acetylcholine

Neurotransmitter

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Acetylcholine, molecular formula CH three COOCH two CH two N + （CH three ） three , is a kind of Neurotransmitter 。 Be quickly cholinesterase destruction. Acetylcholine can specifically act on various kinds of choline recipient , but its role is extensive and its selectivity is not high. It is not used for medicine in clinic, but only for experiment. In nerve cells, acetylcholine is composed of choline and Acetyl CoA Choline acetyltransferase（ Choline acetylase ）Of Catalysis Lower synthetic. Mainstream research believes that the increase in the content of this substance in the human body Alzheimer's disease (Alzheimer's disease) symptoms improved significantly.

Chinese name: acetylcholine
Foreign name: ACh, acetylcholine
Discovery time: 1914

Discover people: Ewins
Role: transmit Nerve impulse
Abbreviation: ACh、AcCh

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definition

Acetylcholine, molecular formula CH three COOCH two CH two N + （CH three ） three In nerve cells, acetyl choline It is composed of choline and Acetyl CoA Choline acetyltransferase（ Choline acetylase ）It is synthesized under the catalysis of. Because this enzyme exists in the cytoplasm, acetylcholine is synthesized in the cytoplasm, and then taken up by vesicles and stored.

get into Synaptic space Acetylcholine acts on Postsynaptic membrane After playing a physiological role (acetylcholine can cause the receptor membrane to produce action potential) cholinesterase Hydrolyze to choline and acetic acid, so that acetylcholine is destroyed and promoted (rapid decomposition is to avoid Receptor cell Conduction block caused by continuous depolarization of membrane), this process is called inactivation.

Cause acetylation choline The key factor of quantum release is Ca caused by depolarization of nerve endings 2+ Internal flow. When the nerve impulse is transmitted to the nerve end plate, the membrane potential drops, leading to Ca 2+ The voltage gate channel passing through is opened to make Ca 2+ It enters the endplate and stimulates the endplate to secrete acetylcholine. Acetylcholine further acts on muscle cells to cause contraction of muscle cells.

Human understanding of it

In 1914, Ewins Ergot fungus Acetyl was found in choline This is the first report that acetylcholine is found in non nerve cells. Later, people began to pay more attention to a variety of bacteria, fungi, lower plants and higher plant Acetylcholine and its related enzymes and receptors were found in. along with Cholinergic system With the further discovery and research in plants, it seems that people are expected to find another similarity between animals and plants at the molecular level, so botanist With great enthusiasm, he devoted himself to this research. However, due to the limitations of research methods at that time, the lack of understanding of the differences between animals and plants, and the fact that some studies were difficult to repeat in other laboratories, the research on plant acetylcholine was mostly sporadic and unsystematic, and the depth and breadth of research were far from comparable to animals. A reasonable explanation for its mechanism of action in plants has not been proposed yet. In recent years, we and several other foreign laboratories have re developed acetylation choline The study of physiological function and mechanism in plants provides a new clue to reveal the mechanism of action of plant acetylcholine.^[1]

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Plant physiological process

seed germination

acetyl choline and acetylcholinesterase It may be involved in the regulation of seed germination and early seedling growth of some plants. The mechanism of acetylcholine affecting these physiological processes may involve the regulation of the transfer of storage from the hypocotyl to the plant rapid growth site. There are many contradictory reports on the effect of acetylcholine on the germination of light - demanding seeds. Tretyn et al. are studying acetylcholine and its analogues Acetylcholinesterase inhibitor It was found that these compounds had no effect on the seed germination of light insensitive plants whether in light or in darkness. However, it can promote the germination of light needed seeds under light, but it has no effect in dark. For seeds that do not need light, acetylcholine inhibits their germination under light, while acetylcholine analogue choline has no effect on the above process. Since acetylcholine and acetylcholinesterase exist widely in seeds, it is reasonable to speculate that acetylcholine is involved in regulating seed germination, and the mechanism of regulation may involve the inhibition of acetylcholinesterase activity in seeds by light.

grow

acetyl choline The effect on growth varies with different experimental conditions, plant species or different tissues of the same plant. Acetylcholine can inhibit the development of soybean lateral roots by simulating the effect of red light, and can also increase the growth and dry weight of wheat seedlings. In vitro, acetylcholine can stimulate the elongation of oat coleoptile and cucumber hypocotyl and the growth of mung bean hypocotyl, stimulate the growth of broad bean hypocotyl and inhibit the growth of its epicotyl. In conclusion, the impact of acetylcholine on plant physiological processes is closely related to the tissues used and experimental conditions, and its maximum effect is in the pH acid region.

Florification

Acetylcholine can simulate the effect of red light and inhibit the Peroxidase So that spinach can blossom without induction. acetyl choline It can inhibit the flower formation of duckweed G1 under continuous light conditions (24 h light/0 h dark) and stimulate the flower formation of duckweed Torr under non induced short day conditions. atropine It can inhibit the growth under continuous light Duckweed G3 flower and tube Curare No effect was observed, suggesting that the induction of flower formation by acetylcholine may be mediated by muscarinic receptors on the plasma membrane. The induction of acetylcholine on flower formation may also be related to its regulation of membrane ion permeability. Photoperiod induced flower formation involves the change of leaf membrane potential, and acetylcholine may also participate in flower formation induction by affecting membrane potential.

Respiration

acetyl choline It can increase the oxygen consumption rate of root tip cells. Jaffe's results with free mitochondria have confirmed this. With the consumption of oxygen, the level of ATP in tissues decreased 10 times, and the level of free phosphorus increased 14 times. This effect of acetylcholine may be caused by its respiration Electron transfer chain It is caused by dissolving and coupling with oxidized phosphoric acid. According to these experimental results, Jaffe proposed the action mode of acetylcholine on soybean root tip cells, that is, when the intercellular concentration of acetylcholine increased, acetylcholine reached its target, followed by the secretion of protons, the consumption of oxygen and ATP hydrolysis These processes are related to the increase of membrane permeability to cations.

photosynthesis

acetyl choline It can reduce ATP synthesis in chloroplasts by more than 80% without affecting electron transfer. In addition, acetylcholine with a concentration lower than 0.1 mmol can stimulate Acyclic photophosphorylation However, the acyclic photophosphorylation was inhibited when the concentration was greater than 0.1 mmol. In both cases, acetylcholine did not affect the reduction of NADP+. Neostigmine (neostigmine) can inhibit the synthesis of ATP, but does not affect the electron from water to Cytochrome f Or NADP+. Muscarine and atropine It can also inhibit the reduction of NADP+and acyclic photophosphorylation.

In addition, acetylcholine can also affect the absorption of oxygen in isolated chloroplasts and inhibit the expansion of chloroplasts stimulated by light; Stimulate the outflow of sodium and potassium ions from chloroplasts. Thus, acetylcholine may regulate the coupling between chloroplast membrane ion permeability and electron transport and ATP synthesis in chloroplasts.

Shed field effect

Red light causes yellowed mung bean and barley root tips to be adsorbed on the inner wall of the negatively charged glass cup, while far red light causes root tips to be released from the cup wall into solution. This phenomenon is called the tanada effect. Acetyl in the dark choline It can make the soybean root tip in vitro absorb to the inner wall of the negatively charged glass cup, and prevent the root tip from leaving the cup wall caused by far red light, Acetylcholinesterase inhibitor Physostigmine (eserine) increased the sensitivity of tissues to acetylcholine. These results suggest that endogenous acetylcholine may play a controlling role in this physiological process.

Red light can increase the level of acetylcholine in tissues, which may be related to the formation of Pfr promoted by red light, which is related to the synthesis of acetylcholine. The increase of acetylcholine level in the tissue can stimulate protons to flow out of the root cells into the solution, thus forming a positive surface potential, so that the root tip is adsorbed to the inner wall of the negatively charged glass cup; Far red light promotes Photosensitizer From far red light absorption (Pfr) to red light absorption (Pr), the root tip was released from the inner wall of the glass cup into the solution. But there are also experiments indicating that acetyl choline In this process, it is only equivalent to the action of monovalent cations.

Blade movement

Jaffe proposes acetylation choline It may regulate the movement of Mimosa pudica leaves. Macroptilium atropurpureum It is a commonly used forage grass, whose leaves can droop under strong light to avoid direct damage to leaves by high light intensity. It is reported that the leaves of tropical varieties droop faster than those of temperate varieties under strong light, and the drooping state recovers faster after light intensity decreases. The determination of acetylcholine in the leaf bedding tissue of this plant showed that the change of acetylcholine level was closely related to the state of leaves. The content and variation range of tropical varieties are larger, and the external application of acetylcholine can make them recover from the drooping state. The results of further research showed that the change of acetylcholine level in leaves was caused by acetylcholinesterase Acetylcholinesterase is mainly distributed around the vascular bundle, so it is speculated that acetylcholine may affect the flow of ions into and out of the vascular bundle, thereby affecting the flow of water in and out of the vascular bundle, and finally realizing the regulation of leaf movement.

permeability

acetyl choline It can stimulate proton outflow from soybean root tip cells, induce changes in membrane potential of spinach leaves, and inhibit blue light induced hyperpolarization of soybean hypocotyl hook membrane potential and absorption of potassium by this tissue. These processes involve the regulation of acetylcholine on membrane permeability.

In addition to influencing the above processes, acetylcholine can also affect the tissue's calcium ion Absorption of. Tretyn found that acetylcholine could stimulate the absorption of calcium ions in the etiolated oat coleoptile. acetylcholinesterase Inhibitors of acetylcholine can increase the sensitivity of tissues to acetylcholine; Inhibitors of calcium channels can inhibit the increase of calcium absorption stimulated by acetylcholine. These results suggest that acetylcholine is involved in the regulation of calcium channels in plants.

Metabolic effects

Acetylcholine can affect the metabolism of membrane lipids in plants. For example, it can inhibit phosphorus incorporation into phospholipid molecules of etiolated soybean stem segments, but it mainly inhibits phosphorus incorporation under aerobic conditions Phosphatidylethanolamine and Phosphatidylcholine In the absence of oxygen, acetylcholine mainly inhibits phosphorus incorporation Phosphatidylinositol 。 These results show that there is similarity between plant phospholipids and animal phospholipids, acetyl choline Can also affect plants Phospholipid metabolism 。

Participation in interaction

Participate in the interaction between plants and between cells

In an ecological environment, there are often interactions between plants and between plants and other organisms. This kind of interaction can be promotive or inhibitory, that is, it is a mutually reinforcing relationship. acetylcholinesterase It exists in the root nodules of soybean infected by rhizobia, and the maximum activity of acetylcholinesterase is consistent with the maximum assimilation period of nitrogen in the root nodules. It is speculated that acetylcholine and its esterase are in Host plant Play a role in the interaction between them. Acetylcholinesterase also exists in Lichens It is mainly distributed at the interface between fungi and algae that make up lichens. The acetylcholinesterase activity increased in the process of spore production in soridia, and the enzyme activity concentrated in the contact area. Acetylcholine and acetylcholinesterase The mechanism involved in this biological interaction of lichens may be that acetylcholine and acetylcholinesterase, which are realized by regulating the permeability of membrane to ions and mediating the influence of light in the environment on the reproduction of lichens, may also participate in the recognition between pollen and stigma. Acetylcholinesterase is mainly distributed on the surface of pistil stigma, and also exists in Pollen grain And the tip of the pollen tube. acetyl choline The activator and antagonist of AChE and the inhibitor of AChE can affect the pollen germination and pollen tube elongation of some plants. Therefore, acetylcholine and acetylcholinesterase may be involved in the interaction between stigma and pollen.

Action mechanism

stay Animal cell Mesoacetyl choline After binding to the receptor, on the one hand, it directly affects the permeability of the membrane to ions, and on the other hand, through various Second Messenger It affects the progress of various physiological processes. In the plant kingdom, although the receptor for acetylcholine has not been finalized biochemically, a series of pharmacological evidences indicate that there is indeed an acetylcholine receptor in plants. Little is known about the events of acetylcholine binding to receptors in plants. About acetylcholine in plant cell In addition to the scattered research above, only Tretyn et al Protoplast The research on expansion and young leaf unfolding is relatively systematic and reveals some details.

signal transduction

Protoplast expansion red light can stimulate etiolated wheat Mesophyll cell The protoplast volume expanded, and this stimulation could be reversed by the subsequent far red light irradiation, indicating that this reaction was caused by Photosensitizer Under control. The stimulating effect of red light on protoplast volume expansion requires that the medium contains Ca 2+ 。 acetyl choline It can replace red light to cause protoplast expansion in the dark. Different from the reaction caused by red light, acetylcholine can not only 2+ In the medium containing Na + Or K + The expansion of protoplasts can also be caused by.

Except acetylcholine, only Carbamyl Choline can stimulate protoplast expansion, while choline, propionyl choline and butyrylcholine have no such effect. Inhibitors of acetylcholinesterase Physostigmine It can increase the sensitivity of protoplasts to acetylcholine. It can be considered that acetyl choline It can specifically stimulate the expansion of yellowing wheat mesophyll protoplasts

Whether the process of acetylcholine induced protoplast expansion involves acetylcholine receptor The participation of can be determined by the activator and inhibitor of acetylcholine receptor. acetylcholine N-type receptor The activator nicotine of + Or K + It can directly stimulate protoplast expansion in the medium containing Ca 2+ Nicotine has no effect in the medium of. Different from the above results, muscarine, the activator of M-type receptor, can be used in the 2+ In the medium containing Na + Or K + Has no effect in the medium of. Studies using acetylcholine receptor inhibitors have reached the same conclusion. Inhibitors of M-type receptors atropine With Na + Or K + It has no effect on acetylcholine stimulated protoplast expansion in the medium containing Ca 2+ In the medium, acetylcholine induced protoplast expansion can be inhibited. N-type receptor inhibitor tube Curare With Ca 2+ Acetyl in medium choline Stimulated protoplast expansion has no effect, but when Na + Or K + It has inhibitory effect in the medium of. Fluorescence localization technique showed that N-type acetylcholine receptors were mainly distributed on the surface of protoplasts.

In the process of protoplast expansion induced by acetylcholine, the signal transduction after acetylcholine as the receptor may involve Ca 2+ And CaM, because Ca 2+ Channel inhibitor nifedipine (nifedipine, NIF) and La 3+ It can completely inhibit acetylcholine induced protoplasts in Ca 2+ Expansion in the medium. Similarly, calmodulin inhibitors and G protein inhibitors also have the same effect, and these compounds + Or K + It has no effect in the medium of.

The development of young leaves of wheat seedlings growing in darkness for 8 days is controlled by the phytochrome system. If the medium contains Ca 2+ , Acetyl choline In the dark, it can stimulate the development of young leaves in excised leaf segments. Without Ca 2+ With Na + Acetylcholine can also stimulate the development of etiolated wheat primary leaves. Among various derivatives of acetylcholine, only carbamoyl acetylcholine can stimulate the unfolding of etiolated wheat primary leaves. Antagonists of acetylcholine receptors, atropine And D-tube Curare It can respectively offset the effect of acetylcholine on Ca 2+ And Na + The expansion of the induced blade in the medium. The activator of acetylcholine receptor, muscarine and nicotine can 2+ And Na + It stimulates the expansion of protoplasts in the medium of. Acetylcholine induced Ca 2+ Dependent blade development can be Ca 2+ The channel inhibitor nifedipine and calmodulin inhibitor trifluoperazine (TFP) were weakened, and only the calmodulin inhibitor TFP could inhibit acetylcholine induced + The unfolding of etiolated wheat primary leaves in medium.

According to the above results, it can be preliminarily considered that acetyl in plants choline It may function in a mechanism similar to that in animals. Acetylcholine first binds to M - and N-type acetylcholine receptors. As in animal cells, M-type acetylcholine receptors may be associated with phosphoinositol Metabolic pathway In this pathway, G protein, Ca 2+ Channels and calmodulin are activated successively, and finally Physiological response 。 N-type receptor It is non phosphoinositol dependent and directly controls the permeability of membrane to ions. These two pathways can independently cause protoplast expansion or leaf opening.

enzymatic activity

acetyl choline In addition to regulating the permeability of membrane to ions, the mechanism of action in plants may also involve the regulation of some enzyme activities in plants. Inhibitory effect of acetylcholine on root growth of Lens culinaris peroxide The activity changes of isozymes are closely related, which can stimulate the activity of some isozymes and inhibit the activity of others.

Acetylcholine itself affects plant Phenylalanine The activity of aminolyase and the synthesis of flavonoids have no effect, but it can offset the stimulation of red light on the activity of phenylalanine aminolyase and the synthesis of flavonoids.

For endogenous Growth regulator Acetylcholine can affect plant body Indole acetic acid And ethylene metabolism. In soybean hypocotyls, acetylcholine inhibits indoleacetic acid stimulated ethylene synthesis and counteracts its inhibition on the straightening of soybean hypocotyls' hooks, and it can also counteract ethylene stimulated growth of fern protonema. This effect of acetylcholine may be achieved by affecting the levels of endogenous indoleacetic acid and ethylene. Acetyl proved by the experiment of soybean leaves in vitro choline It can inhibit the synthesis of ethylene in tissues.

Acetylcholine may also interact with endogenous gibberellin. It can partly replace gibberellin to induce the elongation of cucumber hypocotyl, and can also cause the increase of free gibberellin content in plants, which can atropine Offset.

Effects of physiological activities

the central administration Cholinergic system It is closely related to learning and memory. Acetylcholine (ACh) is an important part of the central cholinergic system Neurotransmitter One of its main functions is to maintain consciousness and play an important role in learning and memory.

Cognitive activity relationship

Brain extracellular acetyl choline The change of (ach) mainly reflects Cholinergic neuron Activity, cortex and a hippocampus Ach in isobrain regions mainly comes from basal forebrain Fiber projections of cholinergic neurons. The application of microdialysis and other techniques in physical examination of acetylcholine content in the brain of conscious, free moving animals during cognitive process can study the relationship between ach and specific behavioral responses and cognitive activities. The study found that when the body needs to analyze new stimuli, the cholinergic neurons in the basal forebrain are activated during cognitive activities such as learning and memory, spatial working memory, attention, spontaneous movement and inquiry behavior, and the release of ach in the brain changes accordingly. The results suggest that the activity of cholinergic transmitter system in brain is closely related to cognitive process.

Parkinson's disease relationship

Parkinson's disease“ Tremor paralysis ", is a kind of central nervous system Degenerative disease, mainly due to midbrain location“ Substantia nigra "The synthesis of dopamine decreases and acetyl is inhibited after the cells in" choline The excitatory effect of acetylcholine is relatively enhanced when the function of acetylcholine is reduced. The result of the imbalance between the two is "tremor paralysis".

The cause of degeneration and necrosis of substantia nigra cells has not yet been understood, which may be related to genetic and environmental factors. Some scholars believe that insufficient intake of protein, fruit, dairy products, alcoholism, trauma, overwork and some mental factors may be risk factors for disease. The tremor paralysis caused by the unexplained decrease of dopamine is called "primary tremor paralysis" in medicine, that is Parkinson Disease;

Human body utilization

Human brain tissue has a large amount of acetyl choline However, the content of acetylcholine will decrease with the increase of age. The normal elderly decreased by 30% compared with young people, while the decline of senile dementia patients was more serious, up to 70%~80%. American doctor Wutman observed the decrease of acetylcholine in the brain tissue of the elderly, so he gave the elderly food rich in choline and found that there was obvious prevention Hypomnesia Role of. Scientists from Britain, Canada and other countries have also carried out research one after another, agreeing that as long as sufficient choline is supplied in a controlled manner, memory loss in the elderly aged around 60 can be avoided. Therefore, maintaining and increasing the content of acetylcholine in the brain is a solution Memory decline The fundamental approach to. In nature, acetylcholine mostly exists in eggs, fish, meat, soybeans, etc. in the form of choline. These choline must have a biochemical reaction in the human body before they can synthesize acetylcholine with physiological activity. In addition, take it regularly Royal jelly It can increase the content of acetylcholine in the brain, thus promoting the activation of brain nerve conduction function, improving the speed of information transmission, enhancing brain memory, comprehensively improving brain function, and delaying aging.^[2]

pharmacological action

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cardiovascular system

Synthesis and function of acetylcholine in synapses

The cardiovascular system ACh mainly has the following effects on the cardiovascular system:

(1) Vasodilatory effect: intravenous injection of small dose of this product can cause a temporary drop in blood pressure due to systemic vasodilation, accompanied by reflexivity heart rate Accelerate. ACh can cause many vasodilations. Such as lungs and coronary vessels. Its vasodilation effect is mainly due to stimulation vascular endothelial cell M， Choline receptor Subtypes, leading to endothelium-dependent Diastolic factor (EDRF) i.e nitric oxide (nitic oxide, No) release, thus causing proximity smooth muscle Cell relaxation may also occur through baroreceptors or Chemoreceptor Caused by reflection. If the vascular endothelium is damaged, the above effects of ACh will no longer exist, on the contrary, it can cause vasoconstriction. In addition, ACh stimulates sympathetic nerve endings Synapse Anterior Membrane M1 Receptor, Inhibitory Norepinephrine The release of NA from ergic nerve endings is also related to the vasodilation effect of ACh.

(2) Slowing heart rate: also called negative frequency effect. ACh enables Sinoatrial node The automatic depolarization in diastole is delayed, and the repolarization current increases, which prolongs the time when the action potential reaches the threshold, leading to a slower heart rate.

(3) Slow down Atrioventricular node And Purkinje fiber conduction: negative conduction. ACh can prolong the refractory period of atrioventricular node and β urkinje fibers and slow their conduction. When cardiac glycosides are used to increase vagus nerve tension or large doses are used by systemic administration cholinoceptor agonists Completeness of Cardiac block It is often related to the obvious inhibition of atrioventricular node conduction.

(4) Weakening Myocardial contractility : negative Myodynamia 。 people say that choline Energetic nerves are mainly distributed in sinoatrial node, atrioventricular node, Purkinje fiber and atria However, the ventricle is less innervated by cholinergic nerve, so ACh inhibits atrial contraction more than the ventricle. However, because vagal nerve endings are closely adjacent to sympathetic nerve endings, ACh released by vagal nerve endings can activate the presynaptic of sympathetic nerve endings muscarinic receptor , Feedback inhibition of sympathetic nerve endings Norepinephrine Release. It weakens the ventricular contractility.

(5) Shortening atrial refractory period: ACh does not affect Atrial muscle However, it can shorten atrial refractory period and action potential duration (that is, vagus nerve effect).

gastrointestinal tract

ACh can obviously excite gastrointestinal smooth muscle, increase its contraction amplitude, tension and peristalsis, and promote gastric and intestinal secretion, causing nausea, belching, vomiting, abdominal pain, defecation and other symptoms.

Urinary tract

ACh can increase the peristalsis of smooth muscle of urinary tract, Detrusor muscle of bladder Contraction, which increases the maximum pressure of bladder self emptying, reduces bladder volume, and Trigone vesicae Area and external sphincter relax, leading to bladder emptying.

other

(1) Glands: ACh can make lacrimal glands, trachea and bronchial glands salivary glands The secretion of digestive gland and sweat gland increased.

(2) Eye: When ACh drops into the eye, it may cause pupil Contraction, adjust to myopia.

(3) Ganglia and skeletal muscle : ACh acts on NN of autonomic ganglia Choline receptor And skeletal muscle Neuromuscular junction NM cholinergic receptor, causing sympathetic and parasympathetic ganglion excitation and skeletal muscle contraction. In addition, due to Adrenal medulla is innervated by sympathetic preganglionic fibers , so activation of NN choline receptor can cause adrenaline Release.

(4) Central: Because ACh is not easy to enter the central, although there are cholinergic receptors in the central nervous system, peripheral administration rarely produces central effects.

(5) Bronchus: ACh can constrict the bronchus.

(6) ACh can also be excited Carotid body and Aortic body Chemical receptors.^[3]

Research progress

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In a new study on rodents, researchers from New York University Grossman School of Medicine and other research institutions described how learning occurs without direct rewards. Relevant research results will be published online in Nature on August 9, 2023, with the title of "Intrinsic dopamine and acetylcholine dynamics in the street of medicine". Studies have shown that drinking water produces typical dopamine and acetylcholine release patterns, which are caused by rewards. However, long before drinking water, dopamine and acetylcholine had followed the "ebb and flow" cycle, about twice a second. During this cycle, the level of one hormone decreased and the level of the other increased.^[4]

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