American Biotech

American Biotech Labs, LLC. is a privately held silver nanotechnology company that is based in Alpine, Utah.
LLC (ABL) was formed in 1998 with a mission to create documentable, stable and powerful nanosilver products. It is a three time recipient of the Best of State award for Medical Innovation.
SilverSol.
The company utilizes SilverSol nano-catalytic technology in their products. SilverSol Technology has twenty plus safety reports and test series as well as the first ever double blind, FDA cleared, human ingestion toxicity study done on any silver product. SilverSol silver particles are Ag404 molecules. The term "Sol" is a chemical designation of a pure mineral permanently suspended in water where the mineral’s charge is transferred to the entire body of water. The technology is also known as Silver Hydrosols.
FDA approval.
FDA Approval has been granted for ASAP Wound Dressing Gel held by sister company, ABL Medical.
Patents.
The company has been issued following patents in relation to the nano-catalytic technology: 7,135,195, 6,743,348 and 6,214,299.
On December 2010 they have also been issued patent 7,850,759 for "Metal Extraction from Various Chalcogenide Minerals Through Interaction with Separate Electric Fields and Magnetic Fields Supplied by Electromagnetic Energy".
Patent 20100316685 for "Dental Uses of Silver Hydrosol" is still pending approval.
Dentistry.
Silversol technology is being used in dentistry for various purposes. In a protocol called VERASIL it is being used for new connective tissue reattachment procedure using an Erbium Laser, new restorative protocols, endodontic protocols, bone grafting protocols, dental implant as well as non-surgical periodontal protocols. It has been approved by EPA for both initial cleaning and maintenance of dental waterlines. The approved product has been found to be effective against biofilms. The CRA Foundation, a leading independent dental testing lab, has also chosen the product as a top dental waterline product based on effectiveness-cost criteria.
Revenue and statistics.
In 2008 the company had generated a revenue of $6 million.
In up to January 2013 the company has sold 10 million of products based on the SilverSol technology.


5-HO-DiPT

5-HO-DiPT (5-hydroxy-"N,N"-di-"iso"-propyltryptamine) is a tryptamine derivative which acts as a serotonin receptor agonist. It is primarily known as a metabolite of the better known psychoactive drug 5-MeO-DiPT, but 5-HO-DiPT has also rarely been encountered as a designer drug in its own right. Tests "in vitro" show 5-HO-DiPT to have high 5-HT2A affinity and good selectivity over 5-HT1A, while being more lipophilic than the related drug bufotenine (5-HO-DMT), which produces mainly peripheral effects.


Alpha-Neoendorphin

α-Neoendorphin is an endogenous opioid peptide with a decapeptide structure and the amino acid sequence Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys.
α-neoendorphin is a neuropeptide. Prodynorphin or Proenkephalin B is its precursor. Researchers and anatomists have not yet studied the distribution of α-neoendorphin in the human in detail. However, some studies have been done which supports the presence of α-neoendorphin immunoreactive fibers throughout the human brainstem. According to a study done by Duque, Ewing, Arturo Mangas, Pablo Salinas, Zaida Díaz-cabiale, José Narváez, and Rafael Coveñas; α-neoendorphin immunoreactive fibers can be found in the caudal part of the solitary nucleus, in the caudal and the gelatinosa parts of the spinal trigeminal nucleus, and only low density was found in the central grey matter of medulla.


Glyoxalase system

The glyoxalase system is a set of enzymes that carry out the detoxification of methylglyoxal and the other reactive aldehydes that are produced as a normal part of metabolism. This system has been studied in both bacteria and eukaryotes.
This detoxification is accomplished by the sequential action of two thiol-dependent enzymes; firstly glyoxalase І, which catalyzes the isomerization of the spontaneously formed hemithioacetal adduct between glutathione and 2-oxoaldehydes (such as methylglyoxal) into S-2-hydroxyacylglutathione. Secondly, glyoxalase ІІ hydrolyses these thiolesters and in the case of methylglyoxal catabolism, produces D-lactate and GSH from S-D-lactoyl-glutathione.
This system shows many of the typical features of the enzymes that dispose of endogenous toxins. Firstly, in contrast to the amazing substrate range of many of the enzymes involved in xenobiotic metabolism, it shows a narrow substrate specificity. Secondly, intracellular thiols are required as part of its enzymatic mechanism and thirdly, the system acts to recycle reactive metabolites back to a form which may be useful to cellular metabolism.
Overview of Glyoxalase Pathway.
Glyoxalase I (GLO1), glyoxalase II (GLO2), and reduced glutathione (GSH). In bacteria, there is an additional enzyme that functions if there is no GSH, it is called the third glyoxalase protein, glyoxalase 3 (GLO3). GLO3 has not been found in humans yet.
The pathway begins with methylglyoxal (MG), which is produced from non-enzymatic reactions with DHAP or G3P produced in glycolysis. Methylglyoxal is then converted into S-d-lactoylglutathione by enzyme GLO1 with a catalytic amount of GSH, of which is hydrolyzed into non-toxic D-lactate via GLO2, during which GSH is reformed to be consumed again by GLO1 with a new molecule of MG. D-lactate ultimately goes on to be metabolized into pyruvate.
Regulation.
There are several small molecule inducers that can induce the glyoxalase pathway by either promoting GLO1 function to increase conversion of MG into D-Lactate, which are called GLO1 activators, or by directly reducing MG levels or levels of MG substrate, which are called MG scavengers. GLO1 activators include the synthetic drug candesartan or natural compounds resveratrol, fisetin, the binary combination of trans-resveratrol and hesperetin (tRES-HESP), mangiferin, allyl isothiocyanate, phenethyl isothiocyanate, sulforaphane, and bardoxolone methyl, and MG scavengers include aminoguanidine, alagebrium, and benfotiamine. There is also the small molecule pyridoxamine, which acts as both a GLO1 activator and MG scavenger.
Many inhibitors of GLO1 have been discovered since GLO1 activity tends to be promoted in cancer cells, thus GLO1 serves as a potential therapeutic target for anti-cancer drug treatment and has been the focus of many research studies regarding its regulation in tumor cells.
Medical Applications/Pharmacology.
Hyperglycemia, a side effect caused by diabetes, combines with oxidative stress to create advanced glycation end-products (AGEs) that can lead to diabetic retinopathy (RD) and cause symptoms such as blindness in adults.
The manipulation of the glyoxalase system in mice retina has shown there is a potential for targeting the glyoxalase system to use as a therapeutic treatment for RD by lowering the production of AGEs.
Oxidative stress can lead to worsening neurological diseases such as Alzheimer’s, Parkinson’s, and Autism Spectrum Disorder. Flavonoids, a type of antioxidant that combats oxidative stress in the body, has been found to help decrease the production of radical oxygen species (ROS) mostly by preventing the formation of free radicals but also partially by promoting the glyoxalase pathway via increasing transcription of GSH and GSH constituent subunits to increase intracellular levels of GSH.
Major metabolic pathways converging on the glyoxalase cycle.
Although the glyoxalase pathway is the main metabolic system that reduces methylglyoxal levels in the cell, other enzymes have also been found to convert methylglyoxal into non-AGE producing species: specifically, 99% of MG is processed by glyoxalase metabolism, while less than 1% is metabolized into hydroxyacetone by aldo-keto reductases (AKRs) or into pyruvate by aldehyde dehydrogenases (ALDH). Other reactions have been found to produce MG that also feeds into the glyoxalase pathway. These reactions include catabolism of threonine and acetone, peroxidation of lipids, autoxidation of glucose, and degradation of glycated proteins.


Maria Anna of Naples and Sicily

Princess Maria Anna of Naples and Sicily (; 23 November 1775 – 22 February 1780) was a member of the Spanish Royal Family (branched out to the Kingdom of the Two Sicilies).
Early life.
Maria Anna was born at the Royal Palace in Naples. Her father was Ferdinand, Duke of Calabria, the third son and ninth child of Charles III of Spain and Maria Amalia of Saxony. Her mother was the Archduchess of Austria, the tenth daughter and thirteenth child of the famous Maria Theresa of Austria and her husband, Francis I, Holy Roman Emperor. She was baptised during the first year of her life. Her full name was "Maria Anna Giuseppa Antoinette Francesca Gaetana Teresa Amalia Clementina", her first four names were the same as her mother's eldest sister Archduchess Maria Anna of Austria (1738-1789). She was born and died while her father was still styled "Duke of Calabria". She was then styled "Princess of Naples and Sicily". Her older siblings were Maria Theresa, namesake of her grandmother, born in 1772; Maria Luisa, born in 1773 and Carlo, Duke of Calabria, born just ten months before her. He also died in childhood, yet Maria Anna outlived him.
Death.
Due to the fact that Maria Anna was born just ten months after her older brother Carlo Francesco Giuseppe Gennaro, her birth was extremely difficult for Maria Carolina, and thus for the baby too. She was a very frail and weak child. Her health was reason for debate and when her brother Carlo, Duke of Calabria became ill with smallpox, he was immediately transferred to the Caserta Palace in order to prevent Maria Anna from getting sick, too. Carlo eventually succumbed to the illness on 17 December 1778, aged just three.
In 1778, against all efforts, she contracted smallpox. She rallied for a while, but died on 22 February 1780.


RNase PH

RNase PH is a tRNA nucleotidyltransferase, present in archaea and bacteria, that is involved in tRNA processing. Contrary to hydrolytic enzymes, it is a phosphorolytic enzyme, meaning that it uses inorganic phosphate as a reactant to cleave nucleotide-nucleotide bonds, releasing diphosphate nucleotides. The active structure of the proteins is a homohexameric complex, consisting of three ribonuclease (RNase) PH dimers. RNase PH has homologues in many other organisms, which are referred to as RNase PH-like proteins. The part of another larger protein with a domain that is very similar to RNase PH is called an RNase PH domain (RPD).
See also.
Two highly related exoribonuclease complexes:


Durham tube

Durham tubes are used in microbiology to detect production of gas by microorganisms. They are simply smaller test tubes inserted upside down in another test tube. This small tube is initially filled with the solution in which the microorganism is to be grown. If gas is produced after inoculation and incubation, a visible gas bubble will be trapped inside the small tube. The initial air gap produced when the tube is inserted upside down is lost during sterilization, usually performed at 121 °C for 15 or so minutes. The method was first reported in 1898 by British microbiologist Herbert Durham.
External links.
1. http://www.vumicro.com/vumie/help/VUMICRO/Nitrate_Broth_with_Durham_Tube.htm
2. http://www.bd.com/ds/technicalCenter/inserts/L007459(07)(0506).pdf


Allscripts

Allscripts Healthcare Solutions, Inc. is a publicly traded American company that provides physician practices, hospitals, and other healthcare providers with practice management and electronic health record technology. Allscripts also provides products for patient engagement and care coordination, as well as financial and analytics technology. The company has more than 180,000 physician users and has products in 2,700 hospitals and 13,000 extended care organizations.
History.
Allscripts was founded in 1981 and is headquartered in Chicago, Illinois. An additional key operations office is located in Raleigh, North Carolina.
In 2008, Allscripts merged with the healthcare systems operations of its rival, Misys. In 2010, Allscripts-Misys merged with another healthcare information technology competitor, Eclipsys, in a $1.3 billion deal, merging patient records, to create the industry’s largest network of clients.
In 2020 Allscripts executed two major divestment moves. In October, Allscripts sold its EPSi business, a provider of financial decision support and planning tools for hospitals and health systems, to Strata Decision Technology for $365 million. Later, in December 2020, Allscripts closed the sale of its care coordination business, CarePort Health, to Wellsky for $1.35 billion.
Acquisitions.
In March 2013, Allscripts acquired dbMotion, Ltd., a developer of system interfaces and data analytics tools, and Jardogs LLC, a developer of a personal health record.
In 2018 Allscripts acquired Practice Fusion.
In 2019, Allscripts acquired ZappRx, a Boston, MA-based prescription drug start-up company, which provides an online platform used by patients, physicians, and pharmacists for the management of specialty medications.
Legal Issues.
In December 2012, four physician practices brought a class-action suit against Allscripts due to selling the "buggy" MyWay EHR and later discontinuing it. It was believed to be a first-of-its-kind case. The parties reached a joint settlement agreement that received final approval from the trial court judge. With this first lawsuit of this nature it has become a reference for future cases in this industry.
In 2015 Allscripts was set to pay nearly $9.75 million to the proposed class to settle claims of securities fraud, after the company allegedly overstated its ability to integrate its Microsoft.NET and SQL Server with those of Eclipsys following their $1.3 billion merger.
In 2019, one year after Allscripts’ acquisition of Practice Fusion, a San Francisco-based electronic health records company intended to expand Allscripts' business with independent physicians, Allscripts agreed to settle with the Department of Justice over "potential issues with the EHR vendor’s health IT certification and Practice Fusion’s compliance with the Anti-Kickback Statute and HIPAA." As part of the settlement, Practice Fusion paid $145 million dollars.
In 2020, the Department of Justice released a press release detailing the $145 million settlement:
Allscripts chief administrative officer Brian Farley said that Practice Fusion's behavior was known to Allscripts prior to the purchase. Farley also noted that Allscripts was working to help combat the opioid epidemic.
Ransomware attack.
On Jan 18, 2018, Allscripts was hit with a ransomware attack. This caused a massive outage which lasted nearly a week and affected clients all over the globe. The attack was a new strain of a known bug, SamSam. Since then, clients have filed a class action lawsuit alleging Allscripts should have taken better steps to protect their data.


5-MeO-MiPT

5-MeO-MiPT is a psychedelic and hallucinogenic drug, used by some as an entheogen. It has structural and pharmacodynamic properties similar to the drugs 5-MeO-DiPT, DiPT, and MiPT. It is commonly used as a "substitute" for 5-MeO-DiPT because of the very similar structure and effects.
Chemistry.
5-MeO-MiPT is in a class of compounds commonly known as tryptamines, and is the N-methyl-N-isopropyl homologue of the psychedelic, 5-MeO-DMT. The full name of the chemical is 5-methoxy-N-methyl-N-isopropyltryptamine.
5-MeO-MiPT causes the ehrlich reagent to turn purple then fade to faint blue. It causes the marquis reagent to go yellow through to black.
Effects.
This is an analogue of the more popular drug 5-MeO-DiPT (nicknamed "foxy methoxy") and has the nickname "moxy". Some users report the tactile effects of 5-MeO-DiPT without some of the unwanted side effects. At higher doses it becomes much more psychedelic sometimes being compared to 5-MeO-DMT. But at doses of 4-10 milligrams users find 5-MeO-MiPT to be a very euphoric and tactile chemical. Its energetic effects can be very strong at high doses, increasing normal heart rate considerably. Sounds can be amplified in perception to a point where synesthetic effects ("touching or/and tasting sounds") occur.
Dosage.
Orally, 5-MeO-MiPT is active at 4-6 mg. The drug can also be smoked, but unlike most other tryptamines, this route requires a much higher dosage. 10–20 mg is usually smoked. It typically produces a very strong odor.
Some users report activity as low as 1 mg while others report no activity up to 20 mg, this compound seems to be highly sensitive to the individual and any potential researchers should keep this in mind. Titrating the dose would be especially important with this compound.
Some users report little to no visual activity until doses of 10 mg or higher are taken. This chemical proves very useful for opening up and expressing oneself much like MDMA (3,4-methylenedioxymethamphetamine) and may be a useful chemical in psychedelic therapy.
Pharmacology.
The mechanism that produces the hallucinogenic and entheogenic effects of 5-MeO-MiPT is thought to result primarily from 5-HT2A receptor agonism, although additional mechanisms of action such as inhibition of MAO may be involved also. 5-MeO-MiPT binds most strongly to 5-HT1A receptors; it also shows fairly strong binding affinity to the SERT and NET, thereby acting as a moderately potent serotonin-norepinephrine reuptake inhibitor. These mechanisms may help explain why there are many anecdotal reports of anti-depressant and anxiolytic effects from modest doses of this compound. For example, SNRIs such as venlafaxine are commonly prescribed to treat depression, and the 5-HT1A agonist buspirone is prescribed primarily for treatment of anxiety.
Dangers.
The toxicity of 5-MeO-MiPT is not known but as with all research chemicals doses should be carefully weighed on an accurate milligram scale and users should take caution because overdoses are not listed. There are many reports of vasoconstriction with it as well. There is no known documentation of death attributed to the use of 5-MeO-MiPT alone.
Note - Some users report that they have a decrease of energy the next day after dosing. Please keep this in mind if you ever take this substance.
Legal status.
China.
As of October 2015 5-MeO-MiPT is a controlled substance in China.
United Kingdom.
5-MeO-MiPT is a Class A drug in the United Kingdom as are most ethers of ring-hydroxy tryptamines.
United States.
5-MeO-MiPT is unscheduled at the federal level in the United States, but it could be considered an analog of 5-MeO-DiPT, in which case purchase, sale, or possession could be prosecuted under the Federal Analog Act.
Florida.
"5-Methoxy-N-methyl-N-isopropyltryptamine" is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida.
Canada.
5-MeO-MiPT is not scheduled in Canada.


Bupranolol

Bupranolol is a non-selective beta blocker without intrinsic sympathomimetic activity (ISA), but with strong membrane stabilizing activity. Its potency is similar to propranolol.
Uses and dosage.
Like other beta blockers, oral bupranolol can be used to treat hypertension and tachycardia. The initial dose is 50 mg two times a day. It can be increased to 100 mg four times a day. Bupranolol eye drops (0.05%-0.5%) are used against glaucoma.
Pharmacology.
Bupranolol is quickly and completely absorbed from the gut. Over 90% undergo first-pass metabolism. Bupranolol has a plasma half life of about two to four hours, with levels never reaching 1 µg/l in therapeutic doses. The main metabolite is carboxybupranolol, 4-chloro-3-[3-(1,1-dimethylethylamino)-2-hydroxy-propyloxy]benzoic acid – that is, the methyl group at the benzene ring is oxidized to a carboxyl group –, of which 88% are eliminated renally within 24 hours.
Adverse effects, contraindications, interactions.
Adverse effects, contraindications and interactions are similar to other beta blockers.


Tecrea

Tecrea Ltd is a biotech company located in the London Bioscience Innovation Centre. The company is involved in research and development to improve the cell and tissue delivery of drugs and reagents. The approach involves nanomedicine, which has the potential to address a wide variety of diseases.
Recently Tecrea along with Cobra Biologics was awarded the Innovate UK Grant worth £112K to Develop AAV Scalable Production Bioprocess
Background.
Founded in 2012, as a spinout from the Royal Veterinary College, University of London, the company has developed a line of tools aimed at improving scientific experiments through enhanced delivery of a range of molecules into cells.
Products.
Tecrea Research Reagents and Drug Formulation products


Extracellular RNA

Extracellular RNA (exRNA) describes RNA species present outside of the cells in which they were transcribed. Carried within extracellular vesicles, lipoproteins, and protein complexes, exRNAs are protected from ubiquitous RNA-degrading enzymes. exRNAs may be found in the environment or, in multicellular organisms, within the tissues or biological fluids such as venous blood, saliva, breast milk, urine, semen, menstrual blood, and vaginal fluid. Although their biological function is not fully understood, exRNAs have been proposed to play a role in a variety of biological processes including syntrophy, intercellular communication, and cell regulation. The United States National Institutes of Health (NIH) published in 2012 a set of Requests for Applications (RFAs) for investigating extracellular RNA biology. Funded by the NIH Common Fund, the resulting program was collectively known as the Extracellular RNA Communication Consortium (ERCC). The ERCC was renewed for a second phase in 2019.
Background.
Both prokaryotic and eukaryotic cells are known to release RNA, and this release can be passive or active. The Endosomal Sorting Complex Required for Transport (ESCRT) machinery was previously considered as a possible mechanism for RNA secretion from the cell, but more recently research studying microRNA secretion in human embryonic kidney cells and "Cercopithecus aethiops" kidney cells identified neutral sphingomyelinase 2 (nSMase2), an enzyme involved in ceramide biosynthesis, as a regulator of microRNA secretion levels. ExRNAs are often found packaged within vesicles such as exosomes, ectosomes, prostasomes, microvesicles, and apoptotic bodies. Although RNAs can be excreted from the cell without an enveloping container, ribonucleases present in extracellular environments would eventually degrade the molecule.
Types.
Extracellular RNA should not be viewed as a category describing a set of RNAs with a specific biological function or belonging to a particular RNA family. Similar to the term "non-coding RNA", "extracellular RNA" defines a group of several types of RNAs whose functions are diverse, yet they share a common attribute which, in the case of exRNAs, is existence in an extracellular environment. The following types of RNA have been found outside the cell:
Though prevalent inside of the cell, ribosomal RNA (rRNA) does not seem to be a common exRNA. Efforts by "Valadi et al." to characterize exosomal RNA using the Agilent Bioanalyzer technology showed little to no trace of 18S and 28S rRNA in exosomes secreted by MC/9 murine mast cells, and similar conclusions were made by "Skog et al." for rRNA in gliobastoma microvesicles.
Function.
To function or even survive as full-length RNA in extracellular environments, exRNA must be protected from digestion by RNases. This requirement does not apply to prokaryotic syntrophy, where digested nucleotides are recycled. exRNA can be shielded from RNases by RNA binding proteins (RBPs), on their own or within/associated with lipoprotein particles and extracellular vesicles. Extracellular vesicles in particular are thought to be a way to transport RNA between cells, in a process that may be general or highly specific, for example, due to incorporation of markers of the parent cell that may be recognized by receptors on the recipient cell. Biochemical evidence supports the idea that exRNA uptake is a common process, suggesting new pathways for intercellular communication. As a result, the presence, absence, and relative abundance of certain exRNAs can be correlated with changes in cellular signaling and may indicate specific disease states.
Despite a limited understanding of exRNA biology, current research has shown the role of exRNAs to be multi-faceted. Extracellular miRNAs are capable of targeting mRNAs in the recipient cell through RNA interference pathways. "In vitro" experiments have shown the transfer of specific exRNAs into recipient cells inhibiting protein expression and preventing cancer cell growth. In addition to mRNAs being regulated by exRNAs, mRNAs can act as exRNAs to carry genetic information between cells. Messenger RNA contained in microvesicles secreted from glioblastomal cells were shown to generate a functional protein in recipient (human brain microvascular endothelial) cells "in vitro". In another study of extracellular mRNAs, mRNAs transported by microvesicles from endothelial progenitor cells (EPCs) to human microvascular and macrovascular endothelial cells triggered angiogenesis in both the "in vitro" and "in vivo" setting. Work by "Hunter et al." used Ingenuity Pathway Analysis (IPA) software that associated exRNAs found in human blood microvesicles with pathways involved in blood cell differentiation, metabolism, and immune function. These experimental and bioinformatics analyses favor the hypothesis that exRNAs play a role in numerous biological processes.
Detection.
Several methods have been developed or adapted to detect, characterize, and quantify exRNA from biological samples. RT-PCR, cDNA microarrays, and RNA sequencing are common techniques for RNA analysis. Applying these methods to study exRNAs mainly differs from cellular RNA experiments in the RNA isolation and/or extraction steps.
RT-PCR.
For known exRNA nucleotide sequences, RT-PCR can be applied to detect their presence within a sample as well as quantify their abundance. This is done through first reverse transcribing the RNA sequence into cDNA. The cDNA then serves as a template for PCR amplification. The major benefits of using RT-PCR are its quantitative accuracy in a dynamic range and increased sensitivity compared to methods such as RNase protection assays and dot blot hybridization. The disadvantage to RT-PCR is the requirement of costly supplies, and the necessity of sound experimental design and an in-depth understanding of normalization techniques in order to obtain accurate results and conclusions.
Microfluidics.
Microfluidic platforms such as the Agilent Bioanalyzer are useful in assessing the quality of exRNA samples. With the Agilent Bioanalyzer, a lab-on-chip technology that uses a sample of isolated RNA measures the length and quantity of RNA in the sample, and the results of the experiment can be represented as a digital electrophoresis gel image or an electropherogram. Because a diverse range of RNAs can be detected by this technology, it is an effective method for more generally determining what types of RNAs are present in exRNAs samples through using size characterization.
cDNA microarrays.
Microarrays allow for larger-scale exRNA characterization and quantification. Microarrays used for RNA studies first generate different cDNA oligonucleotides (probes) that are attached to the microarray chip. An RNA sample can then be added to the chip, and RNAs with sequence complementarity to the cDNA probe will bind and generate a fluorescent signal that can be quantified. Micro RNA arrays have been used in exRNA studies to generate miRNA profiles of bodily fluids.
RNA sequencing.
The advent of massively parallel sequencing (next-generation sequencing) lead to variations in DNA sequencing that allowed for high-throughput analyses of many genomic properties. Among these DNA sequencing-derived methods is RNA sequencing. The main advantage of RNA sequencing over other methods for exRNA detection and quantification is its high-throughput capabilities. Unlike microarrays, RNA sequencing is not constrained by factors such as oligonucleotide generation, and the number of probes that can be added to a chip. Indirect RNA sequencing of exRNA samples involves generating a cDNA library from the exRNAs followed by PCR amplification and sequencing. In 2009, Helicos Biosciences published a method for directly sequencing RNA molecules called Direct RNA sequencing (DRS™). Regardless of the RNA sequencing platform, inherent biases exist at various steps in the experiment, but methods have been proposed to correct for these biases with promising results.
Clinical significance.
As growing evidence supports the function of exRNAs as intercellular communicators, research efforts are investigating the possibility of utilizing exRNAs in disease diagnosis, prognosis, and therapeutics.
Biomarkers.
The potential of extracellular RNAs to serve as biomarkers is significant not only because of their role in intercellular signaling but also due to developments in next generation sequencing that enable high throughput profiling. The simplest form of an exRNA biomarker is the presence (or absence) of a specific extracellular RNA. These biological signatures have been discovered in exRNA studies of cancer, diabetes, arthritis, and prion-related diseases. Recently, a bioinformatics analysis of extracellular vesicles extracted from Trypanosoma cruzi, in which SNPs were mined from transcriptomic data, suggested that exRNAs could be biomarkers of neglected diseases such as Chagas disease.
Cancer.
A major research area of interest for exRNA has been its role in cancer. The table below (adapted from "Kosaka et al.") lists several types of cancer in which exRNAs have been shown to be associated:


William P. Murphy Jr.

William P. Murphy Jr. (born November 11, 1923) is a medical doctor and inventor of medical devices including collaborating on a flexible sealed blood bag used for blood transfusions. He is the son of the American physician William Parry Murphy who shared the Nobel Prize in Physiology for Medicine in 1934, and Harriett Adams, the first licensed female dentist in Massachusetts.
Education.
Murphy graduated from Harvard University in 1946 with a major in pre-medicine and a minor in architecture. He received his M.D. in 1947 from the University of Illinois and also studied physiologic instrumentation at the Massachusetts Institute of Technology from 1947 to 1948.
Career.
Murphy practiced medicine for a short time as an intern at St. Francis Hospital in Honolulu and later, at Peter Bent Brigham Hospital in Boston (now Brigham & Women’s Hospital). While at St. Francis, he developed his first medical invention—a projector for presenting full-size x-rays to large audiences. Murphy and the other interns were regularly required to show x-rays of their patients to doctors. To simplify this task, Murphy created a projector that was capable of showing a full-size x-ray on the screen and was easy to use—quite an accomplishment at that time, since a prompt means for converting x-rays to transparencies did not exist.
Murphy's next contribution to the medical world coincided with the Korean War. The U.S. Army first came to Murphy while he was working with a team of doctors in Boston on the first dialysis machines, a program the Army supported because of concerns over exposure to radiation from the Atomic bomb. An offshoot of this work was the refinement of flexible bags to contain blood during transfusions, which offered many advantages to previously used bottles. Developed with Carl Walter, the bags preserve red blood cells and proteins and ensure that the contents are not exposed to air. In 1952, Murphy joined the U.S. Public Health Service as a blood transfusion consultant, and went to Korea to perform transfusions on soldiers injured in battle.
In 1957, he founded his first company, Medical Development Corporation. The company, which focused on building research instruments, eventually grew into Cordis Corporation, and is now a Johnson & Johnson company. Cordis gave Murphy the resources to create a number of today's standard medical devices, including the first physiologic cardiac pacemaker; the widely used hollow fiber artificial kidney; the first disposable medical procedural trays; the first motor-driven angiographic injectors; and the first disposable catheters.
Murphy's physiologic cardiac pacemaker—which is used to treat heart block—senses what a patient's heart needs and provides suitable stimulation so that the heart can function normally. As more doctors began to use implantable pacemakers, it became clear that there needed to be a way to alter the function of the pacemakers while they were implanted. This led Murphy and his team to develop pacemakers that could be programmed externally and, ultimately, to develop the first DDD (dual chamber demand) pacemaker (1980s).
Murphy's motor-driven, high-pressure angiographic injectors are used for injecting a small amount of radiographic contrast (a solution containing iodine, which is easily visualized with x-ray images) into select vessels in the body. The images that are produced, called an angiogram, accurately reveal the extent and severity of blockages. The disposable, torque-controlled vascular catheters—a related invention, created with colleague Robert Stevens—allow for easy entry into specific vessels, and are a sterile one-time use product.
While at Cordis, Murphy found it difficult to obtain the appropriate quantities and types of materials needed to complete his prototypes. To overcome this, he started Small Parts, Inc., a Miami, FL-based company that provides high quality materials and tools to engineers—in any amount—to help facilitate completion of projects. The company, well-known throughout the medical and engineering communities, is one of several companies founded by Murphy and among 30 companies that emerged from Cordis. In 1986, Murphy, together with colleague John Sterner, purchased Hyperion, Inc. Also based in Miami, Hyperion designs, manufactures and markets medical laboratory diagnostic devices.
Murphy is currently the Chairman of the Board of Directors at U.S. Stem Cell, formerly Bioheart.
U.S. Patents.
Murphy holds 17 U.S. patents issued between 1952 and 1980.
Publications.
He co-authored nearly 30 medical publications and helped to establish several professional organizations such as FIRST (For Inspiration and Recognition of Science and Technology), a non-profit group dedicated to inspiring young people's interest in science, technology and engineering, founded by his friend Dean Kamen.
Awards.
Often recognized for his many achievements, he has received countless awards including the prestigious Lemelson-MIT Lifetime Achievement Award, the Distinguished Service Award of the North American Society of Pacing and Electrophysiology (1985), American Institute of Medical and Biological Engineering Founding Fellow (1993) and the FIRST Founder’s Award (2000).
Medical Licenses.
Murphy is licensed to practice medicine in three states: California (license #C018494), Florida (license #0007401), and Massachusetts (license #23378)


Nitroquinoline-N-oxide reductase

In enzymology, a nitroquinoline-N-oxide reductase () is an enzyme that catalyzes the chemical reaction
The 4 substrates of this enzyme are 4-hydroxyaminoquinoline N-oxide, NAD+, NADP+, and H2O, whereas its 4 products are 4-nitroquinoline N-oxide, NADH, NADPH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on other nitrogenous compounds as donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 4-(hydroxyamino)quinoline N-oxide:NADP+ oxidoreductase. Other names in common use include 4-nitroquinoline 1-oxide reductase, 4NQO reductase, and NAD(P)H2:4-nitroquinoline-N-oxide oxidoreductase.


Creative biomart

Creative Biomart is a New York-based, privately held biotechnology company focused on the development and commercialization of recombinant proteins and protein production.
The company's recombinant protein pipeline includes :


Kruppel-like factors

In molecular genetics, the Krüppel-like family of transcription factors (KLFs) are a set of eukaryotic C2H2 zinc finger DNA-binding proteins that regulate gene expression. This family has been expanded to also include the Sp transcription factor and related proteins, forming the Sp/KLF family.
Members.
The following human genes encode Kruppel-like factors:
KLF1, KLF2, KLF3, KLF4, KLF5, KLF6, KLF7, KLF8, KLF9, KLF10, KLF11, KLF12, KLF13, KLF14, KLF15, KLF16, KLF17
The following genes are Sp factors:
Sp1, Sp2, Sp3, Sp4, Sp5, Sp6, Sp7, Sp8, and Sp9.
Note that although KLF14 was an alias for Sp6 (), it now refers to a protein () derived from KLF16 by a retrotransposon event.
Function and properties.
KLF/Sps are a family of transcription factors that contain three carboxyl-terminal (C-terminal) C2H2-type zinc finger structural motifs that bind to the GC-rich regions in DNA and regulate various cellular functions, such as proliferation, differentiation, and apoptosis, as well as the development and homeostasis of several types of tissue. The C-terminal end binds to the promoter and enhancer regions of a gene. Each KLF also has a unique amino-terminal (N-terminal) end that acts as the functional domain that allows it to bind specifically to a certain partner. KLFs share the similar function of transcription regulation via the recruitment of regulatory proteins. These transcription factors have a conserved structural homology between mammalian species, which allow for similar function due to similar protein interaction motifs at the N-terminal domains. The C-terminal end is also highly conserved with both the first and second zinc finger have 25 amino acids, while the third has 23 amino acids. Each of the three zinc fingers recognize three unique base pairs for their DNA-binding sites, which together make the general form NCR CRC CCN (where N is any base and R is a purine). There is some evidence that positively-charged amino acids within the three zinc fingers may contribute towards localizing the protein in the Nucleus. The N-terminal end allows for the binding of various coactivators, corepressors, and modifiers. All family members share the zinc finger signature KLF-DBD of codice_1 and use a 9aaTAD.
KLFs are divided into three subgroups; Group 1 (KLF 3,8, and 12) are repressors via interaction with the C-terminal Binding Protein 1 and 2 (CtBP1 and CtBP2). Group 2 (KLFs 1,2,4,5,6, and 7) are transcription activators. Group 3 (KLFs 9,10,11,13,12, and 16) have repressor activity via interaction with the common transcriptional co-repressor, Sin3A. KLFs 15 and 17 are distantly related without any defined protein interaction motifs.
The Sp family members diverged from KLFs since Filozoa. They are typically divided into two groups of Sp1-4 and Sp5-9. One of the signatures is the "Btd box" codice_2 preceding the KLF-DBD.
Evolutionary and biochemical mechanisms.
The proliferation of KLF genes, presumably from an ancestral KLF, is also interesting. In some cases different family members are expressed in different tissues. The first KLF, KLF1, originally known as Erythroid KLF (EKLF) is expressed only in red blood cells and megakaryocytes. It drives red blood cell differentiation and represses megakaryocyte formation. It appears that it has arisen as a KLF family member that has a particular role in these two blood lineages. Other KLFs are more broadly expressed and there are interactions between family members. KLF3 for instance is driven by KLF1 as is KLF8. On the other hand, KLF3 represses KLF8. Such cross-regulation occurs extensively in transcription factor families. Many transcription factor genes regulate their own promoters and when a gene duplicates during evolution then cross-regulation often occurs. The cross-regulation can ensure that the total amount of KLFs in the cell is monitored and controlled.
Finally, the biological roles of the KLFs are of wide interest. KLF1 is a very important factor in red cell biology. Naturally occurring human mutations in the KLF1 gene have been associated with de-repression of the fetal globin gene. KLF2 (originally Lung KLF ) also has a role in embryonic globin gene expression, as does KLF3 (originally Basic KLF). KLF3 also has roles in adipocyte or fat formation, and in B lymphocytes. Recently, KLF3 was shown to be important in heart development. KLF4 (originally Gut KLF) is an important gene in the gut and skin but has more recently risen to prominence as one of the four genes that can reprogram body cells to become stem cells. [KLF4] is one of the so-called magic four transcription factors, KLF4, Oct4, Sox2 and Myc. KLF5, like KLF3, is important in adipocytes and KLF6 is an important tumour suppressor gene, that is often mutated in prostate cancers.
Krüppel-like factor 3.
KLF3 has a short motif in the N-terminus (of the form Proline-Isoleucine-Aspartate-Leucine-Serine or PIDLS) that recruits CtBP1 and 2. CtBP in turn recruits histone modifying enzymes. It brings in histone deacetylases, histone demethylases and histone methylases, which are thought to
remove active chromatin marks and lay down repressive marks to eliminate gene expression.
Krüppel-like factors 4 and 5.
Klf4, also known as gut-enriched Krüppel-like factor (GKLF), acts as a transcriptional activator or repressor depending on the promoter context and/or cooperation with other transcription factors. For example, Klf4 transactivates the iNOS promoter in cooperation with p65 (RelA), and the p21Cip1/Waf1 promoter in cooperation with p53, but it directly suppresses the p53 promoter and inhibits ornithine decarboxylase (ODC) promoter activity by competing with specificity protein-1 (Sp-1). Klf4 also interacts with the p300/CBP transcription co-activators. Klf5, also known as intestinal enriched Krüppel-like factor (IKLF) or basic transcription element binding protein 2 (Bteb2), has been assigned purely transcriptional activation activity but, similar to Klf4, binds p300 which acetylates the first zinc finger conferring a trans-activating function. Importantly for Klf4 and Klf5, the amino acids that are predicted to interact with DNA are identical and the two compete for the same CACCC element or GC-rich sequence of the gene promoter region to regulate cell proliferation or differentiation-elated gene expression. Klf4 and Klf5 can act antagonistically during cellular proliferation, differentiation, and promoter activation, either via direct competition or via alterations in their own gene expression. The expression of Klf4 in terminally differentiated, post-mitotic intestinal epithelial cells as opposed to proliferating crypt cells which contain high levels of Klf5 is one example of such opposing effects. Klf4 inhibits proliferation through activation of p21Cip1/Waf1, and direct suppression of cyclin D1 and cyclin B1 gene expression. Both Klf4 & Klf5 proteins act on the Klf4 promoter where Klf4 increases expression and Klf5 decreases expression of Klf4 mRNA. The Wnt/APC signal pathway also plays an important role in the regulation of KLF4 expression. LOH, point mutations in the coding region and promoter hypermethylation are the main causes of klf4 gene silencing.
In the vascular system.
Klf4 is upregulated in vascular injury. It dramatically represses SRF/myocardin-induced activation of gene expression, and directly inhibits myocardin gene expression in vascular smooth muscle cells (VSMCs), therefore inhibiting the transition to a proliferative phenotype . Furthermore, Klf4 has been identified as an anti-proliferative shear stress-responsive gene, and forced over-expression of Klf4 in VSMCs induces growth arrest. Klf4 may therefore be an important protective factor in disease states affected by shear stress, such as thrombosis, restenosis and atherosclerosis. Klf4 also mediates the vascular response to nitric oxide (NO) by activating the promoters of inducible nitric oxide synthase (iNOS) in endothelial cells and cGMP-dependent protein kinase 1α/protein kinase G 1α (PKG 1α) in VSMCs. PKG 1α is activated by NO and mediates VSMC relaxation. This trans-activating effect of Klf4 on the PKG 1α promoter is inhibited by RhoA-induced actin polymerisation, possibly via G-actin regulation of a Klf4 co-activator or co-repressor. RhoA signalling pathways and RhoA activation are implicated in hypertension and increased vascular resistance which to some extent can be explained by this interaction with Klf4 and its effects on the response to NO. Klf5 has no effect on the PKG 1α promoter though the protein expression and nuclear localisation of Klf5 was similar to that of Klf4.
In the myocardium.
Little is known of the Klfs in the myocardium. Klf5 activates the promoter of the hypertrophic agonist platelet derived growth factor (PDGFA) in cardiac fibroblasts a factor previously identified as being upregulated by ET-1, and Klf5+/- transgenic mice heterozygotes (described earlier) exhibited less cardiac fibrosis and hypertrophy when stimulated with angiotensin II compared with controls. Klf5 is itself regulated by the immediate early gene egr-1 in VSMCs, which, if similarly regulated in the cardiomyocyte, places Klf5 potentially in a position to co-ordinate the acute response to external stress and tissue remodelling in the myocardium.
In genomic engineering.
The understanding of the structure and function of KLFs has informed the design of artificial transcription factors. Artificial zinc fingers can be built to recognize chosen sites in DNA and artificial functional domains can be added to either activate or repress genes containing these sites.


Mycena lacrimans

Mycena lacrimans is a species of agaric fungus in the family Mycenaceae. Found in South America, the fruit bodies of the fungus are bioluminescent.


Dan Burton

Danny Lee Burton (born June 21, 1938) is an American politician. Burton is the former U.S. Representative for , and previously the , serving from 1983 until 2013. He is a member of the Republican Party and the Tea Party Caucus.
Early life, education, and early career.
Burton was born in Indianapolis, the son of Bonnie L. (née Hardesty) and Charles W. Burton. His father, a former policeman, was abusive to his mother, and never held a job for very long. The family moved constantly, living in trailer parks, cabins, and motels. In June 1950, some years after the couple divorced, his mother went to the police and got a restraining order against his father. He responded by kidnapping Burton's mother. Burton and his younger brother and sister were briefly sent to the Marion County Children's Guardian Home. After his mother escaped, Burton's father went to jail for two years. Burton's mother remarried, and Burton and his younger brother and sister had happier teenage years.
Burton worked as a caddy at a local country club in order to make ends meet, where he learned the golf skills that led to his winning a statewide golf championship in high school. He graduated from Shortridge High School in 1957, and attended Indiana University (1958–59) and the Cincinnati Bible Seminary (now known as Cincinnati Christian University) (1959–60). He served in the United States Army from 1956 to 1957, before leaving active duty to return to college but remained in the Army Reserves from 1957 to 1962. After school, Burton became a real estate broker and he founded the Dan Burton Insurance Agency in 1968.
Indiana legislature.
Burton was a member of the Indiana House of Representatives from 1967 to 1968 and again from 1977 to 1980 and the Indiana State Senate from 1969 to 1970 and again from 1981 to 1982.
U.S. House of Representatives.
Elections.
Burton first ran for Congress in 1970, losing to Democratic incumbent Andy Jacobs in Indiana's 11th congressional district. Burton ran again in 1972, losing in the Republican primary to William Hudnut.
After the 1980 census, the Republican-controlled state legislature reconfigured the 6th District into a heavily Republican district focused on the suburbs north of Indianapolis. The district's four-term Democratic incumbent, David W. Evans, opted to challenge Jacobs in the Democratic primary (which he lost) rather than face certain defeat. Burton jumped into the Republican primary halfway into his second stint in the state senate, and won a five-way Republican primary with 37% of the vote. He then defeated Democrat George Grabianowski in the general election 65%–35%. He would be reelected 14 times, never dropping below 62% in a general election. His district was renumbered as the 5th District after the 2000 census.
In 2008, Burton faced a reasonably well-funded challenger in the Republican primary for the first time since his initial run for the seat in former Marion County Coroner Brigadier General Dr. John McGoff. Burton defeated McGoff 52% to 45% in the closest Republican primary election of his career.
In 2010, he faced six challengers in the Republican primary. He won the primary with a plurality of 30%. He defeated State Representative Luke Messer (28%), McGoff (19%), State Representative Mike Murphy (9%), Brose McVey (8%), Andy Lyons (4%), and Ann Adcock (3%). Burton only carried a majority in one county (55%): Huntington.
In 2012, Burton was due to face a number of challengers in the Republican primary including McGoff, former U.S. Attorney Susan Brooks, former U.S. Congressman David McIntosh, and attorney Jack Lugar. On the Democratic side, State Representative Scott Reske and labor activist Tony Long entered the race. While the reconfigured 5th is still a Republican stronghold, it is said to be slightly more Democratic than its predecessor. In January 2012, Burton abruptly announced his retirement, saying, "I don't want to get into it, it's about personal problems with family health." Brooks won the election.
Tenure.
In 1995, Burton authored legislation targeting foreign companies that did business with Cuba. The bill allowed foreign companies to be sued in American courts if, in dealings with the government of Fidel Castro, they acquired assets formerly owned by Americans. In February 1996, Cuba shot down two small Brothers to the Rescue planes piloted by anti-Castro Cuban-Americans. As part of the White House response to crack down on Cuba, President Clinton signed the Helms–Burton Act into law.
Burton was a consistently conservative vote in the US House. In the 109th Congress, he had a 100% rating from the National Right to Life Committee. He also has an A rating with the Gun Owners of America.
Burton has received a number of awards from conservative groups, including a Friend of the Farm Bureau Award in 2004 from the American Farm Bureau Federation, a True Blue Award in 2006 the Family Research Council, eight Guardian of Small Business Awards from the National Federation of Independent Business and twenty-two Spirit of Enterprise Awards from the U.S. Chamber of Commerce.
Burton was the primary sponsor for a 1998 effort, opposed by the Clinton administration, to require federal government agencies to do more strategic planning, establish more accountability measurements, and do more reporting on their performance. H.R. 2883, the "Government Performance and Results Act Amendments", was not enacted into law.
In his role as chairman of the House Government Oversight Committee, Burton helped expose FBI corruption that led to the wrongful conviction of Joseph Salvati, Peter Limone, Henry Tameleo and Louis Greco for the murder of Edward "Teddy" Deegan. The three-year investigation that Burton spearheaded helped exonerate the four, who were eventually awarded $102 million by Judge Nancy Gertner of the District of Massachusetts.
Burton served as chairman of the Republican Study Committee, a caucus of conservative House Republicans, during the 101st Congress. After Newt Gingrich yanked funding for the group in 1995, Burton joined fellow congressmen John Doolittle of California, Ernest Istook of Oklahoma and Sam Johnson of Texas in refounding it as the Conservative Action Team. The three men shared the chairmanship from 1994 to 1999. In 2001, the CAT regained its original name, the RSC.
Congressman Burton is a founding member and co-chair of Pakistan Caucus in House of Congress. His consistent support for Pakistan and his voting record has prompted the Indian media to describe him as "anti-India" in the past.
Burton has received at least $10,000 in campaign donations from Syed Ghulam Nabi Fai, who runs the Kashmir Center, a pro-Pakistan advocacy group. Burton was the chief supporter in Congress of the Kashmiri American Council, until it was revealed to be a front of Inter-Services Intelligence Directorate engaging in illegal lobbying activities on US soil.
Burton has been noted for his vocal support of Bahrain's monarchy and criticism of protesters during the Bahraini uprising. In April 2012, Burton and his wife took a paid trip to Bahrain to meet with the country's rulers. The $20,966 trip was paid for by the pro-monarchy Bahrain American Council, a non-profit group established by and closely linked to Policy Impact Communications, a lobbying firm founded by William Nixon.
Post-Congressional career.
Azerbaijan America Alliance.
On February 13, 2013, the Azerbaijan America Alliance announced his appointment as Chairman of the group. Burton is listed as Chairman on the organization's web site as well.
Lobbying.
In October 2015, it was reported that Burton registered as a lobbyist on behalf of the Citizens Commission on Human Rights (CCHR), an organization established by the Church of Scientology. CCHR advocates against psychiatry and psychiatric medicine, and is critical of the Food and Drug Administration (FDA). It has been described by critics as a Scientology front group. While not a member of the Church, Burton attended the opening of the Church's national office in 2012 and has praised CCHR's work in the past.
Controversies.
Tainted funds from Pakistan.
In July 2011, Burton was revealed by an FBI investigation to have received tainted election funds ultimately traced to the military intelligence services of Pakistan, apparently as a "quid pro quo" for "supporting to Pakistan's position on Kashmir". These funds were routed via the so-called Kashmiri American Council, run by Syed Ghulam Nabi Fai, later revealed to be a front for the Pakistani Military. Subsequently, Burton's office donated the funds to charity.
Vince Foster murder claims.
Burton led the House inquiry into the 1993 death of Vince Foster, the deputy White House counsel to President Bill Clinton who committed suicide, but who Burton believed was murdered. He urged extensive investigation into the possible involvement of the Clintons and gained attention for re-enacting the alleged crime in his backyard with his own pistol and a canteloupe standing in for Foster's head. In 1998, Burton said of Clinton, "If I could prove 10 percent of what I believe happened [regarding the death of Foster], he'd be gone. This guy's a scumbag. That's why I'm after him."
After hearings into Democratic fundraising (see section below) began, a Democratic National Committee staffer appeared in a pumpkin suit with a button that read, "Don't shoot." Burton's information during the Whitewater controversy was based on research conducted by Floyd Brown, who founded Citizens United in 1988. Due to problems with the quality of Brown's research and testimony, the investigation was closed.
Golfing.
In 1990, "The New York Times" reported that in 1989, Burton had been a "celebrity player" at the Bob Hope Classic in Palm Springs, Calif., the Kemper Open in Potomac, Md., the Larry Bird Golf Classic in Indianapolis, the Danny Thompson Memorial Tournament in Sun Valley, Idaho, the Sugarloaf Invitational tournament in Maine and the Arte Johnson Tournament in Chicago. Such players received free airline flights, free meals, and free lodging from tournament sponsors and, often, free merchandise.
In November 1995, the House voted to prohibit members and their staffs from receiving gifts, including free meals and free travel to charity sports events. Burton, who led the effort to exempt charity trips, said that he played in two golf tournaments each year, and, "We get more of these lobbyists in our office than we do on the golf course."
In January 1997, Burton played in the AT&T Pebble Beach National Pro-Am, at the invitation of AT&T Corporation, the tournament sponsor. The day before the tournament, he played a practice round with Robert E. Allen, AT&T's chairman and chief executive, at a nearby country club. AT&T also hosted a campaign fund-raising dinner for Burton at a local restaurant. Three weeks earlier, Burton had become the chairman of the House Committee on Government Reform and Oversight, which had jurisdiction over the legislative agency scheduled to soon award at least $5 billion in long-distance and local telephone and telecommunications contracts with the federal government. Burton defended his participation in the tournament, saying it would not affect his objectivity when dealing with telecommunications issues. He said that he had partially paid for the trip, with his re-election campaign funds paying as well because he attended three fund-raising events while in California.
In December 2004, Burton and two aides flew to the island of Guam. The trip was paid for by the Guam government and tourism industry. In addition to some official events, including touring a military facility, Burton played in a charity golf tournament. After he returned, he tried to help Guam's tourism industry get a sought-after change in visa rules.
In January 2007, the House passed a measure by a vote 430–1 that banned members from accepting gifts and free trips from lobbyists and discounted trips on private planes. Burton cast the sole nay vote.
In February 2007, a review by the Indianapolis Star of votes in the House of Representatives for the past decade showed that Burton had missed all votes during the Bob Hope Chrysler Classic golf tournament for five years between 2001 and 2007. The tournament, the third event each season on the PGA Tour, pairs celebrities with golf professionals for four of the five days of play. Since 2004, Burton has played in a guest spot of the Eisenhower Medical Center, the primary charitable beneficiary of the event. The slot carries with it a commitment to donate $10,000 to the event; Burton has made arrangements with the hospital to do this over a period of time. Burton's campaign committee reported donating $1,500 to the medical center in December 2004 and $6,353 in January 2006.
The Indianapolis Star review also found that in 2006, Burton ranked last in voting among members of Congress from Indiana, missing 11 percent of the 541 recorded votes. In 2007, the Indianapolis Star rated his voting record as "one of the strongest in the House, with an attendance record consistently above 95%."
"... off the coast of Bolivia".
On March 29, 1995, during congressional hearings on the US War on Drugs, Burton proclaimed that the US military "should place an aircraft carrier off the coast of Bolivia and crop dust the coca fields." It was later pointed out to him that (a) Bolivia is landlocked and has no coast (Burton was chairman of the Western Hemisphere Subcommittee); (b) the Bolivian coca fields (in the yungas and Amazon lowlands) are beyond the reach of any carrier-borne crop-duster, being separated from the nearest coastline (the Pacific coast of Peru and Chile) by the 20,000+ feet high peaks of the Andes; and (c) F-18s cannot crop-dust. While criticism of this misstatement was muted in Washington, it sparked a major anti-American backlash in Bolivia, derailing the same War on Drugs that Burton purported to be speaking for.
Investigation of Democratic Party fund-raising.
In 1997, Burton headed an investigation into possible Democratic Party campaign finance abuse, focusing on the 1996 presidential election. The committee investigation ran for several years and issued over 1,000 subpoenas of Clinton administration officials and cost over $7 million. The committee, and Burton's leadership, were labeled a "farce", a "travesty", a "parody", and "its own cartoon, a joke, and a deserved embarrassment".
In March 1997, as the investigation began, Burton was accused of demanding a $5,000 contribution from a Pakistani lobbyist. The lobbyist said that when he was unable to raise the funds, Burton complained to the Pakistani ambassador and threatened to make sure "none of his friends or colleagues" would meet with the lobbyist or his associates.
In May 1998, Burton apologized for releasing edited transcripts of prison audiotapes of Webster Hubbell, a former associate of President Bill Clinton. The edited transcripts omitted substantial information and differed significantly from the original recordings. Burton was harshly criticized by members of his own party, including Speaker of the House Newt Gingrich, who called the investigation a "circus" and chided Burton for initially refusing to admit any error.
David Bossie, the staff member who arranged the editing and release of the tapes, resigned on Burton's request. Noting that Burton had personally released the tapes and had supported Bossie's plans over the objections of other committee staffers and attorneys, Democrats urged Burton to step down as well. Minority Leader Richard A. Gephardt said, "A committee staff member should not be made the scapegoat for Chairman Burton's mistakes, missteps, and misdeeds." Burton said, "I take responsibility for those mistakes," but never resigned nor faced any consequences for his actions.
In President Clinton's final year in office, Burton was mentioned in a short film for the White House Correspondent's Dinner. "President Clinton: Final Days", which depicted Clinton as a lonely man closing down a nearly-deserted White House. Clinton is shown hitting golf balls from the South Lawn, and gets excited when he hits a car parked in a spot near the U.S. Capitol that says "Reserved for Chairman Burton."
Autism.
Burton has been an outspoken critic of what he terms the failure of government to determine the cause of an alleged autism epidemic. When his grandson began to show the signs of autism shortly after receiving vaccinations, Burton inferred the relationship to be causal: "My only grandson became autistic right before my eyes – shortly after receiving his federally recommended and state-mandated vaccines."
Burton was instrumental in pressuring the National Institutes of Health to launch a five-year, $30 million study of chelation therapy for cardiovascular disease."
In an October 25, 2000, letter to the Department of Health and Human Services, acting in his role as chairman of the House Committee on Government Reform, Burton asked the agency's director to get the Food and Drug Administration (FDA) to recall all vaccines containing the preservative Thimerosal. "We all know and accept that mercury is a neurotoxin, and yet the FDA has failed to recall the 50 vaccines that contain Thimerosal," Burton wrote, adding "Every day that mercury-containing vaccines remain on the market is another day HHS is putting 8,000 children at risk."
The U.S. Centers for Disease Control and Prevention did not agree that vaccines containing mercury caused autism, and the US FDA refused to ban the vaccines. Most manufacturers removed the preservatives from their vaccines anyway, with no resulting decrease in autism rates.
Burton maintained a page on his Congressional website called House.gov "Autism" which includes his speeches, transcripts from hearings, and newspaper articles on the relationship of autism and vaccines.
In a June 2017 episode of Last Week Tonight with John Oliver a C-SPAN 2 clip from 2002 of Dan Burton was used to highlight Burton's position on vaccines in relation to autism. In the clip Burton says, "I have yet to find any scientist who will say that there is no doubt, no doubt, that the mercury in vaccines does not contribute to autism. Now they'll say there's no scientific evidence, there's no studies or anything that proves that yet. But turn that around. There are no studies that disprove it either." John Oliver correctly highlights this as Burton's demand for "proving a negative" which he calls "an impossible standard."
Constituent mailings.
An Arizona newspaper study ranked Burton as the fifth-biggest user of free congressional mail, sending constituents more than $190,000 worth of mail in 2007.
Daughter.
In June 2007, Citizens for Responsibility and Ethics in Washington reported that during the 2001–2006 period, Burton's campaign fund had paid $143,900 to his daughter Danielle Sarkine, who manages his campaign office. It is not illegal for federal candidates to pay family members for political work, as long as they are paid fair market value, the Federal Election Commission has ruled.
Sibel Edmonds testimony.
On January 6, 2008, FBI whistleblower Sibel Edmonds included Dan Burton's photograph among others featured in the "State Secrets Privilege Gallery" posted on her website, composing images of figures considered to be relevant to her case. Later, on August 8, 2009, she gave sworn testimony about Burton and others during a witness deposition before the Ohio Elections Commission in the "Schmidt v. Krikorian" case, in which she stated that he had engaged in "[E]xtremely illegal activities against the United States citizens ... and against the United States' interests" that involved covert operations by foreign governments and entities, but did not further elaborate on these activities, ostensibly due to the limitations applied by the State Secrets Privilege.
ADA.
On October 2, 1989, Representative Dan Burton took to the floor of the house to argue against the Americans with Disabilities Act (ADA). He stated "The ADA is a last ditch attempt of the remorseless sodomy lobby to achieve its national agenda before the impending decimation of AIDS destroys its political clout. Their Bill simply must be stopped. There will be no second chance for normal America if the ADA is passed."
Personal life.
Burton's first wife, Barbara (Logan) Burton, was diagnosed with breast cancer in 1993 at the age of 56. She died in 2002 after battling breast and colon cancer. They had three children together: Kelly, Danielle and Danny.
Affair.
In 1995 speaking of the then recent affairs of Republican Robert Packwood and the unfolding story of Paula Jones and Bill Clinton, Burton stated "No one, regardless of what party they serve, no one, regardless of what branch of government they serve, should be allowed to get away with these alleged sexual improprieties..." A vocal critic of Clinton, he went on to say, "Above all, Dan Burton believes the people have a right to principled leadership and that character does matter..."
Three years later in 1998, the magazine "Vanity Fair" was to print an article detailing an affair which Burton himself had in 1983 which had produced a child. Before publication, Burton was forced to admit to fathering a son with a former state employee out of wedlock on 1983.
Second wife.
In August 2006, Burton married Dr. Samia Tawil in Park City, Utah. She was the internist who cared for Burton's wife, Barbara, during her battle with cancer. Tawil and her first husband had divorced in 2005.
Burton's brother, Woody Burton, is a Republican member of the Indiana House of Representatives, representing District 58.
Burton is a member of the board of advisors of the Institute on Religion and Public Policy. Burton is a 33° Scottish Rite Freemason, and a member of Evergreen-Oriental Lodge No. 500 in Indianapolis, Indiana.


Streptomyces-metKH RNA motif

A "Streptomyces"-"metKH" RNA motif is a conserved RNA structure that was discovered by bioinformatics.
Such motifs are found in the genus "Streptomyces", and are present upstream of either "metK" genes, which encode the S-adenosylmethionine synthetase enzyme or "metH" genes, which encodes the adenosylcobalamin-dependent form of methionine synthase. The RNA structures upstream of "metK" and "metH" genes are distinct from each other, but exhibit overall similar sequence and secondary structure features, suggesting that they are related to one another. Their presence upstream of protein-coding genes, and the fact that the genes perform related steps in metabolism, suggests that the RNAs function as cis-regulatory elements.


AptarGroup

AptarGroup, Inc., also known as Aptar, is a United States-based global manufacturer of consumer dispensing packaging and drug delivery devices. The group has manufacturing operations in 18 countries.
History.
The company began as Werner Die & Stamping in Cary, Illinois, in 1946 and later incorporated as AptarGroup in 1992. Aptar originally developed spray valves and pumps for consumer and household products. The company also later began producing nasal administration and pulmonary drug delivery devices such as nasal spray systems and metered-dose inhaler valves. Biotech and pharmaceutical companies use Aptar's different Unidose and Bidose devices for the single or two-shot intranasal delivery of different medicines.
In 2012, Aptar acquired Stelmi, a manufacturer of elastomer primary packaging components.
In 2016, Aptar announced that it provided the delivery system for Adapt Pharma's Narcan. Narcan is a naloxone hydrochloride nasal spray used as an emergency treatment for opioid overdoses. Aptar's liquid spray drug delivery technology platform works as a ready-to-use, single-shot, unit-dose system for Narcan. It was the first FDA approved nasally administered, ready-to-use medication used to reverse the effects of an opioid overdose. Narcan does not require any assembly, medical training, or needle injection.
Later in 2016, Aptar acquired Mega Airless, a manufacturer of airless packaging solutions. The company also entered into an agreement with Becton Dickinson & Company to develop new self-injection devices.
Aptar entered into an agreement in 2016 with Propeller Health Partners to develop a digitally connected medication inhaler. The company made an investment in Propeller Health Partners (now part of Resmed) in 2018. The same year, Aptar acquired CSP Technologies, a material science company that manufactures active packaging solutions.
In July 2019, the FDA approved Aptar Pharma's Unidose Powder System as the first intranasally-delivered, needle-free rescue treatment for severe hypoglycemia.
In 2020, during the COVID-19 pandemic, Aptar invested in new tools to accelerate its molding equipment and assembly machines for pumps, but it still wasn't enough to keep up with demand.
Sustainability.
Aptar was named to Barron's list of 2019's Top 100 Most Sustainable U.S. Companies.


Rate-zonal centrifugation

Rate-zonal centrifugation is a centrifugation technique employed to effectively separate particles of different sizes. The tube is first filled with different concentrations of sucrose or another solute establishing layers with different densities and viscosities, forming a density gradient, within which the particles to be separated are added. The larger particles will be able to travel to the bottom layer because they are more massive. The greater mass allows the particles to travel through layers with a greater viscosity, while the smaller particles will remain at the top, as they lack the mass to travel through the more viscous layers. Once the centrifugation is over, fractions are collected.


Baek Sung-hee

Doctor Baek Sung-hee (born 1970) is a South Korean scientist specialising in molecular genetics. Her work is focused on the chromatin dynamics and epigenetic regulatory mechanism in cancer. She received her BS, MS, and Ph.D degrees from Seoul National University. Following her postdoctoral research in Michael Rosenfeld’s lab at HHMI and following research assistant professor at HHMI, she joined the faculty of Seoul National University in 2003, and now works as an associate professor. Dr. Baek received numerous awards and honors, including the L’OREAL-UNESCO for Women in Science Award.


Hematopoietic stem cell niche

Many human blood cells, such as red blood cells (RBCs), immune cells, and even platelets all originate from the same progenitor cell, the hematopoietic stem cell (HSC). As these cells are short-lived, there needs to be a steady turnover of new blood cells and the maintenance of an HSC pool. This is broadly termed hematopoiesis. This event requires a special environment, termed the hematopoietic stem cell niche, which provides the protection and signals necessary to carry out the differentiation of cells from HSC progenitors. This niche relocates from the yolk sac to eventually rest in the bone marrow of mammals. Many pathological states can arise from disturbances in this niche environment, highlighting its importance in maintaining hematopoiesis.
Hematopoiesis.
Hematopoiesis involves a series of differentiation steps from one progenitor cell to a more committed cell type, forming the recognizable tree seen in the adjacent diagram. Pluripotent long-term (LT)-HSCs self-renew to maintain the HSC pool, as well as differentiate into short-term (ST)-HSCs. Through various knock-out models, several transcription factors have been found to be essential in this differentiation, such as RUNX1 and TAL1 (also known as SCL).
ST-HSCs can then differentiate into either the common myeloid progenitor (CMP) or the common lymphoid progenitor (CLP). The CLP then goes on to differentiate into more committed lymphoid precursor cells. The CMP can then further differentiate into the megakaryocyte–erythroid progenitor cell (MEP), which goes on to make RBCs and platelets, or the granulocyte/macrophage progenitor (GMP), which gives rise to the granulocytes of the innate immune response. MEP differentiation was found to be contingent upon the transcription factor GATA1, whereas GMP differentiation needs SPI1. When expression of either was inhibited by morpholino in zebrafish, the other lineage programming pathway resulted.
There are 2 types of hematopoiesis that occur in humans:
Historical development of the theory.
The pioneering work of Till and McCulloch in 1961 experimentally confirmed the development of blood cells from a single precursor hematopoietic stem cell (HSC), creating the framework for the field of hematopoiesis to be studied over the following decades. In 1978, after observing that the prototypical colony-forming stem cells were less capable at replacing differentiated cells than bone marrow cells injected into irradiated animals, Schofield proposed that a specialized environment in the bone marrow allows these precursor cells to maintain their cellular reconstitution potential.
During this time, the field exploded with studies aimed at determining the components of the "hematopoietic stem cell niche" that made this possible. Dexter observed that mesenchymal stromal cells could maintain early HSCs "ex vivo", and both Lord and Gong showed that these cells localized to the endosteal margins in long bones. These studies and others supported the idea that bone cells create the HSC niche, and all the research that elucidated this specialized hematopoietic microenvironment stemmed from these landmark studies.
Niche localization through early fetal development.
Yolk sac and the hemangioblast theory.
Despite the vast work done in this field, there is still controversy over the origins of definitive HSCs. Primitive hematopoiesis is first found in the blood islands (Pander's islands) of the yolk sac at E7.5 (embryonic day 7.5) in mice and 30dpc (30 days post-conception) in humans. As the embryo requires rapid oxygenation due to its high mitotic activity, these islands are the main source of red blood cell (RBC) production via fusing endothelial cells (ECs) with the developing embryonic circulation.
The hemangioblast theory, which posits that the RBCs and ECs derive from a common progenitor cell, was developed as researchers observed that receptor knockout mice, such as Flk1-/-, exhibited defective RBC formation and vessel growth. A year later, Choi showed that blast cells derived from embryonic stem (ES) cells displayed common gene expression of both hematopoietic and endothelial precursors. However, Ueno and Weissman provided the earliest contradiction to the hemangioblast theory when they saw that distinct ES cells mixed into a blastocyst resulted in more than 1 ES cell contributing to the majority of the blood islands found in the resultant embryo. Other studies done in zebrafish have more soundly indicated the existence of the hemangioblast. While the hemangioblast theory appears to be generally supported, most of the studies done have been "in vitro", indicating a need for "in vivo" studies to elucidate its existence.
Aorta-gonad-mesonephros region.
Definitive hematopoiesis then occurs later in the aorta-gonad-mesonephros (AGM), a region of embryonic mesoderm that develops into the ventral wall of the dorsal aorta, at E10.5 in mice and 4wpc (4 weeks post-conception) in humans. New HSCs either enter the aortic circulation or remain within the endothelium. While Notch 1 has been found to stimulate aortic HSC production, Runx1 overexpression in the zebrafish mutant "mindbomb" that lacks Notch signaling rescues HSC production, suggesting Runx1 is downstream of Notch1. Hedgehog signaling is also required for HSC production in the AGM. ECs located in this niche have been found to support new HSCs through the upregulation of factors such as p57 and IGF2. The relocalization of hemogenic endothelium coincides with the migration of distinct endothelial precursors to the AGM.
Niche relocation through late fetal development.
Placenta and the fetal liver.
Hematopoiesis then moves from the AGM to the placenta and fetal liver at E11.5 in mice and 5wpc in humans. While the engraftment of HSCs at these sites are still being elucidated, the interaction between the chemokine CXCL12 expressed by stromal cells and its receptor CXCR4 expressed on HSCs has been proposed as one mechanism. In addition, the cytokine-receptor binding of SCF and KIT have been recognized for its importance in HSC function and amplification of the chemotactic induction of CXCL12.
Additional factors that are important in HSC migration during this period are Integrins, N-cadherin, and Osteopontin that can stimulate Wnt signaling in HSCs. Transcription factors such as PITX2 must be expressed in stromal cells to support normal HSC function. Like with the AGM, the relocation of fetal liver HSCs coincides with the differentiation of functional units, in this case hepatoblasts to hepatocytes. Mice have also shown hematopoietic activity in the umbilical arteries and the allantois, in which HSCs and endothelial cells are colocalized.
Bone marrow.
Hematopoiesis then moves to the bone marrow at E18 in mice and 12wpc in humans, where it will reside permanently for the remainder of the individual's lifetime. In mice, there is a shift from the fetal liver to the spleen at E14, where it persists for many weeks postnatally while it occurs simultaneously in the bone marrow. This relocalization is thought to be supported by the development of osteoblast and chondrocyte precursor cells capable of forming an HSC niche. In addition to the previously mentioned signals that induce HSC migration, TIE2-angiopoietin and CD44-E-cadherin binding appears to be important for this event to occur, as well as for the retention of these HSCs once they are in the bone marrow.
HSCs in the bone marrow do not show the same characteristics as those in other niches. HSCs in fetal liver display increased cell divisions, whereas adult bone marrow HSCs are mostly quiescent. This difference stems, in part, from signaling discrepancies in the two niches. Sox17 has been identified as crucial for the generation of fetal, but not adult, HSCs. Inactivation of Runx1 in adult HSCs does not impair function, but rather prevents the differentiation of specific lineages. Differences such as these in the reactivity of HSCs from different niches suggests that the signaling found there is not the same.
Composition of the bone marrow niche.
In addition to the cytokines and cell signaling molecules mentioned above, the HSC niche in the bone marrow provides soluble factors, forces, and cell-mediated interactions necessary to maintain the hematopoietic potential of the stem cells located there. This niche is generally separated into 2 sections:
Acellular factors.
Recent studies have used hypoxic-staining dyes, such as Hoechst stain, to show that quiescent LT-HSCs and osteoblasts are found in hypoxic and poorly perfused areas of the bone marrow, while ECs and MSCs were found in well-perfused areas. However, this hypoxia may be only caused in part by the niche environment, and the HSCs themselves may be maintaining their hypoxic environment in order to remain quiescent. This oxygen tension upregulates HIF1A, which shifts energy production to glycolysis, allowing for the cell to survive in oxygen-poor surroundings. Indeed, deletion of HIF1A increases HSC proliferation and eventually depletes the LT-HSC storage pool. This suggests that the hypoxic environment of the bone marrow, partially determined by the distance from the sinusoids of the perivascular niche, maintains the quiescent state of LT-HSCs in an effort to retain stem cells with differentiation potential.
It has also been found that calcium ions can act as chemotactic signals to HSCs via the G protein–coupled receptor (GPCR) calcium-sensing receptor (CaSR). CaSR knockout mice have shown hematopoietic cells in the circulation and spleen, but few in the bone marrow, indicating this receptor's importance in this particular niche. Conversely, stimulation of HSC CaSR via its agonist cinacalcet increases migration and engraftment of these cells in the bone marrow. Finally, osteoclast inhibition by the bisphosphonate alendronate has correlated with decreased HSCs and bone marrow engraftment. Taken together, these results suggest that the high calcium ion concentration found in the endosteal niche due to osteoclast activity acts as a homing signal to HSCs for engraftment into the bone marrow via the CaSR.
Thirdly, the shearing forces experienced by HSCs from circulating cells has been suggested to play a role in hematopoietic activation. Fetal HSCs in the AGM have shown upregulated Runx1 in response to these forces, which would result in significant hematopoietic regulation in these cells. Despite the differences between the AGM and bone marrow, both are subjected to the circulation, and it is entirely possible that these same forces exist in this adult stem cell niche. Other characteristics, such as strain, geometry, and ligand profiles of the extracellular matrix (ECM) have been suggested as important in the maintenance of stem cell potential in these niches. Finally, the elasticity modulus of the ECM, partially provided by MSCs in the bone marrow, has been shown to direct the differentiation and activity of stem cells nearby. The landscape of the HSC niche in the bone marrow is constantly changing, and the acellular factors, as much as the cellular factors, are beginning to reveal the complexity of hematopoietic regulation.
Cellular factors.
Osteoblasts, bone-forming cells, interact with HSCs and provide proliferative signals. Studies that have increased or decreased osteoblasts have shown a similar increase or decrease, respectively, in the number of HSCs. Coculturing endosteal cells with HSCs was also found to be sufficient in maintaining their differentiation potential long-term, presumably through the secretion of the cell signaling molecules previously mentioned. These HSCs that interact with the endosteal osteoblasts display a quiescent phenotype, as shown in both "ex vivo" and "in vivo" imaging studies, whereas HSCs that are more actively dividing show less interaction. These results of less active HSCs interacting with the endosteal niche agree with previous results looking at the activity state of HSCs throughout the bone marrow.
In addition to osteoblasts, HSCs interact with many mesenchymal cells as they make their way to the sinusoids in the perivascular niche. Removal of nestin-expressing MSCs has shown a significant decrease in LT-HSCs. These cells secrete high levels of CXCL12 and closely associate with sympathetic nerves that influence cytokine-induced migration of HSCs. Similar to these cells, CAR cells have correlated with reduced HSCs and LT-HSC activity when ablated. One difference between these cell types, despite the similarity in function, is that CAR cells may be found in both endosteal and perivascular niches, while nestin-positive MSCs are found exclusively in the perivascular niche.
Finally, both ECs and adipocytes have been suggested to influence HSC activity in the bone marrow. Studies using antibody-mediated disruption of the VEGF receptors on ECs correlated with poor engraftment of donor cells. HUVECs, or endothelial cells isolated from umbilical veins, that were programmed via viral gene manipulation to signal through the Notch and Angiopoietin pathways were found to support and maintain LT-HSCs. Despite the difficulty in isolating sinusoidal ECs, experimental evidence suggests that these cells may play a role in regulating HSCs. Current research suggests that adipocytes in the bone marrow negatively regulate HSC activity. HSCs isolated from adipocyte-rich vertebrae displayed decreased activity. In addition, isolation of adipocyte-containing stromal cells have shown adipocyte inhibition of the ability of HSCs to proliferate and form hematopoietic colonies.
Dysregulation.
Cancer.
Of the many transcriptional regulators of hematopoiesis, nearly all induce leukemia when aberrant. Chromosomal translocation is a hallmark of leukemia, and "TAL1"-induced translocation deregulates expression at the locus, while "RUNX1"-induced translocation results in chimeric fusion proteins. These chimeric transcription factors can result in the improper repression or activation of the target gene, as well as the inappropriate recruitment of chromatin-modifying enzymes. "PAX5" and Notch mutations can result in B-cell and T-cell leukemias, respectively. Dysregulation of stromal cells can in some cases induce genetic lesions in hematopoietic compartment; for example, mutations in the osteoblastic lineage cells resulted in malignant hematopoiesis. Osteoblasts may also be dysregulated by the presence of solid tumors (outside the bone marrow); one study showed that mouse lung tumors increased osteoblast activity and numbers and that these cells were important to the outgrowth of the tumor in the lung via the production of tumor-infiltrating neutrophils.
Inflammation.
Osteoblasts may be involved in other inflammatory systemic diseases, which is supported by studies using mouse models of sepsis. Mesenchymal cells' response to β-adrenergic stimulation is altered in diabetes, which impairs G-CSF-induced HSCP mobilization. Diabetes influences bone marrow endothelium, which may alter myeloid leukocyte generation. This may be relevant for diabetes-associated morbidities such as atherosclerosis.


MMP7

Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the "MMP7" gene. The enzyme () has also been known as "matrin", "putative (or punctuated) metalloproteinase-1", "matrix metalloproteinase pump 1", "PUMP-1 proteinase", "PUMP", "metalloproteinase pump-1", "putative metalloproteinase", "MMP").
Matrilysin was discovered by Sellers and Woessner in the uterus of the rat in 1988. The complementary DNA (cDNA) of human MMP7 was isolated in 1988 by Muller et al. MMP7 is a member of the matrix metalloproteinase (MMP) family consisting of structural-related zinc-dependent endopeptidases. The primary role of cleaved/activated MMP7 is to break down extracellular matrix by degrading macromolecules including casein, type I, II, IV, and V gelatins, fibronectin, and proteoglycan.
Gene, regulation, and expression.
The human MMP7 is located on chromosome 11 q22.3. "MMP" genes are clustered in q region of human Chromosome 11 including "matrilysin, collagenase-1, stromelysin1, stromelysin-2, and metalloelastase" genes. It consists of 267 amino acids. The cDNA of MMP7 is 49% homologous to stromelysin-1. Comparing to other members of MMP family, MMP7 does not have a C-terminal protein domain.
The promoter of the human MMP7 contains a TATA box, an activator protein 1 (AP-1) site, and two inverted polyomavirus enhancer A-binding proteins 2 (PEA-3). The AP-1/PEA-3 binding motif is required and essential for MMP7 to be responsive to growth factors, oncogenes and phorbol ester. Also, the PEA and AP-1 are required for Matrilysin/CAT reporter constructs induced by tumor promoter 12-O-tetradecanoulphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In addition, the high level expression of AP-1 and its binding proteins were found to be associated with mutant Ki-Ras suggesting the high expression of matrilysin in Ras activated cells is AP-1 dependent.
The expression of MMP7 is regulated by the Wnt/ β catenin signaling pathway, and mediated by transformation growth factor β (TGF-β).TGF-β stimulates ECM and suppresses the steady-state level of MMP7, stromelysin mRNAs, and secretion of zymogens. The isoforms of TGF-β inhibit MMP7 mRNA and protein in the human endometrium via progesterone mediated pathway. However, the opposite effects of TGF-β on MMP7 were observed among transformed cells. In human glioma cell lines and human squamous cell carcinoma cell line II-4, TGF-β stimulates the expression of MMP7 mRNA and proteins, and facilities the invasive behavior of cells.
The promoter region of the human MMP7 gene contains two or more sites that are homologous to the NR-IL6 binding sequences indicating MMP7 can bind to IL-1 and IL-6. In addition, the level of MMP7 mRNA is elevated followed the treatment of tumor necrosis factor α (TNF- α) and IL-1 β in human mesangial cells.
MMP7 are commonly expressed in epithelial cells including ductal epithelium of exocrine glands in skin, salivary glands, pancreas, glandular epithelium of intestine and reproductive organ, liver, and breast. In addition, MMP7 is highly expressed in the luminal surface of dysplastic glands in human colorectal cancers.
Structure.
A MMP7 protein is bounded by four metal ions including a catalytic zinc ion, a structural zinc ion, and two calcium ions. The catalytic zinc ion binds to three His residues in the HEXGHXXGXXH region in tetracoordination. The calcium ion binding play important role in stabilizing the secondary structure. MMP7 has a shallow hydrophobic substrate-binding pocket. In contrast to MMP9 which has the longest hinge, MMP7 lacks hemopexin and does not have a hinge. Instead, MMP7 contains a variable C-terminal hemopexin-like domain facilitates substrate specificity. The protein of MMP7 is secreted as zymogen. The prodoamin of MMP7 contains an approximately 9 kD highly conserved “cysteine switch” PRCGXPD sequence near the C-terminal containing cysteine residues. Cysteine residues bind to the catalytic zinc keeping the protein latent. The dissociation of cysteine –Zinc coordination starts from the cleavage of the first 30 amino acids of the prodomain, which leads to a conformation change, and further results in autoproteolysis and the cleavage of the whole prodomain at Glu-Tyr site. According to Woessner et al., the Mr of MMP7 is 28,000 for the latent form and 19,000 Mr for the active form after the cleavage of its prodomain.
Interactions.
Promatrilysin (Pro-MMP7) is converted from the latent form to the active form by endoproteinases, and plasmin. Plasmin cleaves at the site recognizable to trypsin, is considered as the most possible physiological activator. In vitro, plasmin can activate pro-MMP7 to 50% of its full activity. Also, researchers used activated recombinant pro-MMP7 and purified substrates to investigate the proteolytic activity of MMp7 in vitro, and found that MMP7 cleaves many protein substrates mainly including ECM components, proMMPs, and nonmatrix proteins. MMP7 cleaves the glycoprotein entactin that links laminin and collagen IV at about 100-600 times faster than collagenase-1. In addition, MMP7 can activate other MMPs. Activated MMP7 and APMA can increase the activity of collagenase-1, and MMP7 can also convert the latent progelatinase A to its active form.
Function.
Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades proteoglycans, fibronectin, elastin and casein and differs from most MMP family members in that it lacks a conserved C-terminal protein domain. The enzyme is involved in wound healing, and studies in mice suggest that it regulates the activity of defensins in intestinal mucosa.
MMP7 was initially characterized by Woessner et al. It digests components of the extracellular matrix, cleaves the α 2 (I) chain of gelatin more rapidly, and digests the B chain of insulin at Ala14-Leu and Tyr16-Leu, and has no action on collagen types I, II, IV, V. The optimal pH of MMP7 is at 7 and the pI is at 5.9. MMP4 is inhibited by α 2-macroglobulin and TIMP. The inhibition of MMP7 activity commonly relies on metal-chelating agents including EDTA and 1,10-phenanthroline, especially zinc chelation. Therefore, the selectivity of MMP7 inhibition is challenging since almost all members of MMPs family contain catalytic domains with zinc binding sites. TIMP-1 and 2 noncovalently bound to active MMP7 at the catalytic site inhibiting MMP7 activity. The activated MMP7 can also cleave the propeptides of proMMP2 and proMMP9 to facilitate tumor invasion.
Normal tissue development.
Quondamatteo et al. immunohistochemically stained MMP7, and localized MMP7 in early human liver development. They reported that MMP7 was presented in some hepatocytes and endothelial cells in the 6th gestational week, and only hematopoietic cells remained after that time.
Tissue remodeling.
In order for MMPs to escape TIMP inhibition, active MMP7s are recruited to the plasma membrane of epithelium inducing membrane-associated growth factors processing for epithelial repair and proliferation. In human endometrium, the expression of MMP7 mRNA increases at menstruation and remains high during the proliferative phase. Also, MMP-7 binds to the plasma membrane of epithelium containing cholesterol-rich domain. The bounded MMP7 is active and resistant to TIMP inhibition. It promotes the activity of the epithelial plasma membrane and associated substrates including E-cadherin, β4-integrin, TNF-alpha, RAS, heparin-binding EGF, IGF binding proteins and plasminogen. Further, this process promotes epithelial cell migration, proliferation and apoptosis. For menstruation, it promotes the endometrium regeneration after menstrual breakdown. Huang et al. reported that the proteolytic activity of MMP7 plays major role in tissue remodeling in biliary atresia-associated liver fibrosis.
Clinical significance.
MMP7 cleaves collagen III/IV/V/IX/X/XI and proteoglycan indicating that MMP inhibitors can potentially be used in therapies that are involved in inhibition of tissue degradation, remodeling, anti-angiogenesis and inhibition of tumor invasion.
Role in Cancer.
MMP7 is found to potentially be involved in tumor metastasis and inflammatory processes. The upregulation of MMP7 is associated with many malignant tumors including esophagus, stomach, colon, liver, pancreas, and renal cell carcinomas. High MMP7 expression facilitates cancer invasion and angiogenesis by degrading extracellular matrix macromolecules and connective tissues. These degradations are associated with many mechanisms including embryogenesis, postpartum uterine involution, tissue repair, angiogenesis, bone remodeling, arthritis, decubitus ulcer, and tumor metastasis/invasion. Activated MMP7 activates MMP2 and MMP9 zymogens, and mediates the proteolytic process of the precursors of tumor necrosis factors and urokinase plasminogen activators.
Colon cancer and MMP7 expression.
MMP7 cleaves cell surface proteins, promotes adhesion of cancer cells, and increases the potential of tumor metastasis. Higashi et al. reported that the binding of MMP7 to cholesterol sulfate on the cell surface plays a critical role in the cell membrane-related proteolytic action. Also, the internal Ile 29, Arg33, Arg51, and Trp 55 and 171-173 residues at MMP7 C-terminal located on the opposite side of the catalytic site of MMP7 are required for cholesterol sulfate binding. Wild type MMP7 can digest fibronectin, but mutant MMP7 fails to induce the aggregation of colon cancer cells. In addition, Qasim et al. reported that MMP7 is highly expressed in advanced colorectal adenomatous polys with severe dysplasia. Further, MMP7 is involved in converting colorectal adenomas into malignant state and facilitating the growth.


NADPH peroxidase

In enzymology, a NADPH peroxidase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are NADPH, H+, and H2O2, whereas its two products are NADP+ and H2O.
This enzyme belongs to the family of oxidoreductases, specifically those acting on a peroxide as acceptor (peroxidases). The systematic name of this enzyme class is NADPH:hydrogen-peroxide oxidoreductase. Other names in common use include TPNH peroxidase, NADP peroxidase, nicotinamide adenine dinucleotide phosphate peroxidase, TPN peroxidase, triphosphopyridine nucleotide peroxidase, and NADPH2 peroxidase.