agents. Inflammation provides a protective immune response to such stresses may also result in progressive damage to the CNS. There is significant evidence to indicate that tachykinins are a major component of the neural inflammatory response at peripheral tissues as well as the CNS. The ability to regulate tachykinin secreation represents an important mechanism for designing potentially useful drugs to treat inflammation. Neurokinin A has been associated with the chemokines interleukin-1 and interleukin-6, both of which are heavily involved in the inflammatory process during infections.
Neuronal tissue can be severely damaged either through physical trauma or intracellular stresses, either chronic or acute. Either of these scenarios can result in calcium overload, protein degradation, the unfolded protein response or an accumulation of DNA damage. Endogenous cellular responses are activated within neurve tissue in response to damage in order to protect cellular, protein, and nucleic acid integrity. A large variety of neuroprotective signaling mechanisms exist, which can be manipulated by drugs to reduce damage from cellular damage in neurons. Tachykinins thus have a number of neuroprotective physiological roles in medical conditions
Immune system.
The immune system is a highly integrated system which receives input from many sources, such as sites of injury, nociceptors and white blood cells. Chemical signals therefore are an important component of paracrine, autocrine and endocrine signaling.
Neurokinin A was shown to be a potent chemo attractor for T-cells increasing the migration into infected tissues. This migration is necessary for the pathogen seeking activity of T-cells. Some chemokines trigger the intravascular adhesion of T-cells whereas others direct the migration of leukocytes into and within the extravascular space. Since lymphocytes must be positioned correctly to interact with other cells, the pattern of chemokine receptors and the type and distribution of chemokines in tissues critically influence immune responses. The molecular mechanism behind neurokinin's role as a chemoattractor is currently unclear.
Neurokinin A has an inhibitory effect on the formation of myeloid cells, and appear to be involved in one specific receptor since the effect can be completely abolished by a NK-2 receptor-selective antagonist. The inhibitory effect of neuronkinin A is countered by the excitatory effect of a structurally similar compound: substance P. The opposite effects on myelogenesis by substance P and neurokinin A may represent an important feedback mechanism for maintenance of homeostasis.
Respiratory system.
The binding of neurokinin A to the NKR-2 results in bronchoconstriction, mucus production in the lungs and process neurogenic inflammation. This release is propagated through the stimulation of e-NANC nerves in the bronchial epithelium via an axon-reflex mechanism.
Cardiovascular system.
Neurokinin has been shown to contribute to both bradycardia and myocardial infarctions through the activation of NK2 receptors.
The dual sensory-motor function of neurokinin A containing afferent neurons is a component of the intracardiac nervous system. Varicose processes of tachykinin-containing nerves are abundant in coronary arteries and in the cardiac ganglia. The diverse responses that are triggered by locally released tachykinins produce beneficial effects such as modulation of ganglion transmission. However, it is also possible that excessive stimulation of cardiac afferents and release of tachykinins, during pathological conditions such as myocardial infarction, could contribute to certain human pathologies.
Receptor.
Tachykinins selectively bind and activate the G-protein coupled receptors NK1R, NK2R, and NK3R. Neurokinin A binds to the G-protein coupled receptor ultimately increasing the release of inositol-phosphate and calcium second messengers. Each receptor demonstrates a specific affinity for either neurokinin A or substance P peptides. Both peptides, however, can act as full agonists on either receptor, although their potency is decreased when not bound to their specific receptor.
NK-2 receptor.
NK-2 receptors are expressed predominantly in the CNS. Networks involved in emotional processing, such as the prefrontal cortex, cingulate cortex, and amygdala, show the highest concentration of NK-2 receptors. NK-2 receptor antagonists have been theorized to have antidepressant benefits and are presently in clinical trials. As a consequence of its ability to stimulate intestinal smooth muscle, NKA is considered to be specifically active in regulating intestinal motility by its action on NK2 receptors.
Antagonists.
MEN 11420 has been demonstrated to be a potent, selective and competitive antagonist of tachykinin NK2 receptors, both in animal and human models. In vivo animal models, MEN 11420 produces an effective and long-lasting blockade of the NK2 receptors expressed in the smooth muscle of the intestinal, genito-urinary and respiratory tract.
History.
Neurokinin A was isolated from porcine spinal cord in 1983 by von Euler and Gaddum.
Structure.
Tachykinins are a structurally related group of neuropeptides sharing the C-terminal sequence Phe-X-Gly-Leu-Met-NH2. The amino acid sequence of substance P and neurokinin A are well conserved across mammals species. Structure of mammalian neurokinin A was obtained using CD spectropolarimetry and 2D proton NMR. Analysis showed that in water, the peptide adopts an extended conformation while in the presence of micelles (a model cell membrane system), an alpha helical conformation is induced in the central core (Asp4-Met10).
Genetic overview.
The "pre-protachykinin-1" and "pre-protachykinin-2" genes in mice encode four very distinct peptides with varying physiological function. Alternative splicing of the "pre-protachykinin-1" gene gives rise to four different peptide precursors("alpha"tac1, "beta"tac1, "delta"tac1 und "gamma"tac1), which are further processed into several related peptides including neurokinin A and substance P. The "alpha tac1" and "beta tac1" precursors encode synthesis of both Substance P and neurokinin A.
Modified from:Nakanishi, Shigetada. "Molecular Mechanisms Of Intercellular Communication In The Hormonal And Neural Systems." IUBMB Life 58.5/6 (2006): 349-357
Mouse models.
"pre-protachykinin-1 -/-" mice show normal fertility and behavioral patterns (litter-mate socialization and pup rearing), but have a reduced sense of anxiety when threatened, compared to both wild-type mice and other mouse models of depression.
Applications.
Cancer.
Circulating concentrations of neurokinin A is an independent indicator of poor prognosis in certain cancers such as carcinoids. Patients presenting with neurokinin A plasma concentrations of >50 pmol/l showed a poorer 3 year survival rate than patients presenting with neurokinin A concentrations of less than 50 pmol/l. These types of studies show that measuring tachykinin levels in human patients may have clinical relevance.
Patients with Midgut Carcinoid disease (MGC) commonly receive neurokinin A test to determine the progression of their disease. Midgut Carcinoid disease is an uncommon disease with occurrence rates of approximately 1.4 per 100,000 of the population per year. MGC has an unpredictable disease progression depending on the patient, symptoms and progression range from rapid and aggressive to chronic. Treatment is difficult because of the varying degrees of severity, so assessing the extent of the disease is extremely important in effective treatment.
Asthma.
The blocking of neuropeptide signaling has come become a novel therapeutic target for suppression of bronchial constriction in asthma patients.
Bronchoconstriction is among the most prominent and extensively studied effects caused by tachykinins. Tachykinins have numerous effects in the respiratory systems especially in asthma patients who are more responsive to tachykinin administration. Through studies with human airways researchers have examined the role tachykinins play in bronchoconstriction, most notably through the receptor NK2, though regulation of NK2 receptors seems to be mediated by the activity of NK1 receptors eluting to complicated inhibition mechanism.
Administration of DNK333 (a dual tachykinin receptor NK1/NK2 antagonist) have shown protective activity against neurokinin A induced bronchoconstriction.
Psychiatric disorders.
Neurokinin A is involved in many stress induced neurological disorders, such as depression, schizophrenia and epilepsy.
Affective disorders.
Affective disorders are characterized by a frequent, fluctuating alteration in mood, affecting the patient's thoughts, emotions, and behaviors. Affective disorders include depression, anxiety, and bipolar disorder. A number of approaches have been utilized to study the role that neurokinin A plays in the manifestation and continuation of human affective disorders. The measurement of serum peptide levels in depressed patients as well as anxious patients displayed higher plasma levels of tachykinins than their low-anxiety counterparts. In addition to studies of plasma levels of TKs, cerebrospinal fluid (CSF) levels of neurokinin A have also been directly correlated with depression. Under states of depression, neurokinin immunoreactivity is increased in the frontal cortex, and decreased in the striatum. These peptide levels were not found to be normalized by lithium treatment in mice. Elevated levels of tachykinins in CSF have been found in patients with fibromyalgia syndrome, a disorder that is strongly correlated with depression in human patients. Tachykinin ligands have been extensively studied and determined to be functionally linked to the control of affective phenotypes in a complex physiological manner.
Epilepsy.
Epilepsy is a broad category of disorders with varying types of severity and presented symptoms. Neurokinins have been experimentally determined as possible predictor in the generation of certain forms of epilepsy. Experimentally when substance P is injected into the rat hippocampus, it significantly lowers the initiation threshold for seizures induced in a dose-dependent manner. Experimental data thus has indicated a pro-convulsant role for the "Pre-protachykinin-1" gene and thus substance P and neurokinin A.


Low-molecular-weight chromium-binding substance

Low-molecular-weight chromium-binding substance (LMWCr; also known as chromodulin) is an oligopeptide that seems to transport chromium in the body. It consists of four amino acid residues; aspartate, cysteine, glutamate, and glycine, bonded with four (Cr3+) centers. It interacts with the insulin receptor, by prolonging kinase activity through stimulating the tyrosine kinase pathway, thus leading to improved glucose absorption. and has been confused with glucose tolerance factor.
The exact mechanisms underlying this process are currently unknown. Evidence for the existence of this protein comes from the fact that the removal of 51Cr in the blood exceeds the rate of 51Cr formation in the urine. This indicates that the transport of Cr3+ must involve an intermediate (i.e. chromodulin) and that Cr3+ is moved from the blood to tissues in response to increased levels of insulin. Subsequent protein isolations in rats, dogs, mice and cows have shown the presence of a similar substance, suggesting that it is found extensively in mammals. This oligopeptide is small, having a molecular weight of around 1 500 g/mol and the predominant amino acids present are glutamic acid, glycine, and cysteine. Despite recent efforts to characterize the exact structure of chromodulin, it is still relatively unknown.
Nature of binding.
From spectroscopic data, it has been shown that Cr3+ binds tightly to chromodulin (Kf = 1021 M−4), and that the binding is highly cooperative (Hill Coefficient = 3.47). It has been shown that holochromodulin binds 4 equivalents of Cr3+. Evidence for this comes from in vitro studies which showed that apochromodulin exerts its maximal activity on insulin receptors when titrated with 4 equivalents of Cr3+. Chromodulin is highly specific for Cr3+ as no other metals are able to stimulate tyrosine kinase activity. It is believed to stimulate the phosphorylation of the 3 tyrosine residues of the β subunits of the insulin receptor. From electronic studies, the crystal field stabilization energy was determined to be 1.74 x 103 while the Racah parameter B was 847 cm−1. This indicates that chromium binds to chromodulin in the trivalent form. In addition, magnetic susceptibility studies have shown that chromium does not coordinate to any N-terminal amine groups but rather to carboxylates (although the exact the amino acids involved are still unknown). These magnetic susceptibility studies are consistent with the presence of a mononuclear Cr3+ center and an unsymmetric trinuclear Cr3+ assembly with bridging oxo ligands. In chromodulin isolated from bovine liver, x-ray absorption spectroscopy studies have shown that the chromium (III) atoms are surrounded by 6 oxygen atoms with an average Cr—O distance of 1.98 Å, while the distance between 2 chromium (III) atoms is 2.79 Å. These results are indicative of a multinuclear assembly. No sulfur ligands coordinate to chromium and instead, it has been proposed that a disulfide linkage between 2 cysteine residues occurs owing to a characteristic peak at 260 nm.


Remune

Remune is the first therapeutic HIV vaccine based on the killed whole virus approach.
Remune was initially invented by Jonas Salk in 1987 and is now being developed by Immune Response BioPharma, Inc. (IRBP)
Remune is a therapeutic HIV/AIDS vaccine that has completed over 25 clinical studies to date and shows a robust mechanism of action restoring white blood cell counts in CD4 & CD8 T cells by reducing viral load and increasing immunity.
The FDA is currently reviewing IRBP’s BLA (biologics licensing application) for therapeutic treatment in people with HIV. Once the FDA approves the BLA, Remune will be the first therapeutic HIV vaccine brought to market.
IRBP is set to submit its BLA with the FDA in early 2014. REMUNE granted FDA Pediatric Orphan Designation on Feb 14th 2014.
Vaccine Design.
Remune is made of beta-propiolactone inactive HIV-1 which has been irradiated to destroy the viral genome. The vaccine, however, does not contain gp120 surface antigen as it falls off on fixation of HIV-1.
As a result, only gp41 is remaining on the virion surface. Fortunately the initial clinical trial proved that a significant difference in clinical benefit between Remune vaccine and placebo with a decline in viral load P < 0.05 & HIV-1 lymphocyte proliferation P < 0.001 both favoring the Remune Group.
The International AIDS Vaccine Research (IAVA) issued a report on “Whole Killed AIDS Vaccines” in 1999 reviewing a diverse aspect of the killed virus approach.[
Update.
Trials of Remune have largely shown no benefit. Immune Response Corporation (IRC), one of the developers of Remune, tried unsuccessfully to block negative research findings. Pfizer pulled out of its partnership with IRC and there is now doubt about any further development of Remune.


Methylorosula polaris

Methylorosula polaris is a Gram-negative, aerobic, facultatively methylotrophic, psychrotolerant and motile bacteria from the genus of Methylorosula with bipolar flagella which has been isolated from tundra wetland soil in Vorkuta in Russia.


Metaescaline

Metaescaline (3,4-dimethoxy-5-ethoxyphenethylamine) is a lesser-known psychedelic drug. It is an analog of mescaline. Metaescaline was first synthesized by Alexander Shulgin. In his book "PiHKAL", the dosage range is listed as 200–350 mg, and the duration listed as 8–12 hours. Metaescaline produces mental insights, entactogenic, MDMA-like effects, and TOMSO-like activation. Little data exists about the pharmacological properties, metabolism, and toxicity of metaescaline, though it has been studied to a limited extent in comparison with other related compounds.


Michael Pichichero

Michael E. Pichichero is Director, Rochester General Hospital Research Institute; Research Professor, Rochester Institute of Technology; and a clinical professor in the Department of Pediatrics at the University of Rochester Medical Center. He is the author of a number of scientific studies regarding the safety of thimerosal as a preservative in vaccines.
Biography.
Pichichero received his undergraduate degree from Rutgers University, and his medical degree from the University of Rochester. He did post graduate training at the University of Colorado, Denver. He completed fellowships in Pediatric Infectious Diseases and Adult and Pediatric Allergy and Immunology at the University of Rochester, NY
Scientific career.
Pichichero's studies say that ethylmercury, the metabolite of thimerosal, is rapidly metabolized and excreted after administration of thimerosal-containing vaccines, as well as that administration thereof does not raise blood mercury levels above the EPA's lower limit. In addition, his research has concluded that ethylmercury is metabolized about six times as fast as methylmercury (the kind of mercury found in fish), and that the former has a blood half-life of about 3.7 days whereas the latter has a half-life of 44 days. His research says that after children receive a vaccine with thimerosal in it, their blood mercury levels return to normal within only a month.
Pichichero has written a textbook about streptococcal pharyngitis. A board-certified immunologist, he was on the team of scientists at the University of Rochester who invented the Hib vaccine. His more recent research, however, has focused on ear infections and their treatment with antibiotics.


Ida Maclean

Ida Smedley Maclean (born Ida Smedley 14 June 1877, died 2 March 1944) was an English biochemist and the first woman admitted to the London Chemical Society.
Early life and education.
Ida was born in Birmingham to William Smedley, a businessman, and Annie Elizabeth Duckworth. She was taught by her mother at home until the age of nine and lived in "a cultured and progressive home". She was educated at King Edward VI High School for Girls, Birmingham from 1886 to 1896, when she won a scholarship and began her studies at Newnham College, Cambridge. In the university's Natural Sciences Tripos she got a first class in part one and a second class in part two, studying chemistry and physiology. After a two-year break, holding a Bathurst scholarship, in 1901 she undertook postgraduate research at the Central Technical College in London and later at the Royal Institution's Davy-Faraday Research Laboratory. The University of London awarded her a D.Sc. in 1905.
Academic career.
In 1906 Maclean became an assistant lecturer in at the chemistry department of Manchester University, the department's first female staff member. She taught there until 1910, as well as acting as a demonstrator in the women students' laboratories and researching the optical properties of organic compounds. In 1910, supported by one of the first Beit fellowships, she began her work in biochemistry at the Lister Institute of Preventive Medicine, receiving the American Association of University Women's Ellen Richards prize for her research. She married Hugh Maclean, a co-worker at the Lister Institute, on 28 March 1913; the couple had a son and a daughter. During World War I she worked at the Admiralty in areas such as gas warfare and the large-scale production of acetone by fermentation.
Between 1920 and 1941 Maclean published in the "Biochemical Journal" approximately thirty papers, many in collaboration, on her particular interests, namely the role of fatty acids in animals and the synthesis of fats from carbohydrates. In 1927 she co-authored with Hugh the second edition of his book "The Lipins". She came to be regarded as an authority on biochemistry, and her 1943 monograph "The Metabolism of Fat" was the first published of Methuen's series "Monographs on Biochemical Subjects".
Women's rights.
Maclean worked hard to improve the status of women in universities and was among the founders of the British Federation of University Women in 1907. Having been made a fellow of the Royal Institute of Chemistry in 1918, in 1920 she became the first woman to be formally admitted to the London Chemical Society. From 1931 to 1934 she was on the council of the London Chemical Society and from 1929 to 1935 she was president of the British Federation of University Women, which later named a research fellowship for women after her. From 1941 to 1944 she was on the women's appointments board of the University of Cambridge.
Death.
She died on 2 March 1944 at University College Hospital in London. Her body was cremated.


Histidine operon leader

The Histidine operon leader is an RNA element found in the bacterial histidine operon. At least 6 amino acid operons are known to be regulated by attenuation. In each a leader sequence of 150–200 bp is found upstream of the first gene in the operon. This leader sequence can assume two different secondary structures known as the terminator and the anti-terminator structure. In each case the leader also codes for very short peptide sequence that is rich in the end product amino acid of the operon. The terminator structure is recognised as a termination signal for RNA polymerase and the operon is not transcribed. This structure forms when the cell has an excess of the regulatory amino acid and ribosome movement over the leader transcript is not impeded. When there is a deficiency of the charged tRNA of the regulatory amino acid the ribosome translating the leader peptide stalls and the antiterminator structure can form. This allows RNA polymerase to transcribe the operon.


USNS Schuyler Otis Bland (T-AK-277)

USNS "Schuyler Otis Bland also known as SS "Schuyler Otis Bland is the only ship of the series C3-S-DX1 (Freedom-class).
"Schuyler Otis Bland" was laid down, 9 May 1950, as a Maritime Commission type (C3-S-DX1), under Maritime Commission contract (MC hull 2918), at Ingalls Shipbuilding, Pascagoula, MS.
"Schuyler Otis Bland" was a prototype of the series C3-S-DX1 and what was to have been the "Bland class" of cargo ships, but Maritime Administration designers conceived of the even more modern "Mariner class" following her construction. Following the acquisition of MARCOM by United States Maritime Administration (MARAD) in 1950, the design was done as a C3-S-7. She was launched January 30, 1951, and delivered to the Maritime Commission July 25, 1951.
"Schuyler Otis Bland" was first assigned to the American President Lines under bareboat charter. She completed two round-the-world voyages before being transferred to the Waterman Steamship Corporation under a General Agency Agreement. On July 25, 1952, the C-3 cargo ship went into the National Defense Reserve Fleet at Mobile, Ala.
In 1957, "Schuyler Otis Bland" was acquired by the US Navy for operation by American Mail Lines. The American Mail Line had acquired her to replace the , which had foundered in a violent North Pacific storm. In October 1959, after more than two years with American Mail, she entered the National Defense Reserve Fleet at Olympia, Wash.
On August 4, 1961, "USNS Schuyler Otis Bland" was delivered to the Navy, and on August 28, assigned to the Military Sea Transport Service (MSTS) and placed in service as USNS "Schuyler Otis Bland" (T-AK-277). "USNS Schuyler Otis Bland" departed San Francisco on September 28, 1961, to carry cargo to Bangkok, Saigon, Manila, Kaohsiung, and other Pacific ports, beginning over a decade of service supplying military logistic requirements throughout the world.
She also delivered cargo in the mid 1970s for several consecutive Januaries to the USN and National Science Foundation operations at McMurdo Station, Antarctica. The Navy flew in a Port Handling Cargo Group for 30 days to off-load the ship via the man-made floating wharf (made of ice the previous winter and laced internally with steel cable as reinforcement)
Disposition.
On August 1, 1970, the Military Sea Transportation Service became Military Sealift Command. "Schuyler Otis Bland" was placed out of service in 1979 while at Guam. She was struck from the Naval Register, and transferred to MARAD for disposal. On November 28, 1979, she was sold for scrap to China Dismantled Vessel Trading Corporation, Kaohsiung, China for the price of $814,533.50
Logbook and Okinawa controversy.
The "Bland" was a civilian-owned ship regularly employed by the U.S. Navy to transport defoliants incognito and that was able to bypass customs inspections of military vessels entering foreign ports. The logbook of "USNS Schuyler Otis Bland" records that the ship was carrying classified cargo that was offloaded under armed guard at White Beach, a U.S. Navy port on Okinawa's east coast on April 25, 1962. Three months prior to its arrival at Okinawa, the "Bland" had traveled to South Vietnam to deliver one of the Pentagon's first shipments of defoliants. The account in the ship's logbook states the classified cargo was labeled "agriculture products." The ship's cargo was documented to include herbicide Agents Pink and Purple for covert tests in Southeast Asia.


S9 fraction

The S9 fraction is the product of an organ tissue homogenate used in biological assays. The S9 fraction is most frequently used in assays that measure the metabolism of drugs and other xenobiotics. It is defined by the U.S. National Library of Medicine's "IUPAC Glossary of Terms Used in Toxicology" as the "Supernatant fraction obtained from an organ (usually liver) homogenate by centrifuging at 9000 g for 20 minutes in a suitable medium; this fraction contains cytosol and microsomes." The microsomes component of the S9 fraction contain cytochrome P450 isoforms (phase I metabolism) and other enzyme activities. The cytosolic portion contains the major part of the activities of transferases (phase II metabolism). The S9 fraction is easier to prepare than purified microsomes.
Applications.
The S9 fraction has been used in conjunction with the Ames test to assess the mutagenic potential of chemical compounds. Chemical substances sometimes require metabolic activation in order to become mutagenic. Furthermore, the metabolic enzymes of bacteria used in the Ames test differ substantially from those in mammals. Therefore, to mimic the metabolism of test substance that would occur in mammals, the S9 fraction is often added to the Ames test.
The S9 fraction has also been used to assess the metabolic stability of candidate drugs.


Cryostasis (clathrate hydrates)

The term cryostasis was introduced to name the reversible preservation technology for live biological objects which is based on using clathrate-forming gaseous substances under increased hydrostatic pressure and hypothermic temperatures.
Living tissues cooled below the freezing point of water are damaged by the dehydration of the cells as ice is formed between the cells. The mechanism of freezing damage in living biological tissues has been elucidated by Renfret.
The vapor pressure of the ice is lower than the vapor pressure of the solute water in the surrounding cells and as heat is removed at the freezing point of the solutions, the ice crystals grow between the cells, extracting water from them. As the ice crystals grow, the volume of the cells shrinks, and the cells are crushed between the ice crystals. Additionally, as the cells shrink, the solutes inside the cells are concentrated in the remaining water, increasing the intracellular ionic strength and interfering with the organization of the proteins and other organized intercellular structures. Eventually, the solute concentration inside the cells reaches the eutectic and freezes. The final state of frozen tissues is pure ice in the former extracellular spaces, and inside the cell membranes a mixture of concentrated cellular components in ice and bound water. In general, this process is not reversible to the point of restoring the tissues to life.
Cryostasis utilizes clathrate-forming gases that penetrate and saturate the biological tissues causing clathrate hydrates formation (under specific pressure-temperature conditions) inside the cells and in the extracellular matrix. Clathrate hydrates are a class of solids in which gas molecules occupy "cages" made up of hydrogen-bonded water molecules. These "cages" are unstable when empty, collapsing into conventional ice crystal structure, but they are stabilised by the inclusion of the gas molecule within them. Most low molecular weight gases (including CH4, H2S, Ar, Kr, and Xe) will form a hydrate under some pressure-temperature conditions.
Clathrates formation will prevent the biological tissues from dehydration which will cause irreversible inactivation of intracellular enzymes.


6-Fluoro-AMT

6-Fluoro-α-methyltryptamine (6-fluoro-AMT) is a tryptamine derivative related to compounds such as alpha-methyltryptamine and 5-MeO-AMT, which has been sold as a designer drug. Animal tests showed it to be somewhat less active than AMT or 5-fluoro-AMT, but it was nevertheless allegedly manufactured and sold from the laboratory operated by Leonard Pickard and Gordon Todd Skinner, who described 6-fluoro-AMT as "a beast".
In interviews, Skinner stated that he first began to experiment with 6-fluoro-AMT in the early 1980s by giving it to high school friends. Their experienced made him cautious about the appropriate dosage amounts, which he says ranges from 25mg to 75mg [Skinner weighed about 250lbs at the time of his own bioassay]. Skinner said that it is a long-lasting psychedelic with significantly more time distortion, and felt the drug was enhanced by combining it with ALD-52.


Fet3p

Fet3p is a multicopper oxidase (MCO)2 found in "Saccharomyces cerevisiae" with a structure consisting of three cupredoxin-like β-barrel domains and four copper ions located in three distinct metal sites (T1 in domain 3, T2, and the binuclear T3 at the interface between domains 1 and 3). Fet3p is a type I membrane protein with an orientation that places the amino-terminal oxidase domain in the exocellular space (Nexo) and the carboxyl terminus in the cytoplasm (Ccyt).
Part of the ferroxidase reaction, Fet3p catalyzes the oxidation of Fe(II) to Fe(III) using O2 as substrate. The Fe(III) generated by Fet3p is a ligand for the iron permease, Ftr1p.


N-Methyltryptamine

"N"-Methyltryptamine (NMT) is a member of the substituted tryptamine chemical class and a natural product which is biosynthesized in the human body from tryptamine by certain N-methyltransferase enzymes, such as indolethylamine "N"-methyltransferase. It is a common component in human urine. NMT is an alkaloid derived from -tryptophan that has been found in the bark, shoots and leaves of several plant genera, including "Virola", "Acacia", "Mimosa", and "Desmanthus"—often together with the related compounds "N","N"-dimethyltryptamine (DMT) and 5-methoxy-"N","N"-dimethyltryptamine (5-MeO-DMT).
Orally administered NMT appears to produce no psychoactive effects, likely as a result of extensive first-pass metabolism. However, it may become active upon combination with a MAOA inhibitor (MAOI).
By vaporization NMT shows activity at 50–100 mg, with a duration of 45–70 minutes; duration of visual effects 15–30 seconds. Effects are primarily non-visual.


Amarin Corporation

Amarin Corporation is an Irish-American biopharmaceutical company founded in 1993 and headquartered in Dublin, Ireland and Bridgewater, New Jersey. The company develops and markets medicines for the treatment of cardiovascular disease. It has developed the drug Vascepa (AMR-101), a prescription grade omega-3 fatty acid.
In July 2012, their lead-candidate drug named Vascepa (AMR-101) received FDA-approval, competing against GlaxoSmithKline's Lovaza.
History.
Amarin Corporation plc (formerly Ethical Holdings plc) was originally incorporated in England as a private limited company on March 1, 1989, and later re-registered as a public company on March 19, 1993. In 2002, the company suffered losses worth $37 million; 2003 losses exceeded $19 million. As of 2005, it was developing neurology drugs. It developed Miraxion to treat serious hereditary neurodegenerative disease.
In December 2007, Amarin acquired Ester Neurosciences Limited for US$8.1 million. In 2011, CEO Joe Zakrzewski said that the company would like to first work on building its infrastructure out to commercialize the drug in the United States.
Products and development.
Vascepa (USA) / Vazkepa (EU).
Amarin´s sole product VASCEPA® came on the market in 2013 for triglyceride levels >=500 milligrams per deciliter. In December 2019, the FDA approved "...the use of Vascepa (icosapent ethyl) as an adjunctive (secondary) therapy to reduce the risk of cardiovascular events among adults with elevated triglyceride levels (a type of fat in the blood) of 150 milligrams per deciliter or higher. Patients must also have either established cardiovascular disease or diabetes and two or more additional risk factors for cardiovascular disease...Vascepa is the first FDA approved drug to reduce cardiovascular risk among patients with elevated triglyceride levels as an add-on to maximally tolerated statin therapy.
Furthermore, VASCEPA® is in use in clinical trials by 3rd parties to see, if it has an effect on Alzheimer, Colon Cancer, Nonalcoholic Steatohepatitis (NASH), and other diseases.
HLS Therapeutics, Amarin´s license partner in Canada, presented results of their COVID-19 clinical trial for Vascepa at National Lipid Association Scientific Sessions 2020, December 12. The results demonstrated a 25% reduction of hs-CRP, a biomarker for inflammation. Most people with COVID-19 die, because of a cytokine storm, which causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Two more COVID-19 studies are actually running with Vascepa to validate and proof further benefits.
On January 28, the Committee for Medicinal Products for Human Use gave a positive recommendation for Vazkepa (name for Vascepa in the EU), which the European Comission finally approved on March 30th.
Patent disputes.
On March 30, 2020, the designated patent judge, Judge Du in the U.S. District Court of Nevada, ruled for generic-drug makers Hikma Pharmaceuticals and Dr. Reddy's Laboratories in a lawsuit with Amarin over patents on Amarin's drug, Vascepa. Soon after, on April 2, 2020, Amarin filed an appeal of the district court ruling The appeal was lost and an en-banc was also not granted, afterwards. On November 30, three weeks after Hikma Pharmaceuticals started the distribution of their generic version of Vascepa, Amarin filed a complaint of patent infringement against Hikma. On February 11, 2021 Amarin filed a petition for certiorari with the US Supreme Court.


Katharina Ribbeck

Katharina Ribbeck is a German-American biochemist and biophysicist. She is known for her work on mucus. She studies both the function of mucus as a barrier to viruses and other pathogens and the changes that cervical mucus undergoes before birth, which may lead to a novel diagnostic for risk of preterm birth. She is the Hyman Career Development Professor of Biological Engineering at MIT.
Education.
Ribbeck received her B.S. from the University of Heidelberg in 1998 and her Ph.D., also from the University of Heidelberg, in 2001.
Career.
During her Ph.D. work, Ribbeck investigated the selective transport of molecules through the nuclear pore complex, which is partly mediated by a hydrogel barrier. After post-doctoral research, she moved to Harvard University as an independent Bauer Fellow in 2007, where she began to investigate how particles move through mucin hydrogels. In 2010 she moved to the Massachusetts Institute of Technology as an assistant professor.
Ribbeck has shown that purified foreign mucins can prevent viruses from infecting cells, and suggested that they could be used to supplement the anti-viral activity of native mucins. She has also shown that mucins prevent bacteria such as the pathogen Pseudomonas aeruginosa and Streptococcus mutans, the bacterium that causes tooth decay, from forming biofilms, which make them hard to eradicate. Mucins may also block fungal pathogens such as Candida albicans from becoming virulent in healthy humans. She has extensively investigated the biophysical properties of mucus and other hydrogels and the mechanisms by which some particles and molecules selectively pass through the barrier.
Ribbeck identified a correlation between the properties of the mucus in the cervix in pregnant women and the likelihood of preterm birth, and has developed probes to test mucus permeability as a step towards diagnosis of risk for premature birth. Additionally, Ribbeck was instrumental in founding the company ProMuc Inc., a company that develops synthetic mucins for lubrication and antimicrobial applications.
Ribbeck also studies hydrogels produced by pathogens, and has found that the extracellular matrix formed by the pathogenic bacterium Pseudomonas aeruginosa protects the bacterium against antibiotics.


Mersacidin decarboxylase

Mersacidin decarboxylase "MrsD" is an enzyme that catalyzes the oxidative decarboxylation of the C-terminal cysteine residue of mersacidin to an aminoenethiol residue, intermediate as the first step in the formation of the unusual amino acid S-[(Z)-2-aminovinyl]-methyl-D-cysteine with coenzyme FAD


Tienoxolol

Tienoxolol is a beta adrenergic receptor antagonist.


Metabotropic glutamate receptor 5

Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor predominantly expressed on the postsynaptic sites of neurons. In humans, it is encoded by the "GRM5" gene.
Function.
The amino acid L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacological properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7, and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Alternative splice variants of GRM8 have been described but their full-length nature has not been determined.
There has been extensive research into the role of mGluR5 in psychological disorders, such as addiction and anxiety. Emerging research strongly points to mGluR5 playing a direct role in the pathogenesis of alcohol use disorder in humans, showing intimate involvement in the development of behavioral sensitization towards ethanol in animal models.
Ligands.
In addition to the orthosteric site (the site where the endogenous ligand glutamate binds) at least two distinct allosteric binding sites exist on the mGluR5. A respectable number of potent and selective mGluR5 ligands, which also comprise PET radiotracers, has been developed to date. Selective antagonists and negative allosteric modulators of mGluR5 are a particular area of interest for pharmaceutical research, due to their demonstrated anxiolytic, antidepressant and anti-addictive effects in animal studies and their relatively benign safety profile. mGluR5 receptors are also expressed outside the central nervous system, and mGluR5 antagonists have been shown to be hepatoprotective and may also be useful for the treatment of inflammation and neuropathic pain. The clinical use of these drugs may be limited by side effects such as amnesia and psychotomimetic symptoms, but these could be an advantage for some indications, or conversely mGluR5 positive modulators may have nootropic effects.
mGluR5 and addiction.
Mice with a knocked out mGluR5 show a lack of cocaine self-administration regardless of dose. This suggested that the receptor may be intimately involved in integrating the rewarding properties of cocaine. However, a later study showed that mGluR5 knockout mice responded the same to cocaine reward as wild type mice demonstrated by a cocaine place-preference paradigm. This evidence taken together shows that mGluR5 may be crucial for drug-related instrumental self-administration learning, but not conditioned associations.


Robert W. Newcomb

Robert W. Newcomb is a professor of electrical engineering at the University of Maryland, College Park. He obtained a BSEE degree from Purdue University in 1955, an MS from Stanford University in 1957, and his Ph.D. in Electrical Engineering from the University of California at Berkeley in 1960. He was a professor in the electrical engineering department at Stanford University through 1968, and from 1969 onward has been a professor in the electrical engineering department at the University of Maryland at College Park. He has graduated over 70 Ph.D. students from both Stanford and the University of Maryland.
He currently directs the Microsystems Laboratory at the University of Maryland.
His work during his career has spanned a variety of subdisciplines in electrical engineering, and has produced the following:
He is both a Life Fellow of IEEE and a Fellow of AIMBE. His recognition being the recipient of the IEEE CAS Society Golden Jubilee Medal award and the first recipient of the IEEE CAS Society Education award.


Dihydrobenzophenanthridine oxidase

Dihydrobenzophenanthridine oxidase (DHBP oxidase) is an enzyme. In the IUBMB Enzyme Nomenclature, dihydrobenzophenanthridine oxidase is .
Dihydrobenzophenanthridine oxidase produces oxidized forms of benzophenanthridine alkaloids: