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65-461: The similarity of amino-acid sequence to the eukaryotic LGICs is not localized to any single or particular tertiary domain , indicating the similar function of the GLIC to its eukaryotic equivalents. Regardless, the purpose of regulating the threshold for action potential excitation in the nerve signal transmission of multicellular organisms cannot translate to single-cell organisms, thereby not making

130-422: A black widow spider , one experiences the wastage of ACh supplies and the muscles begin to contract. If and when the supply is depleted, paralysis occurs. Acetylcholine is used by organisms in all domains of life for a variety of purposes. It is believed that choline , a precursor to acetylcholine, was used by single celled organisms billions of years ago for synthesizing cell membrane phospholipids. Following

195-450: A postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands , by channel blockers , ions , or the membrane potential . LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors , ionotropic glutamate receptors and ATP-gated channels . The cys-loop receptors are named after a characteristic loop formed by a disulfide bond between two cysteine residues in

260-462: A second messenger system . The M1, M3, and M5 subtypes are G q -coupled; they increase intracellular levels of IP 3 and calcium by activating phospholipase C . Their effect on target cells is usually excitatory. The M2 and M4 subtypes are G i /G o -coupled; they decrease intracellular levels of cAMP by inhibiting adenylate cyclase . Their effect on target cells is usually inhibitory. Muscarinic acetylcholine receptors are found in both

325-411: A binding site for glutamate formed by the two LBD sections forming a clamshell like shape. Only two of these sites in the tetramer need to be occupied to open the ion channel. The pore is mainly formed by the half helix 2 in a way which resembles an inverted potassium channel . The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor , or quisqualate receptor )

390-560: A chemoreceptor. This prokaryotic nAChR variant is known as the GLIC receptor, after the species in which it was identified; G loeobacter L igand-gated I on C hannel. Cys-loop receptors have structural elements that are well conserved, with a large extracellular domain (ECD) harboring an alpha-helix and 10 beta-strands. Following the ECD, four transmembrane segments (TMSs) are connected by intracellular and extracellular loop structures. Except

455-413: A common homolog, these receptors evolved from separate receptor families. It is estimated that the nicotinic receptor family dates back longer than 2.5 billion years. Likewise, muscarinic receptors are thought to have diverged from other GPCRs at least 0.5 billion years ago. Both of these receptor groups have evolved numerous subtypes with unique ligand affinities and signaling mechanisms. The diversity of

520-419: A group of transmembrane ion-channel proteins which open to allow ions such as Na , K , Ca , and/or Cl to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand ), such as a neurotransmitter . When a presynaptic neuron is excited, it releases a neurotransmitter from vesicles into the synaptic cleft . The neurotransmitter then binds to receptors located on

585-424: A high affinity for sulfhydryl groups , which causes dysfunction of the enzyme choline acetyltransferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function. Botulinum toxin (Botox) acts by suppressing the release of acetylcholine, whereas the venom from a black widow spider ( alpha-latrotoxin ) has the reverse effect. ACh inhibition causes paralysis . When bitten by

650-445: A number of cholinergic areas, each with distinct functions; such as playing an important role in arousal , attention , memory and motivation . Acetylcholine has also been found in cells of non-neural origins as well as microbes. Recently, enzymes related to its synthesis, degradation and cellular uptake have been traced back to early origins of unicellular eukaryotes. The protist pathogens Acanthamoeba spp. have shown evidence of

715-546: A reentrant loop. The structure of the protein starts with the ATD at the N terminus followed by the first half of the LBD which is interrupted by helices 1,2 and 3 of the TMD before continuing with the final half of the LBD and then finishing with helix 4 of the TMD at the C terminus. This means there are three links between the TMD and the extracellular domains. Each subunit of the tetramer has

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780-412: A sequence of steps that finally produce muscle contraction . Factors that decrease release of acetylcholine (and thereby affecting P-type calcium channels ): Calcium channel blockers (nifedipine, diltiazem) do not affect P-channels. These drugs affect L-type calcium channels . The autonomic nervous system controls a wide range of involuntary and unconscious body functions. Its main branches are

845-460: A transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allosteric binding site). This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into

910-491: A type of ionotropic glutamate receptor  – is a ligand-gated ion channel that is gated by the simultaneous binding of glutamate and a co-agonist (i.e., either D-serine or glycine ). Studies show that the NMDA receptor is involved in regulating synaptic plasticity and memory. The name "NMDA receptor" is derived from the ligand N-methyl-D-aspartate (NMDA), which acts as a selective agonist at these receptors. When

975-413: Is "rest and digest" or "feed and breed". Both of these aforementioned systems use acetylcholine, but in different ways. At a schematic level, the sympathetic and parasympathetic nervous systems are both organized in essentially the same way: preganglionic neurons in the central nervous system send projections to neurons located in autonomic ganglia, which send output projections to virtually every tissue of

1040-409: Is a non- NMDA -type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). Its name is derived from its ability to be activated by the artificial glutamate analog AMPA . The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given

1105-415: Is a type of drug that acts on a dual melatonergic - serotonergic pathway, which have shown its efficacy in the treatment of anxious depression during clinical trials, study also suggests the efficacy in the treatment of atypical and melancholic depression . As of this edit , this article uses content from "1.A.9 The Neurotransmitter Receptor, Cys loop, Ligand-gated Ion Channel (LIC) Family" , which

1170-433: Is also a neurotransmitter in the autonomic nervous system , both as an internal transmitter for both the sympathetic and the parasympathetic nervous system , and as the final product released by the parasympathetic nervous system. Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system. In the brain, acetylcholine functions as a neurotransmitter and as a neuromodulator . The brain contains

1235-485: Is an ester of acetic acid and choline . Parts in the body that use or are affected by acetylcholine are referred to as cholinergic . Acetylcholine is the neurotransmitter used at the neuromuscular junction —in other words, it is the chemical that motor neurons of the nervous system release in order to activate muscles. This property means that drugs that affect cholinergic systems can have very dangerous effects ranging from paralysis to convulsions . Acetylcholine

1300-559: Is licensed in a way that permits reuse under the Creative Commons Attribution-ShareAlike 3.0 Unported License , but not under the GFDL . All relevant terms must be followed. Acetylcholine Acetylcholine ( ACh ) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter . Its name is derived from its chemical structure: it

1365-450: Is the nicotinic acetylcholine receptor . It consists of a pentamer of protein subunits (typically ααβγδ), with two binding sites for acetylcholine (one at the interface of each alpha subunit). When the acetylcholine binds it alters the receptor's configuration (twists the T2 helices which moves the leucine residues, which block the pore, out of the channel pathway) and causes the constriction in

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1430-433: Is the nucleus basalis of Meynert in the basal forebrain. The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate . This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at

1495-419: The carbamates ). Many toxins and venoms produced by plants and animals also contain cholinesterase inhibitors. In clinical use, they are administered in low doses to reverse the action of muscle relaxants , to treat myasthenia gravis , and to treat symptoms of Alzheimer's disease ( rivastigmine , which increases cholinergic activity in the brain). Organic mercurial compounds, such as methylmercury , have

1560-449: The neuromuscular junction , causing paralysis of the muscles needed for breathing and stopping the beating of the heart. Acetylcholine functions in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the CNS, cholinergic projections from the basal forebrain to the cerebral cortex and hippocampus support the cognitive functions of those target areas. In

1625-419: The neurotransmitter glutamate . They form tetramers, with each subunit consisting of an extracellular amino terminal domain (ATD, which is involved tetramer assembly), an extracellular ligand binding domain (LBD, which binds glutamate), and a transmembrane domain (TMD, which forms the ion channel). The transmembrane domain of each subunit contains three transmembrane helices as well as a half membrane helix with

1690-418: The postsynaptic neuron . If these receptors are ligand-gated ion channels, a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization , for an excitatory receptor response, or a hyperpolarization , for an inhibitory response. These receptor proteins are typically composed of at least two different domains:

1755-526: The striatum , which is part of the basal ganglia . It is released by cholinergic interneurons . In humans, non-human primates and rodents, these interneurons respond to salient environmental stimuli with responses that are temporally aligned with the responses of dopaminergic neurons of the substantia nigra . Acetylcholine has been implicated in learning and memory in several ways. The anticholinergic drug scopolamine impairs acquisition of new information in humans and animals. In animals, disruption of

1820-416: The sympathetic nervous system and parasympathetic nervous system . Broadly speaking, the function of the sympathetic nervous system is to mobilize the body for action; the phrase often invoked to describe it is fight-or-flight . The function of the parasympathetic nervous system is to put the body in a state conducive to rest, regeneration, digestion, and reproduction; the phrase often invoked to describe it

1885-436: The synaptic cleft (the space between nerve and muscle). Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it. Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting

1950-458: The C and N termini on the intracellular side. Ligand-gated ion channels are likely to be the major site at which anaesthetic agents and ethanol have their effects, although unequivocal evidence of this is yet to be established. In particular, the GABA and NMDA receptors are affected by anaesthetic agents at concentrations similar to those used in clinical anaesthesia. By understanding

2015-399: The M 1 receptor subtype has been implicated in anticholinergic delirium. The addictive qualities of nicotine are derived from its effects on nicotinic acetylcholine receptors in the brain. Acetylcholine is a choline molecule that has been acetylated at the oxygen atom. Because of the charged ammonium group, acetylcholine does not penetrate lipid membranes. Because of this, when

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2080-467: The N terminal extracellular domain. They are part of a larger family of pentameric ligand-gated ion channels that usually lack this disulfide bond, hence the tentative name "Pro-loop receptors". A binding site in the extracellular N-terminal ligand-binding domain gives them receptor specificity for (1) acetylcholine (AcCh), (2) serotonin, (3) glycine, (4) glutamate and (5) γ-aminobutyric acid (GABA) in vertebrates. The receptors are subdivided with respect to

2145-515: The NMDA receptor is activated by the binding of two co-agonists, the cation channel opens, allowing Na and Ca to flow into the cell, in turn raising the cell's electric potential . Thus, the NMDA receptor is an excitatory receptor. At resting potentials , the binding of Mg or Zn at their extracellular binding sites on the receptor blocks ion flux through the NMDA receptor channel. "However, when neurons are depolarized, for example, by intense activation of colocalized postsynaptic AMPA receptors ,

2210-497: The PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system. Like many other biologically active substances, acetylcholine exerts its effects by binding to and activating receptors located on the surface of cells. There are two main classes of acetylcholine receptor, nicotinic and muscarinic . They are named for chemicals that can selectively activate each type of receptor without activating

2275-464: The TMS 3-4 loop, their lengths are only 7-14 residues. The TMS 3-4 loop forms the largest part of the intracellular domain (ICD) and exhibits the most variable region between all of these homologous receptors. The ICD is defined by the TMS 3-4 loop together with the TMS 1-2 loop preceding the ion channel pore. Crystallization has revealed structures for some members of the family, but to allow crystallization,

2340-522: The blood pressure of animals. In 1914, Arthur J. Ewins was the first to extract acetylcholine from nature. He identified it as the blood pressure-decreasing contaminant from some Claviceps purpurea ergot extracts, by the request of Henry Hallett Dale . Later in 1914, Dale outlined the effects of acetylcholine at various types of peripheral synapses and also noted that it lowered the blood pressure of cats via subcutaneous injections even at doses of one nanogram . The concept of neurotransmitters

2405-527: The body inappropriately produces antibodies against acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission. Over time, the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine , physostigmine , or primarily pyridostigmine ) are effective in treating the symptoms of this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in

2470-424: The body. In both branches the internal connections, the projections from the central nervous system to the autonomic ganglia, use acetylcholine as a neurotransmitter to innervate (or excite) ganglia neurons. In the parasympathetic nervous system the output connections, the projections from ganglion neurons to tissues that do not belong to the nervous system, also release acetylcholine but act on muscarinic receptors. In

2535-436: The central nervous system and the peripheral nervous system of the heart, lungs, upper gastrointestinal tract, and sweat glands. Acetylcholine is the substance the nervous system uses to activate skeletal muscles , a kind of striated muscle. These are the muscles used for all types of voluntary movement, in contrast to smooth muscle tissue , which is involved in a range of involuntary activities such as movement of food through

2600-448: The electrical response is fast and short-lived. Curares are arrow poisons, which act at nicotinic receptors and have been used to develop clinically useful therapies. Muscarinic receptors form G protein-coupled receptor complexes in the cell membranes of neurons and other cells. Atropine is a non-selective competitive antagonist with Acetylcholine at muscarinic receptors. Many ACh receptor agonists work indirectly by inhibiting

2665-405: The enzyme acetylcholinesterase , which degrades the receptor ligand. Agonists increase the level of receptor activation; antagonists reduce it. Acetylcholine itself does not have therapeutic value as a drug for intravenous administration because of its multi-faceted action (non-selective) and rapid inactivation by cholinesterase. However, it is used in the form of eye drops to cause constriction of

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2730-440: The enzyme acetylcholinesterase . The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system, which can result in fatal convulsions if the dose is high. They are examples of enzyme inhibitors , and increase the action of acetylcholine by delaying its degradation; some have been used as nerve agents ( Sarin and VX nerve gas) or pesticides ( organophosphates and

2795-565: The evolution of choline transporters, the abundance of intracellular choline paved the way for choline to become incorporated into other synthetic pathways, including acetylcholine production. Acetylcholine is used by bacteria, fungi, and a variety of other animals. Many of the uses of acetylcholine rely on its action on ion channels via GPCRs like membrane proteins. The two major types of acetylcholine receptors, muscarinic and nicotinic receptors, have convergently evolved to be responsive to acetylcholine. This means that rather than having evolved from

2860-449: The gastrointestinal tract and constriction of blood vessels. Skeletal muscles are directly controlled by motor neurons located in the spinal cord or, in a few cases, the brainstem . These motor neurons send their axons through motor nerves , from which they emerge to connect to muscle fibers at a special type of synapse called the neuromuscular junction . When a motor neuron generates an action potential , it travels rapidly along

2925-546: The intracellular loop was usually replaced by a short linker present in prokaryotic cys-loop receptors, so their structures as not known. Nevertheless, this intracellular loop appears to function in desensitization, modulation of channel physiology by pharmacological substances, and posttranslational modifications . Motifs important for trafficking are therein, and the ICD interacts with scaffold proteins enabling inhibitory synapse formation. The ionotropic glutamate receptors bind

2990-576: The label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. AMPARs are found in many parts of the brain and are the most commonly found receptor in the nervous system . The AMPA receptor GluA2 (GluR2) tetramer was the first glutamate receptor ion channel to be crystallized . Ligands include: The N-methyl-D-aspartate receptor ( NMDA receptor ) –

3055-634: The mechanism and exploring the chemical/biological/physical component that could function on those receptors, more and more clinical applications are proven by preliminary experiments or FDA . Memantine is approved by the U.S. F.D.A and the European Medicines Agency for the treatment of moderate-to-severe Alzheimer's disease , and has now received a limited recommendation by the UK's National Institute for Health and Care Excellence for patients who fail other treatment options. Agomelatine ,

3120-554: The memory deficits associated with Alzheimer's disease . ACh has also been shown to promote REM sleep. In the brainstem acetylcholine originates from the Pedunculopontine nucleus and laterodorsal tegmental nucleus collectively known as the meso pontine tegmentum area or pontomesencephalotegmental complex. In the basal forebrain, it originates from the basal nucleus of Meynert and medial septal nucleus : In addition, ACh acts as an important internal transmitter in

3185-407: The molecule is introduced externally, it remains in the extracellular space and at present it is considered that the molecule does not pass through the blood–brain barrier. Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA . Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area

3250-402: The nerve until it reaches the neuromuscular junction, where it initiates an electrochemical process that causes acetylcholine to be released into the space between the presynaptic terminal and the muscle fiber. The acetylcholine molecules then bind to nicotinic ion-channel receptors on the muscle cell membrane, causing the ion channels to open. Sodium ions then flow into the muscle cell, initiating

3315-519: The neuromuscular junction. Drugs that act on muscarinic acetylcholine receptors , such as atropine , can be poisonous in large quantities, but in smaller doses they are commonly used to treat certain heart conditions and eye problems. Scopolamine , or diphenhydramine , which also act mainly on muscarinic receptors in an inhibitory fashion in the brain (especially the M 1 receptor) can cause delirium , hallucinations , and amnesia through receptor antagonism at these sites. So far as of 2016, only

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3380-579: The neuronal-type by hexamethonium . The main location of muscle-type receptors is on muscle cells, as described in more detail below. Neuronal-type receptors are located in autonomic ganglia (both sympathetic and parasympathetic), and in the central nervous system. Muscarinic acetylcholine receptors have a more complex mechanism, and affect target cells over a longer time frame. In mammals, five subtypes of muscarinic receptors have been identified, labeled M1 through M5. All of them function as G protein-coupled receptors , meaning that they exert their effects via

3445-581: The other: muscarine is a compound found in the mushroom Amanita muscaria ; nicotine is found in tobacco. Nicotinic acetylcholine receptors are ligand-gated ion channels permeable to sodium , potassium , and calcium ions. In other words, they are ion channels embedded in cell membranes, capable of switching from a closed to an open state when acetylcholine binds to them; in the open state they allow ions to pass through. Nicotinic receptors come in two main types, known as muscle-type and neuronal-type. The muscle-type can be selectively blocked by curare ,

3510-479: The pore of approximately 3 angstroms to widen to approximately 8 angstroms so that ions can pass through. This pore allows Na ions to flow down their electrochemical gradient into the cell. With a sufficient number of channels opening at once, the inward flow of positive charges carried by Na ions depolarizes the postsynaptic membrane sufficiently to initiate an action potential . A bacterial homologue to an LIC has been identified, hypothesized to act nonetheless as

3575-554: The presence of ACh, which provides growth and proliferative signals via a membrane-located M 1 -muscarinic receptor homolog. Partly because of acetylcholine's muscle-activating function, but also because of its functions in the autonomic nervous system and brain, many important drugs exert their effects by altering cholinergic transmission. Numerous venoms and toxins produced by plants, animals, and bacteria, as well as chemical nerve agents such as sarin , cause harm by inactivating or hyperactivating muscles through their influences on

3640-416: The pupil during cataract surgery, which facilitates quick post-operational recovery. Nicotine binds to and activates nicotinic acetylcholine receptors , mimicking the effect of acetylcholine at these receptors. ACh opens a Na channel upon binding so that Na flows into the cell. This causes a depolarization, and results in an excitatory post-synaptic potential. Thus, ACh is excitatory on skeletal muscle;

3705-432: The purpose of bacterial LGICs immediately obvious. The structure of the open channel structure was solved by two independent research teams in 2009 at low pH values of 4-4.6 (GLIC being proton-gated). This transmembrane receptor -related article is a stub . You can help Misplaced Pages by expanding it . LGIC Ligand-gated ion channels ( LICs , LGIC ), also commonly referred to as ionotropic receptors , are

3770-416: The receptor types enables acetylcholine to create varying responses depending on which receptor types are activated, and allow for acetylcholine to dynamically regulate physiological processes. ACh receptors are related to 5-HT3 ( serotonin ), GABA , and Glycine receptors , both in sequence and structure, strongly suggesting that they have a common evolutionary origin. In 1867, Adolf von Baeyer resolved

3835-483: The structures of choline and acetylcholine and synthesized them both, referring to the latter as acetylneurin in the study. Choline is a precursor for acetylcholine. Acetylcholine was first noted to be biologically active in 1906, when Reid Hunt (1870–1948) and René de M. Taveau found that it decreased blood pressure in exceptionally tiny doses. This was after Frederick Walker Mott and William Dobinson Halliburton noted in 1899 that choline injections decreased

3900-413: The supply of acetylcholine to the neocortex impairs the learning of simple discrimination tasks, comparable to the acquisition of factual information and disruption of the supply of acetylcholine to the hippocampus and adjacent cortical areas produces forgetfulness, comparable to anterograde amnesia in humans. The disease myasthenia gravis , characterized by muscle weakness and fatigue, occurs when

3965-410: The surrounding smooth muscle to relax, leading to vasodilation . In the central nervous system, ACh has a variety of effects on plasticity, arousal and reward . ACh has an important role in the enhancement of alertness when we wake up, in sustaining attention and in learning and memory . Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be associated with

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4030-417: The sympathetic nervous system the output connections mainly release noradrenaline , although acetylcholine is released at a few points, such as the sudomotor innervation of the sweat glands. Acetylcholine in the serum exerts a direct effect on vascular tone by binding to muscarinic receptors present on vascular endothelium . These cells respond by increasing production of nitric oxide , which signals

4095-429: The type of ion that they conduct (anionic or cationic) and further into families defined by the endogenous ligand. They are usually pentameric with each subunit containing 4 transmembrane helices constituting the transmembrane domain, and a beta sheet sandwich type, extracellular, N terminal, ligand binding domain. Some also contain an intracellular domain like shown in the image. The prototypic ligand-gated ion channel

4160-459: The voltage-dependent block by Mg is partially relieved, allowing ion influx through activated NMDA receptors. The resulting Ca influx can trigger a variety of intracellular signaling cascades, which can ultimately change neuronal function through activation of various kinases and phosphatases". Ligands include: ATP-gated channels open in response to binding the nucleotide ATP . They form trimers with two transmembrane helices per subunit and both

4225-527: Was unknown until 1921, when Otto Loewi noted that the vagus nerve secreted a substance that inhibited the heart muscle whilst working as a professor in the University of Graz . He named it vagusstoff ("vagus substance"), noted it to be a structural analog of choline and suspected it to be acetylcholine. In 1926, Loewi and E. Navratil deduced that the compound is probably acetylcholine, as vagusstoff and synthetic acetylcholine lost their activity in

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