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Serotonin
Identifiers
CAS number 50-67-9 Yes check.svgY
PubChem 5202
ChemSpider 5013
MeSH Serotonin
SMILES
InChI
Properties
Molecular formula C10H12N2O
Molar mass 176.215 g/mol
Appearance White powder
Melting point

167.7 °C, 441 K, 334 °F

Solubility in water slightly soluble
Dipole moment 2.98 D
Hazards
MSDS External MSDS
LD50 60 mg/kg (oral, rat)
 Yes check.svgY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Serotonin (pronounced /ˌsɛrəˈtoʊnən/) or 5-Hydroxytryptamine (5-HT) is a monoamine neurotransmitter that is primarily found in the gastrointestinal (GI) tract and central nervous system (CNS) of humans and animals.

Approximately 80 percent of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements.[1][2] The remainder is synthesized in serotonergic neurons in the CNS where it has various functions, including the regulation of mood, appetite, sleep, muscle contraction, and some cognitive functions including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.

Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.

Serotonin is eventually metabolized to 5-HIAA by the liver, and excreted by the kidneys. One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing, diarrhea, and heart problems. Due to serotonin's growth promoting effect on cardiac myocytes, persons with serotinin-secreting carcinoid may suffer a right heart (tricuspid) valve disease syndrome, caused by proliferation of myocytes onto the valve.

In addition to animals, serotonin is also found in insects, fungi and plants.[3] Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side effect of serotonin injection. Serotonin is produced by pathogenic amoebas, 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.

Contents

History

In 1935 Italian Vittorio Erspamer showed that an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later Erspamer was able to show that it was a previously unknown amine which he named enteramine.[4] In 1948 Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone they named it serotonin.[5] In 1952 it was shown that enteramine and serotonin was the same substance, and as the broad range of physiological roles were elucidated the abbreviation 5HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field.[6]

Functions

Serotonin has been used as a neurotransmitter since very early in nerve system evolution, and is found in all bilateral animals where it mediates gut movements and the animals perception of resource availability. In the simplest animals resources are equivalent with food, but in advanced animals such as arthropods and vertebrates resources also can mean social dominance. In response to the perceived abundance or scarcity of resources the animal's growth, reproduction or mood may be elevated or lowered. Recent studies involving the serotonin transporter gene 5-HTT have shown that the short allele of this gene increase synaptic serotonin levels. These genetic studies have demonstrated that serotonin has strong associations with depression in regards to a negative environment.

Gauge of food availability

Serotonin functions as a neurotransmitter in the nervous systems of simple as well as complex animals. For example, in the roundworm C. elegans, which feeds by grazing on bacteria, serotonin is released as a signal in response to positive events i.e., finding a new grazing ground or in male animals finding a hermaphrodite to mate. When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food.[7] The released serotonin activates the muscles used for feeding, while octopamine suppresses them.[8] Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability. This system has been partially conserved during the 700 million years of evolution which separate C. elegans from humans. When humans smell food dopamine is released to increase the appetite. But unlike in worms serotonin does not increase anticipatory behaviour in humans, instead the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs which block 5-HT2C receptors makes the body unable to shut off appetite, and are associated with increased weight gain,[9] especially in people who have a low number of receptors.[10] The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm,[11] just as the serotonin release in the ventromedial nucleus which is characterised by a peak at morning when the motivation to eat is strongest.[12]

Effects of food content

In humans serotonin levels are affected by diet. An increase in the ratio of tryptophan to phenylalanine and leucine will increase serotonin levels. Fruits with a good ratio include dates, papaya and banana. Foods with a lower ratio inhibit the production of serotonin. These include whole wheat and rye bread.[13] Research also suggests that eating a diet rich in whole grain carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition.[14] However, increasing insulin for a long period may trigger the onset of insulin resistance, obesity, type 2 diabetes, and lower serotonin levels. Muscles use many of the amino acids except tryptophan, allowing men to have more serotonin than women.[15] Myo-inositol, a carbocyclic polyol present in many foods, is known to play a role in serotonin modulation.[16]

In the digestive tract

The gut is surrounded by enterochromaffin cells which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin.

If irritants are present in the food the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea so that the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting.[17] The enterochromaffin cells not only react to bad food, they are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment and are considered the gold standard for this purpose.[18]

Gauge of social situation

How much food an animal gets does not only depend on the abundance of food but also on the animal's ability to compete with others. This is especially true for social animals where the stronger individuals might steal food from the weaker. Thus serotonin is not only involved in the perception of food availability but also of social rank. If a lobster is injected with serotonin, it behaves like a dominant animal, while octopamine causes subordinate behavior.[19] A frightened crayfish flips its tail to flee, and the effect of serotonin on this behavior depends on the animal's social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is that social experience alters the proportion between different serotonin receptors (5-HT receptors) that have opposing effects on the fight-or-flight response. The effect of 5-HT1 receptors predominates in subordinate animals while 5-HT2 receptors predominates in dominants.[20] In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression,[21] and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.[22] Most of the brain serotonin is not degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surface. Studies have revealed that nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy,[23] and the effect of this variation was found to interact with the environment in depression.[24][25]

Effects on growth and reproduction

In C. elegans artificial depletion of serotonin or increase of octopamine cues behavior that is typical of a low-food environment: C. elegans becomes more active, and mating and egg-laying is suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal.[26] Serotonin is necessary for normal male mating behavior,[27] and the inclination to leave food to search for a mate.[28] The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin-like signaling and the TGF beta signaling pathway, which control long-term adaption.

In the fruitfly where insulin both regulates blood sugar and acts as a growth factor serotonergic neurons regulate the adult body size by affecting insulin secretion.[29][30] Serotonin has also been identified as the trigger for swarm behavior in locusts.[31] In humans though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones so that serotonin suppresses insulin release from the beta cells in the pancreas,[32] and exposure to SSRIs reduces fetal growth.[33] Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors.[34] Serotonin present in the blood then stimulates cellular growth to repair liver damage.[35] 5HT2B receptors also activate osteoblasts, which build up bone[36] However, serotonin also activates osteoclasts, which degrade bone.[37]

Cardiovascular growth factor

Serotonin in addition evokes endothelial nitric oxide synthase activation and stimulates through a 5-HT1B receptor meditated mechanism the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.[24] In blood, serotonin is collected from plasma, by platelets which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.[38]

Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.[39] In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine and methysergide),[39] the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.[40] As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was in decreasing use since reported in 2003 to be associated with cardiac fibrosis.[41] Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide along with cabergoline in causing valvular heart disease.[42][43] As a result of this, the FDA removed pergolide from the U.S. market in March, 2007.[44] (Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).[45]

Local effects of injection: venoms and pain

Since serotonin is an indicator of bleeding, a sudden large increase in peripheral levels causes pain. The reason for wasps, and deathstalkers to have serotonin in their venom [46][47] may be to increase the pain of their sting on large animals, and also to cause lethal vasoconstriction on smaller prey.

Deficiency

Genetically altered C. elegans that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state.[48][49]

Serotonin in mammals is made by two different tryptophan hydroxylases: TPH1 produces serotonin in the pineal gland and the enterochromaffin cells, while TPH2 produces it in the raphe nuclei and in the myenteric plexus. Genetically altered mice that lack TPH1 develop progressive loss of heart strength early on. They have pale skin and breathing difficulties, are easily tired, and eventually die of heart failure.[50] Genetically altered mice that lack TPH2 are normal when they are born. However, after three days they appear to be smaller and weaker, and have softer skin than their siblings. In a purebred strain 50% of the mutants died during the first four weeks, but in a mixed strain 90% survived. Normally the mother weans the litter for three weeks, but the mutant animals needed five weeks. After that they caught up in growth and had normal mortality rates. Subtle changes in the autonomic nervous system are present, but the most obvious difference from normal mice is the increased aggressiveness and impairment in maternal care of young.[51] Despite the blood-brain barrier, the loss of serotonin production in the brain is partially compensated by intestinal serotonin. The behavioral changes become greatly enhanced if one crosses TPH1- with TPH2-lacking mice and gets animals that lack TPH entirely.[52]

In humans, defective signaling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS). Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy[53] genetically modified lab mice to produce low levels of the neurotransmitter serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age. Researchers now believe that low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death, they said in the July 4, 2008 issue of Science.[34] If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).[54]

Low levels of serotonin may also be associated with intense spiritual experiences.[55] Recent research conducted at Rockefeller University shows that, in both patients who suffer from depression and mice that model the disorder, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.[56] Obsessive-compulsive disorder (OCD) can be a debilitating disorder with the following two anxiety-related essential features: obsessions (undesirable, recurrent, disturbing thoughts) and compulsions (repetitive or ritualized behaviors). SSRIs, and other medicines that alter serotonin levels have been approved for use in the treatment of symptoms of OCD.

Anatomy

 A drawing of the brain, the serotonergic system is red and the mesolimbic dopamine pathway is blue. There is one collection of serotonergic neurons in the upper brainstem that sends axons upwards to the whole cerebrum, and one collection next to the cerebellum that sends axons downwards the spinal cord. Slightly forward the upper serotonergic neurons is the ventral tegmental area, the dopaminergic neurons there sends axons to the nucleus accumbens, hippocampus and the frontal cortex. Over the VTA is another collection of dopamine cells, the substansia nigra, which send axons to the striatum.
Serotonin system, contrasted with dopamine system.

Gross anatomy

The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.[57] The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation.[58] Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord while the axons of the higher nuclei spread out in the entire brain.

Microanatomy

Serotonin is released into the space between neurons, and diffuses over a relatively wide gap (>20 µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.

Receptors

5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade.[59]

Termination

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Interestingly, a 2006 study conducted by the University of Washington suggested that a newly discovered monoamine transporter, known as PMAT, may account for "a significant percentage of 5-HT clearance".[24] Contrasting with the high-affinity SERT, the PMAT has been identified as a low affinity transporter with an apparent Km of 114 micromoles/L for serotonin; approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport capacity than SERT, "..resulting in roughly comparable uptake efficiencies to SERT in heterologous expression systems." The study also suggests that some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC50 values which surpass the therapeutic plasma concentrations by up to four orders of magnitudes; therefore, SSRI monotherapy is ineffective in PMAT inhibition. At present, there are no known pharmaceuticals which would appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine albeit at Km values even higher than that of 5-HT (330–15,000 μmoles/L).

Serotonylation

Serotonin can also signal through a nonreceptor mechanism called serotonylation. In this serotonin modifies proteins.[32] This process underlies serotonin effects upon platelet-forming cells (thrombocyte)s in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis.[60] A similar process underlies the pancreatic release of insulin.[32] The effects of serotonin upon vascular smooth muscle "tone" (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.[61]

Biosynthesis

 On top a L-tryptophan molecule with an arrow down to a 5-HTP molecule. Tryptophan hydroxylase catalyses this reaction with help of O2 and tetrahydrobiopterin which becomes hydroxytetrahydrobiopterin. From the 5-HTP molecule goes an arrow down to a serotonin molecule. Aromatic L-amino acid decarboxylase catalyses this reaction with help of pyridoxal phosphate. From the serotonin molecule goes an arrow to a 5-HIAA molecule at the bottom ot the image. Monoamine oxidase catalyses this reaction, in the process O2 and water is consumed, and ammonia and hydrogen peroxide is produced.
The pathway for the synthesis of serotonin from tryptophan.

In animals including humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a brain-specific isoform.[62]

Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents. One product of serotonin breakdown is 5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.

Drugs targeting the 5-HT system

Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs and empathogens.

Psychedelic drugs

The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD are agonists primarily at 5HT2A/2C receptors.[63][64] The Empathogen-entactogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons.[65]

Antidepressants

The most prescribed drugs in many parts of the world are drugs which alter serotonin levels. They are used in depression, Generalized anxiety disorder and social phobia. The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs. Some drugs inhibit the re-uptake of serotonin, making it stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both serotonin and norepinephrine. The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs. The side effects that have become apparent in recent times include a decrease in bone mass in elderly and increased risk for osteoporosis. However, it is not yet clear whether it is due to SSRI action on peripheral serotonin production and or action in the gut or in the brain.[37] Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases in serotonin. This has been connected to the observation that the benefit of SSRI's may decrease in selected patients after a long-term treatment. A switch in medication will usually resolve this issue (up to 70% of the time).[66] The novel antidepressant tianeptine, a selective serotonin reuptake enhancer, has mood-elevating effects. This provides evidence for the theory that serotonin is most likely used to regulate the extent or intensity of moods.

Although phobias and depression might be attenuated by serotonin-altering-drugs this does not mean that the individual's situation has been improved, but only the individual's perception of the environment. Sometimes a lower serotonin level might be beneficial, for example in the ultimatum game, where players with normal serotonin levels are more prone to accept unfair offers than participants whose serotonin levels have been artificially lowered.[67]

Serotonin syndrome

Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.[68] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.[69]

Antiemetics

5-HT3 antagonists such as ondansetron, granisetron, and tropisetron are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of post-operative nausea and vomiting.

In unicellular organisms

Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae.[70] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.[71][72] Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.[73] Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent.[74] This means that the serotonin secretion not only serves to increase the spread of enteamoebas by giving the host diarrhea, but also to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside a host the density of entoamoebas is low, and hence also the serotonin concentration. Low serotonin signals to the entoamoebas that they are outside a host and they become less virulent in order to conserve energy. When they enter a new host they multiply in the gut and become more virulent as the serotonin concentration increases.

In plants

In drying seeds serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450 monooxygenase, yielding serotonin.[75]

However, since serotonin is a major gastrointestinal tract modulator, it may be produced by plants in fuits as a way of speeding the passage of seeds through the digestive tract, in the same way as many well known-seed and fruit associated laxatives. Serotonin is found in mushrooms, fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. Serotonin concentrations of 3–30 mg/kg have been found in plantain, pineapple, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.[76]

Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms (see above).

Unlike its precursors, 5-HTP and tryptophan, serotonin does not cross the blood–brain barrier, which means that ingesting serotonin in the diet has no effect on brain serotonin levels.

Methyl-tryptamines and hallucinogens

Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and (OH) groups, are N-oxides, or miss the OH group. These compounds do reach the brain, although some portion of them are metabolized by MAO-B enzymes in the liver. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion.

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Wiktionary

Up to date as of January 15, 2010

Definition from Wiktionary, a free dictionary

German

Noun

Serotonin n.

  1. serotonin







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