1.
Protein
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Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, a linear chain of amino acid residues is called a polypeptide. A protein contains at least one long polypeptide, short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called peptides, or sometimes oligopeptides. The individual amino acid residues are bonded together by peptide bonds, the sequence of amino acid residues in a protein is defined by the sequence of a gene, which is encoded in the genetic code. In general, the code specifies 20 standard amino acids, however. Sometimes proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors, proteins can also work together to achieve a particular function, and they often associate to form stable protein complexes. Once formed, proteins only exist for a period of time and are then degraded and recycled by the cells machinery through the process of protein turnover. A proteins lifespan is measured in terms of its half-life and covers a wide range and they can exist for minutes or years with an average lifespan of 1–2 days in mammalian cells. Abnormal and or misfolded proteins are degraded more rapidly due to being targeted for destruction or due to being unstable. Like other biological macromolecules such as polysaccharides and nucleic acids, proteins are essential parts of organisms, many proteins are enzymes that catalyse biochemical reactions and are vital to metabolism. Proteins also have structural or mechanical functions, such as actin and myosin in muscle and the proteins in the cytoskeleton, other proteins are important in cell signaling, immune responses, cell adhesion, and the cell cycle. In animals, proteins are needed in the diet to provide the essential amino acids that cannot be synthesized, digestion breaks the proteins down for use in the metabolism. Methods commonly used to study structure and function include immunohistochemistry, site-directed mutagenesis, X-ray crystallography, nuclear magnetic resonance. Most proteins consist of linear polymers built from series of up to 20 different L-α-amino acids, all proteinogenic amino acids possess common structural features, including an α-carbon to which an amino group, a carboxyl group, and a variable side chain are bonded. Only proline differs from this structure as it contains an unusual ring to the N-end amine group. The amino acids in a chain are linked by peptide bonds. Once linked in the chain, an individual amino acid is called a residue, and the linked series of carbon, nitrogen. The peptide bond has two forms that contribute some double-bond character and inhibit rotation around its axis, so that the alpha carbons are roughly coplanar
2.
Monoamine transporter
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Monoamine transporters are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters, MATs are located just outside the synaptic cleft, transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through phosphorylation and posttranslational modification, furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in a large part by their interaction with MATs, by keeping the transporters from mopping up the dopamine. There are several different monoamine transporters located along the plasma membrane, DAT is responsible for the Na +/Cl − -dependent reuptake of extracellular dopamine. DAT can also transport extracellular norepinephrine, DATs can be found in the central nervous system, where they are localized in the substantia nigra and ventral tegmental area. DATs are also found in the nervous system where they are localized in the stomach. Various kinases have been linked to DAT regulation including PKA, PKC, PI-3K, ERK1, ERK2, Akt, CaMKII, CDK5, NET is responsible for the Na +/Cl − -dependent reuptake of extracellular norepinephrine. NET can also reuptake extracellular DA, within the CNS, NET is localized to the dendrites and axons found in both the hippocampus and cortex. Peripherally, NET can be found in sympathetic neurons, the adrenal medulla, the lung, the placenta. Regulation of NET has been linked to MAPKs, insulin, PKC, SERT is responsible for the reuptake of extracellular serotonin in a Na +/Cl − -dependent process. In the CNS, SERT is found localized in the cortex, CA1 and CA3 regions of the hippocampus, as well as the median. In the PNS, SERT is localized to the tract, adrenal glands, placenta, lung. Expression of SERT in platelets is used as a means to reacquire 5-HT from the extracellular environment, regulation of SERT has been linked to acute depletion of intracellular Ca Na 2+, calmodulin inhibition, CaMKII, Src, p38 MAP kinase, PKC, and activation of NOS/cGMP. Monoamine transporters are members of the group of Na +/Cl − -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family, MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops. The NH2 and COOH termini of the MAT proteins are located within the cytoplasm of presynaptic cells, all MATs contain sites for protein kinase phosphorylation by cAMP-dependent protein kinase, protein kinase C and Ca2+/calmodulin-dependent protein kinase. MATs are responsible for the uptake of monoamines by the binding and co-transport of Na +. The ion concentration gradient generated by the plasma membrane Na+/K+ ATPase provides the force for the transporter-mediated monoamine uptake. In the case of NET and SERT one Na+ and one Cl− ion are transported into the cell with one NE or 5-HT respectively, in the case of DAT two Na+ and one Cl− ion are transported along with one DA
3.
Reuptake
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Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse. Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, much research, both biochemical and structural, has been performed to obtain clues about the mechanism of reuptake. The first primary sequence of a protein was published in 1990. After separation, it was realized that there were similarities between the two DNA sequences. The members of new family include transporters for dopamine, norepinephrine, serotonin, glycine, proline. They were called Na+/Cl− dependent neurotransmitter transporters, Sodium and Chloride ion dependence will be discussed later in the mechanism of action. Using the commonalities among sequences and hydropathy plot analyses, it was predicted that there are 12 hydrophobic membrane spanning regions in the ‘Classical’ transporter family, in addition to this, the N- and C-termini exist in the intracellular space. These proteins also all have an extracellular loop between the third and fourth transmembrane sequences. Site-directed chemical labeling experiments verified the predicted topological organization of the serotonin transporter, in addition to neurotransmitter transporters, many other proteins in both animals and prokaryotes were found with similar sequences, indicating a larger family of Neurotransmitter, Sodium Symporters. They found that the transmembrane helices 1 and 6 contained unwound segments in the middle of the membrane, along with these two helices, TM helices 3 and 8 and the areas surrounding the unwound sections of 1 and 6 formed the substrate and sodium ion binding sites. The crystal structure revealed pseudo-symmetry in LeuT, in which the structure of TM helices 1-5 is reflected in the structure of helices 6-10, there is an extracellular cavity in the protein, into which protrudes a helical hairpin formed by extracellular loop EL4. In TM1, an aspartate distinguishes monoamine NSS transporters from amino acid transporters which contain a glycine at the same position, external and internal “gates” were assigned to pairs of negatively and positively charged residues in the extracellular cavity and near the cytoplasmic ends of TM helices 1 and 8. The classic transporter proteins use transmembrane ion gradients and electrical potential to transport neurotransmitter across the membrane of the presynaptic neuron, typical neurotransmitter sodium symport transporters, which are Na+ and Cl− ion dependent, take advantage of both Na+ and Cl− gradients, inwardly directed across the membrane. The ions flow down their concentration gradients, in many cases leading to transmembrane charge movement that is enhanced by the membrane potential and these forces pull the neurotransmitter substrate into the cell, even against its own concentration gradient. At a molecular level, Na+ ions stabilize amino acid binding at the substrate site, the role of the Cl− ion in the symport mechanism has been proposed to be for stabilizing the charge of the symported Na+. After ion and substrate binding have taken place, some conformational change must occur and this increases neurotransmitter binding to pre- and postsynaptic neurotransmitter receptors. Depending on the system in question, a reuptake inhibitor can have drastic effects on cognition. Non-competitive inhibition of the bacterial homologue LeuT by tricyclic antidepressants resulted from binding of inhibitors in the extracellular permeation pathway
4.
Synaptic cleft
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Chemical synapses are biological junctions through which neurons signals can be exchanged to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the nervous system. They are crucial to the computations that underlie perception and thought. They allow the system to connect to and control other systems of the body. At a chemical synapse, one neuron releases neurotransmitter molecules into a space that is adjacent to another neuron. The neurotransmitters are kept within small sacs called vesicles, and are released into the synaptic cleft by exocytosis and these molecules then bind to receptors on the postsynaptic cells side of the synaptic cleft. The adult human brain is estimated to contain from 1014 to 5 ×1014 synapses, every cubic millimeter of cerebral cortex contains roughly a billion of them. The word synapse comes from synaptein, which Sir Charles Scott Sherrington and colleagues coined from the Greek syn-, chemical synapses are not the only type of biological synapse, electrical and immunological synapses also exist. Without a qualifier, however, synapse commonly means chemical synapse, synapses are functional connections between neurons, or between neurons and other types of cells. A typical neuron gives rise to several thousand synapses, although there are types that make far fewer. Most synapses connect axons to dendrites, but there are other types of connections, including axon-to-cell-body, axon-to-axon. Chemical synapses pass information directionally from a cell to a postsynaptic cell and are therefore asymmetric in structure. Synaptic vesicles are docked at the plasma membrane at regions called active zones. Immediately opposite is a region of the cell containing neurotransmitter receptors. Immediately behind the postsynaptic membrane is a complex of interlinked proteins called the postsynaptic density. Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors, the receptors and PSDs are often found in specialized protrusions from the main dendritic shaft called dendritic spines. Synapses may be described as symmetric or asymmetric, when examined under an electron microscope, asymmetric synapses are characterized by rounded vesicles in the presynaptic cell, and a prominent postsynaptic density. Symmetric synapses in contrast have flattened or elongated vesicles, and do not contain a prominent postsynaptic density, the synaptic cleft is a gap between the pre- and postsynaptic cells that is about 20 nm wide
5.
Serotonin
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Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is found in the gastrointestinal tract, blood platelets. It is popularly thought to be a contributor to feelings of well-being, approximately 90% of the human bodys total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions and these include the regulation of mood, appetite, and sleep. Serotonin also has some functions, including memory and learning. Modulation of serotonin at synapses is thought to be an action of several classes of pharmacological antidepressants. Serotonin secreted from the cells eventually finds its way out of tissues into the blood. There, it is taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, Serotonin is also a growth factor for some types of cells, which may give it a role in wound healing. Serotonin is metabolized mainly to 5-HIAA, chiefly by the liver, metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the acetic acid derivative. The latter is then excreted by the kidneys, in addition to animals, serotonin is found in fungi and plants. Serotonins presence in insect venoms and plant spines serves to cause pain, Serotonin is produced by pathogenic amoebae, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds, Serotonin is a neurotransmitter and is found in all bilateral animals, where it mediates gut movements and the animals perceptions of resource availability. In less complex animals, such as invertebrates, resources simply mean food availability. In more complex animals, such as arthropods and vertebrates, resources also can mean social dominance, in response to the perceived abundance or scarcity of resources, an animals growth, reproduction or mood may be elevated or lowered. This may somewhat depend on how much serotonin the organism has at its disposal, except for the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors that activate an intracellular second messenger cascade. Serotonergic action is terminated primarily via uptake of 5-HT from the synapse and this is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron
6.
Tricyclic antidepressant
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Tricyclic antidepressants are chemical compounds used primarily as antidepressants. TCAs were first discovered in the early 1950s and marketed later in the decade and they are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants, which contain four rings of atoms, are a related group of antidepressant compounds. Adverse effects have been found to be of a level between TCAs and SSRIs. The TCAs were developed amid the explosive birth of psychopharmacology in the early 1950s, the story begins with the synthesis of chlorpromazine in December 1950 by Rhône-Poulencs chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s. Its psychiatric effects were first noticed at a hospital in Paris in 1952, the first widely used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic. Research chemists quickly began to other derivatives of chlorpromazine. The first TCA reported for the treatment of depression was imipramine and it was not originally targeted for the treatment of depression. The drugs tendency to induce manic effects was later described as in some patients, the paradoxical observation of a sedative inducing mania led to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Roland Kuhn in 1957, some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz. Geigy later became Ciba-Geigy and eventually Novartis, dibenzazepine derivatives are described in U. S. patent 3,074,931 issued 1963-01-22 by assignment to Smith Kline & French Laboratories. The compounds described share a tricyclic backbone different from the backbone of the TCA amitriptyline, merck introduced the second member of the TCA family, amitriptyline, in 1961. This compound has a different three-ring structure than imipramine, the TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder, dysthymia, and treatment-resistant variants. For many years the TCAs were the first choice for treatment of clinical depression. However, tricyclic antidepressants are possibly more effective in treating melancholic depression than other antidepressant drug classes, nonetheless, the TCAs are still occasionally used for treatment-resistant depression that has failed to respond to therapy with newer antidepressants. They are not considered addictive and are preferable to the monoamine oxidase inhibitors. ADHD is thought to be caused by an insufficiency of dopamine and norepinephrine activity in the cortex of the brain. Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, the TCAs show efficacy in the clinical treatment of a number of different types of chronic pain, notably neuralgia or neuropathic pain and fibromyalgia
7.
Cytoplasm
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In cell biology, the cytoplasm is the material within a living cell, excluding the cell nucleus. It comprises cytosol and the organelles – the cells internal sub-structures, all of the contents of the cells of prokaryotic organisms are contained within the cytoplasm. Within the cells of organisms the contents of the cell nucleus are separated from the cytoplasm. The cytoplasm is about 80% water and usually colorless, the submicroscopic ground cell substance or cytoplasmatic matrix which remains after exclusion the cell organelles and particles is groundplasm. It is within the cytoplasm that most cellular activities occur, such as many metabolic pathways including glycolysis, the concentrated inner area is called the endoplasm and the outer layer is called the cell cortex or the ectoplasm. Movement of calcium ions in and out of the cytoplasm is an activity for metabolic processes. In plants, movement of the cytoplasm around vacuoles is known as cytoplasmic streaming, the term was introduced by Rudolf von Kölliker in 1863, originally as a synonym for protoplasm, but later it has come to mean the cell substance and organelles outside the nucleus. There has been disagreement on the definition of cytoplasm, as some authors prefer to exclude from it some organelles. The physical properties of the cytoplasm have been contested in recent years and it remains uncertain how the varied components of the cytoplasm interact to allow movement of particles and organelles while maintaining the cell’s structure. The flow of cytoplasmic components plays an important role in cellular functions which are dependent on the permeability of the cytoplasm. An example of function is cell signalling, a process which is dependent on the manner in which signaling molecules are allowed to diffuse across the cell. While small signaling molecules like calcium ions are able to diffuse with ease, larger molecules, the irregular dynamics of such particles have given rise to various theories on the nature of the cytoplasm. There has long been evidence that the cytoplasm behaves like a sol-gel and it is thought that the component molecules and structures of the cytoplasm behave at times like a disordered colloidal solution and at other times like an integrated network, forming a solid mass. Recently it has proposed that the cytoplasm behaves like a glass-forming liquid approaching the glass transition. A cells ability to vitrify in the absence of activity, as in dormant periods. There has been examining the motion of cytoplasmic particles independent of the nature of the cytoplasm. In such an approach, the aggregate random forces within the cell caused by motor proteins explain the non-Brownian motion of cytoplasmic constituents. The three major elements of the cytoplasm are the cytosol, organelles and inclusions, the cytosol is the portion of the cytoplasm not contained within membrane-bound organelles
8.
Membrane potential
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Membrane potential is the difference in electric potential between the interior and the exterior of a biological cell. With respect to the exterior of the cell, typical values of membrane potential range from –40 mV to –80 mV, all animal cells are surrounded by a membrane composed of a lipid bilayer with proteins embedded in it. The membrane serves as both an insulator and a barrier to the movement of ions. Ion pumps and ion channels are electrically equivalent to a set of batteries and resistors inserted in the membrane, and therefore create a voltage between the two sides of the membrane. Virtually all eukaryotic cells maintain a non-zero transmembrane potential, usually with a voltage in the cell interior as compared to the cell exterior ranging from –40 mV to –80 mV. The membrane potential has two basic functions, first, it allows a cell to function as a battery, providing power to operate a variety of molecular devices embedded in the membrane. Second, in electrically excitable cells such as neurons and muscle cells, signals are generated by opening or closing of ion channels at one point in the membrane, producing a local change in the membrane potential. This change in the field can be quickly affected by either adjacent or more distant ion channels in the membrane. Those ion channels can open or close as a result of the potential change. In non-excitable cells, and in cells in their baseline states. For neurons, typical values of the potential range from –70 to –80 millivolts, that is. The opening and closing of ion channels can induce a departure from the resting potential and this is called a depolarization if the interior voltage becomes less negative, or a hyperpolarization if the interior voltage becomes more negative. Action potentials are generated by the activation of certain voltage-gated ion channels, in neurons, the factors that influence the membrane potential are diverse. They include numerous types of ion channels, some of which are chemically gated, the membrane potential in a cell derives ultimately from two factors, electrical force and diffusion. Electrical force arises from the attraction between particles with opposite electrical charges and the mutual repulsion between particles with the same type of charge. Diffusion arises from the tendency of particles to redistribute from regions where they are highly concentrated to regions where the concentration is low. Voltage, which is synonymous with difference in potential, is the ability to drive an electric current across a resistance. Indeed, the simplest definition of a voltage is given by Ohms law, V=IR, where V is voltage, I is current and R is resistance
9.
Sodium
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Sodium is a chemical element with symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal, Sodium is an alkali metal, being in group 1 of the periodic table, because it has a single electron in its outer shell that it readily donates, creating a positively charged atom—the Na+ cation. Its only stable isotope is 23Na, the free metal does not occur in nature, but must be prepared from compounds. Sodium is the sixth most abundant element in the Earths crust, Sodium was first isolated by Humphry Davy in 1807 by the electrolysis of sodium hydroxide. Among many other useful compounds, sodium hydroxide is used in soap manufacture, and sodium chloride is a de-icing agent. Sodium is an element for all animals and some plants. Sodium ions are the major cation in the fluid and as such are the major contributor to the ECF osmotic pressure. Loss of water from the ECF compartment increases the sodium concentration, isotonic loss of water and sodium from the ECF compartment decreases the size of that compartment in a condition called ECF hypovolemia. In nerve cells, the charge across the cell membrane enables transmission of the nerve impulse—an action potential—when the charge is dissipated. The melting and boiling points of sodium are lower than those of lithium but higher than those of the alkali metals potassium, rubidium. All of these high-pressure allotropes are insulators and electrides.3 nm, spin-orbit interactions involving the electron in the 3p orbital split the D line into two, at 589.0 and 589.6 nm, hyperfine structures involving both orbitals cause many more lines. Twenty isotopes of sodium are known, but only 23Na is stable, 23Na is created in the carbon-burning process in stars by fusing two carbon atoms together, this requires temperatures above 600 megakelvins and a star of at least three solar masses. Two nuclear isomers have been discovered, the one being 24mNa with a half-life of around 20.2 milliseconds. Sodium atoms have 11 electrons, one more than the stable configuration of the noble gas neon. This process requires so little energy that sodium is oxidized by giving up its 11th electron. In contrast, the ionization energy is very high, because the 10th electron is closer to the nucleus than the 11th electron. As a result, sodium usually forms ionic compounds involving the Na+ cation, the most common oxidation state for sodium is +1. It is generally less reactive than potassium and more reactive than lithium, Sodium metal is highly reducing, with the reduction of sodium ions requiring −2.71 volts, though potassium and lithium have even more negative potentials
10.
Potassium
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Potassium is a chemical element with symbol K and atomic number 19. It was first isolated from potash, the ashes of plants, in the periodic table, potassium is one of the alkali metals. Potassium in nature only in ionic salts. It is found dissolved in sea water, and is part of many minerals, naturally occurring potassium is composed of three isotopes, of which 40K is radioactive. Traces of 40K are found in all potassium, and it is the most common radioisotope in the human body, Potassium is chemically very similar to sodium, the previous element in Group 1 of the periodic table. They have a similar energy, which allows for each atom to give up its sole outer electron. That they are different elements combine with the same anions to make similar salts was suspected in 1702. Most industrial applications of potassium exploit the high solubility in water of potassium compounds, heavy crop production rapidly depletes the soil of potassium, and this can be remedied with agricultural fertilizers containing potassium, accounting for 95% of global potassium chemical production. Potassium ions are necessary for the function of all living cells, fresh fruits and vegetables are good dietary sources of potassium. Potassium is the second least dense metal after lithium and it is a soft solid with a low melting point, and can be easily cut with a knife. Freshly cut potassium is silvery in appearance, but it begins to tarnish toward gray immediately on exposure to air, in a flame test, potassium and its compounds emit a lilac color with a peak emission wavelength of 766.5 nanometers. Neutral potassium atoms have 19 electrons, one more than the stable configuration of the noble gas argon. This process requires so little energy that potassium is readily oxidized by atmospheric oxygen, in contrast, the second ionization energy is very high, because removal of two electrons breaks the stable noble gas electronic configuration. Potassium therefore does not readily form compounds with the state of +2 or higher. Potassium is an active metal that reacts violently with oxygen in water. With oxygen it forms potassium peroxide, and with water potassium forms potassium hydroxide, the reaction of potassium with water is dangerous because of its violent exothermic character and the production of hydrogen gas. Hydrogen reacts again with atmospheric oxygen, producing water, which reacts with the remaining potassium and this reaction requires only traces of water, because of this, potassium and the liquid sodium-potassium — NaK — are potent desiccants that can be used to dry solvents prior to distillation. Because of the sensitivity of potassium to water and air, reactions with other elements are only in an inert atmosphere such as argon gas using air-free techniques
11.
Adenosine
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Adenosine is a purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule moiety via a β-N9-glycosidic bond. It is also a neuromodulator, believed to play a role in promoting sleep, Adenosine also plays a role in regulation of blood flow to various organs through vasodilation. Common side effects include chest pain, feeling faint, shortness of breath along with tingling of the senses, serious side effects include a worsening dysrhythmia and low blood pressure. It appears to be safe in pregnancy, when it is administered intravenously, adenosine causes transient heart block in the atrioventricular node. It also causes endothelial-dependent relaxation of smooth muscle as is found inside the artery walls and this causes dilation of the normal segments of arteries, i. e. where the endothelium is not separated from the tunica media by atherosclerotic plaque. This feature allows physicians to use adenosine to test for blockages in the coronary arteries, the administration of adenosine also reduces blood flow to coronary arteries past the occlusion. Other coronary arteries dilate when adenosine is administered while the segment past the occlusion is already maximally dilated and this leads to less blood reaching the ischemic tissue, which in turn produces the characteristic chest pain. In individuals suspected of suffering from a supraventricular tachycardia, adenosine is used to identify the rhythm. Certain SVTs can be terminated with adenosine. This includes any re-entrant arrhythmias that require the AV node for the re-entry, e. g. AV reentrant tachycardia, in addition, atrial tachycardia can sometimes be terminated with adenosine. Fast rhythms of the heart that are confined to the atria or ventricles, however, the ventricular response rate is temporarily slowed with adenosine in such cases. Because of the effects of adenosine on AV node-dependent SVTs, adenosine is considered a class V antiarrhythmic agent, when adenosine is used to cardiovert an abnormal rhythm, it is normal for the heart to enter ventricular asystole for a few seconds. This can be disconcerting to a conscious patient, and is associated with angina-like sensations in the chest. Adenosine is used an adjunct to thallous chloride TI201 or Tc99m myocardial perfusion scintigraphy in patients unable to undergo adequate stress testing with exercise, due to adenosines extremely short half-life, the IV line is started as proximal to the heart as possible, such as the antecubital fossa. The IV push is often followed with a flush of 10-20 ccs of saline. If this has no effect, a dose of 12 mg can be given 1–2 minutes after the first dose, some clinicians may prefer to administer a higher dose, rather than repeat a dose that apparently had no effect. When given to dilate the arteries, such as in a stress test, the recommended dose may be increased in patients on theophylline, since methylxanthines prevent binding of adenosine at receptor sites. The dose is often decreased in patients on dipyridamole and diazepam because adenosine potentiates the effects of these drugs
12.
Chemical synapse
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Chemical synapses are biological junctions through which neurons signals can be exchanged to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the nervous system. They are crucial to the computations that underlie perception and thought. They allow the system to connect to and control other systems of the body. At a chemical synapse, one neuron releases neurotransmitter molecules into a space that is adjacent to another neuron. The neurotransmitters are kept within small sacs called vesicles, and are released into the synaptic cleft by exocytosis and these molecules then bind to receptors on the postsynaptic cells side of the synaptic cleft. The adult human brain is estimated to contain from 1014 to 5 ×1014 synapses, every cubic millimeter of cerebral cortex contains roughly a billion of them. The word synapse comes from synaptein, which Sir Charles Scott Sherrington and colleagues coined from the Greek syn-, chemical synapses are not the only type of biological synapse, electrical and immunological synapses also exist. Without a qualifier, however, synapse commonly means chemical synapse, synapses are functional connections between neurons, or between neurons and other types of cells. A typical neuron gives rise to several thousand synapses, although there are types that make far fewer. Most synapses connect axons to dendrites, but there are other types of connections, including axon-to-cell-body, axon-to-axon. Chemical synapses pass information directionally from a cell to a postsynaptic cell and are therefore asymmetric in structure. Synaptic vesicles are docked at the plasma membrane at regions called active zones. Immediately opposite is a region of the cell containing neurotransmitter receptors. Immediately behind the postsynaptic membrane is a complex of interlinked proteins called the postsynaptic density. Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors, the receptors and PSDs are often found in specialized protrusions from the main dendritic shaft called dendritic spines. Synapses may be described as symmetric or asymmetric, when examined under an electron microscope, asymmetric synapses are characterized by rounded vesicles in the presynaptic cell, and a prominent postsynaptic density. Symmetric synapses in contrast have flattened or elongated vesicles, and do not contain a prominent postsynaptic density, the synaptic cleft is a gap between the pre- and postsynaptic cells that is about 20 nm wide
13.
Presynaptic neuron
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Chemical synapses are biological junctions through which neurons signals can be exchanged to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the nervous system. They are crucial to the computations that underlie perception and thought. They allow the system to connect to and control other systems of the body. At a chemical synapse, one neuron releases neurotransmitter molecules into a space that is adjacent to another neuron. The neurotransmitters are kept within small sacs called vesicles, and are released into the synaptic cleft by exocytosis and these molecules then bind to receptors on the postsynaptic cells side of the synaptic cleft. The adult human brain is estimated to contain from 1014 to 5 ×1014 synapses, every cubic millimeter of cerebral cortex contains roughly a billion of them. The word synapse comes from synaptein, which Sir Charles Scott Sherrington and colleagues coined from the Greek syn-, chemical synapses are not the only type of biological synapse, electrical and immunological synapses also exist. Without a qualifier, however, synapse commonly means chemical synapse, synapses are functional connections between neurons, or between neurons and other types of cells. A typical neuron gives rise to several thousand synapses, although there are types that make far fewer. Most synapses connect axons to dendrites, but there are other types of connections, including axon-to-cell-body, axon-to-axon. Chemical synapses pass information directionally from a cell to a postsynaptic cell and are therefore asymmetric in structure. Synaptic vesicles are docked at the plasma membrane at regions called active zones. Immediately opposite is a region of the cell containing neurotransmitter receptors. Immediately behind the postsynaptic membrane is a complex of interlinked proteins called the postsynaptic density. Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors, the receptors and PSDs are often found in specialized protrusions from the main dendritic shaft called dendritic spines. Synapses may be described as symmetric or asymmetric, when examined under an electron microscope, asymmetric synapses are characterized by rounded vesicles in the presynaptic cell, and a prominent postsynaptic density. Symmetric synapses in contrast have flattened or elongated vesicles, and do not contain a prominent postsynaptic density, the synaptic cleft is a gap between the pre- and postsynaptic cells that is about 20 nm wide
14.
Membrane transport protein
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A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, or macromolecules, such as another protein, across a biological membrane. Transport proteins are transmembrane proteins, that is they exist permanently within. The proteins may assist in the movement of substances by facilitated diffusion or active transport, the two main types of proteins involved in such transport are broadly categorized as either channels or carriers. A carrier is not open simultaneously to both the extracellular and intracellular environments, either its inner gate is open, or outer gate is open. In contrast, a channel can be open to both environments at the time, allowing the solutes it transports to diffuse without interruption. Carriers have binding sites, but pores and channels do not, when a channel is opened, millions of ions can pass through the membrane per second, but only 100 to 1000 molecules typically pass through a carrier molecule in the same time. Each carrier protein is designed to only one substance or one group of very similar substances. Research has correlated defects in carrier proteins with specific diseases. Active transport is the movement of a substance across a membrane against its concentration gradient and this is usually to accumulate high concentrations of molecules that a cell needs, such as glucose or amino acids. When the lipid bilayer is impermeable to the molecule needing transport, if the process uses chemical energy, such as adenosine triphosphate, it is called primary active transport. Secondary active transport involves the use of a gradient. A carrier protein is required to move particles from areas of low concentration to areas of high concentration and these carrier proteins have receptors that bind to a specific molecule needing transport. The molecule or ion to be transported must first bind at a site at the carrier molecule. The carrier protein substrate is released at that site, according to its binding affinity there, facilitated diffusion is the passage of molecules or ions across a biological membrane through specific transport proteins and requires no energy input. The type of proteins used in facilitated diffusion is slightly different from those used in active transport. They are still transmembrane carrier proteins, but these are gated transmembrane channels, meaning they do not internally translocate, the substrate is taken in one side of the gated carrier, and without using ATP the substrate is released into the cell. Facilitated diffusion occurs in and out of the membrane via channels/pores. Note, Channels, Channels are either in state or closed state
15.
Synapse
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In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron. Some authors generalize this concept to include the communication from a neuron to any cell type, such as to a motor cell. Santiago Ramón y Cajal proposed that neurons are not continuous throughout the body, yet still communicate with each other, an idea known as the neuron doctrine. Synapses are essential to function, neurons are cells that are specialized to pass signals to individual target cells. At a synapse, the membrane of the signal-passing neuron comes into close apposition with the membrane of the target cell. Both the presynaptic and postsynaptic sites contain extensive arrays of a molecular machinery that link the two together and carry out the signaling process. In many synapses, the part is located on an axon. Astrocytes also exchange information with the neurons, responding to synaptic activity and, in turn. The neurotransmitter may initiate a response or a secondary messenger pathway that may either excite or inhibit the postsynaptic neuron. Chemical synapses can be classified according to the released, glutamatergic, GABAergic, cholinergic. Because of the complexity of receptor signal transduction, chemical synapses can have effects on the postsynaptic cell. The main advantage of a synapse is the rapid transfer of signals from one cell to the next. Synaptic communication is distinct from a coupling, in which communication between neurons occurs via indirect electric fields. Synapses can be classified by the type of cellular structures serving as the pre-, the vast majority of synapses in the mammalian nervous system are classical axo-dendritic synapses, however, a variety of other arrangements exist. These include but are not limited to axo-axonic, dendro-dendritic, axo-secretory, somato-dendritic, dendro-somatic, the axon can synapse onto a dendrite, onto a cell body, or onto another axon or axon terminal, as well as into the bloodstream or diffusely into the adjacent nervous tissue. It is widely accepted that the plays a role in the formation of memory. The strength of two connected neural pathways is thought to result in the storage of information, resulting in memory and this process of synaptic strengthening is known as long-term potentiation. By altering the release of neurotransmitters, the plasticity of synapses can be controlled in the presynaptic cell, the postsynaptic cell can be regulated by altering the function and number of its receptors
16.
Receptor (biochemistry)
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In biochemistry and pharmacology, a receptor is a protein molecule that receives chemical signals from outside a cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, however, sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporters and ion channels. Receptor proteins can be classified by their location, transmembrane receptors include ion channel-linked receptors, G protein-linked hormone receptors, and enzyme-linked hormone receptors. Intracellular receptors are found inside the cell, and include cytoplasmic receptors. The endogenously designated -molecule for a receptor is referred to as its endogenous ligand. E. g. the endogenous ligand for the acetylcholine receptor is acetylcholine but the receptor can also be activated by nicotine. Each receptor is linked to a specific cellular biochemical pathway, while numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure, much like how locks will only accept specifically shaped keys. When a ligand binds to its receptor, it activates or inhibits the receptors associated biochemical pathway. The ligand-binding cavities are located at the interface between the subunits, type 2, G protein-coupled receptors – This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e. g. dopamine, metabotropic glutamate. They are composed of seven transmembrane alpha helices, the loops connecting the alpha helices form extracellular and intracellular domains. The aforementioned receptors are coupled to different intracellular effector systems via G proteins, the insulin receptor is an example. Type 4, Nuclear receptors – While they are called nuclear receptors, they are located in the cytoplasm. They are composed of a C-terminal ligand-binding region, a core DNA-binding domain, the core region has two zinc fingers that are responsible for recognizing the DNA sequences specific to this receptor. The N terminus interacts with other transcription factors in a ligand-independent manner. Steroid and thyroid-hormone receptors are examples of such receptors, membrane receptors may be isolated from cell membranes by complex extraction procedures using solvents, detergents, and/or affinity purification. The structures and actions of receptors may be studied by using methods such as X-ray crystallography, NMR, circular dichroism. Computer simulations of the behavior of receptors have been used to gain understanding of their mechanisms of action. Ligand binding is an equilibrium process, ligands bind to receptors and dissociate from them according to the law of mass action
17.
Romantic love
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Romance is the expressive and pleasurable feeling from an emotional attraction towards another person often associated with sexual attraction. It is eros rather than agape, philia, or storge, historically, the term romance originates with the medieval ideal of chivalry as set out in its chivalric romance literature. Humans have an inclination to form bonds with one another through social interactions. The debate over an exact definition of love may be found in literature as well as in the works of psychologists, philosophers, biochemists and other professionals. The addition of drama to relationships of close, deep and strong love, psychologist Charles Lindholm defined love to be. an intense attraction that involves the idealization of the other, within an erotic context, with expectation of enduring sometime into the future. The word was originally an adverb of the Latin origin Romanicus, the connecting notion is that European medieval vernacular tales were usually about chivalric adventure, not combining the idea of love until late into the seventeenth century. In primitive societies, tension existed between marriage and the erotic, but this was expressed in taboo regarding the menstrual cycle. Anthropologists such as Claude Lévi-Strauss show that there were forms of courtship in ancient as well as contemporary primitive societies. There may not be evidence, however, that members of such societies formed loving relationships distinct from their established customs in a way that would parallel modern romance, before the 18th century, many marriages were not arranged, but rather developed out of more or less spontaneous relationships. After the 18th century, illicit relationships took on an independent role. In bourgeois marriage, illicitness may have become more formidable and likely to cause tension, in Ladies of the Leisure Class, Rutgers University professor Bonnie G. Smith depicts courtship and marriage rituals that may be viewed as oppressive to modern people. She writes When the young women of the Nord married, they did so without illusions of love and they acted within a framework of concern for the reproduction of bloodlines according to financial, professional, and sometimes political interests. Subsequent sexual revolution has lessened the conflicts arising out of liberalism, anthony Giddens, in his book The Transformation of Intimacy, Sexuality, Love and Eroticism in Modern Society, states that romantic love introduced the idea of a narrative into an individuals life. He adds that telling a story was one of the meanings of romance, according to Giddens, the rise of romantic love more or less coincided with the emergence of the novel. It was then that romantic love, associated with freedom and therefore the ideals of romantic love, for the discourse of intimacy emotional closeness was much more important than passion. This does not mean by any means that intimacy is to replace romance, on the contrary, intimacy and romance coexist. The 21st century has seen the growth of globalization and people now live in a world of transformations that affect almost every aspect of our lives, one example of the changes experienced in relationships was explored by Giddens regarding homosexual relationships. According to Giddens since homosexuals were not able to marry they were forced to more open
18.
Platelet
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Platelets, also called thrombocytes, are a component of blood whose function is to stop bleeding by clumping and clotting blood vessel injuries. Platelets have no nucleus, they are fragments of cytoplasm that are derived from the megakaryocytes of the bone marrow. These unactivated platelets are biconvex discoid structures, 2–3 µm in greatest diameter, platelets are found only in mammals, whereas in other animals thrombocytes circulate as intact mononuclear cells. On a stained blood smear, platelets appear as purple spots. The smear is used to examine platelets for size, shape, qualitative number, the ratio of platelets to red blood cells in a healthy adult is 1,10 to 1,20. The main function of platelets is to contribute to hemostasis, the process of stopping bleeding at the site of interrupted endothelium and they gather at the site and unless the interruption is physically too large, they plug the hole. First, platelets attach to substances outside the interrupted endothelium, adhesion, second, they change shape, turn on receptors and secrete chemical messengers, activation. Third, they connect to each other through receptor bridges, aggregation, formation of this platelet plug is associated with activation of the coagulation cascade with resultant fibrin deposition and linking. These processes may overlap, the spectrum is from a predominantly platelet plug, or white clot to a predominantly fibrin clot, the final result is the clot. Some would add the subsequent clot retraction and platelet inhibition as fourth and fifth steps to the completion of the process, low platelet concentration is thrombocytopenia and is due to either decreased production or increased destruction. Elevated platelet concentration is thrombocytosis and is either congenital, reactive, or due to unregulated production, a disorder of platelet function is a thrombocytopathy. An arterial thrombus may partially obstruct blood flow, causing downstream ischemia, or may completely obstruct it, george Gulliver in 1841 drew pictures of platelets using the twin lens microscope invented in 1830 by Joseph Jackson Lister. This microscope improved resolution sufficiently to make it possible to see platelets for the first time, william Addison in 1842 drew pictures of a platelet-fibrin clot. Lionel Beale in 1864 was the first to publish a drawing showing platelets, max Schultze in 1865 described what he called spherules, which he noted were much smaller than red blood cells, occasionally clumped, and were sometimes found in collections of fibrin material. Queens College, Birmingham physician Dr Richard Hill Norris was the first to describe the action of platelets in 1880, giulio Bizzozero in 1882 studied the blood of amphibians microscopically in vivo. He named Schultzs spherules piastrine, little plates, william Osler observed them and, in published lectures in 1886, called them a third corpuscle and a blood plaque and described them as a colorless protoplasmic disc. Thrombocytes are cells found in the blood of non-mammalian vertebrates and they are the functional equivalents of platelets, but circulate as intact mononuclear cells, and are not simply cytoplasmic fragments of bone marrow megakaryocytes. In some contexts, the thrombus is used interchangeably with the word clot
19.
Vasoconstrictive
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Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vessels, the process is particularly important in staunching hemorrhage and acute blood loss. When blood vessels constrict, the flow of blood is restricted or decreased and this makes the skin turn paler because less blood reaches the surface, reducing the radiation of heat. On a larger level, vasoconstriction is one mechanism by which the body regulates, medications causing vasoconstriction, also known as vasoconstrictors, are one type of medicine used to raise blood pressure. Generalized vasoconstriction usually results in an increase in blood pressure. The extent of vasoconstriction may be slight or severe depending on the substance or circumstance, many vasoconstrictors also cause pupil dilation. Medications that cause vasoconstriction include, antihistamines, decongestants, and stimulants, severe vasoconstriction may result in symptoms of intermittent claudication. The mechanism that leads to results from the increased concentration of calcium within vascular smooth muscle cells. However, the mechanisms for generating an increased intracellular concentration of calcium depends on the vasoconstrictor. Smooth muscle cells are capable of generating action potentials, but this mechanism is utilized for contraction in the vasculature. Hormonal or pharmokinetic components are more physiologically relevant, two common stimuli for eliciting smooth muscle contraction are circulating epinephrine and activation of the sympathetic nervous system that directly innervates the muscle. These compounds interact with cell surface adrenergic receptors, the rise in intracellular calcium complexes with calmodulin, which in turn activates myosin light-chain kinase. This enzyme is responsible for phosphorylating the light chain of myosin to stimulate cross-bridge cycling and this reduction in calcium removes the stimulus necessary for contraction, allowing for a return to baseline. Factors that trigger vasoconstriction can be of exogenous or endogenous origin, ambient temperature is an example of the former. Cutaneous vasoconstriction will occur because of the exposure to the severe cold. Examples of endogenous factors include the nervous system, circulating hormones. Examples include amphetamines, antihistamines and cocaine, many are used in medicine to treat hypotension and as topical decongestants. Vasoconstrictors are also used clinically to increase blood pressure or to reduce blood flow
20.
Serotonin reuptake inhibitor
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A serotonin reuptake inhibitor is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin by blocking the action of the serotonin transporter. This in turn leads to increased concentrations of serotonin and, therefore. For example, cocaine, which inhibits the reuptake of serotonin, norepinephrine. SRIs are used predominantly as antidepressants, though they are commonly used in the treatment of other psychological conditions such as anxiety disorders. Less often, SRIs are also used to treat a variety of medical conditions including neuropathic pain and fibromyalgia. A closely related type of drug is a releasing agent. Many SRIs exist, an assortment of which are listed below, note that only SRIs selective for the SERT over the other monoamine transporters are listed below. For a list of SRIs that act at multiple MATs, see other monoamine reuptake inhibitor such as SNRI and SNDRI
21.
Tricyclic antidepressants
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Tricyclic antidepressants are chemical compounds used primarily as antidepressants. TCAs were first discovered in the early 1950s and marketed later in the decade and they are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants, which contain four rings of atoms, are a related group of antidepressant compounds. Adverse effects have been found to be of a level between TCAs and SSRIs. The TCAs were developed amid the explosive birth of psychopharmacology in the early 1950s, the story begins with the synthesis of chlorpromazine in December 1950 by Rhône-Poulencs chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s. Its psychiatric effects were first noticed at a hospital in Paris in 1952, the first widely used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic. Research chemists quickly began to other derivatives of chlorpromazine. The first TCA reported for the treatment of depression was imipramine and it was not originally targeted for the treatment of depression. The drugs tendency to induce manic effects was later described as in some patients, the paradoxical observation of a sedative inducing mania led to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Roland Kuhn in 1957, some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz. Geigy later became Ciba-Geigy and eventually Novartis, dibenzazepine derivatives are described in U. S. patent 3,074,931 issued 1963-01-22 by assignment to Smith Kline & French Laboratories. The compounds described share a tricyclic backbone different from the backbone of the TCA amitriptyline, merck introduced the second member of the TCA family, amitriptyline, in 1961. This compound has a different three-ring structure than imipramine, the TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder, dysthymia, and treatment-resistant variants. For many years the TCAs were the first choice for treatment of clinical depression. However, tricyclic antidepressants are possibly more effective in treating melancholic depression than other antidepressant drug classes, nonetheless, the TCAs are still occasionally used for treatment-resistant depression that has failed to respond to therapy with newer antidepressants. They are not considered addictive and are preferable to the monoamine oxidase inhibitors. ADHD is thought to be caused by an insufficiency of dopamine and norepinephrine activity in the cortex of the brain. Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, the TCAs show efficacy in the clinical treatment of a number of different types of chronic pain, notably neuralgia or neuropathic pain and fibromyalgia
22.
DASB
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DASB, 3-amino-4--benzonitrile, is a compound that binds to the serotonin transporter. Labeled with carbon-11 — a radioactive isotope — it has used as a radioligand in neuroimaging with positron emission tomography since around year 2000. In this context it is regarded as one of the superior radioligands for PET study of the transporter in the brain. The DASB image from a human PET scan shows high binding in the midbrain, thalamus and striatum, moderate binding in the temporal lobe and anterior cingulate. The cerebellum is often regarded as a region with no specific serotonin transporter binding, since the serotonin transporter is the target of SSRIs used in the treatment of major depression it has been natural to examine DASB binding in depressed patients. Several such research studies have been performed, there are a number of alternative PET radioligands for imaging the serotonin transporter, ADAM, AFM, DAPA, McN5652, and -NS4194. A related molecule to DASB, that can be labeled with fluorine-18, has also suggested as a PET radioligand. With single-photon emission computed tomography using the radioisotope iodine-123 there are further radioligands available, ODAM, IDAM, ADAM, a few studies have examined the difference in binding between the radioligands in nonhuman primates, as well as in pigs. Other compounds that can be labeled to work as PET radioligands for the study of the system are, e. g. altanserin. The binding potential of DASB can be estimated with kinetic modeling on a series of brain scans, a test-retest reproducibility PET study indicates that DASB can be used to measure the serotonin transporter parameters with high reliability in receptor-rich brain regions. When the DASB neuroimages are analyzed the kinetic models suggested by Ichise, a test-retest reproducibility experiment has been performed to evaluate this approach. Besides the studies listed below a few studies have been reported
23.
Bioisostere
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In medicinal chemistry, bioisosteres are chemical substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to another chemical compound. The main use of term and its techniques are related to pharmaceutical sciences. Bioisosterism is used to reduce toxicity, change bioavailability, or modify the activity of the lead compound, for example, the replacement of a hydrogen atom with a fluorine atom at a site of metabolic oxidation in a drug candidate may prevent such metabolism from taking place. Because the fluorine atom is similar in size to the atom the overall topology of the molecule is not significantly affected. However, with a pathway for metabolism, the drug candidate may have a longer half-life. Procainamide, an amide, has a duration of action than Procaine. Procainamide is a classical bioisostere because the electron structure of a disubstituted oxygen atom is the same as a trisubstituted nitrogen atom. Non-classical bioisosteres may differ in a multitude of ways from classical bioisosteres, alloxanthine is an inhibitor of xanthine oxidase. It is also an isostere of xanthine, the substrate for the enzyme. Alloxanthine is considered a non-classical bioisostere because of the scaffold change, silafluofen is an organosilicon analogue of pyrethroid insecticide, wherein a carbon center has been replaced by isosteric silicon
24.
Allen Brain Atlas
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They were initiated in September 2003 with a $100 million donation from Paul G. Allen and the first atlas went public in September 2006. There are also three related projects with data banks, Glioblastoma, Mouse Diversity, and Sleep and it is the hope of the Allen Institute that their findings will help advance various fields of science, especially those surrounding the understanding of neurobiological diseases. The atlases are free and available for use online. In 2001, Paul Allen gathered a group of scientists, including James Watson and Steven Pinker, to discuss the future of neuroscience, the project was set in motion in 2003 with a 100 million dollar donation by Allen through the Allen Institute for Brain Science. The project used a technique for mapping gene expression developed by Gregor Eichele and colleagues at the Max Planck Institute for Biophysical Chemistry in Goettingen, the technique uses colorimetric in situ hybridization to map gene expression. The project set a 3-year goal of finishing the project and making it available to the public, an initial release of the first atlas, the mouse brain atlas, occurred in December 2004. Subsequently, more data for this atlas was released in stages, the final genome-wide data set was released in September 2006. However, the release of the atlas was not the end of the project. The overarching goal and motto for all Allen Institute projects is fueling discovery, the project strives to fulfill this goal and advance science in a few ways. First, they create brain atlases to better understand the connections between genes and brain functioning and they aim to advance the research and knowledge about neurobiological conditions such as Parkinsons, Alzheimers, and Autism with their mapping of gene expression throughout the brain. The Brain Atlas projects also follow the Allen Institute motto with their release of data. This policy is also related to goal of the Institute, collaborative. Thus, any scientist from any discipline is able to look at the findings, also available to the public is the Brain Explorer application. The Allen Institute for Brain Science uses a project-based philosophy for their research, each brain atlas focuses on its own project, made up of its own team of researchers. To complete an atlas, each research team collects and synthesizes brain scans, medical data, genetic information, with this information, they are able to construct the 3-D biochemical architecture of the brain and figure out which proteins are expressed in certain parts of the brain. To gather the data, scientists at the Allen Institute use various techniques. One technique involves the use of brains and brain scanning technology to discover where in the brain genes are turned on. Another technique, called in situ hybridization, or ISH, is used to view gene expression patterns as in situ hybridization images, within the Brain Atlases, these 3-D ISH digital images and graphs reveal, in color, the regions where a given gene is expressed
25.
Chromosome 17 (human)
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Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome, chromosome 17 spans more than 83 million base pairs and represents between 2.5 and 3% of the total DNA in cells. Identifying genes on each chromosome is an area of genetic research. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies, in January 2017, two estimates differed by 9%, with one estimate giving 2,432 genes, and the other estimate giving 2,653 genes. Chromosome 17 contains the Homeobox B gene cluster, disease genes and chromosomes, disease maps of the human genome
26.
Human
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Modern humans are the only extant members of Hominina tribe, a branch of the tribe Hominini belonging to the family of great apes. Several of these hominins used fire, occupied much of Eurasia and they began to exhibit evidence of behavioral modernity around 50,000 years ago. In several waves of migration, anatomically modern humans ventured out of Africa, the spread of humans and their large and increasing population has had a profound impact on large areas of the environment and millions of native species worldwide. Humans are uniquely adept at utilizing systems of communication for self-expression and the exchange of ideas. Humans create complex structures composed of many cooperating and competing groups, from families. Social interactions between humans have established a wide variety of values, social norms, and rituals. These human societies subsequently expanded in size, establishing various forms of government, religion, today the global human population is estimated by the United Nations to be near 7.5 billion. In common usage, the word generally refers to the only extant species of the genus Homo—anatomically and behaviorally modern Homo sapiens. In scientific terms, the meanings of hominid and hominin have changed during the recent decades with advances in the discovery, there is also a distinction between anatomically modern humans and Archaic Homo sapiens, the earliest fossil members of the species. The English adjective human is a Middle English loanword from Old French humain, ultimately from Latin hūmānus, the words use as a noun dates to the 16th century. The native English term man can refer to the species generally, the species binomial Homo sapiens was coined by Carl Linnaeus in his 18th century work Systema Naturae. The generic name Homo is a learned 18th century derivation from Latin homō man, the species-name sapiens means wise or sapient. Note that the Latin word homo refers to humans of either gender, the genus Homo evolved and diverged from other hominins in Africa, after the human clade split from the chimpanzee lineage of the hominids branch of the primates. The closest living relatives of humans are chimpanzees and gorillas, with the sequencing of both the human and chimpanzee genome, current estimates of similarity between human and chimpanzee DNA sequences range between 95% and 99%. The gibbons and orangutans were the first groups to split from the leading to the humans. The splitting date between human and chimpanzee lineages is placed around 4–8 million years ago during the late Miocene epoch, during this split, chromosome 2 was formed from two other chromosomes, leaving humans with only 23 pairs of chromosomes, compared to 24 for the other apes. There is little evidence for the divergence of the gorilla, chimpanzee. Each of these species has been argued to be an ancestor of later hominins
27.
Chromosome 17
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Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome, chromosome 17 spans more than 83 million base pairs and represents between 2.5 and 3% of the total DNA in cells. Identifying genes on each chromosome is an area of genetic research. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies, in January 2017, two estimates differed by 9%, with one estimate giving 2,432 genes, and the other estimate giving 2,653 genes. Chromosome 17 contains the Homeobox B gene cluster, disease genes and chromosomes, disease maps of the human genome
28.
Mouse
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A mouse is a small rodent characteristically having a pointed snout, small rounded ears, a body-length scaly tail and a high breeding rate. The best known species is the common house mouse. It is also a popular pet, in some places, certain kinds of field mice are locally common. They are known to invade homes for food and shelter, domestic mice sold as pets often differ substantially in size from the common house mouse. This is attributable both to breeding and to different conditions in the wild, the most well known strain, the white lab mouse, has more uniform traits that are appropriate to its use in research. The American white-footed mouse and the mouse, as well as other common species of mouse-like rodents around the world. These, however, are in other genera, cats, wild dogs, foxes, birds of prey, snakes and even certain kinds of arthropods have been known to prey heavily upon mice. Nevertheless, because of its adaptability to almost any environment. Mice, in contexts, can be considered vermin which are a major source of crop damage, causing structural damage. In North America, breathing dust that has come in contact with mouse excrement has been linked to hantavirus, primarily nocturnal animals, mice compensate for their poor eyesight with a keen sense of hearing, and rely especially on their sense of smell to locate food and avoid predators. Mice build intricate burrows in the wild and these burrows typically have long entrances and are equipped with escape tunnels or routes. In at least one species, the design of a burrow is a genetic trait. Breeding onset is at about 50 days of age in females and males, although females may have their first estrus at 25–40 days. Mice are polyestrous and breed year round, ovulation is spontaneous, the duration of the estrous cycle is 4–5 days and estrus itself lasts about 12 hours, occurring in the evening. Vaginal smears are useful in timed matings to determine the stage of the estrous cycle, mating is usually nocturnal and may be confirmed by the presence of a copulatory plug in the vagina up to 24 hours post-copulation. The presence of sperm on a smear is also a reliable indicator of mating. Female mice housed together tend to go into anestrus and do not cycle, if exposed to a male mouse or the pheromones of a male mouse, most of the females will go into estrus in about 72 hours. This synchronization of the cycle is known as the Whitten effect
29.
Gut (zoology)
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Gastrointestinal is an adjective meaning of or pertaining to the stomach and intestines. A tract is a collection of related anatomic structures or a series of connected body organs, the mouth, oesophagus, stomach, and intestines are part of the human alimentary canal. All bilaterians have a gastrointestinal tract, also called a gut or an alimentary canal and this is a tube that transfers food to the organs of digestion. In large bilaterians, the gastrointestinal tract generally also has an exit, some small bilaterians have no anus and dispose of solid wastes by other means. The gastrointestinal tract contains thousands of different bacteria in their gut flora, the human gastrointestinal tract consists of the esophagus, stomach, and intestines, and is divided into the upper and lower gastrointestinal tracts. In contrast, the digestive system comprises the gastrointestinal tract plus the accessory organs of digestion. The tract may also be divided into foregut, midgut, and hindgut, the whole human GI tract is about nine metres long at autopsy. The GI tract releases hormones from enzymes to help regulate the digestive process, the structure and function can be described both as gross anatomy and as microscopic anatomy or histology. The tract itself is divided into upper and lower tracts, the upper gastrointestinal tract consists of the buccal cavity, pharynx, esophagus, stomach, and duodenum. The exact demarcation between the upper and lower tracts is the muscle of the duodenum. Upon dissection, the duodenum may appear to be an organ, but it is divided into four segments based upon function, location. The four segments of the duodenum are as follows, bulb, descending, horizontal, the suspensory muscle attaches the superior border of the ascending duodenum to the diaphragm. The suspensory muscle is an important anatomical landmark which shows the division between the duodenum and the jejunum, the first and second parts of the small intestine. This is a muscle which is derived from the embryonic mesoderm. The lower gastrointestinal tract includes most of the intestine and all of the large intestine. In humans, the intestine is further subdivided into the duodenum, jejunum and ileum while the large intestine is subdivided into the cecum, colon, rectum. The small intestine begins at the duodenum, which receives food from the stomach and it is a tubular structure, usually between 6 and 7 m long. The area of the human, adult small intestinal mucosa is about 30 m2 and its main function is to absorb the products of digestion into the bloodstream
30.
5-HTTLPR
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5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter. Since the polymorphism was identified in the middle of the 1990s, it has extensively investigated. A2006 scientific article stated that over 300 behavioral, psychiatric, pharmacogenetic, while often discussed as an example of gene-environment interaction, this contention is contested. The polymorphism occurs in the region of the gene. Researchers commonly report it with two variations in humans, A short and a long, but it can be subdivided further, in connection with the region are two single nucleotide polymorphisms, rs25531 and rs25532. One study published in 2000 found 14 allelic variants in a group of around 200 Japanese, the difference between 16-A and 16-D is the rs25531 SNP. It is also the difference between 14-A and 14-D, some studies have found that long allele results in higher serotonin transporter mRNA transcription in human cell lines. Newer studies examining the effects of genotype may compare the LA/LA genotype against all other genotypes, the allele frequency of this polymorphism seems to vary considerably across populations, with a higher frequency of the long allele in Europe and lower frequency in Asia. Despite speculation to the contrary, the variation in the allele frequency is more likely due to neutral evolutionary processes than natural selection. In the 1990s it has been speculated that the polymorphism might be related to disorders. However, another large European study found no such link, a decade later two studies found that 5-HTT polymorphism influences depressive responses to life stress, an example of gene-environment interaction not considered in the previous studies. Two 2009 meta-analyses found no overall GxE effect, while a more recent meta-analysis and this suggests that authors may be data dredging for measures and analytic strategies which yield the results they want. With the results from one study the polymorphism was thought to be related to treatment response so that patients respond better to antidepressants. One study could find a treatment response effect for repetitive transcranial magnetic stimulation to drug-resistant depression with long/long homozygotes benefitting more than short-allele carriers, the researchers found a similar effect for the Val66Met polymorphism in the BDNF gene. 5-HTTLPR may be related to personality traits, Two 2004 meta-analyses found 26 research studies investigating the polymorphism in relation to anxiety-related traits. Some other studies have, however, failed to find this association, nor with peer-rated neuroticism, a meta-analysis published in 2004 stated that the lack of replicability was largely due to small sample size and the use of different inventories. A similar conclusion was reached in an updated 2008 meta-analysis, however, based on over 4000 subjects, the largest study that used the NEO PI-R found no association between variants of the serotonin transporter gene and neuroticism, or its facets. This biased attention of positive emotional stimuli suggests they may tend to be more optimistic, other research indicates carriers of the short 5-HTTLPR allele have difficulty disengaging attention from emotional stimuli compared to long allele homozygotes
31.
Single nucleotide polymorphism
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For example, at a specific base position in the human genome, the base C may appear in most individuals, but in a minority of individuals, the position is occupied by base A. There is a SNP at this base position, and the two possible nucleotide variations - C or A - are said to be alleles for this base position. SNPs underlie differences in our susceptibility to disease, a range of human diseases, e. g. sickle-cell anemia, β-thalassemia. The severity of illness and the way our body responds to treatments are also manifestations of genetic variations, for example, a single base mutation in the APOE gene is associated with a higher risk for Alzheimers disease. A single-nucleotide variant is a variation in a single nucleotide without any limitations of frequency, a somatic single nucleotide variation may also be called a single-nucleotide alteration. Single-nucleotide polymorphisms may fall within coding sequences of genes, non-coding regions of genes, SNPs within a coding sequence do not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy of the genetic code. SNPs in the region are of two types, synonymous and nonsynonymous SNPs. Synonymous SNPs do not affect the sequence while nonsynonymous SNPs change the amino acid sequence of protein. The nonsynonymous SNPs are of two types, missense and nonsense, SNPs that are not in protein-coding regions may still affect gene splicing, transcription factor binding, messenger RNA degradation, or the sequence of non-coding RNA. Gene expression affected by type of SNP is referred to as an eSNP. Association studies can determine whether a variant is associated with a disease or trait. A tag SNP is a representative single-nucleotide polymorphism in a region of the genome with high linkage disequilibrium, tag SNPs are useful in whole-genome SNP association studies in which hundreds of thousands of SNPs across the entire genome are genotyped. Haplotype mapping, sets of alleles or DNA sequences can be clustered so that a single SNP can identify many linked SNPs, linkage Disequilibrium, a term used in population genetics, indicates non-random association of alleles at two or more loci, not necessarily on the same chromosome. It refers to the phenomenon that SNP allele or DNA sequence which are together in the genome tend to be inherited together. LD is affected by two parameters, 1) The distance between the SNPs, other factors, like genetic recombination and mutation rate, can also determine SNP density. There are variations between populations, so a SNP allele that is common in one geographical or ethnic group may be much rarer in another. Within a population, SNPs can be assigned a minor allele frequency — the lowest allele frequency at a locus that is observed in a particular population and this is simply the lesser of the two allele frequencies for single-nucleotide polymorphisms. Variations in the DNA sequences of humans can affect how humans develop diseases and respond to pathogens, chemicals, drugs, vaccines, SNPs are also critical for personalized medicine
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Variable number of tandem repeats
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A variable number tandem repeat is a location in a genome where a short nucleotide sequence is organized as a tandem repeat. These can be found on chromosomes, and often show variations in length between individuals. Each variant acts as an allele, allowing them to be used for personal or parental identification. Their analysis is useful in genetics and biology research, forensics, in the schematic above, the rectangular blocks represent each of the repeated DNA sequences at a particular VNTR location. The repeats are in tandem – i. e. they are clustered together, individual repeats can be removed from the VNTR via recombination or replication errors, leading to alleles with different numbers of repeats. VNTRs were an important source of RFLP genetic markers used in analysis of diploid genomes. Now that many genomes have been sequenced, VNTRs have become essential to forensic crime investigations, via DNA fingerprinting and the CODIS database. When removed from surrounding DNA by the PCR or RFLP methods, when tested with a group of independent VNTR markers, the likelihood of two unrelated individuals having the same allelic pattern is extremely low. VNTR analysis is also being used to study genetic diversity and breeding patterns in populations of wild or domesticated animals, as such, VNTRs can be used to distinguish strains of bacterial pathogens. In this microbial forensics context, such assays are usually called Multiple Loci VNTR Analysis or MLVA, in analyzing VNTR data, two basic genetic principles can be used, Identity Matching – both VNTR alleles from a specific location must match. If two samples are from the individual, they must show the same allele pattern. Inheritance Matching – the VNTR alleles must follow the rules of inheritance, in matching an individual with his parents or children, a person must have an allele that matches one from each parent. If the relationship is distant, such as a grandparent or sibling. Repetitive DNA, representing over 40% of the genome, is arranged in a bewildering array of patterns. Repeats were first identified by the extraction of Satellite DNA, which does not reveal how they are organized, the use of restriction enzymes showed that some repeat blocks were interspersed throughout the genome. DNA sequencing later showed that other repeats are clustered at specific locations, VNTRs are the class of clustered tandem repeats that exhibit allelic variation in their lengths. There are two families of VNTRs, microsatellites and minisatellites. The former are repeats of sequences less than about 5 base pairs in length, the 13 assays used in the CODIS database are usually referred to as STRs, and most analyze VNTRs that involve repeats of 4 base pairs
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Intron
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An intron is any nucleotide sequence within a gene that is removed by RNA splicing during maturation of the final RNA product. The term intron refers to both the DNA sequence within a gene and the sequence in RNA transcripts. Sequences that are joined together in the final mature RNA after RNA splicing are exons. Introns are found in the genes of most organisms and many viruses, and can be located in a range of genes, including those that generate proteins, ribosomal RNA. When proteins are generated from intron-containing genes, RNA splicing takes place as part of the RNA processing pathway that follows transcription, the word intron is derived from the term intragenic region, i. e. a region inside a gene. Introns were first discovered in protein-coding genes of adenovirus, and were identified in genes encoding transfer RNA. Introns are now known to occur within a variety of genes throughout organisms. The frequency of introns within different genomes is observed to vary widely across the spectrum of biological organisms, in contrast, the mitochondrial genomes of vertebrates are entirely devoid of introns, while those of eukaryotic microorganisms may contain many introns. A particularly extreme case is the Drosophila dhc7 gene containing a ≥3.6 Mb intron, splicing of all intron-containing RNA molecules is superficially similar, as described above. However, different types of introns were identified through the examination of intron structure by DNA sequence analysis, together with genetic and they appear to be related to group II introns, and possibly to spliceosomal introns. Nuclear pre-mRNA introns are characterized by specific intron sequences located at the boundaries between introns and exons and these sequences are recognized by spliceosomal RNA molecules when the splicing reactions are initiated. Apart from these three short conserved elements, nuclear pre-mRNA intron sequences are highly variable, nuclear pre-mRNA introns are often much longer than their surrounding exons. Transfer RNA introns that depend upon proteins for removal occur at a location within the anticodon loop of unspliced tRNA precursors. The exons are then linked together by a protein, the tRNA splicing ligase. Note that self-splicing introns are also found within tRNA genes. Group I and group II introns are found in genes encoding proteins, transfer RNA, following transcription into RNA, group I and group II introns also make extensive internal interactions that allow them to fold into a specific, complex three-dimensional architecture. While introns do not encode protein products, they are integral to gene expression regulation, some introns themselves encode functional RNAs through further processing after splicing to generate noncoding RNA molecules. Alternative splicing is widely used to generate multiple proteins from a single gene, furthermore, some introns play essential roles in a wide range of gene expression regulatory functions such as non-sense mediated decay and mRNA export
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Exon
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An exon is any part of a gene that will encode a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term exon refers to both the DNA sequence within a gene and to the sequence in RNA transcripts. In RNA splicing, introns are removed and exons are joined to one another as part of generating the mature messenger RNA. Just as the set of genes for a species constitutes the genome. This definition was made for protein-coding transcripts that are spliced before being translated. Although unicellular eukaryotes such as yeast have either no introns or very few, metazoans, for instance, in the human genome only 1. 1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. The large variation in size and C-value across life forms has posed an interesting challenge called the C-value enigma. Across all eukaryotic genes in GenBank there were, on average,5.48 exons per gene, the average exon encoded 30-36 amino acids. While the longest exon in the genome is 11555 bp long. A single-nucleotide exon has been reported from the Arabidopsis genome, in protein-coding genes, the exons include both the protein-coding sequence and the 5′- and 3′-untranslated regions. Often the first exon includes both the 5′-UTR and the first part of the sequence, but exons containing only regions of 5′-UTR or 3′-UTR occur in some genes. Some non-coding RNA transcripts also have exons and introns, mature mRNAs originating from the same gene need not include the same exons, since different introns in the pre-mRNA can be removed by the process of alternative splicing. Exonization is the creation of a new exon, as a result of mutations in introns, Exon trapping or gene trapping is a molecular biology technique that exploits the existence of the intron-exon splicing to find new genes. The first exon of a trapped gene splices into the exon that is contained in the insertional DNA and this new exon contains the ORF for a reporter gene that can now be expressed using the enhancers that control the target gene. A scientist knows that a new gene has been trapped when the gene is expressed. This has become a technique in developmental biology. Morpholino oligos can also be targeted to prevent molecules that regulate splicing from binding to pre-mRNA, exitron Exon shuffling Interrupted gene Intron mRNA Untranslated region Gilbert W. Statistical features of human exons and their flanking regions, prediction of exact boundaries of exons
. PMID 17690258. doi:10.1126/science.1147614.
