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ZEB2 Zinc finger E-box-binding homeobox 2 is a protein that in humans is encoded by the ZEB2 gene.The ZEB2 protein is a transcription factor that plays a role in the transforming growth factor β (TGFβ) signaling pathways that are essential during early fetal development. # Function ZEB2 (previously also known as SMADIP1, SIP1) and its mammalian paralog ZEB1 belongs to the Zeb family within the ZF (zinc finger) class of homeodomain transcription factors.ZEB2 protein has 8 zinc fingers and 1 homeodomain.The structure of the homeodomain shown on the right. ZEB2 interacts with receptor-mediated, activated full-length SMADs.The activation of TGFβ receptors brings about the phosphorylation of intracellular effector molecules, R-SMADs.ZEB2 is an R-SMAD-binding protein and acts as a transcriptional corepressor. ZEB2 transcripts are found in tissues differentiated from the neural crest such as the cranial nerve ganglia, dorsal root ganglia, sympathetic ganglionic chains, the enteric nervous system and melanocytes.ZEB2 is also found in tissues that are not derived from the neural crest, including the wall of the digestive tract, kidneys, and skeletal muscles. # Clinical significance Mutations in the ZEB2 gene are associated with the Mowat–Wilson syndrome.This disease exhibits mutations and even complete deletions of the ZEB2 gene.Mutations of the gene can cause the gene to produce nonfunctional ZEB2 proteins or inactivate the function gene as a whole.These deficits of ZEB2 protein interferes with the development of many organs.Many of the symptoms can be explained by the irregular development of the structures from the neural crest. Hirschsprung's disease also has many symptoms that can be explained by lack of ZEB2 during development of the digestive tract nerves.This disease causes severe constipation and enlargement of the colon.

ZIC2 Zinc finger protein ZIC2 is a protein that in humans is encoded by the ZIC2 gene.ZIC2 is a member of the Zinc finger of the cerebellum (ZIC) protein family. # Function ZIC2 is classified as a ZIC protein due to conservation of the five C2H2 zinc fingers, which enables the protein to interact with DNA and proteins. # Clinical significance Correct function of these proteins is critical for early development, and as such mutations of the genes encoding these proteins is known to result in various congenital defects.For example, mutation of ZIC2 is known to result in holoprosencephaly due to defect in the function of the organizer region (node), which leads to a defective anterior notochord (ANC).The ANC provides a maintenance signal to the Prechordal plate (PCP), thus a defective ANC results in degradation of the PCP, which is normally responsible for sending a shh signal to the developing forebrain resulting in the formation of the two hemispheres. Holoprosencephaly is the most common structural anomaly of the human forebrain. Recently ZIC2 has also been shown to be critical for establishment of the left-right axis, thus loss of ZIC2 function can result in defects in heart formation.Another member of the ZIC family, ZIC3, has previously been linked to establishment of the left-right axis. A polyhistidine tract polymorphism in this gene may be associated with increased risk of neural tube defects (spina bifida).This gene is closely linked to a gene encoding ZIC5, a related family member on chromosome 13. # Interactions ZIC2 has recently been found to interact with TCF7L2, enabling it to act as a Wnt/β-catenin signalling inhibitor.Such a role is of critical importance, as not only is correct Wnt signalling critical for early development, Wnt signalling has also been found to be upregulated to several cancers.ZIC2 has also been shown to interact with GLI3.

ZIC3 ZIC3 is a member of the Zinc finger of the cerebellum (ZIC) protein family. ZIC3 is classified as a ZIC protein due to conservation of the five C2H2 zinc fingers, which enables the protein to interact with DNA and proteins.Correct function of this protein family in critical for early development, and as such mutations of the genes encoding these proteins is known to result in various congenital defects.For example, mutation of ZIC3 is associated with heterotaxy, that is thought to occur due to the role of ZIC3 in initial left-right symmetry formation, which involves the maintaining redistributed Nodal after the asymmetry of the embryo is initially broken.Mutation of ZIC3 is also associated with various heart defects, such as heart looping, however these are thought to represent a mild form of heterotaxy.Mouse based studies have linked defective ZIC3 with neural tube defects (spina bifida) and skeletal defects. ZIC3 is also of particular interest as it has been shown to be required for maintenance of embryonic stem cell pluripotency. # Involvement in Wnt signalling ZIC2, another member of the ZIC family, has recently been found to interact with TCF7L2, enabling it to act as a Wnt/β-catenin signalling inhibitor.Further experiments have indicated that human ZIC3 is also able to inhibit Wnt signalling and that the Zinc finger domains are absolutely critical for this role.Such a role is of critical importance, as not only is correct Wnt signalling critical for early development, Wnt signalling has also been found to be upregulated to several cancers.

ZIP9 Zinc transporter ZIP9 also known as Zrt- and Irt-like protein 9 (ZIP9) and solute carrier family 39 member 9 (SLC39A9) is a protein that in humans is encoded by the SLC39A9 gene.This protein is the 9th member out of 14 ZIP family proteins, which is a membrane androgen receptor (mAR) coupled to G proteins, and also classified as a zinc transporter protein.ZIP family proteins transport zinc metal from the extracellular environment into cells through cell membrane. # Classification and nomenclature Mammalian cells have two major groups of zinc transporter proteins; the ones that export zinc from the cytoplasm to the extracellular space (efflux), which are called ZnT (SLC30 family) , and ZIP (SLC39 family) proteins whose functions are in the opposite direction (influx).ZIP family proteins are named as Zrt- and Irt-like proteins because of their similarities to Zrt and Irt proteins which are respectively zinc and iron -regulated transporter proteins in yeast and Arabidopsis that were discovered earlier than ZIP and ZnT proteins.ZIP family is consisted of four subfamilies (I, II, LIV-1, and gufA), and ZIP9 is the only member of subfamily I. # Isoforms ZIP9 can be present as 3 different isoforms in human cells.The canonical isoform of this protein has a length of 307 amino acids, with a molecular mass of 32,251Da.In the second isoform, amino acids 135-157 are missing, so its length and molecular weight are respectively reduced to 284 amino acids and 29,931Da.In the third isoform the amino acids 233-307 are missing, so the isoform only has 232 amino acids and its molecular mass is 24,626 Da.Additionally, the last amino acid of isoform 3, which is usually serine, is replaced with aspartic acid. # Discovery ZIP9 membrane androgen receptor was first discovered in Atlantic croaker (Micropogonias undulatus) brain, ovary and testicular tissues and named "AR2" in 1999, together with another androgen receptor which was found only in brain tissue, and it was named "AR1" in that time.AR1 and AR2 were first thought to be nuclear androgen receptors (nAR), however, further studies on their biochemical and functional features in 2003 illustrated that they were involved in non-genomic mechanisms in the plasma membrane of the cells and were membrane androgen receptors.In 2005, the similarities between the nucleotide and amino acid sequences of AR2 and ZIP family proteins were discovered in other vertebrates, suggesting that AR2 is from this family of proteins.A study in 2014 utilised the latest research technologies to clone and express a particular cDNA of the female Atlantic croaker ovaries, which encoded a protein showing the characteristics of the canonical isoform of ZIP9, as a novel membrane androgen receptor(mAR). # Structure Unlike other ZIP subfamilies that are consisted of 8 transmembrane (TM) domains with an extracellular C-terminal, ZIP9 is consisted of a 7 TM structure with an intracellular C-terminus.ZIP9 is shorter than other ZIP proteins, and only has about 307 amino acids within its structure, however, like other ZIP proteins, between its domains III and IV, within the intracellular loop, it contains histidine-rich clusters.ZIP9 and other ZIP proteins have polar or charged amino acids in their TM domains which probably play important roles in making ion transfer channels and therefore in importing zinc ions into cytoplasm. # Location, expression and function ZIP9 influxes zinc ions into the cytosol and its gene is expressed almost in every tissue of human body.The sub-cellular location of ZIP9 is in plasma, nucleus, endoplasmic reticulum and mitochondrial membrane.One of the responsibilities of ZIP9 is the homeostasis of zinc in the secretory pathway, during which this protein stays within the Trans Golgi Network regardless of the change in the concentrations of zinc. ZIP9 is the only ZIP protein that signals through G protein binding, and pharmaceutical agents decrease its ligand binding once ZIP9 is uncoupled from G proteins.ZIP9 is also the only member of ZIP family with mAR characteristics. # Ligands Testosterone has high affinity for ZIP9 with a Kd of 14 nM and acts as an agonist of the receptor.In contrast, the other endogenous androgens dihydrotestosterone (DHT) and androstenedione show low affinity for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating the receptor at sufficiently high concentrations.Moreover, the synthetic androgens mibolerone and metribolone (R-1881), the endogenous androgen 11-ketotestoterone, and the other steroid hormones estradiol and cortisol are all ineffective competitors for the receptor.Since mibolerone and metribolone bind to and activate the nuclear androgen receptor (AR) but not ZIP9, they could potentially be employed to differentiate between AR- and ZIP9-mediated responses of testosterone.The nonsteroidal antiandrogen bicalutamide has been identified as an antagonist of ZIP9. # Clinical significance Zinc homeostasis is very important in human health, because zinc is present in the structure of some proteins like zinc-dependent metalloenzymes and zinc-finger-containing transcriptional factors.In addition, zinc is involved in signalling for cell growth, proliferation, division and apoptosis.As a result, any dysfunction of zinc transporter proteins can be harmful for the cells, and some of them are associated with different cancers, diabetes and inflammation. For instance, through activation of ZIP9, testosterone has been found to increase intracellular zinc levels in breast cancer, prostate cancer, and ovarian follicle cells and to induce apoptosis in these cells, an action which may be mediated partially or fully by increased zinc concentrations. ## Gene mutations Mutations in the SLC39A9 gene can occur due to genetic deletion of the q24.1-24.3 band of base pairs within the human chromosome 14.This interstitial deletion mutation deletes the SLC39A9 gene along with 18 other genes found close to the SLC39A9 gene on chromosome 14 Although specific gene associated diseases have not been determined, the deletion of this band causes diseases such as congenital heart defects, mild intellectual disability, brachydactyly, and all patients with band deletion had hypertelorism and a broad nasal bridge.Patient specific clinical issues included ectopic organs, undescended testes, also called cryptorchidism, and malrotation of the small intestine. Deletion mutation involving the SLC39A9 gene has also been reported in 23 cases of patients with circulation related cancers such as B-cell lymphoma and B-cell chronic lymphocytic leukaemia (CLL). Chimeric genes are a result of faulty DNA replication, and arise when two or more coding sequences of the same or different chromosome combine in order to produce a single new gene.SLC39A9 forms a chimeric gene product with a gene called PLEKHD1, that codes for an intracellular protein found within the cerebellum.A study done in Seattle, USA, established the presence of the fusion protein product of the SLC39A9-PLEKHD1 gene to be present in 124 cases of schizophrenia and was closely related to the pathophysiology of disease.The fusion protein had features from both the parent genes and also possessed the ability to interact with cellular signalling pathways involving kinases such as Akt and Erk, leading to their increased phosphorylation within the brain and a consequent onset of schizophrenia. SLC39A9 gene also forms a fusion transcript with another gene called MAP3K9, that encodes for MAP3 kinase enzyme.This SLC39A9-MAP3K9 fusion gene has a repetitive occurrence in breast cancers, demonstrated by a study done on 120 primary breast cancer samples from Korean women in 2015. ## Cancer ### Breast and prostate A study in 2014, elucidated the intermediary role of ZIP9 in causing human breast and prostate cancer, as it induced the apoptosis of testosterone in breast and prostate cancerous cells.unlike ZIP1, 2 and 3, ZIP9 mRNA expression was increased in human prostate and breast malignant biopsy cancer cells, which probably was because cells that divide rapidly require more zinc. ### Brain Treatment of glioblastoma cells with TPEN showed that upregulation of ZIP9 in glioblastoma cells enhances cell migration in brain cancer by influencing P53 and GSK-3ß, and also ERK and AKT signalling pathways in phosphorylation after activation of B-cell receptors. ## Diabetes Zinc must be constantly supplied to Pancreatic β-cells to function normally and maintain glycaemic control.The insulin secretory pathway in humans is highly dependent on zinc activities.The cells lose many zinc ions during the secretion of insulin, and need to receive more zinc, and expression of ZIP9 mRNA during this process increases.As a result, ZIP9, which is involved in importing zinc into the cells, is potentially a target for therapeutic studies in the future regarding diabetes type2.

ZW10 Centromere/kinetochore protein zw10 homolog is a protein that in humans is encoded by the ZW10 gene.This gene encodes a protein that is one of many involved in mechanisms to ensure proper chromosome segregation during cell division.The encoded protein binds to centromeres during the prophase, metaphase, and early anaphase cell division stages and to kinetochore microtubules during metaphase. # Function Zeste white 10 (ZW10) was initially identified as a mitotic checkpoint protein involved in chromosome segregation, and then implicated in targeting cytoplasmic dynein and dynactin to mitotic kinetochores, but it is also important in non-dividing cells.These include cytoplasmic dynein targeting to Golgi and other membranes, and SNARE-mediated ER-Golgi trafficking.Dominant-negative ZW10, anti-ZW10 antibody, and ZW10 RNA interference (RNAi) cause Golgi dispersal.ZW10 RNAi also disperse endosomes and lysosomes. Drosophila kinetochore components Rough deal (Rod) and Zw10 are required for the proper functioning of the metaphase checkpoint in flies.The eukaryotic spindle assembly checkpoint (SAC) monitors microtubule attachment to kinetochores and prevents anaphase onset until all kinetochores are aligned on the metaphase plate.It is an essential surveillance mechanism that ensures high fidelity chromosome segregation during mitosis.In higher eukaryotes, cytoplasmic dynein is involved in silencing the SAC by removing the checkpoint proteins Mad2 and the Rod-Zw10-Zwilch complex (RZZ) from aligned kinetochores. # Interactions ZW10 has been shown to interact with RINT1

ZZZ3 ZZ-type zinc finger-containing protein 3 is a protein that in humans is encoded by the ZZZ3 gene. # Model organisms Model organisms have been used in the study of ZZZ3 function.A conditional knockout mouse line, called Zzz3tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.Twenty four tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning.The remaining tests were carried out on heterozygous mutant adult mice and no further abnormal phenotypes were identified.

Ziac Synonyms / Brand Names: Bisoprolol Fumarate, Bisoprolol fumerate, Bisoprolol Hemifumarate, Cardicor, Concor, Condyline, Detensiel, Emconcor, Emcor, Euradal, Isoten, Monocor, Soloc, Soprol, Zebeta # Dosing and Administration Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 to 40 mg, while hydrochlorothiazide is effective in doses of 12.5 to 50 mg.In clinical trials of bisoprolol/hydrochlorothiazide combination therapy using bisoprolol doses of 2.5 to 20 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing doses of either component. FDA Package Insert Resources Indications, Contraindications, Side Effects, Drug Interactions, etc. Calculate Creatine Clearance On line calculator of your patients Cr Cl by a variety of formulas. Convert pounds to Kilograms On line calculator of your patients weight in pounds to Kg for dosing estimates. Publication Resources Recent articles, WikiDoc State of the Art Review, Textbook Information Trial Resources Ongoing Trials, Trial Results Guidelines & Evidence Based Medicine Resources US National Guidelines, Cochrane Collaboration, etc. Media Resources Slides, Video, Images, MP3, Podcasts, etc. Patient Resources Discussion Groups, Handouts, Blogs, News, etc. International Resources en Español # FDA Package Insert Resources Indications Contraindications Side Effects Drug Interactions Precautions Overdose Instructions for Administration How Supplied Pharmacokinetics and Molecular Data FDA label FDA on Ziac Return to top # Publication Resources Most Recent Articles on Ziac Review Articles on Ziac Articles on Ziac in N Eng J Med, Lancet, BMJ WikiDoc State of the Art Review Textbook Information on Ziac Return to top # Trial Resources Ongoing Trials with Ziac at Clinical Trials.gov Trial Results with Ziac Return to top # Guidelines & Evidence Based Medicine Resources US National Guidelines Clearinghouse on Ziac Cochrane Collaboration on Ziac Cost Effectiveness of Ziac Return to top # Media Resources Powerpoint Slides on Ziac Images of Ziac Podcasts & MP3s on Ziac Videos on Ziac Return to top # Patient Resources Patient Information from National Library of Medicine Patient Resources on Ziac Discussion Groups on Ziac Patient Handouts on Ziac Blogs on Ziac Ziac in the News Ziac in the Marketplace Return to top # International Resources Ziac en Español Return to top Adapted from the FDA Package Insert.

Élan Élan Corporation plc (Template:Nyse, Template:Lse) is a major drugs firm based in Athlone, County Westmeath, Ireland which has major interests in the United States.In the late 1990's its value on the Irish Stock Exchange reached over €20bn.It has secondary listings on the London Stock Exchange and the New York Stock Exchange.It was one of Ireland's major business success stories.However in the early years of 2000's an accounting scandal and investor reactions to the global slump, caused a major devaluation resulting in a share price slump of over 90%.Since then the company has regained its growth path under the reign of a new American CEO Kelly Martin.Élan employs over 2,000 people worldwide.It is listed on the New York Stock Exchange as ELN, the Irish Stock Exchange as ELN.I, and the London Stock Exchange as ELN.L. Reformulations for client-based projects has contributed to more than $9 billion in in-market sales for these clients.Currently more than 2.5 million patients take Élan's products worldwide. # Products in development In neurology, Élan is focused on building upon its breakthrough research and extensive experience in the area of neuropathology-related disorders such as Alzheimer’s disease, where the company’s efforts include programs focused on small molecule inhibitors of beta secretase and gamma secretase, enzymes whose actions are thought to affect the accumulation of the amyloid plaques found in the brains of patients with Alzheimer’s disease.Élan is also studying other neurodegenerative diseases, such as Parkinson's disease.Élan, in collaboration with Wyeth, initiated a Phase II clinical trial for an experimental humanized monoclonal antibody with a targeted indication of immunotherapeutic treatment of mild to moderate Alzheimer’s disease.The humanized monoclonal antibody is designed and engineered to clear the neurotoxic beta-amyloid peptide that accumulates in the brains of patients with Alzheimer’s disease.Élan is hopeful that its drug "aab-001" (now known as bapineuzumab) is doing well in trials as the first results are due in 2006. In autoimmune diseases, Élan’s primary emphasis is studying cell trafficking to discover ways to provide disease-modifying therapies for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.Research efforts are also focused on physiological and neuropathic pain. ## Natalizumab/Tysabri Previously named Antegren, Natalizumab is a drug co-marketed by Biogen Idec and Élan as "Tysabri".Tysabri is a monoclonal antibody that inhibits immune cells from crossing blood vessel walls to reach various tissues, including the brain.It has proven efficacy in the treatment of two serious autoimmune disorders: multiple sclerosis, and Crohn's disease.In multiple sclerosis, Tysabri was shown to reduce relapses by 67% vs. a placebo in double-blind studies.It slowed the progression of disability by 42%.While it is impossible to compare results across different clinical trials, the older generation drugs, i.e. interferons and Copaxone, are generally acknowledged as demonstrating about a 30-35% decrease in relapse rate vs. placebo; and only two drugs have been shown to decrease the progression of disability, but again only by around 20-40%. ## NanoCrystal Technology For poorly water soluble compounds, Élan's proprietary NanoCrystal technology can enable formulation and improve compound activity and final product characteristics.The NanoCrystal technology can be incorporated into all dosage forms both parenteral and oral, including solid, liquid, fast-melt, pulsed release and controlled release dosage forms. # Drugs Products and drugs that Élan has developed include: - Avinza – once-daily, novel dual release morphine sulphate - Emend – oral table form of aprepitant, a poorly water soluble compound - Focalin XR – once-daily dexmethylphenidate marketed in US and other territories - Herbesser R – once-daily, high-potency, sustained release diltiazem for Japanese and other Asian markets - Megace ES – concentrated oral suspension utilizing NanoCrystal Technology, marketed in the U.S. - NaprÉlan - once-daily, sustained-release naproxen sodium - Rapamune - oral tablet form of poorly water soluble compound - Ritalin LA – once-daily, pulsatile release of methylphenidate - Theo-Dur - twice-daily, sustained-release theophylline - TriCor - new formulation of Abbott’s fenofibrate, which can be taken without regard to food, launched in the U.S. - VerÉlan - once-daily, sustained-release verapamil - VerÉlan PM – modified release, chronotherapeutic verapamil

PMA # Overview PMA (paramethoxyamphetamine, p-methoxyamphetamine or 4-methoxyamphetamine) is a synthetic phenethylamine drug, psychostimulant and hallucinogen.It is commonly sold as "Ecstasy" and both dealers and users are likely to be unaware that a particular batch of pills contains PMA rather than MDMA.Notable batches of pills containing PMA have included Mitsubishi Turbo or Red/Blue Mitsubishi and Yellow Euro pills.PMA is often synthesized from anethole, the flavor compound of anise and fennel, mainly because the starting material for MDMA, safrole has become less available due to law enforcement action, causing illicit drug manufacturers to use anethole as an alternative.Once thought to be a human invention , recent research suggests PMA occurs as a trace alkaloid in plants including certain Acacia species. .It is classified as a Schedule I hallucinogen under the Controlled Substances Act in the United States.Internationally, PMA is a Schedule I drug under the Convention on Psychotropic Substances . PMA has been associated with numerous adverse reactions including death.Effects of PMA ingestion include many effects of the hallucinogenic amphetamines including accelerated and irregular heartbeat, blurred vision, and a strong feeling of intoxication which is often unpleasant.While PMA can reportedly be euphoric at low doses, the dose-response curve is much steeper than that of MDMA, and at higher doses unpleasant effects such as nausea and vomiting, severe hyperthermia and hallucinations quickly overpower any pleasurable effects.The effects of PMA also seem to be much more unpredictable and variable between individuals than those of MDMA, and sensitive individuals may die from a dose of PMA that a less susceptible person might only be mildly affected by.There are approximately twice as many deaths caused by PMA as by MDMA, even though the actual proportion of PMA on the market is only a fraction of that of MDMA. While PMA alone may cause significant toxicity, the combination of PMA with MDMA has a synergistic effect which seems to be particularly hazardous.Since PMA has a slow onset of effects, several deaths have occurred where individuals have taken a pill containing PMA, followed by a pill containing MDMA some time afterwards due to thinking that the first pill was not active. It appears that PMA elevates body temperatures dramatically; the cause of this property is suspected to be related to its ability to inhibit monoamine oxidase A and at the same time releasing large amounts of serotonin, effectively causing serotonin syndrome . Amphetamines, especially serotonergic analogues such as MDMA, are strongly contraindicated to take with MAOIs. Many amphetamines and adrenergic compounds raise body temperatures; whereas some tend to produce more euphoric activity, or peripheral vasoconstriction, or tend to favor one effect over another, it appears that PMA activates the hypothalamus much more strongly than MDMA and other drugs like ephedrine, thereby causing rapid increases in body temperature (which is the major cause of death in PMA mortalities).Many people taking PMA try to get rid of the heat by taking off their clothes, taking cold showers or wrapping themselves in wet towels, and even sometimes by shaving off their hair. Because PMA is given out through the same venues and distribution channels that "Ecstasy" tablets are, the risk of being severely injured, hospitalized or even killed from use of Ecstasy increases significantly when a batch of "Ecstasy" pills containing PMA starts to be sold in a particular area.PMA pills could be a variety of colours or logos, and there is no way of knowing just from the appearance of a pill what drugs it might contain. .Due to the variations in street "Ecstasy" pills, the only way to reduce the risk of ingestion of PMA is to test any "Ecstasy" pill that is bought with a pill testing kit before it is consumed, and to monitor reported results from police or government drug testing laboratories and avoid any pills that are reported to contain PMA. Four analogues of PMA have been reported to be sold on the black market: PMMA, PMEA , 4-ETA and 4-MTA. These are the N-methyl, N-ethyl, 4-ethoxy and 4-methylthio analogues of PMA, respectively.PMMA and PMEA are reportedly weaker, more "ecstasy-like" and somewhat less dangerous than PMA itself, but can still produce nausea and hyperthermia similar to that produced by PMA, albeit at slightly higher doses.4-ETA was briefly sold in Canada in the 1970s but little is known about it. 4-MTA however is more dangerous even than PMA and produces strong stimulant effects and intense hyperthermia, but with little euphoria, and was implicated in several deaths in the late 1990s.

68W # Overview 68W (often pronounced as 6 8 Whiskey using the phonetic alphabet) is the Military Occupational Specialty (MOS) for the United States Army's healthcare specialist, also known as the combat medic. # Description The main role of the 68W in the United States Army is to provide medical treatment to wounded soldiers.Whiskeys are staples in the functionality of the US Army, as every squad is required to have a whiskey in attendance when going on any hazardous mission.They are found in every stage of medical treatment in a combat zone.Whiskeys initiate medical treatment at the accident or injury location, maintain medical treatment during evacuation to healthcare facilities, and provide medical tratment in the medical facilities themselves.68W10s are highly trained to perform medical duties in hazardous and challenging atmospheres. 68Ws work alongside Army PAs, or doctors under their respective jurisdiction and licensure.Their work can range from the administration of immunizations and collection of fluid samples to obtaining vitals and initial information from patients/casualties and treating trauma to surgical assistance and suturing.The 68W, oft times, must work in the absence of medical professionals or healthcare providers through BLS (Basic Life Support) monitoring and maintenance. The 68W health care specialist will and can also work as the senior enlisted person in a clinical setting, as well as the Platoon Sergeant of a medical platoon in field units. As senior personnel, the 68W will have various collateral assignments that must be performed, such as daily, monthly, annual training and counseling sessions for soldiers to better help them in assisting with the treatment and education of patients who visit the clinic along with self improvement. There are constant expansions initiated to the 68W MOS in order to improve the capabilities of the healthcare specialist. Currently, the only civilian equivalent for 68Ws is Emergency Medical Technician - Basic, or upon completion of courses prescribed through MSU (Mountain State University), they may receive an Associate's Degree in medical assisting.There are educational programs at some universities which offer a technical degree in the Emergency Medical Sciences, and allow the 68W to grow in the medical field. Many 68Ws go on to become Physician Assistants, Nurse Practitioners, Registered Nurses, Doctors, and Healthcare Administrators with extra training through continuing their education. # Skill Levels - 1 is the basic entry level Combat medic (e.g. 68W10) - 2 is a combat medic with the rank of Sergeant (E-5) - 3 is a combat medic with the rank of Staff Sergeant (E-6) - 4 is a combat medic with the rank of Sergeant First Class (E-7) - 5 is a combat medic with the rank of Master Sergeant/First Sergeant (E-8) or Sergeant Major (E-9) # Skill Identifiers - F6 is an Army Flight Medic - M6 is the Army's Licensed Practical Nurse - P6 is an orthopedics specialist (clinical) - Y8 is an immunization-allergy specialist (clinical, lab) - N3 is the Army's Occupational Therapy Assistant (clinical) - N9 is a physical therapy technician (clinical) - Y2 is the code used to identify those who have not finished the upgrade classes. - W1 is a special operations combat medic (SOCM) - P3 is an optometry specialist (clinical) - Y6 is a cardiovascular specialist (Cardiac Catheterization Technologist and Echocardiographer) # History Recently known as 91W, the MOS was changed effective October 1, 2006.Formerly known by the MOS codes 91B (9 1 Bravo) and 91A (91 Alpha). The Department of the Army Deputy Chief of Staff for Personnel issued a notice for future change for the MOS 91B&C in September 1999.This notice established the transition to 91W to begin on 1 October 2001 and end on 30 September 2007.During this period all 91B&C will be given the identifier of Y2 until they complete the transition to 68W. To complete their transition to 68W many 91B&C must complete EMT-B which was offered but never required for any medic until now.Failure to conform to these standards has resulted in some medics having to reclassify into another MOS. # Training Upon the completion of their basic training, future 68W10s are shipped to Fort Sam Houston where they undergo Advanced Individual Training (AIT) for 16 to 68 weeks, depending on their identifier training time.During these weeks, soldiers will attend many courses that teach them the various medical tasks that they require in their military career.To maintain their MOS they must also obtain and maintain an EMT, and CPR certification.To provide the necessary hours for their re-certification many medics go through extensive ongoing training for the rest of their military career. As with any medical career or profession, the medical personnel must be willing to be educated throughout their career which may consist of many hours of research. In addition to skills taught at the AIT level, 68W's may, at the request of their unit's Physician's Assistant (PA), attend any number of requested advanced topics.These topic are generally prescribed per each units functional role.For example a front line combat medic (aka "line medic") may learn about advanced trauma treatments including venous cutdowns, placement of chest tubes, or use of specialty hemorrhage control methods such as Chitosan patches or "Quikclot".In the case of those attached to medical units, they may learn and administer medications which result in more definitive treatment than their civilian counterparts are allowed to.Unknown to most, field hospital units don't usually have a large amount if any 68WM6 (LPN) so they use the combat medic who is readily available and partially trained. Hopefully the future will allow for an independent duty medical team or personnel to conduct operations in the absence of qualified health care providers. In order to take their training to the next level many medics opt to become EMT-I or EMT-P certified.The Army also has a IPAP which is oriented toward helping medics become PAs through a two year school program.And yet fewer medics choose to become 18D which is the Special Forces Medical Sergeant, these medics are required to become EMT-P. Some medics choose to enter special operations through the Special Operations Combat Medic (SOCM) course and are awarded additional skill identifier "W1". SOCM-qualified 68W personnel serve in the 75th Ranger Regiment (Ranger Medic), 160th Special Operations Aviation Regiment (SOAR Flight Medic), 96th Civil Affairs Battalion (CA-Med SGT), Special Operations Support Command, and in support positions of the special forces groups.The SOCM 68W is currently the most independent-duty enlisted medical personnel in the CMF 68 field. SOCM medics work relatively independent through specific protocols in a limited scope of practice that may be enhanced during the complete absence of a medical officer. SOCM medics assigned to special operations units attend unique advanced medical and military training to enhance their interoperability with other special operations soldiers. - EMT Basic - ATLS - BTLS/PHTLS - Trauma-AIMS # Responsibilities - Provide cover fire to incapacitate an enemy - Accompany every patrol to provide immediate medical coverage for all soldiers in combat - Initial stabilizing treatment and triage - Plan and conduct Evacuation from the field of battle and en route life support - Preventive medicine - Field sanitation - Clinical medicine - Supportive Care in the event of delayed transport - Plan and Provide instructions for unit Combat Lifesaver programs ## Plan and conduct Combat Lifesaver training CLS (combat lifesaver) trained soldiers are non medic soldiers in their unit (such as infantrymen or engineers) who receive moderate amounts of extra emergency medical training in order to provide point of wounding care and to act as a link between "buddy aid" and the standard Combat Medic. The 68W trains the Combat Lifesaver. Combat lifesaver skills are exactly that, for use in combat conditions. However, skills may be applied in non-combat conditions where soldiers are concerned. The combat lifesaver is instructed in various techniques to treat and stabilize injuries related to combat. To include, but not limited to, blast injury, amputation, severe bleeding, penetrating chest injuries, simple airway management, and evacuation techniques. The combat lifesaver doctrine was developed as an effort to increase survivability in combat environments where the combat medic may not be readily available. The combat lifesaver is a bridge between self aid or buddy aid and the combat medic. The combat lifesaver can augment the combat medic as the situation necessitates. ## Skills of the Combat Lifesaver - Basic casualty evaluation - Airway management - Chest injury and tension pneumothorax management - Controlling Bleeding - Intravenous Drip therapy - Requesting medical evacuation

AK2 Adenylate kinase 2 is an enzyme that is encoded in humans by the AK2 gene.The AK2 protein is found in the intermembrane space of the mitochondrion. # Function Adenylate kinases are involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides.Three isozymes of adenylate kinase, namely 1, 2, and 3, have been identified in vertebrates; this gene encodes isozyme 2.Expression of these isozymes is tissue-specific and developmentally regulated.Isozyme 2 is localized in the mitochondrial intermembrane space and may play a role in apoptosis.Two transcript variants encoding distinct isoforms have been identified for this gene. ## AK2 deficiency Adenylate Kinase 2 (AK2) deficiency in humans causes hematopoietic defects associated with sensorineural deafness. Recticular dysgenesis is an autosomal recessive form of human combined immunodeficiency. It is also characterized by an impaired lymphoid maturation and early differentiation arrest in the myeloid lineage. AK2 deficiency results in absent or a large decrease in the expression of proteins. AK2 is specifically expressed in the stria vascularis of the inner ear which indicates why individuals with an AK2 deficiency will have sensorineural deafness.

AKT # Overview Akt1, also known as "Akt" or protein kinase B (PKB) is an important molecule in mammalian cellular signaling. # AKT family: AKT1, AKT2, AKT3 In humans, there are three genes in the "Akt family": Akt1, Akt2, and Akt3.These enzymes are members of the serine/threonine-specific protein kinase family (EC 2.7.11.1). Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer.Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8 by Dr. Philip Tsichlis at Fox Chase Cancer Center in the 1990's. Akt2 is an important signaling molecule in the Insulin signaling pathway.It is required to induce glucose transport. These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out". In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a diabetic phenotype (insulin resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway . The role of Akt3 is less clear, though it appears to be predominantly expressed in brain.It has been reported that mice lacking Akt3 have small brains . The name Akt does not refer to its function.Presumably, the "Ak" in Akt was a temporary classification name for a mouse strain developing spontaneous thymic lymphomas.The "t" stands for 'transforming', the letter was added when a transforming retrovirus was isolated from the Ak strain, which was termed "Akt-8".When the oncogene encoded in this virus was discovered, it was termed v-Akt.Thus, the later identified human analogues were named accordingly. # Regulation: Activation and Inactivation of Akt ## Binding phospho-lipids in the membrane Akt possesses a protein domain known as a PH domain, or Pleckstrin Homology domain, named after Pleckstrin, the protein in which it was first discovered. This domain binds to phosphoinositides with high affinity. In the case of the PH domain of Akt, it binds either phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3 aka PIP3) or phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2 aka PI(3,4)P2). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide PtdIns(4,5)P2 is only phosphorylated by the family of enzymes, PI 3-kinases (phosphoinositide 3-kinase or PI3K), and only upon receipt of chemical messengers which tell the cell to begin the growth process. For example, PI 3-kinases may be activated by a G protein coupled receptor or receptor tyrosine kinase such as the insulin receptor. Once activated, PI 3-kinases phosphorylates PtdIns(4,5)P2 to form PtdIns(3,4,5)P3. ## Phosphorylation by PDK1 and PDK2 Once correctly positioned in the membrane via binding of PIP3, Akt can then be phosphorylated by its activating kinases, phosphoinositide dependent kinase 1 (PDK1) and mTORC2. First, the mammalian target of rapamycin complex 2 (mTORC2) phosphorylates Akt; mTORC2 therefore functionally acts as the long-sought PDK2 molecule, although other molecules, including Integrin-Linked Kinase (ILK) and Mitogen-Activated Protein Kinase Activated Kinase-2 (MAPKAPK2) can also serve as PDK2. Phosphorylation by mTORC2 stimulates the subsequent phosphorylation of Akt by PDK1. Activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity. See this link for a more thorough and detailed image of the Akt signaling pathway. Besides being a downstream effector of PI 3-kinases, Akt may also be activated in a PI 3-kinase-independent manner.Studies have suggested that cAMP-elevating agents could activate Akt through protein kinase A (PKA), although these studies are disputed and the mechanism of action is unclear. ## Lipid phosphatases control the amount of PIP3, thereby modulating the ability of Akt to be activated PI3K dependent Akt activation can be regulated through the tumor suppressor PTEN, which works essentially as the opposite of PI3K mentioned above (PTEN and PI3K). PTEN acts as a phosphatase to dephosphorylate PtdIns(3,4,5)P3 back to PtdIns(4,5)P2. This removes the membrane-localization factor from the Akt signaling pathway. Without this localization, the rate of Akt activation decreases significantly, as do the all the downstream pathways that depend on Akt for activation. PIP3 can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases, SHIP1 and SHIP2. These poly-phosphate inositil phosphatases dephosphorylate PtdIns(3,4,5)P3 to form PtdIns(3,4)P2. ## Protein phosphatases control the amount of phosphorylated Akt The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly de-phosphorylate, and therefore inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is specific for Akt 2 and Akt3. # Functions Akt regulate the cellular survival and metabolism by binding and regulating many downstream effectors, e.g. Nuclear Factor-κB, Bcl-2 family proteins and murine double minute 2 (MDM2). Akt could promote growth factor-mediated cell survival both directly and indirectly.BAD is a pro-apoptotic protein of the Bcl-2 family.Akt could phosphorylate BAD on Ser136 (BAD phosphorylation by Akt), which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function (BAD interaction with Bcl-2).Akt could also activate NF-κB via regulating IκB kinase (IKK), thus result in transcription of pro-survival genes (regulation of NF-kB). Akt is required for the insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane.Glycogen synthase kinase 3 (GSK-3) could be inhibited upon phosphorylation by Akt, which results in promotion of glycogen synthesis.It's worthy to note that GSK3 is also involved in Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway. Still unknown role in HCV induced steatosis. Akt1 has also been implicated in angiogenesis and tumor development.Deficiency of Akt1 in mice although inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels ,

APC Apc may refer to: - Apc, Hungary, a village in the Heves county of Hungary APC may also refer to: - APC (gene), a human gene that is classified as a tumor suppressor gene - Activated protein C, a protein involved in blood coagulation - Allophycocyanin, a protein from the light-harvesting phycobiliprotein family - Allylpalladium chloride dimer, a chemical compound - Anaphase-promoting complex, a complex of several proteins which is activated during mitosis to initiate anaphase - Antigen-presenting cell, a cell that displays foreign antigen complexed with MHC on its surface # Clinical Trials - Adenoma Prevention With Celecoxib - A Perfect Circle, an alternative rock band - American Presbyterian Church, a small Reformed Christian denomination in the United States formed in 1979 - Associated Presbyterian Churches, a small Scottish Christian denomination - Armour-piercing capped, a category of anti-tank shell that has a soft metal cap on the penetrating nose - Armoured personnel carrier, an armoured fighting vehicle developed to transport infantry on the battlefield - Average propensity to consume, the proportion of income spent. - All People's Congress, a political party of Sierra Leone - Alternate Playing Cost, a cost to play a spell in the game Magic: The Gathering that is an alternative to the mana cost in the upper right hand corner of the card - American Pie Council, the only organization committed to preserving America's pie heritage - American Plastics Council, a major trade association for the U.S. plastics industry - Animal Procedures Committee, a public body and task force of the United Kingdom government - Anti-Poverty Committee, a direct action organization in Vancouver, Canada. - Arab Potash Company in Jordan - Archaeogeophysical Pseudotechnical Consultant, a consultant who utilizes archaeogeophysical pseudotechnical "black box" methods in geoarchaeological site investigations - Arrangers' Publishing Company, a sheet music publishing company in the United States. - Asia Pacific College, a non-profit joint-venture between IBM Philippines and the SM Foundation - Association for Progressive Communications, an international network of organizations that was founded in 1990 to provide communication infrastructure - Attoparsec, an unusual unit of measurement - Australian Press Council, the self-regulatory body of the Australian print media - Australian Provincial Championship, a rugby union competition in Australia - Napa County Airport, California, United States, from its IATA airport code - Armed Proletarians for Communism, an Italian far-left terrorist group of the 1970s. - Argon plasma coagulation, an endoscopic technique for controlling hemorrhage - Adaptive predictive coding, a narrowband analog-to-digital conversion that uses a one-level or multilevel sampling system - Advanced process control, a broad term within the control theory - Alternative PHP Cache, a PHP accelerator program - American Power Conversion, a company with a worldwide presence based in West Kingston, Rhode Island - APC-7 connector, a high grade sexless, 7 mm, coaxial connector used for high frequency applications up to 18 GHz - Application Program Command, a control code; see C0 and C1 control codes - aPOCALYPSE pRODUCTION cREW, a major MP3 warez organization founded by two individuals known under the pseudonyms acid^rain and Viper in May of 1997 - Australian Personal Computer, a computer magazine in Australia - Automatic Performance Control, a system that was introduced on turbo charged Saab H engines in 1982 de:APC ko:APC it:APC nl:APC sv:APC

Abc Synonyms and keywords: # Special consideration when adding information from observational studies # Overview # Historical Perspective was first discovered by , a , in /during/following . The association between and was made in/during . In , was the first to discover the association between and the development of . In , mutations were first implicated in the pathogenesis of . There have been several outbreaks of , including -----. In , was developed by to treat/diagnose . # Classification There is no established system for the classification of . OR may be classified according to into subtypes/groups: , , , and . OR may be classified into subtypes based on , , and . may be classified into several subtypes based on , , and . OR Based on the duration of symptoms, may be classified as either acute or chronic. OR If the staging system involves specific and characteristic findings and features: According to the , there are stages of based on the , , and .Each stage is assigned a and a that designate the and . OR The staging of is based on the . OR There is no established system for the staging of . # Pathophysiology The exact pathogenesis of is not fully understood. OR It is thought that is the result of / is mediated by / is produced by / is caused by either , , or . OR is usually transmitted via the route to the human host. OR Following transmission/ingestion, the uses the to invade the cell. OR arises from s, which are cells that are normally involved in . OR The progression to usually involves the . OR The pathophysiology of depends on the histological subtype. # Causes Disease name] may be caused by , , or . OR Common causes of include , , and . OR The most common cause of is .Less common causes of include , , and . OR The cause of has not been identified.To review risk factors for the development of , click here. # Differentiating ((Page name)) from other Diseases must be differentiated from other diseases that cause , , and , such as , , and . OR must be differentiated from , , and . # Epidemiology and Demographics The incidence/prevalence of is approximately per 100,000 individuals worldwide. OR In , the incidence/prevalence of was estimated to be cases per 100,000 individuals worldwide. OR In , the incidence of is approximately per 100,000 individuals with a case-fatality rate of %. Patients of all age groups may develop . OR The incidence of increases with age; the median age at diagnosis is years. OR commonly affects individuals younger than/older than years of age. OR is usually first diagnosed among . OR commonly affects . There is no racial predilection to . OR usually affects individuals of the race. individuals are less likely to develop . affects men and women equally. OR are more commonly affected by than .The to ratio is approximately to 1. The majority of cases are reported in . OR is a common/rare disease that tends to affect and . # Risk Factors There are no established risk factors for . OR The most potent risk factor in the development of is .Other risk factors include , , and . OR Common risk factors in the development of include , , , and . OR Common risk factors in the development of may be occupational, environmental, genetic, and viral. # Screening There is insufficient evidence to recommend routine screening for . OR According to the , screening for is not recommended. OR According to the , screening for by is recommended every among patients with , , and . # Natural History, Complications, and Prognosis If left untreated, % of patients with may progress to develop , , and . OR Common complications of include , , and . OR Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with is approximately %. # Diagnosis ## Diagnostic Study of Choice The diagnosis of is made when at least of the following diagnostic criteria are met: , , , and . OR The diagnosis of is based on the criteria, which include , , and . OR The diagnosis of is based on the definition, which includes , , and . OR There are no established criteria for the diagnosis of . ## History and Symptoms The majority of patients with are asymptomatic. OR The hallmark of is .A positive history of and is suggestive of .The most common symptoms of include , , and .Common symptoms of include , , and .Less common symptoms of include , , and . ## Physical Examination Patients with usually appear .Physical examination of patients with is usually remarkable for , , and . OR Common physical examination findings of include , , and . OR The presence of on physical examination is diagnostic of . OR The presence of on physical examination is highly suggestive of . ## Laboratory Findings An elevated/reduced concentration of serum/blood/urinary/CSF/other is diagnostic of . OR Laboratory findings consistent with the diagnosis of include , , and . OR is usually normal among patients with . OR Some patients with may have elevated/reduced concentration of , which is usually suggestive of . OR There are no diagnostic laboratory findings associated with . ## Electrocardiogram There are no ECG findings associated with . OR An ECG may be helpful in the diagnosis of .Findings on an ECG suggestive of/diagnostic of include , , and . ## X-ray There are no x-ray findings associated with . OR An x-ray may be helpful in the diagnosis of .Findings on an x-ray suggestive of/diagnostic of include , , and . OR There are no x-ray findings associated with .However, an x-ray may be helpful in the diagnosis of complications of , which include , , and . ## Echocardiography or Ultrasound There are no echocardiography/ultrasound findings associated with . OR Echocardiography/ultrasound may be helpful in the diagnosis of .Findings on an echocardiography/ultrasound suggestive of/diagnostic of include , , and . OR There are no echocardiography/ultrasound findings associated with .However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of , which include , , and . ## CT scan There are no CT scan findings associated with . OR CT scan may be helpful in the diagnosis of .Findings on CT scan suggestive of/diagnostic of include , , and . OR There are no CT scan findings associated with .However, a CT scan may be helpful in the diagnosis of complications of , which include , , and . ## MRI There are no MRI findings associated with . OR MRI may be helpful in the diagnosis of .Findings on MRI suggestive of/diagnostic of include , , and . OR There are no MRI findings associated with .However, a MRI may be helpful in the diagnosis of complications of , which include , , and . ## Other Imaging Findings There are no other imaging findings associated with . OR may be helpful in the diagnosis of .Findings on an suggestive of/diagnostic of include , , and . ## Other Diagnostic Studies There are no other diagnostic studies associated with . OR may be helpful in the diagnosis of .Findings suggestive of/diagnostic of include , , and . OR Other diagnostic studies for include , which demonstrates , , and , and , which demonstrates , , and . # Treatment ## Medical Therapy There is no treatment for ; the mainstay of therapy is supportive care. OR Supportive therapy for includes , , and . OR The majority of cases of are self-limited and require only supportive care. OR is a medical emergency and requires prompt treatment. OR The mainstay of treatment for is . OR The optimal therapy for depends on the stage at diagnosis. OR is recommended among all patients who develop . OR Pharmacologic medical therapy is recommended among patients with , , and . OR Pharmacologic medical therapies for include (either) , , and/or . OR Empiric therapy for depends on and . OR Patients with are treated with , whereas patients with are treated with . ## Surgery Surgical intervention is not recommended for the management of . OR Surgery is not the first-line treatment option for patients with .Surgery is usually reserved for patients with either , , and OR The mainstay of treatment for is medical therapy.Surgery is usually reserved for patients with either , , and/or . OR The feasibility of surgery depends on the stage of at diagnosis. OR Surgery is the mainstay of treatment for . ## Primary Prevention There are no established measures for the primary prevention of . OR There are no available vaccines against . OR Effective measures for the primary prevention of include , , and . OR vaccine is recommended for to prevent .Other primary prevention strategies include , , and . ## Secondary Prevention There are no established measures for the secondary prevention of . OR Effective measures for the secondary prevention of include , , and .

Ion An ion is an atom or molecule which has lost or gained one or more valence electrons, giving it a positive or negative electrical charge. A negatively charged ion, which has more electrons in its electron shells than it has protons in its nuclei, is known as an anion (Template:PronEng; an-eye-on).Conversely, a positively-charged ion, which has fewer electrons than protons, is known as a cation (Template:PronEng; cat-eye-on). An ion consisting of a single atom is called a monatomic ion, but if it consists of two or more atoms, it is a polyatomic ion.Polyatomic ions containing oxygen, such as carbonate and sulfate, are called oxyanions. Ions are denoted in the same way as electrically neutral atoms and molecules except for the presence of a superscript indicating the sign of the net electric charge and the number of electrons lost or gained, if more than one.For example: H+ and SO42−. # Formation ## Formation of polyatomic and molecular ions Polyatomic and molecular ions are often formed by the combination of elemental ions such as H+ with neutral molecules or by the gain of such elemental ions from neutral molecules.A simple example of this is the ammonium ion NH4+ which can be formed by ammonia NH3 accepting a proton, H+.Ammonia and ammonium have the same number of electrons in essentially the same electronic configuration but differ in protons.The charge has been added by the addition of a proton (H+) not the addition or removal of electrons. The distinction between this and the removal of an electron from the whole molecule is important in large systems because it usually results in much more stable ions with complete electron shells. For example NH3·+ is not stable because of an incomplete valence shell around nitrogen and is in fact a radical ion. ## Ionization potential The energy required to detach an electron in its lowest energy state from an atom or molecule of a gas with less net electric charge is called the ionization potential, or ionization energy.The nth ionization energy of an atom is the energy required to detach its nth electron after the first n − 1 electrons have already been detached. Each successive ionization energy is markedly greater than the last.Particularly great increases occur after any given block of atomic orbitals is exhausted of electrons.For this reason, ions tend to form in ways that leave them with full orbital blocks.For example, sodium has one valence electron, in its outermost shell, so in ionized form it is commonly found with one lost electron, as Na+.On the other side of the periodic table, chlorine has seven valence electrons, so in ionized form it is commonly found with one gained electron, as Cl−. Francium has the lowest ionization energy of all the elements and fluorine has the greatest.The ionization energy of metals is generally much lower than the ionization energy of nonmetals, which is why metals will generally lose electrons to form positively-charged ions while nonmetals will generally gain electrons to form negatively-charged ions. A neutral atom contains an equal number of Z protons in the nucleus and Z electrons in the electron shell.The electrons' negative charges thus exactly cancel the protons' positive charges.In the simple view of the Free electron model, a passing electron is therefore not attracted to a neutral atom and cannot bind to it.In reality, however, the atomic electrons form a cloud into which the additional electron penetrates, thus being exposed to a net positive charge part of the time.Furthermore, the additional charge displaces the original electrons and all of the Z + 1 electrons rearrange into a new configuration. # Ions - Anions (see pronunciation above) are negatively charged ions, formed when an atom gains electrons in a reaction.Anions are negatively charged because there are more electrons associated with them than there are protons in their nuclei. - Cations (see pronunciation above) are positively charged ions, formed when an atom loses electrons in a reaction.Cations are the opposite of anions, since cations have fewer electrons than protons. - Dianion: a dianion is a species which has two negative charges on it; for example, the aromatic dianion pentalene. - Radical ions: radical ions are ions that contain an odd number of electrons and are mostly very reactive and unstable. ## Plasma A collection of non-aqueous gas-like ions, or even a gas containing a proportion of charged particles, is called a plasma, often called the fourth state of matter because its properties are quite different from solids, liquids, and gases.Astrophysical plasmas containing predominantly a mixture of electrons and protons, may make up as much as 99.9% of visible matter in the universe. # Applications Ions are essential to life.Sodium, potassium, calcium and other ions play an important role in the cells of living organisms, particularly in cell membranes.They have many practical, everyday applications in items such as smoke detectors, and are also finding use in unconventional technologies such as ion engines. Inorganic dissolved ions are a component of total dissolved solids, an indicator of water quality in the world. # Negative 'Ions' and Air Ionisers Many manufacturers sell devices that release 'negative ions' into the air, claiming that a higher concentration of negative ions will make a room feel less 'stuffy'.Some also claim health benefits such as relieving asthma and depression. The 'ions' referred to are in fact charged oxygen or nitrogen molecules surrounded by a cluster of water molecules, rather than ions.Scientific studies have shown no particular benefit from a greater concentration of negative ions. Negative air ionization can reduce the concentration of bioaerosols and dust particles in the air by causing them to bond, forming larger particles and thus falling out of the air onto horizontal surfaces. This may help reduce infection due to airborne contamination. Ionization was shown to reduce transmission of the Newcastle Disease Virus in an experiment with chickens. # Common ions

Arm # Overview In anatomy, an arm is one of the upper limbs of an animal.The term arm can also be used for analogous structures, such as one of the paired upper limbs of a four-legged animal, or the arms of an octopus.Anatomically, the term arm refers specifically to the segment between the shoulder and the elbow.The segment between the elbow and wrist is the forearm.However, in colloquial speech the term arm often refers to the entire upper limb from shoulder to wrist. In primates the arms are richly adapted for both climbing and for more skilled, manipulative tasks. The ball and socket shoulder joint allows for movement of the arms in a wide circular plane, while the presence of two forearm bones which can rotate around each other allows for additional range of motion at this level. # Anatomy of the human arm The human arm contains bones, joints, muscles, nerves, and blood vessels.Many of these muscles are used for everyday tasks. ## Bony structure and joints The humerus is the (upper) arm bone. It joins with the scapula above at the shoulder joint (or glenohumeral joint) and with the ulna and radius below at the elbow joint. ### Elbow joint The elbow joint is the hinge joint between the distal end of the humerus and the proximal ends of the radius and ulna. The upper arm bone is not easily broken.It is built to handle pressure of up to 300lbs. ## Osteofascial compartments The arm is divided by a fascial layer (known as lateral and medial intermuscular septa) separating the muscles into two osteofascial compartments: - Anterior compartment of the arm - Posterior compartment of the arm The fascia merges with the periosteum (outer bone layer) of the humerus.The compartments contain muscles which are innervated by the same nerve and perform the same action. Two other muscles are considered to be partially in the arm: - The large deltoid muscle is considered to have part of its body in the anterior compartment.This muscle is the main abductor muscle of the upper limb and extends over the shoulder. - The brachioradialis muscle originates in the arm but inserts into the forearm.This muscle is responsible for rotating the hand so its palm faces forward (supination). ## Cubital fossa The cubital fossa is clinically important for venepuncture and for blood pressure measurement.It is an imaginary triangle with borders being: - Laterally, the medial border of brachioradialis muscle - Medially, the lateral border of pronator teres muscle - Superiorly, the intercondylar line, an imaginary line between the two condyles of the humerus - The floor is the brachialis muscle - The roof is the skin and fascia of the arm and forearm The structures which smell through the cubital fossa are vital.The order from which they pass into the forearm are as follows, from medial to lateral: - Median nerve, which starts to branch - Brachial artery - Tendon of the biceps brachii muscle - Radial nerve - Median cubital vein - this important vein is where venepuncture occurs.It connects the basilic and cephalic veins. - lymph nodes ## Nervous supply The musculocutaneous nerve, from C5, C6, C7, is the main supplier of muscles of the anterior compartment.It originates from the lateral cord of the brachial plexus of nerves.It pierces the coracobrachialis muscle and gives off branches to the muscle, as well as to brachialis and biceps brachii.It terminates as the anterior cutaneous nerve of the forearm. The radial nerve, which is from the fifth cervical spinal nerve to the first thoracic spinal nerve, originates as the continuation of the posterior cord of the brachial plexus.This nerve enters the lower triangular space (an imaginary space bounded by, amongst others, the shaft of the humerus and the triceps brachii) of the arm and lies deep to the triceps brachii.Here it travels with a deep artery of the arm (the profunda brachii), which sits in the radial groove of the humerus.This fact is very important clinically as a fracture of the bone at the shaft of the bone here can cause lesions or even transections in the nerve. Other nerves passing through give no supply to the arm.These include: - The median nerve, nerve origin C5-T1, which is a branch of the lateral and medial cords of the brachial plexus.This nerve continues in the arm, travelling in a plane between the biceps and triceps muscles.At the cubital fossa, this nerve is deep to the pronator teres muscle and is the most medial structure in the fossa.The nerve passes into the forearm. - The ulnar nerve, origin C7-T1, is a continuation of the medial cord of the brachial plexus.This nerve passes in the same plane as the median nerve, between the biceps and triceps muscles. At the elbow, this nerve travels posterior to the medial epicondyle of the humerus.This means that condylar fractures can cause lesion to this nerve. ## Blood supply and venous drainage ### Arteries The main artery in the arm is the brachial artery.This artery is a continuation of the axillary artery.The point at which the axillary becomes the brachial is distal to the lower border of teres major.The brachial artery gives off an important branch, the profunda brachii (deep artery of the arm).This branching occurs just below the lower border of teres major. The brachial artery continues to the cubital fossa in the anterior compartment of the arm.It travels in a plane between the biceps and triceps muscles, the same as the median nerve and basilic vein.It is accompanied by venae comitantes (accompanying veins).It gives branches to the muscles of the anterior compartment.The artery is in between the median nerve and the tendon of the biceps muscle in the cubital fossa.It then continues into the forearm. The profunda brachii travels through the lower triangular space with the radial nerve.From here onwards it has an intimate relationship with the radial nerve.They are both found deep to the triceps muscle and are located on the spiral groove of the humerus.Therefore fracture of the bone may not only lead to lesion of the radial nerve, but also haematoma of the internal structures of the arm.The artery then continues on to anastamose with the recurrent radial branch of the brachial artery, providing a diffuse blood supply for the elbow joint. ### Veins The veins of the arm carry blood from the extremities of the limb, as well as drain the arm itself.The two main veins are the basilic and the cephalic veins.There is a connecting vein between the two, the median cubital vein, which passes through the cubital fossa and is clinically important for venepuncture (withdrawing blood). The basilic vein travels on the medial side of the arm and terminates at the level of the seventh rib. The cephalic vein travels on the lateral side of the arm and terminates as the axillary vein.It passes through the deltopectoral triangle, a space between the deltoid and the pectoralis major muscles.

BSc A Bachelor of Science (B.S., B.Sc.or less commonly, S.B. or Sc.B. from the Latin Scientiæ Baccalaureus) is an undergraduate academic degree awarded for completed courses that generally last three to five years (see below). In the United States, a Bachelor of Science degree may be a more specialized version of B.A., with more focus on the subject and less on a broad liberal arts background; for example, a B.S. in economics may require several more advanced economics courses than a B.A. in economics, and possibly more support courses (such as statistics).The B.S. is also frequently used for professional areas of study such as engineering, journalism, accounting, and advertising.At least two American schools (Caltech, MIT) and four of the service academies (United States Military Academy, United States Naval Academy, United States Air Force Academy and United States Coast Guard Academy) award the BS for all subjects, including, e.g., Literature. In the UK and Canada, which subjects are considered science subjects varies, e.g. economics degrees may be B.A. in one university but B.Sc.in another.In addition, some universities, like the London School of Economics, offer the B.Sc.in practically all subject areas even when they are normally associated with arts degrees, while others award arts qualifications almost exclusively, namely the Oxbridge universities.In both instances, this is generally for historical and traditional reasons.A Bachelor of Science receives the designation B.Sc.or B.S. for a major/pass degree and B.Sc. (Hons) or B.S. (Hon) for an honours degree. The B.Sc.from Germany was equivalent to a B.Sc. (Hons). Note that many universities in German speaking countries are changing their systems into the Ba/Ma system, thus of course also offering the full equivalent of a B.Sc. Formerly at the University of Oxford, the degree of B.Sc.was a postgraduate degree.This former degree, still actively granted, has since been renamed M.Sc. In Brazil, a Bachelor of Science degree is a graduation degree and is also more specific, usually containing a one-year mandatory probation time by the end of the course followed by relatively elaborate written and oral evaluations (Monografia). # Typical completion period ## Three years Australia, Austria, Barbados, Belgium, Cameroon, Cote d'Ivoire, Slovak Republic, Czech Republic, Denmark, England (three or four years with a one-year placement in industry), Estonia, Finland, France, Germany (mostly three years, but can be up to four years), Hong Kong, Hungary, Iceland, India, Italy, Jamaica, Latvia, Malaysia, The Netherlands, New Zealand, Northern Ireland, Norway, Poland, Portugal, Romania, Quebec, Scotland (non-Honour),Singapore, South Africa, Spain, Sweden, Switzerland, Trinidad and Tobago, Wales and Zimbabwe. ## Four years Afghanistan, Albania, Bangladesh (three or four years), Bahrain, Brunei, Bulgaria, Canada (except Quebec), Croatia (four or five years), Guatemala, Greece, Indonesia, Iran, Iraq, Ireland, Israel, Japan, Jordan, Kazakhstan, Korea, Malta, Mexico, Myanmar, Pakistan, People's Republic of China, the Philippines, Russia, Saudi Arabia, Scotland (Honour Degree), Slovenia, Taiwan, Turkey, Sri Lanka,Haiti (three or four years), United States, Zambia (four or five years). ## Five years Peru, Argentina, Brazil, Colombia, Mexico (4.5 years), Chile (usually four years dedicated to coursework plus one year of research thesis), Egypt, Haiti (four or five years), Syria, and Serbia.

Bee Bees are flying insects closely related to wasps and ants.Bees are a monophyletic lineage within the superfamily Apoidea, presently classified by the unranked taxon name Anthophila.There are slightly fewer than 20,000 known species of bee, in 9 recognized families, though many are undescribed and the actual number is probably higher.They are found on every continent except Antarctica, in every habitat on the planet that contains flowering dicotyledons. # Introduction Bees are adapted for feeding on nectar and pollen, the former primarily as an energy source, and the latter primarily for protein and other nutrients.Most pollen is used as food for larvae. Bees have a long proboscis (a complex "tongue") that enables them to obtain the nectar from flowers.They have antennae almost universally made up of thirteen segments in males and twelve in females, as is typical for the superfamily.Bees all have two pairs of wings, the hind pair being the smaller of the two; in a very few species, one sex or caste has relatively short wings that make flight difficult or impossible, but none are wingless. The smallest bee is the dwarf bee (Trigona minima), about 2.1 mm (5/64") long.The largest bee in the world is Megachile pluto, which can grow to a size of 39 mm (1.5").Member of the family Halictidae, or sweat bees, are the most common type of bee in the Northern Hemisphere, though they are small and often mistaken for wasps or flies. The best-known bee species is the Western honey bee, which, as its name suggests, produces honey, as do a few other types of bee. Human management of this species is known as beekeeping or apiculture. # Pollination Bees play an important role in pollinating flowering plants, and are the major type of pollinators in ecosystems that contain flowering plants.Bees may focus on gathering nectar or on gathering pollen, depending on their greater need at the time, especially in social species.Bees gathering nectar may accomplish pollination, but bees that are deliberately gathering pollen are more efficient pollinators.It is estimated that one third of the human food supply depends on insect pollination, most of this accomplished by bees. Bees are extremely important as pollinators in agriculture, especially the domesticated Western honey bee, with contract pollination having overtaken the role of honey production for beekeepers in many countries.Monoculture and pollinator decline (of many bee species) have increasingly caused honey bee keepers to become migratory so that bees can be concentrated in areas of pollination need at the appropriate season.Recently, many such migratory beekeepers have experienced substantial losses, prompting the announcement of investigation into the phenomenon, dubbed "Colony Collapse Disorder," amidst great concern over the nature and extent of the losses. Many other species of bees such as mason bees are increasingly cultured and used to meet the agricultural pollination need.Bees also play a major, though not always understood, role in providing food for birds and wildlife.Many of these bees survive in refuge in wild areas away from agricultural spraying, only to be poisoned in massive spray programs for mosquitoes, gypsy moths, or other insect pests. Most bees are fuzzy and carry an electrostatic charge, thus aiding in the adherence of pollen.Female bees periodically stop foraging and groom themselves to pack the pollen into the scopa, which is on the legs in most bees, and on the ventral abdomen on others, and modified into specialized pollen baskets on the legs of honey bees and their relatives.Many bees are opportunistic foragers, and will gather pollen from a variety of plants, but many others are oligolectic, gathering pollen from only one or a few types of plant.A small number of plants produce nutritious floral oils rather than pollen, which are gathered and used by oligolectic bees.One small subgroup of stingless bees (called "vulture bees") is specialized to feed on carrion, and these are the only bees that do not use plant products as food.Pollen and nectar are usually combined together to form a "provision mass", which is often soupy, but can be firm.It is formed into various shapes (typically spheroid), and stored in a small chamber (a "cell"), with the egg deposited on the mass.The cell is typically sealed after the egg is laid, and the adult and larva never interact directly (a system called "mass provisioning"). Visiting flowers can be a dangerous occupation.Many assassin bugs and crab spiders hide in flowers to capture unwary bees.Others are lost to birds in flight.Insecticides used on blooming plants can kill large numbers of bees, both by direct poisoning and by contamination of their food supply.A honey bee queen may lay 2000 eggs per day during spring buildup, but she also must lay 1000 to 1500 eggs per day during the foraging season, mostly to replace daily casualties - note, however, that most casualties are workers simply dying of old age rather than predation.Among solitary and primitively social bees, however, lifetime reproduction is among the lowest of all insects, as it is not uncommon for females of such species to produce fewer than 25 offspring. The population value of bees depends partly on the individual efficiency of the bees, but also on the population itself.Thus, while bumblebees have been found to be about ten times more efficient pollinators on cucurbits, the total efficiency of a colony of honey bees is much greater, due to greater numbers.Likewise, during early spring orchard blossoms, bumblebee populations are limited to only a few queens, and thus are not significant pollinators of early fruit. See also List of plants pollinated by bees # Evolution Bees, like ants, are essentially a highly specialized form of wasp.The ancestors of bees were wasps in the family Crabronidae, and therefore predators of other insects.The switch from insect prey to pollen may have resulted from the consumption of prey insects that were flower visitors and were partially covered with pollen when they were fed to the wasp larvae.This same evolutionary scenario has also occurred within the vespoid wasps, where the group known as "pollen wasps" also evolved from predatory ancestors.Up until recently the oldest non-compression bee fossil had been Cretotrigona prisca in New Jersey amber and of Cretaceous age, a meliponine.A recently reported bee fossil, of the genus Melittosphex, is considered "an extinct lineage of pollen-collecting Apoidea sister to the modern bees", and dates from the early Cretaceous (~100 mya).Derived features of its morphology ("apomorphies") place it clearly within the bees, but it retains two unmodified ancestral traits ("plesiomorphies") of the legs (two mid-tibial spurs, and a slender hind basitarsus), indicative of its transitional status. The earliest animal-pollinated flowers were pollinated by insects such as beetles, so the syndrome of insect pollination was well established before bees first appeared.The novelty is that bees are specialized as pollination agents, with behavioral and physical modifications that specifically enhance pollination, and are much more efficient at the task than beetles, flies, butterflies, pollen wasps, or any other pollinating insect.The appearance of such floral specialists is believed to have driven the adaptive radiation of the angiosperms, and, in turn, the bees themselves. Among living bee groups, the Dasypodaidae are now considered to be the most "primitive", and sister taxon to the remainder of the bees, contrary to earlier hypotheses that the "short-tongued" bee family Colletidae was the basal group of bees; the short, wasp-like mouthparts of colletids are apparently the result of convergent evolution, rather than indicative of a plesiomorphic condition. # Eusocial and semisocial bees Bees may be solitary or may live in various types of communities.The most advanced of these are eusocial colonies found among the honey bees, bumblebees, and stingless bees.Sociality, of several different types, is believed to have evolved separately many times within the bees. In some species, groups of cohabiting females may be sisters, and if there is a division of labor within the group, then they are considered semisocial. If, in addition to a division of labor, the group consists of a mother and her daughters, then the group is called eusocial.The mother is considered the "queen" and the daughters are "workers".These castes may be purely behavioral alternatives, in which case the system is considered "primitively eusocial" (similar to many paper wasps), and if the castes are morphologically discrete, then the system is "highly eusocial". There are many more species of primitively eusocial bees than highly eusocial bees, but they have been rarely studied.The biology of most such species is almost completely unknown.The vast majority are in the family Halictidae, or "sweat bees".Colonies are typically small, with a dozen or fewer workers, on average.The only physical difference between queens and workers is average size, if they differ at all.Most species have a single season colony cycle, even in the tropics, and only mated females (future queens, or "gynes") hibernate (called diapause).A few species have long active seasons and attain colony sizes in the hundreds.The orchid bees include a number of primitively eusocial species with similar biology.Certain species of allodapine bees (relatives of carpenter bees) also have primitively eusocial colonies, with unusual levels of interaction between the adult bees and the developing brood.This is "progressive provisioning"; a larva's food is supplied gradually as it develops.This system is also seen in honey bees and some bumblebees. Highly eusocial bees live in colonies.Each colony has a single queen, together with workers and, at certain stages in the colony cycle, drones.When humans provide a home for a colony, the structure is called a hive.A honey bee hive can contain up to 40,000 bees at their annual peak, which occurs in the spring, but usually have fewer. ## Bumblebees Bumblebees (Bombus terrestris, B. pratorum, et al.)are eusocial in a manner quite similar to the eusocial Vespidae such as hornets.The queen initiates a nest on her own (unlike queens of honey bees and stingless bees which start nests via swarms in the company of a large worker force).Bumblebee colonies typically have from 50 to 200 bees at peak population, which occurs in mid to late summer.Nest architecture is simple, limited by the size of the nest cavity (pre-existing), and colonies are rarely perennial.Bumblebee queens sometimes seek winter safety in honey bee hives, where they are sometimes found dead in the spring by beekeepers, presumably stung to death by the honey bees.It is unknown whether any survive winter in such an environment. ## Stingless bees Stingless bees are very diverse in behavior, but all are highly eusocial.They practice mass provisioning, complex nest architecture, and perennial colonies. ## Honey bees The true honey bees (genus Apis) have arguably the most complex social behavior among the bees. The Western (or European) honey bee, Apis mellifera, is the best known bee species and one of the best known of all insects. ## Africanized honey bee Africanized bees, also called killer bees, are a hybrid strain of Apis mellifera derived from experiments to cross European and African honey bees by Warwick Estevam Kerr.Several queen bees escaped his laboratory in South America and have spread throughout the Americas. Africanized honey bees are more defensive than European honey bees. # Solitary and communal bees Most other bees, including familiar species of bee such as the Eastern carpenter bee (Xylocopa virginica), alfalfa leafcutter bee (Megachile rotundata), orchard mason bee (Osmia lignaria) and the hornfaced bee (Osmia cornifrons) are solitary in the sense that every female is fertile, and typically inhabits a nest she constructs herself.There are no worker bees for these species.Solitary bees typically produce neither honey nor beeswax.They are immune from acarine and Varroa mites (see diseases of the honey bee), but have their own unique parasites, pests and diseases. Solitary bees are important pollinators, and pollen is gathered for provisioning the nest with food for their brood.Often it is mixed with nectar to form a paste-like consistency.Some solitary bees have very advanced types of pollen carrying structures on their bodies.A very few species of solitary bees are being increasingly cultured for commercial pollination. Solitary bees are often oligoleges, in that they only gather pollen from one or a few species/genera of plants (unlike honey bees and bumblebees which are generalists).No known bees are nectar specialists; many oligolectic bees will visit multiple plants for nectar, but there are no bees which visit only one plant for nectar while also gathering pollen from many different sources.Specialist pollinators also include bee species that gather floral oils instead of pollen, and male orchid bees, which gather aromatic compounds from orchids (one of the only cases where male bees are effective pollinators).In a very few cases only one species of bee can effectively pollinate a plant species, and some plants are endangered at least in part because their pollinator is dying off.There is, however, a pronounced tendency for oligolectic bees to be associated with common, widespread plants which are visited by multiple pollinators (e.g., there are some 40 oligoleges associated with creosotebush in the US desert southwest, and a similar pattern is seen in sunflowers, asters, mesquite, etc.) Solitary bees create nests in hollow reeds or twigs, holes in wood, or, most commonly, in tunnels in the ground.The female typically creates a compartment (a "cell") with an egg and some provisions for the resulting larva, then seals it off.A nest may consist of numerous cells.When the nest is in wood, usually the last (those closer to the entrance) contain eggs that will become males.The adult does not provide care for the brood once the egg is laid, and usually dies after making one or more nests.The males typically emerge first and are ready for mating when the females emerge.Providing nest boxes for solitary bees is increasingly popular for gardeners.Solitary bees are either stingless or very unlikely to sting (only in self defense, if ever). While solitary females each make individual nests, some species are gregarious, preferring to make nests near others of the same species, giving the appearance to the casual observer that they are social.Large groups of solitary bee nests are called aggregations, to distinguish them from colonies. In some species, multiple females share a common nest, but each makes and provisions her own cells independently.This type of group is called "communal" and is not uncommon.The primary advantage appears to be that a nest entrance is easier to defend from predators and parasites when there are multiple females using that same entrance on a regular basis. # Cleptoparasitic bees Cleptoparasitic bees, commonly called "cuckoo bees" because their behavior is similar to cuckoo birds, occur in several bee families, though the name is technically best applied to the apid subfamily Nomadinae.Females of these bees lack pollen collecting structures (the scopa) and do not construct their own nests.They typically enter the nests of pollen collecting species, and lay their eggs in cells provisioned by the host bee.When the cuckoo bee larva hatches it consumes the host larva's pollen ball, and if the female cleptoparasite has not already done so, kills and eats the host larva.In a few cases where the hosts are social species, the cleptoparasite remains in the host nest and lays many eggs, sometimes even killing the host queen and replacing her. Many cleptoparasitic bees are closely related to, and resemble, their hosts in looks and size, (i.e., the Bombus subgenus Psithyrus, which are parasitic bumble bees that infiltrate nests of species in other subgenera of Bombus).This common pattern gave rise to the ecological principle known as "Emery's Rule".Others parasitize bees in different families, like Townsendiella, a nomadine apid, one species of which is a cleptoparasite of the dasypodaid genus Hesperapis, while the other species in the same genus attack halictid bees. # "Nocturnal" bees Four bee families (Andrenidae, Colletidae, Halictidae, and Apidae) contain some species that are crepuscular (these may be either the "vespertine" or "matinal" type).These bees have greatly enlarged ocelli, which are extremely sensitive to light and dark, though incapable of forming images.Many are pollinators of flowers that themselves are crepuscular, such as evening primroses, and some live in desert habitats where daytime temperatures are extremely high. # Bee flight There is a reference in the 1934 French book Le vol des insectes by M. Magnan, in which it is written that he and a Mr. Saint-Lague had applied the equations of air resistance to bumblebees and found that their flight was impossible, but that "One shouldn't be surprised that the results of the calculations don't square with reality". In 1996 Charlie Ellington at Cambridge University, UK, showed that vortices created by many insects’ wings and non-linear effects were a vital source of lift—vortices and non-linear phenomena are notoriously difficult areas of hydrodynamics, which has made for slow progress in theoretical understanding of insect flight. In 2005 Michael Dickinson and colleagues at Caltech studied honey bee flight with the assistance of high-speed cinematography and a giant robotic mock-up of a bee wing, which "proves bees can fly, thank God”. # Miscellaneous Bees figure prominently in mythology.See Bee (mythology). Bees are the favorite meal of Merops apiaster, a bird.Other common predators are kingbirds, mockingbirds, bee wolves, and dragonflies. In North America, yellowjackets and hornets, especially when encountered as flying pests, are often misidentified as bees, despite numerous differences between them. Bees are often affected or even harmed by encounters with toxic chemicals in the environment (see Bees and toxic chemicals). Despite the honey bee's painful sting and the stereotype of insects as pests, bees are generally held in high regard. This is most likely due to their usefulness as pollinators and as producers of honey, their social nature and their reputation for diligence.

Bees are one of the few insects used on advertisements, being used to illustrate honey and foods made with honey. Although a bee sting can be deadly to those with allergies, virtually all bee species are non-aggressive if undisturbed and many cannot sting at all. Bee Wilson states that a community of honey bees have often been employed historically by political theorists as a model of human society: This image occurs from ancient to modern times, in Aristotle and Plato; in Virgil and Seneca; in Erasmus and Shakespeare; Tolstoy, as well as by social theorists Bernard Mandeville and Karl Marx. # Gallery - two species together two species together - Western honey bee, Poland Western honey bee, Poland - Western honey bee on a Sphaeralcea flower.Mesa, Az Western honey bee on a Sphaeralcea flower.Mesa, Az - Western honey bee in a Sphaeralcea flower.Mesa, Az Western honey bee in a Sphaeralcea flower.Mesa, Az - Sweat bee, Agapostemon virescens (female) on a Coreopsis flower.Madison, Wi Sweat bee, Agapostemon virescens (female) on a Coreopsis flower.Madison, Wi - Bumblebee, Bombus sp.startles Agapostemon virescens.Madison, Wi Bumblebee, Bombus sp.startles Agapostemon virescens.Madison, Wi - Western honey bee on lavender Western honey bee on lavender - Western honey bee, Kaunakakai, HI Western honey bee, Kaunakakai, HI - Western honey bees, Lebanon. Western honey bees, Lebanon. - Western honey bee, Lebanon. Western honey bee, Lebanon. - Western honey bee collecting pollen from a rose. Western honey bee collecting pollen from a rose. - Western honey bee collecting nectar from small flowers.Location: McKinney, Texas. Western honey bee collecting nectar from small flowers.Location: McKinney, Texas. - Hovering bumblebee at lupine Hovering bumblebee at lupine - Western honey bee on Apple blossom Western honey bee on Apple blossom

HBB Beta globin (also referred to as HBB, β-globin, haemoglobin beta, hemoglobin beta, or preferably haemoglobin subunit beta) is a globin protein, which along with alpha globin (HBA), makes up the most common form of haemoglobin in adult humans, the HbA. It is 146 amino acids long and has a molecular weight of 15,867 Da.Normal adult human HbA is a heterotetramer consisting of two alpha chains and two beta chains. HBB is encoded by the HBB gene on human chromosome 11.Mutations in the gene produce several variants of the proteins which are implicated with genetic disorders such as sickle-cell disease and beta thalassemia, as well as beneficial traits such as genetic resistance to malaria. # Gene locus HBB protein is produced by the gene HBB which is located in the multigene locus of β-globin locus on chromosome 11, specifically on the short arm position 15.5.Expression of beta globin and the neighbouring globins in the β-globin locus is controlled by single locus control region (LCR), the most important regulatory element in the locus located upstream of the globin genes.The normal allelic variant is 1600 base pairs (bp) long and contains three exons.The order of the genes in the beta-globin cluster is 5' - epsilon – gamma-G – gamma-A – delta – beta - 3'. # Transcriptions "DNA sequence analysis of a cloned β-globin gene from a Chinese patient with β-thalassemia revealed a single nucleotide substitution (A→ G) within the ATA box homology and 28 base pairs upstream from the cap site." "Comparison of the level of β-globin transcripts in a variety of deletion mutants shows that for efficient transcription, both the ATA or Goldberg–Hogness box, and a region between 100 and 58 base pairs in front of the site at which transcription is initiated, are required.Deletion of either of these regions results in a decrease in the level of β-globin transcripts by an order of magnitude; deletion of the ATA box causes an additional loss in the specificity of the site of initiation of RNA synthesis.The DNA sequences downstream from the ATA box, including the natural β-globin mRNA cap site, are dispensable for transcription in vivo." "The first is a sequence rich in the nucleic acids adenine and thymine (the Goldberg-Hogness, "TATA," or "ATA" box) which is located 20-30 base pairs upstream from the RNA initiation site (the cap site which is the transcriptional start site for the mRNA) and is characterized by a concensus sequence (5'-TATAA-ATA-3')." # Function GeneID: 3043 HBB hemoglobin subunit beta, "The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains.Mutant beta globin causes sickle cell anemia.Absence of beta chain causes beta-zero-thalassemia.Reduced amounts of detectable beta globin causes beta-plus-thalassemia.The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'." # Interactions HBB interacts with Hemoglobin, alpha 1 (HBA1) to form haemoglobin A, the major haemoglobin in adult humans.The interaction is two-fold.First, one HBB and one HBA1 combine, non-covalently, to form a dimer.Secondly, two dimers combine to form the four-chain tetramer, and this becomes the functional haemolglobin. # Associated genetic disorders ## Beta thalassemia Total or partial absence of HBB causes a genetic disease called beta thalassemia.Total loss called, thalassemia major or beta-0-thalassemia, is due to mutation in both alleles, and this results in failure to form beta chain of haemoglobin.It prevents oxygen supply in the tissues.It is highly lethal.Symptoms, such as severe anaemia and heart attack, appear within two years after birth.They can be treated only by lifelong blood transfusion and bone marrow transplantation.Reduced HBB function called thalassemia minor or beta+ thalassemia is due to mutation in one of the alleles.It is less severe but patients are prone to other diseases such as asthma and liver problems. According to a recent study, the stop gain mutation Gln40stop in HBB gene is a common cause of autosomal recessive Beta- thalassemia in Sardinian people (almost exclusive in Sardinia).Carriers of this mutation show an enhanced red blood cell count.As a curiosity, the same mutation was also associated to a decrease in serum LDL levels in carriers, so the authors suggest that is due to the need of cholesterol to regenerate cell membranes. ## Sickle cell disease More than a thousand naturally occurring HBB variants have been discovered.The most common is HbS, which causes sickle cell disease.HbS is produced by a point mutation in HBB in which the codon GAG is replaced by GTG.This results in the replacement of hydrophilic amino acid glutamic acid with the hydrophobic amino acid valine at the sixth position (β6Glu→Val).This substitution creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent haemoglobin molecule's beta chain.This further causes clumping of HbS molecules into rigid fibers, causing "sickling" of the entire red blood cells in the homozygous (HbS/HbS) condition.The homozygous allele has become one of the deadliest genetic factors.Whereas, people heterozygous for the mutant allele (HbS/HbA) are resistant to malaria and develop minimal effects of the anaemia. ## Haemoglobin C Sickle cell disease is closely related to another mutant haemoglobin called haemoglobin C (HbC), because they can be inherited together.HbC mutation is at the same position in HbS, but glutamic acid is replaced by lysine (β6Glu→Lys).The mutation is particularly prevalent in West African populations.HbC provides near full protection against Plasmodium falciparum in homozygous (CC) individuals and intermediate protection in heterozygous (AC) individuals.This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions. ## Haemoglobin E Another point mutation in HBB, in which glutamic acid is replaced with lysine at position 26 (β26Glu→Lys), leads to the formation of haemoglobin E (HbE).HbE has a very unstable α- and β-globin association.Even though the unstable protein itself has mild effect, inherited with HbS and thalassemia traits, it turns into a life-threatening form of β-thalassemia.The mutation is of relatively recent origin suggesting that it resulted from selective pressure against severe falciparum malaria, as heterozygous allele prevents the development of malaria. # Human evolution Malaria due to Plasmodium falciparum is a major selective factor in human evolution.It has influenced mutations in HBB in various degrees resulting in the existence of numerous HBB variants.Some of these mutations are not directly lethal and instead confer resistance to malaria, particularly in Africa where malaria is epidemic.People of African descent have evolved to have higher rates of the mutant HBB because the heterozygous individuals have a misshaped red blood cell that prevent attacks from malarial parasites.Thus, HBB mutants are the sources of positive selection in these regions and are important for their long-term survival.Such selection markers are important for tracing human ancestry and diversification from Africa.

Myc Myc is a family of regulator genes and proto-oncogenes that code for transcription factors.The Myc family consists of three related human genes: c-myc, l-myc, and n-myc.c-myc (also sometimes referred to as MYC) was the first gene to be discovered in this family, due to homology with the viral gene v-myc. In cancer, c-myc is often constitutively (persistently) expressed.This leads to the increased expression of many genes, some of which are involved in cell proliferation, contributing to the formation of cancer.A common human translocation involving c-myc is critical to the development of most cases of Burkitt lymphoma.Constitutive upregulation of Myc genes have also been observed in carcinoma of the cervix, colon, breast, lung and stomach. Myc is thus viewed as a promising target for anti-cancer drugs. In the human genome, C-myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on enhancer box sequences (E-boxes). In addition to its role as a classical transcription factor, N-myc may recruit histone acetyltransferases (HATs).This allows it to regulate global chromatin structure via histone acetylation. # Discovery The Myc family was first established after discovery of homology between an oncogene carried by the Avian virus, Myelocytomatosis (v-myc) and a human gene over-expressed in various cancers (c-Myc).Later, discovery of further homologous genes in humans led to the addition of n-Myc and l-Myc to the family of genes. The most frequently discussed example of c-Myc as an oncogene is its implication in Burkitt lymphoma.In Burkitt lymphoma, cancer cells show chromosomal translocations, most commonly between chromosome 8 and chromosome 14 .This causes c-Myc to be placed downstream of the highly active immunoglobulin (Ig) promoter region, leading to overexpression of c-Myc. # Structure The protein product of Myc family genes all belong to the Myc family of transcription factors, which contain bHLH (basic helix-loop-helix) and LZ (leucine zipper) structural motifs. The bHLH motif, allows Myc proteins to bind with DNA, while the leucine zipper TF-binding motif allows dimerization with Max, another bHLH transcription factor. Myc mRNA contains an IRES (internal ribosome entry site) that allows the RNA to be translated into protein when 5' cap-dependent translation is inhibited, such as during viral infection. # Function Myc proteins are transcription factors that activate expression of many pro-proliferative genes through binding enhancer box sequences (E-boxes) and recruiting histone acetyltransferases (HATs).Myc is thought to function by upregulating transcript elongation of actively transcribed genes through the recruitment of elongation factors.It can also act as a transcriptional repressor.By binding Miz-1 transcription factor and displacing the p300 co-activator, it inhibits expression of Miz-1 target genes.In addition, myc has a direct role in the control of DNA replication. Myc is activated upon various mitogenic signals such as serum stimulation or by Wnt, Shh and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects.The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation, and stem cell self-renewal.Nucleotide metabolism genes are upregulated by Myc, which are necessary for Myc induced proliferation or cell growth. There have been several studies that have clearly indicated Myc's role in cell competition. A major effect of c-myc is B cell proliferation. c-Myc induces MTDH(AEG-1) gene expression and in turn itself requires AEG-1 oncogene for its expression. # Myc-nick Myc-nick is a cytoplasmic form of Myc produced by a partial proteolytic cleavage of full-length c-Myc and N-Myc.Myc cleavage is mediated by the calpain family of calcium-dependent cytosolic proteases. The cleavage of Myc by calpains is a constitutive process but is enhanced under conditions that require rapid downregulation of Myc levels, such as during terminal differentiation.Upon cleavage, the C-terminus of Myc (containing the DNA binding domain) is degraded, while Myc-nick, the N-terminal segment 298-residue segment remains in the cytoplasm.Myc-nick contains binding domains for histone acetyltransferases and for ubiquitin ligases. The functions of Myc-nick are currently under investigation, but this new Myc family member was found to regulate cell morphology, at least in part, by interacting with acetyl transferases to promote the acetylation of α-tubulin.Ectopic expression of Myc-nick accelerates the differentiation of committed myoblasts into muscle cells. Myc-Nick # Clinical significance Except for early response genes, Myc universally upregulates gene expression. Furthermore, the upregulation is nonlinear. Genes whose expression is already significantly upregulated in the absence of Myc are strongly boosted in the presence of Myc, whereas genes whose expression is low in the absence Myc get only a small boost when Myc is present. Inactivation of SUMO-activating enzyme (SAE1 / SAE2) in the presence of Myc hyperactivation results in mitotic catastrophe and cell death in cancer cells. Hence inhibitors of SUMOylation may be a possible treatment for cancer. Amplification of the MYC gene was found in a significant number of epithelial ovarian cancer cases.In TCGA datasets, the amplification of Myc occurs in several cancer types, including breast, colorectal, pancreatic, gastric, and uterine cancers. In the experimental transformation process of normal cells into cancer cells, the MYC gene can cooperate with the RAS gene. Expression of Myc is highly dependent on BRD4 function in some cancers.BET inhibitors have been used to successfully block Myc function in pre-clinical cancer models and are currently being evaluated in clinical trials. # Animal models In Drosophila Myc is encoded by the diminutive locus, (which was known to geneticists prior to 1935).Calssical diminutive alleles resulted in a viable animal with small body size.Drosophila has subsequently been used to implicate Myc in cell competition, endoreplication, and cell growth. During the discovery of Myc gene, it was realized that chromosomes that reciprocally translocate to chromosome 8 contained immunoglobulin genes at the break-point.Enhancers that normally drive expression of immunoglobin genes now lead to overexpression of Myc proto-oncogene in lymphoma cells.To study the mechanism of tumorigenesis in Burkitt lymphoma by mimicking expression pattern of Myc in these cancer cells, transgenic mouse models were developed.Myc gene placed under the control of IgM heavy chain enhancer in transgenic mice gives rise to mainly lymphomas.Later on, in order to study effects of Myc in other types of cancer, transgenic mice that overexpress Myc in different tissues (liver, breast) were also made.In all these mouse models overexpression of Myc causes tumorigenesis, illustrating the potency of Myc oncogene. In a study with mice, reduced expression of Myc was shown to induce longevity, with significantly extended median and maximum lifespans in both sexes and a reduced mortality rate across all ages, better health, cancer progression was slower, better metabolism and they had smaller bodies.Also, Less TOR, AKT, S6K and other changes in energy and metabolic pathways (such as AMPK, more oxygen consumption, more body movements, etc.). The study by John M. Sedivy and others used Cre-Loxp -recombinase to knockout one copy of Myc and this resulted in a "Haplo-insufficient" genotype noted as Myc+/-.The phenotypes seen oppose the effects of normal aging and are shared with many other long-lived mouse models such as CR (calorie restriction) ames dwarf, rapamycin, metformin and resveratrol.One study found that Myc and p53 genes were key to the survival of Chronic Myeloid Leukaemia (CML) cells.Targeting Myc and p53 proteins with drugs gave positive results on mice with CML. # Relationship to Stem Cells c-Myc plays a major role in the generation of induced pluripotent stem cells (iPSCs).It one of the original factors discovered by Yamanaka et al.to encourage cells to return to a 'stem-like' state alongside transcription factors Oct4, Sox2 and Klf4).It has since been shown that it is possible to generate iPSCs without c-Myc. # Interactions Myc has been shown to interact with: - ACTL6A - BRCA1 - Bcl-2 - Cyclin T1 - CHD8 - DNMT3A - EP400 - GTF2I - HTATIP - let-7 - MAPK1 - MAPK8 - MAX - MLH1 - MYCBP2 - MYCBP - NMI - NFYB - NFYC - P73 - PCAF - PFDN5 - RuvB-like 1 - SAP130 - SMAD2 - SMAD3 - SMARCA4 - SMARCB1 - SUPT3H - TIAM1 - TADA2L - TAF9 - TFAP2A - TRRAP - WDR5 - YY1 and - ZBTB17.

C3b C3b is a one of the elements formed by the cleavage of complement component 3. C3b may bind to microbial cell surfaces within an organism's body.This can lead to the production of surface-bound C3 convertase and thus more C3b components.Also known as C3bBb, this convertase is similar to soluble C3-convertase except that it is membrane bound. Alternatively, bound C3b may aid in opsonization of the microbe by macrophages.Complement receptor 1 or CR1 on macrophages allows the engaging of C3b covered microbes. C3b is cleaved into C3c and C3d.

CD1 CD1 (cluster of differentiation 1) is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are related to the class I MHC molecules, and are involved in the presentation of lipid antigens to T cells.However their precise function is unknown. # Types CD1 glycoproteins can be classified primarily into two groups which differ in their lipid anchoring. - CD1a, CD1b and CD1c (group 1 CD1 molecules) are expressed on cells specialized for antigen presentation. - CD1d (group 2 CD1) is expressed in a wider variety of cells. CD1e is an intermediate form, expressed intracellularly, the role of which is currently unclear. # In humans ## Group 1 Group 1 CD1 molecules have been shown to present foreign lipid antigens, and specifically a number of mycobacterial cell wall components, to CD1-specific T cells. ## Group 2 The natural antigens of group 2 CD1 are not well characterized, but a synthetic glycolipid, alpha-galactosylceramide, originally isolated from a compound found in a marine sponge, has strong biologic activity. Group 2 CD1 molecules activate a group of T cells, known as Natural killer T cells because of their expression of NK surface markers such as CD161.Natural Killer T (NKT) cells are activated by CD1d-presented antigens, and rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and IL-4 production. The group 2 (CD1d) ligand alpha-galactosylceramide is currently in phase I clinical trials for the treatment of advanced non-hematologic cancers. ## Diagnostic relevance CD1 antigens are expressed on cortical thymocytes, but not on mature T cells.This often remains true in neoplastic cells from these populations, so that the presence of CD1 antigens can be used in diagnostic immunohistochemistry to identify some thymomas and malignancies arising from T cell precursors.CD1a, in particular, is a specific marker for Langerhans cells, and can therefore also be used in the diagnosis of Langerhans cell histiocytosis.Other conditions that may show CD1 positivity include myeloid leukaemia and some B cell lymphomas. # In cows and mice Mice lack the group 1 CD1 molecules, and instead have 2 copies of CD1d.Thus, mice have been used extensively to characterize the role of CD1d and CD1d-dependent NKT cells in a variety of disease models. It has recently been shown that cows lack the group 2 CD1 molecules, and have an expanded set of group 1 CD1 molecules.Because of this and the fact that cows are a natural host of Mycobacterium bovis, a pathogen in humans as well, it is hoped that studying cows will yield insights into the group 1 CD1 antigen-presenting system.

CD2 CD2 (cluster of differentiation 2) is a cell adhesion molecule found on the surface of T cells and natural killer (NK) cells. It has also been called T-cell surface antigen T11/Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette receptor. # Function It interacts with other adhesion molecules, such as lymphocyte function-associated antigen-3 (LFA-3/CD58) in humans, or CD48 in rodents, which are expressed on the surfaces of other cells. In addition to its adhesive properties, CD2 also acts as a co-stimulatory molecule on T and NK cells. ## Diagnostic relevance CD2 is a specific marker for T cells and NK cells, and can therefore be used in immunohistochemistry to identify the presence of such cells in tissue sections.The great majority of T cell lymphomas and leukaemias also express CD2, making it possible to use the presence of the antigen to distinguish these conditions from B cell neoplasms. # Classification Due to its structural characteristics, CD2 is a member of the immunoglobulin superfamily; it possesses two immunoglobulin-like domains in its extracellular portion. # Interactions CD2 has been shown to interact with CD2BP2, Lck and PSTPIP1.

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells.It was discovered in the late 1970s and was originally known as leu-3 and T4 (after the OKT4 monoclonal antibody that reacted with it) before being named CD4 in 1984.In humans, the CD4 protein is encoded by the CD4 gene. CD4+ T helper cells are white blood cells that are an essential part of the human immune system.They are often referred to as CD4 cells, T-helper cells or T4 cells.They are called helper cells because one of their main roles is to send signals to other types of immune cells, including CD8 killer cells, which then destroy the infectious particle.If CD4 cells become depleted, for example in untreated HIV infection, or following immune suppression prior to a transplant, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight. # Structure Like many cell surface receptors/markers, CD4 is a member of the immunoglobulin superfamily. It has four immunoglobulin domains (D1 to D4) that are exposed on the extracellular surface of the cell: - D1 and D3 resemble immunoglobulin variable (IgV) domains. - D2 and D4 resemble immunoglobulin constant (IgC) domains. The immunoglobulin variable (IgV) domain of D1 adopts an immunoglobulin-like β-sandwich fold with seven β-strands in 2 β-sheets, in a Greek key topology. CD4 interacts with the β2-domain of MHC class II molecules through its D1 domain. T cells displaying CD4 molecules (and not CD8) on their surface, therefore, are specific for antigens presented by MHC II and not by MHC class I (they are MHC class II-restricted).MHC class I contains Beta-2 microglobulin. The short cytoplasmic/intracellular tail (C) of CD4 contains a special sequence of amino acids that allow it to recruit and interact with the tyrosine kinase Lck. # Function CD4 is a co-receptor of the T cell receptor (TCR) and assists the latter in communicating with antigen-presenting cells.The TCR complex and CD4 each bind to distinct regions of the antigen-presenting MHCII molecule - α1/β1 and β2, respectively.In CD4 the interaction involves its extracellular D1 domain.The resulting close proximity between the TCR complex and CD4 (extracellular and intracellular) allows the tyrosine kinase Lck bound to the cytoplasmic tail of CD4 to tyrosine-phosphorylate the Immunoreceptor tyrosine activation motifs (ITAM) on the cytoplasmic domains of CD3 to amplify the signal generated by the TCR.Lck is essential for the activation of many molecular components of the signaling cascade of an activated T cell. Depending on the signal, different types of T helper cells result. Phosphorylated ITAM motifs on CD3 recruit and activate SH2 domain-containing protein tyrosine kinases (PTK) such as Zap70 to further mediate downstream signalling through tyrosine phosphorylation, leading to transcription factor activation including NF-κB and consequent T cell activation. ## Other interactions CD4 has also been shown to interact with SPG21, Lck and Protein unc-119 homolog. # Disease ## HIV infection HIV-1 uses CD4 to gain entry into host T-cells and achieves this through its viral envelope protein known as gp120.The binding to CD4 creates a shift in the conformation of gp120 allowing HIV-1 to bind to a co-receptor expressed on the host cell.These co-receptors are chemokine receptors CCR5 or CXCR4.Following a structural change in another viral protein (gp41), HIV inserts a fusion peptide into the host cell that allows the outer membrane of the virus to fuse with the cell membrane. ## HIV pathology HIV infection leads to a progressive reduction in the number of T cells expressing CD4.Medical professionals refer to the CD4 count to decide when to begin treatment during HIV infection, although recent medical guidelines have changed to recommend treatment at all CD4 counts as soon as HIV is diagnosed.A CD4 count measures the number of T cells expressing CD4.While CD4 counts are not a direct HIV test—e.g. they do not check the presence of viral DNA, or specific antibodies against HIV—they are used to assess the immune system of a patient. National Institutes of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count Normal blood values are usually expressed as the number of cells per microliter (μL, or equivalently, cubic millimeter, mm3) of blood, with normal values for CD4 cells being 500–1200 cells/mm3.Patients often undergo treatments when the CD4 counts reach a level of 350 cells per microliter in Europe but usually around 500/μL in the US; people with less than 200 cells per microliter are at high risk of contracting AIDS defined illnesses. Medical professionals also refer to CD4 tests to determine efficacy of treatment. Viral load testing provides more information about the efficacy for therapy than CD4 counts.For the first 2 years of HIV therapy, CD4 counts may be done every 3–6 months.If a patient's viral load becomes undetectable after 2 years then CD4 counts might not be needed if they are consistently above 500/mm3.If the count remains at 300–500/mm3, then the tests can be done annually.It is not necessary to schedule CD4 counts with viral load tests and the two should be done independently when each is indicated. ## Other diseases CD4 continues to be expressed in most neoplasms derived from T helper cells.It is therefore possible to use CD4 immunohistochemistry on tissue biopsy samples to identify most forms of peripheral T cell lymphoma and related malignant conditions.The antigen has also been associated with a number of autoimmune diseases such as vitiligo and type I diabetes mellitus. T-cells play a large part in autoinflammatory diseases.When testing a drug's efficacy or studying diseases, it is helpful to quantify the amount of T-cells. -n fresh-frozen tissue with CD4+, CD8+, and CD3+ T-cell markers (which stain different markers on a T-cell - giving different results).

CD6 CD6 (Cluster of Differentiation 6) is a human protein encoded by the CD6 gene. # Function This gene encodes a protein found on the outer membrane of T-lymphocytes as well as some other immune cells.The encoded protein contains three scavenger receptor cysteine-rich (SRCR) domains and a binding site for an activated leukocyte cell adhesion molecule.The gene product is important for continuation of T cell activation. # Clinical significance Certain alleles of this gene may be associated with susceptibility to multiple sclerosis.

CD8 CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR).Like the TCR, CD8 binds to a major histocompatibility complex (MHC) molecule, but is specific for the class I MHC protein.There are two isoforms of the protein, alpha and beta, each encoded by a different gene. In humans, both genes are located on chromosome 2 in position 2p12. # Tissue distribution The CD8 co-receptor is predominantly expressed on the surface of cytotoxic T cells, but can also be found on natural killer cells, cortical thymocytes, and dendritic cells.The CD8 molecule is a marker for cytotoxic T cell population.It is expressed in T cell lymphoblastic lymphoma and hypo-pigmented mycosis fungoides. # Structure To function, CD8 forms a dimer, consisting of a pair of CD8 chains.The most common form of CD8 is composed of a CD8-α and CD8-β chain, both members of the immunoglobulin superfamily with an immunoglobulin variable (IgV)-like extracellular domain connected to the membrane by a thin stalk, and an intracellular tail.Less-common homodimers of the CD8-α chain are also expressed on some cells.The molecular weight of each CD8 chain is about 34 kDa.The structure of the CD8 molecule was determined by Leahy, D.J., Axel, R., and Hendrickson, W.A. by X-ray Diffraction at a 2.6A resolution. The structure was determined to have an immunoglobulin-like beta-sandwich folding and 114 amino acid residues. 2% of the protein is wound into α-helices and 46% into β-sheets, with the remaining 52% of the molecules remaining in the loop portions. # Function The extracellular IgV-like domain of CD8-α interacts with the α3 portion of the Class I MHC molecule.This affinity keeps the T cell receptor of the cytotoxic T cell and the target cell bound closely together during antigen-specific activation.Cytotoxic T cells with CD8 surface protein are called CD8+ T cells.The main recognition site is a flexible loop at the α3 domain of an MHC molecule. This was discovered by doing mutational analyses. The flexible α3 domain is located between residues 223 and 229 in the genome.In addition to aiding with cytotoxic T cell antigen interactions the CD8 co-receptor also plays a role in T cell signaling.The cytoplasmic tails of the CD8 co-receptor interact with Lck (lymphocyte-specific protein tyrosine kinase).Once the T cell receptor binds its specific antigen Lck phosphorylates the cytoplasmic CD3 and ζ-chains of the TCR complex which initiates a cascade of phosphorylation eventually leading to activation of transcription factors like NFAT, NF-κB, and AP-1 which affect the expression of certain genes.

CD9 CD9 antigen is a protein that in humans is encoded by the CD9 gene. # Function The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family.Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains.The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. CD9 is a cell surface glycoprotein that is known to complex with integrins and other transmembrane 4 superfamily proteins.CD9 is found on the surface of exosomes and it can modulate cell adhesion and migration and also trigger platelet activation and aggregation.In addition, the protein appears to promote muscle cell fusion and support myotube maintenance.This protein also seems to be a key part in the egg-sperm fusion during mammalian fertilization. While oocytes are ovulated, CD9-deficient oocytes are not properly fused with sperm upon fertilization.CD9 is located in the microvillar membrane of the oocytes and also appears to intervene in maintaining the normal shape of oocyte microvilli. # Interactions CD9 has been shown to interact with: - CD117, - CD29 - CD46, - CD49c, - CD81, - PTGFRN, and - TSPAN4.

CLS CLS may refer to: # Education and society ## Academic fields - Critical legal studies, a contentious school of legal philosophy, that emerged from Harvard Law School in the 1980s. - Critical language studies - the study of language that evolved into critical discourse analysis ## Educational institutions - City of London School (an all-boys school; see also City of London School for Girls. - Covington Latin School, a high school in Covington, Kentucky ## Academic associations, divisions, programs and facilities - Columbia Law School at Columbia University - Coalition of Latin@ Scholars at Teachers College, Columbia University - Canadian Light Source - a synchrotron research facility located at the University of Saskatchewan, in Saskatoon, Saskatchewan ## Societies and associations - Chicago Linguistic Society - Christian Legal Society # Software - Common Language Specification an open specification developed by Microsoft that describes the executable code and runtime environment.It defines an environment that allows multiple high-level languages to be used on different computer platforms without being rewritten for specific architectures. - cls is a command in some operating systems, including MS-DOS, and programming languages, such as BASIC, that clears the screen. - Call logging system, a transaction logging system or interface. # Occupational terms - Clinical laboratory scientist, another term for medical technician, a type of healthcare professional. - Combat lifesaver (or combat medic) US Military Occupational Specialty 68W # Music - CLS Records, a record label. - Cory Lee Senn, rapper, leader of The M.O.B. # Medicine - Capillary leak syndrome - Coffin-Lowry syndrome, a genetic disorder associated with mental retardation - Clinical laboratory scientist, another term for medical technician, a type of healthcare professional # Aerospace - Capsule launch system for space capsules # Business and finance - Continuous linked settlement, a financial clearing system - CLS Group of Companies (headquartered in France, but with various divisions, including CLS America) - Celestica Inc. (New York Stock Exhchange symbol: CLS). # Miscellaneous products - The Mercedes-Benz CLS-Class, a series of automobile models. - Canadian lumber sizes - a surfaced timber widely used in building for studding.It has 3mm radius eased edges and consistent dimensions. - Nikon's Creative Lighting System, a complete lighting solution for Nikon's camera bodies and external light units. de:CLS it:CLS ksh:CLS (Watt ėßß datt?)

Rib In vertebrate anatomy, ribs (Latin costae) are the long curved bones which form the ribcage. In most animals, ribs surround the chest (Latin thorax) and protect the lungs, heart, and other internal organs of the thorax. In some animals, especially snakes, ribs may provide support and protection for the entire body. # Human anatomy Human beings, both male and female, have 24 ribs (12 pairs).The first seven sets of ribs have their own individual cartilage connections with the sternum.The remaining five sets are known as "false ribs". The first three of these share a common connection to the sternum, while the last two (eleventh and twelfth ribs) are termed floating ribs (costae fluitantes) or vertebral ribs. They are attached to the vertebrae only, and not to the sternum or cartilage coming off of the sternum. Some people are missing one of the two pairs of floating ribs, while others have a third pair. Rib removal is the surgical excision of ribs for therapeutic or cosmetic reasons. The ribcage is separated from the lower abdomen by the thoracic diaphragm which controls breathing. When the diaphragm contracts, the ribcage and thoracic cavity are expanded, reducing intra-thoracic pressure and drawing air into the lungs. # In other animals In mammals, one generally thinks of ribs occurring only in the chest.However, during the development of mammalian embryos, fused-on remnants of ribs can be traced in neck vertebrae (cervical ribs) and sacral vertebrae. In reptiles, ribs sometimes occur in all vertebrae from the neck to the sacrum. The ribs of turtles are developed into a bony or cartilagenous carapace and plastron. Fish can have up to four ribs on each vertebra and this can easily be seen in the herring, although not all fish have this many.

Cud # Overview Cud is a portion of food that returns from a ruminant's stomach in the mouth to be chewed for the second time.More accurately, it is a bolus of semi-degraded food regurgitated from the reticulorumen of a ruminant.Cud is produced during the physical digestive process of rumination, or "chewing the cud".The idiomatic expression chewing one's cud means meditating or pondering. # Explanation The alimentary canal of ruminants, such as the cow, goat, sheep and antelope, is unable to produce the enzymes required to break down the cellulose and hemicellulose of plant matter.Accordingly, these animals have developed a symbiotic relationship with a wide range of microbes, which largely reside in the reticulorumen, and which are able to synthesise the requisite enzymes.The reticulorumen thus hosts a microbial fermentation which yields products (mainly volatile fatty acids and microbial protein), which the ruminant is able to digest and absorb. # Process of rumination The process of rumination is stimulated by the presence of roughage in the upper part of the reticulorumen.The chest cavity is stretched, forming a vacuum in the gullet that sucks the semi-liquid stomach content into the esophagus.From the esophagus it is taken back to the mouth with retro peristaltic movements.When the stomach content, or the cud, arrives in the mouth of the ruminant, it is pushed against the palate with the tongue to remove excess liquid, the latter is swallowed and the solid material is chewed thoroughly.The function of rumination is that food is physically refined to expose more surface area for bacterial working in the reticulorumen, as well as stimulation of saliva secretion to buffer the rumen pH. # Chemistry The reticulorumen has an optimum pH of 6.5 for the microbe population to live and function.Consumption by ruminants of an insufficiently fibrous diet leads to little cud formation and therefore lowered amounts of saliva production.This in turn is associated with rumen acidosis, where the rumen pH can fall to as low as pH 5 or lower.Rumen acidosis is associated with a lowered appetite which leads to still lower rates of saliva secretion.Eventually, a collapse of the microbial ecosystem in the rumen will occur because of the low pH. Acute rumen acidosis can lead to death of the animal, and will occur if the animal is allowed to eat a diet with no roughage but high levels of highly digestible starchy concentrate.It is thought that most dairy cows in intensive systems of milk production have sub-acute acidosis because of the high rates of cereals in their diets relative to an insufficient amount of forage. # Final digestion When food has been degraded efficiently it passes from the reticulorumen through the reticulo-omasal orifice to the omasum followed by the abomasum to continue the digestion process in the lower parts of the alimentary canal.No enzymes are secreted in the rumen.Enzymes and hydrochloric acid are only secreted from the Abomasum (fourth stomach) onwards, and ruminants function from that point onwards much like monogastric animals, such as pigs and humans. lt:Atrajojimas no:Drøvtygging

DES DES may mean: - Data Encryption Standard, a deprecated cryptographic block cipher that falls to brute force attacks due to its short 56-bit key - Diethylstilbestrol, a synthetic estrogen developed to supplement a woman's natural estrogen production - Drug-eluting stent, a device placed in coronary arteries to treat or prevent heart attacks - Diffuse esophageal spasm, a condition resulting from a disorder of the esophagus cs:DES de:DES eo:DES (apartigilo) it:DES nl:DES sk:DES sv:DES

DNA # Overview Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses.The main role of DNA molecules is the long-term storage of information.DNA is often compared to a set of blueprints or a recipe, since it contains the instructions needed to construct other components of cells, such as proteins and RNA molecules.The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in regulating the use of this genetic information. Chemically, DNA is a long polymer of simple units called nucleotides, with a backbone made of sugars and phosphate groups joined by ester bonds.Attached to each sugar is one of four types of molecules called bases.It is the sequence of these four bases along the backbone that encodes information.This information is read using the genetic code, which specifies the sequence of the amino acids within proteins.The code is read by copying stretches of DNA into the related nucleic acid RNA, in a process called transcription. Within cells, DNA is organized into structures called chromosomes.These chromosomes are duplicated before cells divide, in a process called DNA replication.Eukaryotic organisms (animals, plants, and fungi) store their DNA inside the cell nucleus, while in prokaryotes (bacteria and archae) it is found in the cell's cytoplasm.Within the chromosomes, chromatin proteins such as histones compact and organize DNA.These compact structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed. # Physical and chemical properties DNA is a long polymer made from repeating units called nucleotides.The DNA chain is 22 to 26 Ångströms wide (2.2 to 2.6 nanometres), and one nucleotide unit is 3.3 Å (0.33 nm) long.Although each individual repeating unit is very small, DNA polymers can be enormous molecules containing millions of nucleotides.For instance, the largest human chromosome, chromosome number 1, is approximately 220 million base pairs long. In living organisms, DNA does not usually exist as a single molecule, but instead as a tightly-associated pair of molecules.These two long strands entwine like vines, in the shape of a double helix.The nucleotide repeats contain both the segment of the backbone of the molecule, which holds the chain together, and a base, which interacts with the other DNA strand in the helix.In general, a base linked to a sugar is called a nucleoside and a base linked to a sugar and one or more phosphate groups is called a nucleotide.If multiple nucleotides are linked together, as in DNA, this polymer is called a polynucleotide. The backbone of the DNA strand is made from alternating phosphate and sugar residues.The sugar in DNA is 2-deoxyribose, which is a pentose (five-carbon) sugar.The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings.These asymmetric bonds mean a strand of DNA has a direction.In a double helix the direction of the nucleotides in one strand is opposite to their direction in the other strand.This arrangement of DNA strands is called antiparallel.The asymmetric ends of DNA strands are referred to as the 5′ (five prime) and 3′ (three prime) ends, with the 5' end being that with a terminal phosphate group and the 3' end that with a terminal hydroxyl group. One of the major differences between DNA and RNA is the sugar, with 2-deoxyribose being replaced by the alternative pentose sugar ribose in RNA. The DNA double helix is stabilized by hydrogen bonds between the bases attached to the two strands.The four bases found in DNA are adenine (abbreviated A), cytosine (C), guanine (G) and thymine (T).These four bases are attached to the sugar/phosphate to form the complete nucleotide, as shown for adenosine monophosphate. These bases are classified into two types; adenine and guanine are fused five- and six-membered heterocyclic compounds called purines, while cytosine and thymine are six-membered rings called pyrimidines.A fifth pyrimidine base, called uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring.Uracil is not usually found in DNA, occurring only as a breakdown product of cytosine. ## Major and minor grooves The double helix is a right-handed spiral.As the DNA strands wind around each other, they leave gaps between each set of phosphate backbones, revealing the sides of the bases inside (see animation).There are two of these grooves twisting around the surface of the double helix: one groove, the major groove, is 22 Å wide and the other, the minor groove, is 12 Å wide.The narrowness of the minor groove means that the edges of the bases are more accessible in the major groove.As a result, proteins like transcription factors that can bind to specific sequences in double-stranded DNA usually make contacts to the sides of the bases exposed in the major groove. ## Base pairing Each type of base on one strand forms a bond with just one type of base on the other strand.This is called complementary base pairing.Here, purines form hydrogen bonds to pyrimidines, with A bonding only to T, and C bonding only to G. This arrangement of two nucleotides binding together across the double helix is called a base pair.The double helix is also stabilized by the hydrophobic effect and pi stacking, which are not influenced by the sequence of the DNA.As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily.The two strands of DNA in a double helix can therefore be pulled apart like a zipper, either by a mechanical force or high temperature.As a result of this complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication.Indeed, this reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms. The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC forming three hydrogen bonds (see figures, left).The GC base pair is therefore stronger than the AT base pair.As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determine the strength of the association between the two strands of DNA.Long DNA helices with a high GC content have stronger-interacting strands, while short helices with high AT content have weaker-interacting strands.In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in some promoters, tend to have a high AT content, making the strands easier to pull apart.In the laboratory, the strength of this interaction can be measured by finding the temperature required to break the hydrogen bonds, their melting temperature (also called Tm value).When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules.These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others. ## Sense and antisense A DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA copy that is translated into protein.The sequence on the opposite strand is called the "antisense" sequence.Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands contain both sense and antisense sequences).In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear.One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing. A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between sense and antisense strands by having overlapping genes.In these cases, some DNA sequences do double duty, encoding one protein when read along one strand, and a second protein when read in the opposite direction along the other strand.In bacteria, this overlap may be involved in the regulation of gene transcription, while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome. ## Supercoiling DNA can be twisted like a rope in a process called DNA supercoiling.With DNA in its "relaxed" state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound.If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together.If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily.In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases.These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication. ## Alternative double-helical structures DNA exists in many possible conformations.However, only A-DNA, B-DNA, and Z-DNA have been observed in organisms.Which conformation DNA adopts depends on the sequence of the DNA, the amount and direction of supercoiling, chemical modifications of the bases and also solution conditions, such as the concentration of metal ions and polyamines.Of these three conformations, the "B" form described above is most common under the conditions found in cells.The two alternative double-helical forms of DNA differ in their geometry and dimensions. The A form is a wider right-handed spiral, with a shallow, wide minor groove and a narrower, deeper major groove.The A form occurs under non-physiological conditions in dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, as well as in enzyme-DNA complexes.Segments of DNA where the bases have been chemically-modified by methylation may undergo a larger change in conformation and adopt the Z form.Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form.These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription. ## Quadruplex structures At the ends of the linear chromosomes are specialized regions of DNA called telomeres.The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes.These specialized chromosome caps also help protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected.In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence. These guanine-rich sequences may stabilize chromosome ends by forming structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules.Here, four guanine bases form a flat plate and these flat four-base units then stack on top of each other, to form a stable G-quadruplex structure.These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit.Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure. In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops.Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins.At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands.This triple-stranded structure is called a displacement loop or D-loop. # Chemical modifications ## Base modifications The expression of genes is influenced by the chromatin structure of a chromosome and regions of that have low or no gene expression usually contain high levels of methylation of cytosine bases.For example, cytosine methylation, producing 5-methylcytosine, is important for X-chromosome inactivation.The average level of methylation varies between organisms, with Caenorhabditis elegans lacking cytosine methylation, while vertebrates show higher levels, with up to 1% of their DNA containing 5-methylcytosine.Despite the biological role of 5-methylcytosine it can deaminate to leave a thymine base, methylated cytosines are therefore particularly prone to mutations.Other base modifications include adenine methylation in bacteria and the glycosylation of uracil to produce the "J-base" in kinetoplastids. ## DNA damage DNA can be damaged by many different sorts of mutagens, which are agents that change the DNA sequence.These agents include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and X-rays.The type of DNA damage produced depends on the type of mutagen.For example, UV light mostly damages DNA by producing thymine dimers, which are cross-links between adjacent pyrimidine bases in a DNA strand.On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, as well as double-strand breaks.It has been estimated that in each human cell, about 500 bases suffer oxidative damage per day.Of these oxidative lesions, the most dangerous are double-strand breaks, as these are difficult to repair and can produce point mutations, insertions and deletions from the DNA sequence, as well as chromosomal translocations. Many mutagens intercalate into the space between two adjacent base pairs.Intercalators are mostly aromatic and planar molecules, and include ethidium, daunomycin, doxorubicin and thalidomide.In order for an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix.These structural changes inhibit both transcription and DNA replication, causing toxicity and mutations.As a result, DNA intercalators are often carcinogens, with benzopyrene diol epoxide, acridines, aflatoxin and ethidium bromide being well-known examples.Nevertheless, due to their properties of inhibiting DNA transcription and replication, they are also used in chemotherapy to inhibit rapidly-growing cancer cells. # Overview of biological functions DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes.The set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes.The information carried by DNA is held in the sequence of pieces of DNA called genes.Transmission of genetic information in genes is achieved via complementary base pairing.For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides.Usually, this RNA copy is then used to make a matching protein sequence in a process called translation which depends on the same interaction between RNA nucleotides.Alternatively, a cell may simply copy its genetic information in a process called DNA replication.The details of these functions are covered in other articles; here we focus on the interactions between DNA and other molecules that mediate the function of the genome. ## Genes and genomes Genomic DNA is located in the cell nucleus of eukaryotes, as well as small amounts in mitochondria and chloroplasts.In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid.The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype.A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism.Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the transcription of the open reading frame. In many species, only a small fraction of the total sequence of the genome encodes protein.For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences.The reasons for the presence of so much non-coding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species represent a long-standing puzzle known as the "C-value enigma."However, DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression. Some non-coding DNA sequences play structural roles in chromosomes.Telomeres and centromeres typically contain few genes, but are important for the function and stability of chromosomes.An abundant form of non-coding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation.These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence. ## Transcription and translation A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism.Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences.The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code.The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT). In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase.

This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids.Since there are 4 bases in 3-letter combinations, there are 64 possible codons (4^3 combinations).These encode the twenty standard amino acids, giving most amino acids more than one possible codon.There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA, TGA and TAG codons. ## Replication Cell division is essential for an organism to grow, but when a cell divides it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent.The double-stranded structure of DNA provides a simple mechanism for DNA replication.Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase.This enzyme makes the complementary strand by finding the correct base through complementary base pairing, and bonding it onto the original strand.As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix.In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA. # Interactions with proteins All the functions of DNA depend on interactions with proteins.These protein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence.Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important. ## DNA-binding proteins Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions.Within chromosomes, DNA is held in complexes with structural proteins.These proteins organize the DNA into a compact structure called chromatin.In eukaryotes this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved.The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface.These non-specific interactions are formed through basic residues in the histones making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are therefore largely independent of the base sequence.Chemical modifications of these basic amino acid residues include methylation, phosphorylation and acetylation.These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription.Other non-specific DNA-binding proteins found in chromatin include the high-mobility group proteins, which bind preferentially to bent or distorted DNA.These proteins are important in bending arrays of nucleosomes and arranging them into more complex chromatin structures. A distinct group of DNA-binding proteins are the single-stranded-DNA-binding proteins that specifically bind single-stranded DNA.In humans, replication protein A is the best-characterised member of this family and is essential for most processes where the double helix is separated, including DNA replication, recombination and DNA repair.These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases. In contrast, other proteins have evolved to specifically bind particular DNA sequences.The most intensively studied of these are the various classes of transcription factors, which are proteins that regulate transcription.Each one of these proteins bind to one particular set of DNA sequences and thereby activates or inhibits the transcription of genes with these sequences close to their promoters.The transcription factors do this in two ways.Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription.Alternatively, transcription factors can bind enzymes that modify the histones at the promoter; this will change the accessibility of the DNA template to the polymerase. As these DNA targets can occur throughout an organism's genome, changes in the activity of one type of transcription factor can affect thousands of genes.Consequently, these proteins are often the targets of the signal transduction processes that mediate responses to environmental changes or cellular differentiation and development.The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to "read" the DNA sequence.Most of these base-interactions are made in the major groove, where the bases are most accessible. ## DNA-modifying enzymes ### Nucleases and ligases Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds.Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands.The most frequently-used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences.For instance, the EcoRV enzyme shown to the left recognizes the 6-base sequence 5′-GAT|ATC-3′ and makes a cut at the vertical line.In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system.In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting. Enzymes called DNA ligases can rejoin cut or broken DNA strands.Ligases are particularly important in lagging strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a complete copy of the DNA template.They are also used in DNA repair and genetic recombination. ### Topoisomerases and helicases Topoisomerases are enzymes with both nuclease and ligase activity.These proteins change the amount of supercoiling in DNA.Some of these enzyme work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break.Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix.Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription. Helicases are proteins that are a type of molecular motor.They use the chemical energy in nucleoside triphosphates, predominantly ATP, to break hydrogen bonds between bases and unwind the DNA double helix into single strands.These enzymes are essential for most processes where enzymes need to access the DNA bases. ### Polymerases Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates.The sequence of their products are copies of existing polynucleotide chains - which are called templates.These enzymes function by adding nucleotides onto the 3′ hydroxyl group of the previous nucleotide in a DNA strand.Consequently, all polymerases work in a 5′ to 3′ direction.In the active site of these enzymes, the incoming nucleoside triphosphate base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand of their template.Polymerases are classified according to the type of template that they use. In DNA replication, a DNA-dependent DNA polymerase makes a DNA copy of a DNA sequence.Accuracy is vital in this process, so many of these polymerases have a proofreading activity.Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides.If a mismatch is detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed.In most organisms DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases. RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand into DNA.They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres.Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure. Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA.To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands.It then copies the gene sequence into a messenger RNA transcript until it reaches a region of DNA called the terminator, where it halts and detaches from the DNA.As with human DNA-dependent DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome, operates as part of a large protein complex with multiple regulatory and accessory subunits. # Genetic recombination A DNA helix usually does not interact with other segments of DNA, and in human cells the different chromosomes even occupy separate areas in the nucleus called "chromosome territories".This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is during chromosomal crossover when they recombine.Chromosomal crossover is when two DNA helices break, swap a section and then rejoin. Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of natural selection and can be important in the rapid evolution of new proteins.Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks. The most common form of chromosomal crossover is homologous recombination, where the two chromosomes involved share very similar sequences.Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities.The recombination reaction is catalyzed by enzymes known as recombinases, such as RAD51. The first step in recombination is a double-stranded break either caused by an endonuclease or damage to the DNA. A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to the complementary strand in the other helix.The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another.The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA. # Evolution of DNA metabolism DNA contains the genetic information that allows all modern living things to function, grow and reproduce.However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material.RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes.This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution of the current genetic code based on four nucleotide bases.This would occur since the number of unique bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes. Unfortunately, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible.This is because DNA will survive in the environment for less than one million years and slowly degrades into short fragments in solution.Claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250-million years old, but these claims are controversial. # Uses in technology ## Genetic engineering Modern biology and biochemistry make intensive use of recombinant DNA technology.Recombinant DNA is a man-made DNA sequence that has been assembled from other DNA sequences.They can be transformed into organisms in the form of plasmids or in the appropriate format, by using a viral vector.The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research, or be grown in agriculture. ## Forensics Forensic scientists can use DNA in blood, semen, skin, saliva or hair at a crime scene to identify a perpetrator.This process is called genetic fingerprinting, or more accurately, DNA profiling.In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people.This method is usually an extremely reliable technique for identifying a criminal.However, identification can be complicated if the scene is contaminated with DNA from several people.DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys, and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.People convicted of certain types of crimes may be required to provide a sample of DNA for a database.This has helped investigators solve old cases where only a DNA sample was obtained from the scene.DNA profiling can also be used to identify victims of mass casualty incidents. ## Bioinformatics Bioinformatics involves the manipulation, searching, and data mining of DNA sequence data.The development of techniques to store and search DNA sequences have led to widely-applied advances in computer science, especially string searching algorithms, machine learning and database theory.String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides.In other applications such as text editors, even simple algorithms for this problem usually suffice, but DNA sequences cause these algorithms to exhibit near-worst-case behaviour due to their small number of distinct characters.The related problem of sequence alignment aims to identify homologous sequences and locate the specific mutations that make them distinct.These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function.Data sets representing entire genomes' worth of DNA sequences, such as those produced by the Human Genome Project, are difficult to use without annotations, which label the locations of genes and regulatory elements on each chromosome.Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict the presence of particular gene products in an organism even before they have been isolated experimentally. ## DNA nanotechnology DNA nanotechnology uses the unique molecular recognition properties of DNA and other nucleic acids to create self-assembling branched DNA complexes with useful properties. DNA is thus used as a structural material rather than as a carrier of biological information. This has led to the creation of two-dimensional periodic lattices (both tile-based as well as using the "DNA origami" method) as well as three-dimensional structures in the shapes of polyhedra. Nanomechanical devices and algorithmic self-assembly have also been demonstrated, and these DNA structures have been used to template the arrangement of other molecules such as gold nanoparticles and streptavidin proteins. ## History and anthropology Because DNA collects mutations over time, which are then inherited, it contains historical information and by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny.This field of phylogenetics is a powerful tool in evolutionary biology.If DNA sequences within a species are compared, population geneticists can learn the history of particular populations.This can be used in studies ranging from ecological genetics to anthropology; for example, DNA evidence is being used to try to identify the Ten Lost Tribes of Israel. DNA has also been used to look at modern family relationships, such as establishing family relationships between the descendants of Sally Hemings and Thomas Jefferson.This usage is closely related to the use of DNA in criminal investigations detailed above.Indeed, some criminal investigations have been solved when DNA from crime scenes has matched relatives of the guilty individual. # History of DNA research DNA was first isolated by the Swiss physician Friedrich Miescher who, in 1869, discovered a microscopic substance in the pus of discarded surgical bandages.As it resided in the nuclei of cells, he called it "nuclein".In 1919 this discovery was followed by Phoebus Levene's identification of the base, sugar and phosphate nucleotide unit.Levene suggested that DNA consisted of a string of nucleotide units linked together through the phosphate groups.However, Levene thought the chain was short and the bases repeated in a fixed order.In 1937 William Astbury produced the first X-ray diffraction patterns that showed that DNA had a regular structure. In 1928, Frederick Griffith discovered that traits of the "smooth" form of the Pneumococcus could be transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough" form.This system provided the first clear suggestion that DNA carried genetic information, when Oswald Avery, along with coworkers Colin MacLeod and Maclyn McCarty, identified DNA as the transforming principle in 1943.DNA's role in heredity was confirmed in 1952, when Alfred Hershey and Martha Chase in the Hershey-Chase experiment showed that DNA is the genetic material of the T2 phage. In 1953, based on X-ray diffraction images taken by Rosalind Franklin and the information that the bases were paired, James D. Watson and Francis Crick suggested what is now accepted as the first accurate model of DNA structure in the journal Nature.Experimental evidence for Watson and Crick's model were published in a series of five articles in the same issue of Nature.Of these, Franklin and Raymond Gosling's paper was the first publication of X-ray diffraction data that supported the Watson and Crick model, this issue also contained an article on DNA structure by Maurice Wilkins and his colleagues.In 1962, after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine.However, debate continues on who should receive credit for the discovery.

In an influential presentation in 1957, Crick laid out the "Central Dogma" of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis".Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through the Meselson-Stahl experiment.Further work by Crick and coworkers showed that the genetic code was based on non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley and Marshall Warren Nirenberg to decipher the genetic code.These findings represent the birth of molecular biology.

DXN Established in 1993, DXN is a multi-level marketing (MLM) company founded by Dato´ Dr. Lim Siow Jin.Based in Malaysia, the company is well known for its Ganoderma business.Its product lines include dietary supplements, food and beverages, personal care products, household products and water treatment system.DXN Holdings Bhd.was listed on the Main Board of the Kuala Lumpur Stock Exchange (KLSE) on 30 September 2003. DXN sells dietary supplements based on the Chinese mushroom called ganoderma (Polyporus lucidus; also known as reishi or lingzhi), which is considered the food of the immortals in Daoism.Ganoderma has long been used in traditional Chinese medicine for the treatment of such diseases and disorders as cancer and arthritis, and its biomedicinal value is now being established through a wealth of published literature. # Ganoderma Reishi mushroom or "Lingzhi" mushroom is also known as Ganoderma lucidum.For centuries, this mushroom is claimed as "King of Herbs" by herbal practitioners in China and Japan for its efficacy in the maintenance or improvement of general well-being.This mushroom has been listed as a Chinese herb and classified as a superior herb dating back to 2800 BC. Ganoderma contains more than 200 active elements which can be categorized as water soluble, organic soluble and volatile compounds.The major elements found are Polysaccharide, Adenosine and Triterpenoids, each having their own medicinal effects. # DXN Farm DXN’s International headquarter has a 30 acre Ganoderma farms located at Bukit Wang, Malaysia and a 10 acre farm at Bukit Pinang in Kedah, Malaysia. # DXN Pharmaceutical DXN Pharmaceutical, established in June 2001, is a processing factory for DXN supplements with front-to-end facilities and equipment.It is located in an area of 28,000 square meters.

Dol A Dol is a unit of measurement for pain (from the Latin word for pain, dolor). James D. Hardy, Herbert G. Wolff, and Helen Goodell of Cornell University proposed the unit based on their studies of pain during the 1940s-1950s; they defined one dol to equal to "just noticeable differences" (jnd's) in pain. The unit did not come into widespread use and other methods are now used to assess the level of pain experienced by patients.

RNA Ribonucleic acid or RNA is a nucleic acid, consisting of many nucleotides that form a polymer.Each nucleotide consists of a nitrogenous base, a ribose sugar, and a phosphate.RNA plays several important roles in the processes of translating genetic information from deoxyribonucleic acid (DNA) into proteins.One type of RNA acts as a messenger between DNA and the protein synthesis complexes known as ribosomes, others form vital portions of the structure of ribosomes, act as essential carrier molecules for amino acids to be used in protein synthesis, or change which genes are active. RNA is very similar to DNA, but differs in a few important structural details: RNA is usually single stranded, while DNA is usually double stranded.RNA nucleotides contain ribose while DNA contains deoxyribose (a type of ribose that lacks one oxygen atom), and RNA uses the nucleotide uracil in its composition, instead of thymine which is present in DNA.RNA is transcribed from DNA by enzymes called RNA polymerases and is generally further processed by other enzymes, some of them guided by non-coding RNAs. # Chemical and stereochemical structure Each nucleotide in RNA contains a ribose, whose carbons are numbered 1' through 5'.The base – often adenine, cytosine, guanine or uracil – is attached to the 1' position.A phosphate group is attached to the 3' position of one ribose and the 5' position of the next.The phosphate groups have a negative charge each at physiological pH, making RNA a charged molecule. The bases often form hydrogen bonds between adenine and uracil and between cytosine and guanine, but other interactions are possible, such as a group of adenine bases binding to each other in a bulge. There are also numerous modified bases and sugars found in RNA that serve many different roles.Pseudouridine (Ψ), in which the linkage between uracil and ribose is changed from a C–N bond to a C–C bond, and ribothymidine (T), are found in various places (most notably in the TΨC loop of tRNA). Another notable modified base is hypoxanthine, a deaminated guanine base whose nucleoside is called inosine.Inosine plays a key role in the Wobble Hypothesis of the genetic code.There are nearly 100 other naturally occurring modified nucleosides, of which pseudouridine and nucleosides with 2'-O-methylribose are the most common. The specific roles of many of these modifications in RNA are not fully understood.However, it is notable that in ribosomal RNA, many of the post-translational modifications occur in highly functional regions, such as the peptidyl transferase center and the subunit interface, implying that they are important for normal function. The most important structural feature of RNA, that distinguishes it from DNA is the presence of a hydroxyl group at the 2'-position of the ribose sugar.The presence of this functional group enforces the C3'-endo sugar conformation (as opposed to the C2'-endo conformation of the deoxyribose sugar in DNA) that causes the helix to adopt the A-form geometry rather than the B-form most commonly observed in DNA.This results in a very deep and narrow major groove and a shallow and wide minor groove. A second consequence of the presence of the 2'-hydroxyl group is that in conformationally flexible regions of an RNA molecule (that is, not involved in formation of a double helix), it can chemically attack the adjacent phosphodiester bond to cleave the backbone. # Comparison with DNA RNA and DNA differ in three main ways. First, unlike DNA which is double-stranded, RNA is a single-stranded molecule in most of its biological roles and has a much shorter chain of nucleotides.Secondly, while DNA contains deoxyribose, RNA contains ribose, (there is no hydroxyl group attached to the pentose ring in the 2' position in DNA, whereas RNA has two hydroxyl groups).These hydroxyl groups make RNA less stable than DNA because it is more prone to hydrolysis. Thirdly, the complementary nucleotide to adenine is not thymine, as it is in DNA, but rather uracil, which is an unmethylated form of thymine. Like DNA, most biologically active RNAs including tRNA, rRNA, snRNAs and other non-coding RNAs are extensively base paired to form double stranded helices.Structural analysis of these RNAs have revealed that they are highly structured.Unlike DNA, this structure is not just limited to long double-stranded helices but rather collections of short helices packed together into structures akin to proteins.In this fashion, RNAs can achieve chemical catalysis, like enzymes.For instance, determination of the structure of the ribosome – an enzyme that catalyzes peptide bond formation – revealed that its active site is composed entirely of RNA. # Synthesis Synthesis of RNA is usually catalyzed by an enzyme - RNA polymerase, using DNA as a template.Initiation of synthesis begins with the binding of the enzyme to a promoter sequence in the DNA (usually found "upstream" of a gene).The DNA double helix is unwound by the helicase activity of the enzyme.The enzyme then progresses along the template strand in the 3’ -> 5’ direction, synthesizing a complementary RNA molecule with elongation occurring in the 5’ -> 3’ direction.The DNA sequence also dictates where termination of RNA synthesis will occur. There are also a number of RNA-dependent RNA polymerases as well that use RNA as their template for synthesis of a new strand of RNA.For instance, a number of RNA viruses (such as poliovirus) use this type of enzyme to replicate their genetic material.Also, it is known that RNA-dependent RNA polymerases are required for the RNA interference pathway in many organisms. # Biological roles ## Messenger RNA (mRNA) Messenger RNA is RNA that carries information from DNA to the ribosome sites of protein synthesis in the cell.In eukaryotic cells, once mRNA has been transcribed from DNA, it is "processed" before being exported from the nucleus into the cytoplasm, where it is bound to ribosomes and translated into its corresponding protein form with the help of tRNA.In prokaryotic cells, which do not have nucleus and cytoplasm compartments, mRNA can bind to ribosomes while it is being transcribed from DNA.After a certain amount of time the message degrades into its component nucleotides, usually with the assistance of ribonucleases. ## Non-coding RNA RNA genes (also known as non-coding RNA or small RNA) are genes that encode RNA which is not translated into a protein.The most prominent examples of RNA genes are transfer RNA (tRNA) and ribosomal RNA (rRNA), both of which are involved in the process of translation.Two other groups of non-coding RNA are microRNAs (miRNA) which regulate the gene expression and small nuclear RNAs (snRNA), a diverse class that includes for example the RNAs that form spliceosomes that excise introns from pre-mRNA. Certain RNAs are able to catalyse chemical reactions such as cutting and ligating other RNA molecules, and the catalysis of peptide bond formation in the ribosome; these are known as ribozymes. ### Translation In addition to mRNA, two types av RNA are involved in translation: ribosomal RNA (rRNA) and transfer RNA (tRNA). Ribosomal RNA is the catalytic component of the ribosomes, the protein synthesis factories in the cell.Eukaryotic ribosomes contain four different rRNA molecules: 18S, 5.8S, 28S, and 5S rRNA.Three of the rRNA molecules are synthesized in the nucleolus, and one is synthesized elsewhere.rRNA molecules are extremely abundant and make up at least 80% of the RNA molecules found in a typical eukaryotic cell.In the cytoplasm, ribosomal RNA and protein combine to form a nucleoprotein called a ribosome.The ribosome binds mRNA and carries out protein synthesis.Several ribosomes may be attached to a single mRNA at any time. Transfer RNA is a small RNA chain of about 74-95 nucleotides that transfers a specific amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis, during translation.It has sites for amino-acid attachment and an anticodon region for codon recognition that binds to a specific sequence on the messenger RNA chain through hydrogen bonding. ### Gene regulation Several types of RNA can downregulate gene expression by being complementary to a part of a gene. MicroRNAs (miRNA; 21-22 nt) are found in eukaryotes and act through RNA interference (RNAi), where an effector complex of miRNA and enzymes can break down mRNA which the miRNA is complementary to, block the mRNA from being translated, or cause the promoter to be methylated which generally downregulates the gene.Some miRNAs upregulate genes instead (RNA activation).While small interfering RNAs (siRNA; 20-25 nt) are often produced by breakdown of viral RNA, there are also endogenous sources of siRNAs.siRNAs act through RNA interference in a fashion similar to miRNAs.Animals have Piwi-interacting RNAs (piRNA; 29-30 nt) which are active in germline cells and are though to be a defense against transposons and play a role in gametogenesis.X chromosome inactivation in female mammals is caused by Xist, an RNA which coats one X chromosome, inactiving it.Antisense RNAs are widespread among bacteria; most downregulate a gene, but a few are activators of transcription. ### RNA modification RNA can be modified after transcription not only by splicing, but also by having its bases modified to other bases than adenine, cytosine, guanine and uracil. In eukaryotes, modifications of RNA bases are generally directed by small nucleolar RNAs (snoRNA), found in the nucleolus and cajal bodies.snoRNAs associate with enzymes and guide them to a spot on an RNA by basepairing to that RNA.These enzymes then perform the base modification.rRNA and tRNA are extensively modified, but snRNA and mRNA can also be the target of base modification. ## Double-stranded RNA Double-stranded RNA (dsRNA) is RNA with two complementary strands, similar to the DNA found in all cells.dsRNA forms the genetic material of some viruses called double-stranded RNA viruses.In eukaryotes, long double-stranded RNA such as viral RNA can trigger RNA interference, where short dsRNA molecules called siRNAs (small interfering RNAs) can cause enzymes to break down specific mRNAs or silence the expression of genes.siRNA can also increase the transcription of a gene, a process called RNA activation. # RNA world hypothesis The RNA world hypothesis proposes that the earliest forms of life relied on RNA both to carry genetic information (like DNA does now) and to catalyze biochemical reactions like an enzyme.According to this hypothesis, descendants of these early lifeforms gradually integrated DNA and proteins into their metabolism. # RNA secondary structures The functional form of single stranded RNA molecules, just like proteins, frequently requires a specific tertiary structure.The scaffold for this structure is provided by secondary structural elements which are hydrogen bonds within the molecule.This leads to several recognizable "domains" of secondary structure like hairpin loops, bulges and internal loops.The secondary structure of RNA molecules can be predicted computationally by calculating the minimum free energies (MFE) structure for all different combinations of hydrogen bondings and domains.There has been a significant amount of research directed at the RNA structure prediction problem. Online tools for MFE structure prediction from single sequences are provided by MFOLD and RNAfold. Comparative studies of conserved RNA structures are significantly more accurate and provide evolutionary information.Computationally reasonable and accurate online tools for alignment folding are provided by KNetFold, RNAalifold and Pfold. A package of RNA structure prediction programs is also available for Windows: RNAstructure. A database of RNA sequences and secondary structures is available from Rfam, analyses and links to RNA analysis tools are available from Wikiomics. # List of RNA types In addition, the genome of many types of viruses consists of RNA, namely double-stranded RNA viruses, positive-sense RNA viruses, negative-sense RNA viruses and most satellite viruses and reverse transcribing viruses. # History Nucleic acids were discovered in 1868 by Friedrich Miescher, who called the material 'nuclein' since it was found in the nucleus.It was later discovered that prokaryotic cells, which do not have a nucleus, also contain nucleic acids.The role of RNA in protein synthesis had been suspected since 1939, based on experiments carried out by Torbjörn Caspersson, Jean Brachet and Jack Schultz.Gerard Marbaix isolated the first messenger RNA, for rabbit hemoglobin, and found it induced the synthesis of hemoglobin after injection into oocytes.Finally, Severo Ochoa discovered the RNA, winning Ochoa the 1959 Nobel Prize for Medicine.The sequence of the 77 nucleotides of a yeast RNA was found by Robert W. Holley in 1965, winning Holley the 1968 Nobel Prize for Medicine.In 1976, Walter Fiers and his team at the University of Ghent determined the first complete nucleotide sequence of an RNA virus genome, that of bacteriophage MS2. While ribosomal RNA and transfer RNA were found early, since the late 1990s, many new RNA genes have been found, and thus RNA genes may play a much more significant role than previously thought.In the late 1990s and early 2000, there was persistent evidence of more complex transcription occurring in mammalian cells (and possibly others).This could point towards a more widespread use of RNA in biology, particularly in gene regulation.A particular class of non-coding RNA, microRNA, has been found in many eukaryotes and clearly plays an important role in regulating other genes, through RNA interference.

XPB XPB (xeroderma pigmentosum type B) is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex. # Structure The 3D-structure of the archaeal homolog of XPB has been solved by X-ray crystallography by Dr. John Tainer and his group at The Scripps Research Institute. # Function XPB plays a significant role in normal basal transcription, transcription coupled repair (TCR), and nucleotide excision repair (NER).Purified XPB has been shown to unwind DNA with 3’-5’ polarity. The function of the XPB(ERCC3) protein in NER is to assist in unwinding the DNA double helix after damage is initially recognized. NER is a multi-step pathway that removes a wide range of different DNA damages that distort normal base pairing. Such damages include bulky chemical adducts, UV-induced pyrimidine dimers, and several forms of oxidative damage. Mutations in the XPB(ERCC3) gene can lead, in humans, to xeroderma pigmentosum (XP) or XP combined with Cockayne syndrome (XPCS). Mutant XPB cells from individuals with the XPCS phenotype are sensitive to UV irradiation and acute oxidative stress. # Disorders Mutations in XPB and other related complementation groups, XPA-XPG, leads to a number of genetic disorders such as Xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy. # Interactions XPB has been shown to interact with: - BCR gene, - CDK7, - ERCC2, - GTF2H1, - GTF2H2, - GTF2H4, - GTF2H5, - P53, - PSMC5, and - XPC.

Ear The ear is the sense organ that detects sounds. The vertebrate ear shows a common biology from fish to humans, with variations in structure according to order and species.It not only acts as a receiver for sound, but plays a major role in the sense of balance and body position.The ear is part of the auditory system. The word "ear" may be used correctly to describe the entire organ or just the visible portion.In most animals, the visible ear is a flap of tissue that is also called the pinna.The pinna may be all that shows of the ear, but it serves only the first of many steps in hearing and plays no role in the sense of balance.In people, the pinna is often called the auricle.Vertebrates have a pair of ears, placed symmetrically on opposite sides of the head.This arrangement aids in the ability to localize sound sources. # Introduction to ears and hearing Audition is the scientific name for the perception of sound.Sound is a form of energy that moves through air, water, and other matter, in waves of pressure.Sound is the means of auditory communication, including frog calls, bird songs and spoken language.Although the ear is the vertebrate sense organ that recognizes sound, it is the brain and central nervous system that "hears".Sound waves are perceived by the brain through the firing of nerve cells in the auditory portion of the central nervous system.The ear changes sound pressure waves from the outside world into a signal of nerve impulses sent to the brain. The outer part of the ear collects sound.That sound pressure is amplified through the middle portion of the ear and, in land animals, passed from the medium of air into a liquid medium.The change from air to liquid occurs because air surrounds the head and is contained in the ear canal and middle ear, but not in the inner ear.The inner ear is hollow, embedded in the temporal bone, the densest bone of the body.The hollow channels of the inner ear are filled with liquid, and contain a sensory epithelium that is studded with hair cells.The microscopic "hairs" of these cells are structural protein filaments that project out into the fluid.The hair cells are mechanoreceptors that release a chemical neurotransmitter when stimulated.Sound waves moving through fluid push the filaments; if the filaments bend over enough it causes the hair cells to fire. In this way sound waves are transformed into nerve impulses.In vision, the rods and cones of the retina play a similar role with light as the hair cells do with sound.The nerve impulses travel from the left and right ears through the eighth cranial nerve to both sides of the brain stem and up to the portion of the cerebral cortex dedicated to sound.This auditory part of the cerebral cortex is in the temporal lobe. The part of the ear that is dedicated to sensing balance and position also sends impulses through the eighth cranial nerve, the VIIIth nerve's Vestibular Portion.Those impulses are sent to the vestibular portion of the central nervous system. The human ear can generally hear sounds with frequencies between 20 Hz and 20 kHz (the audio range). Although the sensation of hearing requires an intact and functioning auditory portion of the central nervous system as well as a working ear, human deafness (extreme insensitivity to sound) most commonly occurs because of abnormalities of the inner ear, rather than the nerves or tracts of the central auditory system. # Mammalian ear The shape of outer ear of mammals varies widely across species. However the inner workings of mammalian ears (including humans') are very similar. ## Parts of the Ear ### Outer ear (pinna, ear canal, surface of ear drum) The outer ear is the most external portion of the ear.The outer ear includes the pinna (also called auricle), the ear canal, and the very most superficial layer of the ear drum (also called the tympanic membrane).In humans, and almost all vertebrates, the only visible portion of the ear is the outer ear. Although the word "ear" may properly refer to the pinna (the flesh covered cartilage appendage on either side of the head), this portion of the ear is not vital for hearing. The complicated design of the human outer ear does help capture sound (and imposes filtering that helps distinguish the direction of the sound source), but the most important functional aspect of the human outer ear is the ear canal itself.Unless the canal is open, hearing will be dampened.Ear wax (medical name - cerumen) is produced by glands in the skin of the outer portion of the ear canal.This outer ear canal skin is applied to cartilage; the thinner skin of the deep canal lies on the bone of the skull.Only the thicker cerumen-producing ear canal skin has hairs.The outer ear ends at the most superficial layer of the tympanic membrane.The tympanic membrane is commonly called the ear drum. The pinna helps direct sound through the ear canal to the tympanic membrane (eardrum).The framework of the auricle consists of a single piece of yellow fibrocartilage with a complicated relief on the anterior, concave side and a fairly smooth configuration on the posterior, convex side.The Darwinian tubercle, which is present in some people, lies in the descending part of the helix and corresponds to the true ear tip of the long-eared mammals.The lobule merely contains subcutaneous tissue.In some animals with mobile pinnae (like the horse), each pinna can be aimed independently to better receive the sound.For these animals, the pinnae help localize the direction of the sound source.Human beings localize sound within the central nervous system, by comparing arrival-time differences and loudness from each ear, in brain circuits that are connected to both ears. The auricles also have an effect on facial appearance.In Western societies, protruding ears (present in about 5% of ethnic Europeans) have been considered unattractive, particularly if asymmetric.The first surgery to reduce the projection of prominent ears was published in the medical literature in 1881. The ears have also been ornamented with jewellery for thousands of years, traditionally by piercing of the earlobe.In some cultures, ornaments are placed to stretch and enlarge the earlobes to make them very large. Tearing of the earlobe from the weight of heavy earrings, or from traumatic pull of an earring (for example by snagging on a sweater being removed), is fairly common.The repair of such a tear is usually not difficult. A cosmetic surgical procedure to reduce the size or change the shape of the ear is called an otoplasty.In the rare cases when no pinna is formed (atresia), or is extremely small (microtia) reconstruction the auricle is possible.Most often, a cartilage graft from another part of the body (generally, rib cartilage) is used to form the matrix of the ear, and skin grafts or rotation flaps are used to provide the covering skin.However, when babies are born without an auricle on one or both sides, or when the auricle is very tiny, the ear canal is ordinarily either small or absent, and the middle ear often has deformities.The initial medical intervention is aimed at assessing the baby's hearing and the condition of the ear canal, as well as the middle and inner ear.Depending on the results of tests, reconstruction of the outer ear is done in stages, with planning for any possible repairs of the rest of the ear. ### Middle ear The middle ear, an air-filled cavity behind the ear drum (tympanic membrane), includes the three ear bones or ossicles: the malleus (or hammer), incus (or anvil), and stapes (or stirrup).The opening of the Eustachian tube is also within the middle ear.The malleus has a long process (the manubrium, or handle) that is attached to the mobile portion of the eardrum.The incus is the bridge between the malleus and stapes.The stapes is the smallest named bone in the human body.The three bones are arranged so that movement of the tympanic membrane causes movement of the malleus, which causes movement of the incus, which causes movement of the stapes.When the stapes footplate pushes on the oval window, it causes movement of fluid within the cochlea (a portion of the inner ear). In humans and other land animals the middle ear (like the ear canal) is normally filled with air.Unlike the open ear canal, however, the air of the middle ear is not in direct contact with the atmosphere outside the body.The Eustachian tube connects from the chamber of the middle ear to the back of the pharynx.The middle ear is very much like a specialized paranasal sinus, called the tympanic cavity; it, like the paranasal sinuses, is a hollow mucosa-lined cavity in the skull that is ventilated through the nose.The mastoid portion of the human temporal bone, which can be felt as a bump in the skull behind the pinna, also contains air, which is ventilated through the middle ear. Normally, the Eustachian tube is collapsed, but it gapes open both with swallowing and with positive pressure. When taking off in an airplane, the surrounding air pressure goes from higher (on the ground) to lower (in the sky).The air in the middle ear expands as the plane gains altitude, and pushes its way into the back of the nose and mouth.On the way down, the volume of air in the middle ear shrinks, and a slight vacuum is produced. Active opening of the Eustachian tube is required to equalize the pressure between the middle ear and the surrounding atmosphere as the plane descends. The diver also experiences this change in pressure, but with greater rates of pressure change; active opening of the Eustachian tube is required more frequently as the diver goes deeper into higher pressure. The arrangement of the tympanic membrane and ossicles works to efficiently couple the sound from the opening of the ear canal to the cochlea.There are several simple mechanisms that combine to increase the sound pressure.The first is the "hydraulic principle".The surface area of the tympanic membrane is many times that of the stapes footplate.Sound energy strikes the tympanic membrane and is concentrated to the smaller footplate.A second mechanism is the "lever principle".The dimensions of the articulating ear ossicles lead to an increase in the force applied to the stapes footplate compared with that applied to the malleus.A third mechanism channels the sound pressure to one end of the cochlea, and protects the other end from being struck by sound waves.In humans, this is called "round window protection", and will be more fully discussed in the next section. Abnormalities such as impacted ear wax (occlusion of the external ear canal), fixed or missing ossicles, or holes in the tympanic membrane generally produce conductive hearing loss. Conductive hearing loss may also result from middle ear inflammation causing fluid build-up in the normally air-filled space.Tympanoplasty is the general name of the operation to repair the middle ear's tympanic membrane and ossicles.Grafts from muscle fascia are ordinarily used to rebuild an intact ear drum. Sometimes artificial ear bones are placed to substitute for damaged ones, or a disrupted ossicular chain is rebuilt in order to conduct sound effectively. ### Inner ear: cochlea, vestibule, and semi-circular canals The inner ear includes both the organ of hearing (the cochlea) and a sense organ that is attuned to the effects of both gravity and motion (labyrinth or vestibular apparatus). The balance portion of the inner ear consists of three semi-circular canals and the vestibule.The inner ear is encased in the hardest bone of the body.Within this ivory hard bone, there are fluid-filled hollows.Within the cochlea are three fluid filled spaces: the tympanic canal, the vestibular canal, and the middle canal.The eighth cranial nerve comes from the brain stem to enter the inner ear.When sound strikes the ear drum, the movement is transferred to the footplate of the stapes, which presses into one of the fluid-filled ducts of the cochlea.The fluid inside this duct is moved, flowing against the receptor cells of the Organ of Corti, which fire.These stimulate the spiral ganglion, which sends information through the auditory portion of the eighth cranial nerve to the brain. Hair cells are also the receptor cells involved in balance, although the hair cells of the auditory and vestibular systems of the ear are not identical. Vestibular hair cells are stimulated by movement of fluid in the semicircular canals and the utricle and saccule.Firing of vestibular hair cells stimulates the Vestibular portion of the eighth cranial nerve. ## Damage to the human ear ### Outer ear trauma The auricle can be easily damaged.Because it is skin-covered cartilage, with only a thin padding of connective tissue, rough handling of the ear can cause enough swelling to jeopardize the blood-supply to its framework, the auricular cartilage.That entire cartilage framework is fed by a thin covering membrane called the perichondrium (meaning literally: around the cartilage).Any fluid from swelling or blood from injury that collects between the perichondrium and the underlying cartilage puts the cartilage in danger of being separated from its supply of nutrients.If portions of the cartilage starve and die, the ear never heals back into its normal shape.Instead, the cartilage becomes lumpy and distorted.Wrestler's Ear is one term used to describe the result, because wrestling is one of the most common ways such an injury occurs.Cauliflower ear is another name for the same condition, because the thickened auricle can resemble that vegetable. The lobule of the ear (ear lobe) is the one part of the human auricle that normally contains no cartilage.Instead, it is a wedge of adipose tissue (fat) covered by skin.There are many normal variations to the shape of the ear lobe, which may be small or large.Tears of the earlobe can be generally repaired with good results.Since there is no cartilage, there is not the risk of deformity from a blood clot or pressure injury to the ear lobe. Other injuries to the external ear occur fairly frequently, and can leave a major deformity.Some of the more common ones include, laceration from glass, knives, and bite injuries, avulsion injuries, cancer, frostbite, and burns. Ear canal injuries can come from firecrackers and other explosives, and mechanical trauma from placement of foreign bodies into the ear.The ear canal is most often self-traumatized from efforts at ear cleaning.The outer part of the ear canal rests on the flesh of the head; the inner part rests in the opening of the bony skull (called the external auditory meatus).The skin is very different on each part.The outer skin is thick, and contains glands as well as hair follicles.The glands make cerumen (also called ear wax).The skin of the outer part moves a bit if the pinna is pulled; it is only loosely applied to the underlying tissues.The skin of the bony canal, on the other hand, is not only among the most delicate skin in the human body, it is tightly applied to the underlying bone.A slender object used to blindly clean cerumen out of the ear often results instead with the wax being pushed in, and contact with the thin skin of the bony canal is likely to lead to laceration and bleeding. ### Middle ear trauma Like outer ear trauma, middle ear trauma most often comes from blast injuries and insertion of foreign objects into the ear.Skull fractures that go through the part of the skull containing the ear structures (the temporal bone) can also cause damage to the middle ear.Small perforations of the tympanic membrane usually heal on their own, but large perforations may require grafting.Displacement of the ossicles will cause a conductive hearing loss that can only be corrected with surgery.Forcible displacement of the stapes into the inner ear can cause a sensory neural hearing loss that cannot be corrected even if the ossicles are put back into proper position.Because human skin has a top waterproof layer of dead skin cells that are constantly shedding, displacement of portions of the tympanic membrane or ear canal into the middle ear or deeper areas by trauma can be particularly traumatic.If the displaced skin lives within a closed area, the shed surface builds up over months and years and forms a cholesteatoma.The -oma ending of that word indicates a tumour in medical terminology, and although cholesteatoma is not a neoplasm (but a skin cyst), it can expand and erode the ear structures.The treatment for cholesteatoma is surgical. - When the incus is eroded, broken or absent, the ossicular chain is reconstructed with an incus replacement prosthesis. - When both the incus and malleus are eroded or absent, the ossicular chain is reconstructed with a partial ossicular replacement prosthesis (PORP). - When the incus and arch of the stapes are eroded, or when the malleus, incus and arch of the stapes are absent, the ossicular chain is reconstructed with a total ossicular replacement prosthesis (TORP). ### Inner ear trauma There are two principal damage mechanisms to the inner ear in industrialized society, and both injure hair cells.The first is exposure to elevated sound levels (noise trauma), and the second is exposure to drugs and other substances (ototoxicity). In 1972 the U.S. EPA told Congress that at least 34 million people were exposed to sound levels on a daily basis that are likely to lead to significant hearing loss.The worldwide implication for industrialized countries would place this exposed population in the hundreds of millions.

# Vestigial structures It has long been known that humans, and indeed other primates such as the orangutan and chimpanzee have ear muscles that are minimally developed and non-functional, yet still large enough to be easily identifiable.These undeveloped muscles are known as vestigial structures.A muscle that cannot move the ear, for whatever reason, can no longer be said to have any biological function.This serves as evidence of homology between related species.In humans there is variability in these muscles, such that some people are able to move their ears in various directions, and it has been said that it may be possible for others to gain such movement by repeated trials. # Non-vertebrate hearing organs Only vertebrate animals have ears, although many invertebrates are able to detect sound using other kinds of sense organs.In insects, tympanal organs are used to hear distant sounds.They are not confined to the head, but can occur in different locations depending on the group of insects. Simpler structures allow arthropods to detect near-at-hand sounds.Spiders and cockroaches, for example, have hairs on their legs which are used for detecting sound.Caterpillars may also have hairs on their body that perceive vibrations and allow them to respond to the sound.

Ell An ell (from Proto-Indo-European *el- "elbow, forearm"), when used as an English unit of length, is usually 45 inches, i.e. 1.143 m (for the international inch).It was mainly used in the tailoring business but is now obsolete.It was derived from the length of the arm from the shoulder (or the elbow) to the wrist, although the exact length was never defined in English law. Several different national forms existed, with different lengths, including the Scottish ell (approximately 37 inches), the Flemish ell (approximately 27 inches) and the Polish ell (0.78 metres, approximately 31 inches). Sometimes ell is used as an alias for the cubit. An ell-wand or ellwand was a rod of length one ell used for official measurement. Edward I of England required that every town have one. In Scotland, the Belt of Orion was called "the King's Ellwand." - ↑ infoplease.com, OED s. Ell-wand. - ↑ cricinfo br:Gwalenn cs:Loket (délková míra) da:Alen de:Elle (Einheit) it:Auna sw:Ziraa nl:El (lengtemaat) no:Alen nn:Alen simple:Ell sl:Vatel sv:Aln

Eye Eyes are organs that detect light. Different kinds of light-sensitive organs are found in a variety of animals.The simplest eyes do nothing but detect whether the surroundings are light or dark, which is sufficient for the entrainment of circadian rhythms but hardly can be called vision. More complex eyes can distinguish shapes and colors.The visual fields of some such complex eyes largely overlap, to allow better depth perception (binocular vision), as in humans; and others are placed so as to minimize the overlap, such as in rabbits and chameleons. In the human eye, light enters the pupil and is focused on the retina by the lens.Light-sensitive nerve cells called rods (for brightness) and cones (for color) react to the light.They interact with each other and send messages to the brain that indicate brightness, color, and contour. The first proto-eyes evolved among animals 540 million years ago.Almost all animals have eyes, or descend from animals that did. In most vertebrates and some mollusks, the eye works by allowing light to enter it and project onto a light-sensitive panel of cells, known as the retina, at the rear of the eye. The cone cells (for colour) and the rod cells (for low-light contrasts) in the retina detect and convert light into neural signals.The visual signals are then transmitted to the brain via the optic nerve.Such eyes are typically roughly spherical, filled with a transparent gel-like substance called the vitreous humour, with a focusing lens and often an iris which regulates the intensity of the light that enters the eye.The eyes of cephalopods, fish, amphibians and snakes usually have fixed lens shapes, and focusing vision is achieved by telescoping the lens—similar to how a camera focuses. Compound eyes are found among the arthropods and are composed of many simple facets which give a pixelated image (not multiple images, as is often believed).Each sensor has its own lens and photosensitive cell(s).Some eyes have up to 28,000 such sensors, which are arranged hexagonally, and which can give a full 360-degree field of vision.Compound eyes are very sensitive to motion.Some arthropods, including many Strepsiptera, have compound eyes of only a few facets, each with a retina capable of creating an image, creating multiple-image vision.With each eye viewing a different angle, a fused image from all the eyes is produced in the brain, providing very wide-angle, high-resolution images. Possessing detailed hyperspectral color vision, the Mantis shrimp has been reported to have the world's most complex color vision system.Trilobites, which are now extinct, had unique compound eyes.They used clear calcite crystals to form the lenses of their eyes.In this, they differ from most other arthropods, which have soft eyes.The number of lenses in such an eye varied, however: some trilobites had only one, and some had thousands of lenses in one eye. Some of the simplest eyes, called ocelli, can be found in animals like snails, who cannot actually "see" in the normal sense.They do have photosensitive cells, but no lens and no other means of projecting an image onto these cells.They can distinguish between light and dark, but no more.This enables snails to keep out of direct sunlight.Jumping spiders have simple eyes that are so large, supported by an array of other, smaller eyes, that they can get enough visual input to hunt and pounce on their prey.Some insect larvae, like caterpillars, have a different type of simple eye (stemmata) which gives a rough image. # Evolution of eyes Biologists use the theory of evolution to explain the origin and development of eyes, as well as of organs in general. The common origin (monophyly) of all animal eyes is established by shared anatomical and genetic features of all eyes; that is, all modern eyes, varied as they are, have their origins in a proto-eye evolved some 540 million years ago.The majority of the advancements in early eyes are believed to have taken only a few million years to develop, as the first predator to gain true imaging would have touched off an "arms race", or rather, a phylogenetic radiation from the species with that first proto-eye, among the descendents of which, there may well have been an "arms race".Prey animals and competing predators alike would be forced to rapidly match or exceed any such capabilities to survive.Hence multiple eye types and subtypes developed in parallel. Vision in various animals shows adaptation to environmental requirements.For example, birds of prey have much greater visual acuity than humans, and some can see ultraviolet light.The different forms of eyes in, for example, vertebrates and mollusks are often cited as examples of parallel evolution, despite their distant common ancestry. The earliest eyes, called "eyespots", were simple patches of photoreceptor cells, or light-sensitive proteins in unicellular organisms, physically similar to the receptor patches for taste and smell.These eyespots could only sense ambient brightness: they could distinguish light and dark, but not the direction of the lightsource.This gradually changed as the eyespot depressed into a shallow "cup" shape, granting the ability to slightly discriminate directional brightness by using the angle at which the light hit certain cells to identify the source.The pit deepened over time, the opening diminished in size, and the number of photoreceptor cells increased, forming an effective pinhole camera that was capable of slightly distinguishing dim shapes. The thin overgrowth of transparent cells over the eye's aperture, originally formed to prevent damage to the eyespot, allowed the segregated contents of the eye chamber to specialize into a transparent humour that optimized color filtering, blocked harmful radiation, improved the eye's refractive index, and allowed functionality outside of water.The transparent protective cells eventually split into two layers, with circulatory fluid in between that allowed wider viewing angles and greater imaging resolution, and the thickness of the transparent layer gradually increased, in most species with the transparent crystallin protein. # Anatomy of the mammalian eye ## Three layers The structure of the mammalian eye can be divided into three main layers or tunics whose names reflect their basic functions: the fibrous tunic, the vascular tunic, and the nervous tunic. - The fibrous tunic, also known as the tunica fibrosa oculi, is the outer layer of the eyeball consisting of the cornea and sclera.The sclera gives the eye most of its white color.It consists of dense connective tissue filled with the protein collagen to both protect the inner components of the eye and maintain its shape. - The vascular tunic, also known as the tunica vasculosa oculi, is the middle vascularized layer which includes the iris, ciliary body, and choroid.The choroid contains blood vessels that supply the retinal cells with necessary oxygen and remove the waste products of respiration.The choroid gives the inner eye a dark color, which prevents disruptive reflections within the eye. - The nervous tunic, also known as the tunica nervosa oculi, is the inner sensory which includes the retina.The retina contains the photosensitive rod and cone cells and associated neurons.To maximise vision and light absorption, the retina is a relatively smooth (but curved) layer. It has two points at which it is different; the fovea and optic disc.The fovea is a dip in the retina directly opposite the lens, which is densely packed with cone cells.It is largely responsible for color vision in humans, and enables high acuity, such as is necessary in reading.The optic disc, sometimes referred to as the anatomical blind spot, is a point on the retina where the optic nerve pierces the retina to connect to the nerve cells on its inside.No photosensitive cells exist at this point, it is thus "blind". In addition to the rods and cones, a small proportion (about 2% in humans) of the ganglion cells in the retina are photosensitive through the pigment melanopsin. They are generally most excitable by blue light, about 470 nm. Their information is sent to the SCN (suprachiasmatic nuclei), not to the visual center, through the retinohypothalamic tract, not via the optic nerve. It is these light signals which regulate circadian rhythms in mammals and several other animals. Many, but not all, totally blind individuals have their circadian rhythms adjusted daily in this way. ## Anterior and posterior segments The mammalian eye can also be divided into two main segments: the anterior segment and the posterior segment. ### Posterior segment The posterior segment is the back two-thirds of the eye that includes the anterior hyaloid membrane and all structures behind it: the vitreous humor, retina, choroid, and optic nerve. On the other side of the lens is the second humour, the vitreous humour, which is bounded on all sides: by the lens, ciliary body, suspensory ligaments and by the retina.It lets light through without refraction, helps maintain the shape of the eye and suspends the delicate lens.In some animals, the retina contains a reflective layer (the tapetum lucidum) which increases the amount of light each photosensitive cell perceives, allowing the animal to see better under low light conditions. ## Extraocular anatomy In many species, the eyes are inset in the portion of the skull known as the orbits or eyesockets.This placement of the eyes helps to protect them from injury. In humans, the eyebrows redirect flowing substances (such as rainwater or sweat) away from the eye.Water in the eye can alter the refractive properties of the eye and blur vision.It can also wash away the tear fluid—along with it the protective lipid layer—and can alter corneal physiology, due to osmotic differences between tear fluid and freshwater.Osmotic effects are made apparent when swimming in freshwater pools, as the osmotic gradient draws "pool water" into the corneal tissue (the pool water is hypotonic), causing edema, and subsequently leaving the swimmer with "cloudy" or "misty" vision for a short period thereafter.The edema can be reversed by irrigating the eye with hypertonic saline which osmotically draws the excess water out of the eye. In many animals, including humans, eyelids wipe the eye and prevent dehydration.They spread tears on the eyes, which contains substances which help fight bacterial infection as part of the immune system. Some aquatic animals have a second eyelid in each eye which refracts the light and helps them see clearly both above and below water.Most creatures will automatically react to a threat to its eyes (such as an object moving straight at the eye, or a bright light) by covering the eyes, and/or by turning the eyes away from the threat.Blinking the eyes is, of course, also a reflex. In many animals, including humans, eyelashes prevent fine particles from entering the eye.Fine particles can be bacteria, but also simple dust which can cause irritation of the eye, and lead to tears and subsequent blurred vision. # Cytology The structure of the mammalian eye owes itself completely to the task of focusing light onto the retina.This light causes chemical changes in the photosensitive cells of the retina, the products of which trigger nerve impulses which travel to the brain. The retina contains two forms of photosensitive cells important to vision—rods and cones.Though structurally and metabolically similar, their function is quite different.Rod cells are highly sensitive to light, allowing them to respond in dim light and dark conditions; however, they cannot detect color differences.These are the cells that allow humans and other animals to see by moonlight, or with very little available light (as in a dark room).Cone cells, conversely, need high light intensities to respond and have high visual acuity.Different cone cells respond to different wavelengths of light, which allows an organism to see color. The shift from cone vision to rod vision is why the darker conditions become, the less color objects seem to have. The differences between rods and cones are useful; apart from enabling sight in both dim and light conditions, they have further advantages.The fovea, directly behind the lens, consists of mostly densely-packed cone cells.The fovea gives humans a highly detailed central vision, allowing reading, bird watching, or any other task which primarily requires staring at things.Its requirement for high intensity light does cause problems for astronomers, as they cannot see dim stars, or other celestial objects, using central vision because the light from these is not enough to stimulate cone cells.Because cone cells are all that exist directly in the fovea, astronomers have to look at stars through the "corner of their eyes" (averted vision) where rods also exist, and where the light is sufficient to stimulate cells, allowing an individual to observe faint objects. Rods and cones are both photosensitive, but respond differently to different frequencies of light.They contain different pigmented photoreceptor proteins.Rod cells contain the protein rhodopsin and cone cells contain different proteins for each color-range.The process through which these proteins go is quite similar — upon being subjected to electromagnetic radiation of a particular wavelength and intensity, the protein breaks down into two constituent products.Rhodopsin, of rods, breaks down into opsin and retinal; iodopsin of cones breaks down into photopsin and retinal.The opsin in each opens ion channels on the cell membrane, which leads to hyperpolarization; this hyperpolarization of the cell leads to a release of transmitter molecules at the synapse. Differences between the rhodopsin and the iodopsins is the reason why cones and rods enable organisms to see in dark and light conditions — each of the photoreceptor proteins requires a different light intensity to break down into the constituent products.Further, synaptic convergence means that several rod cells are connected to a single bipolar cell, which then connects to a single ganglion cell by which information is relayed to the visual cortex.This convergence is in direct contrast to the situation with cones, where each cone cell is connected to a single bipolar cell.This divergence results in the high visual acuity, or the high ability to distinguish detail, of cone cells compared to rods.If a ray of light were to reach just one rod cell, the cell's reponse may not be enough to hyperpolarize the connected bipolar cell.But because several "converge" onto a bipolar cell, enough transmitter molecules reach the synapses of the bipolar cell to hyperpolarize it. Furthermore, color is distinguishable due to the different iodopsins of cone cells; there are three different kinds, in normal human vision, which is why we need three different primary colors to make a color space. # Acuity Visual acuity is often measured in cycles per degree (CPD), which measures an angular resolution, or how much an eye can differentiate one object from another in terms of visual angles. Resolution in CPD can be measured by bar charts of different numbers of white–black stripe cycles. For example, if each pattern is 1.75 cm wide and is placed at 1 m distance from the eye, it will subtend an angle of 1 degree, so the number of white–black bar pairs on the pattern will be a measure of the cycles per degree of that pattern. The highest such number that the eye can resolve as stripes, or distinguish from a gray block, is then the measurement of visual acuity of the eye. For a human eye with excellent acuity, the maximum theoretical resolution would be 50 CPD (1.2 minute of arc per line pair, or a 0.35 mm line pair, at 1 m).However, the eye can only resolve a contrast of 5%.Taking this into account, the eye can resolve a maximum resolution of 37 CPD, or 1.6 minute of arc per line pair (0.47 mm line pair, at 1 m). A rat can resolve only about 1 to 2 CPD. A horse has higher acuity through most of the visual field of its eyes than a human has, but does not match the high acuity of the human eye's central fovea region. ## Equivalent resolution A maximum resolution of the human eye in good light of 1.6 minute of arc per line pair will correspond to 1.25 lines per minute of arc.Assuming two pixels per line pair (one pixel per line) and a square field of 120 degrees, this would be equivalent to approximately 120×60×1.25 = 9000 pixels in each of the X and Y dimensions, or about 81 megapixels. However, the human eye itself has only a small spot of sharp vision in the middle of the retina, the fovea centralis, the rest of the field of view being progressively lower resolution as it gets further from the fovea.The angle of the sharp vision being just a few degrees in the middle of the view, the sharp area thus barely achieves even a single megapixel resolution.The experience of wide sharp human vision is in fact based on turning the eyes towards the current point of interest in the field of view, the brain thus perceiving an observation of a wide sharp field of view. The narrow beam of sharp vision is easy to test by putting a fingertip on a newspaper and trying to read the text while staring at the fingertip — it is very difficult to read text that's just a few centimeters away from the fingertip. # Spectral response Human eyes respond to light with wavelength in the range of approximately 400 to 700 nm.Other animals have other ranges, with many such as birds including a significant ultraviolet (shorter than 400 nm) response. # Dynamic range The retina has a static contrast ratio of around 100:1 (about 6 1/2 stops).As soon as the eye moves (saccades) it re-adjusts its exposure both chemically and by adjusting the iris.Initial dark adaptation takes place in approximately four seconds of profound, uninterrupted darkness; full adaptation through adjustments in retinal chemistry (the Purkinje effect) are mostly complete in thirty minutes.

Hence, a dynamic contrast ratio of about 1,000,000:1 (about 20 stops) is possible.The process is nonlinear and multifaceted, so an interruption by light nearly starts the adaptation process over again. Full adaptation is dependent on good blood flow; thus dark adaptation may be hampered by poor circulation, and vasoconstrictors like alcohol or tobacco. # Eye movement The visual system in the brain is too slow to process that information if the images are slipping across the retina at more than a few degrees per second.Thus, for humans to be able to see while moving, the brain must compensate for the motion of the head by turning the eyes.Another complication for vision in frontal-eyed animals is the development of a small area of the retina with a very high visual acuity.This area is called the fovea, and covers about 2 degrees of visual angle in people.To get a clear view of the world, the brain must turn the eyes so that the image of the object of regard falls on the fovea.Eye movements are thus very important for visual perception, and any failure to make them correctly can lead to serious visual disabilities. Having two eyes is an added complication, because the brain must point both of them accurately enough that the object of regard falls on corresponding points of the two retinas; otherwise, double vision would occur.The movements of different body parts are controlled by striated muscles acting around joints.The movements of the eye are no exception, but they have special advantages not shared by skeletal muscles and joints, and so are considerably different. ### Extraocular muscles Each eye has six muscles that control its movements: the lateral rectus, the medial rectus, the inferior rectus, the superior rectus, the inferior oblique, and the superior oblique.When the muscles exert different tensions, a torque is exerted on the globe that causes it to turn, in almost pure rotation, with only about one millimeter of translation.Thus, the eye can be considered as undergoing rotations about a single point in the center of the eye.Once the human eye sustains damage to the optic nerve, the impulses will not be taken to the brain.Eye transplants can happen but the person receiving the transplant will not be able to see.As for the optic nerve, once it is damaged it cannot be fixed. ## Rapid eye movement Rapid eye movement, or REM for short, typically refers to the stage during sleep during which the most vivid dreams occur.During this stage, the eyes move rapidly.It is not in itself a unique form of eye movement. ## Saccades Saccades are quick, simultaneous movements of both eyes in the same direction controlled by the frontal lobe of the brain. ## Microsaccades Even when looking intently at a single spot, the eyes drift around.This ensures that individual photosensitive cells are continually stimulated in different degrees.Without changing input, these cells would otherwise stop generating output.Microsaccades move the eye no more than a total of 0.2° in adult humans. ## Vestibulo-ocular reflex The vestibulo-ocular reflex is a reflex eye movement that stabilizes images on the retina during head movement by producing an eye movement in the direction opposite to head movement, thus preserving the image on the center of the visual field.For example, when the head moves to the right, the eyes move to the left, and vice versa. ## Smooth pursuit movement The eyes can also follow a moving object around.This tracking is less accurate than the vestibulo-ocular reflex, as it requires the brain to process incoming visual information and supply feedback.Following an object moving at constant speed is relatively easy, though the eyes will often make saccadic jerks to keep up.The smooth pursuit movement can move the eye at up to 100°/s in adult humans. It is more difficult to visually estimate speed in low light conditions or while moving, unless there is another point of reference for determining speed. ## Optokinetic reflex The optokinetic reflex is a combination of a saccade and smooth pursuit movement.When, for example, looking out of the window in a moving train, the eyes can focus on a 'moving' tree for a short moment (through smooth pursuit), until the tree moves out of the field of vision.At this point, the optokinetic reflex kicks in, and moves the eye back to the point where it first saw the tree (through a saccade). ## Vergence movement File:Stereogram Tut Eye Convergence.png When a creature with binocular vision looks at an object, the eyes must rotate around a vertical axis so that the projection of the image is in the centre of the retina in both eyes.To look at an object closer by, the eyes rotate 'towards each other' (convergence), while for an object farther away they rotate 'away from each other' (divergence).Exaggerated convergence is called cross eyed viewing (focusing on the nose for example) .When looking into the distance, or when 'staring into nothingness', the eyes neither converge nor diverge. Vergence movements are closely connected to accommodation of the eye.Under normal conditions, changing the focus of the eyes to look at an object at a different distance will automatically cause vergence and accommodation. ## Accommodation To see clearly, the lens will be pulled flatter or allowed to regain its thicker form. # Diseases, disorders, and age-related changes There are many diseases, disorders, and age-related changes that may affect the eyes and surrounding structures. As the eye ages certain changes occur that can be attributed solely to the aging process.Most of these anatomic and physiologic processes follow a gradual decline.With aging, the quality of vision worsens due to reasons independent of aging eye diseases.While there are many changes of significance in the nondiseased eye, the most functionally important changes seem to be a reduction in pupil size and the loss of accommodation or focusing capability (presbyopia).The area of the pupil governs the amount of light that can reach the retina.The extent to which the pupil dilates also decreases with age.Because of the smaller pupil size, older eyes receive much less light at the retina.In comparison to younger people, it is as though older persons wear medium-density sunglasses in bright light and extremely dark glasses in dim light.Therefore, for any detailed visually guided tasks on which performance varies with illumination, older persons require extra lighting.Certain ocular diseases can come from sexually transmitted diseases such as herpes and genital warts. If contact between eye and area of infection occurs, the STD will be transmitted to the eye. With aging a prominent white ring develops in the periphery of the cornea- called arcus senilis.Aging causes laxity and downward shift of eyelid tissues and atrophy of the orbital fat.These changes contribute to the etiology of several eyelid disorders such as ectropion, entropion, dermatochalasis, and ptosis.The vitreous gel undergoes liquefaction (posterior vitreous detachment or PVD) and its opacities—visible as floaters—gradually increase in number. Various eye care professionals, including ophthalmologists, optometrists, and opticians, are involved in the treatment and management of ocular and vision disorders.A Snellen chart is one type of eye chart used to measure visual acuity.At the conclusion of an eye examination, an eye doctor may provide the patient with an eyeglass prescription for corrective lenses # Eye injury/safety Accidents involving common household products cause 125,000 eye injuries each year in the U.S. More than 40,000 people a year suffer eye injuries while playing sports. Sports-related eye injuries occur most frequently in baseball, basketball and racquet sports. ## Occupational eye injury Each day about 2000 U.S. workers have a job-related eye injury that requires medical treatment. About one third of the injuries are treated in hospital emergency departments and more than 100 of these injuries result in one or more days of lost work.The majority of these injuries result from small particles or objects striking or abrading the eye.Examples include metal slivers, wood chips, dust, and cement chips that are ejected by tools, wind blown, or fall from above a worker.Some of these objects, such as nails, staples, or slivers of wood or metal penetrate the eyeball and result in a permanent loss of vision.Large objects may also strike the eye/face causing blunt force trauma to the eyeball or eye socket.Chemical burns to one or both eyes from splashes of industrial chemicals or cleaning products are common.Thermal burns to the eye occur as well.Among welders, their assistants, and nearby workers, UV radiation burns (welder’s flash) routinely damage workers’ eyes and surrounding tissue. In addition to common eye injuries, health care workers, laboratory staff, janitorial workers, animal handlers, and other workers may be at risk of acquiring infectious diseases via ocular exposure.

FYN Proto-oncogene tyrosine-protein kinase Fyn (p59-FYN, Slk, Syn, MGC45350, Gene ID 2534) is an enzyme that in humans is encoded by the FYN gene. Fyn is a 59-kDa member of the Src family of kinases typically associated with T-cell and neuronal signaling in development and normal cell physiology.Disruptions in these signaling pathways often have implications in the formation of a variety of cancers.By definition as a proto-oncogene, Fyn codes for proteins that help regulate cell growth.Changes in its DNA sequence transform it into an oncogene that leads to the formation of a different protein with implications for normal cell regulation. Fyn is a member of the protein-tyrosine kinase oncogene family.It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth.The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the fyn-binding protein.Alternatively spliced transcript variants encoding distinct isoforms exist. # History Fyn is a member of the Src-family of kinases (SFK), the first proto-oncogene to be identified.The discovery of the Src-family in 1976 led to the Nobel prize for medicine in 1989 for J.M Bishop and E.M. Varmus.Fyn was first identified in 1986 as Syn or Slk through probes derived from v-yes and v-fgr.A common feature of SFKs is that they are commonly upregulated in cancers.Fyn is functionally distinct from its family members in that it interacts with FAK and paxillin (PXN) in the regulation of cell morphology and motility. # Function Fyn is a protein, present in the signaling pathway of integrins, which activates ras.Fyn is a tyrosine-specific phospho-transferase that is a member of the Src family of non-receptor tyrosine protein kinases. (This family also includes Abl, Src, focal adhesion kinase and Janus kinase.)Fyn is located downstream of several cell surface receptors, commonly associated with neuronal development and T-cell signaling.When fyn is activated it causes downstream activation of molecular signals that drive processes crucial to growth and motility of cells.Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane, where it phosphorylates tyrosine residues on key targets involved in a variety of different signaling pathways.Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules.Fyn also is a tumor suppressor.When this normal biology is compromised, the altered Fyn becomes involved in the neoplastic transformation of normal cells to cancerous ones following the pathway from pre-invasive, to invasive, and ultimately metastasis. # Role in signaling pathways An understanding of the role of fyn in normal biology is crucial to the understanding of its role in cancer, as cancer is the dysregulation of these normal pathways.Knowing which pathways involve Fyn will provide key insight for the development of potential pharmacologic agents to attenuate this uncontrolled signaling. At least three tools have been useful in discerning a requirement for Fyn function in a particular signaling system: - cells derived from Fyn-/- mice (as well as cells derived from Fyn, Src, Yes, Fyn triple knockout mice (SYF)); - a kinase-inactive, dominant negative mutant form of Fyn (K299M); - pharmacologic inhibitors of Src family kinases, such as PP2; note that PP2 also inhibits other tyrosine protein kinases such as Abl, PDGFR and c-Kit. Using these tools, a requirement for Fyn has been shown for the following signaling pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. # Interactions FYN has been shown to interact with: - ADD2, - BCAR1, - C-Raf, - CBLC, - CD36, - CD44, - CDH1, - CHRNA7, - CTNND1, - CBL, - CSF1R, - DLG4, - Dystroglycan, - EPHA8, - FYB, - FASLG, - GNB2L1, - GRIN2A, - ITK, - Janus kinase 2, - KHDRBS1, - Lck, - LKB1, - Nephrin, - PAG1, - PIK3R2, - PRKCQ, - PTK2B, - PTK2, - PTPRT - UNC119, - RICS, - SH2D1A, - SKAP1, - Syk, - TNK2, - TRPC6, - Tau protein, - TrkB, - TYK2, - TUBA3C, - WAS, and - ZAP-70, # Role in cancer biology The Src family of kinases is commonly associated with its role in “invasion and tumor progression, epithelial-to-mesenchymal transition, angiogenesis, and development of metastasis,” all hallmarks of cancer progression.Fyn’s normal function in cellular growth and proliferation has the potential to be exploited in the progression and metastasis of cancer cells.Overexpression of Fyn has been found to drive morphologic transformation in normal cells and increase “anchorage-independent growth and prominent morphologic changes.” Fyn overexpression has been studied in relation to the following cancers: prostate cancer, glioblastoma multiform, squamous cell carcinoma of the head and neck, pancreatic cancer, chronic melogenic leukemia, and melanoma.This overexpression triggers a promotion of “anti-apoptotic activity of Akt” in prostate cancer, meaning that these cells have gained the ability to avoid the normal cell death pathways (a common hallmark of cancer).Additionally, in glioblastoma multiform, Src and Fyn have been found to be “effectors of oncogenic EGFR signaling” which has led to tumor invasion and cancer cell survival. Fyn’s normal role in cell migration and adhesion enables it to utilize the normal cell biology of integrin and FAK for cancer growth.Normal integrin is a cell surface receptor that interacts with the extracellular matrix to send signals influencing cell shape and motility.Normal FAK is a tyrosine kinase that gets recruited to focal adhesion sites and plays a key role in directed cell movement.These normal pathways plan a key role in “mediation of Fyn transmitted cellular events impacting shape and motility.”A compromised version of this pathway would enable cancer cells to change shape and motility, increasing the possibility for advanced invasion and metastasis.Additional pathways under investigation regarding Fyn’s role in cancer progression include: the Rac and Rho family of GTPases, Ras, Erk, and MAPK. Because of this, Fyn has been a common target for anti-cancer therapeutic research.The inhibition of Fyn (like other SFKs) results in decreased cell growth.Furthermore, “expression of kinase-dead-Fyn (KD-Fyn), a specific competitor of endogenous Fyn,” was found to reduce the size of primary tumors in mice.Specifically targeting the unique identifying properties of Fyn as well as inhibiting FAK and PXN has the potential to create a very effective molecularly targeted combination cancer therapy.Fyn inhibitors are also being explored as potential therapies for Alzheimer's Disease.

Fat Fats consist of a wide group of compounds that are generally soluble in organic solvents and largely insoluble in water.Chemically, fats are generally triesters of glycerol and fatty acids.Fats may be either solid or liquid at normal room temperature, depending on their structure and composition.Although the words "oils", "fats" and "lipids" are all used to refer to fats, "oils" is usually used to refer to fats that are liquids at normal room temperature, while "fats" is usually used to refer to fats that are solids at normal room temperature. "Lipids" is used to refer to both liquid and solid fats.The word "oil" is used for any substance that does not mix with water and has a greasy feel, such as petroleum (or crude oil) and heating oil, regardless of its chemical structure. Fats form a category of lipid, distinguished from other lipids by their chemical structure and physical properties.This category of molecules is important for many forms of life, serving both structural and metabolic functions. They are an important part of the diet of most heterotrophs (including humans).Fats or lipids are broken down in the body by enzymes called lipase produced in the pancreas. Examples of edible animal fats are lard (pig fat), butter, ghee, marine fish oils.They are obtained from fats in the milk, meat and under the skin of the animal.Examples of edible plant fats are peanut, soya bean, sunflower, sesame, coconut, olive and vegetable oils.Margarine and vegetable shortening, which can be which derived from the above oils, are used mainly for baking. These examples of fats can be categorized into saturated fats and unsaturated fats. # Chemical structure There are many different kinds of fats, but each is a variation on the same chemical structure. All fats consist of fatty acids (chains of carbon and hydrogen atoms, with a carboxylic acid group at one end) bonded to a backbone structure, often glycerol (a "backbone" of carbon, hydrogen, and oxygen).Chemically, this is a triester of glycerol, an ester being the molecule formed from the reaction of the carboxylic acid and an organic alcohol.As a simple visual illustration, if the kinks and angles of these chains were straightened out, the molecule would have the shape of a capital letter E. The fatty acids would each be a horizontal line; the glycerol "backbone" would be the vertical line that joins the horizontal lines.Fats therefore have "ester" bonds. The properties of any specific fat molecule depend on the particular fatty acids that constitute it. Different fatty acids are comprised of different numbers of carbon and hydrogen atoms. The carbon atoms, each bonded to two neighboring carbon atoms, form a zigzagging chain; the more carbon atoms there are in any fatty acid, the longer its chain will be. Fatty acids with long chains are more susceptible to intermolecular forces of attraction (in this case, van der Waals forces), raising its melting point.Long chains also yield more energy per molecule when metabolized. A fat's constituent fatty acids may also differ in the number of hydrogen atoms that are bonded to the chain of carbon atoms.Each carbon atom is typically bonded to two hydrogen atoms.When a fatty acid has this typical arrangement, it is called "saturated", because the carbon atoms are saturated with hydrogen; meaning they are bonded to as many hydrogens as possible.In other fats, a carbon atom may instead bond to only one other hydrogen atom, and have a double bond to a neighboring carbon atom.This results in an "unsaturated" fatty acid.More specifically, it would be a "monounsaturated" fatty acid, whereas, a "polyunsaturated" fatty acid would be a fatty acid with more than one double bond. Saturated and unsaturated fats differ in their energy content and melting point. Since an unsaturated fat contains fewer carbon-hydrogen bonds than a saturated fat with the same number of carbon atoms, unsaturated fats will yield slightly less energy during metabolism than saturated fats with the same number of carbon atoms. Saturated fats can stack themselves in a closely packed arrangement, so they can freeze easily and are typically solid at room temperature. But the rigid double bond in an unsaturated fat fundamentally changes the chemistry of the fat.There are two ways the double bond may be arranged: the isomer with both parts of the chain on the same side of the double bond (the cis-isomer), or the isomer with the parts of the chain on opposite sides of the double bond (the trans-isomer).Most trans-isomer fats (commonly called trans fats) are commercially produced rather than naturally occurring.The cis-isomer introduces a kink into the molecule that prevents the fats from stacking efficiently as in the case of fats with saturated chains.This decreases intermolecular forces between the fat molecules, making it more difficult for unsaturated cis-fats to freeze; they are typically liquid at room temperature.Trans fats may still stack like saturated fats, and are not as susceptible to metabolization as other fats.Trans fats and saturated fats significantly increase the risk of coronary heart disease. # Importance for living organisms Vitamins A, D, E, and K are fat-soluble, meaning they can only be digested, absorbed, and transported in conjunction with fats.Fats are sources of essential fatty acids, an important dietary requirement. Fats play a vital role in maintaining healthy skin and hair, insulating body organs against shock, maintaining body temperature, and promoting healthy cell function.They also serve as energy stores for the body. Fats are broken down in the body to release glycerol and free fatty acids. The glycerol can be converted to glucose by the liver and thus used as a source of energy. The fat content of a food can be analyzed by extraction.The exact method varies on what type of fat to be analyzed - for example, polyunsaturated and monounsaturated fats are tested quite differently. Fat also serves as a useful buffer towards a host of diseases.When a particular substance, whether chemical or biotic -- reaches unsafe levels in the bloodstream, the body can effectively dilute -- or at least maintain equilibrium of -- the offending substances by storing it in new fat tissue.This helps to protect vital organs, until such time as the offending substances can be metabolized and/or removed from the body by such means as excretion, urination, accidental or intentional bloodletting, sebum excretion, and hair growth. While it is nearly impossible to remove fat completely from the diet, it would be wrong to do so.Some fatty acids are essential nutrients, meaning that they can't be produced in the body from other compounds and need to be consumed in small amounts.All other fats required by the body are non-essential and can be produced in the body from other compounds. # Adipose tissue Adipose, or fatty tissue is the human body's means of storing metabolic energy over extended periods of time.Depending on current physiological conditions, adipocytes store fat derived from the diet and liver metabolism or degrades stored fat to supply fatty acids and glycerol to the circulation.These metabolic activities are regulated by several hormones (i.e., insulin, glucagon and epinephrine).The location of the tissue determines its metabolic profile: "Visceral fat" is located within the abdominal wall (i.e., beneath the wall of abdominal muscle) whereas "subcutaneous fat" is located beneath the skin (and includes fat that is located in the abdominal area beneath the skin but above the abdominal muscle wall). It was briefly thought that visceral fat produced a hormone involved in insulin resistance, but this has been disproved by clinical tests (see, resistin, a hormone, ultimately misnamed, which is produced by adipose tissue and does cause insulin resistance in mice but not in humans).

Fly # Overview True flies are insects of the Order Diptera (Greek: di = two, and pteron = wing), possessing a single pair of wings on the mesothorax and a pair of halteres, derived from the hind wings, on the metathorax.The common housefly is a true fly and is one of the most widely distributed of animals. The presence of a single pair of wings distinguishes true flies from other insects with "fly" in their name, such as mayflies, dragonflies, damselflies, stoneflies, whiteflies, fireflies, alderflies, dobsonflies, snakeflies, sawflies, caddisflies, butterflies or scorpionflies.Some true flies have become secondarily wingless, especially in the superfamily Hippoboscoidea, or among those that are inquilines in social insect colonies. It is a large order, containing an estimated 240,000 species of mosquitos, gnats, midges and others, although under half of these (about 120,000 species) have been described .It is one of the major insect orders both in terms of ecological and human (medical and economic) importance.The Diptera, in particular the mosquitoes (Culicidae), are of great importance as disease transmitters, acting as vectors for malaria, dengue, West Nile virus, yellow fever, encephalitis and other infectious diseases. # Ecology Diptera are a diverse order with an enormous range of ecological roles.Every type of trophic level pattern can be seen in the Diptera.Dipteran predators include the robber flies (Asilidae).A variety of herbivores can be found in the Diptera, such as the economically important fruit flies (Tephritidae).Flies are often parasites, including internal parasites such as the bot fly and external parasites such as the mosquito, black fly, sand fly or louse fly.Myiasis is the special term for diseases cause by flies (such as the screw worm fly) infecting living tissue.Many flies eat dead organic matter (detritovores), plant or animal remains.This is especially common in the larval stage, seen in the filter-feeding mosquitoes and black flies, the dung-feeding blow flies (Calliphoridae), or the organic deposit feeding rat-tailed maggot.A number of taxa feed on blood, including horse flies and mosquitoes. Some flies can be important pollinators for many species of plant (many such fly-specialized plants, such as Stapelia, Rafflesia, and Aristolochia, produce carrion odors), and many flies feed on pollen and nectar of common plants, and can perform incidental pollination.Similar relationships occur between flies and various fungi, with flies dispersing the fungal spores. The basic fly life cycle is egg, larvae (maggots — see below), pupa and adult (winged stage), called holometabolism.There is often a difference in food sources for larvae versus adult dipterans of the same species.For example, mosquito larvae live in standing water and feed on detritus while the adults feed on nectar as their energy source while females utilize blood as their energy source for egg production.Various maggots cause damage in agricultural crop production, including root maggots in rapeseed, midge maggots in wheat, and numerous species of leaf miners (note that since fly maggots have no legs, they almost exclusively feed internally on plants). Flies rely heavily on sight for survival.The compound eyes of flies are composed of thousands of individual lenses and are very sensitive to movement.Some flies have very accurate 3D vision.A few, like Ormia ochracea, have very advanced hearing organs. # Classification There are two generally accepted suborders of Diptera.The Nematocera are usually recognized by their elongated bodies and feathery antennae as represented by mosquitoes and crane flies.The Brachycera tend to have a more roundly proportioned body and very short antennae.A more recent classification has been proposed in which the Nematocera is split into two suborders, the Archidiptera and the Eudiptera, but this has not yet gained widespread acceptance among dipterists. - Suborder Nematocera (77 families, 35 of them extinct) – long antennae, pronotum distinct from mesonotum.In Nematocera, larvae are either eucephalic or hemicephalic and often aquatic. - Suborder Brachycera (141 families, 8 of them extinct) – short antennae, the pupa is inside a puparium formed from the last larval skin.Brachycera are generally robust flies with larvae having reduced mouthparts. Infraorders Tabanomorpha and Asilomorpha – these comprise the majority of what was the Orthorrhapha under older classification schemes.The antennae are short, but differ in structure from those of the Muscomorpha. Infraorder Muscomorpha – (largely the Cyclorrhapha of older schemes).Muscomorpha have 3-segmented, aristate (with a bristle) antennae and larvae with three instars that are acephalic (maggots). - Infraorders Tabanomorpha and Asilomorpha – these comprise the majority of what was the Orthorrhapha under older classification schemes.The antennae are short, but differ in structure from those of the Muscomorpha. - Infraorder Muscomorpha – (largely the Cyclorrhapha of older schemes).Muscomorpha have 3-segmented, aristate (with a bristle) antennae and larvae with three instars that are acephalic (maggots). Most of the Muscomorpha are further subdivided into the Acalyptratae and Calyptratae based on whether or not they have a calypter (a wing flap that extends over the halteres). Beyond that, considerable revision in the taxonomy of the flies has taken place since the introduction of modern cladistic techniques, and much remains uncertain.The secondary ranks between the suborders and the families are more out of practical or historical considerations than out of any strict respect for phylogenetic classifications (some modern cladists tend to spurn the use of Linnaean rank names).Nearly all classifications in use now, including this article, contain some paraphyletic groupings; this is emphasized where the numerous alternative systems are most greatly at odds.See list of families of Diptera. Dipterans belong to the group Mecopterida, that also contains Mecoptera, Siphonaptera, Lepidoptera (butterflies and moths) and Trichoptera.Inside it, they are sometimes classified closely together with Mecoptera and Siphonaptera in the superorder Antliophora . # Evolution Diptera are among the most evolved insects, and are usually thought to derive from Mecoptera or a strictly related group.First true dipterans are known from the Middle Triassic, becoming widespread during the Middle and Late Triassic . # Flies in culture Flies have often been used in mythology and literature to represent agents of death and decay, such as the historicaly accurate Biblical fourth plague of Egypt, or portrayed as nuisances (e.g., in Greek mythology, Myiagros was a god who chased away flies during the sacrifices to Zeus and Athena, and Zeus sent a fly to bite the horse Pegasus causing Bellerophon to fall back to Earth when he attempted to ride to Mount Olympus), though in a few cultures the connotation is not so negative (e.g., in the traditional Navajo religion, Big Fly is an important spirit being).Emily Dickinson's poem "I Heard a Fly Buzz When I Died" also makes reference to flies in the context of death. Not surprisingly, in art and entertainment, flies are also used primarily to introduce elements of horror or the simply mundane; an example of the former is the 1958 science fiction film The Fly (remade in 1986), in which a scientist accidentally exchanges parts of his body with those of a fly.Examples of the latter include trompe l'oeil paintings of the 15th century such as Portrait of a Carthusian by Petrus Christus, showing a fly sitting on a fake frame , a 2001 art project by Garnet Hertz in which a complete web server was implanted into a dead fly, and various musical works (such as Yoko Ono's album Fly, U2's song "The Fly," Dave Matthews' song "The Fly" and Béla Bartók's "From the Diary of a Fly").The ability of flies to cling to almost any surface has also inspired the title of Human Fly for stunt performers who stunts involve climbing buildings, including both real life and fictional individuals. Aside from the fictional and conceptual role flies play in culture, however, there are practical roles that flies can play (e.g., flies are reared in large numbers in Japan to serve as pollinators of sunflowers in greenhouses), especially the maggots of various species. ## Maggots Some types of maggots found on corpses can be of great use to forensic scientists.By their stage of development, these maggots can be used to give an indication of the time elapsed since death, as well as the place the organism died.Maggot species can be identified through the Use of DNA in forensic entomology. The size of the house fly maggot is 10–20 mm (⅜–¾ in).At the height of the summer season, a generation of flies (egg to adult) may be produced in 12–14 days. Other types of maggots are bred commercially, as a popular bait in angling, and a food for carnivorous pets such as reptiles or birds. Maggots have been used in medicine to clean out necrotic wounds , and in food production, particularly of cheeses (casu marzu). # Gallery - Ceratitis capitata, "Mediterranean fruit fly" Ceratitis capitata, "Mediterranean fruit fly" - Anopheles gambiae Anopheles gambiae - Tachinid fly Tachinid fly

Gas A gas is a state of matter, consisting of a collection of particles (molecules, atoms, ions, electrons, etc.)without a definite shape or volume that are in more or less random motion. # Physical characteristics Due to the electronic nature of the aforementioned particles, a "force field" is present throughout the space around them.Interactions between these "force fields" from one particle to the next give rise to the term intermolecular forces.Dependent on distance, these intermolecular forces influence the motion of these particles and hence their thermodynamic properties.It must be noted that at the temperatures and pressures characteristic of many applications, these particles are normally greatly separated.This separation corresponds to a very weak attractive force.As a result, for many applications, this intermolecular force becomes negligible. A gas also exhibits the following characteristics: - Relatively low density and viscosity compared to the solid and liquid states of matter. - Will expand and contract greatly with changes in temperature or pressure, thus the term "compressible". - Will diffuse readily, spreading apart in order to homogeneously distribute itself throughout any container. # Macroscopic When analyzing a system, it is typical to specify a length scale.A larger length scale may correspond to a macroscopic view of the system, while a smaller length scale corresponds to a microscopic view. On a macroscopic scale, the quantities measured are in terms of the large scale effects that a gas has on a system or its surroundings such as its velocity, pressure, or temperature.Mathematical equations, such as the Extended hydrodynamic equations, Navier-Stokes equations and the Euler equations have been developed to attempt to model the relations of the pressure, density, temperature, and velocity of a moving gas. ## Pressure The pressure exerted by a gas uniformly across the surface of a container can be described by simple kinetic theory.The particles of a gas are constantly moving in random directions and frequently collide with the walls of the container and/or each other.These particles all exhibit the physical properties of mass, momentum, and energy, which all must be conserved.In classical mechanics, Momentum, by definition, is the product of mass and velocity.Kinetic energy is one half the mass multiplied by the square of the velocity. The sum of all the normal components of force exerted by the particles impacting the walls of the container divided by the area of the wall is defined to be the pressure.The pressure can then be said to be the average linear momentum of these moving particles.A common misconception is that the collisions of the molecules with each other is essential to explain gas pressure, but in fact their random velocities are sufficient to define this quantity. ## Temperature The temperature of any physical system is the result of the motions of the molecules and atoms which make up the system.In statistical mechanics, temperature is the measure of the average kinetic energy stored in a particle.The methods of storing this energy are dictated by the degrees of freedom of the particle itself (energy modes).These particles have a range of different velocities, and the velocity of any single particle constantly changes due to collisions with other particles.The range in speed is usually described by the Maxwell-Boltzmann distribution. ## Specific Volume When performing a thermodynamic analysis, it is typical to speak of intensive and extensive properties.Properties which depend on the amount of gas are called extensive properties, while properties that do not depend on the amount of gas are called intensive properties.Specific volume is an example of an intensive property because it is the volume occupied by a unit of mass of a material, meaning we have divided through by the mass in order to obtain a quantity in terms of, for example,\textstyle \frac{m^3}{kg} .Notice that the difference between volume and specific volume differ in that the specific quantity is mass independent. ## Density Because the molecules are free to move about in a gas, the mass of the gas is normally characterized by its density.Density is the mass per volume of a substance or simply, the inverse of specific volume.For gases, the density can vary over a wide range because the molecules are free to move.Macroscopically, density is a state variable of a gas and the change in density during any process is governed by the laws of thermodynamics.Given that there are many particles in completely random motion, for a static gas, the density is the same throughout the entire container.Density is therefore a scalar quantity; it is a simple physical quantity that has a magnitude but no direction associated with it.It can be shown by kinetic theory that the density is proportional to the size of the container in which a fixed mass of gas is confined. # Microscopic On the microscopic scale, the quantities measured are at the molecular level.Different theories and mathematical models have been created to describe molecular or particle motion.A few of the gas-related models are listed below. ## Kinetic theory Kinetic theory attempts to explain macroscopic properties of gases by considering their molecular composition and motion. ## Brownian motion Brownian motion is the mathematical model used to describe the random movement of particles suspended in a fluid often called particle theory. Since it is at the limit of (or beyond) current technology to observe individual gas particles (atoms or molecules), only theoretical calculations give suggestions as to how they move, but their motion is different from Brownian Motion.The reason is that Brownian Motion involves a smooth drag due to the frictional force of many gas molecules, punctuated by violent collisions of an individual (or several) gas molecule(s) with the particle.The particle (generally consisting of millions or billions of atoms) thus moves in a jagged course, yet not so jagged as we would expect to find if we could examine an individual gas molecule. ## Intermolecular forces See also: Intermolecular force As discussed earlier, momentary attractions (or repulsions) between particles have an effect on gas dynamics.In physical chemistry, the name given to these "intermolecular forces" is the "Van der Waals force". # Simplified models An equation of state (for gases) is a mathematical model used to roughly describe or predict the state of a gas.At present, there is no single equation of state that accurately predicts the properties of all gases under all conditions.Therefore, a number of much more accurate equations of state have been developed for gases under a given set of assumptions.The "gas models" that are most widely discussed are "Real Gas", "Ideal Gas" and "Perfect Gas".Each of these models have their own set of assumptions to, basically, make our lives easier when we want to analyze a given thermodynamic system. ## Real gas Real gas effects refers to an assumption base where the following are taken into account: - Compressibility effects - Variable heat capacity - Van der Waal forces - Non-equilibrium thermodynamic effects - Issues with molecular dissociation and elementary reactions with variable composition. For most applications, such a detailed analysis is excessive.An example where "Real Gas effects" would have a significant impact would be on the Space Shuttle re-entry where extremely high temperatures and pressures are present. ## Ideal gas An "ideal gas" is a simplified "real gas" with the assumption that the compressibility factor Z is set to 1.So the state variables follow the ideal gas law. This approximation is more suitable for applications in engineering although simpler models can be used to produce a "ball-park" range as to where the real solution should lie.An example where the "ideal gas approximation" would be suitable would be inside a combustion chamber of a jet engine.It may also be useful to keep the elementary reactions and chemical dissociations for calculating emissions. ## Perfect gas By definition, A perfect gas is one in which intermolecular forces are neglected.So, along with the assumptions of an Ideal Gas, the following assumptions are added: - Neglected intermolecular forces By neglecting these forces, the equation of state for a perfect gas can be simply derived from kinetic theory or statistical mechanics. This type of assumption is useful for making calculations very simple and easy to do.With this assumption we can apply the Ideal gas law without restriction and neglect many complications that may arise from the Van der Waals forces. Along with the definition of a perfect gas, there are also two more simplifications that can be made although various textbooks either omit or combine the following simplifications into a general "perfect gas" definition.For sake of clarity, these simplifications are defined separately. ### Thermally perfect - The gas is in Thermodynamic equilibrium - Not chemically reacting - Internal energy, Enthalpy, and Specific Heat are functions of Temperature only. e = e(T) h = h(T) de = C_vdT dh = C_pdT This type of approximation is useful for modeling, for example, an axial compressor where temperature fluctuations are usually not large enough to cause any significant deviations from the Thermally perfect gas model.Heat capacity is still allowed to vary, though only with temperature and molecules are not permitted to dissociate. ### Calorically perfect Finally, the most restricted gas model is one where all the above assumptions apply and we also apply: - Constant Specific Heats e = C_vT h = C_pT Although this may be the most restrictive model, it still may be accurate enough to make reasonable calculations.For example, if a model of one compression stage of the axial compressor mentioned in the previous example was made (one with variable C_p, and one with constant C_p) to compare the two simplifications, the deviation may be found at a small enough order of magnitude that other factors that come into play in this compression would have a greater impact on the final result than whether or not C_p was held constant. (compressor tip-clearance, boundary layer/frictional losses, manufacturing impurities, etc.) # Historical Synthesis Boyle's Law was perhaps the first expression of an equation of state.In 1662 Robert Boyle, an Irishman, performed a series of experiments employing a J-shaped glass tube, which was sealed on one end.Mercury was added to the tube, trapping a fixed quantity of air in the short, sealed end of the tube.Then the volume of gas was carefully measured as additional mercury was added to the tube.The pressure of the gas could be determined by the difference between the mercury level in the short end of the tube and that in the long, open end.Through these experiments, Boyle noted that the gas volume varied inversely with the pressure.In mathematical form, this can be stated as: pV = constant. This law is used widely to describe different thermodynamic processes by adjusting the equation to read pV^n = constant and then varying the n through different values such as the specific heat ratio, γ. In 1787 the French physicist Jacques Charles found that oxygen, nitrogen, hydrogen, carbon dioxide, and air expand to the same extent over the same 80 kelvin interval. In 1802, Joseph Louis Gay-Lussac published results of similar experiments, indicating a linear relationship between volume and temperature: V_1/T_1 = V_2/T_2 In 1801 John Dalton published the Law of Partial Pressures: The pressure of a mixture of gases is equal to the sum of the pressures of all of the constituent gases alone.Mathematically, this can be represented for n species as: Pressure_{total} = Pressure_1 + Pressure_2 + ... + Pressure_n # Special Topics ### Compressibility The compressibility factor (Z) is used to alter the ideal gas equation to account for the real gas behavior.It is sometimes referred to as a "fudge-factor" to make the ideal gas law more accurate for the application.Usually this Z value is very close to unity. ### Reynolds Number In fluid mechanics, the Reynolds number is the ratio of inertial forces (vsρ) to viscous forces (μ/L).It is one of the most important dimensionless numbers in fluid dynamics and is used, usually along with other dimensionless numbers, to provide a criterion for determining dynamic similitude. ### Viscosity As we saw earlier: Pressure acts perpendicular (normal) to the wall.The tangential (shear) component of the force that is left over is related to the viscosity of the gas.As an object moves through a gas, viscous effects become more prevalent. ### Turbulence In fluid dynamics, turbulence or turbulent flow is a flow regime characterized by chaotic, stochastic property changes.This includes low momentum diffusion, high momentum convection, and rapid variation of pressure and velocity in space and time. ### Boundary Layer Particles will, in effect, "stick" to the surface of an object moving through it.This layer of particles is called the boundary layer.At the surface of the object, it is essentially static due to the friction of the surface.The object, with its boundary layer is effectively the new shape of the object that the rest of the molecules "see" as the object approaches.This boundary layer can separate from the surface, essentially creating a new surface and completely changing the flow path.The classical example of this is a stalling airfoil. ### Maximum Entropy Principle As the total number of degrees of freedom approaches infinity, the system will be found in the macrostate that corresponds to the highest multiplicity. ### Thermodynamic Equilibrium Equilibrium thermodynamics applies if the energy change within a system occurs on a timescale large enough for a sufficient number of molecular collisions to occur so that the energy transfer between molecules and between energy modes to allow the new energy value to be distributed in equilibrium among the molecules. (For typical systems, this is on the order of a few nanoseconds) # Etymology The word "gas" was invented by Jan Baptist van Helmont, perhaps as a Dutch pronunciation re-spelling of "chaos".

Fur Fur is a body hair of any non-human mammal, also known as the pelage. It may consist of short ground hair, long guard hair, and, in some cases, medium awn hair. Mammals with reduced amounts of fur are often called "naked", as in The Naked Ape, naked mole rat, and naked dogs.An animal with commercially valuable fur is known within the fur industry as a furbearer. (See fur clothing). The acquisition and use of fur is controversial.Animal welfare advocates object to the trapping and killing of wildlife, and the confinement and killing of animals on fur farms.More than 40 million animals are killed worldwide each year for their fur, 30 million of them on fur farms. # Nature of fur Fur usually consists of two main layers: - Ground hair or underfur — the bottom layer consisting of wool hairs which tend to be shorter, flattened, curly, and denser than the top layer. - Guard hair — the top layer consisting of longer straight shafts of hair that stick out through the underfur.This is usually the visible layer for most mammals and contains most of the pigmentation. # Use in clothing In clothing, fur is basically leather with the hair retained for its insulating properties.Such has long served as a source of clothing for humans, especially in colder climates.Modern cultures continue to wear natural fiber fur and fur trim and for many, such natural fibers are preferred alternatives to synthetic clothing from petrochemicals. Animal furs used in garments and trim may be dyed bright colors or to mimic exotic animal patterns, or shorn down to imitate the feel of a soft velvet fabric.The term "a fur" is often used to refer to a fur coat, wrap, or shawl. Common animal sources for fur clothing and fur trimmed accessories include fox, rabbit, mink, beavers, ermine, otters, sable, seals, cats, dogs, coyotes, and chinchilla.The import and sale of seal products was banned in the US in 1972 over conservation concerns about Canadian seals.While there is no market in the US for products produced by incorporating utilization into feral animal control programs, the import, export and sales of domesticated cat and dog fur was banned in the U.S. under the Dog and Cat Protection Act of 2000. The manufacturing of fur clothing involves obtaining animal pelts where the hair is left on the animal's processed skin.In contrast, leather made from involves removing the hair from the hide or pelt and using only the leather.The use of wool involves shearing the animal's hair from the living animal, so that the wool can be regrown but sheepskin shearling is a fur made by retaining the fleece to the leather and shearing it.Shearling is used for boots, jackets and coats and is probably the most common fur worn. Fur is also used to make felt.A common felt is made from beaver hair and is used in high-end cowboy hats. Fake fur or "faux fur" designates any synthetic material that mimics the appearance and feel of real fur, without the use of animal products.It is not renewable or biodegradable, and there are mounting concerns about its ecological footprint.Plastic Bags on Our Backs # Controversy Animal welfare advocates object to the trapping and killing of wildlife, and the confinement and killing of animals on fur farms.More than 40 million animals are killed worldwide each year for their fur. # Fur fetishes The soft, warm texture of fur appeals to many people; for some, the attraction becomes a fur fetishism, a fetishistic attraction to people wearing fur, or in certain cases, to the fur garments themselves.

Gac Momordica cochinchinensis (Lour.)Spreng.,commonly known as gac (from Vietnamese: gấc, or quả gấc ; in Chinese: 木鳖果) Template:IPA3, is a Southeast Asian fruit found throughout the region from Southern China to Northeastern Australia. It is also known as Baby Jackfruit, Spiny Bitter Gourd, Sweet Gourd, or Cochinchin Gourd. It has been traditionally used as both food and medicine in the regions in which it grows. Because it has a relatively short harvest season (which peaks in December and January), making it less abundant than other foods, gac is typically served at ceremonial or festive occasions in Vietnam, such as Tết (the Vietnamese new year) and weddings. It is most commonly prepared as a dish called xôi gấc, in which the aril and seeds of the fruit are cooked in glutinous rice, imparting both their color and flavor. More recently, the fruit has begun to be marketed outside of Asia in the form of juice dietary supplements because of its allegedly high phytonutrient content. Gac grows on dioecious vines and is usually collected from fence climbers or from wild plants. The vines can be commonly seen growing on lattices at the entrances to rural homes or in gardens. It only fruits once a year, and is found seasonally in local markets. The fruit itself becomes a dark orange color upon ripening, and is typically round or oblong, maturing to a size of about 13 cm in length and 10 cm in diameter. Its exterior skin is covered in small spines while its dark red interior consists of clusters of fleshy pulp and seeds. # Uses Other than the use of its fruit and leaves for special Vietnamese culinary dishes, gac is also used for its medicinal and nutritional properties. In Vietnam, the seed membranes are used to aid in the relief of dry eyes, as well as to promote healthy vision. Similarly, in Traditional Chinese medicine the seeds of gac, known as mubiezi (Chinese: 木鳖子), are employed for a variety of internal and external purposes. Recent attention is also beginning to be attracted in the West because of chemical analysis of the fruit suggesting that it has high concentrations of several important phytonutrients. Gac has been shown to be especially high in lycopene content. Relative to mass, it contains up to 70 times the amount of lycopene found in tomatoes. It has also been found to contain up to 10 times the amount of beta-carotene of carrots or sweet potatoes. Additionally, the carotenoids present in gac are bound to long-chain fatty acids, resulting in what is claimed to be a more bioavailable form. There has also been recent research that suggests that gac contains a protein that may inhibit the proliferation of cancer cells.

Gel A gel (from the lat.gelu—freezing, cold, ice or gelatus—frozen, immobile) is an apparently solid, jelly-like material formed from a colloidal solution. By weight, gels are mostly liquid, yet they behave like solids due to the addition of a gelling agent. # Composition A solid network spans the volume of a liquid medium.Both by weight and volume, gels are mostly liquid in composition and thus exhibit densities similar to liquids.However, they have the structural coherence of a solid.The network can be composed of a wide variety of materials, including particles, polymers and proteins. ## Cationic polymers Cationic polymers are positively charged polymers.Their positive charges prevent the formation of coiled polymers.This allows them to contribute more to viscosity in their stretched state, because the stretched-out polymer takes up more space than a coiled polymer and thus resists the flow of solvent molecules around it. Cationic polymers are a main functional component of hair gel, because the positive charged polymers also bind the negatively charged amino acids on the surface of the keratin molecules in the hair.More complicated polymer formulas exist, e.g., a copolymer of vinylpyrrolidone, methacrylamide, and hydrogel N-vinylimidazole. # Types of gels ## Hydrogels Hydrogel is a network of polymer chains that are water-insoluble, sometimes found as a colloidal gel in which water is the dispersion medium.Hydrogels are superabsorbent (they can contain over 99% water) natural or synthetic polymers. Hydrogels possess also a degree of flexibility very similar to natural tissue, due to their significant water content. Common uses for hydrogels are - currently used as scaffolds in tissue engineering.When used as scaffolds, hydrogels may contain human cells in order to repair tissue. - environmentally sensitive hydrogels.These hydrogels have the ability to sense changes of pH, temperature, or the concentration of metabolite and release their load as result of such a change. - as sustained-release delivery system - provide absorption, desloughing and debriding capacities of necrotics and fibrotic tissue. - hydrogels that are responsive to specific molecules, such as glucose or antigens can be used as biosensors as well as in DDS. - In disposable diapers where they "capture" urine, or in sanitary napkins - contact lenses (silicone hydrogels, polyacrylamides) - medical electrodes using hydrogels composed of cross linked polymers (polyethylene oxide,polyAMPS and polyvinylpyrrolidone) - Water gel explosives Other, less common uses include - breast implants - granules for holding soil moisture in arid areas - dressings for healing of burn or other hard-to-heal wounds.Wound GEL are excellent for helping to create or maintain environment. - reservoirs in topical drug delivery; particularly ionic drugs, delivered by iontophoresis (see ion exchange resin) Common ingredients are e.g. polyvinyl alcohol, sodium polyacrylate, acrylate polymers and copolymers with an abundance of hydrophilic groups. Natural hydrogel materials are being investigated for tissue engineering, these materials include agarose, methylcellulose, hylaronan, and other naturally derived polymers. ## Organogels An organogel is a non-crystalline, non-glassy thermoreversible solid materials composed of a liquid organic phase entrapped in a structuring network.The liquid can be e.g. an organic solvent, a mineral oil or a vegetable oil.The solubility and particle dimensions of the structurant are important characteristics for the elastic properties and firmness of the organogel.Often, these systems are based on self-assembly of the structurant molecules. Organogels have raised interest for use in a number of applications, such as in pharmaceutics , cosmetics, art conservation, and food.An example of formation of an undesired thermoreversible network is the occurrence of wax crystallisation in crude oil . ## Xerogels A xerogel is a solid formed from a gel by drying with unhindered shrinkage. Xerogels usually retain high porosity (25%) and enormous surface area (150-900 m2/g), along with very small pore size (1-10 nm).When solvent removal occurs under hypercritical (supercritical) conditions, the network does not shrink and a highly porous, low-density material known as an aerogel is produced.Heat treatment of a xerogel at elevated temperature produces viscous sintering (shrinkage of the xerogel due to a small amount of viscous flow) and effectively transforms the porous gel into a dense glass. # Properties Many gels display thixotropy - they become fluid when agitated, but resolidify when resting. In general, gels are apparently solid, jelly-like materials. By replacing the liquid with gas it is possible to prepare aerogels, materials with exceptional properties including very low density, high specific surface areas, and excellent thermal insulation properties. ## Sound-Induced Gelation Sound induced gelation is described in 2005 in an organopalladium compound that in solution transforms from a transparent liquid to an opaque gel upon application of a short burst (seconds) of ultrasound.Heating to above the so-called gelation temperature Tgel takes the gel back to the solution.The compound is a dinuclear palladium complex made from palladium acetate and a N,N'-Bis-salicylidene diamine.Both compounds react to form an anti conformer (gelling) and a syn conformer (non-gelling) which are separated by column chromatography.In the solution phase the dimer molecules are bent and self-locked by aromatic stacking interactions whereas in the gel phase the conformation is planar with interlocked aggregates. The anti conformer has planar chirality and both enantiomers were separated by chiral column chromatography.The (-) anti conformer has a specific rotation of -375° but is unable to gelate by itself.In the gel phase the dimer molecules form stacks of alternating (+) and (-) components.This process starts at the onset of the sonication and proceeds even without further sonication. # Applications Many substances can form gels when a suitable thickener or gelling agent is added to their formula.This approach is common in manufacture of wide range of products, from foods to paints, adhesives. In fiber optics communications, a soft gel resembling "hair gel" in viscosity is used to fill the plastic tubes containing the fibers. The main purpose of the gel is to prevent water intrusion if the buffer tube is breached, but the gel also buffers the fibers against mechanical damage when the tube is bent around corners during installation, or flexed. Additionally, the gel acts as a processing aid when the cable is being constructed, keeping the fibers central whist the tube material is extruded around it. ## Hair Gel Hair gel is a hairstyling product that is used to stiffen hair into a particular hairstyle.The results it produces are usually similar to but stronger than those of hair spray and weaker than those of hair glue or hair wax. ### Types Many brands of hair gel in North America and the UK come in numbered variants.Higher numbered gels maintain a greater "hold" on hair, while lower numbers do not make the hair as stiff and in some products give the hair a wet look.A category typically referred to as "ethnic" gels are designed and manufactured specifically for sculpting the hair texture common to African Americans. Ampro Industries is a common example of this category. Some forms of hair gel include temporary hair colouring for the hair, including variants in unnatural colors.

HK1 Hexokinase-1 (HK1) is an enzyme that in humans is encoded by the HK1 gene on chromosome 10.Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways.This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria.Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency.Alternative splicing of this gene results in five transcript variants which encode different isoforms, some of which are tissue-specific.Each isoform has a distinct N-terminus; the remainder of the protein is identical among all the isoforms.A sixth transcript variant has been described, but due to the presence of several stop codons, it is not thought to encode a protein. # Structure HK1 is one of four highly homologous hexokinase isoforms in mammalian cells. ## Gene The HK1 gene spans approximately 131 kb and consists of 25 exons.Alternative splicing of its 5’ exons produces different transcripts in different cell types: exons 1-5 and exon 8 (exons T1-6) are testis-specific exons; exon 6, located approximately 15 kb downstream of the testis-specific exons, is the erythroid-specific exon (exon R); and exon 7, located approximately 2.85 kb downstream of exon R, is the first 5’ exon for the ubiquitously expressed HK1 isoform.Moreover, exon 7 encodes the porin-binding domain (PBD) conserved in mammalian HK1 genes.Meanwhile, the remaining 17 exons are shared among all HK1 isoforms. In addition to exon R, a stretch of the proximal promoter that contains a GATA element, an SP1 site, CCAAT, and an Ets-binding motif is necessary for expression of HK-R in erythroid cells. ## Protein This gene encodes a 100 kDa homodimer with a regulatory N-terminal domain (1-475), catalytic C-terminal domain (residues 476-917), and an alpha-helix connecting its two subunits.Both terminal domains are composed of a large subdomain and a small subdomain.The flexible region of the C-terminal large subdomain (residues 766–810) can adopt various positions and is proposed to interact with the base of ATP.Moreover, glucose and G6P bind in close proximity at the N- and C-terminal domains and stabilize a common conformational state of the C-terminal domain.According to one model, G6P acts as an allosteric inhibitor which binds the N-terminal domain to stabilize its closed conformation, which then stabilizes a conformation of the C-terminal flexible subdomain that blocks ATP.A second model posits that G6P acts as an active inhibitor that stabilizes the closed conformation and competes with ATP for the C-terminal binding site.Results from several studies suggest that the C-terminal is capable of both catalytic and regulatory action.Meanwhile, the hydrophobic N-terminal lacks enzymatic activity by itself but contains the G6P regulatory site and the PBD, which is responsible for the protein’s stability and binding to the outer mitochondrial membrane (OMM). # Function As one of two mitochondrial isoforms of hexokinase and a member of the sugar kinase family, HK1 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P. Physiological levels of G6P can regulate this process by inhibiting HK1 as negative feedback, though inorganic phosphate (Pi) can relieve G6P inhibition.However, unlike HK2 and HK3, HK1 itself is not directly regulated by Pi, which better suits its ubiquitous catabolic role.By phosphorylating glucose, HK1 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism.Moreover, its localization and attachment to the OMM promotes the coupling of glycolysis to mitochondrial oxidative phosphorylation, which greatly enhances ATP production by direct recycling of mitochondrial ATP/ADP to meet the cell’s energy demands.Specifically, OMM-bound HK1 binds VDAC1 to trigger opening of the mitochondrial permeability transition pore and release mitochondrial ATP to further fuel the glycolytic process. Another critical function for OMM-bound HK1 is cell survival and protection against oxidative damage.Activation of Akt kinase is mediated by HK1-VDAC1 coupling as part of the growth factor-mediated phosphatidyl inositol 3-kinase (PI3)/Akt cell survival intracellular signaling pathway, thus preventing cytochrome c release and subsequent apoptosis.In fact, there is evidence that VDAC binding by the anti-apoptotic HK1 and by the pro-apoptotic creatine kinase are mutually exclusive, indicating that the absence of HK1 allows creatine kinase to bind and open VDAC.Furthermore, HK1 has demonstrated anti-apoptotic activity by antagonizing Bcl-2 proteins located at the OMM, which then inhibits TNF-induced apoptosis. In the prefrontal cortex, HK1 putatively forms a protein complex with EAAT2, Na+/K+ ATPase, and aconitase, which functions to remove glutamate from the perisynaptic space and maintain low basal levels in the synaptic cleft. In particular, HK1 is the most ubiquitously expressed isoform out of the four hexokinases, and constitutively expressed in most tissues, though it is majorly found in brain, kidney, and red blood cells (RBCs).Its high abundance in the retina, specifically the photoreceptor inner segment, outer plexiform layer, inner nuclear layer, inner plexiform layer, and ganglion cell layer, attests to its crucial metabolic purpose.It is also expressed in cells derived from hematopoietic stem cells, such as RBCs, leukocytes, and platelets, as well as from erythroid-progenitor cells.Of note, HK1 is the sole hexokinase isoform found in the cells and tissues which rely most heavily on glucose metabolism for their function, including brain, erythrocytes, platelets, leukocytes, and fibroblasts.In rats, it is also the predominant hexokinase in fetal tissues, likely due to their constitutive glucose utilization. # Clinical significance Mutations in this gene are associated with type 4H of Charcot–Marie–Tooth disease, also known as Russe-type hereditary motor and sensory neuropathy (HMSNR).Due to the crucial role of HK1 in glycolysis, hexokinase deficiency has been identified as a cause of erythroenzymopathies associated with hereditary non-spherocytic hemolytic anemia (HNSHA).Likewise, HK1 deficiency has resulted in cerebral white matter injury, malformations, and psychomotor retardation, as well as latent diabetes mellitus and panmyelopathy.Meanwhile, HK1 is highly expressed in cancers, and its anti-apoptotic effects have been observed in highly glycolytic hepatoma cells. ## Neurodegenerative disorders HK1 may be causally linked to mood and psychotic disorders, including unipolar depression (UPD), bipolar disorder (BPD), and schizophrenia via both its roles in energy metabolism and cell survival.For instance, the accumulation of lactate in the brains of BPD and SCHZ patients potentially results from the decoupling of HK1 from the OMM, and by extension, glycolysis from mitochondrial oxidative, phosphorylation.In the case of SCHZ, decreasing HK1 attachment to the OMM in the parietal cortex resulted in decreased glutamate reuptake capacity and, thus, glutamate spillover from the synapses.The released glutamate activates extrasynaptic glutamate receptors, leading to altered structure and function of glutamate circuits, synaptic plasticity, frontal cortical dysfunction, and ultimately, the cognitive deficits characteristic of SCHZ.Similarly, Hk1 mitochondrial detachment has been associated with hypothyroidism, which involves abnormal brain development and increased risk for depression, while its attachment leads to neural growth.In Parkinson’s disease, HK1 detachment from VDAC via Parkin-mediated ubiquitylation and degradation disrupts the MPTP on depolarized mitochondria, consequently blocking mitochondrial localization of Parkin and halting glycolysis.Further research is required to determine the relative HK1 detachment needed in various cell types for different psychiatric disorders.This research can also contribute to developing therapies to target causes of the detachment, from gene mutations to interference by factors such as beta-amyloid peptide and insulin. ## Retinitis pigmentosa A heterozygous missense mutation in the HK1 gene (a change at position 847 from glutamate to lysine) has been linked to retinitis pigmentosa.Since this substitution mutation is located far from known functional sites and does not impair the enzyme’s glycolytic activity, it is likely that the mutation acts through another biological mechanism unique to the retina.Notably, studies in mouse retina reveal interactions between Hk1, the mitochondrial metallochaperone Cox11, and the chaperone protein Ranbp2, which serve to maintain normal metabolism and function in the retina.Thus, the mutation may disrupt these interactions and lead to retinal degradation.Alternatively, this mutation may act through the enzyme’s anti-apoptotic function, as disrupting the regulation of the hexokinase-mitochondria association by insulin receptors could trigger photoreceptor apoptosis and retinal degeneration.In this case, treatments that preserve the hexokinase–mitochondria association may serve as a potential therapeutic approach. # Interactions HK1 is known to interact with: - VDAC, - Parkin, - EAAT2, - Na+/K+ ATPase, and - Aconitase. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

HK2 Hexokinase 2 also known as HK2 is an enzyme which in humans is encoded by the HK2 gene on chromosome 2.Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways.This gene encodes hexokinase 2, the predominant form found in skeletal muscle.It localizes to the outer membrane of mitochondria.Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in the increased rate of glycolysis seen in rapidly growing cancer cells. # Structure HK2 is one of four highly homologous hexokinase isoforms in mammalian cells. ## Gene The HK2 gene spans approximately 50 kb and consists of 18 exons.There is also an HK2 pseudogene integrated into a long interspersed nuclear repetitive DNA element located on the X chromosome.Though its DNA sequence is similar to the cDNA product of the actual HK2 mRNA transcript, it lacks an open reading frame for gene expression. ## Protein This gene encodes a 100-kDa, 917-residue enzyme with highly similar N- and C-terminal domains that each form half of the protein.This high similarity, along with the existence of a 50-kDa hexokinase (HK4), suggests that the 100-kDa hexokinases originated from a 50-kDa precursor via gene duplication and tandem ligation.Both N- and C-terminal domains possess catalytic ability and can be inhibited by G6P, though the C-terminal domain demonstrates lower affinity for ATP and is only inhibited at higher concentrations of G6P. Despite there being two binding sites for glucose, it is proposed that glucose binding at one site induces a conformational change which prevents a second glucose from binding the other site.Meanwhile, the first 12 amino acids of the highly hydrophobic N-terminal serve to bind the enzyme to the mitochondria, while the first 18 amino acids contribute to the enzyme’s stability. # Function As an isoform of hexokinase and a member of the sugar kinase family, HK2 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P. Physiological levels of G6P can regulate this process by inhibiting HK2 as negative feedback, though inorganic phosphate (Pi) can relieve G6P inhibition.Pi can also directly regulate HK2, and the double regulation may better suit its anabolic functions.By phosphorylating glucose, HK2 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism.Moreover, its localization and attachment to the OMM promotes the coupling of glycolysis to mitochondrial oxidative phosphorylation, which greatly enhances ATP production to meet the cell’s energy demands.Specifically, HK2 binds VDAC to trigger opening of the channel and release mitochondrial ATP to further fuel the glycolytic process. Another critical function for OMM-bound HK2 is mediation of cell survival.Activation of Akt kinase maintains HK2-VDAC coupling, which subsequently prevents cytochrome c release and apoptosis, though the exact mechanism remains to be confirmed.One model proposes that HK2 competes with the pro-apoptotic proteins BAX to bind VDAC, and in the absence of HK2, BAX induces cytochrome c release.In fact, there is evidence that HK2 restricts BAX and BAK oligomerization and binding to the OMM.In a similar mechanism, the pro-apoptotic creatine kinase binds and opens VDAC in the absence of HK2.An alternative model proposes the opposite, that HK2 regulates binding of the anti-apoptotic protein Bcl-Xl to VDAC. In particular, HK2 is ubiquitously expressed in tissues, though it is majorly found in muscle and adipose tissue.In cardiac and skeletal muscle, HK2 can be found bound to both the mitochondrial and sarcoplasmic membrane.HK2 gene expression is regulated by a phosphatidylinositol 3-kinaselp70 S6 protein kinase-dependent pathway and can be induced by factors such as insulin, hypoxia, cold temperatures, and exercise.Its inducible expression indicates its adaptive role in metabolic responses to changes in the cellular environment. # Clinical significance ## Cancer HK2 is highly expressed in several cancers, including breast cancer and colon cancer. Its role in coupling ATP from oxidative phosphorylation to the rate-limiting step of glycolysis may help drive the tumor cells’ growth.Notably, inhibition of HK2 has demonstrably improved the effectiveness of anticancer drugs.,Thus, HK2 stands as a promising therapeutic target, though considering its ubiquitous expression and crucial role in energy metabolism, a reduction rather than complete inhibition of its activity should be pursued. ## Non-insulin-dependent diabetes mellitus A study on non-insulin-dependent diabetes mellitus (NIDDM) revealed low basal G6P levels in NIDDM patients that failed to increase with the addition of insulin.One possible cause is decreased phosphorylation of glucose due to a defect in HK2, which was confirmed in further experiments.However, the study could not establish any links between NIDDM and mutations in the HK2 gene, indicating that the defect may lie in HK2 regulation. # Interactions HK2 is known to interact with: - VDAC. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

HK3 Hexokinase 3 also known as HK3 is an enzyme which in humans is encoded by the HK2 gene on chromosome 5.Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways.This gene encodes hexokinase 3.Similar to hexokinases 1 and 2, this allosteric enzyme is inhibited by its product glucose-6-phosphate. # Structure HK3 is one of four highly homologous hexokinase isoforms in mammalian cells.This protein has a molecular weight of 100 kDa and is composed of two highly similar 50-kDa domains at its N- and C-terminals.This high similarity, along with the and the existence of a 50-kDa hexokinase (HK4), suggests that the 100-kDa hexokinases originated from a 50-kDa precursor via gene duplication and tandem ligation.Like with HK1, only the C-terminal domain possesses catalytic ability, whereas the N-terminal domain is predicted to contain glucose and G6P binding sites, as well as a 32-residue region essential for proper protein folding.Moreover, the catalytic activity depends on the interaction between the two terminal domains.Unlike HK1 and HK2, HK3 lacks a mitochondrial binding sequence at its N-terminal. # Function As a cytoplasmic isoform of hexokinase and a member of the sugar kinase family, HK3 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P. Physiological levels of G6P can regulate this process by inhibiting HK3 as negative feedback, though inorganic phosphate can relieve G6P inhibition.Inorganic phosphate can also directly regulate HK3, and the double regulation may better suit its anabolic functions.By phosphorylating glucose, HK3 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism.Compared to HK1 and HK2, HK3 possesses a higher affinity for glucose and will bind the substrate even at physiological levels, though this binding may be attenuated by intracellular ATP.Uniquely, HK3 can be inhibited by glucose at high concentrations.HK3 is also less sensitive to G6P inhibition. Despite its lack of mitochondrial association, HK3 also functions to protect the cell against apoptosis.Overexpression of HK3 has resulted in increased ATP levels, decreased reactive oxygen species (ROS) production, attenuated reduction in the mitochondrial membrane potential, and enhanced mitochondrial biogenesis.Overall, HK3 may promote cell survival by controlling ROS levels and boosting energy production.Currently, only hypoxia is known to induce HK3 expression through a HIF-dependent pathway.The inducible expression of HK3 indicates its adaptive role in metabolic responses to changes in the cellular environment. In particular, HK3 is ubiquitously expressed in tissues, albeit at relatively low abundance.Higher abundance levels have been cited in lung, kidney, and liver tissue.Within cells, HK3 localizes to the cytoplasm and putatively binds the perinuclear envelope.HK3 is the predominant hexokinase in myeloid cells, particularly granulocytes. # Clinical significance HK3 is found to be overexpressed in malignant follicular thyroid nodules.In conjunction with cyclin A and galectin-3, HK3 could be used as diagnostic biomarker to screen for malignancy in patients.Meanwhile, HK3 was found to be repressed in acute myeloid leukemia (AML) blast cells and acute promyelocytic leukemia (APL) patients.The transcription factor PU.1 is known to directly activate transcription of the antiapoptotic BCL2A1 gene or inhibit transcription of the p53 tumor suppressor to promote cell survival, and is proposed to also directly activate HK3 transcription during neutrophil differentiation to support short-term cell survival of mature neutrophils.Regulators repressing HK3 expression in AML include PML-RARA and CEBPA.Regarding acute lymphoblastic leukemia (ALL), functional enrichment analysis revealed HK3 as a key gene and suggests that HK3 shares antiapoptotic function with HK1 and HK2. # Interactions The HK3 promoter is known to interact with PU.1, PML-RARA, and CEBPA. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

Hag # Background A hag (or crone) is a wizened old woman, or a kind of fairy or goddess having the appearance of such a woman, often found in folklore and children's tales such as Hansel and Gretel. Hags are often seen as malevolent, but may also be one of the chosen forms of shapeshifting deities, such as the Morrígan or Badbh, who are seen as neither wholly beneficent nor malevolent.The term appears in Middle English, and might be short for hægtesse, an Old English term for witch. # Hag in folklore A hag, or "the Old Hag", was a nightmare spirit in British and Anglophone North American folklore. This variety of hag is essentially identical to the Anglo-Saxon mæra — a being with roots in ancient Germanic superstition, and closely related to the Scandinavian mara.According to folklore, the Old Hag sat on a sleeper's chest and sent nightmares to him or her.When the subject awoke, he or she would be unable to breathe or even move for a short period of time.Currently this state is called sleep paralysis, but in the old belief the subject had been hagridden.It is still frequently discussed as if it were a para-normal state. In Irish and Scottish mythology, the Cailleach is a hag goddess concerned with creation, harvest, the weather and sovereignty. In partnership with the goddess Brìde, she is a seasonal goddess, seen as ruling the winter months while Brìde rules the summer. In Scotland, a group of hags, known as The Cailleachan (The Storm Hags) are seen as personifications of the elemental powers of nature, especially in a destructive aspect. They are said to be particularly active in raising the windstorms of spring, during the period known as A Chailleach. Hags as sovereignty figures abound in Irish mythology. The most common pattern is that the hag represents the barren land, who the hero of the tale must approach without fear, and come to love on her own terms.When the hero displays this courage, love, and acceptance of her hideous side, the sovereignty hag then reveals that she is also a young and beautiful goddess. The Three Fates (particularly Atropos) are often depicted as hags. In Persian folklore, the Bakhtak has the same role as that of "the Old Hag" in British folklore.The Bakhtak sits on a sleeper's chest, awakening them and causing them to feel they are unable to breathe or even to move.Bakhtak also is used metaphorically to refer to "nightmare" in the modern Persian language. Many stories about hags seem to have been used to frighten children into being good.Peg Powler, for example, was a river hag who lived in river trees and had skin the color of green pond scum. Parents told their children that if they got too close to the water she would pull them in with her extra long arms, drown them, and sometimes eat them. The parents hoped that the children would be afraid of the hag so they wouldn't go anywhere near the water. That way, they'd never fall in and drown. Peg Powler has other regional names, such as Jenny Greenteeth from Yorkshire and Nellie Longarms from several English counties. Many tales about hags do not describe them sufficiently to make it clear whether the tale deals with an old woman who has learned magic or a supernatural being. # In neurobiology The expression Old Hag Attack refers to a hypnagogic state in which paralysis is present and, quite often, it is accompanied by terrifying hallucinations.When excessively recurrent, some consider them to be a disorder, however many populations treat them as simply part of their culture and mythological world-view, rather than any form of disease or pathology. # In popular culture In the Dungeons & Dragons game, "hags" are at least three races of female creatures, sort of female counterparts to ogres.They are the annis (named from an analogous creature from the British folklore), the green hag (a green-skinned version of the Slavic Baba Yaga), and the sea hag (sort of a sea witch, not a mermaid).All three sorts are evil, but not overly powerful. Hags are occasionally mentioned in the Harry Potter series, but never in any great detail (the prologue of "Fantastic Beasts and Where to Find Them" mentions that they are classed as beings (as opposed to beasts) that children are part of their diet and that they can glide).Hags are occasionally encountered in the wizarding village Hogsmeade, where they are distinguished from "conventional" wizards and witches.It is unclear if such Hags live in Hogsmeade or simply visit the village for business and/or social reasons. Hags are also mentioned in the Chronicles of Narnia.In The Lion, the Witch and the Wardrobe, Hags are one of the various kinds of evil creatures whom the White Witch has present at the killing of Aslan.Later, in Prince Caspian, a Hag, along with a Werewolf and the dwarf Nikabrik, tries to persuade Caspian to summon the Witch back to life.They attack after being refused, and are killed. In the Popeye comics and cartoons, Popeye is sometimes pursued by a villainous witch called Sea Hag, who has an unrequited love for the sailor.

ID1 DNA-binding protein inhibitor ID-1 is a protein that in humans is encoded by the ID1 gene. # Function The protein encoded by this gene is a helix-loop-helix (HLH) protein that can form heterodimers with members of the basic HLH family of transcription factors.The encoded protein has no DNA binding activity and therefore can inhibit the DNA binding and transcriptional activation ability of basic HLH proteins with which it interacts.This protein may play a role in cell growth, senescence, and differentiation.Two transcript variants encoding different isoforms have been found for this gene. # Interactions ID1 has been shown to interact weakly with MyoD but very tightly with ubiquitously expressed E proteins.E proteins heterodimerize with tissue restricted bHLH proteins such as Myod, NeuroD, etc.to form active transcription complexes so by sequestering E proteins, Id proteins can inhibit tissue restricted gene expression in multiple cell lineages using the same biochemical mechanism.Other interacting partners include CASK. # Clinical significance ID1 can be used to mark endothelial progenitor cells which are critical to tumor growth and angiogenesis.Targeting ID1 results in decreased tumor growth.

ID2 DNA-binding protein inhibitor ID-2 is a protein that in humans is encoded by the ID2 gene. # Function The protein encoded by this gene belongs to the inhibitor of DNA binding (ID) family, members of which are transcriptional regulators that contain a helix-loop-helix (HLH) domain but not a basic domain.Members of the ID family inhibit the functions of basic helix-loop-helix transcription factors in a dominant-negative manner by suppressing their heterodimerization partners through the HLH domains.This protein may play a role in negatively regulating cell differentiation.A pseudogene has been identified for this gene. A research published by "Nature" in 01/2016, authored by Italian researchers Antonio Iavarone and Anna Lasorella, from Columbia University, states that ID2 protein has a relevant role in the development and resistance to therapies of glioblastoma, the most aggressive of brain cancers. # Interactions ID2 has been shown to interact with MyoD and NEDD9.

ID4 ID4 is a protein coding gene. In humans, it encodes for the protein known as DNA-binding protein inhibitor ID-4. This protein is known to be involved in the regulation of many cellular processes during both prenatal development and tumorigenesis. This is inclusive of embryonic cellular growth, senescence, cellular differentiation, apoptosis, and as an oncogene in angiogenesis. # Structure The gene spans 3.3kb on the plus strand. It is composed of 3 exons and during transcription its mRNA is 2343 bp. The encoded protein consists of 161 amino acids, is 16.6 KDa and contains a poly-Ala segment from amino acid 39 to 48, a helix-loop-helix motif from amino acid 65 to 105 and a poly-Pro region from amino acid 118 to 124. This protein is expressed in various tissues. # Function The ID4 gene is part of the ID gene family. This family is also known as inhibitors of DNA binding protein family and are composed of transcription inhibitory proteins which modulate a number of processes. They are transcriptional regulators that work by negatively regulating their basic helix-loop-helix (bHLH) transcription factors by forming heterodimers. The heterodimer is what inhibits their DNA binding and transcriptional activity. Transcription factors containing a basic helix-loop-helix (bHLH) motif regulate expression of tissue-specific genes in a number of mammalian and insect systems.DNA-binding activity of the bHLH proteins is dependent on formation of homo- and/or heterodimers.Dominant-negative (antimorph) HLH proteins encoded by Id-related genes, such as ID4, also contain the HLH-dimerization domain but lack the DNA-binding basic domain.Consequently, ID proteins inhibit binding to DNA and transcriptional transactivation by heterodimerization with bHLH proteins. ## Regulation during embryogenesis The ID4 gene plays a pivotal role in development and is a key player in many pathways of embryogenesis and foetal development. ID4 expression is upregulated in embryogenesis during days 9.5 and 13.5 of gestation and restricted to specific cells of the central and peripheral nervous system.ID4 transcription control has both negative and positive regulatory elements inclusive of novel inhibitory functions. ID4 expression has been shown to be discrete in the early stages, with transcription transiently expressed in subsets of migrating neural crest cells, the dorsal myocardium, the segmental plate mesoderm, and the tail bud.Later stages show ID4 expression in the telencephalic vesicles and corneal epithelium. ID4 expression is only detected in neuronal tissues and the ventral portion of the epithelium in the developing stomach during embryogenesis. ID4 is expressed in the central nervous system and is required for G1-S transition and to enhance proliferation in early cortical progenitors. It is complexly involved in regulating neural stem cell proliferation and differentiation by inhibiting proliferation of differentiating neurons through enhancement of RB1-mediated pathways. This is either by direct interaction or through interaction with other molecules of the cell cycle machinery. ID4 also regulates the lateral expansion of the proliferative zone in the developing cortex and hippocampus. This is integral to normal brain size formation. ID4 regulates neural progenitor proliferation and differentiation. Its expression is seen in the neural tube much later than other ID genes. ID4 was also shown to be involved in the regulation of cardiac mesoderm function in frog embryos and human embryonic stem cells. Ablation of the ID gene family mouse embryos showed failure of anterior cardiac progenitor specification and the development of heartless embryos.This study also demonstrated that ID4 protein is involved in the regulating cardiac cell fate by a pathway which represses two inhibitors of cardiogenic mesoderm formation (TCF3 and FOXA2) whilst activating inducers (EVX1, GRRP1, and MESP1). # Clinical significance ## Role in endometriosis ID4 has been linked to the molecular pathogenicity of endometriosis. These pathways are still poorly understood. It is thought that ID4 plays a role in the transcription of HOXA9 and CDKN1A which are known to be associated with endometriosis. A genome wide association study revealed over 100 candidate genes associated with endometriosis. Of these, six were shown to have a highly reliable association, of which the ID4 gene was identified. This is thought to be due to an independent single nucleotide polymorphism at loci rs7739264 near ID4 on chromosome 6p22.3. ID4 is implicated in the molecular pathogenicity of endometriosis as being differentially expressed between the proliferative, early and mid-secretory phases. ## Tumorigenesis association ID4 is not expressed in normal ovary and fallopian tubes. It has been shown to be overexpressed in most primary ovarian cancers. The ID4 gene is also seen to be overexpressed in most ovarian, endometrial and breast cancer cell lines. The mechanism behind this is believed to be that ID4 regulates HOXA9 and CDKN1A genes, which are mediators of cell proliferation and differentiation. HOXA genes are known to play a role in the differentiation of fallopian tubes, uterus, cervix and vagina. In B-Cell (B lymphocyte) acute lymphoblastic leukaemia (B-ALL), ID4 is overexpressed due to being located in close proximity to the IgH enhancer region. In Non Hodgkin lymphoma, the ID4 promoter region is implicated in follicular lymphomas, diffuse B Cell lymphomas and lymphoid cell lines due to hypermethylation. In brain tumours, more specifically oligodendroglial tumours and glioblastomas, the ID4 gene has been shown to be expressed in the neoplastic astrocytes but not expressed in the neoplastic oligodendrocytes. The ID4 promoter region has been found to be hypermethylated and its mRNA suppressed in breast cancer cell lines including that of primary breast cancers. Patients with invasive carcinomas have shown ID4 expression in their breast cancer specimens. This has been identified as a significant risk factor in nodal metastasis.ID4 is constitutively expressed in normal human mammary epithelium but found to be suppressed in ER positive breast carcinomas and preneoplastic lesions. ER negative carcinomas also show ID4 expression.There is a hypothesis that ID4 acts as a tumour suppressor factory in human breast tissue where oestrogen is responsible for regulation of ID4 expression in the mammary ductal epithelium. It is unclear whether the ID4 gene plays a role in bladder cancer. ID4 is found on the 6p22.3 amplicon which is frequently associated with advance stage bladder cancer. ID4 has also been shown to be overexpressed in bladder cancer cell lines. This overexpression is equally seen in both normal urothelium which lines the urinary tract inclusive of the renal pelvis, ureters, bladder and parts of the urethra, but also seen in fresh cancer tissues. ID4 is closely associated with gastric cancer. The ID4 promoter region is hypermethylated and infrequently expressed in gastric adenocarcinomas and frequently expressed in gastric cancer cell lines. In contrast, ID4 is highly expressed in normal gastric mucosa. There is an undefined but significant association seen in ID4 promoter hypermethylation (which results in its down regulation) and microsatellite instability. ID4 is not found in normal epitheliums nor adenomas of colorectal cancer. Hypermethylation of ID4 causes silencing of the gene. This has been identified as a significant independent risk factor for poor prognosis of colorectal cancer. It is also frequently observed in liver metastases of colorectal cancer specimens. ## Developmental disorders Rett syndrome is an X linked neurodevelopment disorder. It is often identified after six to eight months of age in females. In human brain tissue specimens of Rett syndrome patients, the family of ID genes are seen to be significantly increased in expression. # Society and culture ## Commonly used names The ID4 gene is also known as DNA-binding protein inhibitor ID-4, Id-4, IDb4, IDB4, Inhibitor of DNA binding 4, Inhibitor of differentiation 4, helix protein 271, Inhibitor of DNA binding 4 HLH Protein, Inhibitor of Differentiation 4, Inhibitor of DNA Binding 4 Dominant Negative Helix-Loop-Helix Protein, Class B Basic Helix-Loop-Helix Protein 27, and BHLHb272.

IPA Below is a basic key to the symbols of the International Phonetic Alphabet.For the smaller set of symbols that is sufficient for English, see Help:pronunciation.Several rare IPA symbols are not included; these are found on the main IPA article. For each IPA symbol, an English example is given where possible; here "RP" stands for Received Pronunciation.The foreign languages that are used to illustrate additional sounds are primarily the ones most likely to be familiar to English speakers, French, German, and Spanish.For symbols not covered by those, recourse is taken to the populous languages Mandarin Chinese, Hindustani, Arabic, and Russian.For sounds still not covered, other smaller but well-known languages are used, such as Swahili, Turkish, and Zulu. The left-hand column displays the symbols like this: Template:Audio-pipe.Click on the speaker icon to hear the sound; click on the symbol itself for a dedicated article with a more complete description and examples from multiple languages.All the sounds are spoken more than once, and the consonant sounds are spoken once followed by a vowel and once between vowels. # Main symbols The symbols are arranged by similarity to letters of the Latin alphabet.Symbols which do not resemble any letter are placed at the end. - ^1 ^2 These symbols are officially written with a tie linking them (e.g. Template:IPA), and are also sometimes written as single characters (e.g. Template:IPA) though the latter convention is no longer official.They are written without ligatures here to ensure correct display in all browsers. # Diacritic marks All diacritics are here shown on a carrier letter such as the vowel a. # Brackets Two types of brackets are commonly used to enclose transcriptions in the IPA: - indicate the phonetic details of the pronunciation, regardless of whether they are actually meaningful to a native speaker.This is what a foreigner who does not know the structure of a language might hear.For instance, the English word lulls is pronounced Template:IPA, with different el sounds at the beginning and end.This is obvious to speakers of some other languages, though a native English speaker might not believe it.Likewise, Spanish la bomba has two different b sounds to foreign ears, Template:IPA, though a Spaniard might not be able to hear it.Omitting such detail does not make any difference to the identity of the word. - /Slashes/ indicate phonemes.That is, changing symbol between slashes would make a difference in the meaning of the word, or produce nonsense.Since there is no meaningful difference between the two el sounds in the word lulls, they need to be transcribed with the same symbol: Template:IPA.Similarly, Spanish la bomba is phonemically transcribed Template:IPA. A third kind of bracket is occasionally seen: - |Pipes| indicate that the sounds are theoretical constructs that aren't actually heard. (This is called morphophonology.)For instance, if it is decided that the -s at the ends of verbs, which surfaces as either Template:IPA, as in talks Template:IPA, or Template:IPA, as in lulls Template:IPA, is actually the former (the difference between /s/ and /z/ is meaningful in English, unlike for example in Spanish), then that could be written |s|, for a claim that phonemic Template:IPA is essentially Template:IPA.This is not standardized; other conventions are Template:IPA, Template:IPA, and Template:IPA. Lastly, - are occasionally used to represent the orthography: , .

Ice Ice is the name given to any one of the 15 known crystalline solid phases of water.In non-scientific contexts, it usually describes ice Ih, which is known to be the most abundant of these phases.It can appear transparent or an opaque bluish-white color depending on the presence of impurities such as air.The addition of other materials such as soil may further alter the appearance. The most common phase transition to ice Ih occurs when liquid water is cooled below 0 °C (273.15 K, 32 °F) at standard atmospheric pressure. It can also deposit from a vapor with no intervening liquid phase, such as in the formation of frost. Ice appears in nature in forms as varied as snowflakes and hail, icicles, glaciers, pack ice, and entire polar ice caps. It is an important component of the global climate, particularly in regard to the water cycle.Furthermore, ice has numerous cultural applications, from the ice cooling one's drink to winter sports and ice sculpture. The word is from Old English ís, in turn derived from Proto-Germanic *isaz. # Characteristics As a naturally occurring crystalline solid, ice is considered a mineral consisting of hydrogen oxide. An unusual property of ice frozen at a pressure of one atmosphere is that the solid is some 8% less dense than liquid water.Water is the only known non-metallic substance to expand when it freezes.Ice has a density of 0.9167 g/cm³ at 0 °C, whereas water has a density of 0.9998 g/cm³ at the same temperature.Liquid water is most dense, essentially 1.00 g/cm³, at 4 °C and becomes less dense as the water molecules begin to form the hexagonal crystals of ice as the temperature drops to 0 °C. (In fact, the word "crystal" derives from Greek word for frost.)This is due to hydrogen bonds forming between the water molecules, which line up molecules less efficiently (in terms of volume) when water is frozen.The result of this is that ice floats on liquid water, which is an important factor in Earth's climate.Density of ice increases slightly with decreasing temperature (density of ice at −180 °C (93 K) is 0.9340 g/cm³). When ice melts, it absorbs as much heat energy (the heat of fusion) as it would take to heat an equivalent mass of water by 80 °C, while its temperature remains a constant 0 °C. It is also theoretically possible to superheat ice beyond its equilibrium melting point.Simulations of ultrafast laser pulses acting on ice show it can be heated up to room temperature for an extremely short period (250 ps) without melting it. Light reflecting from ice can appear blue, because ice absorbs more of the red frequencies than the blue ones. Also, icebergs containing impurities (e.g. sediments, algae, air bubbles) can appear green. ## Slipperiness Until recently, it was widely believed that ice was slippery because the pressure of an object in contact with it caused a thin layer to melt.For example, the blade of an ice skate, exerting pressure on the ice, melted a thin layer, providing lubrication between the ice and the blade. This explanation is no longer widely accepted.There is still debate about why ice is slippery.The explanation gaining acceptance is that ice molecules in contact with air cannot properly bond with the molecules of the mass of ice beneath (and thus are free to move like molecules of liquid water).These molecules remain in a semiliquid state, providing lubrication regardless of pressure against the ice exerted by any object. This phenomenon does not seem to hold true at all temperatures.The extreme conditions found, especially, in Antarctica have been observed to make ice and snow not slippery.Explorers report that at very low temperatures snow loses its "glide", and pulling a sledge across it becomes like pulling a sledge through sand. # Types of ice Everyday ice and snow has a hexagonal crystal structure (ice Ih).Subjected to higher pressures and varying temperatures, ice can form in roughly a dozen different phases.Only a little less stable (metastable) than Ih is the cubic structure (Ic). With both cooling and pressure more types exist, the formation conditions for each being represented on the phase diagram of ice.These are II, III, V, VI, VII, VIII, IX, and X. With care all these types can be recovered at ambient pressure.The types are differentiated by their crystalline structure, ordering and density.There are also two metastable phases of ice under pressure, both fully hydrogen disordered, these are IV and XII.Ice XII was discovered in 1996.In 2006, XIII and XIV were discovered.Ices XI, XIII, and XIV are hydrogen-ordered forms of ices Ih, V, and XII respectively. As well as crystalline forms, solid water can exist in amorphous states as amorphous solid water (ASW), low density amorphous ice (LDA), high density amorphous ice (HDA), very high density amorphous ice (VHDA) and hyperquenched glassy water (HGW). Rime is a type of ice formed on cold objects when drops of water crystalize on them.This can be observed in foggy weather, when the temperature drops during night.Soft rime contains a high proportion of trapped air, making it appear white rather than transparent, and giving it a density about one quarter of that of pure ice.Hard rime is comparatively denser. Aufeis is layered ice that forms in arctic and subarctic stream valleys. Ice frozen in the stream bed blocks normal groundwater discharge and causes the local water table to rise, resulting in water discharge on top of the frozen layer. This water then freezes, causing the water table to rise further and repeat the cycle.The result is a stratified ice deposit, often several meters thick. Ice can also form icicles, similar to stalactites in appearance, as water drips and re-freezes. Clathrate hydrates are forms of ice that contain gas molecules trapped within its crystal lattice.Pancake ice is a formation of ice generally created in areas with less calm conditions. Some other substances (particularly solid forms of those usually found as fluids) are also called "ice": dry ice, for instance, is a popular term for solid carbon dioxide. In outer space hexagonal crystalline ice, the predominant form on Earth, is extremely rare. Amorphous ice is more common; however, hexagonal crystalline ice can be formed via volcanic action. # Uses of ice ## Ice harvesting Ice has long been valued as a means of cooling. Until recently, the Hungarian Parliament building used ice harvested in the winter from Lake Balaton for air conditioning. Icehouses were used to store ice formed in the winter to make ice available year-round, and early refrigerators were known as iceboxes because they had a block of ice in them. In many cities it was not unusual to have a regular ice delivery service during the summer. For the first half of the 19th century, ice harvesting had become big business in America.Frederic Tudor, who became known as the “Ice King,” worked on developing better insulation products for the long distance shipment of ice, especially to the tropics.The advent of artificial refrigeration technology has since made delivery of ice obsolete. In 400 BC Iran, Persian engineers had already mastered the technique of storing ice in the middle of summer in the desert.The ice was brought in during the winters from nearby mountains in bulk amounts, and stored in specially designed, naturally cooled refrigerators, called yakhchal (meaning ice storage).This was a large underground space (up to 5000 m³) that had thick walls (at least two meters at the base) made out of a special mortar called sārooj, composed of sand, clay, egg whites, lime, goat hair, and ash in specific proportions, and which was known to be resistant to heat transfer.This mixture was thought to be completely water impenetrable.The space often had access to a Qanat, and often contained a system of windcatchers that could easily bring temperatures inside the space down to frigid levels in summer days.The ice was then used to chill treats for royalty during hot summer days. ## Sports on ice Ice also plays a role in winter recreation, in many sports such as ice skating, tour skating, ice hockey, ice fishing, ice climbing, curling, broomball and sled racing on bobsled, luge and skeleton.Many of the different sports played on ice get international attention every four years during the Winter Olympic Games. A sort of sailboat on blades gives rise to ice boating.The human quest for excitement has even led to ice racing, where drivers must speed on lake ice while also controlling the skid of their vehicle (similar in some ways to dirt track racing).The sport has even been modified for ice rinks. ## Ice and transportation Ice can also be an obstacle; for harbors near the poles, being ice-free is an important advantage, ideally all-year round.Examples are Murmansk (Russia), Petsamo (Russia, formerly Finland) and Vardø (Norway).Harbors that are not ice-free are opened up using icebreakers. Ice forming on roads is a dangerous winter hazard.Black ice is very difficult to see because it lacks the expected frosty surface. Whenever there is freezing rain or snow that occurs at a temperature near the melting point, it is common for ice to build up on the windows of vehicles. Driving safely requires the removal of the ice build-up. Ice scrapers are tools designed to break the ice free and clear the windows, though removing the ice can be a long and labor-intensive process. Far enough below the freezing point, a thin layer of ice crystals can form on the inside surface of windows. This usually happens when a vehicle has been left alone after being driven for a while, but can happen while driving if the outside temperature is low enough. Moisture from the driver's breath is the source of water for the crystals. It is troublesome to remove this form of ice, so people often open their windows slightly when the vehicle is parked in order to let the moisture dissipate, and it is now common for cars to have rear-window defrosters to combat the problem. A similar problem can happen in homes, which is one reason why many colder regions require double-pane windows for insulation. When the outdoor temperature stays below freezing for extended periods, very thick layers of ice can form on lakes and other bodies of water (although places with flowing water require much colder temperatures). The ice can become thick enough to drive onto with automobiles and trucks. Doing this safely requires a thickness of at least 30 centimeters (one foot). For ships, ice presents two distinct hazards.Spray and freezing rain can produce an ice build-up on the superstructure of a vessel sufficient to make it unstable and to require it to be hacked off or melted with steam hoses.And icebergs — large masses of ice floating in water (typically created when glaciers reach the sea) — can be dangerous if struck by a ship when under way.Icebergs have been responsible for the sinking of many ships, a notable example being the Titanic. For aircraft, ice can cause a number of dangers.As an aircraft climbs, it passes through air layers of different temperature and humidity, some of which may be conducive to ice formation.If ice forms on the wings or control surfaces, this may adversely affect the flying qualities of the aircraft.During the first non-stop flight of the Atlantic, the British aviators Captain John Alcock and Lieutenant Arthur Whitten Brown encountered such icing conditions - Brown left the cockpit and climbed onto the wing several times to remove ice which was covering the engine air intakes of the Vickers Vimy aircraft they were flying. A particular icing vulnerability associated with reciprocating internal combustion engines is the carburettor.As air is sucked through the carburettor into the engine the local air pressure is lowered, which causes adiabatic cooling.So, in humid close-to-freezing conditions, the carburettor will be colder and tend to ice up.This will block the supply of air to the engine, and cause it to fail.Aircraft reciprocating engines with carburettors are provided with carburettor air intake heaters for this reason.The increasing use of fuel injection—which does not require carburettors—has made "carb icing" less of an issue for reciprocating engines. Jet engines do not experience carb icing, but recent evidence indicates that they can be slowed, stopped, or damaged by internal icing in certain types of atmospheric conditions much more easily than previously believed. In most cases, the engines can be quickly restarted and flights are not endangered, but research continues to determine the exact conditions that produce this type of icing, and find the best methods to prevent or reverse it in flight. ## Other uses of ice - Engineers used pack ice's formidable strength when they constructed Antarctica's first floating ice pier in 1973.Such ice piers are used during cargo operations to load and offload ships.Fleet operations personnel make the floating pier during the winter.They build upon naturally occurring frozen seawater in McMurdo Sound until the dock reaches a depth of about 22 feet (6.7056 m).Ice piers have a lifespan of three to five years. - The manufacture and use of ice cubes or crushed ice is common for drinks. - Pagophagia, a type of pica eating disorder, is the compulsive consumption of ice. - Structures and ice sculptures are built out of large chunks of ice. The structures are mostly ornamental (as in the case with ice castles) and not practical for long-term habitation. Ice hotels exist on a seasonal basis in a few cold areas.Igloos are another example of a temporary structure, made primarily from snow. - During World War II, Project Habbakuk was a British program which investigated the use of pykrete (wood fibres mixed with ice) as a possible material for warships, especially aircraft carriers due to the ease with which a large deck could be constructed, but the idea was given up when there were not enough funds for construction of a prototype. - Ice can be used to start a fire by carving it into a lens that will focus sunlight onto kindling.When one waits long enough, a fire will start. - In global warming, ice plays an important part because it reflects 90% of the sun's rays.Furthermore, ice cores help provide historical climate information. - In January and February 1658, the straits between the islands of Denmark, Great Belt and Little Belt froze over, allowing a Swedish army to March across the Belts and defeat the Danish army.The resulting Treaty of Roskilde ceded large areas of Denmark to Sweden. # Ice at different pressures Most liquids freeze at a higher temperature under pressure because the pressure helps to hold the molecules together.However, the strong hydrogen bonds in water make it different: water freezes at a temperature below 0 °C under a pressure higher than 1 atm.Consequently water also remains frozen at a temperature above 0 °C under a pressure lower than 1 atm.The melting of ice under high pressures is thought to contribute to why glaciers move. Ice formed at high pressure has a different crystal structure and density than ordinary ice. Ice, water, and water vapor can coexist at the triple point, which is 273.16 K at a pressure of 611.73 Pa. # Phases of ice

Jaw # Overview The jaw is either of the two opposable structures forming, or near the entrance to, the mouth. The term jaws is also broadly applied to the whole of the structures constituting the vault of the mouth and serving to open and close it. # Arthropods In arthropods, the jaws are chitinous and oppose laterally, and may consist in mandibles, chelicerae, or loosely, pedipalps. Their function is fundamentally for food acquisition, conveyance to the mouth, and/or initial processing (mastication or chewing). # Vertebrates In most vertebrates, the jaws are bony or cartilaginous and oppose vertically, comprising an upper jaw and a lower jaw. ## Bones of the jaw In vertebrates, the lower jaw, dentary or mandible is the mobile component that articulates at its posterior processes, or rami (singular ramus), with the temporal bones of the skull on either side; the word jaw used in the singular typically refers to the lower jaw. The upper jaw or maxilla is more or less fixed with the skull and is composed of two bones, the maxillae, fused intimately at the median line by a suture; incomplete closure of this suture and surrounding structures may be involved in the malformation known as cleft palate. The maxillary bones form parts of the roof of the mouth, the floor and sides of the nasal cavity, and the floor of the orbit or eye socket. The jaws typically accommodate the teeth or form the bases for the attachment of a beak. ## The jaw in fish and amphibians The vertebrate jaw probably originally evolved in the Silurian period and appeared in the Placoderm fish which further diversified in the Devonian. Jaws are thought to derive from the pharyngeal arches that support the gills in fish. The two most anterior of these arches are thought to have become the jaw itself and the hyoid arch, which braces the jaw against the braincase and increases mechanical efficiency. While there is no fossil evidence directly to support this theory, it makes sense in light of the numbers of pharyngeal arches that are visible in extant jawed (the Gnathostomes), which have seven arches, and primitive jawless vertebrates (the Agnatha), which have nine. It is thought that the original selective advantage garnered by the jaw was not related to feeding, but to increased respiration efficiency. The jaws were used in the buccal pump (observable in modern fish and amphibians) that pumps water across the gills of fish or air into the lungs in the case of amphibians. Over evolutionary time the more familiar use of jaws (to humans), in feeding, was selected for and became a very important function in vertebrates. ## The jaw in reptiles In reptiles, the mandible is made up of five bones.In the evolution of mammals, four of these bones were reduced in size and incorporated into the ear.In their reduced form, they are known as the malleus and incus; along with the more ancient stapes, they are the ossicles.This adaptation is advantageous, not only because a one-bone jaw is stronger, but also because the malleus and incus improve hearing. (However, reptiles tend to swallow prey whole because their pace of digestion is different than mammals, so multiple jaw bones may allow flexibility to expand the jaws around prey.)

LYN Tyrosine-protein kinase Lyn is a protein that in humans is encoded in humans by the LYN gene. Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells, in neural tissues liver, and adipose tissue.In various hematopoietic cells, Lyn has emerged as a key enzyme involved in the regulation of cell activation.In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the B cell antigen receptor (BCR), CD40, or CD19.The abbreviation Lyn is derived from Lck/Yes novel tyrosine kinase, Lck and Yes also being members of the Src kinase family. # Function Lyn has been described to have an inhibitory role in myeloid lineage proliferation.Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation.LYN activation triggers a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phosholipase Cγ2 (PLCγ2) and phosphatidyl inositol-3 kinase.These kinases provide activation signals, which play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FCγRIIb1.Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1, which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. In B cells, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition.Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch. Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1). This phosphorylation of IRS1 leads to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization. In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop. The insulin secretagogue, glimepiride (Amaryl®) activates Lyn in adipocytes via the disruption of lipid rafts. This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride. Tolimidone (MLR-1023) is a small molecule lyn activator that is currently under Phase 2a investigation for Type II diabetes. In June, 2016, the sponsor of these studies, Melior Discovery, announced positive results from their Phase 2a study with tolimidone in diabetic patients, and the continuation of additional clinical studies. Lyn has been shown to protect against hepatcellular apoptosis and promote liver regeneration through the preservation of hepatocellular mitochondrial integrity. # Pathology Much of the current knowledge about Lyn has emerged from studies of genetically manipulated mice.Lyn deficient mice display a phenotype that includes splenomegaly, a dramatic increase in numbers of myeloid progenitors and monocyte/macrophage tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells. Mice that expressed a hyperactive Lyn allele were tumor free and displayed no propensity toward hematological malignancy. These mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. With age these animals developed a glomerulonephritis phenotype associated with a 30% reduction in life expectancy. # Interactions LYN has been shown to interact with: c-Kit, - BCAR1, - CD117, - CD22, - Cdk1, - DOK1, - EPOR - GPVI, - INPP5D, - IRS1, - LCP2, - MUC1, - NEDD9, - PLCG2, - PPP1R15A, - PTPRC, - Syk, - TRPV4, and - UNC119.

Lip # Overview Lips are a visible organ at the mouth of humans and many animals. Both lips are soft, protruding, movable, and serve primarily for food intake, as a tactile sensory organ, and in articulation of speech. # Anatomical basics of the human lip One differentiates between the Upper (Labium superioris) and lower lip (Labium inferioris).The lower lip is usually somewhat larger.The border between the lips and the surrounding skin is referred to as the vermilion border, or simply the vermilion.The vertical groove on the upper lip is known as the philtrum.The entire skin between the upper lip and the nose is referred to as the "ergotrid". The skin of the lip, with three to five cellular layers, is very thin compared to typical face skin, having up to 16 layers.With light skin color, the lip skin contains no melanocyte (pigment cells, which give skin its color).Because of this, the blood vessels appear through the skin of the lips, which leads to their notable red coloring.With darker skin color this effect is less prominent, as in this case the skin of the lips contains more melanin and thus is visually thicker. The lip skin is not hairy and does not have sweat glands or sebaceous glands.Therefore, it does not have the usual protection layer of sweat and body oils which keep the skin smooth, kill pathogens, and regulate warmth.For these reasons, the lips dry out faster and become chapped more easily. # Anatomy in detail The skin of the lips is stratified squamous epithelium.The mucous membrane is represented by a large area in the sensory cortex and is therefore highly sensitive.The Frenulum Labii Inferioris is the frenulum of the lower lip.The Frenulum Labii Superioris is the frenulum of the upper lip. ## Sensory nerve supply - Trigeminal nerve The infraorbital nerve is a branch of the maxillary branch.It supplies not only the upper lip, but much of the skin of the face between the upper lip and the lower eyelid, except for the bridge of the nose. The mental nerve is a branch of the mandibular branch ( via the inferior alveolar nerve). It supplies the skin and mucous membrane of the lower lip and labial gingiva (gum) anteriorly. - The infraorbital nerve is a branch of the maxillary branch.It supplies not only the upper lip, but much of the skin of the face between the upper lip and the lower eyelid, except for the bridge of the nose. - The mental nerve is a branch of the mandibular branch ( via the inferior alveolar nerve). It supplies the skin and mucous membrane of the lower lip and labial gingiva (gum) anteriorly. ## Blood supply The facial artery is one of the six non-terminal branches of the external carotid artery.It supplies the lips by its superior and inferior labial branches, each of which bifurcate and anastomose with their companion artery from the other side. ## Muscles acting on the lips The muscles acting on the lips are considered part of the muscles of facial expression. All muscles of facial expression are derived from the mesoderm of the second pharyngeal arch, and are therefore supplied (motor supply) by the nerve of the second pharyngeal arch, the facial nerve (7th cranial nerve).The muscles of facial expression are all specialised members of the paniculus carnosus, which attach to the dermis and so wrinkle or dimple the overlying skin.Functionally, the muscles of facial expression are arranged in groups around the orbits, nose and mouth. The muscles acting on the lips: - sphincters of the oral orifice buccinator -rbicularis oris - buccinator - orbicularis oris - anchor point for several muscles modiolus - modiolus - lip elevation levator labii superioris levator labii superioris alaeque nasi levator anguli oris zygomaticus minor zygomaticus major - levator labii superioris - levator labii superioris alaeque nasi - levator anguli oris - zygomaticus minor - zygomaticus major - lip depression risorius depressor anguli oris depressor labii inferioris mentalis - risorius - depressor anguli oris - depressor labii inferioris - mentalis # Functions of the lips ## Food intake Because they have their own muscles and bordering muscles, the lips are very movable.Lips are used for eating functions, like holding food or to get it in the mouth.In addition, lips serve to close the mouth airtight shut, and to hold food and drink inside, and to keep out unwanted objects.Through making a narrow funnel with the lips, the suction of the mouth is increased.This suction is essential for babies to breast feed. ## Tactile organ The lip has many nerve endings and reacts as part of the tactile (touch) senses. Lips are very sensitive to touch, warmth, and cold. It is therefore an important aide for exploring unknown objects for babies and toddlers. ## Articulation The lips serve for creating different sounds - mainly the labial, bilabial and labiodental consonant sounds - and thus create an important part of the speech apparatus. The lips enable whistling and the performing of wind instruments like the trumpet, clarinet, and flute. ## Facial expressions See Full Article: facial expression. The lips visibly express emotions. ## Erogenous zone Because of its high amounts of nerve endings, the lips make an erogenous zone.Lips play a crucial role in kissing and other acts of intimacy. Lips are a visible expression of fertility.It has been shown that the more estrogen a woman has the fuller her lips and that full lips are considered attractive.(Indeed lipstick "tricks" men into thinking that a women has more estrogen than she actually has and thus finding her more attractive. # Symbolic meaning Lips are often viewed as a symbol for sensuality.This has many origins; above all that they are very sensitive as a tactile organ and feel pleasantly soft.It has been suggested that female lips are seen as sexually attractive because they mimic the appearance and sexual swelling of the labia of the vulva, and that the lips are therefore a secondary sex characteristic. Additionally, they are a part of the mouth and so are associated with its symbolic connections (see for example oral stage of the psychology according to Sigmund Freud). # Changes to the lip - One of the most frequent changes of the lips is a blue coloring due to cyanosis; the blood contains less oxygen and thus has a dark red to blue color, which shows through the thin skin. Cyanosis is the reason why corpses always have blue lips.In cold weather cyanosis can appear, so especially in the winter blue lips may not be an uncommon sight. - Lips can (temporarily) swell. The reasons for this are varied and can be from sexual stimulation, injuries and side effects of medications or misallignment of teeth. - Cracks or splits in the angles of the lips could be the result of an inflammation of the lips, Angular cheilitis. # Diseases As an organ of the body, the lip can be a focus of disease or show symptoms of a disease: - Lip herpes (technically Herpes labialis, a form of herpes simplex) is a viral infection which appears in the formation of painful blisters at the lip. - Carcinoma at the lips is caused predominantly by using tobacco and overexposure of sunlight.To a lesser extent, it could also come from lack of oral hygiene or poor fitting dentures.Alcohol appears to increase the carcinoma risk of tobacco use. - Infections from lip rings.

Lck Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes.Lck is a tyrosine kinase, which phosphorylates tyrosine residues of certain proteins involved in the intracellular signaling pathways of these lymphocytes.It is a member of the Src family of tyrosine kinases. # T cell signaling Lck is most commonly found in T cells. It associates with the cytoplasmic tails of the CD4 and CD8 co-receptors on T helper cells and cytotoxic T cells, respectively, to assist signaling from the T cell receptor (TCR) complex.When the T cell receptor is engaged by the specific antigen presented by MHC, Lck acts to phosphorylate the intracellular chains of the CD3 and ζ-chains of the TCR complex, allowing another cytoplasmic tyrosine kinase called ZAP-70 to bind to them.Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates another molecule in the signaling cascade called LAT (short for Linker of Activated T cells), a transmembrane protein that serves as a docking site for a number of other proteins, the most important of which are Shc-Grb2-SOS, PI3K, and phospholipase C (PLC).Additionally, upon T cell activation, a fraction of kinase active Lck, translocates from outside of lipid rafts (LR) to inside lipid rafts where it interacts with and activates LR-resident Fyn, which is involved in further downstream signaling activation. The tyrosine phosphorylation cascade initiated by Lck and Fyn culminates in the intracellular mobilization of calcium (Ca2+) ions and activation of important signaling cascades within the lymphocyte. These include the Ras-MEK-ERK pathway, which goes on to activate certain transcription factors such as NFAT, NF-κB, and AP-1. These transcription factors regulate the production of a plethora of gene products, most notable, cytokines such as Interleukin-2 that promote long-term proliferation and differentiation of the activated lymphocytes. The function of Lck has been studied using several biochemical methods, including gene knockout (knock-out mice), Jurkat cells deficient in Lck (JCaM1.6), and siRNA-mediated RNA interference. # Structure Lck is a 56-kilodalton protein.The N-terminal tail of Lck is myristoylated and palmitoylated, which tethers the protein to the plasma membrane of the cell.The protein furthermore contains a SH3 domain, a SH2 domain and in the C-terminal part the tyrosine kinase domain.The two main phosphorylation sites on Lck are tyrosines 394 and 505.The former is an autophosphorylation site and is linked to activation of the protein.The latter is phosphorylated by Csk, which inhibits Lck because the protein folds up and binds its own SH2 domain.Lck thus serves as an instructive example that protein phosphorylation may result in both activation and inhibition. # Substrates Lck tyrosine phosphorylates a number of proteins, the most important of which are the CD3 receptor, CEACAM1, ZAP-70, SLP-76, the IL-2 receptor, Protein kinase C, ITK, PLC, SHC, RasGAP, Cbl, Vav1, and PI3K. # Inhibition In resting T cells, Lck is constitutively inhibited by Csk phosphorylation on tyrosine 505.Lck is also inhibited by SHP-1 dephosphorylation on tyrosine 394.Lck can also be inhibited by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway. Saractinib, a specific inhibitor of LCK impairs maintenance of human T-ALL cells in vitro as well as in vivo by targeting this tyrosine kinase in cells displaying high level of lipid rafts. Masitinib also inhibits Lck, which may have some impact on its therapeutic effects in canine mastocytoma. # Interactions Lck has been shown to interact with: - ADAM15, - CD2, - CD44, - CD4, - COUP-TFII, - DLG1, - NOTCH1, - PIK3CA, - PTPN6, - PTPRC, - UNC119, - SYK, - UBE3A, and - ZAP70.

Leg A leg is the part of an animal's body that supports the rest of the animal above the ground betwean the ankle and the hip and is used for locomotion.The end of the leg furthest from the animal's body is often either modified or attached to another structure that is modified to disperse the animal's weight on the ground (see foot). In bipedal vertebrate animals, the two lower limbs are usually referred to as the 'legs' and the two upper limbs as the 'arms' or 'wings' as the case may be. Legs typically come in even-numbered quantities.Many taxonomic groups are characterized by the number of legs its members possess. - Uniped: 1 - Biped: 2 - Tripedal: 3 - Quadruped: 4 - Quinped: 5 - Arthropoda: 4, 6, 8, 12, or 14 Some arthropods have more than a dozen legs; a few species possess over 100.Despite what their names might suggest, Centipedes typically have fewer than one hundred legs Millipedes have fewer than one thousand legs. - Some arthropods have more than a dozen legs; a few species possess over 100.Despite what their names might suggest, Centipedes typically have fewer than one hundred legs Millipedes have fewer than one thousand legs. - Centipedes typically have fewer than one hundred legs - Millipedes have fewer than one thousand legs. # Evolution The leg has evolved several times, most significantly among arthropods (crustaceans, insects, arachnids, et cetera) and vertebrates.In both cases, they are thought to have first evolved for locomotion underwater, then have been exploited for movement over land ever less desperate conditions as the generations passed. # The human leg The bones of the human leg are: - Tibia, or shin bones - Fibula, or calf bones

Lux The lux (symbol: lx) is the SI unit of illuminance and luminous emittance.It is used in photometry as a measure of the intensity of light, with wavelengths weighted according to the luminosity function, a standardized model of human brightness perception.In English, "lux" is used in both singular and plural. # Definition 1 lx = 1 lm·m-2 = 1 cd· sr·m–2 # Explanation Lux is a derived unit based on lumen, and lumen is a derived unit based on candela. One lux is equal to one lumen per square metre, where 4π lumens is the total luminous flux of a light source of one candela of luminous intensity. Unicode has a symbol for "lx": (㏓), but this is just a legacy code to accommodate old code pages in certain Asian languages, and it is not recommended for use in any language today. ## Lux versus lumen The difference between the lux and the lumen is that the lux takes into account the area over which the luminous flux is spread.1000 lumens, concentrated into an area of one square metre, lights up that square metre with an illuminance of 1000 lux.The same 1000 lumens, spread out over ten square metres, produces a dimmer illuminance of only 100 lux. Achieving an illuminance of 500 lux might be possible in a home kitchen with a single fluorescent light fixture with an output of 12000 lumens.To light a factory floor with dozens of times the area of the kitchen would require dozens of such fixtures.Thus, lighting a larger area to the same level of lux requires a greater number of lumens. ## Lux versus footcandle One footcandle ≈ 10.764 lux.The footcandle (or lumen per square foot) is a non-SI unit of illuminance.Like the BTU, it is obsolete but it is still in fairly common use in the United States, particularly in construction-related engineering and in building codes.Because lux and footcandles are different units of the same quantity, it is perfectly valid to convert footcandles to lux and vice versa. The name "footcandle" conveys "the illuminance cast on a surface by a one-candela source one foot away."As natural as this sounds, this style of name is now frowned upon, because the dimensional formula for the unit is not foot · candela, but lumen/sq ft.Some sources do however note that the "lux" can be thought of as a "metre-candle" (i.e. the illuminance cast on a surface by a one-candela source one meter away).A source that is farther away provides less illumination than one that is close, so one lux is less illuminance than one footcandle.Since illuminance follows the inverse-square law, and since one foot = 0.3048 m, one lux = 0.30482 footcandle ≈ 1/10.764 footcandle. In practical applications, as when measuring room illumination, it is very difficult to measure illuminance more accurately than ±10%, and for many purposes it is quite sufficient to think of one footcandle as about ten lux. ## Relationship between illuminance and irradiance Like all photometric units, the lux has a corresponding "radiometric" unit.The difference between any photometric unit and its corresponding radiometric unit is that radiometric units are based on physical power, with all wavelengths being weighted equally, while photometric units take into account the fact that the eye is more sensitive to some wavelengths than others, and accordingly every wavelength is given a different weight.The weighting factor is known as the luminosity function. The lux is one lumen/meter2, and the corresponding radiometric unit, which measures irradiance, is the watt/meter2.There is no single conversion factor between lux and watt/meter2; there is a different conversion factor for every wavelength, and it is not possible to make a conversion unless one knows the spectral composition of the light. The peak of the luminosity function is at 555 nm (green); the eye is more sensitive to light of this wavelength than any other.For monochromatic light of this wavelength, the irradiance needed to make one lumen is minimum, at 1.464 mW/m2; one obtains 683.002 lux per W/m2 (or lumens per watt).Other wavelengths of visible light produce fewer lumens per watt.The luminosity function falls to zero for wavelengths outside the visible spectrum. For a light source with mixed wavelengths, the number of lumens per watt can be calculated by means of the luminosity function.In order to appear reasonably "white," a light source cannot consist solely of the green light to which the eye is most sensitive, but must include a generous mixture of red and blue wavelengths to which it is much less sensitive. This means that white (or whitish) light sources produce far fewer lumens per watt than the theoretical maximum of 683 lumens per watt.The ratio between the actual number of lumens per watt and the theoretical maximum is expressed as a percentage known as the luminous efficiency. For example, a typical incandescent light bulb has a luminous efficiency of only about 2%. In reality, individual eyes vary slightly in their luminosity functions.However, photometric units are precisely defined and precisely measurable.They are based on an agreed-upon standard luminosity function which is based on the measurement of many individual eyes. # SI photometry units # Non-SI units of illuminance - foot-candle (=10.76 lx) - phot (=10 klx) - nox (=1 mlx) # Use in video camera specifications Specifications for camcorders (video cameras) often include a minimum illuminance level in lux at which the camera will record a satisfactory image. A camera with good low-light capability will have a lower lux rating. Still cameras do not use such a specification, since longer exposure times can generally be used to make pictures at very low illuminance levels, as opposed to the case in video cameras where a maximum exposure time is generally set by the frame rate.

MCC What are you looking for? - MCC (gene), a tumor suppressor gene involved in colorectal tumor pathogenesis - Merkel cell carcinoma, a rare and aggressive cancer of the skin - Morbus cordis coronarius, the Latin name for coronary artery disease

MCL What are you looking for? - Johnie McL disease, a synonym for Hurler's syndrome - Mantle cell lymphoma, a subtype of B-cell lymphoma - Mast cell leukemia, an aggressive subtype of acute myeloid leukemia - Medial collateral ligament, one of many ligaments of the knee - Midclavicular line - Mucocutaneous leishmaniasis, an infection caused by Leishmania spp.parasites - Multiple cutaneous leiomyoma, a subtype of leiomyoma (smooth muscle tumor) - Myeloid cell leukemia sequence 1 (MCL-1) gene, a member of the BCL-2 family, that encodes the "induced myeloid leukemia cell differentiation" (mcl-1) protein that is targeted by pharmacologic agents such as Omacetaxine, Mepesuccinate, and Seliciclib

Pus Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief.You may also apply to be an Associate Editor-In-Chief of one of the subtopics below.Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic.Please be sure to attach your CV and or biographical sketch. # Overview Pus is a whitish-yellow or yellow substance produced during inflammatory responses of the body that can be found in regions of pyogenic bacterial infections.An accumulation of pus in an enclosed tissue space is known as an abscess.A visible collection of pus within or beneath the epidermis, on the other hand, is known as a pustule or pimple.Pus is produced from the dead and living white blood cells which travel into the intercellular spaces around the affected cells. Something that creates pus is called suppurative, pyogenic, or purulent.If it creates mucus as well as pus, it is called mucopurulent. Pus consists of a thin, protein-rich fluid, known as liquor puris, and dead neutrophils (white blood cells), which are part of the body's innate immune response. Neutrophils are produced in the bone marrow and released into the blood.When the need to fight infection arises, they move to the site of infection by a process known as chemotaxis, usually triggered by cytokine release from macrophages that sense invading organisms. At the site of infection they engulf and kill bacteria. Eventually, the neutrophils die, and these dead cells are then phagocytosed by macrophages, which break them down further. Pus, therefore, is the viscous material composed of these dead neutrophils. Neutrophils are the most abundant type of leukocyte in human blood, composing anywhere between 40% to 75% of leukocytes. When seen in a wound or dry skin, pus indicates the area is infected and should be cleaned with antiseptic. Despite normally being of a whitish-yellow hue, changes in the color of pus can be observed under certain circumstances.Blue pus is found in certain infections of Pseudomonas aeruginosa as a result of the pyocyanin bacterial pigment it produces; amoebic abscesses of the liver, meanwhile, produce brownish pus.Pus might have a reddish tint to it after mixing with blood.Pus also can have an odour.

NaK NaK (often pronounced as such, rhyming with "sack") is an alloy of sodium (Na) and potassium (K), and particularly one that is liquid at room temperatures.It is a commercially available material in various grades.NaK is highly reactive with air or water, and must be handled with special precautions.Quantities as small as one gram can be a fire or explosion risk. # Physical properties Alloys with between about 40% and 90% potassium by weight are liquid at room temperature.The mixture with the lowest melting point (the eutectic mix), consisting of 78% potassium and 22% sodium, is liquid from −12.6 to 785 °C, and has a density of 866 kg/m³ at 21°C and 855 kg/m³ at 100°C. # Usage ## As coolant One notable use is as the coolant in experimental fast neutron nuclear reactors.Unlike commercial plants, these are frequently shut down and defuelled.Use of lead or pure sodium, the other materials used in practical reactors, would require continual heating to maintain the coolant as a liquid.Use of NaK overcomes this.NaK is used in many other heat transfer applications for similar reasons. The Soviet RORSAT radar satellites were powered by a NaK-cooled reactor.Apart from the wide liquid temperature range, NaK has a very low vapor pressure, important in the vacuum of space.Some of the coolant has leaked and these NaK droplets constitute a significant space debris hazard. ## In catalysis NaK is also used as a catalyst for many reactions, including precursors of ibuprofen. ## As desiccant Both sodium and potassium are used as desiccants in drying solvents prior to distillation.However, without heating, the solid metal is only able to react at the surface.Formation of crusts of oxide also helps to reduce the reactivity.As a liquid metal alloy at room temperature, the use of NaK as a desiccant helps to avoid these problems.

Oat The oat (Avena sativa) is a species of cereal grain, and the seeds of this plant.They are used for food for people and as fodder for animals, especially poultry and horses.Oat straw is used as animal bedding and sometimes as animal feed. Since oats are unsuitable for making bread on their own, due to their lack of gluten, they are often served as a porridge made from crushed or rolled oats (see oatmeal), and are also baked into cookies (oatcakes), which can have added wheat flour.As oat flour or oatmeal, they are also used in a variety of other baked goods (e.g. bread made from a mixture of oatmeal and wheat flour) and cold cereals, and as an ingredient in muesli and granola.Oats may also be consumed raw, and cookies with raw oats are becoming popular.Oats are also occasionally used in Britain for brewing beer.Oatmeal stout is one variety brewed using a percentage of oats for the wort.The more rarely used Oat Malt is produced by the Thomas Fawcett & Sons Maltings and was used in the Maclay Oat Malt Stout before Maclay ceased independent brewing operations. Oats also have non-food uses.Oat straw is also used in corn dolly making, and it is the favourite filling for home made lace pillows.Oat extract can be used to soothe the skin conditions, e.g. in baths, skin products, etc. A now obsolete Middle English name for the plant was haver (still used in most other Germanic languages), surviving in the name of the livestock feeding bag haversack.In contrast with the names of the other grains, "oat" is usually used in the plural. # Origin The wild ancestor of Avena sativa and the closely-related minor crop, A. byzantina, is the hexaploid wild oat A. sterilis.Genetic evidence shows that the ancestral forms of A. sterilis grow in the Fertile Crescent of the Near East.Domesticated oats appear relatively late, and far from the Near East, in Bronze Age Europe.Oats, like rye, are usually considered a secondary crop, i.e. derived from a weed of the primary cereal domesticates wheat and barley.As these cereals spread westwards into cooler, wetter areas, this may have favoured the oat weed component, leading to its eventual domestication. # Cultivation Oats are grown throughout the temperate zones.They have a lower summer heat requirement and greater tolerance of rain than other cereals like wheat, rye or barley, so are particularly important in areas with cool, wet summers such as Northwest Europe, even being grown successfully in Iceland.Oats are an annual plant, and can be planted either in autumn (for late summer harvest) or in the spring (for early autumn harvest). Historical attitudes towards oats vary.Oat bread was first manufactured in England, where the first oat bread factory was established in 1899.In Scotland they were, and still are, held in high esteem, as a mainstay of the national diet.A traditional saying in England is that "oats are only fit to be fed to horses and Scotsmen", to which the Scottish riposte is "and England has the finest horses, and Scotland the finest men".Samuel Johnson notoriously defined oats in his Dictionary as "a grain, which in England is generally given to horses, but in Scotland supports the people".While frequently seen as derogatory, this is no less than the literal truth.Oats are so central to traditional Scottish cuisine that the Scottish English word "corn" refers to oats instead of wheat, as in England, and maize in North America and Australia.Oats grown in Scotland command a premium price throughout the United Kingdom as a result of these traditions. # Health Oats are generally considered "healthy", or a health food, being touted commercially as nutritious.The discovery of the healthy cholesterol-lowering properties has led to wider appreciation of oats as human food. ## Soluble fiber Oat bran is the outer casing of the oat.Its consumption is believed to lower LDL ("bad") cholesterol, and possibly to reduce the risk of heart disease. After reports found that oats can help lower cholesterol, an "oat bran craze" swept the U.S. in the late 1980s, peaking in 1989, when potato chips with added oat bran were marketed.The food fad was short-lived and faded by the early 1990s.The popularity of oatmeal and other oat products again increased after the January 1998 decision by the Food and Drug Administration (FDA) when it issued its final rule allowing a health claim to be made on the labels of foods containing soluble fiber from whole oats (oat bran, oat flour and rolled oats), noting that 3 grams of soluble fiber daily from these foods, in conjunction with a diet low in saturated fat, cholesterol, and fat may reduce the risk of heart disease. In order to qualify for the health claim, the whole oat-containing food must provide at least 0.75 grams of soluble fiber per serving.The soluble fiber in whole oats comprise a class of polysaccharides known as Beta-D-glucan. Beta-D-glucans, usually referred to as beta-glucans, comprise a class of non-digestible polysaccharides widely found in nature in sources such as grains, barley, yeast, bacteria, algae and mushrooms.In oats, barley and other cereal grains, they are located primarily in the endosperm cell wall. Oat beta-glucan is a soluble fiber.It is a viscous polysaccharide made up of units of the sugar D-glucose.Oat beta-glucan is comprised of mixed-linkage polysaccharides.This means that the bonds between the D-glucose or D-glucopyranosyl units are either beta-1, 3 linkages or beta-1, 4 linkages.This type of beta-glucan is also referred to as a mixed-linkage (1→3), (1→4)-beta-D-glucan.The (1→3)-linkages break up the uniform structure of the beta-D-glucan molecule and make it soluble and flexible.In comparison, the non-digestible polysaccharide cellulose is also a beta-glucan but is non-soluble.The reason that it is non-soluble is that cellulose consists only of (1→4)-beta-D-linkages.The percentages of beta-glucan in the various whole oat products are: oat bran, greater than 5.5% and up to 23.0%; rolled oats, about 4%; whole oat flour about 4%. Oats after corn (maize) has the highest lipid content of any cereal, e.g., greater than 10 percent for oats and as high as 17 percent for some maize cultivars compared to about 2–3 percent for wheat and most other cereals.The polar lipid content of oats (about 8–17% glycolipid and 10–20% phospholipid or a total of about 33% ) is greater than that of other cereals since much of the lipid fraction is contained within the endosperm. ## Protein Oat is the only cereal containing a globulin or legume-like protein, avenalin, as the major (80%) storage protein.Globulins are characterized by water solubility; because of this property, oats may be turned into milk but not into bread.The more typical cereal proteins such as gluten and zein are prolamines(prolamins).The minor protein of oat is a prolamine: avenin. Oat protein is nearly equivalent in quality to soy protein, which has been shown by the World Health Organization to be the equal to meat, milk, and egg protein.The protein content of the hull-less oat kernel (groat) ranges from 12–24%, the highest among cereals. ## Celiac Disease Coeliac disease, or celiac disease, from Greek "koiliakos", meaning "suffering in the bowels", is a disease often associated with ingestion of wheat, or more specifically a group of proteins labelled prolamines, or more commonly, gluten. Oats lack many of the prolamines found in wheat; however, oats do contain avenin.Avenin is a prolamine that is toxic to the intestinal submucosa and can trigger a reaction in some celiacs. Although oats do contain avenin, there are several studies suggesting that oats can be a part of a gluten free diet if it is pure.The first such study was published in 1995.A follow-up study indicated that it is safe to use oats even in a longer period Additionally, oats are frequently processed near wheat, barley and other grains such that they become contaminated with other glutens. Because of this, the FAO's Codex Alimentarius Commission officially lists them as a crop containing gluten.Oats from Ireland and Scotland, where less wheat is grown, are less likely to be contaminated in this way. Oats are part of a gluten free diet in, for example, Finland and Sweden.In both of these countries there are "pure oat" products on the market. # Agronomy Oats are sown in the spring, as soon as the soil can be worked.An early start is crucial to good yields as oats will go dormant during the summer heat.Oats are cold-tolerant and will be unaffected by late frosts or snow.Typically about 100 kg/hectare (about 2 bushels per acre) are sown, either broadcast or drilled in 150 mm (6 inch) rows.Lower rates are used when underseeding with a legume.Somewhat higher rates can be used on the best soils.Excessive sowing rates will lead to problems with lodging and may reduce yields. Winter oats may be grown as an off-season groundcover and plowed under in the spring as a green fertilizer. Oats remove substantial amounts of nitrogen from the soil.They also remove phosphorus in the form of P2O5 at the rate of .25 pounds per bushel per acre (1 bushel = 32 pounds at 14% moisture).Oats remove potash (K2O) at a rate of .19 pounds per bushel per acre. If the straw is removed from the soil rather than being ploughed back, the removal rate of phosphorus is 8 pounds per ton per acre and the rate of potash removal is 40 pounds per ton per acre.Usually 50–100 kg/hectare (50–100 pounds per acre) of nitrogen in the form of urea or ammonium sulphate is sufficient.A sufficient amount of nitrogen is particularly important for plant height and hence straw quality and yield.When the prior-year crop was a legume, or where ample manure is applied, nitrogen rates can be reduced somewhat. The vigorous growth habit of oats will tend to choke out most weeds.A few tall broadleaf weeds, such as ragweed, goosegrass and buttonweed (velvetleaf), can occasionally be a problem as they complicate harvest.These can be controlled with a modest application of a broadleaf herbicide such as 2,4-D while the weeds are still small. Modern harvest technique is a matter of available equipment, local tradition, and priorities.Best yields are attained by swathing, cutting the plants at about 10 cm (4 inches) above ground and putting them into windrows with the grain all oriented the same way, just before the grain is completely ripe.The windrows are left to dry in the sun for several days before being combined using a dummy head.Then the straw is baled. Oats can also be left standing until completely ripe and then combined with a grain head.This will lead to greater field losses as the grain falls from the heads and to harvesting losses as the grain is threshed out by the reel.Without a draper head, there will also be somewhat more damage to the straw since it will not be properly oriented as it enters the throat of the combine.Overall yield loss is 10–15% compared to proper swathing. Historical harvest methods involved cutting with a scythe or sickle, and threshing under the feet of cattle.Late 19th and early 20th century harvesting was performed using a binder.Oats were gathered into shocks and then collected and run through a stationary threshing machine. A good yield is typically about 3,000 kg/hectare (100 bushels/acre) of grain and two tonnes of straw. # Trivia - The eruption of Mount Tambora caused a change in world climate resulting in a volcanic winter and the "year without a summer" in 1816, during which time the price of oats rose dramatically, for example in the USA from 12 to 92 cents per bushel.This led to the starvation of many horses, which in turn led to transportation problems, which Baron Karl von Drais attempted to solve by inventing the dandy horse, the direct precursor to the bicycle. - Oats are sometimes marketed, while in seed-form, as 'Cat Grass'.This is then grown and fed to the cat as a treat, or as aid to digestion.

p16 p16 (also known as p16INK4a, cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1 and as several other synonyms), is a tumor suppressor protein, that in humans is encoded by the CDKN2A gene.p16 plays an important role in cell cycle regulation by decelerating the cell's progression from G1 phase to S phase, and therefore acts as a tumor suppressor that is implicated in the prevention of cancers, notably melanoma, oropharyngeal squamous cell carcinoma, cervical cancer, and esophageal cancer.p16 can be used as a biomarker to improve the histological diagnostic accuracy of CIN3.Expression of the CDKN2A gene is frequently changed in a wide variety of tumors. p16 was originally found in an “open reading frame of 148 amino acids encoding a protein with a molecular weight of 16 kDa that comprises four ankyrin repeats.” The name of p16 is derived from its molecular weight, while the alternative name p16INK4a additionally refers to its role in inhibiting CDK4. # Nomenclature p16 is also known as: - p16INK4A - p16Ink4 - Cyclin-dependent kinase inhibitor 2A (CDKN2A) - CDKN2 - CDK 4 Inhibitor - Multiple Tumor Suppressor 1 (MTS1) - TP16 - ARF - MLM - P14 # Gene In humans, p16 is encoded by the CDKN2A gene, located on chromosome 9 (9p21.3).This gene generates several transcript variants that differ in their first exons.At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4.The remaining transcript includes an alternate exon 1 located 20 kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein that is structurally unrelated to the products of the other variants. The ARF product functions as a stabilizer of the tumor suppressor protein p53, as it can interact with and sequester MDM2, a protein responsible for the degradation of p53.In spite of their structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in controlling the G1 phase of the cell cycle.This gene is frequently mutated or deleted in a wide variety of tumors and is known to be an important tumor suppressor gene. When organisms age, the expression of p16 increases to reduce the proliferation of stem cells. This reduction in the division and production of stem cells protects against cancer while increasing the risks associated with cellular senescence. # Function p16 is an inhibitor of cyclin-dependent kinases (CDK).It slows down the cell cycle by prohibiting progression from G1 phase to S phase.Otherwise, CDK4/6 binds cyclin D and forms an active protein complex that phosphorylates retinoblastoma protein (pRB).Once phosphorylated, pRB dissociates from the transcription factor E2F1.This liberates E2F1 from its bound state in the cytoplasm and allows it to enter the nucleus.Once in the nucleus, E2F1 promotes the transcription of target genes that are essential for transition from G1 to S phase. This pathway connects the processes of tumor oncogenesis and senescence, fixing them on opposite ends of a spectrum.On one end, the hypermethylation, mutation, or deletion of p16 leads to downregulation of the gene and can lead to cancer through the dysregulation of cell cycle progression.Conversely, activation of p16 through reactive oxygen species, DNA damage, or senescence leads to the buildup of p16 in tissues and is implicated in the aging of cells. # Regulation Regulation of p16 is complex and involves the interaction of several transcription factors, as well as several proteins involved in epigenetic modification through methylation and repression of the promoter region. PRC1 and PRC2 are two protein complexes that modify the expression of p16 through the interaction of various transcription factors that execute methylation patterns that can repress transcription of p16. These pathways are activated in the cellular response to reduce senescence. # Clinical significance ## Role in cancer Mutations resulting in deletion or reduction of function of the CDKN2A gene are associated with increased risk of a wide range of cancers, and alterations of the gene are frequently seen in cancer cell lines.Examples include: Pancreatic adenocarcinoma is often associated with mutations in the CDKN2A gene. Carriers of germline mutations in CDKN2A have, besides their high risks of melanoma, also increased risks of pancreatic, lung, laryngeal and oropharyngeal cancers.Tobacco smoking increases the carriers’ susceptibility for such non-melanoma cancers. Homozygous deletions of p16 are frequently found in esophageal cancer and gastric cancer cell lines. Germline mutations in CDKN2A are associated with an increased susceptibility to develop skin cancer. Hypermethylation of tumor suppressor genes has been implicated in various cancers.In 2013, a meta-analysis revealed an increased frequency of DNA methylation of the p16 gene in esophageal cancer.As the degree of tumor differentiation increased, so did the frequency of p16 DNA methylation. Tissue samples of primary oral squamous cell carcinoma (OSCC) often display hypermethylation in the promoter regions of p16.Cancer cells show a significant increase in the accumulation of methylation in CpG islands in the promoter region of p16.This epigenetic change leads to loss of the tumor suppressor gene function through two possible mechanisms: first, methylation can physically inhibit the transcription of the gene, and second, methylation can lead to the recruitment of transcription factors that repress transcription.Both mechanisms cause the same end result: downregulation of gene expression that leads to decreased levels of the p16 protein.It has been suggested that this process is responsible for the development of various forms of cancer serving as an alternative process to gene deletion or mutation. p16 positivity has been shown to be favorably prognostic in oropharyngeal squamous cell carcinoma.In a retrospective trial analysis of patients with Stage III and IV oropharyngeal cancer, HPV status was assessed and it was found that the 3-year rates of overall survival were 82.4% (95% CI, 77.2 to 87.6) in the HPV-positive subgroup and 57.1% (95% CI, 48.1 to 66.1) in the HPV-negative subgroup, and the 3-year rates of progression-free survival were 73.7% (95% CI, 67.7 to 79.8) and 43.4% (95% CI, 34.4 to 52.4), respectively.p16 status is so prognostic that the AJCC staging system has been revised to include p16 status in oropharyngeal squamous cell cancer group staging. # Clinical use ## Biomarker for cancer types Expression of p16 is used as a prognostic biomarker for certain types of cancer.The reason for this is different types of cancer can have different effects on p16 expression: cancers that overexpress p16 are usually caused by the human papillomavirus (HPV), whereas cancers in which p16 is downregulated will usually have other causes.For patients with oropharyngeal squamous cell carcinoma, using immunohistochemistry to detect the presence of the p16 biomarker has been shown to be the strongest indicator of disease course. Presence of the biomarker is associated with a more favorable prognosis as measured by cancer-specific survival (CSS), recurrence-free survival (RFS), locoregional control (LRC), as well as other measurements.The appearance of hypermethylation of p16 is also being evaluated as a potential prognostic biomarker for prostate cancer. ## p16 FISH p16 deletion detected by FISH in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma. ## p16 immunochemistry As consensus grows regarding the strength of p16 as a biomarker for detecting and determining prognoses of cancer, p16 immunohistochemistry is growing in importance. ### gynecologic cancers p16 is a widely used immunohistochemical marker in gynecologic pathology.Strong and diffuse cytoplasmic and nuclear expression of p16 in squamous cell carcinomas (SCC) of the female genital tract is strongly associated with high-risk human papilloma virus (HPV) infection and neoplasms of cervical origin.The majority of SCCs of uterine cervix express p16.However, p16 can be expressed in other neoplasms and in several normal human tissues. ## Urinary bladder SCCs More than a third of urinary bladder SCCs express p16.SCCs of urinary bladder express p16 independent of gender.p16 immunohistochemical expression alone cannot be used to discriminate between SCCs arising from uterine cervix versus urinary bladder. ## Role in senescence Concentrations of p16INK4a increase dramatically as tissue ages.p16INK4a, along with senescence-associated beta-galactosidase, is regarded to be a biomarker of cellular senescence.Therefore, p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level.Notably, a recent survey of cellular senescence induced by multiple treatments to several cell lines does not identify p16 as belonging to a "core signature" of senescence markers. It has been used as a target to delay some aging changes in mice. # Discovery Researchers Manuel Serrano, Gregory J. Hannon and David Beach discovered p16 in 1993 and correctly characterized the protein as a cyclin-dependent kinase inhibitor.Since its discovery, p16 has become significant in the field of cancer research.The protein was suspected to be involved in carcinogenesis due to the observation that mutation or deletion in the gene was implicated in human cancer cell lines.The detection of p16 inactivation in familial melanoma supplied further evidence.p16 deletion, mutation, hypermethylation, or overexpression is now associated with various cancers.Whether mutations in p16 can be considered to be driver mutations requires further investigation. # Interactions p16 has been shown to interact with: - CCNG1, - CDK4, - CDK6, - DAXX, - E4F1, - MDM2, - P53, - PPP1R9B, - RPL11, and - SERTAD1.

p21 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated with inhibition of CDK2.p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest.This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans. # Function ## CDK inhibition p21 is a potent cyclin-dependent kinase inhibitor (CKI).The p21 (CIP1/WAF1) protein binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G1 and S phase.The binding of p21 to CDK complexes occurs through p21's N-terminal domain, which is homologous to the other CIP/KIP CDK inhibitors p27 and p57.Specifically it contains a Cy1 motif in the N-terminal half, and weaker Cy2 motif in the C-terminal domain that allow it to bind CDK in a region that blocks its ability to complex with cyclins and thus prevent CDK activation. Experiments looking at CDK2 activity within single cells have also shown p21 to be responsible for a bifurcation in CDK2 activity following mitosis, cells with high p21 enter a G0/quiescent state, whilst those with low p21 continue to proliferate.Follow up work, found evidence that this bistability is underpinned by double negative feedback between p21 and CDK2, where CDK2 inhibits p21 activity via ubiquitin ligase activity. ## PCNA inhibition p21 interacts with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair.Specifically, p21 has a high affinity for the PIP-box binding region on PCNA, binding of p21 to this region is proposed to block the binding of processivity factors necessary for PCNA dependent S-phase DNA synthesis, but not PCNA dependent nucleotide excision repair (NER).As such, p21 acts as an effective inhibitor of DNA S-phase DNA synthesis though permits NER, leading to the proposal that p21 acts to preferentially select polymerase processivity factors depending on the context of DNA synthesis. ## Apoptosis inhibition This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation.However p21 may inhibit apoptosis and does not induce cell death on its own.The ability of p21 to inhibit apoptosis in response to replication fork stress has also been reported. # Regulation ## p53 dependent response Studies of p53 dependent cell cycle arrest in response to DNA damage identified p21 as the primary mediator of downstream cell cycle arrest.Notably, El-Deiry et al.identified a protein p21 (WAF1) which was present in cells expressing wild type p53 but not those with mutant p53, moreover constitutive expression of p21 led to cell cycle arrest in a number of cell types.Dulcic et al.also found that γ-irradiation of fibroblasts induced a p53 and p21 dependent cell cycle arrest, here p21 was found bound to inactive cyclin E/CDK2 complexes.Working in mouse models, it was also shown that whilst mice lacking p21 were healthy, spontaneous tumours developed and G1 checkpoint control was compromised in cells derived from these mice.Taken together, these studies thus defined p21 as the primary mediator of p53-dependent cell cycle arrest in response to DNA damage. Recent work exploring p21 activation in response to DNA damage at a single-cell level have demonstrated that pulsatile p53 activity leads to subsequent pulses of p21, and that the strength of p21 activation is cell cycle phase dependent.Moreover, studies of p21-levels in populations of cycling cells, not exposed to DNA damaging agents, have shown that DNA damage occurring in mother cell S-phase can induce p21 accumulation over both mother G2 and daughter G1 phases which subsequently induces cell cycle arrest; this responsible for the bifurcation in CDK2 activity observed in Spencer et al.. ## Degradation p21 is negatively regulated by ubiquitin ligases both over the course of the cell cycle and in response to DNA damage.Specifically, over the G1/S transition it has been demonstrated that the E3 ubiquitin ligase complex SCFSkp2 induces degradation of p21.Studies have also demonstrated that the E3 ubiquitin ligase complex CRL4Cdt2 degrades p21 in a PCNA dependent manner over S-phase, necessary to prevent p21 dependent re-replication, as well as in response to UV irradiation.Recent work has now found that in human cell lines SCFSkp2 degrades p21 towards the end of G1 phase, allowing cells to exit a quiescent state, whilst CRL4Cdt2 acts to degrade p21 at a much higher rate than SCFSkp2 over the G1/S transition and subsequently maintain low levels of p21 throughout S-phase. # Clinical significance Cytoplasmic p21 expression can be significantly correlated with lymph node metastasis, distant metastases, advanced TNM stage (a classification of cancer staging that stands for: tumor size, describing nearby lymph nodes, and distant metastasis), depth of invasion and OS (overall survival rate).A study on immunohistochemical markers in malignant thymic epithelial tumors shows that p21 expression has a negatively influenced survival and significantly correlated with WHO (World Health Organization) type B2/B3.When combined with low p27 and high p53, DFS (Disease-Free Survival) decreases. p21 mediates the resistance of hematopoietic cells to an infection with HIV by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus.HIV infected individuals who naturally suppress viral replication have elevated levels of p21 and its associated mRNA.p21 expression affects at least two stages in the HIV life cycle inside CD4 T cells, significantly limiting production of new viruses. Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation. Mice that lack the p21 gene gain the ability to regenerate lost appendages. # Interactions P21 has been shown to interact with: - Nrf2 - BCCIP, - CIZ1, - CUL4A, - CCNE1, - CDK, - DDB1, - DTL, - GADD45A, - GADD45G, - HDAC, - PCNA, - PIM1, - TK1, and - TSG101.

p53 Lua error in Module:Effective_protection_level at line 60: attempt to index field 'TitleBlacklist' (a nil value). Tumor protein p53, also known as p53, cellular tumor antigen p53 (UniProt name), phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice).This homolog (originally thought to be, and often spoken of as, a single protein) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor.As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation.Hence TP53 is classified as a tumor suppressor gene. (Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.) The name p53 was given in 1979 describing the apparent molecular mass; SDS-PAGE analysis indicates that it is a 53-kilodalton (kDa) protein.However, the actual mass of the full-length p53 protein (p53α) based on the sum of masses of the amino acid residues is only 43.7 kDa.This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is.In addition to the full-length protein, the human TP53 gene encodes at least 15 protein isoforms, ranging in size from 3.5 to 43.7 kDa.All these p53 proteins are called the p53 isoforms.The TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation.TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome. # Gene In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1).The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb.The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53.TP53 orthologs have been identified in most mammals for which complete genome data are available. In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72.Many studies have investigated a genetic link between this variation and cancer susceptibility; however, the results have been controversial.For instance, a meta-analysis from 2009 failed to show a link for cervical cancer.A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males.A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer.One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women.A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer. Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk and endometrial cancer risk.A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer.Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma. # Structure - an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factors.The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes. - activation domain 2 (AD2) important for apoptotic activity: residues 43-63. - proline rich domain important for the apoptotic activity of p53 by nuclear exportation via MAPK: residues 64-92. - central DNA-binding core domain (DBD).Contains one zinc atom and several arginine amino acids: residues 102-292.This region is responsible for binding the p53 co-repressor LMO3. - Nuclear Localization Signaling (NLS) domain, residues 316-325. - homo-oligomerisation domain (OD): residues 307-355.Tetramerization is essential for the activity of p53 in vivo. - C-terminal involved in downregulation of DNA binding of the central domain: residues 356-393. A tandem of nine-amino-acid transactivation domains (9aaTAD) was identified in the AD1 and AD2 regions of transcription factor p53. KO mutations and position for p53 interaction with TFIID are listed below: The competence of the p53 transactivation domains 9aaTAD to activate transcription as small peptides was reported. File:Piskacek p53b.jpg p53 transactivation Piskacek M, Havelka M, Rezacova M, Knight A. "The 9aaTAD Transactivation Domains: From Gal4 to p53".PLOS One.11 (9): e0162842.doi:10.1371/journal.pone.0162842.PMC 5019370.PMID 27618436. 9aaTADs mediate p53 interaction with general coactivators – TAF9, CBP/p300 (all four domains KIX, TAZ1, TAZ2 and IBiD), GCN5 and PC4, regulatory protein MDM2 and replication protein A (RPA). File:Piskacek p53a.jpg p53 conversion Piskacek M, Havelka M, Rezacova M, Knight A. "The 9aaTAD Transactivation Domains: From Gal4 to p53".PLOS One.11 (9): e0162842.doi:10.1371/journal.pone.0162842.PMC 5019370.PMID 27618436. Mutations that deactivate p53 in cancer usually occur in the DBD.Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes.As such, mutations in the DBD are recessive loss-of-function mutations.Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription.Therefore, OD mutations have a dominant negative effect on the function of p53. Wild-type p53 is a labile protein, comprising folded and unstructured regions that function in a synergistic manner. # Function p53 has many mechanisms of anticancer function and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis.In its anti-cancer role, p53 works through several mechanisms: - It can activate DNA repair proteins when DNA has sustained damage.Thus, it may be an important factor in aging. - It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle). - It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable. - It is essential for the senescence response to short telomeres. Activated p53 binds DNA and activates expression of several genes including microRNA miR-34a , WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes.p21 (WAF1) binds to the G1-S/CDK (CDK4/CDK6, CDK2, and CDK1) complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division.A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division.Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR).Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable.In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs. Research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other. p53 by regulating LIF has been shown to facilitate implantation in the mouse model and possibly in humans. p53 expression can be stimulated by UV light, which also causes DNA damage.In this case, p53 can initiate events leading to tanning. The p21 protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place.p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence.The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein. ## Stem cells Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. ### Embryonic stem cells p53 is maintained at low inactive levels in human embryonic stem cells (hESCs).This is because activation of p53 leads to rapid differentiation of hESCs.Studies have shown that knocking out p53 delays differentiation and that adding p53 causes spontaneous differentiation, showing how p53 promotes differentiation of hESCs and plays a key role in cell cycle as a differentiation regulator.When p53 becomes stabilized and activated in hESCs, it increases p21 to establish a longer G1.This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation.p53 also activates miR-34a and miR-145, which then repress the hESCs pluripotency factors, further instigating differentiation. ### Adult stem cells In adult stem cells, p53 regulation is important for maintenance of stemness in adult stem cell niches.Mechanical signals such as hypoxia affect levels of p53 in these niche cells through the hypoxia inducible factors, HIF-1α and HIF-2α.While HIF-1α stabilizes p53, HIF-2α suppresses it.Suppression of p53 plays important roles in cancer stem cell phenotype, induced pluripotent stem cells and other stem cell roles and behaviors, such as blastema formation.Cells with decreased levels of p53 have been shown to reprogram into stem cells with a much greater efficiency than normal cells.Papers suggest that the lack of cell cycle arrest and apoptosis gives more cells the chance to be reprogrammed.Decreased levels of p53 were also shown to be a crucial aspect of blastema formation in the legs of salamanders.p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being cancerous. # Regulation p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress, osmotic shock, ribonucleotide depletion, and deregulated oncogene expression.This activation is marked by two major events.First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells.Second, a conformational change forces p53 to be activated as a transcription regulator in these cells.The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain.The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups.A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc.A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress.Oncogenes also stimulate p53 activation, mediated by the protein p14ARF. In unstressed cells, p53 levels are kept low through a continuous degradation of p53.A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from the nucleus to the cytosol.Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome.However, ubiquitylation of p53 is reversible. MI-63 binds to MDM2 making the action of p53 again possible in situations were p53's function has become inhibited. A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway.This is one means by which p53 is stabilized in response to oncogenic insults.USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress. Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria.Overexpression of HAUSP results in p53 stabilization.However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2.It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells. USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cytoplasmic p53, reversing Mdm2 ubiquitination.Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability.Also USP10 does not interact with Mdm2. Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding.Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more.Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes.Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis.Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity. # Role in disease If the TP53 gene is damaged, tumor suppression is severely compromised.People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome. The TP53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division.More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene.Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype. Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading.This, however, is not a usable method of treatment, since it can cause premature aging.Restoring endogenous normal p53 function holds some promise.Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process.The ways by which tumor regression occurs depends mainly on the tumor type.For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels.Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option.The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma.It delivers a functional copy of the p53 gene using an engineered adenovirus. Certain pathogens can also affect the p53 protein that the TP53 gene expresses.One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it.This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by the HPV protein E7, allows for repeated cell division manifested clinically as warts.Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions.Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer.This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome. The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation.The degradation of the p53 protein is associated with binding of MDM2.In a negative feedback loop, MDM2 itself is induced by the p53 protein.Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels.Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels.In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function. Suppression of p53 in human breast cancer cells is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13. One study found that p53 and Myc proteins were key to the survival of Chronic Myeloid Leukaemia (CML) cells.Targeting p53 and Myc proteins with drugs gave positive results on mice with CML. # Experimental analysis of p53 mutations Most p53 mutations are detected by DNA sequencing.However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional affects. The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer.Mutations in TP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe.Recents studies show that p53 isoforms are differentially expressed in different human tissues, and the loss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provides cancer stem cell potential in different tissues.TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.

The dynamics of p53 proteins, along with its antagonist Mdm2, indicate that the levels of p53, in units of concentration, oscillate as a function of time.This "damped" oscillation is both clinically documented and mathematically modelled.Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as double-stranded breaks (DSB) or UV radiation, are introduced to the system.This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see p53 regulation for more information).Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug discovery. # Discovery p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, working at Imperial Cancer Research Fund (UK) Princeton University/UMDNJ (Cancer Institute of New Jersey), and Memorial Sloan-Kettering Cancer Center, respectively.It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors.The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences in 1982, and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science).The human TP53 gene was cloned in 1984 and the full length clone in 1985. It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumor cell mRNA.Its role as a tumor suppressor gene was revealed in 1989 by Bert Vogelstein at the Johns Hopkins School of Medicine and Arnold Levine at Princeton University. Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.In a series of publications in 1991–92, Michael Kastan of Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage. In 1993, p53 was voted molecule of the year by Science magazine. # Isoforms As with 95% of human genes, TP53 encodes more than one protein.In 2005 several isoforms were discovered and until now, 12 human p53 isoforms were identified (p53α, p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, ∆160p53γ).Furthermore, p53 isoforms are expressed in a tissue dependent manner and p53α is never expressed alone. The full length p53 isoform proteins can be subdivided into different protein domains.Starting from the N-terminus, there are first the amino-terminal transactivation domains (TAD 1, TAD 2), which are needed to induce a subset of p53 target genes.This domain is followed by the Proline rich domain (PXXP), whereby the motif PXXP is repeated (P is a Proline and X can be any amino acid).It is required among others for p53 mediated apoptosis.Some isoforms lack the Proline rich domain, such as Δ133p53β,γ and Δ160p53α,β,γ; hence some isoforms of p53 are not mediating apoptosis, emphasizing the diversifying roles of the TP53 gene.Afterwards there is the DNA binding domain (DBD), which enables the proteins to sequence specific binding.The carboxyl terminal domain completes the protein.It includes the nuclear localization signal (NLS), the nuclear export signal (NES) and the oligomerisation domain (OD).The NLS and NES are responsible for the subcellular regulation of p53.Through the OD, p53 can form a tetramer and then bind to DNA.Among the isoforms, some domains can be missing, but all of them share most of the highly conserved DNA-binding domain. The isoforms are formed by different mechanisms.The beta and the gamma isoforms are generated by multiple splicing of intron 9, which leads to a different C-terminus.Furthermore, the usage of an internal promoter in intron 4 causes the ∆133 and ∆160 isoforms, which lack the TAD domain and a part of the DBD.Moreover, alternative initiation of translation at codon 40 or 160 bear the ∆40p53 and ∆160p53 isoforms. Due to the isoformic nature of p53 proteins, there have been several sources of evidence showing that mutations within the TP53 gene giving rise to mutated isoforms are causative agents of various cancer phenotypes, from mild to severe, due to single mutation in the TP53 gene (refer to section Experimental analysis of p53 mutations for more details). # Interactions p53 has been shown to interact with: - AIMP2, - ANKRD2, - APTX, - ATM, - ATR, - ATF3, - AURKA, - BAK1, - BARD1, - BLM, - BRCA1, - BRCA2, - BRCC3, - BRE, - CEBPZ, - CDC14A, - Cdk1, - CFLAR, - CHEK1, - CCNG1, - CREBBP, - CREB1, - Cyclin H, - CDK7, - DNA-PKcs, - E4F1, - EFEMP2, - EIF2AK2, - ELL, - EP300, - ERCC6, - GNL3, - GPS2, - GSK3B, - HSP90AA1, - HIF1A, - HIPK1, - HIPK2, - HMGB1, - HSPA9, - Huntingtin, - ING1, - ING4, - ING5, - IκBα, - KPNB1, - LMO3, - Mdm2, - MDM4, - MED1, - MAPK9, - MNAT1, - NDN, - NCL, - NUMB, - NF-κB, - P16, - PARC, - PARP1, - PIAS1, - CDC14B, - PIN1, - PLAGL1, - PLK3, - PRKRA, - PHB, - PML, - PSME3, - PTEN, - PTK2, - PTTG1, - RAD51, - RCHY1, - RELA, - Reprimo - RPA1, - RPL11, - S100B, - SUMO1, - SMARCA4, - SMARCB1, - SMN1, - STAT3, - TBP, - TFAP2A, - TFDP1, - TIGAR, - TOP1, - TOP2A, - TP53BP1, - TP53BP2, - TOP2B, - TP53INP1, - TSG101, - UBE2A, - UBE2I, - UBC, - USP7, - WRN, - WWOX, - XPB, - YBX1, - YPEL3, - YWHAZ, - Zif268, - ZNF148. - SIRT1.

p73 p73 is a protein related to the p53 tumor protein.Because of its structural resemblance to p53, it has also been considered a tumor suppressor.It is involved in cell cycle regulation, and induction of apoptosis.Like p53, p73 is characterized by the presence of different isoforms of the protein.This is explained by splice variants, and an alternative promoter in the DNA sequence. p73, also known as tumor protein 73 (TP73), protein was the first identified homologue of the tumor suppressor gene, p53.Like p53, p73 has several variants.It is expressed as distinct forms differing at either at the C- or the N-terminus.Currently, six different C-terminus splicing variants have been found in normal cells.The p73 gene encodes a protein with a significant sequence homology and a functional similarity with the tumor suppressor p53.The over-expression of p73 in cultured cells promotes a growth arrest and/or apoptosis similarly to p53. The p73 gene has been mapped to a chromosome region (1p36.2-3) a locus commonly deleted in various tumor entities and human cancers.Similar to p53 the protein product of p73 induces cell cycle arrest or apoptosis, hence its classification as a tumor suppressor.However unlike its counterpart, p73 is infrequently mutated in cancers.Perhaps, even more shocking is the fact that p73 – deficient mice do not show a tumorigenic phenotype.A deficiency of p53 almost certainly leads to unchecked cell proliferation and is noted in 60% of cancers. Analyses of many tumors typically found in humans including breast and ovarian cancer show a high expression of p73 when compared to normal tissues in corresponding areas.Adenoviruses that cause cellular transformations have also been found to result in increased p73 expression.Furthermore, recent finding are suggesting that over-expression of transcription factors involved in cell cycle regulation and synthesis of DNA in mammalian cells (e.g.: E2F-1) induces the expression of p73.Many researchers believe that these results imply that p73 may not be a tumor suppressor but rather an oncoprotein.Some suggest that the TP73 locus encodes both a tumor suppressor (TAp73) and a putative oncogene (ΔNp73).This is a strong theory and causes much confusion, as it is unknown which of the two p73 variants is over-expressed and ultimately plays a role in tumorigenesis. Genes of the p53 family are known to be complex.The viral oncoproteins (e.g. Adenovirus E1B) that efficiently inhibit p53 function are unable to inactivate p73, and those that seem to inhibit p73 have no effect on p53. Debate persists about the exact function of p73.Recently it has been reported that p73 is enriched in the nervous system and that the p73-deficient mice, which do not exhibit an increased susceptibility to spontaneous tumorigenesis, have neurological and immunological defects.These results have been expanded and it has also been shown that p73 is present in early stages of neurological development and neuronal apoptosis by blocking the proapoptotic function of p53.This strongly implicates p73 as playing a large role in cellular differentiation.

PGY PGY, short for post-graduate year, refers to a North American numerical scheme denoting the progress of post-medical school graduation medical residents in their residency program.It is used to stratify responsibility in most training programs and to determine salary. The length of residency depends mostly on the field a medical school graduate chooses to take.Specialties such as family medicine and internal medicine often require only three years, whereas surgery usually requires a minimum of five.Subspecialization (vascular or orthopedic spine surgery as a branch of surgery, for example) in any field will add time to post-graduate training. For more information on specific medical residency programs, see the American Medical Association's Fellowship and Residency Electronic Interactive Database. Pharmacy residencies, which are becoming more popular, also use the PGY nomenclature.Here, PGY-1 is the usual general pharmacy practice residency, and PGY-2 can be completed, often as an option, for pharmacy specialties such as critical care, cardiology, oncology, etc. In some teaching institutions, trainees are required to indicate level of training on all signatures (John Doe, M.D., PGY-1 or R-1).

Paw A paw is the soft foot of a mammal, generally a quadruped, that has claws or nails.A hard foot is called a hoof.Paws are used to pad feet for walking and reduce friction. # Common characteristics The paw is characterised by thick, pigmented, keratinised, hairless epidermis covering subcutaneous, collagenous, adipose tissue which make up the pads.These pads act as a cushion for the load-bearing limbs of the animal.The paw consists of the large, heart-shaped metacarpal pad (forelimb) or metatarsal pad (rear limb), and generally four load bearing digital pads, although there can be five or six toes in the case of bears and the Giant Panda.A carpal pad is also found on the forelimb which is used for additional traction when stopping or descending a slope in digitigrade species.Additional dew claws can also be present. The paw also includes a horny, beak shaped claw on each digit.Though usually hairless, certain animals do have fur on the soles of their paws. An example being the Red Panda, whose furry soles help insulate them in their snowy habitat. # Animals with paws - Members of the Canidae family, such as dogs and foxes - Felines, such as cats and tigers, some of these animals may have toe tufts - Bears and Raccoons - Weasels and other mustelids - Rodents - A dog's paw resting on a hard concrete surface. A dog's paw resting on a hard concrete surface. - A tiger's paw, showing pads. A tiger's paw, showing pads. - A cat's paw, showing pads. A cat's paw, showing pads.

QKI Quaking homolog, KH domain RNA binding (mouse), also known as QKI, is a protein which in humans is encoded by the QKI gene. QKI belongs to a family of RNA-binding proteins called STAR proteins for Signal Transduction and Activation of RNA.They have an HNRNPK homology (KH) domain embedded in a 200-amino acid region called the GSG domain.Other members of this family include SAM68 (KHDRBS1) and SF1 .Two more new members are KHDRBS3 and KHDRBS2. The QKI gene is implicated as being important in schizophrenia, and QKI controls translation of many oligodendrocyte-related genes.

RP9 Retinitis pigmentosa 9 (autosomal dominant), also known as RP9 or PAP-1, is a protein which in humans is encoded by the RP9 gene. # Function The removal of introns from nuclear pre-mRNAs occurs on a complex called a spliceosome, which is made up of 4 small nuclear ribonucleoprotein (snRNP) particles and an undefined number of transiently associated splicing factors.The exact role of PAP-1 in splicing is not fully understood, but it is thought that PAP-1 localizes in nuclear speckles containing the splicing factor SC35 and interacts directly with another splicing factor, U2AF35. # Clinical significance Mutations in PAP1 underlie autosomal dominant retinitis pigmentosa mapped to the RP9 gene locus. # Interactions RP9 has been shown to interact with U2 small nuclear RNA auxiliary factor 1.

RRH Peropsin, a visual pigment-like receptor, is a protein that in humans is encoded by the RRH gene. Peropsin is an opsin and so belongs to the guanine nucleotide-binding protein (G protein)-coupled receptors.Peropsin genes have seven-exons as neuropsin and RGR-opsin genes. # Phylogeny The peropsins are one of the four subgroups of the Go/RGR opsins, also known as RGR/Go or Group 4 opsins.Go/RGR opsins are one of the four major groups of type-II opsins, also known as metazoan or animal opsins.The Go/RGR opsins consist of four groups: The Go-opsins, the RGR-opsins, the peropsins, and the neuropsins.Animal opsins belong to four classes: C-opsins (ciliary), R-opsins (rhabdomeric), Cnidops (cnidarian), and Go/RGR-opsins.Three of these subclades occur only in Bilateria (all but Cnidops).However, the bilaterian clades constitute a parphyletic taxon without the Cnidops.

RUQ # Overview RUQ refers to the right-upper quadrant of the human abdomen.The term allows a doctor to localise pain and tenderness, scars, lumps and other items of interest.The RUQ extends from the median plane to the right of the patient, and from the umbilical plane to the right ribcage. The RUQ may be painful and/or tender in such conditions as hepatitis, cholecystitis, and peptic ulcer. The term is not used in comparative anatomy, since most other animals do not stand erect.The equivalent term for animals is 'right anterior quadrant'.

Ras # Overview In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs.The Ras superfamily of small GTPases includes the Ras, Rho, Arf, Rab, and Ran families. # History Ras gene was the first human oncogene discovered by Robert A. Weinberg of MIT in early 80's from a bladder cancer cell line. # Functions Proteins in the Ras family are very important molecular switches for a wide variety of signal pathways that control such processes as cytoskeletal integrity, proliferation, cell adhesion, apoptosis, and cell migration. Ras and ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis. RAS activates a number of pathways but an especially important one seems to be the mitogen-activated protein (MAP) kinases, which themselves transmit signals downstream to other protein kinases and gene regulatory proteins. # Activated and inactivated forms RAS is a G protein (specifically a small GTPase): a regulatory GTP hydrolase that cycles between two conformations – an activated or inactivated form, respectively RAS-GTP and RAS-GDP. It is activated by guanine exchange factors (GEFs, eg.CDC25, SOS1 and SOS2, SDC25 in yeast), which are themselves activated by mitogenic signals and through feedback from Ras itself.A GEF usually heightens the dissociation rate of the nucleotide – while not changing the association rate (effectively lower the affinity of the nucleotide) – thereby promoting its exchange.The cellular concentration of GTP is much higher than that of GDP so the exchange is usually GDP vs. GTP. It is inactivated by GTPase-activating proteins (GAPs, the most frequently cited one being RasGAP), which increase the rate of GTP hydrolysis, returning RAS to its GDP-bound form, simultaneously releasing an inorganic phosphate. # Attachments Ras is attached to the cell membrane by prenylation, and in health is a key component in many pathways which couple growth factor receptors to downstream mitogenic effectors involved in cell proliferation or differentiation.The C-terminal CaaX box of Ras first gets farnesylated at its Cys residue in the cytosol and then inserted into the membrane of the endoplasmatic reticulum.The Tripeptid (aaX) is then cleaved from the C-terminus by a specific prenyl-protein specific endoprotease, the new C-terminus is the methylated by a methyltransferase.The so processed Ras is now transported to the plasma membrane.Most Ras forms are now further palmityolated, while K-Ras with its long positively charged stretch interacts electrostaticly with the membrane. # Ras in cancer Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours. ## Inappropriate activation of the gene Inappropriate activation of the gene has been shown to play a key role in signal transduction, proliferation and malignant transformation. Mutations in a number of different genes as well as RAS itself can have this effect.Oncogenes such as p210BCR-ABL or the growth receptor erbB are upstream of Ras, so if they are constitutively activated their signals will transduce through Ras. The tumour suppressor gene NF1 encodes a Ras-GAP – its mutation in neurofibromatosis will mean that Ras is less likely to be inactivated.Ras can also be amplified, although this only occurs occasionally in tumours. Finally, Ras oncogenes can be activated by point mutations so that its GTPase reaction can no longer be stimulated by GAP – this increases the half life of active Ras-GTP mutants. ## Constitutively active Ras Constitutively active Ras (RasD) is one which contains mutations that prevent GTP hydrolysis, thus locking Ras in a permanently 'On' state. The most common mutations are found at residue G12 in the P-loop and the catalytic residue Q61. - The glycine to valine mutation at residue 12 renders the GTPase domain of Ras insensitive to activation by GAP and thus stuck in the "on state". Ras requires a GAP for inactivation as it is a relatively poor catalyst on its own, as opposed to other G-domain-containing proteins such as the alpha subunit of heterotrimeric G proteins. - Residue 61 is responsible for stabilizing the transition state for GTP hydrolysis. Because enzyme catalysis in general is achieved by lowering the energy barrier between substrate and product, mutation of Q61 necessarily reduces the rate of intrinsic Ras GTP hydrolysis to physiologically meaningless levels. See also "dominant negative" mutants such as S17N and D119N. # Human proteins containing Ras domain ARHE; ARHGAP5; CDC42; DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; GRLF1; HRAS; KRAS; LOC393004; MRAS; NKIRAS1; NRAS; RAB10; RAB11A; RAB11B; RAB12; RAB13; RAB14; RAB15; RAB17; RAB18; RAB19; RAB1A; RAB1B; RAB2; RAB20; RAB21; RAB22A; RAB23; RAB24; RAB25; RAB26; RAB27A; RAB27B; RAB28; RAB2B; RAB30; RAB31; RAB32; RAB33A; RAB33B; RAB34; RAB35; RAB36; RAB37; RAB38; RAB39; RAB39B; RAB3A; RAB3B; RAB3C; RAB3D; RAB40A; RAB40AL; RAB40B; RAB40C; RAB41; RAB42; RAB43; RAB4A; RAB4B; RAB5A; RAB5B; RAB5C; RAB6A; RAB6B; RAB6C; RAB7A; RAB7B; RAB7L1; RAB8A; RAB8B; RAB9; RAB9B; RABL2A; RABL2B; RABL4; RAC1; RAC2; RAC3; RALA; RALB; RAN; RANP1; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASEF; RASL11A; RASL12; RBJ; REM1; REM2; RERG; RHEB; RHEBL1; RHOA; RHOB; RHOBTB1; RHOBTB2; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RIT1; RIT2; RND1; RND2; RND3; RRAD; RRAS; RRAS2; TC4;

Rue Rue (Ruta) is a genus of strongly scented evergreen subshrubs 20-60 cm tall, in the family Rutaceae, native to the Mediterranean region, Macronesia and southwest Asia.Different authors accept between 8-40 species in the genus.The most well-known species is the Common Rue. The leaves are bipinnate or tripinnate, with a feathery appearance, and green to strongly glaucous blue-green in colour.The flowers are yellow, with 4-5 petals, about 1 cm diameter, and borne in cymes.The fruit is a 4-5 lobed capsule, containing numerous seeds. It was used extensively in Middle Eastern cuisine in olden days, as well as in many ancient Roman recipes (according to Apicius), but because it is very bitter, it is usually not suitable for most modern tastes.However, it is still used in certain parts of the world, particularly in northern Africa. # Literary references Rue has sometimes been called "herb-of-grace" in literary contexts.It is one of the flowers distributed by the mad Ophelia in William Shakespeare's Hamlet (IV.5): It was also planted by the gardener in Shakespeare's Richard II to mark the spot where the Queen wept upon hearing news of Richard's capture (III.4.104-105): In a song named Her Ghost in the Fog by the black metal band, Cradle of Filth on their Midian album. The progressive metal band Symphony X named a song "Absinthe and Rue" on their first album, Symphony X. Many traditional English folk songs use rue to symbolise regret.Often it is paired with thyme: thyme used to symbolise virginity, and rue the regret supposed to follow its loss. Rue is considered a national herb of Lithuania and it is the most frequently referred herb in Lithuanian folk songs, as an attribute of young girls, associated with virginity and maidenhood. # Side effects Fresh rue contains volatile oils that can damage the kidneys or liver.Deaths have been attributed to the use of fresh rue. Rue is probably best known for its effects on the female reproductive tract.Chemicals in rue may stimulate muscles in the uterus, which, in turn, may initiate menstrual periods, act as contraceptive agents, and promote abortion.Rue is thought to contain chemicals that may decrease fertility and may also block the implanting of a fertilized egg.In male laboratory animals, oral doses of rue decreased the movement and number of sperm and reduced the desire for sexual activity.Even though rue is a mainstay of midwives in many developing countries, its risks generally outweigh any benefits it might have for contraception or abortion.Deaths have been reported due to uterine hemorrhaging caused by repeated doses of rue.Taking it orally is strongly discouraged. Occasionally, rue oil is applied to the skin to relieve arthritis pain and also for treating soft tissue injuries such as bruises and sprains.Rue may contain chemicals that interrupt the body’s release of nitric oxide and cyclooxygenase II (which are involved in producing inflammation), so it may have limited usefulness.Prescription anti-inflammatory drugs are more effective and safer, however.The source from this ,3923,552392%7CRuda,00.html # Songs associated with rue Chervona Ruta (Червона Рута) Red Rue - A song, written by Volodymyr Ivasyuk - a popular Ukrainian poet and composer.

SK3 SK3 (small conductance calcium-activated potassium channel 3) also known as KCa2.3 is a protein that in humans is encoded by the KCNN3 gene. SK3 is a small-conductance calcium-activated potassium channel partly responsible for the calcium-dependent after hyperpolarisation current (IAHP).It belongs to a family of channels known as small-conductance potassium channels, which consists of three members – SK1, SK2 and SK3 (encoded by the KCNN1, 2 and 3 genes respectively), which share a 60-70% sequence identity.These channels have acquired a number of alternative names, however a NC-IUPHAR has recently achieved consensus on the best names, KCa2.1 (SK1), KCa2.2 (SK2) and KCa2.3 (SK3).Small conductance channels are responsible for the medium and possibly the slow components of the IAHP. # Structure KCa2.3 contains 6 transmembrane domains, a pore-forming region, and intracellular N- and C- termini and is readily blocked by apamin.The gene for KCa2.3, KCNN3, is located on chromosome 1q21. # Expression KCa2.3 is found in the central nervous system (CNS), muscle, liver, pituitary, prostate, kidney, pancreas and vascular endothelium tissues.KCa2.3 is most abundant in regions of the brain, but has also been found to be expressed in significant levels in many other peripheral tissues, particularly those rich in smooth muscle, including the rectum, corpus cavernosum, colon, small intestine and myometrium. The expression level of KCNN3 is dependent on hormonal regulation, particularly by the sex hormone estrogen.Estrogen not only enhances transcription of the KCNN3 gene, but also affects the activity of KCa2.3 channels on the cell membrane.In GABAergic preoptic area neurons, estrogen enhanced the ability of α1 adrenergic receptors to inhibit KCa2.3 activity, increasing cell excitability.Links between hormonal regulation of sex organ function and KCa2.3 expression have been established.The expression of KCa2.3 in the corpus cavernosum in patients undergoing estrogen treatment as part of gender reassignment surgery was found to be increased up to 5-fold.The influence of estrogen on KCa2.3 has also been established in the hypothalamus, uterine and skeletal muscle. # Physiology KCa2.3 channels play a major role in human physiology, particularly in smooth muscle relaxation.The expression level of KCa2.3 channels in the endothelium influences arterial tone by setting arterial smooth muscle membrane potential.The sustained activity of KCa2.3 channels induces a sustained hyperpolarisation of the endothelial cell membrane potential, which is then carried to nearby smooth muscle through gap junctions.Blocking the KCa2.3 channel or suppressing KCa2.3 expression causes a greatly increased tone in resistance arteries, producing an increase in peripheral resistance and blood pressure. # Pathology Mutations in KCa2.3 are suspected to be a possible underlying cause for several neurological disorders, including schizophrenia, bipolar disorder, Alzheimer's disease, anorexia nervosa and ataxia as well as myotonic muscular dystrophy.

SRY # Overview SRY (Sex-determining Region Y) is a sex-determining gene on the Y chromosome in humans and other primates. The SRY gene encodes the testis determining factor, which is also referred to as the SRY protein. This intronless gene encodes a transcription factor that is a member of the high mobility group (HMG)-box family of DNA-binding proteins.This protein is the testis-determining factor (TDF), which initiates male sex determination.Mutations in this gene give rise to XY females with gonadal dysgenesis (Swyer syndrome); translocation of part of the Y chromosome containing this gene to the X chromosome causes XX male syndrome. # Impact upon anatomical sex Since its discovery, the importance of the SRY gene in sex determination has been extensively documented: - Humans with one Y chromosome and multiple X chromosomes (XXY, XXXY etc.)are usually males. - Individuals with a male phenotype and an XX (female) genotype have been observed; these males have the SRY gene in one or both X chromosomes, moved there by chromosomal translocation. (However, these males are infertile.) - Similarly, there are females with an XXY or XY genotype. These females have no SRY gene in their Y chromosome, or the SRY gene exists but is defective (mutated). # SRY and the Olympics One of the most controversial uses of this discovery was as a means for gender verification at the Olympic Games, under a system implemented by the International Olympic Committee in 1992.Athletes with a SRY gene were not permitted to participate as females, although all athletes in whom this was "detected" at the 1996 Summer Olympics were ruled false positives and were not disqualified.In the late 1990s, a number of relevant professional societies in United States called for elimination of gender verification, including the American Medical Association, the American Academy of Pediatrics, the American College of Physicians, the American College of Obstetricians and Gynecologists, the Endocrine Society and the American Society of Human Genetics, stating that the method used was uncertain and ineffective.The screening was eliminated as of the 2000 Summer Olympics. # SRY-related diseases and defects Individuals with XY genotype and functional SRY gene can have a female phenotype, where the underlying cause is androgen insensitivity syndrome (AIS). SRY has been linked to the fact that men are more likely than women to develop dopamine-related diseases such as schizophrenia and Parkinson's disease. SRY makes a protein that controls concentrations of dopamine, the neurotransmitter that carries signals from the brain that control movement and coordination.

Set A set is a collection of distinct objects considered as a whole.Sets are one of the most fundamental concepts in mathematics.The study of the structure of sets, set theory, is rich and ongoing.Having only been invented at the end of the 19th century, set theory is now a ubiquitous part of mathematics education, being introduced from primary school in many countries.Set theory can be viewed as a foundation from which nearly all of mathematics can be derived. In philosophy, sets are ordinarily considered to be abstract objects the physical tokens of which are, for instance; three cups on a table when spoken of together as "the cups", or the chalk lines on a board in the form of the opening and closing curly bracket symbols along with any other symbols in between the two bracket symbols.However, proponents of mathematical realism including Penelope Maddy have argued that sets are concrete objects. # Definition At the beginning of his Beiträge zur Begründung der transfiniten Mengenlehre, Georg Cantor, the principal creator of set theory, gave the following definition of a set: By a "set" we mean any collection M into a whole of definite, distinct objects m (which are called the "elements" of M) of our perception or of our thought. The elements of a set, also called its members, can be anything: numbers, people, letters of the alphabet, other sets, and so on. Sets are conventionally denoted with capital letters.The statement that sets A and B are equal means that they have precisely the same members (i.e., every member of A is also a member of B and vice versa). Unlike a multiset, every element of a set must be unique; no two members may be identical.All set operations preserve the property that each element of the set is unique.The order in which the elements of a set are listed is irrelevant, unlike a sequence or tuple. # Describing sets There are two ways of describing, or specifying the members of, a set.One way is by intensional definition, using a rule or semantic description.See this example: The second way is by extension, that is, listing each member of the set. An extensional definition is notated by enclosing the list of members in braces: The order in which the elements of a set are listed in an extensional definition is irrelevant, as are any repetitions in the list.For example, are equivalent, because the extensional specification means merely that each of the elements listed is a member of the set. For sets with many elements, the enumeration of members can be abbreviated.For instance, the set of the first thousand positive whole numbers may be specified extensionally as: where the ellipsis ("...") indicates that the list continues in the obvious way.Ellipses may also be used where sets have infinitely many members. Thus the set of positive even numbers can be written as {2, 4, 6, 8, ... }. The notation with braces may also be used in an intensional specification of a set. In this usage, the braces have the meaning "the set of all ..." So E = {playing-card suits} is the set whose four members are ♠, ♦, ♥, and ♣. A more general form of this is set-builder notation, through which, for instance, the set F of the twenty smallest integers that are four less than perfect squares can be denoted: In this notation, the colon (":") means "such that", and the description can be interpreted as "F is the set of all numbers of the form n2 − 4, such that n is a whole number in the range from 0 to 19 inclusive."Sometimes the vertical bar ("|") is used instead of the colon. One often has the choice of specifying a set intensionally or extensionally. In the examples above, for instance, A = C and B = D. # Membership If something is or is not an element of a particular set then this is symbolised by ∈ and ∉ respectively. So, with respect to the sets defined above: - 4 ∈ A and 285 ∈ F (since 285 = 17² − 4); but - 9 ∉ F and green ∉ B. # Cardinality The cardinality |S| of a set S is "the number of members of S." For example, since the French flag has three colors, |B| = 3. There is a set with no members and zero cardinality, which is called the empty set (or the null set) and is denoted by the symbol ø.For example, the set A of all three-sided squares has zero members (|A| = 0), and thus A = ø.Though, like the number zero, it may seem trivial, the empty set is quite important in mathematics. The existence of this set is one of the fundamental concepts of axiomatic set theory. Some sets have infinite cardinality. The set N of natural numbers, for instance, is infinite.Some infinite cardinalities are greater than others. For instance, the set of real numbers has greater cardinality than the set of natural numbers.However, it can be shown that the cardinality of (which is to say, the number of points on) a straight line is the same as the cardinality of any segment of that line, of an entire plane, and indeed of any Euclidean space. # Subsets If every member of set A is also a member of set B, then A is said to be a subset of B, written A \subseteq B (also pronounced A is contained in B).Equivalently, we can write B \supseteq A, read as B is a superset of A, B includes A, or B contains A. The relationship between sets established by \subseteq is called inclusion or containment. If A is a subset of, but not equal to, B, then A is called a proper subset of B, written A \subsetneq B (A is a proper subset of B) or B \supsetneq A (B is proper superset of A). Note that the expressions A\subset B and A\supset B are used differently by different authors; some authors use them to mean the same as A\subseteq B (respectively A\supseteq B), whereas other use them to mean the same as A\subsetneq B (respectively A\supsetneq B). Example: - The set of all men is a proper subset of the set of all people. - \{1,3\} \subsetneq \{1,2,3,4\} - \{1, 2, 3, 4\} \subseteq \{1,2,3,4\}. The empty set is a subset of every set and every set is a subset of itself: - \emptyset \subseteq A - A \subseteq A. ## Power set The power set of a set S can be defined as the set of all subsets of S. This includes the subsets formed from the members of S and the empty set.If a finite set S has cardinality n then the power set of S has cardinality 2n.If S is an infinite (either countable or uncountable) set then the power set of S is always uncountable.The power set can be written as 2S. As an example, the power set 2{1, 2, 3} of {1, 2, 3} is equal to the set {{1, 2, 3}, {1, 2}, {1, 3}, {2, 3}, {1}, {2}, {3}, ø}. The cardinality of the original set is 3, and the cardinality of the power set is 23, or 8. This relationship is one of the reasons for the terminology power set. Similarly, its notation is an example of a general convention providing notations for sets based on their cardinalities. # Special sets There are some sets which hold great mathematical importance and are referred to with such regularity that they have acquired special names and notational conventions to identify them.One of these is the empty set.Many of these sets are represented using Blackboard bold typeface.Special sets of numbers include: - \mathbb{P}, denoting the set of all primes. - \mathbb{N}, denoting the set of all natural numbers.That is to say, \mathbb{N} = {1, 2, 3, ...}. - \mathbb{W}, denoting the set of all whole numbers.That is to say, \mathbb{W} = {0, 1, 2, 3, ...}. - \mathbb{Z}, denoting the set of all integers (whether positive, negative or zero). So \mathbb{Z} = {..., -2, -1, 0, 1, 2, ...}. - \mathbb{Q}, denoting the set of all rational numbers (that is, the set of all proper and improper fractions). So, \mathbb{Q} = \left\{ \begin{matrix}\frac{a}{b} \end{matrix}: a,b \in \mathbb{Z}, b \neq 0\right\}.For example, \begin{matrix} \frac{1}{4} \end{matrix} \in \mathbb{Q} and \begin{matrix}\frac{11}{6} \end{matrix} \in \mathbb{Q}.All integers are in this set since every integer a can be expressed as the fraction \begin{matrix} \frac{a}{1} \end{matrix}. - \mathbb{R}, denoting the set of all real numbers.This set includes all rational numbers, together with all irrational numbers (that is, numbers which cannot be rewritten as fractions, such as \pi, e, and √2). - \mathbb{C}, denoting the set of all complex numbers. Each of these sets of numbers has an infinite number of elements, and \mathbb{P} \subsetneq \mathbb{N} \subsetneq \mathbb{W} \subsetneq \mathbb{Z} \subsetneq \mathbb{Q} \subsetneq \mathbb{R} \subsetneq \mathbb{C}.The primes are used less frequently than the others outside of number theory and related fields. # Basic operations ## Unions There are ways to construct new sets from existing ones. Two sets can be "added" together.The union of A and B, denoted by A ∪ B, is the set of all things which are members of either A or B. Examples: - {1, 2} ∪ {red, white} = {1, 2, red, white} - {1, 2, green} ∪ {red, white, green} = {1, 2, red, white, green} Some basic properties of unions are: - A ∪ B   =   B ∪ A - A  ⊆  (A ∪ B) - A ∪ A   =  A - A ∪ ø   =  A - A  ⊆  B if and only if A ∪ B = B. ## Intersections A new set can also be constructed by determining which members two sets have "in common".The intersection of A and B, denoted by A ∩ B, is the set of all things which are members of both A and B. If A ∩ B  =  ø, then A and B are said to be disjoint. Examples: - {1, 2} ∩ {red, white} = ø - {1, 2, green} ∩ {red, white, green} = {green} Some basic properties of intersections: - A ∩ B   =   B ∩ A - A ∩ B  ⊆  A - A ∩ A   =   A - A ∩ ø   =   ø - A  ⊆  B if and only if A ∩ B = A. ## Complements Two sets can also be "subtracted".The relative complement of A in B (also called the set theoretic difference of B and A), denoted by B \ A, (or B − A) is the set of all elements which are members of B, but not members of A. Note that it is valid to "subtract" members of a set that are not in the set, such as removing green from {1,2,3}; doing so has no effect. In certain settings all sets under discussion are considered to be subsets of a given universal set U. In such cases, U \ A, is called the absolute complement or simply complement of A, and is denoted by A′. Examples: - {1, 2} \ {red, white} = {1, 2} - {1, 2, green} \ {red, white, green} = {1, 2} - If U is the set of integers, E is the set of even integers, and O is the set of odd integers, then the complement of E in U is O, or equivalently, E′ = O. Some basic properties of complements: - A ∪ A′ = U - A ∩ A′ = ∅ - (A′ )′ = A - A \ A = ∅ - A \ B = A ∩ B′. ## Cartesian product A new set can be constructed by associating every element of one set with every element of another set. The Cartesian product of two sets A and B, denoted by A × B is the set of all ordered pairs (a, b) such that a is a member of A and b is a member of B. Examples: - {1, 2} × {red, white} = {(1,red), (1,white), (2,red), (2,white)} - {1, 2, green} × {red, white, green} = {(1,red), (1,white), (1,green), (2,red), (2,white), (2,green), (green,red), (green,white), (green,green)} Some basic properties of cartesian products: - A × ∅ = ∅ - A × (B ∪ C) = (A × B) ∪ (A × C) - |A × B| = |A| × |B| # Applications Set theory is seen as the foundation from which virtually all of mathematics can be derived.For example, structures in abstract algebra, such as groups, fields and rings, are sets closed under one or more operations. One of the main applications of naive set theory is constructing relations. A relation from a domain A to a codomain B is nothing but a subset of A × B. Given this concept, we are quick to see that the set F of all ordered pairs (x, x2), where x is real, is quite familiar. It has a domain set \mathbb{R} and a codomain set that is also \mathbb{R}, because the set of all squares is subset of the set of all reals. If placed in functional notation, this relation becomes f(x) = x2. The reason these two are equivalent is for any given value, y that the function is defined for, its corresponding ordered pair, (y, y2) is a member of the set F. # Axiomatic set theory Although initially the naive set theory, which defines a set merely as any well-defined collection, was well accepted, it soon ran into several obstacles.It was found that this definition spawned several paradoxes, most notably: - Russell's paradox - It shows that the "set of all sets which do not contain themselves," i.e. the "set" \left \{ x: x\mbox{ is a set and }x\notin x \right \} does not exist. - Cantor's paradox - It shows that "the set of all sets" cannot exist. The reason is that the phrase well-defined is not very well-defined.It was important to free set theory of these paradoxes because nearly all of mathematics was being redefined in terms of set theory.In an attempt to avoid these paradoxes, set theory was axiomatized based on first-order logic, and thus the axiomatic set theory was born. For most purposes however, the naive set theory is still useful.

SnS - -itis - Aaron's sign - Abadie's symptom - Abdominal angina - Abdominal angina (patient information) - Abdominal bruit - Abdominal distension - Abdominal enlargement - Abdominal guarding - Abdominal mass - Abdominal pain - Abnormal posturing - Abnormalities in erythrocyte morphology - Absence seizure - Acanthosis nigricans - Accommodative insufficiency - Achalasia - Acid indigestion - Acne vulgaris - Acral necrosis - Acrocyanosis - Acrocyanosis (benign) - Acrocyanosis (not benign) - Acroosteolysis - Actinic conjunctivitis - Acute abdomen - Acute brachial neuritis - Acute brachial neuritis causes - Acute brachial neuritis diagnosis - Acute brachial neuritis epidemiology and demographics - Acute brachial neuritis history and symptoms - Acute brachial neuritis medical therapy - Acute brachial neuritis natural history - Acute brachial neuritis overview - Acute brachial neuritis pathophysiology - Acute brachial neuritis physical examination - Acute brachial neuritis risk factors - Acute brachial neuritis surgery - Acute lumbar syndrome - Acute muscle soreness - Adenomyomatous hyperplasia - Adhesion (medicine) - Adson's sign - Adynamia - Ageusia - Agonal respiration - Air crescent sign - Air hunger - Airway obstruction - Alexia (disorder) - Alexithymia - All signs and symptoms - Allen's test - Allodynia - Alogia - Amaurosis - Amaurosis fugax - Amenorrhea - Amnesia - Anasarca - Angioedema - Angor animi - Anisocoria - Ankle pain and swelling - Anomalous pancreaticobiliary junction - Anorectal pain - Anorexia (symptom) - Anosmia - Anterior drawer test - Anxiety - Aortic insufficiency physical examination - Aortic stenosis - Aortic stenosis physical examination - Aphasia - Aphasia (patient information) - Apnea - Apneustic respirations - Appearance and color of urine - Apraxia - Aprosody - Apyrexy - Arachnodactyly - Argyll Robertson pupil - Arterial bruit - Arthralgia - Arthritis - Arthrosis - Ascites - Ashman phenomenon - Ashrafian sign - Aspermia - Astasia-abasia - Astereognosis - Asthenia - Asthenopia - Asthma history and symptoms - Asthma physical examination - Ataxia - Ataxia (patient information) - Ataxic respiration - Atelectasis - Athetosis - Atonic seizure - Atrophy - Austin Flint murmur - Automatic behavior - Avolition - B symptoms - Back pain - Back pain (patient information) - Balanitis - Balanitis circinata - Barclay's sign - Barrel chest - Beau's lines - Becker sign - Beeturia - Benign paroxysmal positional vertigo - Bertolotti's syndrome - Bezold-Jarisch reflex - Biliary colic - Biot's respiration - Bladder discomfort - Bleeding (Excessive) - Bleeding gums - Blepharospasm - Bloating - Blood pressure - Bloody show - Blue sclera - Blurred vision - Boas' sign - Body fat percentage - Body mass index - Bone pain - Borborygmus - Bouchard's nodes - Bouveret's syndrome - Bowel obstruction - Bradykinesia - Bradypnea - Brain freeze - Brain zap - Breakthrough cancer pain - Breast examination - Breast lumps - Breast pain and discharge - Breath sounds - Brittle nails - Brodie-Trendelenburg test - Bronchophony - Bronchospasm - Brownout (medical) - Bruise - Bruit - Bubo - Buerger's test - Bulging fissure sign - Bulging flanks - Burping - Bursitis - Butterflies in the stomach - Cabot's ring - Cachexia - Café au lait spot - Canga's bead symptom - Caput medusae - Cardarelli's sign - Cardiac disease in pregnancy physical examination - Cardiac dysrhythmias - Carotid bruit - Carpal coalition - Carvallo's maneuver - Castell's sign - Catarrh - Central neurogenic hyperventilation - Central obesity - Cervical motion tenderness - Cervicitis - Chadwick's sign - Chancre - Charcot's triad 2 - Chemical colitis - Chest pain - Chest pain (patient information) - Cheyne-Stokes respiration - Cholecystitis - Chorea - Chorioamnionitis - Chronic pain - Chronic paroxysmal hemicrania - Chronic pelvic pain - Chronic vision loss - Chvostek's sign - Cinchonism - Clanging - Claudication - Claudication (patient information) - Clitorism - Clonus - Closed-eye hallucination - Clubbing - Cluster headache - Coated tongue - Coccydynia - Coffee ground vomiting - Coital cephalalgia - Colic - Collapse (medical) - Collapsing pulse - Comet tail sign - Complex partial seizure - Compulsive hoarding - Confusion - Confusion (patient information) - Congenital insensitivity to pain - Congenital insensitivity to pain with anhidrosis - Constipation - Coprolalia - Cotton wool spots - Cotton-wool spot - Cough - Cough test - Crepitus - Crystalluria - Cubitus valgus - Cullen's sign - Cyanosis - Cylindruria - Dactylitis - Dandruff - De Musset sign - Deafness - Decrease of urinary stream - Decreased bowel sounds - Decreased libido - Decreased skin pigmentation - Deep sulcus sign - Dehydration - Delayed gastric emptying - Delayed milestone - Delayed onset muscle soreness - Delusion - Delusional parasitosis - Dementia - Depigmentation - Depression (mood) - Dermatitis - Dermatological lesions - Dermatomyositis - Developmental milestones - Diaphoresis - Diaphragmatic breathing - Diaphragmatic dysfunction - Diaphragmatic elevation - Diarrhea - Diastematomyelia - Difficulty walking - Diffuse pain - Diplopia - Directed attention fatigue - Discitis - Disordered eating - Disorientation - Displaced point of maximal impulse - Dix-Hallpike test - Dizziness - Dizziness (patient information) - Dock's murmur - Drawer test - Drooling - Drop attack - Dry eyes - Dry mouth - Duct ectasia of breast - Duroziez sign - Dysarthria - Dyschondroplasia - Dysdiadochokinesia - Dysesthesia - Dysgeusia - Dysmenorrhea - Dysopia - Dyspareunia - Dyspepsia - Dysphagia - Dyspnea - Dystonia (patient information) - Dysuria - Edema - Egophony - Elbow pain - Emetophobia - Encephalopathy - Enophthalmos - Eosinophiluria - Epilepsy - Epistaxis - Erectile dysfunction - Erythema chronicum migrans - Erythema marginatum - Esophageal motility disorders - Esophagitis - Euphoria (emotion) - Euthymia (medicine) - Exercise intolerance - Exophthalmos - Extrasystoles - Eye circles - Eye discharge - Eye pain - Eye puffiness - Facial nerve paralysis - Facial pain - Faget's sign - Failed back syndrome - Fallen lung sign - Fasciculation - Fasciitis - Fatigue - Fatigue (patient information) - Fetor hepaticus - Fever - Fever of unknown origin - Flaccid paralysis - Flame hemorrhages - Flank pain - Flash pulmonary edema - Flatulence - Floater - Floater (patient information) - Flushing - Focal neurologic signs - Focal seizures - Football sign - Fremitus - Froment's sign - Gaenslen's test - Galactorrhea - Gallbladder wall thickening - Gallop rhythm - Gangrene - Gastric anacidity - Gastrointestinal bleeding - Gelastic seizure - Genital skin lesions - Genital ulcer - Gerhardt sign - Gibson's murmur - Glasgow coma scale - Globus pharyngis - Glossodynia - Glucosuria - Gnathitis - Goiter - Golfer's vasculitis - Goodell's sign - Gorlin's sign - Graham-Steell murmur - Grey-Turner's sign - Ground glass opacification on CT - Gynecomastia - Hairy leukoplakia - Halitosis - Halitosis (patient information) - Hallucination - Halo sign - Hamman's sign - Hampton's hump - Hand and foot rashes - Hand contracture - Headache - Headache (patient information) - Headache attributed to a substance or its withdrawal - Headache attributed to infection - Hearing impairment - Heart murmur - Heart rate - Heart sounds - Heberden's node - Hegar's sign - Hemarthrosis - Hematemesis - Hematochezia - Hematuria - Hematuria (patient information) - Hemiparesis - Hemiparesis and Hemiplegia - Hemiplegia - Hemoglobinuria - Hemoptysis - Hemorrhagic diathesis - Hepatic cysts - Hepatojugular reflux - Hepatomegaly - Hepatosplenomegaly - Herxheimer reaction - Heterophoria - Hiccup - Hill sign - Hippocratic face - Hirschberg's test - Hoarseness - Hoffmann's sign - Homans' sign - Hutchinson's teeth - Hydrocephalus - Hydropenia - Hymenal atresia - Hyperabduction syndrome - Hyperalgesia - Hyperesthesia - Hypergeusia - Hyperglobulinemic purpura - Hyperhidrosis - Hyperkinetic heart syndrome - Hypermineralocorticoid - Hyperosmia - Hyperostosis - Hyperpathia - Hyperprolactinaemia - Hyperprolactinemia - Hyperpyrexia - Hyperreflexia - Hypersomnia - Hypersomnia (patient information) - Hypertrophic gums - Hypertrophy (medical) - Hypertrophy of the heart - Hyperventilation - Hypesthesia - Hypoalgesia - Hypoesthesia - Hypogeusia - Hypogonadism - Hypokinesia - Hypomelanosis - Hypophysitis - Hypopnea - Hyporeflexia - Hyposmia - Hypotension - Hypothenar Hammer Syndrome - Hypothermia - Hypoventilation - Hypovolemia - Ictal - Ictal headache - Iminoaciduria - Impaired wound healing - Inappetence - Incontinence - Increased bowel sounds - Indigestion - Inferior vena cava syndrome - Inguinodynia - Inner bone pain - Insomnia - Internal hernia - Internuclear ophthalmoplegia - Intracranial calcification - Intracranial pressure - Intraocular hemorrhage - Irregular heart rhythms - Isaac's syndrome - Itchy nipple - Ivory vertebra sign - Janeway lesions - Jaundice - Jaw claudication - Jaw pain/swelling - Job's syndrome - Joint hypermobility - Jugular venous pressure - Karnofsky performance scale - Keratoconjunctivitis - Keratoderma - Kerley lines - Kernig's sign - Knee pain/swelling - Koilonychia - Kussmaul's sign - Landolfi sign - Leg length discrepancy - Leg pain - Leg swelling - Leg ulcer - Leopold's maneuvers - Lethargy - Leukoplakia - Lightheadedness and vertigo - Lighthouse sign - Limp - Lincoln sign - Linea negra - Low back pain - Low-grade fever - Lucid interval - Lymph node metastases - Lymphadenopathy - Macroglossia - Macular edema - Magnetism (neurological sign) - Malassimilation - Male pseudohermaphroditism - Mania - Mann syndrome - Manning criteria - Mass effect (medicine) - Mayen sign - McGill pain index - Mediastinal mass - Melasma suprarenale - Melena - Meningism - Mesenteric cyst - Metabolic encephalopathy - Metatarsalgia - Microstomia - Microtia - Migraine - Migraine (patient information) - Miosis - Monoarthritis - Mood congruence - Mucopurulent discharge - Mucosa hemorrhage - Muehrcke's lines - Muscle atrophy - Muscle weakness - Muscle weakness (patient information) - Muscular atrophy of the hand - Myalgia - Mydriasis - Myerson's sign - Myocarditis - Myocarditis history and symptoms - Myofascial pain syndrome - Myoglobinuria - Myokmia - Müller sign - NICE guidelines for management of chest pain - NICE guidelines for the management of patients with acute chest pain - NICE guidelines for the management of patients with stable chest pain - Nail changes - Nasal congestion - Nausea and Vomiting - Neck masses - Neck stiffness/pain - Neck stiffness/pain (patient information) - Necrolytic migratory erythema - Nocturia - Nocturia (patient information) - Nodular lesions - Non ST elevation myocardial infarction pathophysiology & etiology - Obdormition - Obstructive sleep apnea - Obstructive sleep apnea overview - Obturator sign - Occult blood - Odynophagia - Oligoarthritis - Oliguria - Oliguria (patient information) - Oliver's sign - Opioid-induced hyperalgesia - Opisthotonus - Oral candidiasis - Oral lesions - Oral ulcer - Orchialgia - Organomegaly - Orthopnea - Oscillopsia - Osler nodes - Osler's node - Osler's sign - Osteolysis - Otalgia - Otorrhea - Overeating - Pain - Pain and nociception - Pain asymbolia - Pain withdrawal reflex - Palindromic rheumatism - Pallor - Palmar erythema - Palpitation - Palpitation (patient information) - Pancreatic trauma - Papilledema - Papulosquamous lesions - Parageusia - Paralysis - Paraphimosis (patient information) - Parodontosis - Paronychia - Parosmia - Parotid gland enlargement - Parrot's sign - Paruresis - Patrick's test - Pedal edema - Pelvic masses - Pelvic myoneuropathy - Pelvic pain - Pemberton's sign - Penile discharge - Pericardial friction rub - Periorbital edema - Peritonitis - Perseveration - Petechia - Phantom pain - Pharyngitis - Pharyngitis causes - Pharyngitis differential diagnosis - Pharyngitis history and symptoms - Pharyngitis medical therapy - Pharyngitis natural history - Pharyngitis overview - Pharyngitis pathophysiology - Pharyngitis primary prevention - Pharyngitis risk factors - Phlebitis - Photophobia - Photopsia - Pica - Pigmented lesions - Piskacek's sign - Platypnea - Pleural friction rub - Pleural friction rubs - Pleurisy - Pleurisy (patient information) - Pneumatosis intestinalis - Pneumaturia - Pneumomediastinum - Pneumonia severity index - Pneumoperitoneum - Pneumothorax (patient information) - Pollakisuria - Polyarthritis - Polydipsia - Polydipsia (patient information) - Polyphagia - Polyuria - Post-vasectomy pain syndrome - Posterior drawer test - Postoperative fever - Priapism (patient information) - Proteinuria - Pruritis - Pruritis (patient information) - Pseudoathetosis - Pseudodiarrhea - Psoas sign - Psychalgia - Psychedelic experience - Psychomotor retardation - Ptosis - Ptosis (eyelid) - Pubertal delay - Puddle sign - Pulmonary edema - Pulmonary edema cardiac catheterization - Pulmonary edema causes - Pulmonary edema chest x ray - Pulmonary edema differential diagnosis - Pulmonary edema echocardiography - Pulmonary edema history and symptoms - Pulmonary edema laboratory tests - Pulmonary edema medical therapy - Pulmonary edema overview - Pulmonary edema pathophysiology - Pulmonary edema physical examination - Pulmonary edema risk factors - Pulmonary embolism physical examination - Pulse pressure - Pulsus - Pulsus alternans - Pulsus bigeminus - Pulsus bisferiens - Pulsus paradoxus - Pulsus parvus et tardus - Pungency - Pupillary constriction - Pupillary dilation - Purpura - Purpura (patient information) - Pyuria - Quincke sign - Radial neuropathy - Radiculopathy - Radiologic sign - Rales - Rash - Rash with fever - Rebound headache - Rebound tenderness - Rectal masses - Rectal pain - Red eye - Red eye (medicine) - Red face - Red palms - Red tongue - Red wine headache - Reduced respiratory displacement - Referred pain - Renal colic - Respiratory sounds - Respiratory splinting - Retching - Rhonchi - Right heart failure - Right heart failure history and symptoms - Rigler's sign - Rigor - Romana's sign - Rosenbach sign - Rovsing's sign - Rug burn - Salivary gland enlargement - Satiety - Scalp rash - Schizophasia - Schmidt Sting Pain Index - Scrotal masses - Scrotal swelling - Scrotal swelling (patient information) - Seizure - Seizure (patient information) - Sensorineural hearing loss - Sensory ataxia - Septic arthritis - Shallow breathing - Shallow water blackout - Sherman sign - Shifting dullness - Shoulder arthritis - Side stitch - Simmonds' test - Sister Mary Joseph nodule - Skin changes - Skin crepitation - Skipped beat - Sleep Apnea Epidemiology - Sleep Apnea Overview - Sleep apnea - Sleep apnea causes - Sleep apnea history and symptoms - Sleep apnea home oximetry - Sleep apnea medical treatment - Sleep apnea natural history - Sleep apnea natural history, complications and prognosis - Sleep apnea other treatment - Sleep apnea polysomnography - Sleep apnea risk factors - Sleep apnea surgical treatment - Smoker's cough - Snoring - Snoring (patient information) - Solitary pulmonary nodule - Somatization disorder - Spasm - Splenomegaly - Splinter hemorrhage - Sputum - Starr sting pain scale - Steeple sign - Stenosing tenosynovitis - Stomatitis - Straight leg raise - Strangury - Striae - Stridor - Stupor - Stupor (patient information) - Stye (patient information) - Subcutaneous emphysema - Sulcus sign - Superior limbic keratoconjunctivitis - Superior vena cava syndrome - Suspension trauma - Swimmer's itch - Swinging-flashlight test - Swollen face - Syncope - Syncope (patient information) - Synovitis - T-shaped uterus - Tabes Dorsalis CT - Tabes Dorsalis MRI - Tabes Dorsalis causes - Tabes Dorsalis chest x ray - Tabes Dorsalis classification - Tabes Dorsalis cost-effectiveness of therapy - Tabes Dorsalis dietary management - Tabes Dorsalis differential diagnosis - Tabes Dorsalis echocardiography or ultrasound - Tabes Dorsalis electrocardiogram - Tabes Dorsalis epidemiology and demographics - Tabes Dorsalis future or investigational therapies - Tabes Dorsalis historical perspective - Tabes Dorsalis history and symptoms - Tabes Dorsalis laboratory tests - Tabes Dorsalis medical therapy - Tabes Dorsalis natural history, complications, and prognosis - Tabes Dorsalis other diagnostic studies - Tabes Dorsalis other imaging findings - Tabes Dorsalis overview - Tabes Dorsalis pathophysiology - Tabes Dorsalis physical examination - Tabes Dorsalis primary prevention - Tabes Dorsalis risk factors - Tabes Dorsalis screening - Tabes Dorsalis secondary prevention - Tabes Dorsalis surgery - Tabes dorsalis - Tachycardia - Tachypnea - Tactile fremitus - Tardive dyskinesia - Tardive dyskinesia (patient information) - Tarsal coalition - Tears - Telangiectasia - Tennis elbow - Tenosynovitis - Tension headache - Terminal burrowing - Testicular pain - Tetanic contraction - Tetany - Tetany (medical sign) - Thermoregulation - Thought disorder - Thrombophlebitis - Thumbprint sign - Thunderclap headache - Thyromegaly - Thyroxin binding globulin - Tic - Tinnitus - Toddler fracture - Toe pain and swelling - Toe-Brachial Index - Tongue pain - Tongue swelling - Tonic-clonic seizure - Tonsillitis - Tonsillitis causes - Tonsillitis history and symptoms - Tonsillitis medical therapy - Tonsillitis natural history - Tonsillitis overview - Tonsillitis surgery - Tooth loss - Tooth squeeze - Toothache - Tourettism - Toxic headache - Toxic leukoencephalopathy - Transmarginal inhibition - Traube sign - Traube's space - Traveler's diarrhea - Trepopnea - Trigeminal neuralgia - Trigger finger - Trigonitis - Trousseau sign of malignancy - Tubulointerstitial diseases of the kidney - Tumorlet - Twitching - Ulcerative colitis - Unequal pulses - Unicornuate uterus - Unstable angina / non ST elevation myocardial infarction - Unstable angina / non ST elevation myocardial infarction ACC/AHA guidelines for early risk stratification - Unstable angina / non ST elevation myocardial infarction ACC/AHA guidelines for risk stratification before discharge - Unstable angina / non ST elevation myocardial infarction natural history, complications and prognosis - Unstable angina / non ST elevation myocardial infarction overview - Unstable angina / non ST elevation myocardial infarction risk stratification and prognosis - Unstable angina / non ST elevation myocardial infarction symptoms - Unstable angina / non ST elevation myocardial infarction treatment - Unstable angina pathophysiology & etiology - Unterberger test - Upper airway resistance syndrome - Upper back pain - Upper motor neuron lesion - Uremia - Urethritis - Urethritis causes - Urethritis history and symptoms - Urethritis laboratory tests - Urethritis medical therapy - Urethritis overview - Urinary incontinence - Urinary retention - Urinary urgency - Urine calcium - Urine catecholamines - Urine osmolality - Urine pH - Uveitis - Uveoparotitis - VLDL hyperlipidemia - Vaginal bleeding - Vaginal discharge - Vaginitis - Vascular headache - Vasculitis - Vasogenic edema - Vasomotor rhinitis - Venous insufficiency - Vertigo - Vertigo (medical) - Vesicular and bullous lesions - Vesicular breathing - Virchow's node - Vision loss - Vital signs - Vitamin B12 - Vocal cord paresis - Vocal fremitus - Volvulus - Vulvar pruritus - Vulvitis - Vulvodynia - Waddell's signs - Walking ghost phase - Watson's water hammer pulse - Waxy flexibility - Webbed neck - Webbed toes - Wegener's granulomatosis - Wegener's granulomatosis CT - Wegener's granulomatosis differential diagnosis - Wegener's granulomatosis epidemiology and demographics - Wegener's granulomatosis historical perspective - Wegener's granulomatosis history and symptoms - Wegener's granulomatosis medical therapy - Wegener's granulomatosis natural history - Wegener's granulomatosis other imaging findings - Wegener's granulomatosis overview - Wegener's granulomatosis pathophysiology - Wegener's granulomatosis secondary prevention - Wegener's granulomatosis surgery - Weight and height percentile - Weight gain - Weight loss - Westermark sign - Wheeze - Wheeze causes - Wheeze differential diagnosis - Wheeze medical therapy - Wheeze overview - Wheeze pathophysiology - White hand sign - White out of the hemithorax - Wide pulse pressure - Widened mediastinum - Wrist and hand pain - Wrist drop - Xanthelasma - Xanthoma - Xeroderma - Xerophthalmia - Xerosis - Xerostomia - Xiphodynia - Yellow sclera - Category:Abdominal pain - Category:Abnormal respiration - Category:Chronic pain syndromes - Category:Digestive disease symptoms - Category:Headaches - Category:Migraine - Category:Pain - Category:Pain scales - Category:Vomiting

Sss # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY.WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling.Please read our full disclaimer here. # Overview Sss is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Condition 1 - Dosing Information ## Off-Label Use and Dosage (Adult) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Sss FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) # Contraindications There is limited information regarding Sss Contraindications in the drug label. # Warnings There is limited information regarding Sss Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Sss Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Sss Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Sss Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Sss in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sss in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sss during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Sss in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Sss in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Sss in geriatric settings. ### Gender There is no FDA guidance on the use of Sss with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sss with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sss in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sss in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sss in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sss in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Sss Administration in the drug label. ### Monitoring There is limited information regarding Sss Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Sss and IV administrations. # Overdosage There is limited information regarding Sss overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Sss Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Sss Mechanism of Action in the drug label. ## Structure There is limited information regarding Sss Structure in the drug label. ## Pharmacodynamics There is limited information regarding Sss Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Sss Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Sss Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Sss Clinical Studies in the drug label. # How Supplied There is limited information regarding Sss How Supplied in the drug label. ## Storage There is limited information regarding Sss Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Sss Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Sss interaction has not been established.Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Sss Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Sss Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Syk Spleen tyrosine kinase, also known as Syk, is an enzyme which in humans is encoded by the SYK gene. # Function SYK, along with Zap-70, is a member of the Syk family of tyrosine kinases.These non-receptor cytoplasmic tyrosine kinases share a characteristic dual SH2 domain separated by a linker domain.However, activation of SYK relies less on phosphorylation by Src family kinases than Zap-70. While Syk and Zap-70 are primarily expressed in hematopoietic tissues, there is expression of Syk in a variety of tissues.Within B and T cells respectively, Syk and Zap-70 transmit signals from the B-Cell receptor and T-Cell receptor.Syk plays a similar role in transmitting signals from a variety of cell surface receptors including CD74, Fc Receptor, and integrins. ## Function during development Mice that lack Syk completely (Syk−/−, Syk-knockout) die during embryonic development around midgestation.They show severe defects in the development of the lymphatic system.Normally, the lymphatic system and the blood system are strictly separated from each other.However, in Syk deficient mice the lymphatics and the blood vessels form abnormal shunts, leading to leakage of blood into the lymphatic system.The reason for this phenotype was identified by a genetic fate mapping approach, showing that Syk is expressed in myeloid cells which orchestrate the proper separation of lymphatics and blood system during embryogenesis and beyond.Thus, Syk is an essential regulator of the lymphatic system development in mice. # Clinical significance Abnormal function of Syk has been implicated in several instances of hematopoeitic malignancies including translocations involving Itk and Tel. Constitutive Syk activity can transform B cells.Several transforming viruses contain "Immunoreceptor Tyrosine Activation Motifs" (ITAMs) which lead to activation of Syk including Epstein Barr virus, bovine leukemia virus, and mouse mammary tumor virus. ## SYK inhibition Given the central role of SYK in transmission of activating signals within B-cells, a suppression of this tyrosine kinase might aid in the treatment of B cell malignancies and autoimmune diseases. Syk inhibition has been proposed as a therapy for both lymphoma and chronic lymphocytic leukemia.Syk inhibitors are in clinical development, including cerdulatinib and entospletinib.Other inhibitors of B-cell receptor (BCR) signaling including ibrutinib (PCI-32765) which inhibits BTK, and idelalisib (PI3K inhibitor - CAL-101 / GS-1101) showed activity in the diseases as well. The orally active SYK inhibitor fostamatinib (R788) in the treatment of rheumatoid arthritis. The Syk inhibitor nilvadipine has been shown to regulate amyloid-β production and Tau phosphorylation and hence has been proposed as a treatment for Alzheimer's Disease and has entered phase III clinical trials. ## Epithelial malignancies The role of Syk in epithelial malignancies is controversial. Several authors have suggested that abnormal Syk function facilitates transformation in Nasopharyngeal carcinoma and head and neck cancer while other authors have suggested a tumor suppressor role in breast and gastric cancer. Without Syk, the protein it makes, and genetic disruption in a panel of 55 genes thought also to be controlled by Syk, breast ductal carcinoma in situ (breast DCIS, which can become invasive), it is believed that the cancer has a markedly increased tendency to invade and metastasize. # Interactions Syk has been shown to interact with: - Cbl gene - CRKL, - FCGR2A, - FYN, - Grb2, - Lck, - LYN, - PTK2, - PTPN6, and - VAV1.

TLX Nuclear receptor TLX (homologue of the Drosophila tailless gene) also known as NR2E1 (Nuclear receptor subfamily 2 group E member 1) is a protein that in humans is encoded by the NR2E1 gene.TLX is a member of the nuclear receptor family of intracellular transcription factors. # Function TLX regulates the expression of another nuclear receptor, RAR. TLX also is essential for normal brain-eye coordination and appears to play a role in control of aggressive behavior. Adult neural stem cells are nuclear receptor TLX-positive and TLX expression in these cells is crucial in maintaining their undifferentiated state.Furthermore, TLX regulates adult neural stem cell proliferation.Removal of TLX from the adult mouse brain resulted in a reduction of stem cell proliferation and spatial learning. Tlx-positive cells of the subventricular zone of adult mouse brain are self-renewing stem cells.Mutation of the Tlx gene in adult mouse brain leads to complete loss of neurogenesis in the subventricular zone.Tlx is also required for transition from radial glial cells to astrocyte-like neural stem cells.

TNM # Overview TNM Classification of Malignant Tumours (TNM) is the cancer staging system developed and maintained by the International Union Against Cancer (UICC) to achieve consensus on one globally recognised standard for classifying the extent of spread of cancer. The TNM classification is also used by the American Joint Committee on Cancer (AJCC) and the International Federation of Gynecology and Obstetrics (FIGO). In 1987, the UICC and AJCC staging systems were unified into a single staging system. # Broad outline Each tumor has its own TNM classification. Not all tumors have TNM classifications, but most do. For instance, there is no TNM classification for brain tumors. The general outline for the TNM classification is below. The values given in parenthesis give a range of what can be used for all cancer types, but not all cancers use this full range. ## Mandatory parameters ('T', 'N', and 'M') - T (a,is,(0),1-4): size or direct extent of the primary tumour - N (0-3): spread to regional lymph nodes - M (0/1): distant metastasis Use of an "X" instead of a number or other suffix means that the parameter was not assessed. ## Other parameters - G (1-4): the grade of the cancer cells (i.e. they are "low grade" if they appear similar to normal cells, and "high grade" if they appear poorly differentiated) - R (0/1/2): the completeness of the operation (resection-boundaries free of cancer cells or not) - L (0/1): invasion into lymphatic vessels - V (0/1): invasion into vein - C (1-4): a modifier of the certainty (quality) of the last mentioned parameter ## Prefix modifiers - c: stage given by clinical examination of a patient.The c-prefix is implicit in absence of the p-prefix - p: stage given by pathologic examination of a surgical specimen - y: stage assessed after neoadjuvant therapy For the T, N and M parameters exist subclassifications for some cancer-types (e.g. T1a, Tis, N1i) # Examples - Small, low grade cancer, no metastasis, no spread to regional lymph nodes, cancer completely removed, resection material seen by pathologist - pT1 pN0 M0 R0 G1; this grouping of T, N, and M would be considered Stage I - Large, high grade cancer, with spread to regional lymph nodes and other organs, not completely removed, seen by pathologist - pT4 pN2 M1 R1 G3; this grouping of T, N, and M would be considered Stage IV Most Stage I tumors are curable; most Stage IV tumors are inoperable. - N0 tumor cells absent from regional lymph nodes - N1 tumor cells spread to closest or small number of regional lymph nodes - N3 tumor cells spread to most distant or numerous regional lymph nodes - M0 no distant metastasis - M1 metastasis to distant organs (beyond regional lymph nodes) # Uses and aims Some of the aims for adopting a global standard are to: - Aid medical staff in staging the tumour helping to plan the treatment. - Give an indication of prognosis. - Assist in the evaluation of the results of treatment. - Enable facilities around the world to collate information more productively. Since the number of combinations of categories is high, combinations are grouped to stages for better analysis. # Versions The current version of TNM is TNM6, released in 2002.However, some still prefer TNM5, and recommend its continued use.

Tar Sometimes used as a street name for heroin. Tar is a viscous black liquid derived from the destructive distillation of organic matter. Most tar is produced from coal as a byproduct of coke production, but it can also be produced from petroleum, peat or wood. # Types of tar ## General The word "tar" is used to describe several distinct substances.Naturally occurring "tar pits" (e.g. the La Brea Tar Pits in Los Angeles) actually contain asphalt, not tar, and are more accurately known as asphalt pits.Tar sand deposits contain various mixtures of sand (or rock) with bitumen or heavy crude oil rather than tar, as does the Tar Tunnel in Shropshire. "Rangoon tar", also known as "Burmese Oil" or "Burmese Naphtha", is actually petroleum. "Tar" and "pitch (resin)" are sometimes used interchangeably; however, pitch is considered more solid while tar is more liquid. ## Coal In English and French, "tar" is a substance primarily derived from coal. It was formerly one of the products of a gasworks. Tar made from coal or petroleum is considered toxic and carcinogenic because of its high benzene content, however, coal tar in low concentrations is used as a topical medicine.Coal and petroleum tar has a pungent odor. ## Wood In Northern Europe, the word "tar" refers primarily to a substance derived from wood, which is used even as an additive in the flavoring of candy and other foods.Wood tar is microbicidial and has a pleasant odor. The heating (dry distilling) of pine wood causes tar and pitch to drip away from the wood and leave behind charcoal. Birchbark is used to make particularly fine tar (tökötti). The by-products of wood tar are turpentine and charcoal.When deciduous tree woods are subjected to destructive distillation the by-products are methanol (wood alcohol) and charcoal. # Uses Tar is used in treatment of the skin-disease psoriasis, where coal tar is the most effective.Tar is also a general disinfectant. Petroleum tar was also used in ancient Egyptian mummification circa 1000 BC. Tar was a vital component of the first sealed, or "tarmac", roads.It was also used as seal for roofing shingles and to seal the hulls of ships and boats.For millennia wood tar was used to waterproof sails and boats, but today sails made from inherently waterproof synthetic substances have negated the need for tar. Wood tar is still used to seal traditional wooden boats and the roofs of historical shingle-roofed churches, as well painting exterior walls of log buildings. In Finland wood tar was once considered a panacea reputed to heal "even those cut in twain through their midriff".A Finnish proverb states that if sauna, vodka and tar won't help, the disease is fatal.The use of wood tar in traditional Finnish medicine is because of its microbicidial properties. Wood tar is also available diluted as tar water, which has numerous uses: - As a flavoring for candies (e.g. Terva Leijona) and alcohol (Terva Viina) - As a spice for food, like meat - As a scent for saunas.Tar water is mixed into water that is turned to steam to the air - As an anti-dandruff agent in shampoo - As a component of cosmetics Mixing tar with linseed oil varnish produces tar paint.Tar paint has a translucent brownish hue, and can be used to saturate and tone wood and protect it from weather.Tar paint can also be toned with various pigments, producing translucent colours and preserving the wood texture.Because of its paint-like properties, wet tar should not be touched with bare skin, as it can dry to produce a stain, though paint thinner is effective in removing it. Coal tar is listed at number 1999 in the United Nations list of dangerous goods.

Tic # Overview A tic is a sudden, repetitive, stereotyped, nonrhythmic movement (motor tic) or sound (phonic tic) that involves discrete groups of muscles.Tics can be invisible to the observer (e.g.; abdominal tensing or toe crunching). Movements of other movement disorders (e.g.; chorea, dystonia, myoclonus) must be distinguished from tics. Other conditions (e.g.; autism, stereotypic movement disorder) also include movements which may be confused with tics. Tics must also be distinguished from compulsions of OCD and seizure activity. # Description and classification Tics are classified as motor vs. phonic, and simple vs. complex. Motor tics are movement-based tics affecting discrete muscle groups. Phonic tics are involuntary sounds produced by moving air through the nose, mouth, or throat. They may be alternately referred to as verbal tics or vocal tics, but most diagnosticians prefer the term phonic tics to reflect the notion that the vocal cords are not involved in all tics that produce sound. Tics may increase as a result of stress, tiredness, or high energy emotions, which can include negative emotions, such as anxiety, but positive emotions as well, such as excitement or anticipation.Relaxation may result in a tic decrease or a tic increase (for instance, watching television or using a computer), while concentration in an absorbing activity often leads to a decrease in tics. Neurologist and writer Oliver Sacks describes a physician with severe Tourette syndrome, (Canadian Mort Doran, M.D., a pilot and surgeon in real life, although a pseudonym was used in the book), whose tics remit almost completely while he is performing surgery. Immediately preceding tic onset, most individuals are aware of an urge that is similar to the need to yawn, sneeze, blink, or scratch an itch.Individuals describe the need to tic as a buildup of tension which they consciously choose to release, as if they "had to do it". Examples of this premonitory urge are the feeling of having something in one's throat, or a localized discomfort in the shoulders, leading to the need to clear one's throat or shrug the shoulders.The actual tic may be felt as relieving this tension or sensation, similar to scratching an itch. Another example is blinking to relieve an uncomfortable sensation in the eye. Tics are described as semi-voluntary or "unvoluntary", because they are not strictly involuntary—they may be experienced as a voluntary response to the unwanted, premonitory urge. A unique aspect of tics, relative to other movement disorders, is that they are suppressible yet irresistible; they are experienced as an irresistible urge that must eventually be expressed. Some people with tics may not be aware of the premonitory urge.Children may be less aware of the premonitory urge associated with tics than are adults, but their awareness tends to increase with maturity. ## Simple tics Simple motor tics are typically sudden, brief, meaningless movements, such as eye blinking or shoulder shrugging. Motor tics can be of an endless variety and may include such movements as hand-clapping, neck stretching, mouth movements, head, arm or leg jerks, and facial grimacing. A simple phonic tic can be almost any possible sound or noise, with common vocal tics being throat clearing, coughing, sniffing, or grunting. ## Complex tics Complex motor tics are typically more purposeful-appearing and of a longer nature. Examples of complex motor tics are pulling at clothes, touching people, touching objects, echopraxia and copropraxia. Complex phonic tics may fall into various categories, including echolalia (repeating words just spoken by someone else), palilalia (repeating one's own previously spoken words), lexilalia (repeating words after reading them) and coprolalia (the spontaneous utterance of socially-objectionable or taboo words or phrases). Coprolalia is a highly-publicized symptom of Tourette syndrome; however, according to the Tourette Syndrome Association, Inc. (TSA), fewer than 15% of TS patients exhibit coprolalia. Complex tics are rarely seen in the absence of simple tics. Tics "may be challenging to differentiate from compulsions", as in the case of klazomania (compulsive shouting). # Tic disorders Tic disorders occur along a spectrum, ranging from mild to more severe, and are classified according to duration and severity (transient tics, chronic tics, or Tourette syndrome). Tourette syndrome is the more severe expression of a spectrum of tic disorders, which are thought to be due to the same genetic vulnerability. Nevertheless, most cases of Tourette syndrome are not severe. The treatment for the spectrum of tic disorders is similar to the treatment of Tourette syndrome. # Controversy and confusion There is some confusion in media portrayals of tics. For example, in comedies, a person with muscle tics may haplessly raise their hand at an obviously inappropriate time and suffer the consequences. This is implausible: tics are semi-voluntary actions to alleviate the feeling of an unwanted, premonitory urge. One would not thrust his or her arm in the air as in Alien hand syndrome. Tics must be distinguished from fasciculations. Small twitches of the upper or lower eyelid, for example, are not tics because they don't involve a whole muscle. They are twitches of a few muscle fibre bundles, which you can feel but barely see. ### Contraindicated medications Motor tic is considered an absolute contraindication to the use of the following medications: - Methylphenidate

UXT Protein UXT (Ubiquitously eXpressed Transcript protein) also known as androgen receptor trapped clone 27 (ART-27) protein is a protein that in humans is encoded by the UXT gene. # Function UXT interacts with the N-terminus of the androgen receptor and plays a role in facilitating receptor-induced transcriptional activation.It is also likely to be involved in tumorigenesis as it is abundantly expressed in tumor tissues.This gene is part of a gene cluster on chromosome Xp11.23.Alternative splicing results in 2 transcript variants encoding different isoforms. Transcript variant 2 is 575 bp in length, and it codes for a polypeptide sequence that is 157 amino acids long (~ 18 kDa). It has been shown to interact with two AR N-terminal activation domains that are both required for full transcriptional activation.In addition, it is largely localized to the nucleus and is highly expressed in human prostate epithelial cells as well as breast tissues.ART-27 likely serves to link AR to a larger transcription factor complex as evidenced by its association with a number of proteins including RNA pol II subunit 5, a pair of prefoldin β-subunits, and TATA-binding protein-interacting proteins.It also shows homology to prefoldins which are small molecular weight proteins that assemble into molecular chaperone complexes to affect protein folding. ART-27 is shown to be subject to both cell type and developmental regulation in humans. Its expression is associated with an abundance of differentiated prostate epithelial cells, and regulated expression in prostate cancer cells results in decreased cell proliferation. Significantly, because decreased levels of ART-27 are consistently found in prostate cancer cells, it likely plays a role in promoting epithelial differentiation via suppression of proliferative pathways.More recent studies have more definitively identified ART-27 as a corepressor of AR.The fact that the increase in gene transcription exhibited upon ART-27 depletion requires the presence of AR implies that it specifically functions as a corepressor of this receptor. Despite the lack of information regarding its mechanisms of suppression, ART-27 likely plays multiple roles that inhibit AR-mediated transcription. In the absence of androgens, ART-27 may bind the AR N terminus and thereby prevent AR-dependent activation of genes involved in cell proliferation. Other mechanisms may include recruitment of ART-27 to AREs or inhibition of histone methylation which otherwise allows for increased transcription of target genes. # Interactions UXT has been shown to interact with Androgen receptor.

WT1 Wilms tumor protein is a protein that in humans is encoded by the WT1 gene on chromosome 11p. # Function This gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-rich DNA-binding domain at the N-terminus.It has an essential role in the normal development of the urogenital system, and it is mutated in a subset of patients with Wilms' tumor, the gene's namesake.Multiple transcript variants, resulting from alternative splicing at two coding exons, have been well characterized.There is also evidence for the use of non-AUG (CUG) translation initiation site upstream of, and in-frame with the first AUG, leading to additional isoforms. # Structure The WT1 gene product shows similarity to the zinc fingers of the mammalian growth regulated early growth response protein 1 (EGR1) and (EGR2) proteins. # Clinical significance Wilms tumour tumor suppressor gene1 (WT1) causes an embryonic malignancy of the kidney, affecting around 1 in 10,000 infants.It occurs in both sporadic and hereditary forms.Inactivation of WT1 causes Wilms tumour, and Denys-Drash syndrome (DDS), leading to nephropathy and genital abnormalities.The WT1 protein has been found to bind a host of cellular factors, e.g. p53, a known tumor suppressor. WT1 is mutated in a mutually exclusive manner with TET2, IDH1, and IDH2 in acute myeloid leukemia.TET2 can be recruited by WT1 to its target genes and activates WT1-target genes by converting 5mC into 5hmC residues at the genes’ promoters, representing an important feature of a new regulatory WIT pathway linked to the development of AML. The serine protease HtrA2 binds to WT1 and it cleaves WT1 at multiple sites following the treatment with cytotoxic drugs. Using immunohistochemistry, WT1 protein can be demonstrated in the cell nuclei of 75% of mesotheliomas and in 93% of ovarian serous carcinomas, as well as in benign mesothelium and fallopian tube epithelium.This allows these tumours to be distinguished from other, similar, cancers, such as adenocarcinoma.Antibodies to the WT1 protein, however, also frequently cross-react with cytoplasmic proteins in a variety of benign and malignant cells, so that only nuclear staining can be considered diagnostic. ## As a drug target WT1 has been ranked by the National Cancer Institute (NCI) as the Number 1 target for cancer immunotherapy. A vaccine that induces an acquired immune response against WT1 is in clinical trials for various cancers. # Interactions WT1 has been shown to interact with TET2, U2AF2, PAWR, UBE2I and WTAP.In combination with Cited2 activates WT1 the Steroidogenic factor 1 # RNA editing There is some evidence for RNA editing of human WT1 mRNA.As with alternative splicing of the gene RNA editing increases the number of isoforms of this protein. Editing is tissue specific and developmentally regulated.Editing shown to be restricted in testis and kidney in the rat.Editing of this gene product has been found to occur in mice and rats as well as humans. ## Editing type The editing site is found at nucleotide position 839 found in exon 6 of the gene.It causes a codon change from a Proline codon (CCC) to a Leucine codon (CUC) The type of editing is a Uridine to Cytidine( U to C) base change .The editing reaction is thought to be an amidation of uridine which converts it to a Cytidine.The relevance of this editing is unknown as is the enzyme responsible for this editing.The region where editing occurs like that of other editing sites e.g. ApoB mRNA editing is conserved.Mice, rat and humans have conserved sequences flanking the editing site consisting of 10 nucleotides before the editing site and four after the site. ## Effects of editing RNA editing results in an alternative amino acid being translated.The changes in amino acid occur in a region identified as a domain involved in transcription activation function. Editing has been shown to decrease repressive regulation of transcription of growth promoting genes in vitro compared to the non edited protein.Although the physiological role of editing has yet to be determined, suggestions have been made that editing may play a role in the pathogenesis of Wilms tumour.

YY1 YY1 (Yin Yang 1) is a transcriptional repressor protein in humans that is encoded by the YY1 gene. # Function YY1 is a ubiquitously distributed transcription factor belonging to the GLI-Kruppel class of zinc finger proteins.The protein is involved in repressing and activating a diverse number of promoters.Hence, the YY in the name stands for "yin-yang."YY1 may direct histone deacetylases and histone acetyltransferases to a promoter in order to activate or repress the promoter, thus implicating histone modification in the function of YY1.YY1 promotes enhancer-promoter chromatin loops by forming dimers and promoting DNA interactions.Its disregulation disrupts enhancer-promoter loops and gene expression. # Clinical significance YY1 heterozygous deletions, missense, and nonsense mutations cause Gabriele-DeVries syndrome (GADEVS) , an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, dysmorphic facial features, feeding problems, intrauterine growth restriction, variable cognitive impairment, behavioral problems and other congenital malformations.It is available a website to share and collect clinical information between clinical doctors and families of mutated indididuals. # Interactions YY1 has been shown to interact with: - ATF6, - EP300, - FKBP3, - HDAC3, - Histone deacetylase 2, - Myc, - NOTCH1, - RYBP, and - SAP30. - Seryl-tRNA Synthetase.

ZP2 Zona pellucida sperm-binding protein 2 is a protein that in humans is encoded by the ZP2 gene. # Function The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo.It is composed primarily of three (mouse) or four (human) glycoproteins (ZP1-4) with various functions during fertilization and preimplantation development.The protein encoded by this gene is a structural component of the zona pellucida and functions in secondary binding and penetration of acrosome-reacted spermatozoa.The nascent protein contains a N-terminal signal peptide sequence, a conserved ZP domain, a consensus furin cleavage site, and a C-terminal transmembrane domain.It is hypothesized that furin cleavage results in release of the mature protein from the plasma membrane for subsequent incorporation into the zona pellucida matrix.However, the requirement for furin cleavage in this process remains controversial based on mouse studies. The sperm-binding domain on the ZP2 protein is necessary in both humans and mice for oocyte-sperm recognition and penetration of the zona pellucida.It is also responsible for the primary block to polyspermy in mammals. The oocyte has cortical granules peripherally located under the cortex that contain a proteolytic protein called ovastacin.After the sperm binds to ZP2, the cortical granules are exocytosed releasing ovastacin into the perivitelline space. Ovastacin cleaves ZP2 at the N terminus, preventing more sperm from binding and penetrating the oocyte, thus hardening the zona pellucida.Ovastacin is only found in oocytes, and is part of the astacin family of metalloendoproteases.Female mice engineered without ovastacin showed that ZP2 was not cleaved after fertilization. # 3D structure The crystal structure of the sperm-binding domain of ZP2 at 0.95 Å resolution (PDB: 5II6​) showed that is shares the same ZP-N fold first identified in structures of ZP3 (PDB: 3D4C, 3D4G, 3EF7, 3NK3, 3NK4​).This provided experimental evidence for the suggestion that the N-terminal region of ZP2 consists of three ZP-N repeats and revealed that - despite insignificant sequence identity - ZP2 is structurally similar to VERL, the vitelline envelope receptor for egg lysin of the mollusk abalone (PDB: 5II4, 5II5, 5MR2, 5IIC, 5IIA, 5IIB, 5MR3​).This established a link between invertebrate and vertebrate fertilization by suggesting that, despite being separated by 600 million years of evolution, mollusk and human use a common protein fold to interact with sperm.

ZP3 Zona pellucida sperm-binding protein 3, also known as zona pellucida glycoprotein 3 (Zp-3) or the sperm receptor, is a ZP module-containing protein that in humans is encoded by the ZP3 gene.ZP3 is the receptor in the zona pellucida which binds sperm at the beginning of fertilization. # Function The zona pellucida (ZP) is a specialized extracellular matrix that surrounds the oocyte and early embryo.It is composed of three or four glycoproteins (ZP1-4) with various functions during oogenesis, fertilization and preimplantation development.The protein encoded by this gene is a major structural component of the ZP and functions in primary binding and stimulation of the sperm acrosome reaction.The nascent protein contains a N-terminal signal peptide sequence, a conserved "ZP domain" module, a consensus furin cleavage site (CFCS), a polymerization-blocking external hydrophobic patch (EHP), and a C-terminal transmembrane domain.Cleavage at the CFCS separates the mature protein from the EHP, allowing it to incorporate into nascent ZP filaments.A variation in the last exon of this gene has previously served as the basis for an additional ZP3 locus; however, sequence and literature review reveals that there is only one full-length ZP3 locus in the human genome.Another locus encoding a bipartite transcript designated POMZP3 contains a duplication of the last four exons of ZP3, including the above described variation, and maps closely to this gene. # 3D Structure X-ray crystallographic studies of the N-terminal half of mammalian ZP3 (PDB: 3D4C, 3D4G, 3EF7​) as well as its full-length avian homolog (PDB: 3NK3, 3NK4​) revealed that the protein's ZP module consists of two immunoglobulin-like domains, ZP-N and ZP-C. The latter, which contains EHP as well as a ZP3-specific subdomain, interacts with the ZP-N domain of a second molecule to generate an antiparallel homodimeric arrangement required for protein secretion.