Channing Robertson

Channing Rex Robertson is Emeritus Professor of Chemical Engineering at Stanford University. He received his Ph.D. from Stanford under the supervision of Andreas Acrivos. He originally joined the faculty of Stanford in 1970, and formerly served as the Ruth G. and William K. Bowes Professor and Senior Associate Dean for Faculty & Academic Affairs in the School of Engineering there. In 2000, he was featured in a special issue of "Upside", entitled "100 People Who Have Changed the World". He is a founding fellow of the American Institute for Medical and Biological Engineering. He retired from Stanford in 2012 to join the Theranos board of directors, becoming an emeritus professor. Since his active role in the Theranos scandal, he is no longer teaching classes in the School of Engineering.
Theranos.
Robertson taught Theranos founder Elizabeth Holmes when she was a student at Stanford, and he went on to become the company's first board member. He convinced Ian Gibbons to work for Theranos in 2005. In 2017, Theranos named him the co-leader of their technology advisory board. Even as Theranos was coming under growing scrutiny, as of May 2018, Robertson still believed the company was successful in developing novel blood testing technology. According to lawyer Reed Kathrein, who sued Theranos on behalf of some of its former investors, the company only paid Robertson to lend itself credibility.


Peptide loading complex

The peptide-loading complex (PLC) is a short-lived, multisubunit membrane protein complex that is located in the endoplasmic reticulum (ER). It orchestrates peptide translocation and selection by major histocompatibility complex class I (MHC-I) molecules. Stable peptide-MHC I complexes are released to the cell surface to promote T-cell response against malignant or infected cells. In turn, T-cells recognize the activated peptides, which could be immunogenic or non-immunogenic.
Overview.
A PLC assembly consists of seven subunits, including the transporters associated with antigen processing (TAP1 and TAP2 – jointly referred to as TAP), the oxidoreductase ERp57, the MHC-I heterodimer, and the chaperones tapasin and calreticulin. TAP transports proteasomal degradation products from the cytosol into the lumen of the ER, where they are loaded onto MHC-I molecules. The peptide-MHC-I complexes then move via a secretory pathway to the cell surface, presenting their antigenic load to cytotoxic T-cells.
In general, preliminary MHC-I heavy chains are chaperoned by the calnexin–calreticulin system in the ER. Together with β2-microglobulin (β2m), MHC-I heavy chains form assemblies of heterodimers that act as receptors for antigenic peptides. Empty MHC-I heterodimers are recruited by calreticulin and form short-lived macromolecular PLC where the chaperone tapasin further provides stabilization in the MHC-I molecules. Furthermore, ERp57 and tapasin form disulfide-linked conjugates, and tapasin is crucial for maintaining the structural stability of the PLC as well as facilitating optimal peptide loading. After final quality control, during which MHC-I heterodimers undergo peptide editing, stable peptide–MHC-I complexes are released to the cell surface for T-cell recognition. The PLC can serve a large variety of MHC-I allomorphs, thus playing a central role in the differentiation and priming of T lymphocytes, and in controlling viral infections and tumour development.
Structure.
So far, only the structure of human PLC has been elucidated using single-particle electron cryo-microscopy (cryo-EM). The structural organization consists of tapasin, calreticulin, ERp57, and MHC-I molecules that are centered around TAP, bearing a pseudo-symmetric orientation. PLC size is 150 Å by 150 Å with a total height of 240 Å across the ER membrane. Two opposing tapasin molecules shape the central domain in the PLC. In this model, residue E225 of the N-terminal immunoglobulin-like domain of one molecule and R60, which is located in the short helical motif of the seven-stranded N-terminal β-barrel of the second molecule, in salt-bridge distance. These residues are conserved among jawed vertebrates, but missing in avian PLC. This is consistent with the existence of a single copy of tapasin in avian PLC and the absence of an N-terminal transmembrane domain (TMD0) in avian TAP1. The ER-luminal domains of the opposing tapasin molecules are tilted 30° towards each other, positioning the two membrane entry points of the transmembrane helices 60 Å apart. The resulting domain twist excludes binding of calreticulin or calnexin to the glycan of the dimeric tapasin scaffold and explains why only mature tapasin can assemble into the PLC. Another structural feature is that ERp57 in its typical U-shaped conformation is complexed to tapasin via the catalytically active a and a′ domains. The unexpected orientation of tapasin enables the C-terminal extension of the a′ domain of the trans ERp57 to interact with the C-terminal immunoglobulin-like domain of the cis tapasin, potentially adding to the stability of the PLC.
This cryo-EM structure reveals a high degree of plasticity of the N-terminal three β-sheet sandwich of tapasin and shows that flexible fastening of MHC-I is essential for tapasin to exert its proofreading function. Calreticulin is crucial and is highly dependant in the assembly and maturation of MHC-I in the PLC. The globular lectin domain of calreticulin harbours a glycan-binding site, which senses monoglucose moieties of N-core glycosylated MHC-I before it associates with tapasin. The monoglucosylated branch of the N-core glycan that emanates from N86 of MHC-I is binding to the glycan-binding surface of calreticulin, whereas another mannose branch is likely to lie close among residues at the edge of the lectin β-sandwich. Consistent with its proposed calcium-dependent lipid-sensing activity, the C-terminal acidic tail of calreticulin points towards the ER-luminal membrane leaflet, where it is located close to the C-terminal immunoglobulin-like domain of tapasin. In the cryo-EM structure emphasis is given in the central role of the C-terminal immunoglobulin-like domain of tapasin, which acts as an essential multivalent interaction core for the remaining PLC subunits. A central cavity that connects the exit of the peptide translocation pathway of TAP with the ER lumen via two lateral windows might serve as a molecular basket for transported peptides before they are edited by ER-resident aminopeptidases.
TAP.
TAP is a heterodimeric complex, consisting of TAP1 (ABCB2) and TAP2 (ABCB3) members of the ABC transporter superfamily. The common feature of all ABC transporters is their organization: 1) into two transmembrane domains (TMDs) and 2) into two nucleotide-binding domains (NBDs). Both intramolecular domains are coupled to each other and when ATP binding is in progress, conformational changes in the TMDs allow proteasomal degradation products to move across the membrane. TAP recognizes and transports the antigen peptides produced in the cytosol straight into the ER, while tapasin recognizes the kind of peptides that have the ability to form stable complexes with MHC-I. This process is known as peptide proofreading or editing. Peptides selected through proofreading improve MHC-I stability; tapasin also contributes to the editing of immunogenic peptide epitopes. However, only lately it was proven via biochemical, biophysical, and structural studies that a key function in adaptive immunity, the catalytic mechanism of peptide proofreading, is performed by tapasin and TAPBPR (TAP-binding protein-related, a tapasin homologue).
Tapasin.
Cresswell and co-workers first discovered tapasin (TAP-associated glycoprotein) as a 48 kDa protein in complexes isolated with TAP1 antibodies from digitonin lysates of human B lymphoblastoid cells. Tapasin binds HC/β2m along with ER chaperones to the peptide transporter. It is located in the ER and its function comprises holding together class I molecules jointly with the chaperone calreticulin and the ERp57 to TAP. Studies of a tapasin-deficient cell line and from mice bearing a disrupted tapasin gene, the short-lived complex of class I molecules.
Tapasin and TAP are very important for the stabilization of the class I molecules and also for the optimization of the peptide presented to cytotoxic T cells. A PLC-independent tapasin homologue protein named TAPBPR was found that has the ability to act as a second MHC-I specific peptide proofreader or editor, but does not possess a transmembrane domain. Tapasin and TAPBPR share similar binding interfaces on MHC-I, as shown with the X-ray structure of TAPBPR with MHC-I (heavy chain and β2 microglobulin). The use of a photo-cleavable high-affinity peptide allowed researchers to form a stable (bound) MHC-I molecules and afterwards to form a stable TAPBPR and MHC-I complex with cleavage by UV light of the photoinduced peptide.
ERp57.
ERp57 is an enzyme of the thiol oxidoreductase family located in the ER. It is attached to substrates in an indirect fashion through association with the molecular chaperone calreticulin of the peptide-loading complex, In early stages of generation of MHC-I molecules, ERp57 is associated with free MHC-I heavy chains. As a result, its function is determined by the formation of disulfide bonds in heavy chains, by oxidative folding of the heavy chain, and finally by the fact that ERp57 is loading the peptides onto MHC-I molecules.
MHC-I.
Preliminary MHC-I heavy chains form chaperones with the aid of the calnexin-calreticulin complex in the ER. In addition to this, β2-microglobulin (β2m) is attached to the heavy chains of the heterodimers and as a whole they act as receptors for antigenic peptides. When MHC-I chains are empty, they are recruited by calreticulin and form a transient PLC. Tapasin regularly plays a role in the stabilization of MHC-I. Only after MHC-I heterodimers are deployed for peptide proofreading or editing, stable pMHC-I (peptide-MHC-I) complexes are released to the cell surface for recognition and destruction of virus-infected or malignantly neoplastic cells. In general, each individual organism owns a collection of six MHC-I molecules (three from each parent). Thus, in autoimmune emergencies, compatible donors are relatives who own a similar collection of MHC-I molecules, apart from those of the recipient.
Calreticulin.
Calreticulin – especially its lectin-like domain – interacts with MHC-I. The P domain faces the MHC-I peptide-binding site towards ERp57. This orientation makes it possible for tapasin to attach and secure MHC-I. This translocation of TAP facilitates its opening out into an ER luminal cavity, edged by standard membrane entry points such as those for tapasin and MHC-I. These two entry points facilitate the recruitment of MHC-I with optimal peptide loading and eventual release of MHC-I in T-cell surfaces for recognition.


Soquinolol

Soquinolol is a beta adrenergic receptor antagonist.


Shrew-toothed shrew tenrec

The shrew-toothed shrew tenrec ("Microgale soricoides") is a species of mammal in the family Tenrecidae. It is endemic to Madagascar. Its natural habitats are subtropical or tropical moist lowland forest and subtropical or tropical moist montane forest. It is threatened by habitat loss.


Bufetolol

Bufetolol is a beta-adrenoceptor antagonist.


Operation Magic Sword

Operation Magic Sword was a 1965 U.S. military operation designed to test the effectiveness of the sea-borne release of insect vectors for biological agents.
Operation.
Operation Magic Sword was U.S. military operation undertaken in 1965. It was designed to ascertain the effectiveness of releasing mosquito vectors for biological agents at sea. It took place off the southeastern coast of the United States and employed yellow fever mosquitoes with the hope of assessing their biting habits following an ocean-borne release.
Results.
Magic Sword showed that when coupled with ocean winds that the mosquitoes could travel up to three and one-half miles to shore. The operation also showed that if needed the mosquitoes could be kept alive for cross-ocean journeys.


Halozyme

Halozyme Therapeutics is an American biotechnology company that develops novel oncology therapies designed to target the tumor microenvironment and licenses a novel drug delivery technology through corporate partnerships.
The company was founded in 1998 and went public in 2004. Halozyme is headquartered in San Diego, California.
Company history.
Halozyme's business is primarily focused on its proprietary and patented recombinant human hyaluronidase enzyme, rHuPH20. The company's development pipeline is concentrated in clinical stage and pre-clinical stage oncology products, including its proprietary investigational drug, PEGPH20, a pegylated version of rHuPH20, which targets hyaluronan (HA) high tumors. The company is in various phases of clinical trials with PEGPH20 across multiple solid tumor types, including pancreatic cancer, non-small cell lung cancer (NSCLC), and gastric cancer, to test the drug's safety and efficacy. Halozyme has one FDA approved product (Hylenex recombinant, hyaluronidase human injection). The company also licenses its drug delivery technology Enhanze to other biopharmaceutical companies, including Roche, Baxalta, Pfizer, Janssen, AbbVie, and Lilly.
Company leadership.
Since January 2014, Dr. Helen I. Torley, M.B. Ch. B., M.R.C.P. has been Chief Executive Officer and President of Halozyme Therapeutics, Inc. Prior to her role at Halozyme, she was Chief Commercial Officer at Onyx Pharmaceuticals, Inc., and also served in senior level management positions at Amgen and Bristol-Myers Squibb. She began her career at Novartis in 1990 and spent 7 years there, with her final role as Vice President of Medical Affairs.
Approved products.
Hylenex: Approved by the U.S. Food and Drug Administration (FDA) on 12/02/2005. Hylenex is a hyaluronidase (human recombinant) injection indicated for use in subcutaneous fluid administration, dispersion and absorption of injected drugs, and subcutaneous urography.
Technology.
Enhanze: Uses recombinant human hyaluronidase to degrade HA and aids in the absorption and dispersion of co-administered injected drugs. Halozyme licenses its Enhanze drug delivery platform technology to other biopharmaceutical companies to enable intravenous to subcutaneous administration conversion and dose optimization.
Product candidates.
PEGPH20: A PEGylated drug candidate based on Halozyme's proprietary rHuPH20 enzyme (a recombinant human hyaluronidase enzyme). It breaks down or depletes hyaluronan (HA), which can build up in certain tumors. The goal of PEGPH20 is to break down HA so that some anti-cancer therapies and activated immune cells can better reach the cancer cells of HA-high tumors. On November 4, 2019, Halozyme announced it has halted development of PEGPH20.
Pipeline candidates.
PEG-ADA2: An engineered human recombinant enzyme, adenosine deaminase 2, for decreasing the concentration of immune-suppressive adenosine in the tumor microenvironment, and PEGylated to prolong its circulation in the body. It has been tested in colon, lung, and pancreatic cancer models in preclinical studies.
HTI-1511 Anti-EGFR ADC: An antibody-drug conjugate (ADC) with a strong cytotoxin, monomethyl auristatin E, designed to treat EGFR-positive tumors, including those with KRAS and BRAF mutations. It has been tested in colon, lung, and cholangiocarcinoma models in preclinical studies.
Clinical trial pipeline.
Halozyme has many ongoing and completed clinical trials testing the safety and efficacy of its primary investigational drug, PEGPH20, in combination with other therapies, with the goal of finding new treatments for pancreatic cancer, NSCLC, gastric cancer, breast cancer, and others. As of October 2016, the company was sponsoring or collaborating on several clinical trials that were recruiting patients, including:


Zyklophin

Zyklophin is a semisynthetic peptide derived from dynorphin A and a highly selective antagonist of the κ-opioid receptor (KOR). It is systemically-active, displaying good metabolic stability and blood-brain-barrier penetration. Similarly to other KOR antagonists, it has been shown to block stress-induced reinstatement of cocaine-seeking in animals. The drug is currently experimental, and thus cannot be considered safe for consumption or usage.


Dimethoxymethamphetamine

3,4-Dimethoxy-"N"-methylamphetamine (DMMA) is a psychoactive drug and research chemical of the phenethylamine and amphetamine chemical classes. It appears to act as a serotonin-norepinephrine-dopamine releasing agent (SNDRA), although it is significantly less potent than MDMA.


Beta blocker

Beta blockers (beta-blockers, β-blockers, etc.) are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary prevention). They are also widely used to treat high blood pressure (hypertension), although they are no longer the first choice for initial treatment of most patients.
Beta blockers are competitive antagonists that block the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response. Some block activation of all types of β-adrenergic receptors and others are selective for one of the three known types of beta receptors, designated β1, β2 and β3 receptors. β1-adrenergic receptors are located mainly in the heart and in the kidneys. β2-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3-adrenergic receptors are located in fat cells.
Beta receptors are found on cells of the heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues that are part of the sympathetic nervous system and lead to stress responses, especially when they are stimulated by epinephrine (adrenaline). Beta-blockers interfere with the binding to the receptor of epinephrine and other stress hormones and weaken the effects of stress hormones.
In 1964, James Black synthesized the first clinically significant beta blockers—propranolol and pronethalol; it revolutionized the medical management of angina pectoris and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.
For the treatment of primary hypertension, meta-analyses of studies which mostly used atenolol have shown that although beta blockers are more effective than placebo in preventing stroke and total cardiovascular events, they are not as effective as diuretics, medications inhibiting the renin–angiotensin system (e.g., ACE inhibitors), or calcium channel blockers.
Medical uses.
Large differences exist in the pharmacology of agents within the class, thus not all beta-blockers are used for all indications listed below.
Indications for beta-blockers include:
Beta-blockers have also been used for:
Congestive heart failure.
Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition due to their effect of decreasing cardiac contractility, studies in the late 1990s showed their efficacy at reducing morbidity and mortality.
Bisoprolol, carvedilol, and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure, although at doses typically much lower than those indicated for other conditions. Beta-blockers are only indicated in cases of compensated, stable congestive heart failure; in cases of acute decompensated heart failure, beta-blockers will cause a further decrease in ejection fraction, worsening the patient's current symptoms.
Beta-blockers are known primarily for their reductive effect on heart rate, although this is not the only mechanism of action of importance in congestive heart failure. Beta-blockers, in addition to their sympatholytic β1 activity in the heart, influence the renin–angiotensin system at the kidneys. Beta-blockers cause a decrease in renin secretion, which in turn reduces the heart oxygen demand by lowering the extracellular volume and increasing the oxygen-carrying capacity of the blood. Heart failure characteristically involves increased catecholamine activity on the heart, which is responsible for several deleterious effects, including increased oxygen demand, propagation of inflammatory mediators, and abnormal cardiac tissue remodeling, all of which decrease the efficiency of cardiac contraction and contribute to the low ejection fraction. Beta-blockers counter this inappropriately high sympathetic activity, eventually leading to an improved ejection fraction, despite an initial reduction in ejection fraction.
Trials have shown beta blockers reduce the absolute risk of death by 4.5% over a 13-month period. In addition to reducing the risk of mortality, the numbers of hospital visits and hospitalizations were also reduced in the trials.
Therapeutic administration of beta-blockers for congestive heart failure ought to begin at very low doses (1/8 of target) with a gradual escalation of the dose. The heart of the patient must adjust to decreasing stimulation by catecholamines and find a new equilibrium at a lower adrenergic drive.
Anxiety.
Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration. However, many controlled trials in the past 25 years indicate beta blockers are effective in anxiety disorders, though the mechanism of action is not known. The physiological symptoms of the fight-or-flight response (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand.
Musicians, public speakers, actors, and professional dancers have been known to use beta-blockers to avoid performance anxiety, stage fright, and tremor during both auditions and public performances. The application to stage fright was first recognized in "The Lancet" in 1976, and by 1987, a survey conducted by the International Conference of Symphony Orchestra Musicians, representing the 51 largest orchestras in the United States, revealed 27% of its musicians had used beta-blockers and 70% obtained them from friends, not physicians. Beta-blockers are inexpensive, said to be relatively safe, and on one hand, seem to improve musicians' performances on a technical level, while some, such as Barry Green, the author of "The Inner Game of Music" and Don Greene, a former Olympic diving coach who teaches Juilliard students to overcome their stage fright naturally, say the performances may be perceived as "soulless and inauthentic".
Cardiac surgery.
The use of beta blockers around the time of cardiac surgery decreases the risk of heart dysrhythmias. Starting them around the time of other types of surgery, however, may worsen outcomes.
Performance-enhancing use.
Because they promote lower heart rates and reduce tremors, beta blockers have been used in professional sports where high accuracy is required, including archery, shooting, golf and snooker. Beta blockers are banned by the International Olympic Committee. In the 2008 Summer Olympics, 50-metre pistol silver medalist and 10-metre air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medals.
For similar reasons, beta blockers have also been used by surgeons.
Classical musicians have commonly used beta blockers since the 1970's to reduce stage fright.
Adverse effects.
Adverse drug reactions associated with the use of beta blockers include: nausea, diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, alopecia (hair loss), abnormal vision, hallucinations, insomnia, nightmares, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed α1/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema. Due to the high penetration across the blood–brain barrier, lipophilic beta blockers, such as propranolol and metoprolol, are more likely than other less lipophilic beta blockers to cause sleep disturbances, such as insomnia, vivid dreams and nightmares.
Adverse effects associated with β2-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β1-selective (often termed "cardioselective") agents, but receptor selectivity diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula densa, inhibits renin release, thus decreasing the release of aldosterone. This causes hyponatremia and hyperkalemia.
Hypoglycemia can occur with beta blockade because β2-adrenoceptors normally stimulate glycogen breakdown (glycogenolysis) in the liver and pancreatic release of the hormone glucagon, which work together to increase plasma glucose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. β1-blockers have fewer metabolic side effects in diabetic patients; however, the fast heart rate that serves as a warning sign for insulin-induced low blood sugar may be masked, resulting in hypoglycemia unawareness. This is termed beta blocker-induced hypoglycemia unawareness. Therefore, beta blockers are to be used cautiously in diabetics.
A 2007 study revealed diuretics and beta blockers used for hypertension increase a patient's risk of developing diabetes mellitus, while ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes. Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta blockers as first-line treatment of hypertension due to the risk of diabetes.
Beta blockers must not be used in the treatment of selective alpha-adrenergic agonist overdose. The blockade of only beta receptors increases blood pressure, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha-adrenergic system stimulation unopposed. Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity from a methamphetamine overdose. The mixed alpha- and beta blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine. The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta blockers for treatment of methamphetamine toxicity. Other appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant overdose are vasodilators such as nitroglycerin, diuretics such as furosemide, and alpha blockers such as phentolamine.
Contraindications.
Contraindications for beta-blockers include:
Asthma.
The 2007 National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines recommend against the use of non-selective beta blockers in asthmatics, while allowing for the use of cardioselective beta blockers.
Cardioselective beta-blocker (β1 blockers), if really required, can be prescribed at the least possible dose to those with mild to moderate respiratory symptoms. β2-agonists can somewhat mitigate β-Blocker-induced bronchospasm where it exerts greater efficacy on reversing "selective" β-blocker-induced bronchospasm than the "nonselective" β-blocker-induced worsening asthma and/or COPD.
Diabetes mellitus.
Epinephrine signals early warning of the upcoming hypoglycemia.
Beta-blockers' inhibition on epinephrine's effect can somewhat exacerbate hypoglycemia by interfering with glycogenesis and mask signs of hypoglycemia such as tachycardia, palpitations, diaphoresis, and tremors. Diligent blood glucose level monitoring is necessary for a patient with diabetes mellitus on beta-blocker.
Hyperthyroidism.
Abrupt withdrawal can result in a thyroid storm.
Bradycardia or AV block.
Unless a pacemaker is present, beta-blockers can severely depress conduction in the AV node, resulting in a reduction of heart rate and cardiac output. Usage of beta-blockers in tachycardic patients with Wolff-Parkinson-White Syndrome can result in severe bradycardia, necessitating treatment with a pacemaker.
Toxicity.
Glucagon, used in the treatment of overdose, increases the strength of heart contractions, increases intracellular cAMP, and decreases renal vascular resistance. It is, therefore, useful in patients with beta blocker cardiotoxicity. Cardiac pacing is usually reserved for patients unresponsive to pharmacological therapy.
People experiencing bronchospasm due to the β2 receptor-blocking effects of nonselective beta blockers may be treated with anticholinergic drugs, such as ipratropium, which are safer than beta agonists in patients with cardiovascular disease. Other antidotes for beta blocker poisoning are salbutamol and isoprenaline.
β-receptor antagonism.
Stimulation of β1 receptors by epinephrine and norepinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of β1 receptors on the kidney causes renin release. Stimulation of β2 receptors induces smooth muscle relaxation, induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle. Stimulation of β3 receptors induces lipolysis.
Beta blockers inhibit these normal epinephrine- and norepinephrine-mediated sympathetic actions, but have minimal effect on resting subjects.
That is, they reduce the effect of excitement or physical exertion on heart rate and force of contraction, and also tremor, and breakdown of glycogen. Beta blockers can have a constricting effect on the bronchi of the lungs, possibly worsening or causing asthma symptoms.
Since β2 adrenergic receptors can cause vascular smooth muscle dilation, beta blockers may cause some vasoconstriction. However, this effect tends to be small because the activity of β2 receptors is overshadowed by the more dominant vasoconstricting α1 receptors. By far the greatest effect of beta blockers remains in the heart. Newer, third-generation beta blockers can cause vasodilation through blockade of alpha-adrenergic receptors.
Accordingly, nonselective beta blockers are expected to have antihypertensive effects. The primary antihypertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to negative chronotropic and inotropic effects). It may also be due to reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity (for those beta blockers that do cross the blood–brain barrier, e.g. propranolol).
Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand. Negative chronotropic properties of beta-blockers allow the lifesaving property of heart rate control. Beta-blockers are readily titrated to optimal rate control in many pathologic states.
The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade—resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade.
Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin–angiotensin–aldosterone system, with a resultant decrease in blood pressure due to decreased sodium and water retention.
Intrinsic sympathomimetic activity.
Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta-blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (beta-blocker) and the concentration of the antagonized agent (usually an endogenous compound, such as norepinephrine). See partial agonist for a more general description.
Some beta blockers (e.g. oxprenolol, pindolol, penbutolol, labetalol and acebutolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low-level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy.
Agents with ISA are not used after myocardial infarctions, as they have not been demonstrated to be beneficial. They may also be less effective than other beta-blockers in the management of angina and tachyarrhythmia.
α1-receptor antagonism.
Some beta blockers (e.g., labetalol and carvedilol) exhibit mixed antagonism of both β- and α1-adrenergic receptors, which provides additional arteriolar vasodilating action.
Examples.
Nonselective agents.
Nonselective beta blockers display both β1 and β2 antagonism.
β1-selective agents.
β1-selective beta blockers are also known as cardioselective beta blockers.
Comparative information.
Indication differences.
Propranolol is the only agent indicated for the control of tremor, portal hypertension, and esophageal variceal bleeding, and used in conjunction with α-blocker therapy in phaeochromocytoma.
Other effects.
Beta blockers, due to their antagonism at beta-1 adrenergic receptors, inhibit both the synthesis of new melatonin and its secretion by the pineal gland. The neuropsychiatric side effects of some beta blockers (e.g. sleep disruption, insomnia) may be due to this effect.
Some pre-clinical and clinical research suggests that some beta blockers may be beneficial for cancer treatment. However, other studies do not show a correlation between cancer survival and beta blocker usage. Also, a 2017 meta-analysis failed to show any benefit for the use of beta blockers in breast cancer.
Beta blockers have also been used for the treatment of schizoid personality disorder. However, there is limited evidence supporting the efficacy of supplemental beta-blocker use in addition to antipsychotic drugs for treating schizophrenia.
Contrast media are not contraindicated in patients receiving beta blockers.


Guanethidine

Guanethidine is an antihypertensive drug that reduces the release of catecholamines, such as norepinephrine. Guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the drug's action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine. It may also inhibit the release of granules by decreasing norepinephrine.
Side effects.
Side effects include postural and exercise hypotension, sexual dysfunction (delayed or retrograde ejaculation), and diarrhea.
Pharmacology.
Guanethidine is transported by uptake 1 into the presynaptic terminal transported by norepinephrine transporter (NET). (In this it competes with norepinephrine so can potentiate exogenously applied norepinephrine.) It becomes concentrated in norepinephrine transmitter vesicles, replacing norepinephrine in these vesicles. This leads to a gradual depletion of norepinephrine stores in the nerve endings. Once inside the terminal it blocks the release of norepinephrine in response to arrival of an action potential. Spontaneous release is not affected.
Uses.
Guanethidine was once a mainstay for hypertension resistant to other agents, and was often used safely during pregnancy, but it is no longer used in the US due to lack of availability. It is still licensed in some countries, e.g., UK, for the rapid control of blood pressure in a hypertensive emergency.
Intravenous nerve block (Bier block) using guanethidine has been used to treat chronic pain caused by complex regional pain syndrome.
Experimentally, guanethidine has been used in chemical sympathectomy in the research fields of neurophysiology and pharmacology. Daily injections of guanethidine into newborn rats causes irreversible destruction of the sympathetic ganglia and nerves.


Castration cell

A castration cell is a basophilic cell with a large vacuole found in the anterior pituitary after castration, effective (drug) castration, or long-term use of alcohol.


David E. Clemmer

David E. Clemmer (February 23, 1965, Alamosa, Colorado) is an analytical chemist and the Distinguished Professor and Robert and Marjorie Mann Chair of Chemistry at Indiana University in Bloomington, Indiana, where he leads the Clemmer Group. Clemmer develops new scientific instruments for ion mobility mass spectrometry (IMS/MS), including the first instrument for nested ion-mobility time-of-flight mass spectrometry. He has received a number of awards, including the Biemann Medal in 2006 "for his pioneering contributions to the integration of ion mobility separations with a variety of mass spectrometry technologies."
Early life and education.
Clemmer was born on February 23, 1965, to Ed Clemmer, an artist, and his wife MaryAnn, a teacher, of Alamosa, Colorado. He attended Adams State College, where he originally majored in music, before changing to science. He received his B.S. in chemistry with honors in 1987. He then attended the University of Utah, receiving his Ph.D. in physical chemistry in 1992. His thesis advisor was Peter B. Armentrout, with whom he studied transition metal ions in gaseous reactions.
Career.
During 1992–1993, Clemmer was a postdoctoral fellow in Japan, supported by the Japan Society for the Promotion of Science Fellowship at the Himeji Institute of Technology. He worked with Kenji Honma on electron transfer mechanisms and reactions of excited-state metal atoms and gaseous molecules.
From 1993 to 1995, Clemmer was a postdoctoral research associate at Northwestern University, where he worked with Martin F. Jarrold, studying protein folding and protein conformation in the gas phase, using techniques such as Ion-mobility spectrometry.
In 1995, Clemmer joined the Department of Chemistry at Indiana University. He served as chair of the Chemistry Department from 2002 to 2006. He is a full professor, and holds the Robert and Marjorie Mann Chair of Chemistry, to which he was named in 2002. He has published more than 230 papers.
Among those who have influenced him, he includes Michael T. Bowers, Jesse L. Beauchamp, R. Graham Cooks, Scott A. McLuckey, Fred McLafferty, Evan R. Williams, Joseph A. Loo, Vicki Wysocki, and Julie A. Leary. His graduate students have included Renã A. S. Robinson, Stephen Valentine, Cherokee Hoaglund-Hyzer, and Catherine Srebalus Barnes.
Research.
Clemmer is particularly interested in studying the structural characterization and conformational dynamics of complex low-symmetry systems. Clemmer develops scientific instruments and methods for the examination of biomolecular structure and complex biomolecular mixtures in the gas phase using ion-mobility spectrometry.
Ion mobility methods separate ions into different groups based on their ability to move through an electrically-charged buffer gas. This enables complex mixtures to be differentiated in ways that could not be achieved by mass spectrometry alone. Even minute amounts of compounds can be distinguished and differentially examined according to characteristics such as size, shape and charge as well as mass.
Clemmer has helped to establish ion mobility as both a powerful tool and a field of research through his "thorough studies" and "revolutionary instrumental methods".
In early work, Clemmer and Jarrold used long drift tubes with nonclustering gas atmospheres to increase the resolving power of ion-mobility spectrometry.
Clemmer's work on gas-phase separation methods for ion mobility-mass spectrometry (IM-MS) and their application to the structural analysis of intact proteins is considered a "particularly important milestone" in the application of IM-MS to the examination of biomolecular structures.
Clemmer and his colleagues have developed at least a dozen different configurations combining modular components for ion-mobility with mass spectrometry instruments. These include combining ion mobility with Time-of-flight mass spectrometry (TOF).
They also developed the first instrument for nested ion-mobility time-of-flight mass spectrometry.
Such equipment allows researchers to learn more about both the structures and the conformational dynamics of systems.
Clemmer has identified fundamental relationships between charge states and structures, and has shown that a single charge state can exist in more than one conformation in gaseous states.
Such techniques can be used for the study of both proteins and peptides.
In early work, Clemmer showed that multiple conformations of the hemeprotein cytochrome c could be differentiated based on their mobilities.
In addition, the mobility of different chiral isomers was related to their protein folding.
More recent techniques enable researchers to track transitions in the conformations of macromolecular ions during the gas phase. A short pulse of ions is introduced into a drift tube by electrospray ionization. Structures separate based on differences in their mobilities. By exposing specific states to energizing collisions, new structures can be established and tracked through different conformational changes. Changes in conformation during the gas-phase data can then be mapped back to the original populations of structures. In this way, researchers can understand the possible pathways between structures.
Understanding how protein folding occurs in three-dimensional molecules is one of biology's enduring problems. Proteins with different shapes often have very different biological activity and medical usefulness. Clemmer's work has applications in the life sciences for understanding the conformation of structures in large protein complexes, profiling the plasma proteome, examining the role of proteins and protein folding in neurodegenerative diseases, identifying possible cancer-related markers in blood, urine, or saliva, and increasing the efficiency of drug-discovery. Ion mobility-mass spectrometry techniques also allow the measurement and correlation of a wide variety of different characteristics simultaneously in a single analysis. Researchers can use these techniques to examine complex biological samples for lipidomics, proteomics, glycomics, and metabolomics information.
Companies.
Clemmer is a co-founder of "Beyond Genomics", a systems biology company, and the founder of "Predictive Physiology and Medicine", a biotechnology company specializing in personalized medicine.
Hobbies.
In addition to playing several instruments, Clemmer enjoys running marathons.


NADPH dehydrogenase (quinone)

In enzymology, a NADPH dehydrogenase (quinone) () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are NADPH, H+, and acceptor, whereas its two products are NADP+ and reduced acceptor.
This enzyme belongs to the family of oxidoreductases, specifically those acting on NADH or NADPH with other acceptors. The systematic name of this enzyme class is NADPH:(quinone-acceptor) oxidoreductase. Other names in common use include reduced nicotinamide adenine dinucleotide phosphate (quinone), dehydrogenase, NADPH oxidase, and NADPH2 dehydrogenase (quinone). It has 2 cofactors: FAD, and Flavoprotein. Several compounds are known to inhibit this enzyme, including Folate, and Dicumarol.
Structural studies.
As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code .


Pteridine reductase

In enzymology, a pteridine reductase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 5,6,7,8-tetrahydrobiopterin and NADP+, whereas its 3 products are biopterin, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 5,6,7,8-tetrahydrobiopterin:NADP+ oxidoreductase. Other names in common use include PTR1, and pteridine reductase 1.
Structural studies.
As of late 2007, 7 structures have been solved for this class of enzymes, with PDB accession codes , , , , , , and .


SB-242084

SB-242084 is a psychoactive drug and research chemical which acts as a selective antagonist for the 5HT2C receptor. It has anxiolytic effects, and enhances dopamine signalling in the limbic system, as well as having complex effects on the dopamine release produced by cocaine, increasing it in some brain regions but reducing it in others. It has been shown to increase the effectiveness of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants, and may also reduce their side effects. In animal studies, SB-242084 produced stimulant-type activity and reinforcing effects, somewhat similar to but much weaker than cocaine or amphetamines.


Sphingomonas glacialis

Sphingomonas glacialis is a Gram-positive, rod-shaped, psychrophilic and non-motile bacteria from the genus of Sphingomonas which has been isolated from cryoconite from the Stubai Glacier in Tyrol in Austria.


LPAR5

Lysophosphatidic acid receptor 5 also known as LPA5 is a protein that in humans is encoded by the "LPAR5" gene. LPA5 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).


CY-208,243

CY-208,243 is a drug which acts as a dopamine agonist selective for the D1 subtype. Unlike most D1-selective agonists, it shows efficacy in animal models of Parkinson's disease.


GlmY RNA

The GlmY RNA (formally known as tke1) family consists of a number of bacterial RNA genes of around 167 bases in length. The GlmY RNA gene is present in "Escherichia coli", "Shigella flexneri", "Yersinia pestis" and "Salmonella" species, where it is found between the "yfhK" and "purL" genes. It was originally predicted in a bioinformatic screen for novel ncRNAs in "E. coli".
The GlmY sRNA has been shown to activate the synthesis of GlmS. It achieves this by influencing the action of another sRNA called GlmZ in a hierarchical fashion. GlmY functions as an anti-adaptor, it binds to RapZ (RNase adaptor protein for sRNA GlmZ), this binding prevents RapZ from binding to GlmZ and targeting it for cleavage by RNase E.
Further studies have shown that GlmY mutants are sensitive to cell envelope stress.


Uniject

Uniject is a disposable, pre-filled, single-use syringe which was developed to promote vaccination in developing countries. It was developed by PATH as part of the solution to the problem of delivering vaccines to areas which have insufficient medical workers to meet the needs of traditional, doctor-mediated vaccination programs.
History.
The Uniject was invented by PATH in 1987.
In 2003 PATH accepted a Tech Award from The Tech Museum of Innovation for its development of the Uniject.
Use.
The introduction of the Uniject has been called the single greatest leap forward in the battle against tetanus because it has allowed tetanus vaccines to be used in places which were previously inaccessible to health programs.


UDP-N-acetylglucosamine diphosphorylase

In enzymology, an UDP-N-acetylglucosamine diphosphorylase () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are UTP and[N-acetyl-alpha-D-glucosamine 1-phosphate, whereas its two products are diphosphate and UDP-N-acetyl-D-glucosamine. This enzyme participates in aminosugars metabolism.
Nomenclature.
This enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing nucleotide groups (nucleotidyltransferases). The systematic name of this enzyme class is UTP:N-acetyl-alpha-D-glucosamine-1-phosphate uridylyltransferase. Other names in common use include UDP-N-acetylglucosamine pyrophosphorylase, uridine diphosphoacetylglucosamine pyrophosphorylase, UTP:2-acetamido-2-deoxy-alpha-D-glucose-1-phosphate, uridylyltransferase, UDP-GlcNAc pyrophosphorylase, GlmU uridylyltransferase, Acetylglucosamine 1-phosphate uridylyltransferase, UDP-acetylglucosamine pyrophosphorylase, uridine diphosphate-N-acetylglucosamine pyrophosphorylase, uridine diphosphoacetylglucosamine phosphorylase, and acetylglucosamine 1-phosphate uridylyltransferase.


Anne Killigrew

Anne Killigrew (1660–1685) was an English poet and painter. Born in London, she and her family were active in literary and court circles. Killigrew's poems were circulated in manuscript and collected and published posthumously in 1686 after her death from smallpox at age 25. Killigrew was eulogized by John Dryden in his poem "To The Pious Memory of the Accomplish'd Young Lady Mrs. Anne Killigrew" (1686). Dryden compared her poetic abilities to the famous Greek poet of antiquity, Sappho.
Several paintings attributed to Killigrew are known. These include a self-portrait in Berkeley Castle, and a portrait of James II of England in the Royal Collection (in 2019 on display in Hillsborough Castle). Both of these are about half life-size but full-length.
Early life and inspiration.
Anne Killigrew was born in early 1660, before the Restoration, at St Martin's Lane in London. Not much is known about her mother Judith Killigrew, but her father Dr. Henry Killigrew published several sermons and poems as well as a play called "The Conspiracy". Her two paternal uncles were also published playwrights. Sir William Killigrew (1606–1695) published two collections of plays and Thomas Killigrew (1612–1683) not only wrote plays but built the theatre now known as Drury Lane.
Her family had close connections with the Stuart Court, serving Charles I, Charles II, and his Queen, Catherine of Braganza. Her father had been a chaplain to Charles I, and after the English Restoration was given positions such as Master of the Savoy Hospital. Her aunt, also named Anne Killigrew (1607-1641), was a Lady-in-waiting to Queen Henrietta Maria. The younger Anne Killigrew is believed to have been a Maid of Honour to Mary of Modena, Duchess of York.
Little is recorded about Anne's education, but it was consistent with the literary tastes of the family, and she received instruction in both poetry and painting in which she excelled. Because of her father's work—he was a clergyman and a playwright, and her uncle was the well-known playwright and theatrical patentee Thomas Killigrew—she was encouraged to pursue her creative talents, unusual for women in the 17th century. Her theatrical background added to her use of shifting voices in her poetry. In John Dryden's "Ode To the Pious Memory of the accomplished young lady, Mrs. Anne Killigrew," he points out that "Art she had none, yet wanted none, / For Nature did that want supply". Killigrew most likely got her education through studying the Bible, Greek mythology, and philosophy. Mythology was often expressed throughout her paintings and poetry.
Inspiration for Killigrew's poetry came from her knowledge of Greek myths and Biblical proverbs as well as from some very influential female poets who lived during the Restoration period: Katherine Philips and Anne Finch (also a maid to Mary of Modena at the same time as Killigrew). Mary of Modena encouraged the French tradition of "precieuses" (patrician women intellectuals) which pressed women's participation in theatre, literature, and music. In effect, Killigrew was surrounded with a poetic feminist inspiration on a daily basis in Court: she was encompassed by strong intelligent women who encouraged her writing career as much as their own.
It was not abnormal for poets, especially for women, never to see their work published in their lifetime. Anne Killigrew's poems were circulated in manuscript before her death. Some, like "To my Lord Colrane", were complimentary verses written according to "conventions of compliment and courtly exchange".
Soon after her death, a short book of only thirty-three poems was published by her father. Since Killigrew died at the young age of 25 she was only able to produce a small collection of poetry. In fact, the last three poems were only found among her papers and it is still being debated about whether or not they were actually written by her. Inside the book is also a self painted portrait of Anne and the Ode by family friend and poet John Dryden.
The Poet and the Painter.
Anne Killigrew excelled in multiple media, which was noted by contemporary poet, mentor, and family friend, John Dryden in his dedicatory ode to Killigrew. He addresses her as "the Accomplisht Young LADY Mrs Anne Killigrew, Excellent in the two Sister-Arts of Poësie, and Painting." Scholars believe that Kelligrew painted a total of 15 paintings; however, only four are known to exist today.
Many of her paintings display biblical and mythological imagery. Yet, Killigrew was also skilled at portraits, and her works include a self-portrait and a portrait of James, Duke of York. Some of her poetry references her own paintings, such as her poem "On a Picture Painted by her self, representing two Nimphs of DIANA's, one in a posture to Hunt, the other Batheing." Both her poems and her paintings place emphasis on women and nature, suggesting female rebellion in a male-dominated society.
Critical reception.
John Dryden's famous, extolling ode praises Killigrew for her beauty, virtue, and literary talent. Dryden was one of several contemporary admirers of Killigrew, and the posthumous collection of her work published in 1686 included additional poems commending her literary merit, irreproachable piety, and personal charm.
Anthony Wood in his 1721 essay defends Dryden's praise, confirming that Killigrew "was equal to, if not superior" to any of the compliments lavished upon her. Furthermore, Wood asserts that Killigrew must have been well received in her time, otherwise “her Father would never have suffered them to pass the Press” after her death.
In contrast, Alexander Pope, a prominent critic and leading poet of the time, labelled Killigrew's work "crude" and "unsophisticated." Pope, however, is often considered a misogynist. His critiques built upon the view that women were "characterless" people incapable of writing great works. It has been suggested that he "could envisage authorship only as a system of competitive differentiation", and that he sought to exclude women and tradesman-class men as writers not because of what they wrote, but because of who they were.
Critics have condemned Killigrew for addressing conventional topics, such as death, love, and the human condition, in her poetry and pastoral dialogues.
Some critics assert that Dryden's praise is too excessive, and must be ironic. Others suggest that Dryden defended all poets because he believed them to be teachers of moral truths; thus, he felt Killigrew, as an inexperienced yet dedicated poet, deserved his praise.
Authorship controversy.
Then, there is the question of the last three poems that were found among her papers. They seem to be in her handwriting, which is why Killigrew's father added them to her book. The poems are about the despair the author has for another woman, and could possibly be autobiographical if they are in fact by Killigrew. Some of her other poems are about failed friendships, possibly with Anne Finch, so this assumption may have some validity.
An early death.
Killigrew died of smallpox on 16 June 1685, when she was only 25 years old. She is buried in the Chancel of the Savoy Chapel (dedicated to St John the Baptist) where a monument was built in her honour, but has since been destroyed by a fire.


Pablo Sinues

Pablo Sinues (also published as Pablo Martinez-Lozano Sinues) is tenure-track assistant professor at the Department of Biomedical Engineering at the University of Basel (Basel, Switzerland) and lecturer at the Department of Chemistry and Applied Biosciences at ETH Zürich... He received his Ph.D. in Mechanical Engineering from the Charles III University of Madrid (Spain) and Habilitation in Analytical Chemistry at ETH Zürich. Sinues heads the Translational Breath Research group located at the University Children’s Hospital Basel
Academic activity.
Sinues has pioneered Secondary electrospray ionization with a focus in Breath gas analysis applications. He co-authored over 50 peer-reviewed articles covering fields ranging from engineering to medicine. He is President of the Society of Spanish Researchers in Switzerland (ACECH) and Vice-president of the Swiss Metabolomics Society (SMS). He also serves as an expert for InnoSuisse, the Swiss Innovation Agency
Sinues is principal investigator of the Research Network Zurich Exhalomics, which is an initiative by scientists from the Zurich area with the goal to provide technical solutions for the rapid and sensitive on-line analysis of breath. He is co-inventor of five patents and winner of the 2020 SGMS award. He co-founded the start-up company 'Deep Breath Initiative (DBI)' to uncover the full potential of Molecular Breath Analysis to advance precision medicine and make it available for general health care.


Doxanthrine

Doxanthrine is a synthetic compound which is a potent and selective full agonist for the dopamine D1 receptor. Doxanthrine has been shown to be orally active in producing contralateral rotation in the 6-hydroxy-dopamine rat model of Parkinson's disease.


Acyl-CoA

Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way, fats are converted to ATP, the universal biochemical energy carrier.
Functions.
Fatty acid activation.
Fats are broken down by conversion to acyl-CoA. This conversion is one response to high energy demands such as exercise.
The oxidative degradation of fatty acids is a two-step process, catalyzed by acyl-CoA synthetase. Fatty acids are converted to their acyl phosphate, the precursor to acyl-CoA. The latter conversion is mediated by acyl-CoA synthase"
Three types of acyl-CoA synthases are employed, depending on the chain length of the fatty acid. For example, the substrates for medium chain acyl-CoA synthase are 4-11 carbon fatty acids. The enzyme acyl-CoA thioesterase takes of the acyl-CoA to form a free fatty acid and coenzyme A.
Beta Oxidation of Acyl-CoA.
The second step of fatty acid degradation is beta oxidation. Beta oxidation occurs in mitochondria.  After formation in the cytosol, acyl-CoA is transported into the mitochondria, the locus of beta oxidation.  Transport of acyl-CoA into the mitochondria requires carnitine palmitoyltransferase 1 (CPT1), which converts acyl-CoA into acylcarnitine, which gets transported into the mitochondrial matrix.  Once in the matrix, acylcarnitine is converted back to acyl-CoA by CPT2.  Beta oxidation may begin now that Acyl-CoA is in the mitochondria.
Beta oxidation of acyl-CoA occurs in four steps.
1.      Acyl-CoA dehydrogenase catalyzes dehydrogenation of the acyl-CoA, creating a double bond between the alpha and beta carbons.   FAD is the hydrogen accceptor, yielding FADH2.
2.      Enoyl-CoA hydrase catalyzes the addition of water across the newly formed double bond to make an alcohol.
3.      3-hydroxyacyl-CoA dehydrogenase oxidizes the alcohol group to a ketone. NADH is produced from NAD+.
4.      Thiolase cleaves between the alpha carbon and ketone to release one molecule of Acetyl-CoA and the Acyl-CoA which is now 2 carbons shorter.
This four step process repeats until acyl-CoA has removed all carbons from the chain, leaving only Acetyl-CoA. During one cycle of beta oxidation, Acyl-CoA creates one molecule of Acetyl-CoA, FADH2, and NADH.  Acetyl-CoA is then used in the citric acid cycle while FADH2 and NADH are sent to the electron transport chain. These intermediates all end up providing energy for the body as they are ultimately converted to ATP.
Beta oxidation, as well as alpha-oxidation, also occurs in the peroxisome. The peroxisome handles beta oxidation of fatty acids that have more than 20 carbons in their chain because the peroxisome contains very-long-chain Acyl-CoA synthetases.  These enzymes are better equipped to oxidize Acyl-CoA with long chains that the mitochondria cannot handle.
Example using Stearic Acid.
Beta oxidation removes 2 carbons at a time, so in the oxidation of an 18 carbon fatty acid such as Stearic Acid 8 cycles will need to occur to completely break down Acyl-CoA. This will produce 9 Acetyl-CoA that have 2 carbons each, 8 FADH2, and 8 NADH.
Clinical Significance.
Heart muscle primarily metabolizes fat for energy and Acyl-CoA metabolism has been identified as a critical molecule in early stage heart muscle pump failure.
Cellular acyl-CoA content correlates with insulin resistance, suggesting that it can mediate lipotoxicity in non-adipose tissues. Acyl-CoA: diacylglycerol acyltransferase (DGAT) plays an important role in energy metabolism on account of key enzyme in triglyceride biosynthesis. The synthetic role of DGAT in adipose tissue such as the liver and the intestine, sites where endogenous levels of its activity and triglyceride synthesis are high and comparatively clear. Also, any changes in the activity levels might cause changes in systemic insulin sensitivity and energy homeostasis.
A rare disease called multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid metabolism disorder. Acyl-CoA is important because this enzyme helps make Acyl-CoA from free fatty acids, and this activates the fatty acid to be metabolized. This compromised fatty acid oxidation leads to many different symptoms, including severe symptoms such as cardiomyopathy and liver disease and mild symptoms such as episodic metabolic decomposition, muscle weakness and respiratory failure. MADD is a genetic disorder, caused by a mutation in the ETFA, ETFB, and ETFDH genes. MADD is known as an “autosomal recessive disorder” because for one to get this disorder, one must receive this recessive gene from both parents.


David W. Green (biochemist)

David W. Green ( - 1976) was a crystallographer at the Medical Research Council Unit for the Study of the Molecular Structure of Biological Systems, Cavendish Laboratory, University of Cambridge.
David W. Green was a graduate student in the laboratory of Max Perutz at the University of Cambridge from 1952 to 1955 and obtained a Ph.D. He is known for demonstrating the first use of isomorphous replacement to solve the phase problem in X-ray crystallography.
After completing his Ph.D., Green moved to the Davy-Faraday Research Laboratory at The Royal Institution in autumn 1955.
He was recruited by Linus Pauling but ultimately moved to MIT to work with Alexander Rich. With Rich, Green solved the structure of N-methyluracil. After his postdoctoral work, he returned to the Davy-Faraday Research Laboratory at The Royal Institution in London, England to continue his crystallographic research. Later he moved to the Department of Physics at the University of Edinburgh. In Edinburgh, Green was a senior lecturer and ran a group in solid state physics.
Green died in 1976.


Leucine operon leader

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


Interleukin-8 receptor

Overview.
The interleukin-8 receptors (IL-8R) are two 7-transmembrane proteins in the G-protein coupled-receptor family: interleukin-8 receptor A (IL-8RA) and interleukin-8 receptor B (IL-8RB). These receptors are generally found on human neutrophils, a type of white blood cell of the myeloid lineage, with approximately 65,000 receptors per neutrophil. Both receptors have a size of 60kDa, are glycosylated (contains covalent attachments and modifications) and G-protein linked, and can cause an increase in intracellular Ca2+ levels. Binding of Interleukin 8 leads to activation of the cell (commonly a neutrophil), allowing it to recruit more white blood cells to the site of Interleukin 8 release and to produce enzymes that would assist in the destruction of foreign material at the site of infection
Structure.
IL-8 receptors are 7-transmembrane proteins; they contain 7 alpha helices that each span the thickness of the phospholipid bilayer of a cell membrane. IL-8RA is a peptide of 350 amino acids, and IL-8RB is composed of 355 amino acids. Receptors A and B share 78% of their sequence identity, and are considered to be the only two biologically significant receptors of IL-8. The genes for both receptors are located on chromosome 2q35 and are each encoded by a single exon, and are 20 kb apart in distance. The close proximity and location of these two genes on the chromosome suggest that they are derived from the same ancestor sequence. The reported size of the translated protein is approximately 40kD, differing from the native purified receptors from the surface of neutrophils by 20kD. This difference could be due to the N-terminus glycosylations that occur post-translation and contribute to an increase in apparent size of the mature receptor.
N-terminus activity.
The amino terminus of the receptors is located on the extracellular side of the protein, and function to determine the binding specificity of ligands to the receptor. The N-terminus of both receptors A and B are rich in acidic residues, which correlate to their high binding affinities for IL-8, which is rich in basic residues. Asp11 on the N-terminus, Glu275 and Arg280 (both on the loop between the 7th and 6th transmembrane domains) are the three main peptide residues that participate in ligand binding on IL-8A. IL-8B shows a similar binding structure. These three residues are brought close together via a disulfide bridge.
C-terminus activity.
The carboxyl terminus of the receptors is located on the intracellular side of the protein, and is rich in serine and threonine residues (a characteristic of many proteins of the 7-transmembrane G-protein coupled receptor family). The C-terminus is a target for phosphorylation and exhibits kinase activity. This is the beginning of signaling pathways and phosphorylation cascades to recruit neutrophils and angiogenesis, the development and growth of new blood vessels.
Expression and function.
Both IL-8RA and IL-8RB are expressed in neutrophils, monocytes, macrophages, basophils, T-lymphocytes, and endothelial cells. IL-8RB is expressed additionally in neurons of the central nervous system. IL-8RA is highly specific for interleukin-8 and only responds when this particular ligand is bound to its receptor site, exhibiting "specific" binding behavior. IL-8RB binds to IL-8 with the same affinity as IL-8RA, but also binds to neutrophil-activating protein 2 (NAP-2) and other small receptor molecules of the CXC chemokine family with lower affinity than IL-8 binding, exhibiting a "shared" binding behavior. Chemokines are a class of small molecules that induce the recruitment of leukocytes and stimulate pro-inflammatory responses; the responsiveness of IL-8R to chemokines suggests that is heavily involved in recruitment of white blood cells for inflammatory and immunological response purposes.
The binding of IL-8 to the receptor induces the following three main responses in neutrophils, all of which assist a neutrophil in developing molecular mechanisms to target and kill pathogens: shape and conformational change of the neutrophil (which allows for transendothelial migration of the cell), degranulation (causing the release of enzymes within the cell), and the dissociation of heterotrimeric G-proteins (a typical effect of ligands binding to 7TM G-protein coupled receptors), thereby activating them. The activation of G-proteins leads to signal transduction and phosphorylation cascades, with the ultimate effect of changing gene expression of the neutrophil to allow for recruitment of other white blood cells to the local area.


TCL6

In molecular biology, T-cell leukemia/lymphoma 6 (non-protein coding), also known as TCL6 is a long non-coding RNA. It is expressed in T-cell leukemia with a t(14;14)(q11;q32.1) chromosome translocation in humans and in a mouse model. It is not expressed in normal T-cells. It may be involved in leukemogenesis.


Ferring Pharmaceuticals

Ferring Pharmaceuticals is a Swiss multinational biopharmaceutical company specialising in areas such as reproductive health, maternal health, gastroenterology and urology. Ferring has been developing treatments for mothers and babies for over 50 years.
Headquartered in Saint-Prex, Switzerland, Ferring has its own manufacturing facilities in several European countries, in South America, China, India, and the United States.
Founded in 1950, privately-owned Ferring employs more than 6,500 people worldwide, has its own operating subsidiaries in nearly 60 countries and markets its products in 110 countries.
History.
The company was founded by Dr. Frederik Paulsen Sr and Dr Eva Paulsen in Malmö, Sweden, in 1950, initially as the Nordiska Hormon Laboratoriet, renamed Ferring in 1954. A "ferring" in Frisian is a person from the island Föhr off the western coast of Germany. Mr. Paulsen's family originates from that island.
The first major breakthrough was the synthetic production of oxytocin and vasopressin in 1961. With further growth and expansion, the headquarters moved to Copenhagen, Denmark, and subsequently to Switzerland.
In October 2011, Ferring acquired Cytokine PharmaSciences Inc. (CPSI) and its UK subsidiary Controlled Therapeutics (Scotland) Ltd., a global biopharmaceutical company with a particular focus in obstetrics.
In August 2016, the company announced it would acquire the phase III sciatica candidate drug - Condoliase (SI-6603) from Seikagaku for approximately $95 million.
In April 2018, Ferring announced its acquisition of Rebiotix Inc. an innovative biotechnology company and pioneer in the field of the human microbiome.
In November 2019, Ferring Pharmaceuticals and Blackstone Life Sciences announced the joint investment of over $570 million USD in an investigational novel gene therapy in late stage development for patients with high-grade, Bacillus Calmette-Guérin (BCG) unresponsive, non-muscle invasive bladder cancer (NMIBC). Ferring and Blackstone spun out a new gene therapy company called Fergene to bring the therapy to patients.
Location.
Ferring Pharmaceuticals' global headquarters are located in Saint-Prex, Switzerland. The company has over 6,500 employees with manufacturing facilities in Europe, South America, China and has built two new facilities in the US and in India.
In Copenhagen, Ferring has a R&D centre in the Ferring Tower in Ørestad. The company has commissioned Foster and Partners to design a new building in the Scanport development. It will have area of 30,000 square metres and have room for 750 employees.
Dutch subsidiary Ferring B.V. expanded to the US in 1980.
Ferring established a research group at the Ferring Research Institute in San Diego, CA (USA) in 1996. Ferring assembled a peptide research group that collaborates with academic scientists. The Ferring Research Institute moved to its new home in San Diego in February 2009 with the opening of a 38,000-square-foot facility in Sorrento Valley. The new facility houses expanded research laboratories for peptide medicinal chemistry, biochemistry, bioanalytical, and pharmacology.
Corporate governance.
Ferring's Chairman of the Board of Directors is Frederik Paulsen Jr, son of founder Frederik Paulsen Sr. Mr Paulsen studied Chemistry in Germany at the Christian-Albrechts-University, Kiel followed by Business Administration at the University of Lund, in Sweden. He joined Ferring in 1976, became Managing Director of Ferring AB, Sweden in 1983 and Chief Executive Officer of the Ferring Group in 1988.
The President is Dr Per Falk who joined Ferring in 2015 and was appointed President on 1 January 2019. Before joining Ferring Per had held executive and senior leadership positions at Novo Nordisk and AstraZeneca in research, medical and clinical development roles. Per has over 30 years’ experience investigating and evolving microbiome science, holding faculty positions at some of the world’s leading institutions to advance research in this field. During his career, he has held the role of Associate Professor at the Karolinska Institute, Sweden and the Washington University School of Medicine, United States. Per is a qualified medical doctor and also has a Ph.D. in Biochemistry and Clinical Chemistry.
The role of Chief Medical and Science Officer has been held by Mirjam Mol-Arts since July 2020 - who joined the company in January 2018. She is responsible for overseeing research & development, real world evidence, global pharmacovigilance and global medical affairs. Mirjam’s former career includes various leadership roles at Solvay Pharmaceuticals, Schering-Plough, Organon, and MSD.
Mirjam qualified as a medical doctor having graduated with honors from Utrecht University, Netherlands.
Controversies.
Ferring director's close ties to Russia.
Since 2009, Frederik Paulsen has been the honorary consul of Russia in Lausanne, Switzerland and is reported to have a privileged relationship with the country and its president, Vladimir Putin.
According to an article published by Swiss newspaper, Le Temps, Frederik Paulsen accompanied on several occasions Swiss politicians to Russia such as Pascal Couchepin, Isabelle Chassot, François Longchamp, Géraldine Savary and Pascal Broulis.
The nature of these visits has been the object of criticism and interrogations by Swiss judicial authorities, who have launched investigations on Pascal Broulis and Géraldine Savary. The magistrate wished to clear if these trips were perceived as a bribe in return for fiscal arrangements for Frederik Paulsen and his company, Ferring Pharmaceuticals.
The year before, on 21 February 2008, Russian president Vladimir Putin awarded Frederik Paulsen with the Order of Friendship. Three other expedition members of Arktika 2007 were also awarded titles at the occasion. During the expedition, a Russian flag was planted on the ocean floor of the North Pole, which sparked up controversy.
Legal procedures against Ferring.
In the past, Ferring has been accused of disclosing misleading information about several of its products (Desmopressin, Glypressin, Penstasa) at the benefit of consumers.
In July 2020, the Medicines and Healthcare products Regulatory Agency, based in the United Kingdom, drew attention to the fact that Ferring Pharmaceuticals is recalling all Desmopressin nasal sprays.
In 2016, a class action was filled against Ferring Pharmaceuticals regarding the Bravelle product. One year earlier, the company recalled Bravelle products after tests revealed that the drug was not as effective as declared, therefore exposing women to serious health risks.
Ferring Pharmaceuticals is currently engaged in a legal battle opposing it to Professor Claudio de Simone. In the early 1990s, Professor Claudio de Simone invented a probiotic formulation fighting against intestinal disorders. The "De Simone formula" was the subject of several clinical tests, attesting of its efficiency to treat certain diseases.
The pharmaceutical company distributed the formula under the name VSL#3. A few years after the end of the agreement between the two parties, Ferring Pharmaceuticals continued to distribute a product referred to as "VSL#3" in several countries, containing a modified formula.
Products.
Products are used in reproductive health, gastroenterology, urology, orthopaedics and endocrinology.
Reproductive health / Fertility
Gastroenterology
Urology
Orthopaedics
Endocrinology


DR-4485

DR-4485 is a compound which acts as a potent and selective antagonist for the 5-HT7 receptor, with good oral bioavailability. It has been used to research the function of this still comparatively little studied serotonin receptor subtype.


Pseudoprotease

Pseudoproteases are catalytically-deficient pseudoenzyme variants of proteases that are represented across the kingdoms of life.


Ashwani Kumar (scientist)

Ashwani Kumar is an Indian bacteriologist, biotechnologies, and the principal scientist at the Institute of Microbial Technology (ImTech). He is known for his studies on Mycobacterium tuberculosis, the causative agent of tuberculosis. His laboratory focuses on understanding the reasons for drug tolerance observed in humans. His laboratory hypothesise that tuberculosis is a biofilm infection and that is why its treatment needs administration of multiple drugs for at least six months. The Department of Science and Technology has awarded him Swarnajayanti Fellowship for years 2016-2017.
Biography.
Ashwani Kumar is a principal scientist at the Institute of Microbial Technology (ImTech) where he heads a laboratory, popularly known as "Ashwani Kumar's Lab". and serves as a principal investigator. He is known to have done extensive research on Mycobacterium tuberculosis and has served as a member of MDRIpred project, an open source server for predicting inhibitors against drug-tolerant M.tb H37Rv. He has published a number of articles; ResearchGate, an online repository of scientific articles has listed 31 of them. His laboratory has demonstrated the presence of cellulose encased biofilms inside the hosts including human. He also works on regulation of autophagy by signalling gases such as carbon monoxide and hydrogen sulfide. The Department of Biotechnology of the Government of India awarded him the National Bioscience Award for Career Development, one of the highest Indian science awards, for him contributions to biosciences, in 2017–18.


Shewanella sediminis

Shewanella sediminis is a hexahydro-1,3,5-trinitro-1,3,5-triazine-degrading bacterium from marine sediment. It is psychrophilic and rod-shaped, with type strain HAW-EB3T (=NCIMB 14036T =DSM 17055T).


Donald E. Ingber

Donald E. Ingber (born 1956) is an American cell biologist and bioengineer. He is the founding director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, the "Judah Folkman Professor of Vascular Biology" at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences. He is also a member of the American Institute for Medical and Biological Engineering, the National Academy of Medicine, the National Academy of Inventors, and the American Academy of Arts and Sciences.
Ingber is a founder of the emerging fields of biologically inspired engineering. He has made pioneering contributions to numerous other disciplines including mechanobiology, cytoskeletal biology, extracellular matrix biology, integrin signaling, tumor angiogenesis, tissue engineering, nanobiotechnology, systems biology, and translational medicine. Ingber has authored more than 470 publications in scientific journals and books, and is an inventor on more than 190 patents spanning anti-cancer therapeutics, tissue engineering, medical devices, drug delivery systems, biomimetic materials, nanotherapeutics, and bioinformatics software.
Ingber has been scientific founder of five companies: Neomorphics, Inc., a tissue engineering startup which led to clinical products through subsequent acquisitions (Advanced Tissue Sciences Inc.); Tensegra, Inc. (formerly known as Molecular Geodesics, Inc.,) which 3D-printed medical devices; and most recently, Emulate, Inc., which formed to commercialize human "organs-on-chips" that accelerate drug development, detect toxicities and advance personalized medicine by replacing animal testing; Boa Biomedical, Inc. (originally known as Opsonix, Inc.), which aims to reduce deaths due to sepsis and blood infections by removing pathogens from the blood; and FreeFlow Medical Devices, LLC, which develops special coatings for medical devices to eliminate the formation of blood clots and biofilms on materials.
Education and academic research.
Ingber grew up in East Meadow, New York. He received a combined B.A./M.A. in molecular biophysics and biochemistry from Yale College and Yale Graduate School of Arts and Sciences in 1977; an M.Phil. in cell biology from Yale Graduate School of Arts and Sciences in 1981; and a combined M.D./Ph.D. from Yale School of Medicine and Yale Graduate School of Arts and Sciences in 1984. At Yale, he carried out undergraduate research on DNA repair with Paul Howard-Flanders, and on cancer metastasis with Alan Sartorelli.
Ingber worked on development of cancer therapeutics with Kenneth Harrap at the Royal Cancer Hospital/Royal Marsden Hospital in England, with support from a Bates Traveling Fellowship. He carried out his Ph.D. dissertation research under the direction of Dr. James Jamieson in the department of cell biology, and his advisory committee included George Palade, Elizabeth Hay and Joseph Madri. From 1984 to 1986 he completed his training as an Anna Fuller Postdoctoral Fellow under the mentorship of Dr. Judah Folkman in the Surgical Research Laboratory at Boston Children's Hospital and Harvard Medical School.
Scientific career.
Significant contributions.
Ingber is best known for his discovery of the role mechanical forces play in developmental control and in cancer formation, and for his application of these principles to develop bioinspired medical devices, nanotechnologies, and therapeutics. Ingber's early scientific work led to the discovery that tensegrity architecture - first described by the architect Buckminster Fuller and the sculptor Kenneth Snelson - is a fundamental design principle that governs how living systems are structured, from individual molecules and cells to whole tissues, organs and organisms.
Ingber's work on tensegrity led him to propose that mechanical forces play as important a role in biological control as chemicals and genes do, and to investigate the molecular mechanism by which cells convert mechanical signals into changes in intracellular biochemistry and gene expression, a process known as "mechanotransduction." Ingber determined that living cells use tensegrity architecture to stabilize their shape and cytoskeleton, that cellular integrins function as mechanosensors on the cell surface, and that cytoskeletal tension (or "prestress," which is central to the stability of tensegrity structures) is a fundamental regulator of many cellular responses to mechanical cues. Ingber's tensegrity theory also led to the prediction in the early 1980s that changes in extracellular matrix structure and mechanics play a fundamental role in tissue and organ development, and that deregulation of this form of developmental control can promote cancer formation.
Ingber's contributions in translational medicine include discovery of one of the first angiogenesis inhibitor compounds (TNP-470) to enter clinical trials for cancer, creation of tissue engineering scaffolds that led to clinical products, development of a dialysis-like blood cleansing device for treatment of blood stream infections that is moving towards clinical testing, creation of a mechanically-activated nanotechnology for targeting clot-busting drugs to sites of vascular occlusion, and co-development of a new surface coating based on Slippery Liquid Infused Porous Surfaces (SLIPS) for medical devices and implants that could eliminate the conventional dependency on anticoagulant drugs that pose life-threatening side-effect risks.
One of his more recent innovations is the creation of tiny, complex, three-dimensional models of living human organs, known as "organs-on-chips" (Organ Chips), which mimic complicated human organ functions "in vitro" as a way to potentially replace traditional animal-based methods for testing of drugs and toxins. The first human Organ Chip, a human Lung Chip, was reported in Science in 2010. Created using microchip manufacturing methods, the Lung Chip is a complex three-dimensional model of a breathing lung that incorporates living human lung alveolar epithelial cells interfaced with endothelial cells within microfluidic channels cast in silicone rubber, which recapitulate structure and function of the tissue-vasculature interface of lung alveolus (air sacs). In 2012, Ingber and his team demonstrated in a study in "Science Translational Medicine" the ability to mimic a complex human disease on the Lung Chip — specifically pulmonary edema, known commonly as “fluid on the lungs” — and to identify new therapeutics using this model. As an alternative to animal studies, Organ Chips could be used to study the safety and efficacy of new drugs, accelerating the introduction of new drugs to market while significantly lowering research costs. Ingber's group has since expanded this technology to develop other model organs, including the intestine, kidney, bone marrow, blood-brain barrier, and liver. In 2012, Ingber's team was awarded a DARPA contract to string together multiple Organ Chips to build an automated human body-on-chips that will recapitulate whole-body physiology. This system could be used in combination with computational modeling to rapidly assess responses to new drug candidates, providing critical information on their safety, efficacy, and pharmacokinetics.
Other new technologies from Ingber's lab include development of a fully biodegradable plastic alternative inspired by natural cuticle material found in shrimp shells and insect exoskeletons, known as “Shrilk”; a mechanically activated nanotherapeutic that selectively directs clot-busting drugs to sites of vascular occlusion while minimizing unintended bleeding; an siRNA nanoparticle therapy that prevents breast cancer progression; a dialysis-like sepsis device that cleanses blood of all infectious pathogens, fungi and toxins without requiring prior identification; a surface coating for medical materials and devices that prevents clot formation and bacteria accumulation that reduces the need for use of conventional anticoagulant drugs that frequently result in life-threatening side effects, and a computational approach to diagnostics and therapeutics that incorporates both animation and molecular modeling software to virtually develop and test potential drugs designed to fit precisely into their targets’ molecular structures.
Leadership and public service.
Earlier in his career, Ingber helped to bridge Harvard University, its affiliated hospitals, and the Massachusetts Institute of Technology (MIT) through his involvement in the Center for Integration in Medicine and Innovative Technology, Harvard-MIT Division of Health Sciences and Technology, and Dana-Farber/Harvard Cancer Center. He also has been a member of the Center for Nanoscale Systems and the Materials Research Science and Engineering Center at Harvard, as well as the MIT Center for Bioengineering.
In 2009, Ingber was named Founding Director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, which was launched with a $125 million gift— which at the time was the largest philanthropic gift in Harvard's history—from Swiss billionaire Hansjörg Wyss. The Wyss Institute was founded to enable high-risk research and disruptive innovation, and to catalyze the field of biologically inspired engineering in which newly uncovered biological design principles are leveraged to develop new engineering innovations in the form of bioinspired materials and devices for medicine, industry, and the environment. The Institute is a partnership among Harvard University, its major affiliated hospitals (Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, Spaulding Rehabilitation Hospital), Boston University, Massachusetts Institute of Technology, Tufts University, University of Massachusetts Medical School, Charité - Universitätsmedizin Berlin, and University of Zurich.
Ingber is a member of the National Academy of Medicine, the National Academy of Inventors, the American Institute for Medical and Biological Engineering, and the American Academy of Arts and Sciences. He served as a member of the Space Studies Board of the U.S. National Research Council (NRC), which advises the National Academy of Sciences, National Academy of Engineering, and National Institute of Medicine, and he chaired its Committee on Space Biology and Medicine. He has been an external reviewer of multiple NRC reports, including “Plan for the International Space Station,” “Future Biotechnology Research on the International Space Station,” "Assessment of Directions in Microgravity and Physical Sciences Research at NASA", and “The Astrophysical Context of Life.”
Ingber also has served as a consultant to numerous companies in the pharmaceutical, biotechnology, and cosmetics industries, including Merck, Roche, Astrazeneca, Biogen, Chanel, and L’Oreal, among others. He currently chairs the Scientific Advisory Boards of Emulate, Inc. and Boa Biomedical, Inc.
He is an advisory board member for "Integrative Biology".
Awards.
Ingber has received numerous awards and distinctions, including:
Ingber has also been named to multiple Who's Who lists for his diverse contributions including: Science and Engineering (1991), America (1994), the World (1997), Medicine and Healthcare (1999), Business Leaders and Professionals—Honors Edition (2007), and was honored with the Albert Nelson Marquis Lifetime Achievement Award in 2018.
Art and design exhibitions.
Ingber collaborates internationally with artists, architects, and designers, as well as scientists, physicians, engineers, and the public. Examples of his involvement in the art/design community include:


Polyporus

Polyporus is a genus of poroid fungi in the family Polyporaceae.
The first mention of Polyporus is in the Talmud, regarding someone who touches his nose or mouth multiple times, can cause Polypus to grow. This was written in approximately 200 B.C.
Taxonomy.
Italian botanist Pier Antonio Micheli introduced the genus in 1729 to include 14 species featuring fruit bodies with centrally-placed stipes, and pores on the underside of the cap. The generic name combines the Ancient Greek words ("many") and ("pore").
Elias Fries divided "Polyporus" into three subgenera in his 1855 work "Novae Symbol Mycologici": "Eupolyporus", "Fomes", and "Poria". In a 1995 monograph, Maria Núñez and Leif Ryvarden grouped 32 "Polyporus" species into 6 morphologically-based infrageneric groups: "Admirabilis", "Dendropolyporus", "Favolus", "Polyporellus", "Melanopus", and "Polyporus" "sensu stricto".
The identity of the type species of "Polyporus" has long been a matter of contention among mycologists. Some have preferred "P. brumalis", some "P. squamosus", while others have preferred "P. tuberaster".
Several molecular phylogenetics studies have shown that "Polyporus", as currently circumscribed, is polyphyletic and will need to have its generic limits revised.


Patrick Couvreur

Patrick Couvreur, born in Schaerbeek (Brussels), is a French pharmacologist who specialises in medical nanotechnology and is currently professor at the University of Paris-Sud.
Biography.
Patrick Couvreur obtained his Candidature in pharmaceutical science in 1969, at the University of Namur, followed by a diploma in pharmacy in 1972, at the Catholic University of Louvain (UCL). He received a Doctorate in pharmaceutical science in 1975 from the same university, where he worked in the laboratory next door to the Belgian Nobel Prize winner, Christian de Duve, who was an inspiration for his subsequent career.
From 1976 to 1977 he was a postdoctoral researcher at ETH Zurich, before joining the Catholic University of Louvain, first as a senior research assistant, and then as a senior researcher.
In 1984 he was appointed to a professorship at the Institut Galien Paris Sud (University of Paris-Sud/CNRS).
In 2009-2010, he held the Liliane Bettencourt Chair of Technological Innovation at the Collège de France.
He has three children and several grandchildren.
Principal achievements.
Patrick Couvreur is known for his work in the field of drug vectorization for the treatment of cancer.
In 1997 he founded BioAlliance, a company that employs more than 60 people. In 2007, he founded Medsqual, a start-up that seeks to develop nanomedicines based on squalene
Prizes and distinctions.
Patrick Couvreur was awarded the Prix Galien in 2009 for his work on "squalenization", a significant advance in drug vectorization that involves coupling an active ingredient with squalene. In the same year he received 2,2 million euros of funding from the European Research Council (ERC).
On , he shared the CNRS Innovation Medal with Alain Benoit and José-Alain Sahel.
In 2013 Patrick Couvreur was awarded the European Inventor Award for his work on nanocapsules for cancer treatment.
Patrick Couvreur is a member of the French Academy of Sciences, the French Academy of Technologies the Académie Nationale de Médecine and the Académie de Pharmacie. He is also a foreign member of the National Academy of Medicine (USA), the National Academy of Engineering (USA), the Belgian Royal Academy of Medicine and the Real Academia Nacional de Farmacia (Spain).
On , he was appointed a Chevalier of the Legion of Honor.
In 2019, he received the Journal of Drug Targeting’s Lifetime Achievement Award.


Dibenzylpiperazine

Dibenzylpiperazine (DBZP) is a piperazine derivative often found as an impurity in the recreational stimulant drug benzylpiperazine (BZP). Presence of DBZP is a marker for low quality or badly made BZP. It can be made as a reaction byproduct during BZP synthesis, either because the reaction has been run at too high a temperature, or because an excess of benzyl chloride has been used.
Pharmacology and effects.
It is not known to have any stimulant effects in its own right, although this has not been tested.
Toxicity.
The toxicity of DBZP is unknown.
Legal status.
China.
As of October 2015 DBZP is a controlled substance in China.
United States.
DBZP is not scheduled as a controlled substance at the federal level in the United States. It is possible that it could be considered an analog BZP, in which case, sales or possession intended for human consumption could be prosecuted under the Federal Analog Act.
Florida.
DBZP is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida.


Eltoprazine

Eltoprazine (DU-28,853) is a drug of the phenylpiperazine class which is a serenic or antiaggressive agent. It acts as an agonist at the 5-HT1A and 5-HT1B receptors and as an antagonist at the 5-HT2C receptor. It is closely related to fluprazine and batoprazine, which are similarly acting drugs.
It is also a known precursor to S-15535 & Lecozotan.


Anne Julie de Melun

Anne Julie de Melun (Anne Julie Adélaïde; 1698 – 18 May 1724) was a French court office holder. She served as deputy Governess of the Children of France.
Biography.
Born in 1698, she was baptised with the names Anne Julie Adélaïde and was known as "Anne Julie". Born as the second of two children to , and his wife Élisabeth Thérèse de Lorraine, "princesse de Lillebonne", and thus member of . Her brother Louis de Melun disappeared in 1724, two months after her death.
She was the Lady of Boubers in her own right. The peerage was confiscated in 1789.
At the age of roughly fifteen, she married Jules, Prince of Soubise. The couple were wed in Paris on 16 September 1714. Her husband was a member of the Princely House of Rohan and with the marriage, Anne Julie took on the style of "Her Highness".
She and her husband were second cousins. Anne Julie was an under governess to the children of France working with Madame de Ventadour, her husband's maternal grandmother.
The couple had five children in all, among them Charles de Rohan, Duke of Rohan-Rohan the famous general of Louis XV as well as "Madame de Marsan". She and her husband died in Paris of smallpox. Her eldest son Charles succeeded as Prince of Soubise. Her brother's disappearance, led to the Principality of Epinoy (previously enjoyed by Anne Julie's father) was given to her son, Charles.
She died of smallpox in her twenties.


Aequorivita crocea

Aequorivita crocea is a Gram-negative, psychrotolerant, strictly aerobic, rod-shaped, chemoheterotrophic and non-motile bacterium from the genus of Aequorivita which has been isolated from the Antarctic.


Pseudaminic acid cytidylyltransferase

Pseudaminic acid cytidylyltransferase (, "PseF") is an enzyme with systematic name "CTP:5,7-diacetamido-3,5,7,9-tetradeoxy-L-glycero-alpha-L-manno-nonulosonic acid cytidylyltransferase". This enzyme catalyses the following chemical reaction
Mg2+ is required for activity.


Aleksandr Aleksandrovich Shmuk

Aleksandr Aleksandrovich Shmuk () ( in Moscow - January 22, 1945, Moscow) was a Soviet biochemist and recipient of the Stalin Prize in 1942.
In 1913 Shmuk finished his studies at the Moscow Agricultural Academy. Between 1923 and 1937 he worked at the All-Union Institute of Tobacco and Low-Grade Tobacco while simultaneously holding a professorship at the Kuban Institute of Agriculture. He studied the biochemistry of tobacco and won (in 1942) the Stalin Prize for his work deriving nicotine, citric acid, and malic acid from low-grade tobacco (makhorka). He is known primarily for his three volume work "The Chemistry and Technology of Tobacco" and for his development of a tobacco quality index which is calculated as the ratio between soluble carbohydrates and proteins.
In 1935 he became a member of the All-Union Academy of Agricultural Sciences of the Soviet Union. He finished his career at the Soviet Academy of Science's Institute of Biochemistry.
Selected publications.
Shmuk, A., “State Institute Tobacco Investigations”, Krasnodar (U.S.S.R.) Bull., 69, 15 (1930)

Shmuk, A., Vscsoyus. Inst. Tabach. i. Makhoroch Prom. No. 139, 3 (1937)

Shmuk, A., Bull. Acad. Sci. USSR, 6 (1937)

Shmuk, A., Papers, Acad. Sci. USSR, 2 (1940)

Shmuk A., Smirnov A., Ilyin G. "Formation of nicotine in plants grafted on tobacco" CR (Doklady) Acad. Sci. URSS. (1941)

Shmuk, A., Papers, V. I. Lenin, All-Union Academy of Agricultural Science, 1, 2 and 3 (1945)

Shmuk, A., The Chemistry and Technology of Tobacco, Vols 1,2,3 Pishchepromizdat, Moscow, 1953)
Note: Shmuk appears in the English-language literature various as Schmuck, Shmuck, and Shmuk.