Protein-disulfide reductase

In enzymology, a protein-disulfide reductase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are protein dithiol, NAD+, and NADP+, whereas its 4 products are protein disulfide, NADH, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on a sulfur group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is protein-dithiol:NAD(P)+ oxidoreductase. Other names in common use include protein disulphide reductase, insulin-glutathione transhydrogenase, disulfide reductase, and NAD(P)H2:protein-disulfide oxidoreductase.
Structural studies.
As of late 2007, 8 structures have been solved for this class of enzymes, with PDB accession codes , , , , , , , and .


Lipogenesis

Lipogenesis is the metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. The triglycerides in fat are packaged within cytoplasmic lipid droplets. The process begins with acetyl-CoA, which is an organic compound used to transfer energy from metabolism of carbohydrates, fatty acids, and ethanol. Through the citric acid cycle, acetyl-CoA is broken down to produce ATP, which is then an energy source for many metabolic processes, including protein synthesis and muscle contraction.
Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triglycerides, on the other hand, are produced in the endoplasmic reticulum of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenes in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.
Fatty acid synthesis.
Fatty acid synthesis starts with acetyl-CoA and builds up by the addition of two-carbon units. Fatty acid synthesis occurs in the cytoplasm of cells while oxidative degradation occurs in the mitochondria. Many of the enzymes for the fatty acid synthesis are organized into a multienzyme complex called fatty acid synthase. The major sites of fatty acid synthesis are adipose tissue and the liver.
Triglyceride synthesis.
Triglycerides are synthesized by esterification of fatty acids to glycerol. Fatty acid esterification takes place in the endoplasmic reticulum of cells by metabolic pathways in which acyl groups in fatty acyl-CoAs are transferred to the hydroxyl groups of glycerol-3-phosphate and diacylglycerol. Three fatty acid chains are bonded to each glycerol molecule. Each of the three -OH groups of the glycerol reacts with the carboxyl end of a fatty acid chain (-COOH). Water is eliminated and the remaining carbon atoms are linked by an -O- bond through dehydration synthesis.
Both the adipose tissue and the liver can synthesize triglycerides. Those produced by the liver are secreted from it in the form of very-low-density lipoproteins (VLDL). VLDL particles are secreted directly into blood, where they function to deliver the endogenously derived lipids to peripheral tissues.
Hormonal regulation.
Insulin is a peptide hormone that is critical for managing the body's metabolism. Insulin is released by the pancreas when blood sugar levels rise, and it has many effects that broadly promote the absorption and storage of sugars, including lipogenesis.
Insulin stimulates lipogenesis primarily by activating two enzymatic pathways. Pyruvate dehydrogenase (PDH), converts pyruvate into acetyl-CoA. Acetyl-CoA carboxylase (ACC), converts acetyl-CoA produced by PDH into malonyl-CoA. Malonyl-CoA provides the two-carbon building blocks that are used to create larger fatty acids.
Insulin stimulation of lipogenesis also occurs through the promotion of glucose uptake by adipose tissue. The increase in the uptake of glucose can occur through the use of glucose transporters directed to the plasma membrane or through the activation of lipogenic and glycolytic enzymes via covalent modification. The hormone has also been found to have long term effects on lipogenic gene expression. It is hypothesized that this effect occurs through the transcription factor SREBP-1, where the association of insulin and SREBP-1 lead to the gene expression of glucokinase. The interaction of glucose and lipogenic gene expression is assumed to be managed by the increasing concentration of an unknown glucose metabolite through the activity of glucokinase.
Another hormone that may affect lipogenesis through the SREBP-1 pathway is leptin. It is involved in the process by limiting fat storage through inhibition of glucose intake and interfering with other adipose metabolic pathways. The inhibition of lipogenesis occurs through the down regulation of fatty acid and triglyceride gene expression. Through the promotion of fatty acid oxidation and lipogenesis inhibition, leptin was found to control the release of stored glucose from adipose tissues.
Other hormones that prevent the stimulation of lipogenesis in adipose cells are growth hormones (GH). Growth hormones result in loss of fat but stimulates muscle gain. One proposed mechanism for how the hormone works is that growth hormones affects insulin signaling thereby decreasing insulin sensitivity and in turn down regulating fatty acid synthase expression. Another proposed mechanism suggests that growth hormones may phosphorylate with STAT5A and STAT5B, transcription factors that are a part of the Signal Transducer And Activator Of Transcription (STAT) family.
There is also evidence suggesting that acylation stimulating protein (ASP) promotes the aggregation of triglycerides in adipose cells. This aggregation of triglycerides occurs through the increase in the synthesis of triglyceride production.
PDH dephosphorylation.
Insulin stimulates the activity of pyruvate dehydrogenase phosphatase. The phosphatase removes the phosphate from pyruvate dehydrogenase activating it and allowing for conversion of pyruvate to acetyl-CoA. This mechanism leads to the increased rate of catalysis of this enzyme, so increases the levels of acetyl-CoA. Increased levels of acetyl-CoA will increase the flux through not only the fat synthesis pathway but also the citric acid cycle.
Acetyl-CoA carboxylase.
Insulin affects ACC in a similar way to PDH. It leads to its dephosphorylation via activation of PP2A phosphatase whose activity results in the activation of the enzyme. Glucagon has an antagonistic effect and increases phosphorylation, deactivation, thereby inhibiting ACC and slowing fat synthesis.
Affecting ACC affects the rate of acetyl-CoA conversion to malonyl-CoA. Increased malonyl-CoA level pushes the equilibrium over to increase production of fatty acids through biosynthesis. Long chain fatty acids are negative allosteric regulators of ACC and so when the cell has sufficient long chain fatty acids, they will eventually inhibit ACC activity and stop fatty acid synthesis.
AMP and ATP concentrations of the cell act as a measure of the ATP needs of a cell. When ATP is depleted, there is a rise in 5'AMP. This rise activates AMP-activated protein kinase, which phosphorylates ACC and thereby inhibits fat synthesis. This is a useful way to ensure that glucose is not diverted down a storage pathway in times when energy levels are low.
ACC is also activated by citrate. When there is abundant acetyl-CoA in the cell cytoplasm for fat synthesis, it proceeds at an appropriate rate.
Transcriptional regulation.
SREBPs have been found to play a role with the nutritional or hormonal effects on the lipogenic gene expression.
Overexpression of SREBP-1a or SREBP-1c in mouse liver cells results in the build-up of hepatic triglycerides and higher expression levels of lipogenic genes.
Lipogenic gene expression in the liver via glucose and insulin is moderated by SREBP-1. The effect of glucose and insulin on the transcriptional factor can occur through various pathways; there is evidence suggesting that insulin promotes SREBP-1 mRNA expression in adipocytes and hepatocytes. It has also been suggested that the hormone increases transcriptional activation by SREBP-1 through MAP-kinase-dependent phosphorylation regardless of changes in the mRNA levels. Along with insulin glucose also have been shown to promote SREBP-1 activity and mRNA expression.


Duane F. Bruley

Duane Frederick Bruley is an American researcher, entrepreneur, and academician.
Positions.
Bruley has served as Dean of the School of Engineering at the University of Maryland, Baltimore County, Dean of Engineering at the California Polytechnic State University, San Luis Obispo, Vice President of Academic Affairs at Rose-Hulman Institute of Technology, Head of Biomedical Engineering and Director of the Rehabilitation Engineering and Environmental Systems at the National Science Foundation, and Head of the Chemical Engineering Department at Tulane University. Dr. Bruley is a co-founder and former President (1983) of the International Society on Oxygen Transport to Tissue (ISOTT) and one of the contributors to the formation of the Bioengineering Section at the NSF and initiator of a joint review and funding effort between the NSF and the National Institutes of Health (NIH).
Work.
Bruley's field of research includes oxygen transfer in the brain and human tissue, simulation of the human microcirculation system, and symbiosis of biomedical and bioprocess engineering utilizing the principles of Total Quality Management to enhance health care quality and delivery. This latter research has led to a computational strategy (BWK) that performs 3-D, time dependent, heterogeneous, convection, diffusion, conduction, reaction simulations on small computers. Bruley's work also spans bioprocess engineering for the production of anticoagulants (particularly, PROTEIN C) and hyperthermia.
Bruley and James Haim I. Bicher have extensively worked and researched together in the field of oxygen transport. Both scientists had joined, published, and collaborated in about eighteen papers, many of which can be found in PubMed, US National Library of Medicine National Institutes of Health
Honors and awards.
In 2003 ISOTT established "The Duane F. Bruley Award". This award was created to provide travel funds for student researchers in all aspects of areas of oxygen transport to tissue. The breath of Bruley's contributions to engineering administration, research, education, and public service is reflected in his election to Fellow Grade in AIChE and ASME and to Founding Fellow of the American Institute for Medical and Biological Engineering (AIMBE). He has published more than 180 papers.
Education.
Bruley received his Ph.D. in Chemical Engineering from the University of Tennessee, a M.S. in Mechanical Engineering at Stanford University, ORSORT degree in Nuclear Engineering from Oak Ridge School of Reactor Technology, a B.S. in Chemical Engineering at the University of Wisconsin-Eau Claire.


Muscarinic acetylcholine receptor M5

The human muscarinic acetylcholine receptor M5, encoded by the gene, is a member of the G protein-coupled receptor superfamily of integral membrane proteins. It is coupled to Gq protein. Binding of the endogenous ligand acetylcholine to the M5 receptor triggers a number of cellular responses such as adenylate cyclase inhibition, phosphoinositide degradation, and potassium channel modulation. Muscarinic receptors mediate many of the effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor have not been fully explored; however, stimulation of this receptor is known to effectively decrease cyclic AMP levels and downregulate the activity of protein kinase A (PKA).
Ligands.
No highly selective agonists or antagonists for the M5 receptor have been discovered as of 2018, but several non-selective muscarinic agonists and antagonists have significant affinity for M5.
The lack of selective M5 receptor ligands is one of the main reasons that the medical community has such a limited understanding of the M5 receptors effects as the possibility that any and/or all effects of non-selective ligands may be due to interactions with other receptors can not be ruled out. Some data may be obtained by observing which effects are common among semi-selective ligands (ex. a ligand of M1 and M5, a ligand of M2 and M5, and a ligand of M3 and M5), but until both a selective agonist and a selective antagonist of the M5 receptor are developed this data must be considered merely theoretical.


Set and setting

Set and setting, when referring to a psychedelic drug experience, means one's mindset (shortened to "set") and the physical and social environment (the setting) in which the user has the experience. This is especially relevant for psychedelic experiences in either a therapeutic or recreational context. According to the book "How to Change Your Mind" by Michael Pollan, the concept of set and setting was observed by the "Johnny Appleseed" of LSD, Al Hubbard visiting mushroom ceremonies in Mexico. The terms were used at least as early as 1958 by Ludwig von Bertalanffy and popularized by Timothy Leary in 1961, and became widely accepted by researchers in psychedelic therapy. Norman Zinberg has also discussed this in "Drug, Set, And Setting: The Basis for Controlled Intoxicant Use" (1984).
"Set" is the mental state a person brings to the experience, like thoughts, mood and expectations. "Setting" is the physical and social environment. Social support networks have shown to be particularly important in the outcome of the psychedelic experience. They are able to control or guide the course of the experience, both consciously and subconsciously. Stress, fear, or a disagreeable environment, may result in an unpleasant experience (bad trip). Conversely, a relaxed, curious person in a warm, comfortable and safe place is more likely to have a pleasant experience. A curated playlist can be part of a favourable setting.
Due to the importance of setting in early psychedelic therapy, Hubbard introduced a "treatment space decorated to feel more like a home than a hospital", which came to be known as a "Hubbard Room".
In 1966, Timothy Leary conducted a series of experiments with dimethyltryptamine (DMT) with controlled set and setting. The aim was to see whether DMT, which had then been mostly thought of as a terror-inducing drug, could produce pleasant experiences under a supportive set and setting. It was found that it could.
Set and setting has also been investigated from a religious perspective.


MMP28

Matrix metalloproteinase 28 also known as epilysin is an enzyme that in humans is encoded by the "MMP28" gene.
Function.
Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix for both normal physiological processes, such as embryonic development, reproduction and tissue remodeling, and disease processes, such as asthma and metastasis. This gene encodes a secreted enzyme that degrades casein. Its expression pattern suggests that it plays a role in tissue homeostasis and in wound repair. Transcript variants encoding different isoforms have been described.


Anabolism

Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-down aspect. Anabolism is usually synonymous with biosynthesis.
Pathway.
Polymerization, an anabolic pathway used to build macromolecules such as nucleic acids, proteins, and polysaccharides, uses condensation reactions to join monomers. Macromolecules are created from smaller molecules using enzymes and cofactors.
Energy source.
Anabolism is powered by catabolism, where large molecules are broken down into smaller parts and then used up in cellular respiration. Many anabolic processes are powered by the cleavage of adenosine triphosphate (ATP). Anabolism usually involves reduction and decreases entropy, making it unfavorable without energy input. The starting materials, called the precursor molecules, are joined together using the chemical energy made available from hydrolyzing ATP, reducing the cofactors NAD+, NADP+, and FAD, or performing other favorable side reactions. Occasionally it can also be driven by entropy without energy input, in cases like the formation of the phospholipid bilayer of a cell, where hydrophobic interactions aggregate the molecules.
Cofactors.
The reducing agents NADH, NADPH, and FADH2, as well as metal ions, act as cofactors at various steps in anabolic pathways. NADH, NADPH, and FADH2 act as electron carriers, while charged metal ions within enzymes stabilize charged functional groups on substrates.
Substrates.
Substrates for anabolism are mostly intermediates taken from catabolic pathways during periods of high energy charge in the cell.
Functions.
Anabolic processes build organs and tissues. These processes produce growth and differentiation of cells and increase in body size, a process that involves synthesis of complex molecules. Examples of anabolic processes include the growth and mineralization of bone and increases in muscle mass.
Anabolic hormones.
Endocrinologists have traditionally classified hormones as anabolic or catabolic, depending on which part of metabolism they stimulate. The classic anabolic hormones are the anabolic steroids, which stimulate protein synthesis and muscle growth, and insulin.
Photosynthetic carbohydrate synthesis.
Photosynthetic carbohydrate synthesis in plants and certain bacteria is an anabolic process that produces glucose, cellulose, starch, lipids, and proteins from CO2. It uses the energy produced from the light-driven reactions of photosynthesis, and creates the precursors to these large molecules via carbon assimilation in the photosynthetic carbon reduction cycle, a.k.a. the Calvin cycle.
Amino acid biosynthesis.
All amino acids are formed from intermediates in the catabolic processes of glycolysis, the citric acid cycle, or the pentose phosphate pathway. From glycolysis, glucose 6-phosphate is a precursor for histidine; 3-phosphoglycerate is a precursor for glycine and cysteine; phosphoenol pyruvate, combined with the "3-phosphoglycerate"-derivative erythrose 4-phosphate, forms tryptophan, phenylalanine, and tyrosine; and pyruvate is a precursor for alanine, valine, leucine, and isoleucine. From the citric acid cycle, α-ketoglutarate is converted into glutamate and subsequently glutamine, proline, and arginine; and oxaloacetate is converted into aspartate and subsequently asparagine, methionine, threonine, and lysine.
Glycogen storage.
During periods of high blood sugar, glucose 6-phosphate from glycolysis is diverted to the glycogen-storing pathway. It is changed to glucose-1-phosphate by phosphoglucomutase and then to UDP-glucose by UTP--glucose-1-phosphate uridylyltransferase. Glycogen synthase adds this UDP-glucose to a glycogen chain.
Gluconeogenesis.
Glucagon is traditionally a catabolic hormone, but also stimulates the anabolic process of gluconeogenesis by the liver, and to a lesser extent the kidney cortex and intestines, during starvation to prevent low blood sugar. It is the process of converting pyruvate into glucose. Pyruvate can come from the breakdown of glucose, lactate, amino acids, or glycerol. The gluconeogenesis pathway has many reversible enzymatic processes in common with glycolysis, but it is not the process of glycolysis in reverse. It uses different irreversible enzymes to ensure the overall pathway runs in one direction only.
Regulation.
Anabolism operates with separate enzymes from catalysis, which undergo irreversible steps at some point in their pathways. This allows the cell to regulate the rate of production and prevent an infinite loop, also known as a futile cycle, from forming with catabolism.
The balance between anabolism and catabolism is sensitive to ADP and ATP, otherwise known as the energy charge of the cell. High amounts of ATP cause cells to favor the anabolic pathway and slow catabolic activity, while excess ADP slows anabolism and favors catabolism. These pathways are also regulated by circadian rhythms, with processes such as glycolysis fluctuating to match an animal's normal periods of activity throughout the day.
Etymology.
The word "anabolism" is from New Latin, which got the roots from , "upward" and , "to throw".


Geeta Bali

Geeta Bali (born Harkirtan Kaur; 1930 ‒ 21 January 1965) was an Indian film actress who appeared in Hindi language films. She was considered one of the most spontaneous and expressive stars of Bollywood for her acting.
Early life.
Geeta Bali was born in the pre-partition Punjab in the city of Sargodha in British India as Harkirtan Kaur in 1930.
Career.
Geeta Baali started her film career as a child actress, at the age of 12, with the film "The Cobbler". She made her debut as a heroine in "Badnaami" (1946).
Bali became a star in the 1950s. She had also worked earlier with her future brother-in-law Raj Kapoor in Bawre Nain (1950) and with her future father-in-law Prithviraj Kapoor in Anand Math. Unlike other actresses who gave up films after marrying into the Kapoor family, Bali kept acting until her death. Her last film was "Jab Se Tumhe Dekha Hai" in 1963. She did more than 70 films in a 10 year career.
Bali helped Surinder Kapoor become a producer.
Personal life.
On 23 August 1955, Geeta married Shammi Kapoor, with whom she was working in the film "Coffee House". They had two children, a son (Aditya Raj Kapoor) and a daughter (Kanchan).
She died on 21 January 1965 due to small pox.


Universal Soldier (film series)

Universal Soldier is a series of science fiction action films. The franchise began in 1992 with "Universal Soldier" and as of 2012 comprises six entries (some of which are now considered non-canon). The films centered on the character of Luc Deveraux (played first by Jean-Claude Van Damme and then by Matt Battaglia) until "", which focuses on a new protagonist named John (played by Scott Adkins).
Film and television critic Matt Zoller Seitz stated that the "Universal Soldier" franchise "is a rare series that takes more creative risks as it goes along."
Films.
"Universal Soldier" (1992).
Directed by Roland Emmerich, written by Richard Rothstein, Christopher Leitch, and Dean Devlin. Starring Jean-Claude Van Damme, Dolph Lundgren, and Ally Walker.
In the first installment of the franchise, American soldier Luc Deveraux (Van Damme) finds that his superior officer, Andrew Scott (Lundgren), has turned violently deranged, and the two fight to the death during the Vietnam War. After their bodies are retrieved, they are placed into a secret program in which they are reanimated as superhuman agents and trained to become unquestioning killing machines. While Devereaux and Scott initially have no memory of their former lives, glimpses of their pasts start to return, rekindling their intense conflict.
"Universal Soldier II: Brothers in Arms" (1998).
After the original film was released, Carolco, the production company that backed the film, went bankrupt and sold the rights of the series to Skyvision Entertainment, located in Toronto, in 1995. As a result, two TV films were released direct-to-video starring Matt Battaglia as Luc Deveraux and Chandra West as Veronica Roberts in "Universal Soldier II: Brothers in Arms" and "Universal Soldier III: Unfinished Business". The films were produced for Showtime / The Movie Channel as a miniseries meant as a backdoor pilot for a series.
Directed by Jeff Woolnough, written by Peter M. Lenkov. Starring Matt Battaglia, Chandra West, and Gary Busey.
This direct-to-video sequel takes place exactly after the events of the original "Universal Soldier". Following the terrible events of the original Universal Soldier testing, the budget has been slashed by the government; however, under the orders of a CIA director, a gang of mercenaries take control of the new line of Universal Soldiers and try to use them into helping to smuggle diamonds to the highest foreign buyer. Meanwhile, Luc Deveraux (Matt Battaglia) and Veronica Roberts (Chandra West) are in hiding on his parents’ farm. The UniSol controllers then activate a homing beacon embedded inside Deveraux's body that makes him return to the UniSol base in Chicago where his memory is reprogrammed. Veronica follows and while sneaking into the UniSol lab to rescue Luc, she discovers that his older brother Eric, a deceased soldier from Vietnam, has also been resurrected.
"Universal Soldier III: Unfinished Business" (1998).
Directed by Jeff Woolnough, written by Peter M. Lenkov. Starring Matt Battaglia, Chandra West, Jeff Wincott, and Burt Reynolds.
Luc Devereaux (Battaglia) and Veronica Roberts (Chandra West) continue their attempts to expose the Universal Soldier unit. After a hostage situation mistakenly leaves Veronica a fugitive, the two escape the city and go into hiding. Meanwhile, CIA Deputy Director Mentor (Burt Reynolds) and Dr. Walker are in the process of creating a powerful UniSol clone of Luc's brother, Eric (Jeff Wincott), to assassinate him and Veronica.
"Universal Soldier: The Return" (1999).
Directed by Mic Rodgers, written by William Malone and John Fasano. Starring Jean-Claude Van Damme, Michael Jai White, and Bill Goldberg.
In this theatrical sequel to the original film, Luc Deveraux (Van Damme) had been reverted to human state and has a 13 years old daughter called Hillary. He works with scientist Dylan Cotner to create a new, safer breed of fighters that are connected through an artificially intelligent computer system called S.E.T.H. (Self-Evolving Thought Helix). The project loses funding, and the supercomputer is scheduled to be turned off. To preserve itself S.E.T.H. takes over a superior UniSol model (White) and kidnaps Hillary. Deveraux must save his daughter and prevent the machine from destroying mankind.
"Universal Soldier: Regeneration" (2009).
Directed by John Hyams, and written by Victor Ostrovsky. Starring Jean-Claude Van Damme, Dolph Lundgren, and Andrei "The Pit Bull" Arlovski.
In this revival of the franchise, “Regeneration” disregards the events of “The Return,” as well as its made-for-cable predecessors by beginning the film with Former UniSol Luc Deveraux (Van Damme) undergoing rehabilitation therapy in Switzerland under Dr. Sandra Fleming with the goal of rejoining society. However, when a terrorist sect uses an experimental Next Generation UniSol (NGU) to seize the atomic reactor at Chernobyl, Deveraux is reactivated to save the country from a nuclear catastrophe. Unfortunately, Deveraux will also have to contend with his nemesis, "Andrew" (Dolph Lundgren), the clone of his former Universal Soldier colleague who's been employed by the terrorists.
"Universal Soldier: Day of Reckoning" (2012).
Directed by John Hyams, written by John Hyams, Doug Magnuson, and Jon Greenlagh. Starring Jean-Claude Van Damme, Dolph Lundgren, Andrei "The Pit Bull" Arlovski, and Scott Adkins.
Luc Devereaux has created a terrifying army of cloned UniSols determined to infiltrate the government which they hold responsible for their pain.
A special agent called John, willing to avenge his murdered family, is pitted against Deveraux and a new clone of Andrew Scott.
Future.
On October 9, 2018, Todd Black and Jason Blumenthal hired Richard Wenk to write the reboot. The story will focus on one resurrected soldier.
Storyline continuity.
"Universal Soldier: Regeneration" revived the franchise in 2009 by disregarding the events of "The Return", as well as its made-for-cable predecessors. A Collider article that focuses on "Days of Reckoning" and interviews the film's director states that the latest installment in the franchise is "either the third, fourth or sixth film in the franchise depending on if you include the pair of non-canon Direct-to-Television sequels and/or the totally retconned "Universal Soldier: The Return"; however, minor elements from these films can be found within the canon series including UniSol clones and UniSol sleeper-agents (from , ).
Production.
Development.
The "Universal Soldier" franchise began in 1992 with "Universal Soldier", starring Jean-Claude Van Damme and Dolph Lundgren. The series centers on two American soldiers, Luc Deveraux (Van Damme) and Andrew Scott (Lundgren), who are killed during the Vietnam War and reanimated in the 1990s as highly advanced Universal Soldiers.
After "Universal Soldier" was released, Carolco, the production company that backed the film, went bankrupt and sold the rights of the series to Skyvision Entertainment, located in Toronto, in 1995. As a result, two TV films were released as television films starring Matt Battaglia as Luc Deveraux and Chandra West as Veronica Roberts in ' and '. The films were produced for Showtime / The Movie Channel as a miniseries meant as a backdoor pilot for a series.
In 1999, Van Damme returned for the fourth installment, "". An overwhelming critical and financial failure, "The Return" contradicted several elements of the previous film's plot by making Luc Deveraux no longer a Universal Soldier, giving him a daughter, and removing female protagonist Veronica Roberts.
The subsequent film in the series, ', revived the franchise in 2009; disregarding the events of "The Return", as well as its made-for-cable predecessors. ' featured Van Damme and Lundgren in much smaller roles, and introduced a new protagonist named John (Scott Adkins) fighting against both Deveraux and Scott.
Other media.
Comic books.
In 1992, a short-lived comic book tie in was released by Now Comics.
Video games.
A "Universal Soldier" video game was developed by The Code Monkeys and published by Accolade in 1992. The game was a conversion of "" for the Sega Genesis and Game Boy. Another version was developed later for the SNES, but it was never released.
Attempted television series.
In October 2011, writer Damien Kindler was set to write a “Universal Soldier” TV series for FreeMantle Media North America with producers from the original film Allen Shapiro and Craig Baumgarten attached to the project.


Ajay Kumar Parida

Ajay Kumar Parida is an Indian biologist noted for his contributions in the fields of agriculture, plant molecular biology and biotechnology. In 2014, Parida was awarded the Padma Shri Award by the President of India for his contribution in the field of Science and Technology.
Parida, who was born and raised in Bhagabanpur, a village in the Jajpur district of Odisha, is the Director of the Institute of Life Sciences (ILS), Bhubaneswar, Odisha, India. ILS (www.ils.res.in) is an autonomous institution of the Department of Biotechnology, Govt. of India. He served as the Executive Director of the M. S. Swaminathan Research Foundation, Chennai during 2009-2017.
Research.
Parida's major scientific contribution is in the area of application of frontier technology for addressing major challenges in global and national declining agriculture productivity threatened due to climate change, sea level rise and reduced precipitation. His research aims at developing location specific crop varieties to cope with the adverse impact of climate change and has significant implications in bringing in stability and sustainability of the major farming systems.
Parida has used advanced biotechnological tools for crop improvement. He has made pioneering contributions in identifying stress tolerant genes specifically for salt and drought stress.
Parida's research has also contributed to the basic understanding of the genetic architecture and species relationship in mangroves, and wild relatives of cultivated cereals, legumes and other cultivated crop species. He has supervised 20 students for their Ph.D. degree. With more than 70 peer reviewed publications in international journals, Parida's research contributions has been widely cited and many of the publications are of significant value to increasing the basic understanding of the process and mechanisms associated with genetic resources characterization, conservation genetics, stress biology and biotechnology related policy issues.
Awards and recognition.
Parida has won the following awards:
He was elected as President of the Agriculture Science and Forestry section of the Indian Science Congress in 2012. Dr. Parida was the President of Biological Sciences Session of the National Academy of Sciences India in 2014.
Parida is involved in application of science and technology for rural development. He has played an active role in organisation of school level Genome Clubs for creating awareness on relevant issues in biology and biotechnology that has been adopted as a national initiative of DNA clubs supported by the Govt. of India. He is actively involved in working with grassroots organizations and local communities in identifying the issues affecting food and livelihood security and providing solutions based on participatory problem solving and providing solutions.


Thomas Morgan (of Dderw)

Sir Thomas Morgan, JP (7 September 1664 – 16 December 1700) was a Welsh Whig politician of the 17th century.
The eldest son of Sir William Morgan and his first wife Blanche, Morgan inherited his father's estate upon the latter's death in 1680. He married Martha Mansel, by whom he had several children, all of whom predeceased him.
Morgan entered the House of Commons in 1689 as Member of Parliament for Brecon, and was High Sheriff of Monmouthshire the same year. In 1690, he sat as MP for Monmouthshire instead, and continued to be returned there for the rest of his life. He also unseated Jeffrey Jeffreys at Brecon in 1698, who appealed on petition. Before the matter could be resolved, Morgan died of smallpox in 1700. His estates, valued at £7000, went to his brother Sir John Morgan.


Pericentriolar material

Pericentriolar material (PCM, sometimes also called pericentriolar matrix) is a highly structured, dense mass of protein which makes up the part of the animal centrosome that surrounds the two centrioles. The PCM contains proteins responsible for microtubule nucleation and anchoring including γ-tubulin, pericentrin and ninein.
Although the PCM appears amorphous by electron microscopy, super-resolution microscopy finds that it is highly organized. The PCM have 9 fold symmetry that mimics the symmetry of the centriole. Some PCM proteins are organized such that one end of the protein is found near the centriole and the other end is farther away from the centriole.
The PCM size is dynamic during the cell cycle. After the cell division the PCM size is reduced in a process named centrosome reduction. During the G2 phase of the cell cycle the PCM size grow in a process named centrosome maturation.
According to the Gene Ontology, the following human proteins are associated with the PCM :


Russell C. Eberhart

Russell C. Eberhart, an American electrical engineer, best known as the co-developer of particle swarm optimization concept (with James Kennedy (social psychologist)). He is professor of Electrical and Computer Engineering, and adjunct professor of Biomedical Engineering at the Purdue School of Engineering and Technology, Indiana University Purdue University Indianapolis (IUPUI). Fellow of the IEEE. Fellow of the American Institute for Medical and Biological Engineering.
He earned a Ph.D. in electrical engineering from Kansas State University in 1972. And he was Associate Editor of IEEE Transactions on Evolutionary Computation and Past president of IEEE Neural Networks Council.


Domesticine

Domesticine is an alpha-1D adrenoceptor antagonist.


Peptide-tryptophan 2,3-dioxygenase

In enzymology, a peptide-tryptophan 2,3-dioxygenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are peptide tryptophan and O2, whereas its product is peptide formylkynurenine.
This enzyme belongs to the family of oxidoreductases, specifically those acting on single donors with O2 as oxidant and incorporation of two atoms of oxygen into the substrate (oxygenases). The oxygen incorporated need not be derived from O2. The systematic name of this enzyme class is peptide-tryptophan:oxygen 2,3-oxidoreductase (decyclizing). Other names in common use include pyrrolooxygenase, peptidyltryptophan 2,3-dioxygenase, and tryptophan pyrrolooxygenase.


TDIQ

TDIQ (also known as 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline or MDTHIQ) is a drug used in scientific research, which has anxiolytic and anorectic effects in animals. It has an unusual effects profile in animals, with the effects generalising to cocaine and partially to MDMA and ephedrine, but the effects did not generalise to amphetamine and TDIQ does not have any stimulant effects. It is thought these effects are mediated via a partial agonist action at Alpha-2 adrenergic receptors, and TDIQ has been suggested as a possible drug for the treatment of cocaine dependence.


List of biotech and pharmaceutical companies in the New York metropolitan area

Biotech and pharmaceutical companies in the New York metropolitan area represent a significant and growing economic component of the New York metropolitan area, the most populous combined statistical area in the United States and one of the most populous megacities in the world.
The biotechnology sector is growing in the New York City area, based upon the region's strength in academic scientific research and public and commercial financial support. By mid-2014, Accelerator, a biotech investment firm, had raised more than US$30 million from investors, including Eli Lilly and Company, Pfizer, and Johnson & Johnson, for initial funding to create biotechnology startups at the Alexandria Center for Life Science, which encompasses more than on East 29th Street and promotes collaboration among scientists and entrepreneurs at the center and with nearby academic, medical, and research institutions. The New York City Economic Development Corporation's Early Stage Life Sciences Funding Initiative and venture capital partners, including Celgene, General Electric Ventures, and Eli Lilly, committed a minimum of US$100 million to help launch 15 to 20 ventures in life sciences and biotechnology in 2014, and in January 2018, the City of New York itself committed up to US$100 million into the venture.
In December 2014, the State of New York announced a US$50 million venture-capital fund to encourage enterprises working in biotechnology and advanced materials; according to Governor Andrew Cuomo, the seed money would facilitate entrepreneurs in bringing their research into the marketplace.
New Jersey has a nickname "Medicine Chest of the World" due to its large workforce in biopharmaceutical industry. As of 2019, twelve of top 20 biopharmaceutical companies in the world has U.S. headquarters in the state.
Below is a list of notable New York metropolitan area biotechnology and pharmaceutical corporations, including companies with either global or U.S. headquarters in the metropolitan region encompassing and surrounding New York City.


Hydrogen dehydrogenase

In enzymology, a hydrogen dehydrogenase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are H2 and NAD+, whereas its two products are H+ and NADH.
This enzyme belongs to the family of oxidoreductases, specifically those acting on hydrogen as donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is hydrogen:NAD+ oxidoreductase. Other names in common use include H2:NAD+ oxidoreductase, NAD+-linked hydrogenase, bidirectional hydrogenase, and hydrogenase. This enzyme participates in glyoxylate and dicarboxylate metabolism and methane metabolism. It has 6 cofactors: FAD, Iron, FMN, Flavin, Nickel, and Iron-sulfur.


N-methyl-L-amino-acid oxidase

In enzymology, a N-methyl-L-amino-acid oxidase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are N-methyl-L-amino acid, H2O, and O2, whereas its 3 products are L-amino acid, formaldehyde, and H2O2.
It has 2 cofactors: FAD, and Flavoprotein.
Nomenclature.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donors with oxygen as acceptor. The systematic name of this enzyme class is N-methyl-L-amino-acid:oxygen oxidoreductase (demethylating). Other names in common use include N-methylamino acid oxidase, and demethylase.


Larry Eisenberg

Lawrence Eisenberg (December 21, 1919 – December 25, 2018) was an American biomedical engineer and science fiction writer. He is best known for his short story "What Happened to Auguste Clarot?", published in Harlan Ellison's anthology "Dangerous Visions". Eisenberg's stories have also been printed in a number of leading science fiction magazines, including "The Magazine of Fantasy & Science Fiction", "Galaxy Science Fiction", and "Asimov's Science Fiction". His stories have been reprinted in anthologies such as "Great Science Fiction of the 20th Century", "The 10th Annual of the Year’s Best S-F", and "Great Science Fiction By the World's Great Scientists". He is also known for the limericks he posted in the comments sections of various articles in "The New York Times".
Life.
Eisenberg was born in New York City in 1919 to Sidney Eisenberg, a furniture salesman, and Yetta Yellen, and grew up in the Bronx during the Great Depression. Eisenberg graduated from James Monroe High School in the Bronx, then attended City College of New York before going to Polytechnic Institute of Brooklyn, where he received his Ph.D. in Electronics. After serving as a radar operator in the Air Force during World War II, Eisenberg married Frances Brenner, a political scientist and social worker, in 1950; she died in 2017. They had one daughter and one son. The couple had lived for many years on the Upper East Side of Manhattan, but by the time of Eisenberg's death he had been living in Somerville, Massachusetts. His death on December 25, 2018, was reported by "The New York Times" under the headline, "Larry Eisenberg, 99, Dead; His Limericks Were Very Well Read". His daughter, Beth Eisenberg, told the "Times" he died in a hospice in Lincoln, Massachusetts, of complications of acute myeloid leukemia.
Eisenberg was for many years a biomedical engineer at Rockefeller University, where he and Dr. Robert Schoenfeld were co-heads of the Electronics Laboratory, and taught there until 2000. He designed the first transistorized radio-frequency coupled cardiac pacemaker circa 1960, in collaboration with Dr. Alexander Mauro. It is on display at Caspary Hall, Rockefeller University.
"Meet Larry Eisenberg", a feature-length documentary about Eisenberg's life, is in production.
Writing.
Eisenberg published his first short story, "Dr. Beltzov's Polyunsaturated Kasha Oil Diet", in "Harper's Magazine" in 1962. His first science fiction publication was later that year with his story "The Mynah Matter" in the August 1962 "Fantastic Stories of Imagination", with Eisenberg debuting alongside Roger Zelazny.
Shortly after that, Eisenberg began publishing his stories in many of the leading science fiction magazines of the day, including "The Magazine of Fantasy & Science Fiction", "Galaxy Science Fiction", and "If". Eisenberg's science fiction takes a humorous approach to storytelling. As Eisenberg has said, "I enjoy wedding humor with science fiction, particularly where some unsavory aspect of our society can be pricked."
Many of Eisenberg's stories feature his character Professor Emmet Duckworth, a research scientist and two-time winner of the Nobel Prize. Duckworth's "bright ideas seem great at first but always end in disaster" with one of the professor's many inventions being "an addictive aphrodisiac clocking in at 150,000 calories per ounce —along with a propensity to turn those taking it into walking bombs." A number of the Duckworth stories were collected in Eisenberg's short story collection, "The Best Laid Schemes", published in 1971 by MacMillan.
Eisenberg is best known for his short story "What Happened to Auguste Clarot?," which was published in the anthology "Dangerous Visions" edited by Harlan Ellison. His stories have also been reprinted in anthologies such as "Great Science Fiction of the 20th Century", "The 10th Annual of the Year’s Best SF", and "Great Science Fiction By the World's Great Scientists".
He published two books of limericks (both with George Gordon) in 1965: "Limericks for the Loo" and "Limericks for Lantzmen"; and one collection of short stories, "Best Laid Schemes". Latterly he gained a cult following for the limericks he posted in the comments sections of various "New York Times" articles and was referred to as the "closest thing this paper has to a poet in residence".
Eisenberg wrote the following limerick about his life
A nonagenarian, I,
A sometime writer of sci-fi,
Biomed engineer,
Gen’rally of good cheer,
With lim’ricks in ready supply.
From a "New York Times" reader: "The Eisenberg Certainty Principle":
There once was a poet named Larry
Whose thoughts one could never quite parry
For when Larry had spoken
The mold it was broken
Though the topics invariably vary.


Bam A

BamA is a β-barrel, outer membrane protein found in Gram-negative bacteria and it is the main and vital component of the β-barrel assembly machinery (BAM) complex in those bacteria. BAM Complex consists of five components; BamB, BamC, BamD, BamE (all are lipoproteins) and BamA (Outer membrane protein). This complex is responsible in catalyzing folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria.
β-barrel membrane proteins can only be found in the outer membrane of Gram-negative bacteria and in organelles such as mitochondria and chloroplasts which were evolved from bacteria. In Gram-negative bacteria, outer membrane proteins are synthesized in the cytoplasm and then exported into the periplasm by Sec translocon machinery. Then they are escorted to the inner surface of the outer membrane by molecular chaperons. Finally those nascent proteins interact with BAM Complex and insert into the outer membrane as β-barrel proteins.
Structure and function.
According to the fully resolved BamA structure of "N. gonorrhoeae", BamA has a large periplasmic domain connected to a transmembrane β-barrel domain which is made of 16 antiparallel β strands. There are five polypeptide translocation-associated (POTRA) domains extending from the barrel at the periplasmic domain of BamA. Current studies suggest that the four lipoproteins in the BAM Complex (BamB, BamC, BamD, BamE ) assemble on to the POTRA domains of BamA, making it the vital component of BAM Complex. The first and the last or 16th β-strands associate in closing the barrel. Extracellular loops (eL) eL4, eL6 and eL7 of the barrel forms a dome over the barrel by isolating the interior of the barrel from the extracellular space and interior of the BamA barrel is completely empty.
The external rim of the β-barrel has a narrow, reduced hydrophobic surface and it reduces lipid order and thickness of the membrane around the barrel. Transient separation of 1st and 16th β-strands which are associated in closing the barrel causes lateral opening of the barrel making a route from interior cavity of the BamA into the outer membrane. POTRA 5 domain of BamA sits close to the β–barrel and interacts with periplasmic loops (pL) pL3, pL4, pL5, pL7 and stabilize the closed conformation of the barrel. Swing movements of POTRA 5 domain and having no interactions with pLs make the opening of the barrel. Thus POTRA domains act as a gate to regulate the access into the interior of β–barrel. Hence there are three structural features associate with BamA that regulates the entry of β-barrel proteins into the outer membrane. First, open and closed conformation of BamA β-barrel. Second, the narrow and reduced hydrophobic rim on the surface of the β –barrel causes local destabilization of the outer membrane. Third, ability to undergo lateral opening of the barrel by transient separation of 1st and 16th β–barrel strands.


Perfluoroisobutene

Perfluoroisobutene (PFIB) is the perfluorocarbon counterpart of the hydrocarbon isobutene and has the formula (CF3)2C=CF2. An alkene, it is a colorless gas that is notable as a highly toxic perfluoroalkene. Few simple alkenes are as toxic.
Safety.
Perfluoroisobutene is quite toxic with an LCt = 880 mg⋅min⋅m−3 (mice). It is a Schedule 2 substance of the Chemical Weapons Convention.
Perfluoroisobutene is highly reactive toward nucleophiles. It hydrolyzes readily to give the relatively innocuous (CF3)2CHCO2H, which readily decarboxylates to give hexafluoropropane. It forms addition compounds with thiols, and it is this reactivity that may be related to its toxicity.
PFIB is a product of pyrolysis of polytetrafluoroethylene (PTFE), one of the substances invoked to explain polymer fume fever.


Stroma (fluid)

Stroma, in botany, refers to the colorless fluid surrounding the grana within the chloroplast.
Within the stroma are grana (stacks of thylakoid), and the sub-organelles or daughter cells, where photosynthesis is commenced before the chemical changes are completed in the stroma.
Photosynthesis occurs in two stages. In the first stage, "light-dependent reactions" capture the energy of light and use it to make the energy-storage molecules ATP and NADPH. During the second stage, the "light-independent reactions" use these products to fix carbon by capturing and reducing carbon dioxide.
The series of biochemical redox reactions which take place in the stroma are collectively called the Calvin cycle or "light-independent reactions". There are three phases: carbon fixation, reduction reactions, and ribulose 1,5-bisphosphate (RuBP) regeneration.
The stroma is also the location of chloroplast DNA and chloroplast ribosomes, and thus also the location of molecular processes including chloroplast DNA replication, and transcription/translation of some chloroplast proteins.


Mycena singeri

Mycena singeri is a species of agaric fungus in the family Mycenaceae. Described as new to science in 1988, it is bioluminescent.


James McEwen (engineer)

James McEwen (born June 10, 1948) is a biomedical engineer and the inventor of the microprocessor-controlled automatic tourniquet system, which is now standard for 15,000-20,000 procedures daily in operating rooms worldwide. Their widespread adoption and use has significantly improved surgical safety, quality and economy. McEwen is President of Western Clinical Engineering Ltd., a biomedical engineering research and development company and he is a director of Delfi Medical Innovations Inc., a company he founded to commercialize some results of that research and development. He is also an adjunct professor in the School of Biomedical Engineering, in the Department of Orthopaedics and in the Department of Electrical and Computer Engineering at the University of British Columbia.
In 2020, to recognize his invention of automatic tourniquets for surgery and other applications he was inducted to the U.S. National Inventors Hall of Fame, joining others including Thomas Edison, Alexander Graham Bell, the Wright brothers, Banting and Best, Nikola Tesla and Steve Jobs. The National Inventors Hall of Fame, in partnership with the United States Patent and Trademark Office, recognizes individuals ‘who hold a U.S. patent of highly significant technology’ and honors ‘the people responsible for the great technological advances that make human, social and economic progress possible.’
He currently resides in Vancouver, British Columbia, Canada.
Career.
McEwen received the B.A.Sc. degree in electrical engineering (biomedical) from the University of British Columbia in 1971. He received the Ph.D. degree in the same field in 1975.
McEwen founded the Biomedical Engineering Department at the Vancouver Hospital & Health Sciences Centre in 1975. He served as the Director from 1975-1990. During his tenure at the Vancouver General Hospital, McEwen invented the automatic tourniquet system for surgery. His improvements to tourniquet systems in general led to greater safety and their wider acceptance as the de facto standard for procedures involving bloodless surgical fields and Bier block anaesthesia.
For several years, he served on the Board of Governors of the British Columbia Institute of Technology and the (BC) Premier's Advisory Council on Science and Technology, to help advance post-secondary educational programs.
McEwen also served as Chairman of the Board of Directors of the ALS Society of British Columbia. As a result, 'in recognition of outstanding community service', he was honoured with a British Columbia Community Achievement Award and the William Fraser Leadership Development Award from the ALS Society of Canada.
Currently, he is President of Western Clinical Engineering Ltd., a biomedical engineering research and development company that he founded, and he is a director of Delfi Medical Innovations Inc., a company he founded to commercialize some results of that research and development. At University of British Columbia, he is an Adjunct Professor in the School of Biomedical Engineering, in the Department of Orthopaedics and in the Department of Electrical and Computer Engineering. He is a past member of the Institute of Electrical and Electronic Engineers (IEEE) and is a registered Professional Engineer (P.Eng).
For 15 years, McEwen served as a Trustee and Vice Chairman of the Board of Trustees of the Ernest C. Manning Awards Foundation. In that capacity, he worked with like-minded individuals to help increase public awareness of the importance of innovation and innovators to the economy and to society. He also created and funds a number of scholarships and bursaries annually at various high schools to recognize outstanding students who overcome adversities to achieve excellence while at the same time helping others, and to advance public education.
Recognition.
McEwen was appointed as an Officer of the Order of Canada for his contribution to biomedical engineering as an inventor and entrepreneur, in December 2011. The Order of Canada is one of the highest civilian honours in Canada. Appointment as an Officer 'recognizes a lifetime of achievement and merit of a high degree, especially in service to Canada or to humanity at large'.
In April 2012, McEwen received the Queen Elizabeth II Diamond Jubilee Medal.
McEwen was awarded a Fellowship in the Canadian Medical Biomedical Engineering Society in 2006.
In 2009, he was awarded a Doctor of Science (honoris causa) degree from Simon Fraser University.
Subsequently, in 2011, he was awarded a Doctor of Science (honoris causa) degree from the University of British Columbia.
In 2016, he was awarded the Dean's Medal of Distinction from the Faculty of Applied Science at the University of British Columbia 'for outstanding contributions to applied science'.
McEwen also received the Research and Innovation Award in 2018 from the UBC Alumni Association for his biomedical inventions, for founding several medical technology companies, for establishing the non-profit Medical Device Development Centre, and for having taken the lead on important issues to create positive social change.
In 2020 he was inducted into the United States National Inventors Hall of Fame.


Emery N. Brown

Emery Neal Brown is an American statistician, neuroscientist, and anesthesiologist. He is the Warren M. Zapol Professor of Anesthesia at Harvard Medical School and at Massachusetts General Hospital (MGH), and a practicing anesthesiologist at MGH. At MIT he is the Edward Hood Taplin Professor of Medical Engineering and professor of computational neuroscience, the Associate Director of the Institute for Medical Engineering and Science, and the Director of the Harvard–MIT Program in Health Sciences and Technology. Brown is one of only 19 individuals who has been elected to all three branches of the National Academies of Sciences, Engineering, and Medicine, as well as the first African American and the first anesthesiologist to be elected to all three National Academies.
Biography.
Brown grew up in Ocala, Florida, where he attended Fessenden Elementary and Middle Schools, Osceola Junior High School and North Marion High School. He graduated from Phillips Exeter Academy, in Exeter, New Hampshire in 1974 after spending the second semester of his senior year at Exeter in the School Year Abroad Program studying Spanish in Barcelona, Spain. In 1978, he received his Bachelor of Arts (magna cum laude) in applied mathematics from Harvard College. Following graduation, Brown received an International Rotary Foundation Fellowship to study mathematics at the Institut Fourier des Mathèmatiques Pures in Grenoble, France.
Upon returning from Grenoble, he entered the Harvard Medical School MD/PhD Program. He received his Master of Arts in 1984 in statistics and his PhD in statistics in 1988 from Harvard University and his MD (magna cum laude) in 1987 from Harvard Medical School.
Brown completed his internship in internal medicine in 1989 at the Brigham and Women’s Hospital, a research fellowship in endocrinology at the Brigham and Women’s Hospital in 1992 and his residency in anesthesiology at MGH in 1992. In 1992, Brown joined the staff in the Department of Anesthesia at MGH and the faculty at Harvard Medical School. In 2005 he joined the faculty at Massachusetts Institute of Technology.
Currently, Brown is the Warren M. Zapol Professor of Anesthesia at Harvard Medical School, the Edward Hood Taplin Professor of Medical Engineering at MIT's Institute for Medical Engineering and Science, and a Professor of Computational Neuroscience at MIT. In addition to his professorial positions, Brown serves as the Director of the Neuroscience Statistics Research Laboratory at the Massachusetts Institute of Technology, the co-director of the Harvard-MIT Division of Health Sciences and Technology and an associate director of MIT's Institute for Medical Engineering & Science. Brown also works as an anesthesiologist at MGH.
Scientific career.
Brown has published widely on topics in Computational Neuroscience and Anesthesiology. Brown is the principal investigator of the Neuroscience Statistics Research Laboratory at MGH and MIT, where he currently conducts his research.
Measuring time on the human biological clock.
Brown developed statistical methods to characterize the properties of the human circadian system (biological clock) from core temperature data recorded under the constant routine and free-running and forced desynchrony protocols. Through the early part of his career, Brown collaborated with circadian researchers to apply his methods to answer fundamental research questions in circadian physiology. Brown’s statistical methods were critical for: estimating accurately the period and internal time on human circadian clocks from continuous core temperature measurement; showing that bright lights could be used to shift the phase of the human circadian clock; properly timed administration of light and dark periods could be used to realign the internal clocks of shift workers with external time; and that, contrary to beliefs at the time, the period of the human biological clock, like that of other animals, was closer to 24 hours rather than 25 hours.
Deciphering brain signals.
Brown later focused his statistics research on developing signal processing algorithms and statistical methods for neuronal data analysis. He developed a state-space point process (SSPP) paradigm to study how neural systems maintain dynamic representations of information. For the analysis of neural spiking activity and binary behavioral tasks represented as multivariate or univariate point processes (0-1 events that occur in continuous time), his research produced analogs of the Kalman filter, Kalman smoothing, sequential Monte Carlo algorithms, and combined state and parameter estimation algorithms commonly applied to continuous-valued time series observations.
Brown used the methods to: show that ensembles of neurons in the rodent hippocampus maintained a highly accurate representation of the animal’s spatial location; track the formation of neural receptive fields on a millisecond time scale; track concurrent changes in neural activity and behavior during learning experiments; decode how groups of motor neurons represent movement information; and track burst suppression in patients under general anesthesia.
Brown applied the state-space paradigm to: analyze learning in behavioral neuroscience experiments; study the relationship between learning and changes in hippocampal function in humans; assess the efficacy of deep brain stimulation in enhancing behavior performance in humans and non-human primates; and define precisely changes in levels of consciousness under propofol-induced general anesthesia.
With Partha Mitra, Brown co-founded and co-directed the Neuroinformatics Summer Course at the Marine Biological Laboratory in Woods Hole, MA from 2002-2006. He co-directs with Robert Kass the biannual Statistical Analysis of Neural Data Conference at the Carnegie Mellon University Center for the Neural Basis of Cognition. He co-authored a textbook in neuroscience data analysis with Robert Kass and Uri Eden.
Nature of general anesthesia.
Unraveling the mystery of general anesthesia is another major question facing modern medicine. In 2004, Brown began a systems neuroscience research program to study the mechanisms of anesthetic action by forming and leading an interdisciplinary collaboration of anesthesiologists, neuroscientists, a statistician, a neurosurgeon, neurologists, bioengineers and a mathematician at MGH, MIT and Boston University.<ref name="labmembers/collaboration"></ref> In 2007 he received an NIH Director’s Pioneer Award to support this research making him, the first anesthesiologist and the first statistician to receive this award. His anesthesiology research has made fundamental theoretical and experimental contributions to understanding the neurophysiology of general anesthesia. In two seminal papers, Brown provided the first systems neuroscience analysis of how anesthetics act at specific receptors in specific neural circuits to produce commonly observed altered arousal states. This analysis provided an essential missing link between the substantial body of research on the molecular pharmacology of anesthetic action and the behavioral responses commonly seen in anesthetized patients. Brown also shows that, contrary to common dogma general anesthesia is not sleep, but rather a reversible coma.
Brown’s research group has provided detailed insights into how anesthetics produce unconsciousness. The brain is not shut off under general anesthesia. Instead, anesthetics induce highly structured oscillations between key brain regions. These oscillations, which are readily visible in standard electroencephalogram (EEG) recordings, alter arousal by impairing normal communication between regions. This is analogous to what happens when an epilepsy patient loses consciousness with the appearance of the regular, hypersynchronous oscillations of a seizure. Anesthetic-induced oscillations are also akin to what happens when a hum in a phone line makes it impossible to sustain a normal conversation.
Brown has performed many studies on the properties of propofol-induced anesthesia in particular. He found that propofol-induced unconsciousness is mediated simultaneously by two different oscillatory processes. The first is strong coherent alpha oscillations (8 to 10 cycles per second) between the cortex and the thalamus (26-28) and the second are strong incoherent cortical slow-wave oscillations (<1 cycle per second). The alpha oscillations impair communication between the thalamus and cortex. The slow-waves restrict to narrow time intervals the times at which cortical neurons can discharge, thus making it difficult to sustain communication within the cortex. Furthermore, each anesthetic has a different EEG signature reflecting different neural circuit mechanisms action. These signatures change with age and the anesthetic dose. A practical implication of this finding is that the EEG can be used in real time to monitor accurately the anesthetic state of patients. Brown’s group has developed an online teaching program to train anesthesiologists on this monitoring approach.
Brown and colleagues are establishing a new paradigm for waking patients up following general anesthesia. They have shown that the anesthetic state can be rapidly reversed by administering methylphenidate (Ritalin) or activation of dopaminergic systems. This suggests a new, feasible way to actively restore cognitive function in patients after anesthesia and sedation. They have received FDA approval to undertake a clinical trial to test this idea in humans (NCT 02051452). They have also shown that burst-suppression, a state of profound brain inactivation seen in deep general anesthesia, hypothermia, coma and developmental brain disorders, can be simply explained by a unifying neural-metabolic model. Brown’s group have also shown that burst suppression can be precisely controlled to maintain a therapeutic, medically-induced coma. This research uses a closed-loop control system based on his SSPP paradigm. This could have important implications for treating patients, such as Gabby Giffords, Michael Schumaker, Malala Yousafzai, and Joan Rivers, who sustain brain injuries or have intracranial hypertension and require a medically-induced coma to facilitate brain recovery.
Brown's anesthesiology research has been featured on National Public Radio, in Scientific American, the MIT Technology Review, the New York Times and in TEDMED 2014.
National committee service.
Brown has served on numerous national panels and advisory committees. Most recently he served on the NIH BRAIN Initiative Working Group. His current committee service includes being a member of the Burroughs-Wellcome Fund Board of Directors, the NSF Mathematical and Physical Sciences Advisory Committee, the NIH Council of Councils, the Board of Trustees of the International Anesthesia Research Society, the Scientific Advisory Committee of CURE Epilepsy and the Governing Council of the American Academy of Arts and Sciences.
Awards and honors.
Brown has received a number of awards throughout his career, including: the Robert Wood Johnson Minority Medical Faculty Development Fellowship, an NSF Minority Career Development Fellowship, an National Institute of Mental Health Independent Scientist Award, the Jerome Sacks Award from the National Institute of Statistical Sciences for Outstanding Cross Disciplinary Research, an NIH Director’s Pioneer Award, an NIH Director’s Transformative Research Award, a Guggenheim Fellowship, and the American Society of Anesthesiologists Award for Excellence in Research. Brown was named as one of America's leading doctors by Black Enterprise Magazine and was named one of Get Konnected's GK50 Boston’s 50 Most Influential People of Color in Healthcare & Life Sciences In 2018, Brown received the Dickson Prize in Science for his work on the statistical analysis of neuronal data and research on anesthesia. One of Carnegie Mellon's nominators, Professor Robert E. Kass, noted that Brown is the "world's expert on statistical analysis of neuronal data" and that Brown's work on anesthesia has been "truly transformative" for the field.
Brown has presented several memorial lectures, including: the American Society of Anesthesiology's Lewis H. Wright Memorial Lecture and John W. Severinghaus Lecture in Translational Science and the Institute of Mathematical Sciences Medallion Lecture.
Brown is a fellow of the American Institute for Medical and Biological Engineering, the American Statistical Association, the IEEE, the American Association for the Advancement of Sciences, and the American Academy of Arts and Sciences. Brown was inducted into the Florida Inventors Hall of Fame. Brown is a member of all three branches of the National Academies, which are the National Academy of Medicine, the National Academy of Sciences and the National Academy of Engineering. He is the first African American and the first anesthesiologist elected to all three branches.


Ciladopa

Ciladopa (AY-27,110) is a dopamine agonist with a similar chemical structure to dopamine. It was under investigation as an antiparkinsonian agent but was discontinued due to concerns of tumorogenesis in rodents.


Homebake (slang)

Homebake is a slang name used in New Zealand and Australia for morphine produced from codeine when it is difficult to obtain heroin.


N-hydroxy-2-acetamidofluorene reductase

In enzymology, a N-hydroxy-2-acetamidofluorene reductase () is an enzyme that catalyzes the chemical reaction
The 4 substrates of this enzyme are 2-acetamidofluorene, NAD+, NADP+, and H2O, whereas its 4 products are N-hydroxy-2-acetamidofluorene, NADH, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on other nitrogenous compounds as donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 2-acetamidofluorene:NAD(P)+ oxidoreductase. Other names in common use include N-hydroxy-2-acetylaminofluorene reductase, and NAD(P)H:N-hydroxy-2-acetamidofluorene N-oxidoreductase.


List of biochemists

This is a list of biochemists. It should include those who have been important to the development or practice of biochemistry. Their research or applications have made significant contributions in the area of basic or applied biochemistry.
See also.
Scientists in fields close to biochemistry


FlpD RNA motif

The "flpD" RNA motif is a conserved RNA structure discovered using bioinformatics. It is detected only in methanogenic archaea, and is generally located in the apparent 5' untranslated region of genes encoding hydrogenases that are likely involved in methane metabolism. For example, the "flpD" gene itself encodes a subunit of methyl-viologen-reducing hydrogenase.


Fred Weibell

Fred John Weibell (October 18, 1927-2015) was an American biomedical engineer. He served for many years as the Secretary-Treasurer of the Biomedical Engineering Society (BMES). In 1992, he was the first recipient of the BMES Distinguished Service Award in recognition of his "extraordinary contributions to the Society."
Together with Leslie Cromwell and Erich A. Pfieffer, he was a coauthor of Biomedical Instrumentation and Measurements (Prentice Hall ). For several decades, this text has been "considered by many to be the 'Bible' for biomedical technicians," and is still used in the curriculum of colleges and universities worldwide.
He died August 6, 2015 from causes incident to age and Parkinson's disease.


Lynne Jones

Lynne Mary Jones (born 26 April 1951) is a British Labour Party politician, who was the Member of Parliament (MP) for Birmingham Selly Oak from 1992 until the dissolution of parliament in April 2010.
Early life.
Jones was born in Birmingham, and attended the local Bartley Green Girls' Grammar School (now the comprehensive Hillcrest School) in Woodgate. She studied Biochemistry at the University of Birmingham, eventually gaining her Ph.D. in 1979. She also has a post-graduate Diploma in Housing Studies from Birmingham Polytechnic (now Birmingham City University). She worked in research at the University of Birmingham from 1972–86. She was a housing association manager from 1987–92. She joined the Labour Party in 1974.
She has worked in both science and housing, and was a Councillor on Birmingham City Council representing Kings Norton ward from 1980–94.
Research interests.
She first studied stimulus-response coupling in the rat parotid gland and at alpha adrenergic receptors. This led to a discovery that there are cell-surface receptors that are stimulated by hormones and neurotransmitters controlled by changes of intracellular calcium ion levels. It also involves the conversion of inositol phospholipids in the cell membrane. She also worked on the process of agonist-stimulated incorporation of radioactive phosphate into inositol phospholipids.
Parliamentary career.
Jones was first elected to the House of Commons at the 1992 general election. She was a member of the Socialist Campaign Group and took part in almost all of the backbench rebellions against the Labour government. She was also Chair of the Parliamentary Forum on Transsexualism, and is a patron of Press for Change.
From 1993–2001 she was on the Science and Technology Select Committee. During the 2005–10 parliament she was a member of the Environment, Food and Rural Affairs Select Committee.
Leadership challenge.
In February 2006, she announced her intention to stand against then Chancellor Gordon Brown in the Labour Party leadership contest expected to follow Prime Minister Tony Blair's resignation if nobody else did, so that Brown could not simply be "crowned". Subsequently, Socialist Campaign Group Chair John McDonnell (now Shadow Chancellor of the Exchequer) attempted to stand instead, but failed to gain enough nominations from MPs and Brown was unopposed.
Retirement.
Following boundary changes in Birmingham, which reduced its parliamentary representation from eleven to ten seats, Jones was expected to apply for selection for the redrawn Selly Oak constituency which contained wards from the former Selly Oak and Hall Green constituencies. However, in January 2007 Jones announced her intention to stand down at the 2010 general election. Jones refused to endorse Roger Godsiff in Hall Green, instead supporting the Respect candidate Salma Yaqoob, who came second.
Personal life.
She is married, and has two sons (including one born in January 1990). She married Chris Kirk in April 1994 in Lambeth. He is Chief Executive of the Biochemical Society. She is a keen cyclist.
In November 2009, she announced she was having treatment for breast cancer after a tumour was discovered at an early stage.


FinP

FinP encodes an antisense non-coding RNA gene that is complementary to part of the TraJ 5' UTR. The FinOP system regulates the transfer of F-like plasmids. The traJ gene encodes a protein required for transcription from the major transfer promoter, pY. The FinO protein is essential for effective repression, acting by binding to FinP and protecting it from RNase E degradation.


Omid Veiseh

Omid Veiseh is an American biomaterials researcher and entrepreneur. As a postdoctorate candidate at MIT, he co-founded Siglion Therapeutics, a biotechnology company which would commercialize the discoveries he and his co-founders developed. In 2016, Veiseh was offered a faculty position in the Department of Bioengineering at Rice University.
Early life and education.
Veiseh earned his Bachelor of Science degree from Western Washington University and his PhD from the University of Washington. Upon completing his PhD, Veiseh completed his post-doctoral research at MIT's Koch Institute for Integrative Cancer Research where he co-developed a way to reduce immune-system rejection using biomedical devices. While at MIT, he co-founded Sigilon Therapeutics, a biotechnology company which would commercialize the discoveries he and his co-founders developed.
Career.
Veiseh left MIT in 2016, after Rice University won a $2 million grant from the Cancer Prevention and Research Institute of Texas to recruit him to their Department of Bioengineering. As an assistant professor of bioengineering, Veiseh and his laboratory earned funding from the National Institutes of Health to design hydrogel-encapsulated cells can sense blood glucose levels and produce insulin on demand. He also collaborated with Jordan Miller to combine cell-based therapy applications with 3D-printed technologies for use in Type-1 diabetes therapies.
While at Rice, Veiseh's Sigilon Therapeutics partnered with Eli Lilly and Company to develop "living drug factories" that could be safely implanted in the body and produce insulin. As a result of his efforts, Veiseh was recognized by MedTech Boston on their 40 under 40 Healthcare Innovators in 2017. During the COVID-19 pandemic in North America, Veiseh's Sigilon Therapeutics raised funding to compose their first-in-human clinical trial of their novel encapsulated cell therapy for hemophilia A. Individually, he also worked alongside Ravi Ghanta to develop a novel biomaterial improve the cells’ ability to heal heart injuries.


MTT assay

The MTT assay is a colorimetric assay for assessing cell metabolic activity. NAD(P)H-dependent cellular oxidoreductase enzymes may, under defined conditions, reflect the number of viable cells present. These enzymes are capable of reducing the tetrazolium dye MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to its insoluble formazan, which has a purple color. Other closely related tetrazolium dyes including XTT, MTS and the WSTs, are used in conjunction with the intermediate electron acceptor, 1-methoxy phenazine methosulfate (PMS). With WST-1, which is cell-impermeable, reduction occurs outside the cell via plasma membrane electron transport. However, this traditionally assumed explanation is currently contended as proof has also been found of MTT reduction to formazan in lipidic cellular structures without apparent involvement of oxidoreductases.
Tetrazolium dye assays can also be used to measure cytotoxicity (loss of viable cells) or cytostatic activity (shift from proliferation to quiescence) of potential medicinal agents and toxic materials. MTT assays are usually done in the dark since the MTT reagent is sensitive to light.
MTT and related tetrazolium salts.
MTT, a yellow tetrazole, is reduced to purple formazan in living cells. A solubilization solution (usually either dimethyl sulfoxide, an acidified ethanol solution, or a solution of the detergent sodium dodecyl sulfate in diluted hydrochloric acid) is added to dissolve the insoluble purple formazan product into a colored solution. The absorbance of this colored solution can be quantified by measuring at a certain wavelength (usually between 500 and 600 nm) by a spectrophotometer. The degree of light absorption is dependent on the degree of formazan concentration accumulated inside the cell and on the cell surface. The greater the formazan concentration, the deeper the purple colour and thus the higher the absorbance.
XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) has been proposed to replace MTT, yielding higher sensitivity and a higher dynamic range. The formed formazan dye is water-soluble, avoiding a final solubilization step.
Water-soluble tetrazolium salts are more recent alternatives to MTT: they were developed by introducing positive or negative charges and hydroxy groups to the phenyl ring of the tetrazolium salt, or better with sulfonate groups added directly or indirectly to the phenyl ring.
MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium), in the presence of phenazine methosulfate (PMS), produces a formazan product that has an absorbance maximum at 490 nm in phosphate-buffered saline. The MTS assay is often described as a 'one-step' MTT assay, which offers the convenience of adding the reagent straight to the cell culture without the intermittent steps required in the MTT assay. However this convenience makes the MTS assay susceptible to colormetric interference as the intermittent steps in the MTT assay remove traces of coloured compounds, whilst these remain in the microtitre plate in the one-step MTS assay. Precautions are needed to ensure accuracy when using this assay and there are strong arguments for confirming MTS results using qualitative observations under a microscope. (This, however, is prudent for all colormetric assays.)
WSTs (water-soluble tetrazolium salts) are a series of other water-soluble dyes for MTT assays, developed to give different absorption spectra of the formed formazans. WST-1 and in particular WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium), are advantageous over MTT in that they are reduced outside cells, combined with PMS electron mediator, and yield a water-soluble formazan. Finally, WST assays (1) can be read directly (unlike MTT that needs a solubilization step), (2) give a more effective signal than MTT, and (3) decrease toxicity to cells (unlike cell-permeable MTT, and its insoluble formazan that accumulate inside cells).
MTT assay's significance.
Tetrazolium dye reduction is generally assumed to be dependent on NAD(P)H-dependent oxidoreductase enzymes largely in the cytosolic compartment of the cell. Therefore, reduction of MTT and other tetrazolium dyes depends on the cellular metabolic activity due to NAD(P)H flux. Cells with a low metabolism such as thymocytes and splenocytes reduce very little MTT. In contrast, rapidly dividing cells exhibit high rates of MTT reduction. It is important to keep in mind that assay conditions can alter metabolic activity and thus tetrazolium dye reduction without affecting cell viability. In addition, the mechanism of reduction of tetrazolium dyes, "i.e." intracellular (MTT, MTS) "vs." extracellular (WST-1), will also determine the amount of product. Additionally, proof has been provided as to the spontaneous MTT reduction in lipidic cellular compartments/structures, without enzymatic catalysis involved. Nevertheless, even under this alternative paradigm, MTT assay still assesses the reduction potential of a cell (i.e. availability of reducing compounds to drive cellular energetics). As such, the final cell viability interpretation remains unchanged.


Glowing Plant project

The Glowing Plant project was the first crowdfunding campaign for a synthetic biology application. The project was started by the Sunnyvale-based hackerspace Biocurious as part of the DIYbio philosophy. According to the project's goals, funds were used to create a glowing "Arabidopsis thaliana" plant. Long-term ambitions (never realized) included the development of glowing trees that can be used to replace street lights, reducing CO2 emissions by not requiring electricity.
Project funding.
Using Kickstarter, the project's founders raised $484,000 on June 8, 2013. This was significantly more than the initial target of $65,000.
Seeds were initially scheduled to be delivered in April 2014. In March 2016, delivery of seeds was forecast for 2016 on the Glowing Plant website. The company encountered difficulty getting plants to emit significant amounts of light, and announced via email December 2017 that it was permanently ceasing operations.
Interest in synthetic biology.
Washington Post writes that Glowing Plant Project sparked interest in synthetic biology.
Controversy.
The project generated widespread media attention and a discussion of appropriate uses of biotechnology. As a result of the controversy, Kickstarter decided to prohibit genetically modified organisms as rewards to project backers.
Though the U.S. Department of Agriculture has shown no regulatory concerns about the project, some synthetic biologists and policy researchers have questioned the project's feasibility and impact on future oversight or public opinion of synthetic biology.


6-MAPDB

6-MAPDB (1-(2,3-dihydrobenzofuran-6-yl)-N-methylpropan-2-amine) is a chemical compound which might be an entactogenic drug. It is structurally related to drugs like 6-APDB and 6-MAPB, which have similar effects to MDMA and have been used as recreational drugs. 6-MAPDB has never been studied to determine its pharmacological activity, though it is the N-methyl derivative of 6-APDB which is known to be a selective serotonin releaser.
Legality.
6-MAPDB was banned in the UK in June 2013 as a temporary class drug along with 9 other related compounds, despite having never been sold as a street drug itself. This was due to concerns that it would have similar effects to drugs such as 6-APB that had been widely sold already, and 6-MAPDB might therefore be likely to become used recreationally also, if it were not banned preemptively.


OmcS oxidoreductase

OmcS oxidoreductase (Geobacter nanowire, G-NET) are enzymes found in some species of bacteria, including "Geobacter sulfurreducens", where they catalyze the transfer of electrons. They are multiheme c-Type cytochromes localized outside of the cell along the pili of some exoelectrogenic bacterial species, serving as mediator of extracellular electron transfer from pili to Fe(III) oxides and other extracellular electron acceptors.
OmcS may also facilitate temporary electron storage, acting as capacitor, allowing "Geobacter" species to move towards distant terminal electron acceptors.
OmcS has six low-spin bis-histidinyl hexacoordinated heme groups, and the OmcS gene is the most highly up-regulated of all genes in the "Geobacter sulfurreducens" KN400 strain when cultivated in a microbial fuel cell, as compared to the PCA strain.


Landiolol

Landiolol (INN) is an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. In comparison to other betablockers, landiolol has the shortest elimination half-life (3 to 4 minutes), ultra-rapid onset of effect (heart rate begins to decrease immediately after completion of administration), and predectible effectiveness with inactive metabolites (heart rate returns to baseline levels at 30 min after completion of landiolol hydrochloride administration). The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired.
Landiolol was developed by modifying the chemical structure of esmolol to produce a compound with a higher rate of cardioselectivity and a greater potency without increasing its duration of action. It is sold as landiolol hydrochloride. Based on its positive benefit risk profile, landiolol has been granted the marketing authorization and introduced to the European markets under the brand names "Rapibloc", "Raploc", "Runrapiq", "Landibloc" mid 2016 (in 2 formulations of 300 mg vial and 20 mg ampoule). Landiolol is available in Japan under the brand names "Onoact" (50 mg) and "Corbeta" (12.5 mg for Improvement of Image Quality in Coronary CT Angiography).
Mode of action.
The drug acts as an ultra-short-acting β1-selective blocking agent. It is rapidly hydrolyzed to an inactive
form by both carboxylesterase in the liver and pseudocholinesterase in the plasma, resulting in an elimination half-life of about 4 minutes.
Landiolol is a highly selective beta-1-adrenoreceptor antagonist (the selectivity for beta-1-receptor blockade is 255 times higher than for beta-2-receptor blockade) that inhibits the positive chronotropic effects of the catecholamines adrenaline and noradrenaline on the heart, where beta-1-receptors are predominantly located. Landiolol, as other beta-blockers, is thought to reduce the sympathetic drive, resulting in reduction in heart rate, decrease in spontaneous firing of ectopic pacemakers, slowing the conduction and increase the refractory period of the AV node. Landiolol does not exhibit any membrane-stabilizing activity or intrinsic sympathomimetic activity in vitro. In preclinical and clinical studies, landiolol controlled tachycardia in an ultra-short acting manner with a fast onset and offset of action and further demonstrated anti-ischaemic and cardioprotective effects. To date, landiolol has the shortest plasma half-time and the highest cardio-selectivity among β-blockers in clinical use. The selectivity of landiolol for β1-receptor blockade is 255 times higher than for β2-receptor blockade. In comparison, Metoprolol, has a much less cardioselectivity (landiolol is 100 times more cardioselective than metoprolol, and 8 times more cardioselectove than esmolol), and sixty times longer half-life (3–4 hours comparing to 3–4 minutes in case of landiolol). FDA points out that CYP2D6 poor metabolizers will have decreased cardioselectivity for metoprolol due to increased metoprolol blood levels, since the gene variation reduces the conversion of metoprolol to inactive metabolites leading to almost 5-fold higher plasma concentrations of metoprolol.
Activation of β2 adrenergic receptors contributes to bronchial dilation and acceleration of alveolar fluid clearance in the pulmonary airway system. Consequently, a cardio-selective β1-blocker with limited effect on β2-receptor decreases the heart rate without the pulmonary adverse effects in patients with COPD or Asthma.
Pharmacological stimulation of β2 receptors increases coronary blood flow in healthy humans and in patients with mildly atherosclerotic coronary arteries. Thus, not only does a cardio-selective β1-blocker reduce myocardial oxygen demand during exercise, but it also unveils β2-receptor-mediated coronary exercise hyperemia, while reducing the heart rate selectively. Interestingly, landiolol does not possess any sodium and calcium antagonistic properties, which makes it a more suitable cardio-selective β-blocker for patients with heart failure due to its lesser potency for negative inotropy, while offering higher potency for heart rate reduction. Contrary to landiolol, exposure to other β-blockers such as esmolol amplifies the re-expression of β-receptors which explains the drug tolerance effect seen during long-term esmolol infusion. Long term exposure of cells to betablockers which act as pharmacochaperones will raise the total surface level of β1-adrenergic receptors, resulting in exaggerating responses to endogenous agonists such as catecholamines, if the treatment is suddenly stopped. This phenomenon has been described as the betablocker withdrawal rebound. However, landiolol lacks appreciable pharmacochaperoning activity, as landiolol can hardly permeate cell membranes due to its large polar surface area.
Biotransformation.
Landiolol is metabolised via hydrolysis of the ester moiety. In vitro and in vivo data suggest that landiolol is mainly metabolised in the plasma by pseudocholinesterases and carboxylesterases. Hydrolysis releases a ketal (the alcoholic component) that is further cleaved to yield glycerol and acetone, and the carboxylic acid component (metabolite M1), which subsequently undergoes beta-oxidation to form metabolite M2 (a substituted benzoic acid). The beta-1-adrenoreceptor blocking activity of landiolol metabolites M1 and M2 is 1/200 or less of the parent compound indicating a negligible effect on pharmacodynamics taking into account the maximum recommended landiolol dose and infusion duration.
Neither landiolol nor the metabolites M1 and M2 showed inhibitory effects on the metabolic activity of different cytochrome P450 molecular species (CYP1A2, 2C9, 2C19, 2D6 and 3A4) in vitro. The cytochrome P450 content was not affected in rats after repeated intravenous administration of landiolol. There are no data on a potential effect of landiolol or its metabolites on CYP P450 induction or time dependent inhibition available.
Uses.
Landiolol is indicated as an antiarrhythmic agent in Europe for
Additionally, landiolol has been approved for the treatment of ventricular fibrillation or ventricular tachycardia in Japan.
Landiolol can be used as first-line treatment for acute ventricular rate control in patients with atrial fibrillation (Level I recommendation- 2020 Guidelines of the European Society of Cardiology)
The beneficial effects of landiolol have been demonstrated in over sixty clinical trials (pubmed search -August 2018). Landiolol was generally well tolerated, with a relatively low risk of hypotension and bradycardia. Most clinical trials with landiolol have been conducted in peri-operative settings for the treatment or prophylaxis of supraventricular tachycardia or tachyarrhythmia before or after cardiac and non-cardiac surgeries. Randomized clinical trials have been published to compare landiolol with placebo< diltiazem, and amiodaron in patients with or without heart failure. Case reports on the use of landiolol after myocardial infarction, refractory electrical storm have been published. The fast turnover of landiolol will diminish most adverse events due to self-limiting administration. Landiolol may be cardio-protective in septic rats by normalizing coronary microcirculation through blockage of sepsis-induced decrease in expression of VEGF signaling system but independent of inflammatory cytokines.
The efficacy and safety of landiolol in septic shock has been investigated in a multi-center prospective randomized controlled trial, and the results of the study have been published in the renown Journal Lancet Respiratory in 2020, demonstrating clinical impact of landiolol in sepsis patients through significant reduction of new-onset arrhythmia and keeping the patients within the target heart rate range.
Furthermore, landiolol demonstrated a positive clinical impact regarding ventilation-free days, ICU-free days and hospital-free days. Patients in the landiolol group had a survival rate of 88% by day 28, in contrast to a mortality rate of 20% in the control group by day 28. These are very important findings which may include landiolol in the standard of care for sepsis patients, since tachycardia and atrial fibrillation are key prognostic factors for sepsis. Additionally, tachycardia exceeding 100 beats per min (bpm) on admission to an intensive care unit (ICU) is a risk factor for worsening prognosis.
A recent publication in the Journal of Cardiology illustrated in a prospective real-world setting, the safety and effectiveness of landiolol for the treatment of atrial fibrillation or atrial flutter in chronic heart failure (over one thousand patients at 209 medical institutions throughout Japan). In this survey, which is one of the largest studies ever performed in patients with chronic heart failure requiring intravenous rate control, report of serious hypotension was in less than 1% of patients, which highlights the cardio-selectivity of landiolol with limited effect on blood pressure. Noteworthy, over 70% of patients were in the NYHA class III or IV (35% NYHA IV), and close to 50% had a LVEF below 40%. The median time to first return to sinus rhythm after administration of landiolol was 14 hours, and the median highest infusion rate was 3 μg/kg/min.
Landiolol is a promising drug to manage postoperative atrial fibrillation in non-cardiac surgery with a profile that allow for control of heart rate with minimal impact on blood pressure. Landiolol has limited negative inotropic effect and is well tolerated by the respiratory system. Additional benefits related to the regulation of inflammatory response and blunting of the adrenergic pathway probably contribute to the decreased incidence of POAF. The use of low dosage (5–10 μg/kg/min) is usually sufficient to rapidly control heart rate which is associated with earlier and higher rate of conversion to sinus rhythm as compared to the controls.
The excellent tolerance of landiolol at lower dosage (3–5 μg/kg/min) allows to initiate prophylactic use during surgery and post-operatively. Landiolol prophylaxis is associated with reduced incidence of postoperative atrial fibrillation without triggering adverse events related to a beta-blockade. Optimized infusion scheme with continuing landiolol infusion in the post-operative period seems to be associated with better response, while infusion limited to the intraoperative period may not be sufficient
In patients with impaired left ventricular function (LVEF <40%, CI <2.5 L/min/m2, NYHA 3-4) e.g. after cardiac surgery, during ischemia or in sepsis states, lower doses starting from 1 microgram/kg BW/min and increased in a stepwise fashion under close blood pressure monitoring up to 10 μg/kg/min have been used to achieve heart rate control.
Conversion table for continuous intravenous infusion: μg/kg/min to ml/h (Example below for Rapibloc 300 mg/50 ml = 6 mg/ml strength):
The formula for the calculation of the hourly infusion rate in ml/h = (Body weight in kg x Dosage in μg/kg/min) / 100


Kathy Nguyen