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Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration hypertension organ damage nifedipine 30 mg low cost. Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport arteria rectalis media purchase nifedipine 30mg without prescription. Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals heart attack people order nifedipine 30mg free shipping. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1 hypertension diagnosis buy 20 mg nifedipine with mastercard. Notch and presenilin: Regulated intramembrane proteolysis links development and degeneration. Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. Amyloid deposition is associated with impaired default network function in older persons without dementia. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Alzheimer disease: Evidence for selective loss of cholinergic neurons in the nucleus basalis. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. In 1907, Alois Alzheimer in Munich and Oskar Fischer in Prague described neuritic plaques and neurofibrillary tangles in the disease that Emil Kraepelin, head of the Munich Institute, named after Alzheimer three years later. Over the past 30 years, a direct correspondence between inclusion formation and the degenerative process has emerged. On the one hand, the biochemical study of the neuropathological lesions resulted in the identification of their major molecular components. Remarkably, the defective genes were found to encode or increase the expression of the main components of the neuropathological lesions. It therefore appears that a toxic property conferred by these mutations causes disease. Lewy bodies, neurofibrillary tangles and Pick bodies are intracellular filamentous inclusions. Lewy bodies are made of the protein -synuclein, whereas neurofibrillary tangles and Pick bodies are made of the microtubule-associated protein tau. Synucleinopathies and tauopathies account for the majority of cases of late-onset neurodegenerative disease (Tables 47-1 and 47-2). Synucleins are lipid-binding proteins For a long time, synucleins were believed to have little ordered structure. However, recent work has shown that native -synuclein is a homotetramer with a predominantly -helical conformation. Experimental studies have shown that -synuclein binds to lipid membranes (Davidson et al. Monomeric -synuclein adopts structures rich in -helical character upon binding to lipid membranes containing acidic phospholipids. In cell lines and primary neurons treated with fatty acids, -synuclein accumulates on phospholipid monolayers surrounding triglyceride-rich droplets. Synucleins are phosphoproteins, with serine and tyrosine phosphorylation having been observed in transfected cells. It remains to be established whether phosphorylation of synucleins plays a physiological role in brain. This positively charged region is followed by a hydrophobic middle part and a negatively charged carboxy-terminal region. By immunohistochemistry, - and -synucleins are abundant and concentrated in nerve terminals, with little staining of cell bodies and dendrites. In rat, -synuclein is most abundant in telencephalon and diencephalon, with lower levels in more caudal regions. Positively charged regions are indicated in green, hydrophobic regions in blue and negatively charged regions in red. Curiously, the amino acid at position 53 in mouse and rat -synuclein is a threonine, not an alanine, suggesting that it is not simply the presence of a threonine at position 53 that is pathogenic, but instead some difference in conformation of mutant protein that is characteristic of human, but not rodent -synuclein. The core of the filament extends over 70 amino acids and overlaps with the lipid-binding region of -synuclein. The patient received a transplant of fetal human mesencephalic dopaminergic nerve cells into the putamen 16 years previously. Immunohistochemistry for -synuclein visualizes Lewy bodies and Lewy neurites in (A) the host substantia nigra and (B, C) the transplant.

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H1-receptor antagonists can be proconvulsive in children and animals heart attack is recognized by a severe pain order nifedipine without a prescription, and H1 receptor numbers are increased in some types of human epileptic foci (Iinuma et al arrhythmia ablation is a treatment for quizlet buy cheap nifedipine 30 mg on line. H3 antagonists increase seizure threshold in a variety of models high pulse pressure young age generic 20mg nifedipine with visa, consistent with an elevation in neuronal histamine release heart attack meme buy nifedipine 20 mg low price. Centrally administered histamine agonists can also enhance learning and retention in laboratory animals (Giovannini et al. Histamine is a powerful regulator of many hypothalamic functions concerned with the homoeostasis of the whole organism, the control of the endocrine (Knigge & Warberg, 1991) and the vegetative nervous systems, energy administration, temperature regulation and even breathing and blood pressure (Prast & Philippu, 1991). Histamine excites the neurons in the supraoptic and paraventricular nuclei that release the antidiuretic hormone (vasopressin) from their nerve endings in the neurohypophysis (Haas et al. Neuronal histamine is also an effective modulator of both food and water intake (Onodera et al. Histamine and compounds that increase extracellular histamine concentrations are powerful suppressants of food intake, whereas H1 receptor antagonists. Evidence that histamine contributes to the physiological control of appetite includes findings with genetically obese Zucker rats, which have very low concentrations of hypothalamic histamine. Furthermore, several studies suggest that leptin, the most powerful physiological suppressant of appetite, signals through histaminergic activation of H1 receptors. Histamine is also a powerful dipsogen (an agent that induces drinking), whether administered systemically or directly into the hypothalamus. Histamine also induces antinociceptive (pain-relieving) responses in animals after microinjection into several brain regions (Hough & Rice, 2011). H1 and H2 mechanisms are significant, and both neuronal and humoral mechanisms may be involved. Brain H2 receptors appear to mediate some forms of endogenous analgesic responses, especially those elicited by exposure to stressors. Many of the modulatory actions of histamine discussed above appear to be activated as part of stress responses. Outside the brain, both H1 and H3 receptors exist on certain types of sensory nerves, and activation of these receptors promotes and inhibits, respectively, peripheral nerve transmission related to pain and/or inflammation (Raffa, 2001). There are specific nerve endings for itching that are activated by histamine (Schmelz, 2002). The pain and itch caused by nettles is mediated by histamine located in the spines on the leaves. In some of these cases, there are clear changes in the number or morphology of histaminergic neurons. However, increases in neuronal histamine do not always enhance brain damage; histamine seems to exert a protective effect in some models of cerebral ischemia. Alterations in brain histamine content or dynamics may also be important for cognitive changes resulting from liver disease or histidineamia (an inborn error of histidine metabolism). In addition, histaminergic neurons are activated by vestibular disturbances, leading to the release of histamine in brainstem emetic centers. Both acute and chronic pain states can result from inflammation or peripheral nerve cell injury, and there is substantial evidence that mast cell histamine participates in these disorders. These undesired side effects are essentially mediated by the blockade of brain H1 receptors that are crucial for the regulation of the sleep/wake pattern and the diurnal rhythm of food intake. Nearly all of the over-the-counter sleep aids are brain-penetrating antagonists of the H1 receptor. These limitations have prompted the synthesis of more selective H1-receptor antagonists with optimized pharmacokinetic properties. Drugs that modify pain perception act in part through the histaminergic system Although pain-relieving opioid drugs such as morphine initiate many neurochemical changes, the activation of neuronal histamine release by these agents and the subsequent stimulation of brain H2 receptors are critical for the mechanism of action of these compounds (Gogas et al. Stress responses also can contribute to opioid analgesia, and histaminergic neurons appear to mediate the stressinduced potentiation of morphine antinociception. Although no pain-relieving drugs have been developed based on H2 receptors, a family of novel analgesics has been discovered from drugs related to cimetidine (an H2 antagonist) and burimamide (a drug with both H2 and H3 properties). Outside the brain, H1 receptors on sensory nerve fibers are activated during some kinds of pain and inflammation, and H1 antagonists are used for their anti-inflammatory and analgesic profiles (Raffa, 2001). By an opposing mechanism, H3 agonists reduce pain transmission evoked by chemical and mechanical stimuli (Hough & Rice, 2011). This discovery is important for drug development, since the ability to compete with constitutively active H3 receptor states (inverse agonism) has important therapeutic implications. Primary narcolepsy, a disorder characterized by excessive daytime sleepiness, cataplexy, and narcoleptic episodes, as well as sleepiness of various causes, are currently treated mainly by wake-promoting compounds such as modafinil or psychostimulants, like amphetamine, that act through the dopaminergic system. The brain H3 receptor is currently the most promising target to treat hypersomnia, as its blockade increases histamine release, which stimulates postsynaptic H1 receptors. Indeed, H3 antagonists show a remarkable wake-promoting effect in experimental animals, and clinical studies confirm the validity of this drug class for treating somnolence and vigilance deficiency of diverse pathological origins (Lin et al. All these compounds show a better pharmacological profile than other psychostimulants, because unlike amphetamines, caffeine or modafinil, they do not provoke rebound effects or behavioral excitation. H3 antagonists may also present unique therapeutic options for the treatment of cognition disorders, the dreadful hallmarks across a broad range of neuropsychiatric diseases in patients of all ages. These encouraging results have prompted clinical trials testing the procognitive properties of H3 antagonists in these diseases. H3 receptor blockade can elevate concentrations of histamine, acetylcholine, dopamine, serotonin and noradrenaline in the cortex and may offer a better target for affecting cognitive processes, which often rely on the integration of multiple neurotransmitter systems. It is noteworthy that H3 antagonists do not increase dopamine release in the striatum and nucleus accumbens, a favorable attribute for clinical use in light of extrapyramidal side effects and addiction liabilities. Constantin von Economo described sleep disturbances in some of the victims associated with characteristic lesions in the hypothalamus (Von Economo, 1930): hypersomnia "Encephalitis lethargica" was associated with destruction of neurons in the posterior hypothalamus comprising, as we know now, the histamine and the orexin/hypocretin neurons.

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The fibroblasts do not convert cyanocobalamin or hydroxocobalamin to methylcobalamin or adenosyl-cobalamin blood pressure chart microsoft excel order nifedipine amex, resulting in diminished activity of both N5-methyltetrahydrofolat e:homocysteine methyltransferase and methylmalonyl-CoA mutase arteria umbilical percentil 90 cheap nifedipine 20mg online. Diagnosis should be suspected in a child with homocystinuria blood pressure chart in hindi cheap nifedipine 20 mg mastercard, methylmalonic aciduria hypertension stage 1 discount nifedipine 30 mg otc, megaloblastic anemia, hypomethioninemia and normal blood levels of folate and vitamin B12. A definitive diagnosis requires demonstration of these abnormalities in fibroblasts. Treatment involves the administration of large doses (as much as 1 mg) of intramuscular hydroxocobalamin. One form of remethylation deficit involves defective metabolism of folic acid, a key cofactor in the conversion of homocysteine to methionine Methylenetetrahydrofolate reductase. In brain this enzyme also is important for the reduction of dihydropteridines (see Disorders of Phenylalanine Metabolism, above). The blood concentration of vitamin B12 is normal, and, unlike individuals with defects of cobalamin metabolism, these patients manifest neither anemia nor methylmalonic aciduria. Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration Levels of folate in both the blood and the cerebrospinal fluid have been very low. A urea cycle enzymopathy, whether associated with cirrhosis or an inherited metabolic defect, often causes a hyperammonemic encephalopathy and irreversible brain injury. Congenital hyperammonemia syndromes usually are caused by a deficiency of one of the enzymes of the urea cycle. Administration of phenylacetate or of benzoate favors the formation of phenylacetylglutamine and hippurate, respectively, thereby providing an effective "antidote" to ammonia toxicity. Enzymes: 1, carbamyl phosphate synthetase; 2, ornithine transcarbamylase; 3, argininosuccinate synthetase; 4, argininosuccinate lyase; 5, arginase; 6, glutamine synthetase; 7, glycine-cleavage system; 8, glycine-N-acylase; 9, glutamate dehydrogenase; 10, alanine aminotransferase; 11, cytosolic pathway of orotic acid synthesis, which becomes prominent when there is a block at the level of reaction 2, thus resulting in increased orotic acid excretion; 12, N-acetylglutamate synthetase; 13, phenylacetyl-CoA:glutamine transferase. Urea cycle defects cause a variety of clinical syndromes, including a metabolic crisis in the newborn infant Severe urea cycle defects become manifest in infants with a syndrome of coma, convulsions and vomiting during the first few days of life. Clinical confusion with septicemia is common, and many infants are treated futilely with antibiotics. Hyperammonemia is usually severe, even in excess of 1 mmol/l (normal in term infants 100 mol/l). The plasma concentrations of glutamine and alanine, the major nitrogen-carrying amino acids, are typically high and that of arginine is low. The presence of this blood aminogram without orotic aciduria suggests carbamyl phosphate synthetase deficiency. Patients may present with psychomotor retardation, growth failure, vomiting, behavioral abnormalities, perceptual difficulties, recurrent cerebellar ataxia and headache. It is therefore essential to monitor the blood ammonia in any patient with unexplained neurological symptoms, but hyperammonemia is inconstant with partial enzymatic defects. Molecular diagnosis by gene sequencing now is commercially available for virtually all urea cycle defects. Hyperammonemia also occurs in some organic acidurias, particularly those that affect neonates. Therefore, the urine organic acids should be quantitated in all patients with significant hyperammonemia. Except for patients with argininosuccinic aciduria, who may demonstrate varying degrees of hepatic fibrosis, there is little pathological change outside of the central nervous system. Ornithine transcarbamylase deficiency this is the most common of the urea cycle defects. Presentation is variable, ranging from a fulminant, fatal disorder of neonates to a schizophrenic-like illness in an otherwise healthy adult. Males characteristically fare more poorly than do females with this X-linked disorder because of random inactivation (lyonization) of the X chromosome. More than 80% of carriers can be detected, and antenatal diagnosis often is possible. Approximately one-third of the mothers of males and two-thirds of the mothers of females have been found to be noncarriers, reflecting the greater propensity for mutation in the male gamete. Asymptomatic heterozygotes form urea at a normal rate but overproduce [5-15N]-glutamine. Thus, whole body nitrogen metabolism is abnormal even in this group (Yudkoff et al. Both kinds of mutant mouse manifest hyperammonemia, orotic aciduria, growth failure and sparse fur. The absence of hyperammonemia should not rule out the diagnosis, especially with a history of protein intolerance, a suggestive family history or an untoward reaction to infections. The blood amino acids and urinary orotic acid should be quantified in such individuals. Patients with a partial deficiency may have a milder course, and a few individuals with citrullinemia have been phenotypically normal. The diagnosis usually is apparent from the hyperammonemia and the extreme hypercitrullinemia. The gene can be sequenced in amniocytes or chorionic villus samples, thus simplifying the problem of antenatal diagnosis. Carbamyl phosphate synthetase deficiency Carbamyl phosphate synthetase deficiency is rare.

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Subsequent to axonal outgrowth arteria carotis communis quality nifedipine 20mg, some of the other neurites are stabilized and begin to extend heart attack questions buy nifedipine from india. The number of dendrites varies with type of neuron blood pressure keeps changing generic nifedipine 30 mg on line, ranging from the single dendritic process that partially fuses with the axon to produce the single branched process of dorsal root ganglion pseudo-unipolar neuron blood pressure medication questions 30mg nifedipine free shipping, to the elaborate branching dendrite of the Purkinje cell and to multipolar motor neurons with both apical and basal dendritic arbors. As axons and dendrites mature, their differences become more apparent (Conde & Caceres, 2009; Mandell & Banker, 1995). No other cytoskeletal protein has been found to display a similar expression pattern, and protein synthetic machinery for the other proteins is excluded from the axon. Neuron-specific isoforms of spectrin and ankyrin exist only in axons (Beck & Nelson, 1996). While tau is not restricted to the growing axonal process, tau expression appears to be critical for the initial elongation event that defines an axon-to-be. If tau expression is blocked before the commitment to axonal outgrowth through use of antisense oligonucleotides, no axon is formed (Caceres & Kosik, 1990). For both axons and dendrites, cytoskeletal composition and organization are carefully orchestrated during differentiation and maturation. Although axonal and dendritic microtubules differ in their associated proteins and organization, both are thought to originate in the cell body. Microtubules are likely to continue to grow after entry in the axon or dendrite, but there is little evidence for de novo formation of microtubules in either region. The sites where most elongation occurs and where specific microtubule-associated proteins are added remains a matter of dispute. Similarly, the molecular mechanisms by which different cytoskeletal compositions are maintained in different neuronal compartments are unknown. For example, in many neurons peripherin and-internexin are expressed very early in neuronal differentiation, then downregulated. Such interactions can be seen during development of the nervous system, in mature neuron/glia interactions and in neuropathologies. Microfilament and microtubule dynamics underlie growth cone motility and function the mechanisms by which neurons make appropriate synaptic connections are a subject of great interest. As the growing tip of a growth cone advances across a substrate, the growth cone must interpret extracellular cues to steer the growing neurite in the right direction (Lowery & Van Vactor, 2009; Pak et al. This section briefly describes how extracellular signals mediate rearrangements of the cytoskeleton. Filopodia are long, thin, spike-like projections that grow and retreat rapidly from the growth cone surface; lamellipodia are web-like veils of cytoplasm that also spread and retract, often between filopodia. The body of the growth cone similarly includes two domains: the area of cytoplasm beyond the cylindrical neurite that adheres to the substratum, which is actin rich, and the central microtubules that enter from the shaft of the axon (Lowery & Van Vactor, 2009). Filopodia and lamellipodia sample the environment for favorable conditions; then the body of the growth cone moves forward as the axon elongates. The distribution of the three cytoskeletal elements in the growth cone is well established. They form a complex meshwork that includes a number of actin-associated proteins beneath the entire plasma membrane of lamellipodia and the growth cone body. The diameter of a growth cone is often much greater than that of the neurite, allowing it to sample a large volume of the environment. Typically, the shape of a growth cone is constantly changing, with filopodia and lamellipodia extending and retracting, receiving signals from the surface of other cells, the extracellular matrix or the surrounding media. A number of factors may elicit a growth response, including soluble neurotrophins and membrane or matrix-bound ligands. In addition, repulsive signals have been identified that lead to collapse of filopodia or lamellipodia and to retraction of growth cones. Signals in response to extracellular guidance cues that cause growth cones to steer probably involve multiple pathways (Gallo & Letourneanu, 2004; Lowery & Van Vactor, 2009). When one or a few filopodia receive an attractive cue, the growth cone will turn in that direction. At least two things occur in the region of the growth cone chosen for further growth. First, extracellular signals activate cell surface receptors to recruit a multiprotein complex that links the receptor to the actin meshwork beneath the surface. This burst of actin polymerization is probably due to the concerted actions of a number of different actin-binding proteins (Lowery & Van Vactor, 2009; Pak et al. While this description is an oversimplification of growth cone steering events, it nevertheless illustrates that growth cones are highly motile and very dynamic entities. Such images suggest a static cross-linked cytoskeleton and do not reveal the underlying dynamics of the axonal cytoskeleton. In fact, fully mature neurons also have a dynamic cytoskeleton that is both engaged in axonal transport (Chapter 8) and responsive to the local environment. The relationships between an axon and its myelinating glia are both intimate and extensive. However, more recent studies indicate that the axonal cytoskeleton is also altered locally by glial contacts. Axonal cytoskeletal elements are subject to constant modulation via signals from the axonal environment, including both target cells and cells forming the myelin sheath. Such signals appear to influence axonal branching, synapse formation and axonal caliber. The result is a thin or absent peripheral myelin sheath and a reduction in axonal caliber. Remarkably, this reduction in axonal caliber is highly localized to segments of axon with disrupted myelin. The local nature of these changes was proven by studies in which regions of Trembler sciatic nerve were grafted into normal nerves.

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A way to study the fate of glutamine in the intact brain is to use isotopically labeled acetate to label glutamine pulse pressure emt buy nifedipine with paypal. Carbon-13-labeled acetate does not enter neurons but it readily enters astrocytes lennox pulse pressure test kit buy discount nifedipine 20mg on-line, where it becomes metabolized to glutamine blood pressure phobia cheap 20mg nifedipine. After intravenous injection of 13C-labeled acetate hypertension 1 symptoms purchase nifedipine with mastercard, magnetic resonance spectroscopy of the brain is consistent with the formation of 13C-glutamine in astrocytes and the formation of 13 C-glutamate from that glutamine in neurons. Because the carbon backbone of glutamate derives from serum glucose, the formation and further metabolism of glutamate. The labeling of glutamine lags somewhat behind that of glutamate, probably reflecting the time involved in release of glutamate from nerve endings, uptake by astrocytes, and conversion to glutamine. This value may seem small considering the high level of glutamate in the brain, but the high level of glutamate is mainly caused by the high metabolic activity of the brain rather than by vesicular glutamate. The higher the metabolic flux, the higher the level of metabolic intermediates, among them glutamate. The concentration of glutamate in the cytosol is only a few mmol/l, so glutamate is concentrated inside the vesicles. The inner radius of a glutamate- containing vesicle is on average about 17 nm, which gives a volume of 2 1020 liters; a glutamate concentration of 100 mmol/l (or 6 1022 molecules/l) would therefore yield 1200 molecules of glutamate in each vesicle. This gradient is the main driving force for the accumulation of glutamate, but the low pH of the vesicular lumen also contributes. However, if we consider the small volume of a vesicle, a vesicular pH in excess of 5 (a measured value) would imply less than 0. This probably means that a free proton is present in the vesicle less than 10% of the time, and that this is enough to attract glutamate. Approximately 10% of the synaptic vesicles of glutamatergic terminals in the hippocampus contain a substantial amount of zinc, which is released together with glutamate. Vesicles accumulate zinc through the ZnT3 zinc transporter, which is located in the vesicular membrane. Aspartate, like glutamate, can be released from brain slices in a calcium-dependent manner by depolarizing the slices with potassium chloride at high concentration, and intriguingly the ratio of released aspartate to glutamate is not fixed, meaning that the two amino acids could be released from different cell types or cellular compartments. Aspartate, which is closely related to glutamate and which has excitatory properties, does not appear to be concentrated in synaptic vesicles and for this reason may not be a transmitter in the classic sense. This is true for the motor, sensory, emotional and cognitive components of behavior (see also Ch. There is no general agreement as to whether these changes occur predominantly on the presynaptic or on the postsynaptic side of the synaptic cleft, but several molecular mechanisms that could be important for learning have been identified on both sides. Electrophysiologically, two phenomena can be seen that may be components of learning at the synaptic level. A glutamatergic synapse that is briefly but strongly activated by high-frequency stimulation. However, even astrocytes, oligodendrocytes and microglia express some types of glutamate receptor that may be stimulated by glutamate released from nerve terminals. Glutamate receptors belong to one of two main categories: Ionotropic receptors are cation channels whose opening is favored (over the closed state) when glutamate binds to the receptor. Metabotropic receptors do not conduct ion fluxes; instead they activate intracellular enzymes through G proteins when they bind glutamate. The hippocampus is essential for (declarative) memory formation; in rats the role of hippocampus in acquisition of spatial information has been studied in great detail. In the hippocampus the neuronal connections are highly ordered, so it is easy to identify specific populations of neurons and synapses. Such slices are excellent for electrophysiological recordings, a technique pioneered by Skrede and colleagues in the early 1970s. Agonist binding forces a conformational change in the receptor that increases the probability of channel opening. Seven functional families of ionotropic glutamate receptor subunits can be defined by structural homologies Since the cloning of the first glutamate receptor, GluA1, in 1989 (Hollmann et al. Currently, seven families of ionotropic glutamate receptor subunit have been described. Within a given family, members show at least 75% identity at the amino acid level over the 400 amino acid stretch of membrane-spanning regions. The function of the seventh family, consisting of GluD1 and GluD2 (not shown In Figure 17-5), is unknown although GluD2 can be activated by D-serine. The ligand-gated ion channel receptors are tetrameric assemblies of the individual subunits. A significant feature of the glutamate receptors is that different subunit combinations produce functionally different receptors as described below. In situ hybridization and immunohistochemistry have highlighted regional differences in expression of subunits encoding glutamate receptors. The terminals (or boutons: b) are recognizable by their vesicles, and the postsynaptic spines (s) have the characteristic postsynaptic density (arrowhead).

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