Raloxifene is an oral selective estrogen receptor modulator (SERM) that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast. It is used in the prevention of osteoporosis in postmenopausal women. It was announced on April 17, 2006, that raloxifene is as effective as tamoxifen in reducing the incidence of breast cancer in certain high risk groups of females, though with a reduced risk of thromboembolic events and cataracts in patients taking raloxifene versus those taking tamoxifen. On September 14, 2007, the U.S. Food and Drug Administration announced approval of raloxifene for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.
There has been criticism in the mainstream oncology press of the way that information about the drug was released.There has been some confusion in the lay media about the meaning of the trial results. There is no specific clinical evidence for the use of raloxifene in the adjuvant treatment of breast cancer over established drugs such as tamoxifen or anastrozole.
The official name of PAX3 gene is “paired box 3". The PAX3 gene belongs to a family of genes that plays a critical role in the formation of tissues and organs during embryonic development. The PAX gene family is also important for maintaining the normal function of certain cells after birth. To carry out these roles, the PAX genes provide instructions for making proteins that attach to specific areas of DNA. By attaching to critical DNA regions, these proteins help control the activity of particular genes. On the basis of this action, PAX proteins are called transcription factors.
During embryonic development, the PAX3 gene is active in cells called neural crest cells. These cells migrate from the developing spinal cord to specific regions in the embryo. The protein made by the PAX3 gene directs the activity of other genes (such as MITF) that signal neural crest cells to form specialized tissues or cell types such as limb muscles, bones in the face and skull (craniofacial bones), some nerve tissue, and pigment-producing cells called melanocytes. Melanocytes produce the pigment melanin, which contributes to hair, eye, and skin color. Melanocytes are also found in certain regions of the brain and inner ear.
Location:
PAX3 Gene is present in human chromosome 2 and its coded from region 222,772,850 to 222,871,943 Complement base pairs with 9 exons, the cytogenetic location 2q35-q37.
PAX3 Protein
Disease
Mutations in PAX3 gene causes Waardenburg syndrome Several PAX3 mutations have been identified in people with Waardenburg syndrome, types I and III. Some of these mutations change one of the chemical building blocks (amino acids) used to make the PAX3 protein. Other mutations lead to an abnormally small version of the PAX3 protein. Researchers believe that all PAX3 mutations have the same effect; they destroy the ability of the PAX3 protein to bind to DNA and regulate the activity of other genes. As a result, melanocytes do not develop in certain areas of the skin, hair, eyes, and inner ear, leading to hearing loss and the patchy loss of pigmentation that are characteristic features of Waardenburg syndrome. Additionally, loss of PAX3 protein function disrupts development of craniofacial bones and certain muscles, producing the limb and facial features that are unique to Waardenburg syndrome, types I and III.
Alterations in the activity of the PAX3 gene are associated with some cases of cancer of muscle tissue (alveolar rhabdomyosarcoma) that occur mainly in adolescents and young adults. Gene activity is altered when the PAX3 gene on chromosome 2 is fused with the FOXO1A gene (also called FKHR) on chromosome 13. This fusion event occurs when segments of chromosomes 2 and 13 are rearranged in certain cells that develop into muscle tissue. The fused PAX3-FOXO1A gene may enhance changes that can lead to cancer, such as uncontrolled cell division and cell growth.
# Arnold K., Bordoli L., Kopp J., and Schwede T. (2006). The SWISS-MODEL Workspace: A web-based environment for protein structure homology modelling. Bioinformatics, 22,195-201.
# Schwede T, Kopp J, Guex N, and Peitsch MC (2003) SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Research 31: 3381-3385.
# Guex, N. and Peitsch, M. C. (1997) SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modelling. Electrophoresis 18: 2714-2723.
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death".[1] It typically results in a number of symptoms including an itchy rash, throat swelling, and low blood pressure. Common causes include insect bites, foods, and medications.
On a pathophysiologic level, anaphylaxis is due to the release of mediators from certain types of white blood cells triggered either by immunologic or non-immunologic mechanisms. It is diagnosed based on the presenting symptoms and signs. The primary treatment is injection of epinephrine, with other measures being complementary.
Vancomycin INN ( /væŋkɵˈmaɪsɨn/) is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed,[citation needed] although the emergence of vancomycin-resistant organisms means that it is increasingly being displaced from this role by linezolid (Zyvox) available PO and IV and daptomycin (Cubicin) IV and quinupristin/dalfopristin (Synercid) IV.
Estrogen receptor refers to a group of receptors which are activated by the hormone 17β-estradiol (estrogen). Two types of estrogen receptor exist: ER which is a member of the nuclear hormone family of intracellular receptors and the estrogen G protein coupled receptor GPR30 (GPER), which is a G-protein coupled receptor. This article refers to the nuclear hormone receptor ER.
The main function of the estrogen receptor is as a DNA binding transcription factor which regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding.
Estrogen receptor Molecular and cellular mechanism,Steroid hormones are chemical substances secreted by glands in the abdomen with involved in the regulation of variety of the functions including sodium balace,metabolism and reproductive functions.For example
Nerve growth factor (NGF) is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons (nerve cells). It also functions as a signaling molecule.[1][2] It is perhaps the prototypical growth factor, in that it is one of the first to be described. While "nerve growth factor" refers to a single factor,[3] "nerve growth factors" refers to a family of factors also known as neurotrophins.[4] Other members of the neurotrophin family that are well recognized include Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin 4/5 (NT-4/5).
Function and mechanism of action
NGF is critical for the survival and maintenance of sympathetic and sensory neurons. Without it, these neurons undergo apoptosis.[5] Nerve growth factor causes axonal growth. Studies have shown that it causes axonal branching and a bit of elongation.[6] NGF binds with at least two classes of receptors: the p75 LNGFR (for "low-affinity nerve growth factor receptor") neurotrophin receptor (p75(NTR)) and TrkA, a transmembrane tyrosine kinase. Both are associated with neurodegenerative disorders.
NGF binds to high-affinity tyrosine kinase receptor TrkA. This phosphorylates TrkA, which leads to the activation of PI 3 Kinase, ras, and PLC signaling pathways.
There is evidence that NGF circulates throughout the entire body and is important for maintaining homeostasis.
There is also evidence that shows that the precursor to NGF, pro-NGF, may also play important roles due to its abundance. These include apoptotic and neurotrophic properties.
Your brain is the key player in nicotine's action. Like a computer, your brain processes, stores and uses information. In a computer, information travels in the form of electricity moving through wires; information transfer is a binary process, with switches being either "on" or "off." In your brain, neurons are the cells that transfer and integrate information. Each neuron has thousands of inputs from other neurons throughout the brain. Each of these signals is included in the calculation of whether or not the neuron will pass the signal it receives on to other neurons in the pathway.
Hormones are chemicals released by cells that affect cells in other parts of the body. Only a small amount of hormone is required to alter cell metabolism. It is essentially a chemical messenger that transports a signal from one cell to another. All multicellular organisms produce hormones; plant hormones are also called phytohormones. Hormones in animals are often transported in the blood. Cells respond to a hormone when they express a specific receptor for that hormone. The hormone binds to the receptor protein, resulting in the activation of a signal transduction mechanism that ultimately leads to cell type-specific responses.
Endocrine hormone molecules are secreted (released) directly into the bloodstream, while exocrine hormones (or ectohormones) are secreted directly into a duct, and from the duct they either flow into the bloodstream or they flow from cell to cell by diffusion in a process known as paracrine signalling.
Nature of hormonal control
Hormonal regulation of some physiological activities involves a hierarchy of cell types acting on each other either to stimulate or to modulate the release and action of a particular hormone. The secretion of hormones from successive levels of endocrine cells is stimulated by chemical signals originating from cells higher up the hierarchical system. The master coordinator of hormonal activity in mammals is the hypothalamus, which acts on input that it receives from the central nervous system.
Other hormone secretion occurs in response to local conditions, such as the rate of secretion of parathyroid hormone by the parathyroid cells in response to fluctuations of ionized calcium levels in extracellular fluid.
Hormone signaling Hormonal signaling across this hierarchy involves the following: 1. Biosynthesis of a particular hormone in a particular tissue 2. Storage and secretion of the hormone 3. Transport of the hormone to the target cell(s) 4. Recognition of the hormone by an associated cell membrane or intracellular receptor protein. 5. Relay and amplification of the received hormonal signal via a signal transduction process: This then leads to a cellular response. The reaction of the target cells may then be recognized by the original hormone-producing cells, leading to a down-regulation in hormone production. This is an example of a homeostatic negative feedback loop. 6. Degradation of the hormone.
As can be inferred from the hierarchical diagram, hormone biosynthetic cells are typically of a specialized cell type, residing within a particular endocrine gland (e.g., the thyroid gland, the ovaries, or the testes). Hormones may exit their cell of origin via exocytosis or another means of membrane transport. However, the hierarchical model is an oversimplification of the hormonal signaling process. Cellular recipients of a particular hormonal signal may be one of several cell types that reside within a number of different tissues, as is the case for insulin, which triggers a diverse range of systemic physiological effects. Different tissue types may also respond differently to the same hormonal signal. Because of this, hormonal signaling is elaborate and hard to dissect.
Interactions with receptors
Most hormones initiate a cellular response by initially combining with either a specific intracellular or cell membrane associated receptor protein. A cell may have several different receptors that recognize the same hormone and activate different signal transduction pathways, or alternatively different hormones and their receptors may invoke the same biochemical pathway.
For many hormones, including most protein hormones, the receptor is membrane associated and embedded in the plasma membrane at the surface of the cell. The interaction of hormone and receptor typically triggers a cascade of secondary effects within the cytoplasm of the cell, often involving phosphorylation or dephosphorylation of various other cytoplasmic proteins, changes in ion channel permeability, or increased concentrations of intracellular molecules that may act as secondary messengers (e.g. cyclic AMP). Some protein hormones also interact with intracellular receptors located in the cytoplasm or nucleus by an intracrine mechanism.
For hormones such as steroid or thyroid hormones, their receptors are located intracellularly within the cytoplasm of their target cell. In order to bind their receptors these hormones must cross the cell membrane. The combined hormone-receptor complex then moves across the nuclear membrane into the nucleus of the cell, where it binds to specific DNA sequences, effectively amplifying or suppressing the action of certain genes, and affecting protein synthesis. However, it has been shown that not all steroid receptors are located intracellularly, some are plasma membrane associated.
An important consideration, dictating the level at which cellular signal transduction pathways are activated in response to a hormonal signal is the effective concentration of hormone-receptor complexes that are formed. Hormone-receptor complex concentrations are effectively determined by three factors:
1. The number of hormone molecules available for complex formation 2. The number of receptor molecules available for complex formation and 3. The binding affinity between hormone and receptor.
The number of hormone molecules available for complex formation is usually the key factor in determining the level at which signal transduction pathways are activated. The number of hormone molecules available being determined by the concentration of circulating hormone, which is in turn influenced by the level and rate at which they are secreted by biosynthetic cells. The number of receptors at the cell surface of the receiving cell can also be varied as can the affinity between the hormone and its receptor.
Physiology of hormones
Most cells are capable of producing one or more molecules, which act as signaling molecules to other cells, altering their growth, function, or metabolism. The classical hormones produced by cells in the endocrine glands mentioned so far in this article are cellular products, specialized to serve as regulators at the overall organism level. However they may also exert their effects solely within the tissue in which they are produced and originally released.
The rate of hormone biosynthesis and secretion is often regulated by a homeostatic negative feedback control mechanism. Such a mechanism depends on factors which influence the metabolism and excretion of hormones. Thus, higher hormone concentration alone can not trigger the negative feedback mechanism. Negative feedback must be triggered by overproduction of an "effect" of the hormone.
Hormone secretion can be stimulated and inhibited by:
* Other hormones (stimulating- or releasing-hormones) * Plasma concentrations of ions or nutrients, as well as binding globulins * Neurons and mental activity * Environmental changes, e.g., of light or temperature
One special group of hormones is the tropic hormones that stimulate the hormone production of other endocrine glands. For example, thyroid-stimulating hormone (TSH) causes growth and increased activity of another endocrine gland, the thyroid, which increases output of thyroid hormones.
A recently-identified class of hormones is that of the "hunger hormones" - ghrelin, orexin and PYY 3-36 - and "satiety hormones" - e.g., leptin, obestatin, nesfatin-1.
In order to release active hormones quickly into the circulation, hormone biosynthetic cells may produce and store biologically inactive hormones in the form of pre- or prohormones. These can then be quickly converted into their active hormone form in response to a particular stimulus.
Haplotype is a set of single nucleotide polymorphisms (SNPs) on a single chromatid that are statistically associated. It is thought that these associations, and the identification of a few alleles of a haplotype block, can unambiguously identify all other polymorphic sites in its region. Such information is very valuable for investigating the genetics behind common diseases, and is collected by the International HapMap Project.
An organism's genotype may not uniquely define its haplotype. For example, consider a diploid organism and two bi-allelic loci on the same chromosome such as Single Nucleotide Polymorphisms (SNPs). The first locus has alleles A and T with three possible genotypes AA, AT, and TT, the second locus having G and C, again giving three possible genotypes GG, GC, and CC. For a given individual, there are therefore nine possible configurations for the genotypes at these two loci, as shown in the punnett square , which shows the possible genotypes that an individual may carry and the corresponding haplotypes that these resolve to. For individuals that are homozygous at one or both loci, it is clear what the haplotypes are; it is only when an individual is heterozygous at both loci that the phase is ambiguous.
Within the human genome SNPs occur on an average of 1 in 1000 base pairs .researchers have shown the groups of SNPs occur in predictable patterns within sections of DNA.
these inherent sections of 68 SNPs are called haplotype.Within one section of DNA it is believed that there are only 3 to 5 different haplotypes throughout the entire population.
The only unequivocal method of resolving phase ambiguity is by sequencing. However, it is possible to estimate the probability of a particular haplotype when phase is ambiguous using a sample of individuals.
Given the genotypes for a number of individuals, the haplotypes can be inferred by haplotype resolution or haplotype phasing techniques. These methods work by applying the observation that certain haplotypes are common in certain genomic regions. Therefore, given a set of possible haplotype resolutions, these methods choose those that use fewer different haplotypes overall. The specifics of these methods vary - some are based on combinatorial approaches (e.g., parsimony), whereas others use likelihood functions based on different models and assumptions such as the Hardy-Weinberg principle, the coalescent theory model, or perfect phylogeny. These models are combined with optimization algorithms such as expectation-maximization algorithm (EM) or Markov chain Monte Carlo (MCMC).
Aids and HIV Life cycle lecture was given by Dr.Bruce Walker ,He is Howard Hughes Medical Institute Investigator,and Director for Center for AIDS Research at Harvard University.The lecture starts from HIV structure , various component of HIV virus,Mechanism of HIV , and how HIV causes AIDS,He also talks about why our immune system is unable to stop HIV virus.The lecture uses various case studies of show HIV variability,he also talk about various challenges for designing drugs for HIV .
Hiv was first found among few gay persons in califonia,it later spread all aroung USA,
This virus are essentially packages of genetic material and are not able to replicate on their won ,But they carry all the information acquired for replication
if you had chickenpox or infectious mono as child you have that virus still alive in your body now the reason it's not causing diseases that you have an effective immune response that it will help you to keep it in check now
when you first became infected with chickenpox you felt really lousy .The part of that feeling of lousy as your immune system trying to respond and fight the invading pathogen and ultimately even though the virus persists in your body you enter into a phase where your a symptomatic and the virus is not causing any problems again with immune system keeping in check
Early symptoms for Aids Patient had fever, chills, shaking, Headache at times loss of appetite joint and muscle pain and malaise skin rashes,and swollen lymph nodes .
It takes more than 3 weeks produce Hiv Antibody
polymerase chain reaction helps to directly quantitative the amount of virus in the bloodstream
people have a transient drop in Cd4 helper cell counts and then T-helper cell levels decline slowly over time until the ultimate development of AIDS.
HIV it's a typical retrovirus ,meaning that it has in outer envelope. in the center it has two copies of RNA as well as an reverse transcriptase Enzyme, which will ultimately turn that RNA into DNA,
The first step in HIV1 life cycle is viral attachment to the CD4 T-cell surface the next step is viral entry which involves a cascade of molecular interactions between the viral envelope glycoprotein and Two T-cell surface receptors a primary receptor and a co-receptor.
The GP 120 subunit of the envelope protein first binds the CD4 primary receptor this induces a conformational change in GP 120 This allows to binds to the co- receptor binding triggers conformational changes in the GP 41 subunit leading to insertion of its N-terminal fusion peptide into the host cell's membrane
Cytotoxic T-cells is a sub group of T lymphocytes cells that are capable of inducting the death of infected somatic or tumor cells; they kill virus-affected cells, pathogens, and damaged or dysfunctional cells. Most cytotoxic T cells express T-cell receptors (TcRs) that can recognize a specific antigenic peptide bound to Class I MHC molecules, present on all nucleated cells, and a glycoprotein called CD8, which is attracted to non-variable portions of the Class I MHC molecule. The affinity between CD8 and the MHC molecule keeps the TC cell and the target cell bound closely together during antigen-specific activation. CD8+ T cells are recognized as TC cells once they become activated and are generally classified as having a pre-defined cytotoxic role within the immune system.
When a virus attacks the cell, cell starts produces a viral proteins. The ubiquitin molecule tags these proteins and carries it to proteosome, where it digested into small peptide fragments. A peptidase enzyme breaks these fragments, the fragments further move to endoplasm reticulm and gain entry via TAP molecule. Inside the endoplasm reticulum it binds to developing MHC class 1 molecule (only if it has right conformation with it), MHC class1 molecule is carried to cell surface and embedded. This alerts CTL (cytotoxic tcells), which identifies the foreign virus protein in the MHC class 1 molecule.The T-cell receptor in CTL engages a conformational recognition along with the CD8 molecule, which leads to release Granzymes and perfornin to kill virus-affected cell.
Researchers at Whitehead Institute for Biomedical Research in Cambridge, Mass., have manipulated mouse fibroblasts and turned them into cells with such developmental elasticity that they appear identical to embryonic stem cells.
Embryonic stem cells have potential to provide people with donor cells which can be used transplantation medicine, one of the problems of embryonic stem cells are they are derived from the embryo and it will not be compatible with immune system of the donor, so the real goal is to generate customized embryonic stem cells, A way that it thought to be accomplished was by nuclear transfer, for example If u take skin cell from a patient and introduce nucleus from the cells into a egg for whose nucleus is removed. The egg is able to reprogram the somatic cell into an embryonic state, from this people are able to isolate customized embryonic cells and those could be new for customized transplantation therapy, there will be no immune rejection.
The problem with this approach is many, it is very complex and inefficient procedure and it only so far in animals (mice only) and secondly there lot of ethical objection in using human embryo and human egg cells for therapy or research, so goal of field is to understand how the egg accomplishes reprogramming the somatic nucleus into embryonic stage once we know the reprogramming rules we could do without the egg.
What we have done in our laboratory was to use the knowledge coming from investigating and finding of molecular circulatory of embryonic stem cells and comparing it with the somatic cells and taking some key regulators or Key switches and express those into the somatic cells .In long process (few weeks) we found that these skin cells become embryonic cells,. Signatures of the reprogrammed cells these cells were indistingusble with normal embryonic stem cells, Molecular expression pattern of the genes is identical, epigenetic stage of these cells are indistinguisable from embryonic stem cells the most important is these reprogrammed cells can do anything biologically as embryonic stem cells with same developmental potency and we tested this by introducing these cells back to embryos of form prim Eric mice and even can contribute to germline, so that it can generate fibroblast after the reprogramming process being introduced we can generate mice, from all,the test we have done ,it appears that these cells have same potential for forming all lineages of the animal but also for therapy has Embryonic stem cell have.
An action potential,depicted as a red band, is propagated in one directional along the axon.During an action potential , the inside of the cell membrane becomes positive with respect to the outside.An action potential generates local current that tends to depolarize the membrane immediately adjacent to the action potential,When depolarization caused by the local currents threshold, a new action potential adjacent to the original one.Action potential propagation occurs in one directional because the recently depolarized area of the membrane is in absolute refractory period and cannot generate an action potential.
Southern blot is a method routinely used in molecular biology to check for the presence of a DNA sequence in a DNA sample. Southern blotting combines agarose gel electrophoresis for size separation of DNA with methods to transfer the size-separated DNA to a filter membrane for probe hybridization. The method is named after its inventor, the British biologist Edwin Southern.The southern blot is used to verify the presence or absence of a specific nucleotide sequence in the DNA from different sources and to identify the size of the restriction fragment that contains the sequence.
In this procedure, the DNA is isolated from each source and then digested with a specific restriction enzyme. The DNA restriction fragments are then loaded onto an agrose gel and the fragments separated by electrophoresis according to size, with the smaller fragments migrating faster than larger fragments. The DNA is then transferred from the fragile gel to a nylon filter.
Next the radioactively labeled nucleic acid probe is added. The probe binds to complementary DNA segments. Note that the DNA segment being probed is not present in organism B
To detect the position of the radioactive probe, the nylon membrane is covered with an X-ray film. After development, the positions of the probe become visible.
Epinephrine is a hormone and neurotransmitter.It is catecholomine, a sympathomimetic monoamine derived from the amino acids phenylalanine and tryosine,Epinephrine is often shortened to epi or to EP in American medical jargon.It is also referred to as adrenaline Epinephrine is a "fight or flight" hormone, and plays a central role in the short-term stress reaction. It is released from the adrenal glands when danger threatens or in an emergency. Such triggers may be threatening, exciting, or environmental stressor conditions such as high noise levels, or bright light and high ambient temperature
Epinephrine is one of many hormones that is water soluble(hydrophilic) and therefore unable to cross the hydrophobic plasma membranes of its target cells.Instead it binds to receptor proteins located in the plasma membrane and does not enter the cell.
when Epinephrine binds to beta-adrenergic receptors on teh liver cell, G proteins on the inner side of the cell membrane are activated.Each G protein is composed to three subunits and the binding of epinephrine to its receptor protein causes one of the G protein subunits to dissociate from the other two.
The G protein subunit which dissociates from the others carries a GDP,which is replaced by GTP when the subunit is activated
The activated G protein subunit then diffuses within the plasma membrane until it encounters adenylyl cyclase, a membrane enzyme that is inactive until it interacts with the G protein subunit.
When activated by the G protein subunit,adenylyl cyclase that formation of cAMP from ATP.The cAMP formed at the inner surface of the membrane diffuses within the cytoplasm,where it binds to and activates protein kinase-A, An enzyme that adds phosphate groups to specific cellular proteins.
In liver cells, protein kinase-A phosphorylates and thereby activates another enzyme called phosphorylase,which converts glycogen into glucose-6-phosphate.The glucose-6-phosphate is then converted to glucose.
Through this multistage mechanism,epinephrine causes the liver to secrete glucose into the blood during the fight-or-flight reaction.
Epinephrine is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in diminished or absent cardiac output; its action is to increase peripheral resistance via α1-adrenoceptor vasoconstriction, so that blood is shunted to the body's core, and the β1-adrenoceptor response which is increased cardiac rate and output (the speed and pronouncement of heart beats). This beneficial action comes with a significant negative consequence—increased cardiac irritability—which may lead to additional complications immediately following an otherwise successful resuscitation. Alternatives to this treatment include vasopressin, a powerful antidiuretic which also increases peripheral vascular resistance leading to blood shunting via vasoconstriction, but without the attendant increase in myocardial irritability.
Due to its suppressive effect on the immune system, epinephrine is the drug of choice for treating anaphylaxis. It is also useful in treating sepsis. Allergy patients undergoing immunotherapy may receive an epinephrine rinse before the allergen extract is administered, thus reducing the immune response to the administered allergen. It is also used as a bronchodilator for asthma if specific beta2-adrenergic receptor agonists are unavailable or ineffective.
Because of various expression of α1 or β2-receptors, depending on the patient, administration of epinephrine may raise or lower blood pressure, depending whether or not the net increase or decrease in peripheral resistance can balance the positive inotropic and chronotropic effects of epinephrine on the heart, effects which respectively increase the contractility and rate of the heart.
Kinesins are a class of motor proteins found in eukaryotic cells.This protein is coded by KIF1B(Kinesin family member 1B)gene. Kinesins move along microtubule cables powered by the hydrolysis of ATP (thus kinesins are ATPases). The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cargo such as axonal transport.
In the cell, small molecules such as gases and glucose diffuse to where they are needed. Large molecules synthesised in the cell body, intracellular components such as vesicles, and organelles such as mitochondria are too large (and the cytosol too crowded) to diffuse to their destinations. Motor proteins fulfill the role of transporting large cargo about the cell to their required destinations. Kinesins are motor proteins that transport such cargo by walking unidirectionally along microtubule tracks hydrolysing one molecule of adenosine triphosphate (ATP) at each step. It was thought that ATP hydrolysis powered each step, the energy released propelling the head forwards to the next binding site. It now seems that the head diffuses forward and the force of binding to the microtubule is what pulls the cargo along.
Motor proteins travel in a specific direction along a microtubule. This is because the microtubule is polar and the heads only bind to the microtubule in one orientation, while ATP binding gives each step its direction through a process known as neck linker zippering.
Most kinesins walk towards the positive end of a microtubule which, in most cells, entails transporting cargo from the centre of the cell towards the periphery. This form of transport is known as anterograde transport.
A different type of motor protein known as dyneins, move towards the minus end of the microtubule. Thus they transport cargo from the periphery (terminal buttons) of the cell towards the centre (soma). This is known as retrograde transport. Anterograde axoplasmic transport is the fastest of the two transports, moving at a speed of up to 500 mm per day, while retrograde transport moves about half as fast.
Kinesin accomplishes transport by "walking" along a microtubule. Two mechanisms have been proposed to account for this movement.
In the "hand-over-hand" mechanism, the kinesin heads step past one another, alternating the lead position.
In the "inchworm" mechanism, one kinesin head always leads, moving forward a step before the trailing head catches up.
Hutchinson-Gilford progeria syndrome is a genetic condition characterized by the dramatic, rapid appearance of aging beginning in childhood. Affected children typically look normal at birth and in early infancy, but then grow more slowly than other children and do not gain weight at the expected rate (failure to thrive). They develop a characteristic facial appearance including prominent eyes, a thin nose with a beaked tip, thin lips, a small chin, and protruding ears. Hutchinson-Gilford progeria syndrome also causes hair loss (alopecia), aged-looking skin, joint abnormalities, and a loss of fat under the skin (subcutaneous fat). This condition does not disrupt intellectual development or the development of motor skills such as sitting, standing, and walking.
Hutchinson-Gilford Progeria syndrome is an extremely rare condition in which physical aspects of aging are greatly accelerated, and few affected children live past age 13. About 1 in 8 million babies are born with this condition. It is a genetic condition, but occurs sporadically and is usually not inherited in families.progeria syndrome is considered an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. The condition results from new mutations in the LMNA gene, and almost always occurs in people with no history of the disorder in their family.
Causes
Mutaion is LMNA gene causes Progeria syndrome,LMNA is a gene which povides instruction to make a parotein called Lamin A,Lamin A protein plays important role in determining the shape of the nuclues within cells,It si essential component for nuclear envelope,Mutationsin this gene causes abnormal version of lamin A protein,This altered protein makes teh nuclear envelope unstable and progressively damages the nuclues,making cells more likely to die Prematurely.
Every year, millions of people in the U.S. sustain head and brain injuries. Some are minor because the skull is quite good at protecting the brain. More than half are bad enough that people must go to the hospital. Serious head injuries can lead to permanent brain damage or death.
Symptoms of minor head injuries usually go away without treatment. Serious head injuries need emergency treatment. Clues that a head injury may be serious include
EGFR is a transmembrane tyrosine kinase receptor that plays a central role in regulating cell division and death. EGFR belongs to the HER family of receptors which comprise four related proteins (EGFR(HER1/ErbB1), ERBB2(HER2), ERBB3(HER3) and ERBB4(HER4)). The HER receptors are known to be activated by binding to different ligands, including EGF, TGFA, heparin-binding EGF-like growth factor, amphiregulin, betacellulin, and epiregulin. After a ligand binds to the extracellular domain of the receptor, the receptor forms functionally active dimers (EGFR-EGFR (homodimer) or EGFR-HER2, EGFR-HER3, EGFR-HER4 (heterodimer)). Dimerization induces the activation of the tyrosine kinase domain, which leads to autophosphorylation of the receptor on multiple tyrosine residues. This leads to recruitment of a range of adaptor proteins (such as SHC, GRB2) and activates a series of intracellular signaling cascades to affect gene transcription, which in turn results in cancer cell proliferation, reduced apoptosis, invasion and metastasis and also stimulates tumor-induced angiogenesis.
The pathways mediating downstream effects of EGFR have been well studied and three major signalling pathways have been identified. The first pathway involves RAS-RAF-MAPK pathway, where phosphorylated EGFR recruits the guanine-nucleotide exchange factor via the GRB2 and Shcadapter proteins, activating RAS and subsequently stimulating RAF and the MAP kinase pathway to affect cell proliferation, tumor invasion, and metastasis. The second pathway involves PI3K/AKT pathway, which activates the major cellular survival and anti-apoptosis signals via activating nuclear transcription factors such as NFKB. The third pathway involves JAK/STAT pathway which is also implicated in activating transcription of genes associated with cell survival. EGFR activation may also lead to phosphorylation of PLCG and subsequent hydrolysis of phosphatidylinositol 4,5 biphosphate (PIP2) into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), resulting in activation of protein kinase C (PRKC) and CAMK.
Given the prominent importance of EGFR signaling in cancer development, both anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors have been developed. Anti-EGFR antibodies, eg. cetuximab and panitumumab, bind to the extracellular domain of EGFR monomer and compete for receptor binding by the endogenous ligands; in this way they block ligand-induced receptor activation. The small molecule EGFR inhibitors, such as erlotinib, gefitinib and lapatinib, compete with ATP to bind the catalytic domain of the kinase which in turn inhibits EGFR autophosphorylation and downstream signaling. However, these inhibitors are known to be effective in only a small subset of patients. Mutations in the EGFR gene and possible down-stream effectors have been shown to be associated with various clinical outcomes associated with EGFR inhibitor treatments
A cerebral aneurysm (also known as an intracranial or intracerebral aneurysm) is a weak or thin spot on a blood vessel in the brain that balloons out and fills with blood. The bulging aneurysm can put pressure on a nerve or surrounding brain tissue. It may also leak or rupture, spilling blood into the surrounding tissue (called a hemorrhage). Some cerebral aneurysms, particularly those that are very small, do not bleed or cause other problems. Cerebral aneurysms can occur anywhere in the brain, but most are located along a loop of arteries that run between the underside of the brain and the base of the skull.
Most cerebral aneurysms are congenital, resulting from an inborn abnormality in an artery wall. Cerebral aneurysms are also more common in people with certain genetic diseases, such as connective tissue disorders and polycystic kidney disease, and certain circulatory disorders, such as arteriovenous malformations.
Other causes include trauma or injury to the head, high blood pressure, infection, tumors, atherosclerosis (a blood vessel disease in which fats build up on the inside of artery walls) and other diseases of the vascular system, cigarette smoking, and drug abuse. Some investigators have speculated that oral contraceptives may increase the risk of developing aneurysms.
Aneurysms that result from an infection in the arterial wall are called mycotic aneurysms. Cancer-related aneurysms are often associated with primary or metastatic tumors of the head and neck. Drug abuse, particularly the habitual use of cocaine, can inflame blood vessels and lead to the development of brain aneurysms.
The amino-acid sequence (or primary structure) of a protein predisposes it towards its native conformation or conformations. It will fold spontaneously during or after synthesis. While these macromolecules may be regarded as "folding themselves", the mechanism depends equally on the characteristics of the cytosol, including the nature of the primary solvent (water or lipid), macromolecular crowding, the concentration of salts, the temperature, and molecular chaperones.
Most folded proteins have a hydrophobic core in which side chain packing stabilizes the folded state, and charged or polar side chains on the solvent-exposed surface where they interact with surrounding water molecules. It is generally accepted that minimizing the number of hydrophobic side-chains exposed to water is the principal driving force behind the folding process, although a recent theory has been proposed which reassesses the contributions made by hydrogen bonding The strengths of hydrogen bonds in a protein vary, i.e. they are dependent on their microenvironment, thus H-bonds enveloped in a hydrophobic core contribute more than H-bonds exposed to the aqueous environment to the stability of the native state.
The process of folding in vivo often begins co-translationally, so that the N-terminus of the protein begins to fold while the C-terminal portion of the protein is still being synthesized by the ribosome. Specialized proteins called chaperones assist in the folding of other proteins. A well studied example is the bacterial GroEL system, which assists in the folding of globular proteins. In eukaryotic organisms chaperones are known as heat shock proteins. Although most globular proteins are able to assume their native state unassisted, chaperone-assisted folding is often necessary in the crowded intracellular environment to prevent aggregation; chaperones are also used to prevent misfolding and aggregation which may occur as a consequence of exposure to heat or other changes in the cellular environment.
Arteriosclerosis is a cardiovascular disease, Thickening and loss of elasticity of the coronary arteries leads to a progressive insuffiency of the artheries,plaque builds up in the coronary arteries. These arteries supply oxygen-rich blood to your heart. When blood flow to your heart is reduced or blocked, it can lead to chest pain and heart attack. CAD also is called heart disease, and it's the leading cause of death in the United States.
Arteriosclerosis is a disease in which the fatty materials is deposited on the wall of the artery, normally walls on the artery was smooth allowing blood to flow blood un-pleted ,however if damaged occurs to interlining ,Fat ,cholesterol platelets other substances may accumulate in damaged section of the arterial wall, eventually the tissue buildup up and plaque is formed narrowing the lumen of the artery ,when narrowing is severe there is risk vessel becoming blocked completely ,If the thrombus formed is diseased segment
Embryonic stem cells (ES cells) are stem cells derived from the inner cell mass of an early stage embryo known as a blastocyst. Human embryos reach the blastocyst stage 4-5 days post fertilization, at which time they consist of 50-150 cells. Subscribe in a reader
Proton pump inhibitors (or "PPI"s) are a group of drugs whose main action is pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar effects, but different mode-of-action, called H2-receptor antagonists. These drugs are among the most widely-selling drugs in the world as a result of their outstanding efficacy and safety. Structurally, the vast majority of these drugs are benzimidazole derivatives; however, promising new research indicates that imidazopyridine derivatives may be a more effective means of treatment.
Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or more commonly just gastric proton pump) of the gastric parietal cell. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.
Targeting the terminal-step in acid production, as well as the irreversible nature of the inhibition, result in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%.
The lack of the acid in the stomach will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, which can be exacerbated by stomach acid. However, lack of stomach acid may also contribute to hypochlorhydria, a lack of sufficient hydrochloric acid, or HCl. Hydrochloric acid is required for absorption of nutrients, particularly calcium.
The proton pump inhibitors are given in an inactive form. The inactive form is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) that have acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.
Adverse effects
Proton pump inhibitors are generally well tolerated, and the incidence of short-term adverse effects is relatively uncommon. The range and occurrence of adverse effects are similar for all of the proton pump inhibitors, though they have been reported more frequently with omeprazole. This may be due to its longer availability and hence clinical experience.
Infrequent adverse effects include: rash, itch, flatulence, constipation. Decreased cyanocobalamin (vitamin B12) absorption may occur with long-term use. Rarely PPI cause ‘idiosyncratic’ reactions such as erythema multiforme, pancreatitis, Stevens Johnson syndrome and acute interstitial nephritis.
It has been observed that gastric acid suppression, using H2-receptor antagonists and proton pump inhibitors, is associated with an increased risk of community-acquired pneumonia. It is suspected that acid suppression results in insufficient elimination of pathogenic organisms. It has therefore been suggested that patients at higher risk of pneumonia should only be prescribed proton pump inhibitors at lower doses and only when necessary.
PPIs have also been shown to raise risk of C. dif infection.
Long-term use of proton pump inhibitors has been less studied. But in a study of 135,000 people 50 or older, those taking high doses of PPIs for longer than one year have been found to be 2.6 times more likely to break a hip. Those taking smaller doses for 1 to 4 years were 1.2 to 1.6 times more likely to break a hip. The risk of a fracture increased with the length of time taking PPIs. Theories as to the cause of the increase are the possibility that the reduction of stomach acid reduces the amount of calcium dissolved in the stomach or that PPIs may interfere with the breakdown and rebuilding of bone by interfering with the acid production of osteoclasts
