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Sample records for 5-hydroxytrytamine 2c receptor

  1. Serotonin2C receptors and drug addiction: focus on cocaine.

    Devroye, Céline; Filip, Malgorzata; Przegaliński, Edmund; McCreary, Andrew C; Spampinato, Umberto

    2013-10-01

    This review provides an overview of the role of central serotonin2C (5-HT2C) receptors in drug addiction, specifically focusing on their impact on the neurochemical and behavioral effects of cocaine, one of the most worldwide abused drug. First, we described the neurochemical and electrophysiological mechanisms underlying the interaction between 5-HT2C receptors and the mesocorticolimbic dopaminergic network, in keeping with the key role of this system in drug abuse and dependence. Thereafter, we focused on the role of 5-HT2C receptors in the effects of cocaine in various preclinical behavioral models used in drug addiction research, such as locomotor hyperactivity, locomotor sensitization, drug discrimination, and self-administration, to end with an overview of the neurochemical mechanisms underlying the interactions between 5-HT2C receptors, mesocorticolimbic dopamine system, and cocaine. On their whole, the presented data provide compelling preclinical evidence that 5-HT2C receptor agonists may have efficacy in the treatment of cocaine abuse and dependence, thereby underlying the need for additional clinical studies to ascertain whether preclinical data translate to the human. PMID:23748692

  2. Serotonin 2c receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

    Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor a...

  3. Sleep and Sleep Homeostasis in Mice Lacking the 5-HT2c Receptor

    Frank, Marcos G.; Stryker, Michael P.; Tecott, Laurence H.

    2002-01-01

    Studies in humans and rats indicate that serotonin (5-hydroxytryptamine, 5-HT) receptors are involved in mammalian sleep expression. We investigated the contribution of the 5-HT2c receptor to sleep expression by examining sleep patterns in mice bearing a targeted null mutation of this receptor. 5-HT2c receptor knock-out mice had more wakefulness, several abnormalities in rapid eye movement sleep expression and an enhanced response to sleep deprivation compared with wild-type control mice. The...

  4. THE NUCLEOTIDE RECEPTORS ON MOUSE C2C12 MYOTUBES

    HENNING, RH; NELEMANS, A; VANDENAKKER, J; DENHERTOG, A

    1992-01-01

    1 The response of C2C12 mouse myotubes to stimulation with adenosine triphosphate (ATP) and other nucleotides was studied by measuring changes in membrane potential. 2 A transient hyperpolarization followed by a slowly declining depolarization of the cells was observed in the presence of ATP (10-mu-

  5. The time course of serotonin 2C receptor expression after spinal transection of rats

    Ren, Li-Qun; Wienecke, Jacob; Chen, Meng;

    2013-01-01

    of spasticity after spinal cord injury. In conjunction with our 5-HT2A receptor study, using a same sacral spinal transection rat model we have in this study examined 5-HT2C receptor immunoreactivity (5-HT2CR-IR) changes at seven different time intervals after spinal injury. We found that 5-HT2CR......In the spinal cord 5-HT systems modulate the spinal network via various 5-HT receptors. 5-HT2A and 2C receptors are likely the most important 5-HT receptors for enhancing the motoneuron excitability by facilitating the persistent inward current, and thus play an important role for the pathogenesis...

  6. Serotonin (2C) receptor regulation of cocaine-induced conditioned place preference and locomotor sensitization

    Craige, Caryne P.; Unterwald, Ellen M.

    2012-01-01

    Previous studies have identified an inhibitory regulatory role of the 5-HT2C receptor in serotonin and dopamine neurotransmission. As cocaine is known to enhance serotonin and dopamine transmission, the ability of 5-HT2C receptors to modulate cocaine-induced behaviors was investigated. Alterations in cocaine reward behavior were assessed in the conditioned place preference (CPP) paradigm. Mice were injected with a selective 5-HT2C receptor agonist, Ro 60-0175 (0, 1, 3, 10 mg/kg, i.p.) prior t...

  7. Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac)

    Ni, Y. G.; Miledi, R

    1997-01-01

    Fluoxetine (Prozac) inhibited the membrane currents elicited by serotonin (5-hydroxytryptamine; 5HT) in Xenopus oocytes expressing either cloned 5HT2C receptors or 5HT receptors encoded by rat cortex mRNA. Responses of 5HT2C receptors, elicited by nM concentrations of 5HT, were rapidly and reversibly blocked by micromolar concentrations of fluoxetine. For responses elicited by 1 μM 5HT, the IC50 of fluoxetine inhibition was ≈20 μM. In accord with the electrophysiological results, fluoxetine i...

  8. 5-Hydroxytryptamine 2C receptors tonically augment synaptic currents in the nucleus tractus solitarii

    Austgen, James R.; Dantzler, Heather A.; Barger, Brenna K.; Kline, David D.

    2012-01-01

    The nucleus tractus solitarii (nTS) is the primary termination and integration point for visceral afferents in the brain stem. Afferent glutamate release and its efficacy on postsynaptic activity within this nucleus are modulated by additional neuromodulators and transmitters, including serotonin (5-HT) acting through its receptors. The 5-HT2 receptors in the medulla modulate the cardiorespiratory system and autonomic reflexes, but the distribution of the 5-HT2C receptor and the role of these...

  9. Insulin signaling inhibits the 5-HT2C receptor in choroid plexus via MAP kinase

    Guan Kunliang

    2003-06-01

    Full Text Available Abstract Background G protein-coupled receptors (GPCRs interact with heterotrimeric GTP-binding proteins (G proteins to modulate acute changes in intracellular messenger levels and ion channel activity. In contrast, long-term changes in cellular growth, proliferation and differentiation are often mediated by tyrosine kinase receptors and certain GPCRs by activation of mitogen-activated protein (MAP kinases. Complex interactions occur between these signaling pathways, but the specific mechanisms of such regulatory events are not well-understood. In particular it is not clear whether GPCRs are modulated by tyrosine kinase receptor-MAP kinase pathways. Results Here we describe tyrosine kinase receptor regulation of a GPCR via MAP kinase. Insulin reduced the activity of the 5-HT2C receptor in choroid plexus cells which was blocked by the MAP kinase kinase (MEK inhibitor, PD 098059. We demonstrate that the inhibitory effect of insulin and insulin-like growth factor type 1 (IGF-1 on the 5-HT2C receptor is dependent on tyrosine kinase, RAS and MAP kinase. The effect may be receptor-specific: insulin had no effect on another GPCR that shares the same G protein signaling pathway as the 5-HT2C receptor. This effect is also direct: activated MAP kinase mimicked the effect of insulin, and removing a putative MAP kinase site from the 5-HT2C receptor abolished the effect of insulin. Conclusion These results show that insulin signaling can inhibit 5-HT2C receptor activity and suggest that MAP kinase may play a direct role in regulating the function of a specific GPCR.

  10. Regulation of adipogenesis by nucelar receptor PPARγ is modulated by the histone demethylase JMJD2C

    Lizcano Fernando

    2011-01-01

    Full Text Available A potential strategy to combat obesity and its associated complications involves modifying gene expression in adipose cells to reduce lipid accumulation. The nuclear receptor Peroxisome Proliferator-activated receptor gamma (PPARγ is the master regulator of adipose cell differentiation and its functional activation is currently used as a therapeutic approach for Diabetes Mellitus type 2. However, total activation of PPARγ induces undesirable secondary effects that might be set with a partial activation. A group of proteins that produce histone demethylation has been shown to modify the transcriptional activity of nuclear receptors. Here we describe the repressive action of the jumonji domain containing 2C/lysine demethylase 4 C (JMJD2C/KDM4C on PPARγ transcriptional activation. JMJD2C significantly reduced the rosiglitazone stimulated PPARγ activation. This effect was mainly observed in experiments performed using the Tudor domains that may interact with histone deacetylase class 1 (HDAC and this interaction probably reduces the mediated activation of PPARγ. Trichostatin A, a HDAC inhibitor, reduces the repressive effect of JMJD2C. When JMJD2C was over-expressed in 3T3-L1 cells, a reduction of differentiation was observed with the Tudor domain. In summary, we herein describe JMJD2C-mediated reduction of PPARgamma transcriptional activation as well as preadipocyte differentiation. This novel action of JMJD2C might have an important role in new therapeutic approaches to treat obesity and its complications.

  11. Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders.

    Higgins, Guy A; Fletcher, Paul J

    2015-07-15

    The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014. PMID:25870913

  12. SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist.

    Kennett, G A; Wood, M D; Bright, F; Trail, B; Riley, G; Holland, V; Avenell, K Y; Stean, T; Upton, N; Bromidge, S; Forbes, I T; Brown, A M; Middlemiss, D N; Blackburn, T P

    1997-01-01

    SB 242084 has a high affinity (pKi 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cloned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SB 242084 acted as an antagonist with a pKb of 9.3, which closely resembled its corresponding receptor binding affinity. SB 242084 potently inhibited m-chlorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test)-induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084 (0.1-1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SB 242084 (0.1-1 mg/kg i.p.) also markedly increased punished responding in a rat Geller-Seifter conflict test of anxiety, but had no consistent effect on unpunished responding. A large acute dose of SB 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SB 242084 (2 and 6 mg/kg p.o. 1 hr pre-test) antagonized the hypophagic response to mCPP, neither acute nor subchronic administration of the drug, for 5 days at 2 or 6 mg/kg p.o. twice daily, affected food intake or weight gain. The results suggest that SB 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2C receptor. PMID:9225286

  13. Identification of a cys-ser substitution in the 5-HT{sub 2C} (HTR2C) receptor gene and allelic association to violent behavior and alcoholism

    Lappalainen, J.; Ozaki, N.; Goldman, D. [National Institute on Alcohol Abuse and Alcoholism, Rockville, MD (United States)] [and others

    1994-09-01

    Several lines of evidence suggest that brain serotonergic functions, including behavioral and neurochemical responses to 5-HT{sub 2C} agonist, are abnormal in some individuals with alcoholism and aggressive behaviors. The aim of the present study was to identify coding sequence variants in the human 5-HT{sub 2C} receptor gene which may cause abnormal or variant function of this receptor. Using SSCP analysis, a non-conservative cys-ser substitution was found in the 5-HT{sub 2C} receptor (designated 5-HT{sub 2Ccys} and 5-HT{sub 2Cser}). The polymorphism was typed in CEPH families to genetically map the gene. To test for association of the variant to alcoholism, violent behavior and serotonin function, the 5-HT{sub 2C} genotypes of 151 non-related Finnish male alcoholic violent offenders and impulsive fire setters and 127 Finnish psychiatrically interviewed healthy male volunteers were determined. CSF 5-HIAA concentrations were available for 74 alcoholic violent offenders and 25 healthy volunteers. Linkage analysis placed the 5-HT{sub 2C} gene on Xq21, a region that has been previously shown to contain genes for several mental retardation syndromes. The 5-HT{sub 2Ccys}/5-HT{sub 2Cser} genotype frequencies in alcoholic violent offenders and controls differed significantly (0.90/0.10 and 0.82/0.18, respectively, P=0.048). The association was found to be strongest in the violent offenders who did not fulfill the criteria for antisocial personality disorder (5-HT{sub 2Ccys}/5-HT{sub 2Cser} 0.93/0.07, p=0.021). No association was found between CSF 5-HIAA concentrations and 5-HT{sub 2C} genotype. These results implicate a 5-HT{sub 2C} receptor amino acid substitution in predisposition to alcohol abuse and violent behavior in a subgroup of alcoholics.

  14. Pharmacological and genetic interventions in serotonin (5-HT)(2C) receptors to alter drug abuse and dependence processes

    Filip, Malgorzata; Spampinato, Umberto; McCreary, Andrew C.; Przegalinski, Edmund

    2012-01-01

    The present review provides an overview on serotonin (5-hydroxytryptamine; 5-HT)(2C) receptors and their relationship to drug dependence. We have focused our discussion on the impact of 5-HT2C receptors on the effects of different classes of addictive drugs, illustrated by reference to data using ph

  15. Role of 5-HT2C receptor gene variants in antipsychotic-induced weight gain

    Brandl EJ

    2011-08-01

    Full Text Available Tessa JM Wallace, Clement C Zai, Eva J Brandl, Daniel J MüllerNeurogenetics Section, Center for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, CanadaAbstract: Antipsychotic-induced weight gain is a serious side effect of antipsychotic medication that can lead to increased morbidity, mortality, and non-compliance in patients. Numerous single nucleotide polymorphisms have been studied for association with antipsychotic-induced weight gain in an attempt to find genetic predictors of this side effect. An ability to predict this side effect could lead to personalized treatment plans for predisposed individuals, which could significantly decrease the prevalence and severity of weight gain. Variations in the serotonin receptor 2c gene (HTR2C have emerged as promising candidates for prediction of antipsychotic-induced weight gain. Specifically, the well-studied -759C/T promoter polymorphism has been associated with weight gain in diverse populations, although some studies have reported no association. This discrepancy is likely due to heterogeneity in study design with respect to ethnicity, treatment duration, and other variables. Notably, the association between HTR2C and antipsychotic-induced weight gain appears strongest in short-term studies on patients with limited or no previous antipsychotic treatment. Other, less extensively studied promoter polymorphisms (-697C/G, -997G/A, and -1165A/G have also emerged as potential predictors of antipsychotic-induced weight gain. Conversely, the well-studied intronic polymorphism Cys23Ser does not appear to be associated. With further research on both HTR2C and other genetic and environmental predictors of antipsychotic-induced weight gain, a predictive test could one day be created to screen patients and provide preventative or alternative treatment for those who are predisposed to this serious side effect.Keywords: HTR2C, pharmacogenomics, promoter polymorphism

  16. Human alpha 2-adrenergic receptor subtype distribution: widespread and subtype-selective expression of alpha 2C10, alpha 2C4, and alpha 2C2 mRNA in multiple tissues.

    Eason, M G; Liggett, S B

    1993-07-01

    At present, molecular cloning and pharmacological studies have delineated three human alpha 2-adrenergic receptor (alpha 2AR) subtypes, alpha 2C10, alpha 2C4, and alpha 2C2. Assignment of the alpha 2AR subtypes to specific functions has been limited by an unclear definition of tissue alpha 2AR expression outside of the central nervous system. It has been suggested that alpha 2C4 expression is confined to the brain, that alpha 2C2 expression is only in the liver and kidney, and that there is nearly ubiquitous expression of alpha 2C10. However, this is based on studies of a limited number of rat tissues or on studies using non-species-specific approaches. Therefore, to define alpha 2C10, alpha 2C4, and alpha 2C2 tissue expression, we used reverse transcription of total RNA isolated from 20 human tissues, followed by amplification of alpha 2AR cDNA using the polymerase chain reaction. This technique provided two advantages: high sensitivity and, with the use of subtype-specific oligonucleotide primers and probes, differentiation between the alpha 2AR subtypes. The tissues studied were aorta, vena cava, heart (epicardium and endocardium), lung, skeletal muscle, liver, pancreas (head and tail), fat (perinephric and subcutaneous), kidney (cortex and medulla), prostate, stomach, ileum, jejunum, colon, adrenal gland, and spleen. We found that the majority of these tissues expressed alpha 2C10, with the exceptions being the head of the pancreas, subcutaneous fat, colon, and spleen. In marked distinction to other studies, however, we found a prolific expression of the alpha 2C4 and alpha 2C2 subtypes. Expression of alpha 2C4 was found in all tissues with the exception of liver, fat, stomach, and colon, and a virtually ubiquitous expression of alpha 2C2 was found, with the exception of epicardium. Of all tissues studied, only colon and subcutaneous fat expressed a single alpha 2AR subtype, which was alpha 2C2. Thus, the alpha 2AR subtypes do not have a confined expression but

  17. Down-regulation of the alpha-2C adrenergic receptor: involvement of a serine/threonine motif in the third cytoplasmic loop

    Deupree, Jean D; Borgeson, Claudia D.; Bylund, David B.

    2002-01-01

    Background The mechanisms by which alpha-2 adrenergic receptors are down-regulated following chronic exposure to agonist are not well understood. Interestingly, the human alpha-2C receptor does not down-regulate, whereas the opossum alpha-2C receptor does down-regulate. A comparison of the amino acid sequence of the third intracellular loop of these two receptors shows that the opossum alpha-2C receptor contains a potential G protein-coupled receptor kinase (GRK)phosphorylation motif (EESSTSE...

  18. Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors.

    Smith, R L; Canton, H; Barrett, R J; Sanders-Bush, E

    1998-11-01

    Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor density and cellular microenvironment, we also examined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native preparation. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT. PMID:9768567

  19. 盐酸舍曲林治疗前后早泄患者血浆瘦素及5-羟色胺水平的变化%Serum level changes of leptin and 5-hydroxytrytamine in patients with premature ejaculation before and after hydrochloride sertraline treatment

    周勇; 汤坤龙; 王宝龙; 杨琳; 李黎明; 杨长海

    2013-01-01

    A total of 71 patients with premature ejaculation (PE) received hydrochloride sertraline treatment for 8 weeks and their serum levels of leptin and 5-hydroxytrytamine (5-HT) were determined.Their ejaculation functions were assessed with intravaginal ejaculation latency time (IELT) and Chinese index of premature ejaculation (CIPE-5) value.The study was compared with 64 normal males as control.The baseline level of leptin in the trial group was obviously higher than the controls (P < 0.05) while the level of 5-HT in the trial group far lower than the controls (P < 0.05).At 8 weeks,the level of leptin dropped while the level of 5-HT rose in the trial group after treatment.Therefore a high serum level of leptin and a low serum level of 5-HT may become biological indicators for PE.%对71例早泄患者行盐酸舍曲林治疗8周,测定治疗前后血浆瘦素及5-羟色胺(5-HT)水平,并通过射精潜伏期、中国早泄患者性功能评分表对受试者射精功能进行评估.与64例健康男性相比,早泄患者治疗前血浆瘦素水平增高[中位数为8和29 μg/L,P2.5 ~ P97.5为(4 ~ 15)和(7~40) μg/L],5-HT水平降低[121(72 ~240)和62(34 ~ 108)μg/L](均P<0.01);治疗后瘦素水平下降[8(3 ~13) μgL],与健康对照比较差异无统计学意义(P>0.05),血浆5-HT水平有明显升高[98(87 ~ 178) μg/L],但与健康对照差异仍有统计学意义(P<0.05).提示,血浆高瘦素与低5-HT水平可作为早泄治疗的监测指标.

  20. Relevance of dorsal raphe nucleus firing in serotonin 5-HT2C receptor blockade-induced augmentation of SSRIs effects

    Sotty, Florence; Folgering, Joost H. A.; Brennum, Lise T.; Hogg, Sandra; Mork, Arne; Hertel, Peter; Cremers, Thomas I. F. H.

    2009-01-01

    Selective serotonin reuptake inhibitors are the most widely prescribed antidepressant drugs. However, they exhibit a slow onset of action, putatively due to the initial decrease in serotonin cell firing mediated via somato-dendritic autoreceptors. Interestingly, blockade of 5-HT2C receptors signific

  1. Developmental Changes is Expression of Beta-Adrenergic Receptors in Cultures of C2C12 Skeletal Muscle Cells

    Young, Ronald B.; Bridge, K. Y.; Vaughn, J. R.

    2000-01-01

    beta-Adrenergic receptor (bAR) agonists have been reported to modulate growth in several mammalian and avian species, and bAR agonists presumably exert their physiological action on skeletal muscle cells through this receptor. Because of the importance of bAR regulation on muscle protein metabolism in muscle cells, the objectives of this study were to determine the developmental expression pattern of the bAR population in C2C12 skeletal muscle cells, and to analyze changes in both the quantity and isoform expression of the major muscle protein, myosin. The number of bAR in mononucleated C2C12 cells was approximately 8,000 bAR per cell, which is comparable with the population reported in several other nonmuscle cell types. However, the bar population increased after myoblast fusion to greater than 50,000 bAR per muscle cell equivalent. The reasons for this apparent over-expression of bAR in C2C12 cells is not known. The quantity of myosin also increased after C2C12 myoblast fusion, but the quantity of myosin was less than that reported in primary muscle cell cultures. Finally, at least five different isoforms of myosin heavy chain could be resolved in C2C12 cells, and three of these exhibited either increased or decreased developmental regulation relative to the others. Thus, C2C12 myoblasts undergo developmental regulation of bAR population and myosin heavy chain isoform expression.

  2. Modulation of dopamine transmission by 5HT2C and 5HT3 receptors: a role in the antidepressant response.

    Dremencov, Eliyahu; Weizmann, Yifat; Kinor, Noa; Gispan-Herman, Iris; Yadid, Gal

    2006-02-01

    Dopaminergic mesolimbic and mesocortical systems are fundamental in hedonia and motivation. Therefore their regulation should be central in understanding depression treatment. This review highlights the dopaminergic activity in relation to depressive behavior and suggests two putative receptors as potential targets for research and development of future antidepressants. In this article we review data that describe the role of serotonin in regulating dopamine release, via 5HT2C and 5HT3 receptors. This action of serotonin appears to be linked to depressive-like behavior and to onset of behavioral effects of antidepressants in an animal model of depression. We suggest that drugs or strategies that decrease 5HT2C and increase 5HT3 receptor-mediated dopamine release in the limbic areas of the brain may provide a fast onset of therapeutic effect. Clinical and basic research data supporting this hypothesis are discussed. PMID:16475958

  3. Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures.

    Venzi, Marcello; David, François; Bellet, Joachim; Cavaccini, Anna; Bombardi, Cristiano; Crunelli, Vincenzo; Di Giovanni, Giuseppe

    2016-09-01

    Absence seizures (ASs) are the hallmark of childhood/juvenile absence epilepsy. Monotherapy with first-line anti-absence drugs only controls ASs in 50% of patients, indicating the need for novel therapeutic targets. Since serotonin family-2 receptors (5-HT2Rs) are known to modulate neuronal activity in the cortico-thalamo-cortical loop, the main network involved in AS generation, we investigated the effect of selective 5-HT2AR and 5-HT2CR ligands on ASs in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well established polygenic rat model of these non-convulsive seizures. GAERS rats were implanted with fronto-parietal EEG electrodes under general anesthesia, and their ASs were later recorded under freely moving conditions before and after intraperitoneal administration of various 5-HT2AR and 5-HT2CR ligands. The 5-HT2A agonist TCB-2 dose-dependently decreased the total time spent in ASs, an effect that was blocked by the selective 5-HT2A antagonist MDL11,939. Both MDL11,939 and another selective 5-HT2A antagonist (M100,907) increased the length of individual seizures when injected alone. The 5-HT2C agonists lorcaserin and CP-809,101 dose-dependently suppressed ASs, an effect blocked by the selective 5-HT2C antagonist SB 242984. In summary, 5-HT2ARs and 5-HT2CRs negatively control the expression of experimental ASs, indicating that selective agonists at these 5-HT2R subtypes might be potential novel anti-absence drugs. PMID:27085605

  4. Gene structure and expression of serotonin receptor HTR2C in hypothalamic samples from infanticidal and control sows

    Quilter Claire R

    2012-04-01

    Full Text Available Abstract Background The serotonin pathways have been implicated in behavioural phenotypes in a number of species, including human, rat, mouse, dog and chicken. Components of the pathways, including the receptors, are major targets for drugs used to treat a variety of physiological and psychiatric conditions in humans. In our previous studies we have identified genetic loci potentially contributing to maternal infanticide in pigs, which includes a locus on the porcine X chromosome long arm. The serotonin receptor HTR2C maps to this region, and is therefore an attractive candidate for further study based on its function and its position in the genome. Results In this paper we describe the structure of the major transcripts produced from the porcine HTR2C locus using cDNA prepared from porcine hypothalamic and pooled total brain samples. We have confirmed conservation of sites altered by RNA editing in other mammalian species, and identified polymorphisms in the gene sequence. Finally, we have analysed expression and editing of HTR2C in hypothalamus samples from infanticidal and control animals. Conclusions The results confirm that although the expression of the long transcriptional variant of HTR2C is raised in infanticidal animals, the overall patterns of editing in the hypothalamus are similar between the two states. Sequences associated with the cDNA and genomic structures of HTR2C reported in this paper are deposited in GenBank under accession numbers FR720593, FR720594 and FR744452.

  5. CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver.

    Makia, Ngome L; Goldstein, Joyce A

    2016-01-01

    Human cytochrome P450 (CYP) 2C enzymes metabolize ∼30% of clinically prescribed drugs and various environmental chemicals. CYP2C8, an important member of this subfamily, metabolizes the anticancer drug paclitaxel, certain antidiabetic drugs, and endogenous substrates, including arachidonic acid, to physiologically active epoxyeicosatrienoic acids. Previous studies from our laboratory showed that microRNA 107 (miR107) and microRNA 103 downregulate CYP2C8 post-transcriptionally. miR107 is located in intron 5 of the pantothenate kinase 1 (PANK1) gene. p53 has been reported to coregulate the induction of PANK1 and miR107. Here, we examine the possible downregulation of CYP2C8 by drugs capable of inducing miR107. Hypolipidemic drugs, such as bezafibrate, known activators of the peroxisome proliferator-activated receptor α (PPARα), induce both the PANK1 gene and miR107 (∼2.5-fold) in primary human hepatocytes. Surprisingly, CYP2C8 mRNA and protein levels were induced by bezafibrate. CYP2C8 promoter activity was increased by ectopic expression of PPARα in HepG2 cells, with a further increase after bezafibrate (∼18-fold), 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (∼10-fold) treatment, or the antidiabetic drug rosiglitazone, all known PPAR activators. Promoter sequence analyses, deletion studies, mutagenesis studies, and electrophoretic mobility shift assays identified a PPARα response element located at position -2109 base pair relative to the translation start site of CYP2C8. Chromatin immunopreciptation assay analysis confirmed recruitment of PPARα to this PPARα response element after bezafibrate treatment of human hepatocytes. Thus, we show for the first time that CYP2C8 is transcriptionally regulated by PPARα, suggesting the potential for drug-drug interactions due to upregulation of CYP2C8 by PPAR activators. PMID:26467040

  6. Enhanced Food Anticipatory Activity Associated with Enhanced Activation of Extrahypothalamic Neural Pathways in Serotonin2C Receptor Null Mutant Mice

    Hsu, Jennifer L.; Lisa Yu; Elinor Sullivan; Melodi Bowman; Mistlberger, Ralph E.; Tecott, Laurence H.

    2010-01-01

    The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin(2C) receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enha...

  7. Enhanced Food Anticipatory Activity Associated with Enhanced Activation of Extrahypothalamic Neural Pathways in Serotonin2C Receptor Null Mutant Mice

    Mistlberger, Ralph; Hsu, Jennifer; Yu, Lisa; Bowman, Melody; Tecott, Laurence; Sullivan, Elinor

    2010-01-01

    The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin2C receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enhanc...

  8. Effects of RO 60 0175, a 5-HT(2C) receptor agonist, in three animal models of anxiety.

    Kennett, G; Lightowler, S; Trail, B; Bright, F; Bromidge, S

    2000-01-10

    There is some controversy as to whether 5-HT(2C) receptor agonists are anxiogenic or anxiolytic. The effects of the novel 5-HT(2C) receptor agonist, (S)-2-chloro-5-fluoro-indol-1-yl)-1-methyl ethylamine fumarate (RO 60 0175), in three models of anxiety were therefore tested. RO 60 0175 was found to induce hypolocomotion in rats at doses greater than 0.5 mg/kg s.c., an effect reversed by the selective 5-HT(2C) receptor antagonist, SB-242084. RO 60 0175 did not elicit anxiolytic-like responses in the social interaction test under high light unfamiliar conditions, but suppressed both time spent in social interaction and locomotion at doses of 1 and 3 mg/kg s.c., suggesting a sedative response. In the Vogel conflict test, RO 60 0175 had no significant action on the number of shocks taken. In the Geller-Seifter test, RO 60 0175 (0.3 and 1 mg/kg s.c.) simultaneously reduced both unpunished and punished lever pressing, a profile consistent with sedation. Finally, RO 60 0175 was tested in a rat social interaction test under low light familiar conditions optimal for the detection of anxiogenic-like responses. At 1 and 3 mg/kg s.c., RO 60 0175 reduced both time spent in social interaction and concurrent locomotion, a profile more consistent with sedation than anxiogenesis. In conclusion, RO 60 0175 induced sedative-like responses via 5-HT(2C) receptor activation, but was neither anxiolytic, nor clearly anxiogenic at the doses tested. PMID:10650160

  9. Decreased Incentive Motivation Following Knockout or Acute Blockade of the Serotonin Transporter: Role of the 5-HT2C Receptor.

    Browne, Caleb J; Fletcher, Paul J

    2016-09-01

    Acute pharmacological elevation of serotonin (5-hydroxytryptamine; 5-HT) activity decreases operant responding for primary reinforcers, suggesting that 5-HT reduces incentive motivation. The mechanism by which 5-HT alters incentive motivation is unknown, but parallel evidence that 5-HT2C receptor agonists also reduce responding for primary reinforcers implicates this receptor as a potential candidate. These experiments examined whether chronic and acute disruptions of serotonin transporter (SERT) activity altered incentive motivation, and whether the 5-HT2C receptor mediated the effects of elevated 5-HT on behavior. To assess incentive motivation, we measured responding for three different reinforcers: a primary reinforcer (saccharin), a conditioned reinforcer (CRf), and an unconditioned sensory reinforcer (USRf). In the chronic condition, responding was compared between SERT knockout (SERT-KO) mice and their wild-type littermates. In the acute condition, responding was examined in wild-type mice following treatment with 10 or 20 mg/kg citalopram, or its vehicle. The ability of the selective 5-HT2C antagonist SB 242084 to prevent the effects of SERT-KO and citalopram on responding was subsequently examined. Both SERT-KO and citalopram reduced responding for saccharin, a CRf, and a USRf. Treatment with SB 242084 enhanced responding for a CRf and a USRf in SERT-KO mice and blocked the effects of citalopram on CRf and USRf responding. However, SB 242084 was unable to prevent the effects of SERT-KO or citalopram on responding for saccharin. These results support a powerful inhibitory function for 5-HT in the control of incentive motivation, and indicate that the 5-HT2C receptor mediates these effects of 5-HT in a reinforcer-dependent manner. PMID:27125304

  10. Identification, expression, and pharmacology of a Cys{sub 23}-Ser{sub 23} substitution in the human 5-HT{sub 2C} receptor gene (HTR2C)

    Lappalainen, J.; Ozaki, N.; Goldman, D. [National Institute on Alcohol Abuse and Alcoholism, Rockville, MD (United States)] [and others

    1995-05-20

    The function of brain serotonin-2C (5-HT{sub 2C}) receptors, including behavioral and neurochemical responses to 5-HT{sub 2C} agonist challenge, has been suggested to be abnormal in individuals with neuropsychiatric disorders. Thus, it is important to identify polymorphisms and functional variants within this gene. Using SSCP analysis, the authors identified a Cys{sub 23}-Ser{sub 23} substitution (designated 5-HT{sub 2Ccys} and 5-HT{sub 2Cser}) in the first hydrophobic region of the human 5-HT{sub 2C} receptor. Allele frequencies in unrelated Caucasians were 0.13 and 0.87 for 5-HT{sub 2Cser} and 5-HT{sub 2Ccys}, respectively. DNAs from informative CEPH families were typed for this polymorphism and analyzed with respect to 20 linked markers on the X chromosome. Linkage analysis placed the 5-HT{sub 2C} receptor gene (HTR2C) on Xq24. To evaluate whether this amino acid substitution causes a variant function of this receptor, recombinant human 5-HT{sub 2Ccys} and 5-HT{sub 2Cser} receptors were expressed in Xenopus oocytes and tested for responses to 5-HT using electrophysiological techniques. Concentration-response curves for 5-HT were not significantly different in oocytes expressing either form of the receptor, suggesting that the 5-HT{sub 2Ccys} and 5-HT{sub 2Cser} receptor proteins may not differ in their responses to serotonin under baseline physiological conditions. 43 refs., 3 figs., 1 tab.

  11. Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism

    Graves, Steven M.; Clark, Mary J.; Traynor, John R.; Hu, Xiu-Ti; Napier, T. Celeste

    2014-01-01

    Methamphetamine profoundly increases brain monoamines and is a widely abused psychostimulant. The effects of methamphetamine self-administration on neuron function are not known for the nucleus accumbens, a brain region involved in addictive behaviors, including drug-seeking. One therapeutic target showing preclinical promise at attenuating psychostimulant-seeking is 5-HT2C receptors; however, the effects of 5-HT2C receptor ligands on neuronal physiology are unclear. 5-HT2C receptor agonism decreases psychostimulant-mediated behaviors, and the putative 5-HT2C receptor inverse agonist, SB 206553, attenuates methamphetamine-seeking in rats. To ascertain the effects of methamphetamine, and 5-HT2C receptor inverse agonism and agonism, on neuronal function in the nucleus accumbens, we evaluated methamphetamine, SB 206553, and the 5-HT2C receptor agonist and Ro 60-0175, on neuronal excitability within the accumbens shell subregion using whole-cell current-clamp recordings in forebrain slices ex vivo. We reveal that methamphetamine self-administration decreased generation of evoked action potentials. In contrast, SB 206553 and Ro 60-0175 increased evoked spiking, effects that were prevented by the 5-HT2C receptor antagonist, SB 242084. We also assessed signaling mechanisms engaged by 5-HT2C receptors, and determined that accumbal 5-HT2C receptors stimulated Gq, but not Gi/o. These findings demonstrate that methamphetamine-induced decreases in excitability of neurons within the nucleus accumbens shell were abrogated by both 5-HT2C inverse agonism and agonism, and this effect likely involved activation of Gq–mediated signaling pathways. PMID:25229719

  12. Expression of Thyroid Stimulating Hormone Receptor mRNA in Mouse C2C12 Skeletal Muscle Cells

    Ohn, Jung Hun; Han, Sun Kyoung; Park, Do Joon; Park, Kyong Soo; Park, Young Joo

    2013-01-01

    Background We analyzed whether thyroid stimulating hormone receptor (TSH-R) is expressed in a skeletal muscle cell line and if TSH has influence on the differentiation of muscle cells or on the determination of muscle fiber types. Methods TSH-R gene expression was detected with nested real-time polymerase chain reaction (RT-PCR) in C2C12, a mouse skeletal muscle cell line. The effect of TSH on myotube differentiation was assessed by microscopic examination of myotube formation and through the...

  13. Functional Divergence of the Nuclear Receptor NR2C1 as a Modulator of Pluripotentiality During Hominid Evolution.

    Baker, Jennifer L; Dunn, Katherine A; Mingrone, Joseph; Wood, Bernard A; Karpinski, Beverly A; Sherwood, Chet C; Wildman, Derek E; Maynard, Thomas M; Bielawski, Joseph P

    2016-06-01

    Genes encoding nuclear receptors (NRs) are attractive as candidates for investigating the evolution of gene regulation because they (1) have a direct effect on gene expression and (2) modulate many cellular processes that underlie development. We employed a three-phase investigation linking NR molecular evolution among primates with direct experimental assessment of NR function. Phase 1 was an analysis of NR domain evolution and the results were used to guide the design of phase 2, a codon-model-based survey for alterations of natural selection within the hominids. By using a series of reliability and robustness analyses we selected a single gene, NR2C1, as the best candidate for experimental assessment. We carried out assays to determine whether changes between the ancestral and extant NR2C1s could have impacted stem cell pluripotency (phase 3). We evaluated human, chimpanzee, and ancestral NR2C1 for transcriptional modulation of Oct4 and Nanog (key regulators of pluripotency and cell lineage commitment), promoter activity for Pepck (a proxy for differentiation in numerous cell types), and average size of embryological stem cell colonies (a proxy for the self-renewal capacity of pluripotent cells). Results supported the signal for alteration of natural selection identified in phase 2. We suggest that adaptive evolution of gene regulation has impacted several aspects of pluripotentiality within primates. Our study illustrates that the combination of targeted evolutionary surveys and experimental analysis is an effective strategy for investigating the evolution of gene regulation with respect to developmental phenotypes. PMID:27075724

  14. Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice

    Spoida, Katharina; Masseck, Olivia A.; Deneris, Evan S.; Herlitze, Stefan

    2014-01-01

    Serotonin is an important modulator of anxious states. Serotonergic neurotransmission in the dorsal raphe nuclei is known to be regulated by different presynaptic and postsynaptic feedback mechanisms involving G protein-coupled receptor signals, but the influence of such feedback mechanisms on anxiety-related behavior has not been investigated until now. We found that optogenetic activation of the Gq-coupled receptor signals in 5-HT2c receptor locations in GABAergic neurons in dorsal raphe nu...

  15. Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice.

    Halberstadt, Adam L; Sindhunata, Ivan S; Scheffers, Kees; Flynn, Aaron D; Sharp, Richard F; Geyer, Mark A; Young, Jared W

    2016-08-01

    Timing deficits are observed in patients with schizophrenia. Serotonergic hallucinogens can also alter the subjective experience of time. Characterizing the mechanism through which the serotonergic system regulates timing will increase our understanding of the linkage between serotonin (5-HT) and schizophrenia, and will provide insight into the mechanism of action of hallucinogens. We investigated whether interval timing in mice is altered by hallucinogens and other 5-HT2 receptor ligands. C57BL/6J mice were trained to perform a discrete-trials temporal discrimination task. In the discrete-trials task, mice were presented with two levers after a variable interval. Responding on lever A was reinforced if the interval was 6.5 s. A 2-parameter logistic function was fitted to the proportional choice for lever B (%B responding), yielding estimates of the indifference point (T50) and the Weber fraction (a measure of timing precision). The 5-HT2A antagonist M100907 increased T50, whereas the 5-HT2C antagonist SB-242,084 reduced T50. The results indicate that 5-HT2A and 5-HT2C receptors have countervailing effects on the speed of the internal pacemaker. The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg IP), a 5-HT2 agonist, flattened the response curve at long stimulus intervals and shifted it to the right, causing both T50 and the Weber fraction to increase. The effect of DOI was antagonized by M100907 (0.03 mg/kg SC) but was unaffected by SB-242,084 (0.1 mg/kg SC). Similar to DOI, the selective 5-HT2A agonist 25CN-NBOH (6 mg/kg SC) reduced %B responding at long stimulus intervals, and increased T50 and the Weber fraction. These results demonstrate that hallucinogens alter temporal perception in mice, effects that are mediated by the 5-HT2A receptor. It appears that 5-HT regulates temporal perception, suggesting that altered serotonergic signaling may contribute to the timing deficits observed in schizophrenia and other psychiatric disorders. PMID

  16. Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice.

    Spoida, Katharina; Masseck, Olivia A; Deneris, Evan S; Herlitze, Stefan

    2014-04-29

    Serotonin 2c receptors (5-HT2c-Rs) are drug targets for certain mental disorders, including schizophrenia, depression, and anxiety. 5-HT2c-Rs are expressed throughout the brain, making it difficult to link behavioral changes to circuit specific receptor expression. Various 5-HT-Rs, including 5-HT2c-Rs, are found in the dorsal raphe nucleus (DRN); however, the function of 5-HT2c-Rs and their influence on the serotonergic signals mediating mood disorders remain unclear. To investigate the role of 5-HT2c-Rs in the DRN in mice, we developed a melanopsin-based optogenetic probe for activation of Gq signals in cellular domains, where 5-HT2c-Rs are localized. Our results demonstrate that precise temporal control of Gq signals in 5-HT2c-R domains in GABAergic neurons upstream of 5-HT neurons provides negative feedback regulation of serotonergic firing to modulate anxiety-like behavior in mice. PMID:24733892

  17. The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

    Paddy KC Janssen

    2014-08-01

    Full Text Available It has been postulated that the persistent short intravaginal ejaculation latency time (IELT of men with lifelong premature ejaculation (LPE is related to 5-hydroxytryptamine (HT2C receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2C receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for Cys23Ser 5-HT2C receptor gene polymorphism. Allele frequencies and genotypes of Cys and Ser variants of 5-HT2C receptor gene polymorphism were determined. Association between Cys/Cys and Ser/Ser genotypes and the natural logarithm of the IELT in men with LPE were investigated. As a result, the geometric mean, median and natural mean IELT were 25.2, 27.0, 33.9 s, respectively. Of all men, 20.0%, 10.8%, 23.1% and 41.5% ejaculated within 10, 10-20, 20-30 and 30-60 s after vaginal penetration. Of the 64 men, the Cys/Cys and Ser/Ser genotype frequency for the Cys23Ser polymorphism of the 5-HT2C receptor gene was 81% and 19%, respectively. The geometric mean IELT of the wildtypes (Cys/Cys is significantly lower (22.6 s; 95% CI 18.3-27.8 s than in male homozygous mutants (Ser/Ser (40.4 s; 95% CI 20.3-80.4 s (P = 0.03. It is concluded that Cys23Ser 5-HT2C receptor gene polymorphism is associated with the IELT in men with LPE. Men with Cys/Cys genotype have shorter IELTs than men with Ser/Ser genotypes.

  18. The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

    Paddy KC Janssen; Ron van Schaik; Berend Olivier; Waldinger, Marcel D.

    2014-01-01

    It has been postulated that the persistent short intravaginal ejaculation latency time (IELT) of men with lifelong premature ejaculation (LPE) is related to 5-hydroxytryptamine (HT)2C receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2C receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-m...

  19. Functional interaction between peroxisome proliferator-activated receptors-α and Mef-2C on human carnitine palmitoyltransferase 1β (CPT1β) gene activation

    Baldán, Ángel; Relat, Joana; Marrero, Pedro F.; Haro, Diego

    2004-01-01

    Muscle-type carnitine palmitoyltransferase 1 (CPT1β) is considered to be the gene that controls fatty acid mitochondrial β-oxidation. A functional peroxisome proliferator-activated receptor (PPAR) responsive element (PPRE) and a myocite-specific (MEF2) site that binds MEF2A and MEF2C in the promoter of this gene had been previously identified. We investigated the roles of the PPRE and the MEF2 binding sites and the potential interaction between PPARα and MEF2C regulating the CPT1β gene promoter. Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1β promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1β gene promoter by MEF2C and PPARα-RXRα, a precise arrangement of its binding sites was essential. PMID:15356291

  20. Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: A pharmacoepidemiological-pharmacodynamic study in VigiBase.

    Montastruc, François; Palmaro, Aurore; Bagheri, Haleh; Schmitt, Laurent; Montastruc, Jean-Louis; Lapeyre-Mestre, Maryse

    2015-10-01

    Pharmacodynamic mechanisms of diabetes induced by antipsychotic drugs remain unclear, while numerous receptors have been suspected to be involved in the genesis of this Adverse Drug Reaction (ADR). We investigated potential relationships between antipsychotics׳ receptor occupancy (serotonin 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, muscarinic M3, adrenergic α1, α2 or dopaminergic D2 D3 occupancies) and reports of diabetes using VigiBase(®), the World Health Organization (WHO) global Individual Case Safety Report (ICSR) database. All ADR reports from 15 first and second generation antipsychotic drugs recorded in VigiBase(®) were extracted. Logistic regression models, completed by disproportionality analysis, were used to determine the associations between antipsychotics׳ receptor occupancy and ICSRs of diabetes on VigiBase(®). During the study period, 94,460 ICSRs involved at least one of the 15 antipsychotics of interest. Diabetes was reported in 1799 (1.9%) patients. Clozapine was the most frequently suspected drug (n=953; 53.0%). A significant and positive association was found between histamine H1, muscarinic M3 and serotonin 5-HT2C, 5-HT2A receptor occupancies and reports of diabetes. A multivariable stepwise regression model showed that only serotonin 5-HT2c (AOR=2.13, CI 95% 1.72-2.64) and histamine H1 (AOR=1.91, CI 95% 1.38-2.64) predicted the risk for diabetes mellitus (p<0.001). Using an original pharmacoepidemiology-pharmacodynamic (PE-PD) approach, our study supports that antipsychotic drugs blocking simultaneously histamine H1 and serotonin 5-HT2C receptors are more frequently associated with diabetes reports in VigiBase(®) than other antipsychotics. These findings should encourage investigation of histamine H1 and serotonin 5-HT2C properties for predicting the risk of glycemic effects in candidate antipsychotics. PMID:26256010

  1. Serotonin 5-HT2C receptor-independent expression of hypothalamic NOR1, a novel modulator of food intake and energy balance, in mice

    Nonogaki, Katsunori, E-mail: knonogaki-tky@umin.ac.jp [Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine (Japan); Department of Lifestyle Medicine, Biomedical Engineering Center, Tohoku University (Japan); Kaji, Takao [Department of Lifestyle Medicine, Biomedical Engineering Center, Tohoku University (Japan); Ohba, Yukie; Sumii, Makiko [Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine (Japan); Wakameda, Mamoru; Tamari, Tomohiro [Charles River Laboratories Japan, Inc. (Japan)

    2009-08-21

    NOR1, Nur77 and Nurr1 are orphan nuclear receptors and members of the NR4A subfamily. Here, we report that the expression of hypothalamic NOR1 was remarkably decreased in mildly obese {beta}-endorphin-deficient mice and obese db/db mice with the leptin receptor mutation, compared with age-matched wild-type mice, whereas there were no genotypic differences in the expression of hypothalamic Nur77 or Nurr1 in these animals. The injection of NOR1 siRNA oligonucleotide into the third cerebral ventricle significantly suppressed food intake and body weight in mice. On the other hand, the decreases in hypothalamic NOR1 expression were not found in non-obese 5-HT2C receptor-deficient mice. Moreover, systemic administration of m-chlorophenylpiperazine (mCPP), a 5-HT2C/1B receptor agonist, had no effect on hypothalamic NOR1 expression, while suppressing food intake in {beta}-endorphin-deficient mice. These findings suggest that 5-HT2C receptor-independent proopiomelanocortin-derived peptides regulate the expression of hypothalamic NOR1, which is a novel modulator of feeding behavior and energy balance.

  2. Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

    Córdova-Sintjago, Tania; Villa, Nancy; Fang, Lijuan; Booth, Raymond G.

    2014-02-01

    The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ∼75% transmembrane (TM) sequence identity. Agonists for 5-HT2C receptors are under development for psychoses; whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists - in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function; however, ligand interactions with these residues at the 5-HT2C receptor have not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modelling, ligand docking, and molecular dynamics simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors.

  3. Effect of alkyl glycerophosphate on the activation of peroxisome proliferator-activated receptor gamma and glucose uptake in C2C12 cells

    Highlights: •Alkyl-LPA specifically interacts with PPARγ. •Alkyl-LPA treatments induces lipid accumulation in C2C12 cells. •Alkyl-LPA enhanced glucose uptake in C2C12 cells. •Alkyl-LPA-treated C2C12 cells express increased amounts of GLUT4 mRNA. •Alkyl-LPA is a novel therapeutic agent that can be used for the treatment of obesity and diabetes. -- Abstract: Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear hormone receptor implicated in many human diseases, including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPARγ. However, the mechanism by which the alkyl-LPA–PPARγ axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPARγ activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPARγ1 mRNA is more abundant than PPARγ2 mRNA in C2C12 cells. We showed that alkyl-LPA (3 μM) significantly activated PPARγ and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPARγ and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance

  4. Effect of alkyl glycerophosphate on the activation of peroxisome proliferator-activated receptor gamma and glucose uptake in C2C12 cells

    Tsukahara, Tamotsu, E-mail: ttamotsu@shinshu-u.ac.jp [Department of Integrative Physiology and Bio-System Control, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621 (Japan); Haniu, Hisao [Department of Orthopedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621 (Japan); Matsuda, Yoshikazu [Clinical Pharmacology Educational Center, Nihon Pharmaceutical University, Ina-machi, Saitama 362-0806 (Japan)

    2013-04-12

    Highlights: •Alkyl-LPA specifically interacts with PPARγ. •Alkyl-LPA treatments induces lipid accumulation in C2C12 cells. •Alkyl-LPA enhanced glucose uptake in C2C12 cells. •Alkyl-LPA-treated C2C12 cells express increased amounts of GLUT4 mRNA. •Alkyl-LPA is a novel therapeutic agent that can be used for the treatment of obesity and diabetes. -- Abstract: Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear hormone receptor implicated in many human diseases, including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPARγ. However, the mechanism by which the alkyl-LPA–PPARγ axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPARγ activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPARγ1 mRNA is more abundant than PPARγ2 mRNA in C2C12 cells. We showed that alkyl-LPA (3 μM) significantly activated PPARγ and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPARγ and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance.

  5. Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice.

    Zhang, Gongliang; Wu, Xian; Zhang, Yong-Mei; Liu, Huan; Jiang, Qin; Pang, Gang; Tao, Xinrong; Dong, Liuyi; Stackman, Robert W

    2016-02-01

    Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT(2C) receptor (5-HT(2C)R) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT(2C)R agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT(2C)R activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT(2C)R agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT(2C)R antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT(2C)R protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT(2C)R can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT(2C)R may represent a new avenue for the treatment of opioid addiction. PMID:26432939

  6. Functional interaction between peroxisome proliferator-activated receptors-α and Mef-2C on human carnitine palmitoyltransferase 1β (CPT1β) gene activation

    Baldán, Ángel; Relat, Joana; Marrero, Pedro F.; Haro, Diego

    2004-01-01

    Muscle-type carnitine palmitoyltransferase 1 (CPT1β) is considered to be the gene that controls fatty acid mitochondrial β-oxidation. A functional peroxisome proliferator-activated receptor (PPAR) responsive element (PPRE) and a myocite-specific (MEF2) site that binds MEF2A and MEF2C in the promoter of this gene had been previously identified. We investigated the roles of the PPRE and the MEF2 binding sites and the potential interaction between PPARα and MEF2C regulating the CPT1β gene promot...

  7. Functional interaction between peroxisome proliferator-activated receptors-alpha and Mef-2C on human carnitine palmitoyltransferase 1beta (CPT1beta) gene activation

    Baldán Aranda, Ángel; Relat Pardo, Joana; Marrero González, Pedro F.; Haro Bautista, Diego

    2004-01-01

    Muscle-type carnitine palmitoyltransferase 1 (CPT1β) is considered to be the gene that controls fatty acid mitochondrial β-oxidation. A functional peroxisome proliferator-activated receptor (PPAR) responsive element (PPRE) and a myocite-specific (MEF2) site that binds MEF2A and MEF2C in the promoter of this gene had been previously identified. We investigated the roles of the PPRE and the MEF2 binding sites and the potential interaction between PPARα and MEF2C regulating the CPT1β gene promot...

  8. Comparative desensitization of the human 5-HT2A and 5-HT2C receptors expressed in the human neuroblastoma cell line SH-SY5Y

    Briddon, S J; Leslie, R.A.; Elliott, J. M.

    1998-01-01

    We have used previously characterized clones of the human neuroblastoma cell line, SH-SY5Y, constitutively expressing either the human 5-HT2A or 5-HT2C receptor to compare their desensitization profiles after exposure to 5-HT.5-HT stimulated [3H]-inositol phosphate ([3H]-IPx) production at both the 5-HT2C (pEC50=8.03±0.15) and 5-HT2A receptors (pEC50=7.15±0.08), with maximal responses occurring after exposure to 1 μM and 10 μM 5-HT, respectively.Exposure of cells to maximally effective concen...

  9. Maternal aggression in Wistar rats: effect of 5-HT2A/2C receptor agonist and antagonist microinjected into the dorsal periaqueductal gray matter and medial septum

    Almeida R.M.M. de

    2005-01-01

    Full Text Available The objective of the present study was to assess the role of the 5-HT2A/2C receptor at two specific brain sites, i.e., the dorsal periaqueductal gray matter (DPAG and the medial septal (MS area, in maternal aggressive behavior after the microinjection of either a 5-HT2A/2C receptor agonist or antagonist. Female Wistar rats were microinjected on the 7th postpartum day with the selective agonist alpha-methyl-5-hydroxytryptamine maleate (5-HT2A/2C or the antagonist 5-HT2A/2C, ketanserin. The agonist was injected into the DPAG at 0.2 (N = 9, 0.5 (N = 10, and 1.0 µg/0.2 µl (N = 9, and the antagonist was injected at 1.0 µg/0.2 µl (N = 9. The agonist was injected into the medial septal area (MS at 0.2 (N = 9, 0.5 (N = 7, and 1.0 µg/0.2 µl (N = 6 and the antagonist was injected at 1.0 µg/0.2 µl (N = 5. For the control, saline was injected into the DPAG (N = 7 and the MS (N = 12. Both areas are related to aggressive behavior and contain a high density of 5-HT receptors. Non-aggressive behaviors such as horizontal locomotion (walking and social investigation and aggressive behaviors such as lateral threat (aggressive posture, attacks (frontal and lateral, and biting the intruder were analyzed when a male intruder was placed into the female resident's cage. For each brain area studied, the frequency of the behaviors was compared among the various treatments by analysis of variance. The results showed a decrease in maternal aggressive behavior (number of bites directed at the intruder after microinjection of the agonist at 0.2 and 1.0 µg/0.2 µl (1.6 ± 0.7 and 0.9 ± 0.3 into the DPAG compared to the saline group (5.5 ± 1.1. There was no dose-response relationship with the agonist. The present findings suggest that the 5-HT2A/2C receptor agonist has an inhibitory effect on maternal aggressive behavior when microinjected into the DPAG and no effect when microinjected into the MS. Ketanserin (1.0 µg/0.2 µl decreased locomotion when microinjected

  10. Rat exposure in mice with neuropathic pain induces fear and antinociception that is not reversed by 5-HT2C receptor activation in the dorsal periaqueductal gray.

    Furuya-da-Cunha, Elke Mayumi; Souza, Rimenez Rodrigues de; Canto-de-Souza, Azair

    2016-07-01

    Previous studies have demonstrated that serotonin 5-HT2C receptors in the dorsal periaqueductal gray (dPAG) mediate both anxiety and antinociception in mice submitted to the elevated plus maze. The present study examined the effects of intra-dPAG infusion of the serotonin 5-HT2C receptor agonist (MK-212) in the defensive reactions and antinociception in mice with neurophatic pain confronted by a predator. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve, and predator confrontation was performed using the rat exposure test (RET). Our results demonstrated that both sham-operated and CCI mice exhibited intense defensive reactions when confronted by rats. However, rat-exposed CCI mice showed reduced pain reactivity in comparison to CCI mice exposed to a toy rat. Intra-dPAG infusion of MK-212 prior to predator exposure did not significantly alter defensive or antinociceptive responses. To our knowledge, our results represent the first evidence of RET-induced antinociception in mice. Moreover, the results of the present study suggest that 5-HT2C receptor activation in the dPAG is not critically involved in the control of predator-evoked fearful or antinociceptive responses. PMID:27059332

  11. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes

    Kring, Sofia I I; Werge, Thomas; Holst, Claus;

    2009-01-01

    BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs) of these...

  12. Splicing factors control C. elegans behavioural learning in a single neuron by producing DAF-2c receptor

    Tomioka, Masahiro; Naito, Yasuki; Kuroyanagi, Hidehito; Iino, Yuichi

    2016-01-01

    Alternative splicing generates protein diversity essential for neuronal properties. However, the precise mechanisms underlying this process and its relevance to physiological and behavioural functions are poorly understood. To address these issues, we focused on a cassette exon of the Caenorhabditis elegans insulin receptor gene daf-2, whose proper variant expression in the taste receptor neuron ASER is critical for taste-avoidance learning. We show that inclusion of daf-2 exon 11.5 is restri...

  13. A novel multivalent 99mTc-labeled EG2-C4bpα antibody for targeting the epidermal growth factor receptor in tumor xenografts

    Introduction: The C4b binding protein (C4bp) α/β-chain C-terminal effectively induces polymerization during protein synthesis. Using this fragment and the single-domain antibody EG2, which targets the epidermal growth factor receptor (EGFR), we generated the novel multimeric antibody EG2-C4bpα. We radiolabeled EG2-C4bpα with 99mTc and evaluated its targeting efficiency and pharmacokinetics in tumor xenografts. Methods: EGFR expression and EGFR-EG2-C4bpα binding was evaluated in A431 and OCM-1 cells by Western blotting and flow cytometry, respectively. EG2-C4bpα was radiolabeled with [99mTc(CO)3(OH2)3]+ using a tricarbonyl vial followed by purification on a PD-10 column. In vitro studies with 99mTc-EG2-C4bpα were performed in A431 and/or OCM-1 cells. Single photon emission computed tomography (SPECT) imaging and biodistribution studies were carried out in 99mTc-EG2-C4bpα-injected mice bearing A431- and OCM-1-derived tumors. EGFR immunofluorescent staining in A431 and OCM-1 tumors was performed. Results: A431 cells showed higher EGFR expression levels than OCM-1 cells, and flow cytometry confirmed EG2-C4bpα bound more A431 cells than OCM-1 cells. 99mTc-EG2-C4bpα was successfully prepared with radiochemical yields of 30.3–50.4%. The binding affinity of 99mTc-EG2-C4bpα to A431 cells was approximately 20 nM. 99mTc-EG2-C4bpα specifically bound A431 cells and this binding was blocked by 41% in the presence of 50 nM excess unlabeled EG2-C4bpα. In vivo radioactivity uptake in A431 tumors was detected 2 h after 99mTc-EG2-C4bpα administration and sustained up to 18 h. The highest ratio of A431 tumor-to-muscle and tumor-to-blood was 3.69 ± 0.48 at 10 h and 0.77 ± 0.14 at 20 h, respectively. Excess unlabeled EG2-C4bpα blocked radioactivity uptake in A431 tumors by 55% at 10 h. 99mTc-EG2-C4bpα was barely detectable in OCM-1 tumors, and biodistribution analysis confirmed that radioactivity uptake was significantly lower than in A431 tumors. Conclusions: 99m

  14. 5-HT(2C) serotonin receptor blockade prevents tau protein hyperphosphorylation and corrects the defect in hippocampal synaptic plasticity caused by a combination of environmental stressors in mice.

    Busceti, Carla Letizia; Di Pietro, Paola; Riozzi, Barbara; Traficante, Anna; Biagioni, Francesca; Nisticò, Robert; Fornai, Francesco; Battaglia, Giuseppe; Nicoletti, Ferdinando; Bruno, Valeria

    2015-09-01

    Exposure to multimodal sensory stressors is an everyday occurrence and sometimes becomes very intense, such as during rave parties or other recreational events. A growing body of evidence suggests that strong environmental stressors might cause neuronal dysfunction on their own in addition to their synergistic action with illicit drugs. Mice were exposed to a combination of physical and sensory stressors that are reminiscent of those encountered in a rave party. However, this is not a model of rave because it lacks the rewarding properties of rave. A 14-h exposure to environmental stressors caused an impairment of hippocampal long-term potentiation (LTP) and spatial memory, and an enhanced phosphorylation of tau protein in the CA1 and CA3 regions. These effects were transient and critically depended on the activation of 5-HT2C serotonin receptors, which are highly expressed in the CA1 region. Acute systemic injection of the selective 5-HT2C antagonist, RS-102,221 (2 mg/kg, i.p., 2 min prior the onset of stress), prevented tau hyperphosphorylation and also corrected the defects in hippocampal LTP and spatial memory. These findings suggest that passive exposure to a combination of physical and sensory stressors causes a reversible hippocampal dysfunction, which might compromise mechanisms of synaptic plasticity and spatial memory for a few days. Drugs that block 5-HT2C receptors might protect the hippocampus against the detrimental effect of environmental stressors. PMID:26145279

  15. Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors

    Introduction: Malignant glioma remains a significant therapeutic challenge, and immunotherapeutics might be a beneficial approach for these patients. A monoclonal antibody (MAb) specific for multiple molecular targets could expand the treatable patient population and the fraction of tumor cells targeted, with potentially increased efficacy. This motivated the generation of MAb D2C7, which recognizes both wild-type epidermal growth factor receptor (EGFRwt) and a tumor-specific mutant, EGFRvIII. Methods: D2C7 binding affinity was determined by surface plasmon resonance and its specificity characterized through comparison to EGFRwt-specific EGFR.1 and EGFRvIII-specific L8A4 MAbs by flow cytometry and immunohistochemical analysis. The three MAbs were labeled with 125I or 131I using Iodogen, and paired-label internalization assays and biodistribution experiments in athymic mice with human tumor xenografts were performed. Results: The affinity of D2C7 for EGFRwt and EGFRvIII was 5.2×109 M−1 and 3.6×109 M−1, and cell-surface reactivity with both receptors was documented by flow cytometry. Immunohistochemical analyses revealed D2C7 reactivity with malignant glioma tissue from 90 of 101 patients. Internalization assays performed on EGFRwt-expressing WTT cells and EGFRvIII-expressing NR6M cells indicated a threefold lower degradation of 125I-labeled D2C7 compared with 131I-labeled EGFR.1. Uptake of 125I-labeled D2C7 in NR6M xenografts (52.45±13.97 %ID g−1 on Day 3) was more than twice that of 131I-labeled L8A4; a threefold to fivefold tumor delivery advantage was seen when compared to 131I-labeled EGFR.1 in mice with WTT xenografts. Conclusions: These results suggest that D2C7 warrants further evaluation for the development of MAb-based therapeutics against cancers expressing EGFRwt and EGFRvIII.

  16. C2C12 myotubes inhibit the proliferation and differentiation of 3T3-L1 preadipocytes by reducing the expression of glucocorticoid receptor gene.

    Chu, Weiwei; Wei, Wei; Yu, Shigang; Han, Haiyin; Shi, Xiaoli; Sun, Wenxing; Gao, Ying; Zhang, Lifan; Chen, Jie

    2016-03-25

    Obesity is a well-established risk factor to health for its relationship with insulin resistance, diabetes and metabolic syndrome. Myocyte-adipocyte crosstalk model plays a significant role in studying the interaction of muscle and adipose development. Previous related studies mainly focus on the effects of adipocytes on the myocytes activity, however, the influence of myotubes on the preadipocytes development remains unclear. The present study was carried out to settle this issue. Firstly, the co-culture experiment showed that the proliferation, cell cycle, and differentiation of 3T3-L1 preadipocytes were arrested, and the apoptosis was induced, by differentiated C2C12 myotubes. Next, the sensitivity of 3T3-L1 preadipocytes to glucocorticoids (GCs), which was well known as cell proliferation, differentiation, apoptosis factor, was decreased after co-cultured with C2C12 myotubes. What's more, our results showed that C2C12 myotubes suppressed the mRNA and protein expression of glucocorticoid receptor (GR) in 3T3-L1 preadipocytes, indicating the potential mechanism of GCs sensitivity reduction. Taken together, we conclude that C2C12 myotubes inhibited 3T3-L1 preadipocytes proliferation and differentiation by reducing the expression of GR. These data suggest that decreasing GR by administration of myokines may be a promising therapy for treating patients with obesity or diabetes. PMID:26896766

  17. Distinct regions within the GluN2C subunit regulate the surface delivery of NMDA receptors

    Lichnerová, Katarina; Kaniaková, Martina; Skřenková, Kristýna; Vyklický ml., Ladislav; Horák, Martin

    2014-01-01

    Roč. 8, Nov 10 (2014), s. 375. ISSN 1662-5102 R&D Projects: GA ČR(CZ) GP14-09220P; GA ČR(CZ) GA14-02219S; GA ČR(CZ) GAP303/12/1464; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : glutamate receptor * ion channel * intracellular trafficking Subject RIV: ED - Physiology Impact factor: 4.289, year: 2014

  18. Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

    Cummings, David F.; Canseco, Diana C.; Sheth, Pratikkumar; Johnson, James E.; Schetz, John A.

    2010-01-01

    Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure-affinity relationships of derivatives based on the aplysinop...

  19. Molecular and genetic analyses of the PP2C-ABA receptor interaction in the abscisic acid signaling pathway.

    Antoni Alandes, Regina

    2013-01-01

    La fitohormona ácido abscísico (ABA) juega un papel crucial en el control de la respuesta a estrés y en la regulación del crecimiento y desarrollo de la planta. La unión del ABA a los receptores intracelulares PYR/PYL/RCAR conlleva la inhibición de las PP2Cs del clado A tales como ABI1 o HAB1, causando la activación de la ruta de señalización del ABA. Para obtener más información en la señalización del ABA nos hemos centrado en la caracterización de miembros de estas dos famil...

  20. Region-specific alterations of A-to-I RNA editing of serotonin 2c receptor in the cortex of suicides with major depression.

    Weissmann, D; van der Laan, S; Underwood, M D; Salvetat, N; Cavarec, L; Vincent, L; Molina, F; Mann, J J; Arango, V; Pujol, J F

    2016-01-01

    Brain region-specific abnormalities in serotonergic transmission appear to underlie suicidal behavior. Alterations of RNA editing on the serotonin receptor 2C (HTR2C) pre-mRNA in the brain of suicides produce transcripts that attenuate 5-HT2CR signaling by impairing intracellular G-protein coupling and subsequent intracellular signal transduction. In brain, the distribution of RNA-editing enzymes catalyzing deamination (A-to-I modification) shows regional variation, including within the cerebral cortex. We tested the hypothesis that altered pre-mRNA 5-HT2CR receptor editing in suicide is region-specific. To this end, we investigated the complete 5-HT2CR mRNA-editing profile in two architectonically distinct cortical areas involved in mood regulation and decision-making in a clinically well-characterized cohort of age- and sex-matched non-psychiatric drug-free controls and depressed suicides. By using an original biochemical detection method, that is, capillary electrophoresis single-stranded conformational polymorphism (CE-SSCP), we corroborated the 5-HT2CR mRNA-editing profile previously described in the dorsolateral prefrontal cortex (Brodmann area 9 (BA9)). Editing of 5-HT2CR mRNA displayed clear regional difference when comparing dorsolateral prefrontal cortex (BA9) and anterior cingulate cortex (BA24). Compared with non-psychiatric control individuals, alterations of editing levels of 5-HT2CR mRNA were detected in both cortical areas of depressed suicides. A marked increase in editing on 5-HT2CR was especially observed in the anterior cingulate cortex in suicides, implicating this cortical area in suicide risk. The results suggest that region-specific changes in RNA editing of 5-HT2CR mRNA and deficient receptor function likely contribute to the etiology of major depressive disorder or suicide. PMID:27576167

  1. Electrophysiological evidence for the presence of NR2C subunits of N-methyl-D-aspartate receptors in rat neurons of the nucleus tractus solitarius

    V. Baptista

    2005-01-01

    Full Text Available The nucleus tractus solitarius (NTS plays an important role in the control of autonomic reflex functions. Glutamate, acting on N-methyl-D-aspartate (NMDA and non-NMDA ionotropic receptors, is the major neurotransmitter in this nucleus, and the relative contribution of each receptor to signal transmission is unclear. We have examined NMDA excitatory postsynaptic currents (NMDA-EPSCs in the subpostremal NTS using the whole cell patch clamp technique on a transverse brainstem slice preparation. The NMDA-EPSCs were evoked by stimulation of the solitary tract over a range of membrane potentials. The NMDA-EPSCs, isolated pharmacologically, presented the characteristic outward rectification and were completely blocked by 50 µM DL-2-amino-5-phosphonopentanoic acid. The I-V relationship of the NMDA response shows that current, with a mean (± SEM amplitude of -41.2 ± 5.5 pA, is present even at a holding potential of -60 mV, suggesting that the NMDA receptors are weakly blocked by extracellular Mg2+ at near resting membrane potentials. This weak block can also be inferred from the value of 0.67 ± 0.17 for parameter delta obtained from a fit of the Woodhull equation to the I-V relationship. The maximal inward current measured on the I-V relationship was at -38.7 ± 4.2 mV. The decay phase of the NMDA currents was fitted with one exponential function with a decay time constant of 239 ± 51 and 418 ± 80 ms at a holding potential of -60 and +50 mV, respectively, which became slower with depolarization (e-fold per 145 mV. The biophysical properties of the NMDA receptors observed in the present study suggest that these receptors in the NTS contain NR2C subunits and may contribute to the synaptic signal integration.

  2. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats.

    Martin-Gronert, Malgorzata S; Stocker, Claire J; Wargent, Edward T; Cripps, Roselle L; Garfield, Alastair S; Jovanovic, Zorica; D'Agostino, Giuseppe; Yeo, Giles S H; Cawthorne, Michael A; Arch, Jonathan R S; Heisler, Lora K; Ozanne, Susan E

    2016-04-01

    Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist. PMID:26769798

  3. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

    Malgorzata S. Martin-Gronert

    2016-04-01

    Full Text Available Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC peptides within the arcuate nucleus of the hypothalamus (ARC. We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus of in utero growth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist.

  4. Citalopram-induced hypophagia is enhanced by blockade of 5-HT1A receptors: role of 5-HT2C receptors

    Grignaschi, G.; Invernizzi, R W; Fanelli, E.; Fracasso, C; Caccia, S.; Samanin, R.

    1998-01-01

    The selective 5-hydroxytryptamine reuptake inhibitor citalopram (10 and 20 mg kg−1, i.p.) significantly reduced food intake in male rats (CD-COBS) habituated to eat their daily food during a 4-h period.The 5-HT1A receptor antagonist WAY100635 (0.3 mg kg−1) administered systemically did not modify feeding but significantly potentiated the reduction in food intake caused by 10 mg kg−1 i.p. citalopram. The dose of 5 mg kg−1 i.p. citalopram was not active in animals pretreated with vehicle but si...

  5. Angiotensin II reduces cardiac AdipoR1 expression through AT1 receptor/ROS/ERK1/2/c-Myc pathway.

    Li Li

    Full Text Available Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2 mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1 receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII.

  6. Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors

    Erreger, Kevin; Geballe, Matthew T.; Kristensen, Anders Skov;

    2007-01-01

    dynamics (MD) simulations comparing a crystallography-based hydrated NR1/NR2A model with a homology-based NR1/NR2D hydrated model of the agonist binding domains suggest that glutamate exhibits a different binding mode in NR2D compared with NR2A that accommodates a 4-methyl substitution in SYM2081....... Mutagenesis of functionally divergent residues supports the conclusions drawn based on the modeling studies. Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited......, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic agents. We evaluated the potency and efficacy of a wide range of glutamate-like compounds at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors. Twenty-five of 53 compounds examined exhibited agonist...

  7. A candidate gene study of serotonergic pathway genes and pain relief during treatment with escitalopram in patients with neuropathic pain shows significant association to serotonin receptor2C (HTR2C)

    Brasch-Andersen, Charlotte; Møller, Malik U; Christiansen, Lene;

    2011-01-01

    the association between polymorphisms in genes involved in the serotonergic pathway and the effect of escitalopram on peripheral neuropathic pain. METHODS: We genotyped 34 participants from a placebo-controlled trial of escitalopram in peripheral neuropathic pain for polymorphisms in five genes: the.......047), with 75% carrying the C allele being responders. The same tendency was seen in women. Similarly, carriership of the C allele at rs6318 was associated with better pain relief during treatment with escitalopram [odds ratio (OR) 15.5, p = 0.014)] Furthermore, there was a tendency of better relief with...... increasing number of short alleles for the 5-HTTLPR polymorphism of the serotonin transporter (OR 5.7, p = 0.057). None of the other polymorphisms showed a significant association with treatment response to escitalopram. CONCLUSION: This study indicates that variation in the HTR2C gene is associated to the...

  8. A double dissociation in the effects of 5-HT2A and 5-HT2C receptors on the acquisition and expression of conditioned defeat in Syrian hamsters

    Harvey, Marquinta L.; Swallows, Cody L.; Cooper, Matthew A.

    2012-01-01

    Previous research indicates that serotonin enhances the development of stress-induced changes in behavior, although it is unclear which serotonin receptors mediate this effect. 5-HT2 receptors are potential candidates because activation at these receptors is associated with increased fear and anxiety. In this study we investigated whether pharmacological treatments targeting 5-HT2 receptors would alter the acquisition and expression of conditioned defeat. Conditioned defeat is a social defeat...

  9. Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task.

    Simon R O Nilsson

    Full Text Available Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS-, in a T- or Y-maze configuration. This was followed by three conditions; (1 Full reversal, where contingencies reversed; (2 Perseverance, where the previous CS+ became CS- and the previous CS- was replaced by a novel CS+; (3 Learned non-reward, where the previous CS- became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss

  10. 5-HT2A/2C receptor and 5-HT transporter densities in mice prone or resistant to chronic high-fat diet-induced obesity: a quantitative autoradiography study.

    Huang, Xu-Feng; Huang, Xin; Han, Mei; Chen, Feng; Storlien, Len; Lawrence, Andrew J

    2004-08-27

    The present study examined the density of 5-HT2A/2C receptors and 5-HT transporters in the brains of chronic high-fat diet-induced obese (cDIO) and obese-resistant (cDR) mice. Thirty-five male mice were used in this study. Twenty-eight mice were fed with a high-fat diet (40% of calories from fat) for 6 weeks and then classified as the cDIO (n=8) or cDR (n=8) mice according to the highest and lowest body weight gainers. Seven mice were placed on a low-fat diet (LF: 10% of calories from fat) and were used as controls. After 20 weeks of feeding, the sum of epididymal, perirenal, omental and inguinal fat masses was 9.3+/-0.3 g in the cDIO group versus 3.1+/-0.5 g in the cDR (pcDIO mice had a significantly higher 5-HT2A/2C binding density in the anterior olfactory nucleus and ventromedial hypothalamic nucleus (VMH) compared to the cDR and LF mice (+39% and +47%, p=0.003 and 0.045, respectively), whereas the latter two groups did not differ. The density of 5-HT2A/2C receptors in the VMH was associated with total amount of fat mass (r=0.617, p=0.032). On the other hand, the cDR mice had significantly lower 5-HT transporter binding than the cDIO and LF mice, respectively, in the nucleus accumbens (-44%, -38%, both pcDIO and cDR mice. It provides neural anatomical bases by which genetic variability in 5-HT2A/2C receptors and 5-HT transporter may influence satiety and sensory aspects of energy balance. PMID:15276882

  11. Association of Polymorphisms within the Serotonin Receptor Genes 5-HTR1A, 5-HTR1B, 5-HTR2A and 5-HTR2C and Migraine Susceptibility in a Turkish Population

    Yücel, Yavuz; Coşkun, Salih; Cengiz, Beyhan; Özdemir, Hasan H.; Uzar, Ertuğrul; Çim, Abdullah; Camkurt, M. Akif; Aluclu, M. Ufuk

    2016-01-01

    Objective Migraine, a highly prevelant headache disorder, is regarded as a polygenic multifactorial disease. Serotonin (5-HT) and their respective receptors have been implicated in the patogenesis. Methods We investigated the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor gene polymorphisms and their association with migraine in Turkish patients. The rs6295, rs1300060, rs1228814, rs6311, rs6313, rs6314, rs6318, rs3813929 (−759C/T) and rs518147 polymorphisms were analyzed in 135 patients with migraine and 139 healthy subjects, using a BioMark 96.96 dynamic array system. Results We found no difference in the frequency of the analyzed eight out of nine polymorpisms between migraine and control groups. However, a significant association was found between the rs3813929 polymorphism in the promoter region of 5-HTR2C gene and migraine. Also, the allele of rs3813929 was more common in the migraine group. Conclusion This result suggests that the 5-HTR2C rs3813929 polymorphism can be a genetic risk factor for migraine in a Turkish population. PMID:27489378

  12. Comparative pharmacology of the human NMDA-receptor subtypes R1-2A, R1-2B, R1-2C and R1-2D using an inducible expression system.

    Feuerbach, Dominik; Loetscher, Erika; Neurdin, Stephanie; Koller, Manuel

    2010-07-10

    Pharmacological characterization of N-methyl-D-aspartate (NMDA) receptors has been hampered by the difficulty to outwit cytotoxicity after functional expression in recombinant systems. In this study a muristerone-inducible expression system for the NNMDA-R1 subunit was used. This was combined with constitutive expression of NMDA-R2A, 2B, 2C and 2D in different cell clones. After establishment of the cell lines, quantitative RT-PCR demonstrated the inducibility of the NNMDA-R1 subunit, and verified the expression of the NMDA-R2 subunits in the different cell clones. Functional responses were characterized using calcium influx through the ion channel as a robust assay system. Stimulation of the NMDA-receptor subtypes in the different cell lines led to calcium transients which were rising gradually, peaked after 30-160 s and declined thereafter very slowly. The expression of the four different NMDA-receptor subtypes in the same cellular background allowed a direct pharmacological comparison of the different receptors. Glutamate showed the highest potency at the NMDA-R1-2D. NMDA displayed at all subtypes a lower potency compared to glutamate and was a partial agonist except at the NMDA-R1-2D. 20 antagonists were tested in this study and the pharmacological characterization of the inhibition of glutamate-evoked elevation of intracellular free Ca(2+) revealed a distinct rank order of antagonist potency for each receptor subtype. These data illustrate that assessment of calcium transients upon receptor stimulation in the same cellular background is a powerful tool to compare the functional effects of compounds acting at the different NMDA-R2 receptors. PMID:20394742

  13. A Peroxisome Proliferator-Activated Receptor-α Activator Induces Renal CYP2C23 Activity and Protects from Angiotensin II-Induced Renal Injury

    Muller, Dominik N.; Theuer, Juergen; Shagdarsuren, Erdenechimeg; Kaergel, Eva; Honeck, Horst; Park, Joon-Keun; Markovic , Marija; Barbosa-Sicard, Eduardo; Dechend, Ralf; Wellner, Maren; Kirsch, Torsten; Fiebeler, Anette; Rothe, Michael; Haller, Hermann; Luft, Friedrich C.

    2004-01-01

    Cytochrome P450 (CYP)-dependent arachidonic acid (AA) metabolites are involved in the regulation of renal vascular tone and salt excretion. The epoxygenation product 11,12-epoxyeicosatrienoic acid (EET) is anti-inflammatory and inhibits nuclear factor-κB activation. We tested the hypothesis that the peroxisome proliferator-activated receptor-α-activator fenofibrate (Feno) induces CYP isoforms, AA hydroxylation, and epoxygenation activity, and protects against inflammatory organ damage. Double...

  14. Effects of central activation of serotonin 5-HT2A/2C or dopamine D2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test

    Feng, Min; Gao, Jun; Sui, Nan; Li, Ming

    2014-01-01

    Rationale: Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect. Objective: The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats. Methods: DOI (2,5-dimethoxy-4-iodo-amphetamine, a preferential 5-HT2A/2C agonist) or quinpirole (a preferential dopamine D2/3 agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance-disruptive effect of clozapine were tested. Results: Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance. Conclusions: Acute behavioral effect of clozapine can be enhanced by activation of the D2/3 receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT2A/2C receptors in the mPFC. PMID:25288514

  15. Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system.

    Swinford-Jackson, S E; Anastasio, N C; Fox, R G; Stutz, S J; Cunningham, K A

    2016-06-01

    Intensification of craving elicited by drug-associated cues during abstinence occurs over time in human cocaine users while elevation of cue reactivity ("incubation") is observed in rats exposed to extended forced abstinence from cocaine self-administration. Incubation in rodents has been linked to time-dependent neuronal plasticity in the medial prefrontal cortex (mPFC). We tested the hypothesis that incubation of cue reactivity during abstinence from cocaine self-administration is accompanied by lower potency and/or efficacy of the selective serotonin (5-HT) 5-HT2C​ receptor (5-HT2CR) agonist WAY163909 to suppress cue reactivity and a shift in the subcellular localization profile of the mPFC 5-HT2CR protein. We observed incubation of cue reactivity (measured as lever presses reinforced by the discrete cue complex) between Day 1 and Day 30 of forced abstinence from cocaine relative to sucrose self-administration. Pharmacological and biochemical analyses revealed that the potency of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity, the expression of synaptosomal 5-HT2CR protein in the mPFC, and the membrane to cytoplasmic expression of the 5-HT2CR in mPFC were lower on Day 30 vs. Day 1 of forced abstinence from cocaine self-administration. Incubation of cue reactivity assessed during forced abstinence from sucrose self-administration did not associate with 5-HT2CR protein expression in the mPFC. Collectively, these outcomes are the first indication that neuroadaptations in the 5-HT2CR system may contribute to incubation of cocaine cue reactivity. PMID:26926963

  16. Endogenous 5-HT2C Receptors Phosphorylate the cAMP Response Element Binding Protein via Protein Kinase C-Promoted Activation of Extracellular-Regulated Kinases-1/2 in Hypothalamic mHypoA-2/10 Cells.

    Lauffer, Lisa; Glas, Evi; Gudermann, Thomas; Breit, Andreas

    2016-07-01

    Serotonin 5-HT2C receptors (5-HT2CR) activate Gq proteins and are expressed in the central nervous system (CNS). 5-HT2CR regulate emotion, feeding, reward, or cognition and may serve as promising drug targets to treat psychiatric disorders or obesity. Owing to technical difficulties in isolating cells from the CNS and the lack of suitable cell lines endogenously expressing 5-HT2CR, our knowledge about this receptor subtype in native environments is rather limited. The hypothalamic mHypoA-2/10 cell line was recently established and resembles appetite-regulating hypothalamic neurons of the paraventricular nucleus (PVN), where 5-HT2CR have been detected in vivo. Therefore, we tested mHypoA-2/10 cells for endogenous 5-HT2CR expression. Serotonin or the 5-HT2CR preferential agonist WAY-161,503 initiated cAMP response element (CRE)-dependent gene transcription with EC50 values of 15.5 ± 9.8 and 1.1 ± 0.9 nM, respectively. Both responses were blocked by two unrelated 5-HT2CR-selective antagonists (SB-242,084, RS-102,221) but not by a 5-HT2AR (EMD-281,014) or 5-HT2BR (RS-127,455) antagonists. By single-cell calcium imaging, we found that serotonin and WAY-161,503 induced robust calcium transients, which were also blunted by both 5-HT2CR antagonists. Additionally we revealed, first, that 5-HT2CR induced CRE activation via protein kinase C (PKC)-mediated engagement of extracellular-regulated kinases-1/2 and, second, that intrinsic activity of WAY-161,503 was in the range of 0.3-0.5 compared with serotonin, defining the frequently used 5-HT2CR agonist as a partial agonist of endogenous 5-HT2CR. In conclusion, we have shown that hypothalamic mHypoA-2/10 cells endogenously express 5-HT2CR and thus are the first cell line in which to analyze 5-HT2CR pharmacology, signaling, and regulation in its natural environment. PMID:27189964

  17. Design, Synthesis, and Pharmacological Characterization of N- and O-Substituted 5,6,7,8-Tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol Analogues: Novel 5-HT2A/5-HT2C Receptor Agonists with Pro-Cognitive Properties

    Jensen, Anders A.; Plath, Niels; Pedersen, Martin Holst Friborg;

    2013-01-01

    to be selective for the two receptors. Administration of 3d substantially improved the cognitive performance of mice in a place recognition Y-maze model, an effect fully reversible by coadministration of the selective 5-HT2C antagonist SB242084. In conclusion, as novel bioavailable cognitive enhancers that most...

  18. Studies on the role of 5-HT2A and 5-HT2C receptor antagonist and effects of co-administration of Fluoxetines in regulating generalized seizures in albino rats

    Vasant R Chavan

    2010-07-01

    Full Text Available Introduction: Epilepsy is due to imbalance between inhibitory & excitatory neurotransmitter release at synaptic level in brain such as GABA, Serotonin, Glutamate and nor epinephrine. Recently there are few reports suggesting that, 5-HT1A receptor antagonist with co-administration of fluoxetine has shown anticonvulsant activity. The present study is undertaken to evaluate the action of 5-HT2A/2C mediated anticonvulsant action of Trazodone in MES (Maximum Electro Shock model in albino rats. Materials & Methods: Fifty albino rats of 200-250 gms of either sex were divided into five groups each of 10 rats(n=10, Group–I received distil water 0.5ml oral, Group –II- received sodium valproate - 200mg/kg bw intra peritoneal(i.p.acted as positive control, Group –III- received Trazodone 54mg/bw, orally Group- IV- received sub-anticonvulsant dose of Fluoxetine 6mg/kg/bw i.p. Group- V- received Trazodone 54mg/kg/bw and Fluoxetine 6mg/kg bw. Subsequently all groups were subjected for MES. The results were analyzed by calculating the mean duration of convulsions & absence of HLE and comparison was done by student‘t’ test. Results: The present study revealed that sodium valproate showed 100% protection against MES as compared to negative control,(P<0.05. Trazodone showed 40% protection against MES& decrease in the duration of convulsions by 60%, and Fluoxitine sub-anticonvulsive dose combined with Trazodone 54 mg /kg b.w. has shown 90% protection against MES. The results are parallel to standard drug sodium valproate. Conclusion: Trazodone has exerted anticonvulsant activity, by enhancing 5-HT&NE extra cellular level in brain, and probably potentiated the action of sub anticonvulsive dose of fluoxetine in combination. However, further investigative studies are needed to confirm the potention of trazodone action.

  19. The serotonin transporter (5-HTTLPR) but not serotonin receptor (5-HT2C Cys23Ser) variant is associated with bipolar I disorder in Kurdish population from Western Iran.

    Mohammadi, Sahar; Khazaie, Habibolah; Rahimi, Ziba; Vaisi-Raygani, Asad; Zargooshi, Newsha; Rahimi, Zohreh

    2015-03-17

    The role of 5-HTTLPR and 5-HT2C Cys23Ser polymorphisms in the psychopathology of mood disorders and suicide behavior is controversial. The aim of present study was to investigate the association between 5-HTTLPR and 5-HT2C Cys23Ser variants and susceptibility to bipolar I disorder (BID). The 5-HT2C genotypes were studied in 152 patients with BID and 173 gender- and age-matched healthy individuals with Kurds ethnic background from Western Iran using PCR and PCR-RFLP methods. In recessive model (SS vs. LL+LS) the SS genotype was associated with 1.79-fold increased risk of BID (p=0.018). Also, the presence of S allele increased the risk of adult-onset BID by 1.76-fold (p=0.027). No association was detected between 5-HTTLPR genotypes and alleles with suicide attempt. The frequency of 5-HT2C Ser allele in patients and controls were 12.3 and 12.5%, respectively. Mutant allele of HT2C Ser had higher frequency in female (14.7%) than male (10.5%, p=0.27) patients. The frequency of HT2C Ser allele in patients with a family history of BID tended to be higher (15.7%) than those without a family history of the disease (11.8%). The frequency of HT2C Ser allele in suicide attempter women was higher (16.7%) than those without a suicide attempt (14.3%). Our findings demonstrate 5-HTTLPR polymorphism might be a risk factor for BID and adult-onset BID in Kurds population. However, we found the lack of an association between 5-HT2C Cys/Ser variants and the risk of BID. PMID:25596490

  20. A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives.

    Lazzari, Paolo; Distinto, Rita; Manca, Ilaria; Baillie, Gemma; Murineddu, Gabriele; Pira, Marilena; Falzoi, Matteo; Sani, Monica; Morales, Paula; Ross, Ruth; Zanda, Matteo; Jagerovic, Nadine; Pinna, Gérard Aimè

    2016-10-01

    8-Chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold. Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed. PMID:27240274

  1. Characterization of [(11)C]Cimbi-36 as an agonist PET radioligand for the 5-HT(2A) and 5-HT(2C) receptors in the nonhuman primate brain

    Finnema, Sjoerd J; Stepanov, Vladimir; Ettrup, Anders; Nakao, Ryuji; Amini, Nahid; Svedberg, Marie; Lehmann, Charlotte; Hansen, Martin; Knudsen, Gitte M; Halldin, Christer

    2014-01-01

    conducted after injection of [(11)C]MDL 100907. All PET measurements were performed for 2h in a HRRT PET system and arterial blood was obtained for measurement of the [(11)C]Cimbi-36 input function. Quantification of [(11)C]Cimbi-36 receptor binding was performed using kinetic and graphical analysis. After...

  2. Cholinergic cells in the nucleus basalis of mice express the N-methyl-D-aspartate-receptor subunit NR2C and its replacement by the NR2B subunit enhances frontal and amygdaloid acetylcholine levels

    De Souza Silva, M. A.; Dolga, Amalia; Pieri, I.; Marchetti, L.; Eisel, U. L. M.; Huston, J. P.; Dere, E.

    2006-01-01

    It is known that glutamatergic and cholinergic systems interact functionally at the level of the cholinergic basal forebrain. The N-methyl-D-aspartate receptor (NMDA-R) is a multiprotein complex composed of NR1, NR2 and/or NR3 subunits. The subunit composition of NMDA-R of cholinergic cells in the n

  3. Molecular Mimicry Regulates ABA Signaling by SnRK2 Kinases and PP2C Phosphatases

    Abscisic acid (ABA) is an essential hormone for plants to survive environmental stresses. At the center of the ABA signaling network is a subfamily of type 2C protein phosphatases (PP2Cs), which form exclusive interactions with ABA receptors and subfamily 2 Snfl-related kinase (SnRK2s). Here, we report a SnRK2-PP2C complex structure, which reveals marked similarity in PP2C recognition by SnRK2 and ABA receptors. In the complex, the kinase activation loop docks into the active site of PP2C, while the conserved ABA-sensing tryptophan of PP2C inserts into the kinase catalytic cleft, thus mimicking receptor-PP2C interactions. These structural results provide a simple mechanism that directly couples ABA binding to SnRK2 kinase activation and highlight a new paradigm of kinase-phosphatase regulation through mutual packing of their catalytic sites.

  4. Molecular Mimicry Regulates ABA Signaling by SnRK2 Kinases and PP2C Phosphatases

    Soon, Fen-Fen; Ng, Ley-Moy; Zhou, X. Edward; West, Graham M.; Kovach, Amanda; Tan, M.H. Eileen; Suino-Powell, Kelly M.; He, Yuanzheng; Xu, Yong; Chalmers, Michael J.; Brunzelle, Joseph S.; Zhang, Huiming; Yang, Huaiyu; Jiang, Hualiang; Li, Jun; Yong, Eu-Leong; Cutler, Sean; Zhu, Jian-Kang; Griffin, Patrick R.; Melcher, Karsten; Xu, H. Eric (Van Andel); (Scripps); (NWU); (Purdue); (UCR); (Chinese Aca. Sci.); (NU Singapore)

    2014-10-02

    Abscisic acid (ABA) is an essential hormone for plants to survive environmental stresses. At the center of the ABA signaling network is a subfamily of type 2C protein phosphatases (PP2Cs), which form exclusive interactions with ABA receptors and subfamily 2 Snfl-related kinase (SnRK2s). Here, we report a SnRK2-PP2C complex structure, which reveals marked similarity in PP2C recognition by SnRK2 and ABA receptors. In the complex, the kinase activation loop docks into the active site of PP2C, while the conserved ABA-sensing tryptophan of PP2C inserts into the kinase catalytic cleft, thus mimicking receptor-PP2C interactions. These structural results provide a simple mechanism that directly couples ABA binding to SnRK2 kinase activation and highlight a new paradigm of kinase-phosphatase regulation through mutual packing of their catalytic sites.

  5. Augmentative effect of tetrandrine on pentobarbital hypnosis mediated by 5-HT1A and 5-HT2A/2C receptors in mice%5-HT1A和5-HT2A/2C受体在粉防己碱增强戊巴比妥钠睡眠中的介导作用

    杜楠; 王黎恩; 师晓荣; 崔翔宇; 崔素颖; 张帆; 张永鹤

    2008-01-01

    前期研究表明粉防己碱增强戊巴比妥钠诱导的催眠作用与5-HT系统相关.本研究采用戊巴比妥钠(45 mg/kg,协)诱导的小鼠翻正反射消失和恢复实验方法,对粉防己碱与不同5-HT受体在增强戊巴比妥钠诱导睡眠中的相互作用进行了探讨.结果表明粉防己碱分别与选择性5-HT1A受体拮抗剂p-MPPI(1 mg/kg,i.p.),选择性5-HT2A/2C受体拮抗剂ketanserin(1.5mg/kg,i.p.)合用可以显著增强戊巴比妥钠诱导的催眠作用.选择性5-HT1A受体激动剂8-OH-DPAT(0.1 mg/kg,s.c.)或5-HT2A/2C受体激动剂DOI(0.2 mg/kg.i.p.)能够显著减少戊巴比妥钠诱导的小鼠睡眠时间,而粉防己碱(60 mg/kg,i.p.)可以显著拮抗这种睡眠抑制作用.此结果提示,粉防己碱增强戊巴比妥钠诱导的催眠作用可能与5-HT1A受体和5-HT2A/2C受体有关.%It has been reported that augmentative effect of tetrandrine on pentobarbital hypnosis in mice may be related to sero-tonergic system. The present study was undertaken to investigate the interaction of tetrandrine and different 5-HT receptors on pentobarbital-induced sleep by using the loss-of-righting reflex method. The results showed that augmentative effect of tetrandrine on pentobarbital hypnosis in mice were potentiated by the p-MPPI (5-HT1A receptor antagonist) (1 mg/kg, i.p.) and ketanserin (5-HT2A/2C receptor antagonist) (1.5 mg/kg, i.p.), respectively. Pretreatment with either 8-OH-DPAT (5-HT1A receptor agonist)(0.1 mg/kg, s.c.) or DOI (5-HT2A/2C receptor agonist) (0.2 mg/kg, i.p.) significantly decreased pentobarbital-induced sleep time,and tetrandrine (60 mg/kg, i.g.) significantly reversed this effect. These results suggest that both the 5-HTtA and 5-HT2A/2C subfamily may be involved in the potentiating mechanism of tetrandrine's effects on pentobarbital hypnosis.

  6. receptores

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  7. Myostatin stimulates, not inihibits, C2C12 myoblast proliferation.

    Rodgers, Buel D; Wiedeback, Benjamin D; Hoversten, Knut E; Jackson, Melissa F; Walker, Ryan G; Thompson, Thomas B

    2014-03-01

    The immortal C2C12 cell line originates from dystrophic mouse thigh muscle and has been used to study the endocrine control of muscle cell growth, development, and function, including those actions regulated by myostatin. Previous studies suggest that high concentrations of recombinant myostatin generated in bacteria inhibit C2C12 proliferation and differentiation. Recombinant myostatin generated in eukaryotic systems similarly inhibits the proliferation of primary myosatellite cells, but consequently initiates, rather than inhibits, their differentiation and is bioactive at far lower concentrations. Our studies indicate that 2 different sources of recombinant myostatin made in eukaryotes stimulate, not inhibit, C2C12 proliferation. This effect occurred at different cell densities and serum concentrations and in the presence of IGF-I, a potent myoblast mitogen. This stimulatory effect was comparable to that obtained with TGFβ1, a related factor that also inhibits primary myosatellite cell proliferation. Attenuating the myostatin/activin (ie, Acvr2b) and TGFβ1 receptor signaling pathways with the Alk4/5 and Alk5 inhibitors, SB431542 and SB505142, respectively, similarly attenuated proliferation induced by serum, myostatin or TGFβ1 and in a dose-dependent manner. In serum-free medium, both myostatin and TGFβ1 stimulated Smad2 phosphorylation, but not that of Smad3, and a Smad3 inhibitor (SIS3) only inhibited proliferation in cells cultured in high serum. Thus, myostatin and TGFβ1 stimulate C2C12 proliferation primarily via Smad2. These results together question the physiological relevance of the C2C12 model and previous studies using recombinant myostatin generated in bacteria. They also support the alternative use of primary myosatellite cells and recombinant myostatin generated in eukaryotes. PMID:24424069

  8. Developing 2 C-compatible investment criteria

    Roeser, Frauke [NewClimate - Institute for Climate Policy and Global Sustainability gGmbH, Bonn (Germany); Weischer, Lutz [Germanwatch e.V., Koeln (Germany); Thomae, Jakob [2degrees Investing Initiative, New York, NY (United States); Hoehne, Niklas; Hagemann, Markus; El Alaoui, Alexander; Bals, Christoph; Eckstein, David; Kreft, Soenke; Rosse, Morten

    2015-11-30

    This report studies the development of criteria for assessing the compatibility of financial investments with the international goal to limit global temperature increase to below 2 C above pre-industrial levels. The findings are intended as a starting point and a key input for a longer term process to develop consensus-based 2 C investing criteria. The focus here is placed on investments in projects and physical assets, in particular of development and climate finance organisations. In order to limit global temperature increase to 2 C, global greenhouse gas (GHG) emissions will have to be reduced significantly, eventually to zero, during the course of this century. This requires shifting capital from high to low carbon investments as well as significant capital mobilisation for investments in 2 C-compatible infrastructure. Given the long lifetime of physical assets, and the urgency of decarbonisation over the coming decades, this needs to begin today. Public financial institutions can play a prominent role in contributing to aligning investment flows with the 2 C limit, as well as in closing the current infrastructure investment gap, responding to their explicit or implicit climate mandates and leadership role in the finance sector. The majority of international financial institutions integrate climate considerations into their finance decisions to some degree, and are familiar with different types of criteria, including positive and negative lists, qualitative and quantitative benchmarks, and the use of shadow carbon pricing. However, current approaches do not link to the 2 C limit. 2 C investment criteria are therefore needed to guide investors in this regard. Such criteria may also support other purposes, including an understanding of climate risks and improved reporting and accountability.

  9. Developing 2 C-compatible investment criteria

    This report studies the development of criteria for assessing the compatibility of financial investments with the international goal to limit global temperature increase to below 2 C above pre-industrial levels. The findings are intended as a starting point and a key input for a longer term process to develop consensus-based 2 C investing criteria. The focus here is placed on investments in projects and physical assets, in particular of development and climate finance organisations. In order to limit global temperature increase to 2 C, global greenhouse gas (GHG) emissions will have to be reduced significantly, eventually to zero, during the course of this century. This requires shifting capital from high to low carbon investments as well as significant capital mobilisation for investments in 2 C-compatible infrastructure. Given the long lifetime of physical assets, and the urgency of decarbonisation over the coming decades, this needs to begin today. Public financial institutions can play a prominent role in contributing to aligning investment flows with the 2 C limit, as well as in closing the current infrastructure investment gap, responding to their explicit or implicit climate mandates and leadership role in the finance sector. The majority of international financial institutions integrate climate considerations into their finance decisions to some degree, and are familiar with different types of criteria, including positive and negative lists, qualitative and quantitative benchmarks, and the use of shadow carbon pricing. However, current approaches do not link to the 2 C limit. 2 C investment criteria are therefore needed to guide investors in this regard. Such criteria may also support other purposes, including an understanding of climate risks and improved reporting and accountability.

  10. F2c at low x

    Illarionov, A Yu

    2011-01-01

    We study the heavy-quark contributions to the proton structure function F2(x,Q2) at next-to-leading order using compact formulas at small values of Bjorken's x variable. The formulas provide a good agreement with the modern HERA data for F2c(x,Q2).

  11. LM-2C Series Launch Vehicles

    XueFuxing

    2004-01-01

    On December 30, 2003, a LM-2C/SM launch vehicle was launched from Xichang Satellite Launch Center (XSLC), successfully sending TC-1 satellite into orbit. The satellite is the first one of the two scientific satellites known as Double Star. The operation orbit of the satellite is the highest compared with China's other satellites ever launched.

  12. PPARα activators down-regulate CYP2C7, a retinoic acid and testosterone hydroxylase

    Peroxisome proliferators (PP) are a large class of structurally diverse chemicals that mediate their effects in the liver mainly through the peroxisome proliferator-activated receptor α (PPARα). Exposure to PP results in down-regulation of CYP2C family members under control of growth hormone and sex steroids including CYP2C11 and CYP2C12. We hypothesized that PP exposure would also lead to similar changes in CYP2C7, a retinoic acid and testosterone hydroxylase. CYP2C7 gene expression was dramatically down-regulated in the livers of rats treated for 13 weeks by WY-14,643 (WY; 500 ppm) or gemfibrozil (GEM; 8000 ppm). In the same tissues, exposure to WY and GEM and to a lesser extent di-n-butyl phthalate (20 000 ppm) led to decreases in CYP2C7 protein levels in both male and female rats. An examination of the time and dose dependence of CYP2C7 protein changes after PP exposure revealed that CYP2C7 was more sensitive to compound exposure compared to other CYP2C family members. Protein expression was decreased after 1, 5 and 13 weeks of PP treatment. CYP2C7 protein expression was completely abolished at 5 ppm WY, the lowest dose tested. GEM and DBP exhibited dose-dependent decreases in CYP2C7 protein expression, becoming significant at 1000 ppm or 5000 ppm and above, respectively. These results show that PP exposure leads to changes in CYP2C7 mRNA and protein levels. Thus, in addition to known effects on steroid metabolism, exposure to PP may alter retinoic acid metabolism

  13. Expression of paired-like homeodomain transcription factor 2c (PITX2c) in epidermal keratinocytes

    Paired-like homeodomain transcription factor 2 (PITX2) has been implicated as one of the genes responsible for Rieger syndrome. It has been also shown to play a central role during development. In this study, we investigated the functional role of PITX2 in keratinocyte differentiation. RT-PCR analysis showed that PITX2c isoform was predominantly expressed in a differentiation-dependent manner. Consistent with, immunohistochemical staining showed that PITX2 expression was increased in the upper layer of epidermis. When PITX2c was overexpressed in cultured keratinocytes by a recombinant adenovirus, the differentiation markers such as involucrin and loricrin were significantly increased at both mRNA and protein levels. In addition, PITX2c overexpression led to the decrease of cell growth, concomitantly with the upregulation of cell cycle-related genes p21. To investigate the effect of PITX2c in vivo, we microinjected PITX2c expression vector into zebrafish embryo. Interestingly, overexpression of PITX2c in zebrafish embryo led to the formation of horn-like structure and thickening of epidermis, together with the increase of keratin 8 (K8) expression. These results suggest that PITX2c has a role in proliferation and differentiation of epidermal keratinocytes.

  14. Expression of paired-like homeodomain transcription factor 2c (PITX2c) in epidermal keratinocytes

    Shi, Ge [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Department of Dermatology, The First Affiliated Hospital, Guangxi Traditional Chinese Medical University, Guangxi, Nanning, 530023 (China); Sohn, Kyung-Cheol; Choi, Tae-Young; Choi, Dae-Kyoung; Lee, Sang-Sin [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Ou, Bai-sheng [Department of Dermatology, The First Affiliated Hospital, Guangxi Traditional Chinese Medical University, Guangxi, Nanning, 530023 (China); Kim, Sooil; Lee, Young Ho [Department of Anatomy, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Yoon, Tae-Jin [Department of Dermatology, School of Medicine, Gyeongsang National University, Jinju, 660-702 (Korea, Republic of); Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, 660-702 (Korea, Republic of); Kim, Seong-Jin [Department of Dermatology, Chonnam National University Medical School, Gwangju, 501-757 (Korea, Republic of); Lee, Young; Seo, Young-Joon; Lee, Jeung-Hoon [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Kim, Chang Deok, E-mail: cdkimd@cnu.ac.kr [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of)

    2010-11-15

    Paired-like homeodomain transcription factor 2 (PITX2) has been implicated as one of the genes responsible for Rieger syndrome. It has been also shown to play a central role during development. In this study, we investigated the functional role of PITX2 in keratinocyte differentiation. RT-PCR analysis showed that PITX2c isoform was predominantly expressed in a differentiation-dependent manner. Consistent with, immunohistochemical staining showed that PITX2 expression was increased in the upper layer of epidermis. When PITX2c was overexpressed in cultured keratinocytes by a recombinant adenovirus, the differentiation markers such as involucrin and loricrin were significantly increased at both mRNA and protein levels. In addition, PITX2c overexpression led to the decrease of cell growth, concomitantly with the upregulation of cell cycle-related genes p21. To investigate the effect of PITX2c in vivo, we microinjected PITX2c expression vector into zebrafish embryo. Interestingly, overexpression of PITX2c in zebrafish embryo led to the formation of horn-like structure and thickening of epidermis, together with the increase of keratin 8 (K8) expression. These results suggest that PITX2c has a role in proliferation and differentiation of epidermal keratinocytes.

  15. Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists

    Hansen, Martin; Phonekeo, Karina; Paine, James S; Leth-Petersen, Sebastian; Begtrup, Mikael; Bräuner-Osborne, Hans; Kristensen, Jesper Langgaard

    2014-01-01

    N-benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a...

  16. Isolation and characterization of canine parvovirus type 2c (CPV-2c from symptomatic puppies

    R Puentes

    2012-09-01

    Full Text Available Canine parvovirus type 2 (CPV-2 is a leading cause of diarrhea in puppies in several parts of the world. In this study CPV-2 was detected and recovered from puppies showing clinical disease from Montevideo, Uruguay. Samples were processed and used to infect CRFK and MDCK cells in order to isolate the virus. Out of twelve, two samples were positive for CPV-2. A genomic region of 583 bp was amplified and the molecular characterization was performed by sequencing, phylogenetic analysis and Restriction Fragment Length Polymorphism (RFLP. Two isolated viruses (UY1 and UY2 were CPV-2c-like viruses. The comparison between the cytophatic effect (CPE of CPV-2 (vaccinal virus and CPV-2c (isolated virus on primary canine cells cultures and on CRFK line cells, demonstrated that CPV-2c is less citopathogenic in CRFK than in primary cultures. Our study represents the first report on isolation and characterization of canine parvovirus type 2c (CPV-2c in cell cultures from South American dogs.

  17. Design, Synthesis, and Application of OB2C Combinatorial Peptide and Peptidomimetic Libraries

    Liu, Ruiwu; Shih, Tsung-Chieh; Deng, Xiaojun; Anwar, Lara; Ahadi, Sara; Kumaresan, Pappanaicken; Lam, Kit S.

    2015-01-01

    The “one-bead two-compound” (OB2C) combinatorial library is constructed on topologically segregated trifunctional bilayer beads such that each bead has a fixed cell-capturing ligand and a random library compound co-displayed on its surface and a chemical coding tag (bar code) inside the bead. An OB2C library containing thousands to millions of compounds can be synthesized and screened concurrently within a short period of time. When live cells are incubated with such OB2C libraries, every bead will be coated with a monolayer of cells. The cell membranes of the captured cells facing the bead surface are exposed to the library compounds tethered to each bead. A specific biochemical or cellular response can be detected with an appropriate reporter system. The OB2C method enables investigators to rapidly discover synthetic molecules that not only interact with cell-surface receptors but can also stimulate or inhibit downstream cell signaling. To demonstrate this powerful method, one OB2C peptide library and two OB2C peptidomimetic libraries were synthesized and screened against Molt-4 lymphoma cells to discover “death ligands.” Apoptosis of the bead-bound cells was detected with immunocytochemistry using horseradish peroxidase (HRP)-conjugated anti-cleaved caspase-3 antibody and 3,3′-diaminobenzidine as a substrate. Two novel synthetic “death ligands” against Molt-4 cells were discovered using this OB2C library approach. PMID:25616322

  18. Telecom 2-B and 2-C (TC2B and TC2C)

    Dulac, J.; Alvarez, H.

    1991-01-01

    The DSN (Deep Space Network) mission support requirements for Telecom 2-B and 2-C (TC2B and TC2C) are summarized. These Telecom missions will provide high-speed data link applications, telephone, and television service between France and overseas territories as a follow-on to TC2A. Mission objectives are outlined and the DSN support requirements are defined through the presentation of tables and narratives describing the spacecraft flight profile; DSN support coverage; frequency assignments; support parameters for telemetry, command and support systems; and tracking support responsibility.

  19. Nonsynonymous HTR2C polymorphism predicts cortisol response to psychosocial stress II: Evidence from two samples.

    Way, Baldwin M; Brown, Kirk Warren; Quaglia, Jordan; McCain, Nancy; Taylor, Shelley E

    2016-08-01

    The 5-HT2C receptor is the primary serotonin receptor located in the corticotrophin releasing hormone (CRH) neurons of the hypothalamus. These neurons initiate the signaling cascade that culminates in cortisol release. Therefore, genetic variation in the 5-HT2C receptor gene (HTR2C) is a prime candidate for affecting cortisol reactivity to stress. Accordingly, we examined the association of a nonsynonymous polymorphism (Cys23Ser; rs6318) in HTR2C with stress reactivity in two Trier Social Stress Tests conducted at separate sites. In both Study 1 (N=128) and Study 2 (N=185), Cys23 homozygous females and hemizygous males had greater cortisol reactivity. There was no relation between this polymorphism and self-reported affective response (Studies 1 and 2) or cardiovascular reactivity (Study 2). Additionally, the short/short genotype of a polymorphism (5-HTTLPR) in the serotonin transporter gene was associated with greater cortisol reactivity in Study 1 as well as in Study 2 (previously reported). The Cys23Ser polymorphism and the 5-HTTLPR were independently associated with cortisol reactivity in both studies. These findings emphasize the important role of genetic variation in the serotonin system on regulating cortisol reactivity to social evaluative stress. Comparison of the present associations with those of prior studies underscores the likely importance of situational and psychological factors in determining the direction and magnitude of the association between genotype and phenotype. PMID:27211696

  20. Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol.

    Hermida, José; Zarza, José; Alberca, Ignacio; Montes, Ramón; López, María Luz; Molina, Eva; Rocha, Eduardo

    2002-06-01

    The 2C9*3 and 2C9*2 polymorphisms of cytochrome P-450 CYP2C9 are associated with hypersensitivity to warfarin and bleeding. The effect of these polymorphisms on sensitivity to acenocoumarol is unknown. Three groups of patients, with low, medium, or high acenocoumarol-dose requirements, were studied. Age influenced the acenocoumarol sensitivity. Bearing the 2C9*3 allele was associated with the need for a lower acenocoumarol dose (odds ratio [OR], 6.02; 95% confidence interval [CI], 1.50-24.18); 80% of carriers of the 2C9*3 allele required a low dose. The 2C9*2 allele was associated with a lower acenocoumarol-dose requirement (OR, 2.70; 95% CI, 1.11-6.58) because of a reduced risk of the need for a high acenocoumarol dose (4.8% of the patients in the high-dose group carried the 2C9*2 allele versus 34.1% and 30.2%, respectively, in the medium-dose and low-dose groups). Therefore, carriers of 2C9*3 may need a low initial loading dose of acenocoumarol. Because acenocoumarol sensitivity with the 2C9*2 variant does not seem to be clinically relevant, the drug could be an alternative to warfarin in 2C9*2 carriers. PMID:12010835

  1. The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia.

    Mulder, Hans; Franke, Barbara; van der-Beek van der, Annemarie Aart; Arends, Johan; Wilmink, Frederik W; Scheffer, Hans; Egberts, Antoine C G

    2007-08-01

    The use of antipsychotics is associated with metabolic side effects, which put patients with schizophrenia or related disorders at risk for cardiovascular morbidity. The high interindividual variability in antipsychotic-induced metabolic abnormalities suggests that genetic makeup is a possible determinant. In this cross-sectional study, we investigated whether genotypes of the HTR2C receptor are associated with the metabolic syndrome in patients using antipsychotics. Patients were identified from a schizophrenia disease management program. In this program, patients' blood pressure, triglycerides, high-density lipoprotein-cholesterol, and waist circumference are measured regularly during follow-up. The primary end point of our study was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Program's Adult Treatment Panel III. Primary determinants were polymorphisms in the HTR2C receptor gene (HTR2C:c.1-142948[GT]n, rs3813928 [-997 G/A], rs3813929 [-759 C/T], rs518147 [-697 G/C], and rs1414334 [C > G]). The included patients (n = 112) mainly (>80%) used atypical antipsychotics (clozapine, olanzapine, and risperidone). Carriership of the variant alleles of the HTR2C polymorphisms rs518147, rs1414334, and HTR2C:c.1-142948(GT)n was associated with an increased risk of the metabolic syndrome (adjusted odds ratio [OR], 2.62 [95% confidence interval {CI}, 1.00-6.85]; OR, 4.09 [95% CI, 1.41-11.89]; and OR, 3.12 [95% CI, 1.13-8.16]), respectively. Our findings suggest that HTR2C genotypes are associated with antincreased risk of metabolic syndrome in patients taking antipsychotics. PMID:17632216

  2. Analysis list: TFAP2C [Chip-atlas[Archive

    Full Text Available TFAP2C Breast,Epidermis,Uterus + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TFA...P2C.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TFAP2C.5.tsv http://dbarchive....biosciencedbc.jp/kyushu-u/hg19/target/TFAP2C.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TFA...P2C.Breast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TFAP2C.Epider...mis.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TFAP2C.Uterus.tsv http://dbarchive.biosciencedb

  3. Intracellular Distribution and Involvement of GPR30 in the Actions of E2 on C2C12 Cells.

    Ronda, Ana C; Boland, Ricardo L

    2016-03-01

    G-protein-coupled receptor 30 (GPR30) is an estrogen receptor that initiates several rapid, non-genomic signaling events triggered by E2. GPR30 has recently been identified in C2C12 cells; however, little is known about the intracelular distribution and its role in C2C12 myoblasts and myotubes. By western blotting and immunohistochemistry, we evidenced expression of GPR30. While in C2C12 myoblasts, the receptor was present in nucleus, mitochondria, and endoplasmic reticulum, in C2C12 myotubes, it was additionally found in cytoplasm. Using trypan blue uptake assay to determine cellular death and fluorescent microscopy to evaluate picnotic nuclei and mitochondrial distribution, we demonstated that treatment of C2C12 myoblasts with G1 (GPR30 agonist) did not protect the cells against apoptosis induced by H2 O2 as E2. However, when G15 (GPR30 antagonist) was used, E2 could not prevent the damage caused by the oxidative stress. Further, some of the molecular mechanisms involved were investigated by wertern blot assays. Thus, E2 was able to induce AKT phosphorylation in apoptotic conditions and ERK phosphorylation in proliferating C2C12 cells but not when the cultures were incubated with G15. Additionally, using G15 antagonist we have found that GPR30 participates in the myogenin expression and creatine kinase activity stimulated by E2 in the first steps of C2C12 differentiation. Althogether these findings provide evidences showing that GPR30 is expressed in diverse intracellular compartments in undifferentiated and differentiated C2C12 cells and mediates E2 actions. J. Cell. Biochem. 117: 793-805, 2016. © 2015 Wiley Periodicals, Inc. PMID:26359786

  4. Biquaternion Construction of SL(2,C) Yang-Mills Instantons

    Lee, Jen-Chi

    2015-01-01

    We use biquaternion to construct SL(2,C) ADHM Yang-Mills instantons. The solutions contain 16k-6 moduli parameters for the kth homotopy class, and include as a subset the SL(2,C) (M,N) instanton solutions constructed previously. In constrast to the SU(2) instantons, the SL(2,C) instantons inhereit jumping lines or singulariries which are not gauge artifacts and can not be gauged away.

  5. Activated Integrin-Linked Kinase Negatively Regulates Muscle Cell Enhancement Factor 2C in C2C12 Cells

    Zhenguo Dong

    2015-01-01

    Full Text Available Our previous study reported that muscle cell enhancement factor 2C (MEF2C was fully activated after inhibition of the phosphorylation activity of integrin-linked kinase (ILK in the skeletal muscle cells of goats. It enhanced the binding of promoter or enhancer of transcription factor related to proliferation of muscle cells and then regulated the expression of these genes. In the present investigation, we explored whether ILK activation depended on PI3K to regulate the phosphorylation and transcriptional activity of MEF2C during C2C12 cell proliferation. We inhibited PI3K activity in C2C12 with LY294002 and then found that ILK phosphorylation levels and MEF2C phosphorylation were decreased and that MCK mRNA expression was suppressed significantly. After inhibiting ILK phosphorylation activity with Cpd22 and ILK-shRNA, we found MEF2C phosphorylation activity and MCK mRNA expression were increased extremely significantly. In the presence of Cpd22, PI3K activity inhibition increased MEF2C phosphorylation and MCK mRNA expression indistinctively. We conclude that ILK negatively and independently of PI3K regulated MEF2C phosphorylation activity and MCK mRNA expression in C2C12 cells. The results provide new ideas for the study of classical signaling pathway of PI3K-ILK-related proteins and transcription factors.

  6. High expression of ubiquitin-conjugating enzyme 2C (UBE2C) correlates with nasopharyngeal carcinoma progression

    Overexpression of ubiquitin-conjugating enzyme 2C (UBE2C) has been detected in many types of human cancers, and is correlated with tumor malignancy. However, the role of UBE2C in human nasopharyngeal carcinoma (NPC) is unclear. In this study, we investigated the role of aberrant UBE2C expression in the progression of human NPC. Immunohistochemical analysis was performed to detect UBE2C protein in clinical samples of NPC and benign nasopharyngeal tissues, and the association of UBE2C expression with patient clinicopathological characteristics was analyzed. UBEC2 expression profiles were evaluated in cell lines representing varying differentiated stages of NPC and immortalized nasopharyngeal epithelia NP-69 cells using quantitative RT-PCR, western blotting and fluorescent staining. Furthermore, UBE2C was knocked down using RNA interference in these cell lines and proliferation and cell cycle distribution was investigated. Immunohistochemical analysis revealed that UBE2C protein expression levels were higher in NPC tissues than in benign nasopharyngeal tissues (P<0.001). Moreover, high UBE2C protein expression was positively correlated with tumor size (P=0.017), lymph node metastasis (P=0.016) and distant metastasis (P=0.015) in NPC patients. In vitro experiments demonstrated that UBE2C expression levels were inversely correlated with the degree of differentiation of NPC cell lines, whereas UBE2C displayed low level of expression in NP-69 cells. Knockdown of UBE2C led to significant arrest at the S and G2/M phases of the cell cycle, and decreased cell proliferation was observed in poorly-differentiated CNE2Z NPC cells and undifferentiated C666-1 cells, but not in well-differentiated CNE1 and immortalized NP-69 cells. Our findings suggest that high expression of UBE2C in human NPC is closely related to tumor malignancy, and may be a potential marker for NPC progression

  7. Nucleon-nucleon correlations in sup 1 sup 2 C

    Edelhoff, R

    2000-01-01

    In this thesis at the three-spectrometer facility of the A1 collaboration at the Mainz microtron an electron scattering experiment for the study of short-range correlations in sup 1 sup 2 C was performed. Measured were cross sections of the reactions sup 1 sup 2 C(e,e'), sup 1 sup 2 C(e,e'p), and sup 1 sup 2 C(e,e'pp). The cross sections were compared with calculations based on models of the theoretical groups from Valencia and Gent.

  8. NOAA-CIRES 20th Century Reanalysis (V2c)

    National Oceanic and Atmospheric Administration, Department of Commerce — The 20th Century Reanalysis version 2c (20CRV2c)is an effort led by PSD and the CIRES at the University of Colorado to produce a reanalysis dataset spanning the...

  9. 27 CFR 21.34 - Formula No. 2-C.

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Formula No. 2-C. 21.34... OF THE TREASURY LIQUORS FORMULAS FOR DENATURED ALCOHOL AND RUM Specially Denatured Spirits Formulas and Authorized Uses § 21.34 Formula No. 2-C. (a) Formula. To every 100 gallons of alcohol add:...

  10. Predicting drug metabolism by cytochrome P450 2C9

    Rydberg, Patrik; Olsen, Lars

    2012-01-01

    By the use of knowledge gained through modeling of drug metabolism mediated by the cytochrome P450 2D6 and 3A4 isoforms, we constructed a 2D-based model for site-of-metabolism prediction for the cytochrome P450 2C9 isoform. The similarities and differences between the models for the 2C9 and 2D6...

  11. Selective 5-HT2C agonists as potential antidepressants.

    Leysen, D C

    1999-02-01

    The antidepressants currently used need improvement, especially in terms of efficacy, relapse rate and onset of action. In this review the clinical and experimental data which support the rationale for 5-HT2C agonists in the treatment of depression are listed. Next, the results obtained with the non-selective 5-HT2C agonists on the market and in clinical development are described. Finally, the preclinical data on the more selective 5-HT2C agonists are summarized. These recent preclinical results reveal a greater potency and effect size compared to fluoxetine, good tolerability and no evidence of tolerance development. Selective 5-HT2C agonists might become innovative drugs for the treatment of depression, panic, obsessive-compulsive disorder (OCD), some forms of aggression and eating disorders. PMID:16160946

  12. The interstellar chemistry of H2C3O isomers

    Loison, Jean-Christophe; Agúndez, Marcelino; Marcelino, Núria; Wakelam, Valentine; Hickson, Kevin M.; Cernicharo, José; Gerin, Maryvonne; Roueff, Evelyne; Guélin, Michel

    2016-01-01

    We present the detection of two H2C3O isomers, propynal and cyclopropenone, toward various starless cores and molecular clouds, together with upper limits for the third isomer propadienone. We review the processes controlling the abundances of H2C3O isomers in interstellar media showing that the reactions involved are gas-phase ones. We show that the abundances of these species are controlled by kinetic rather than thermodynamic effects.

  13. The interstellar chemistry of H2C3O isomers

    Loison, Jean-Christophe; Agúndez, Marcelino; Marcelino, Núria; Wakelam, Valentine; Hickson, Kevin M.; Cernicharo, José; Gerin, Maryvonne; Roueff, Evelyne; Guélin, Michel

    2016-03-01

    We present the detection of two H2C3O isomers, propynal and cyclopropenone, toward various starless cores and molecular clouds, together with upper limits for the third isomer propadienone. We review the processes controlling the abundances of H2C3O isomers in interstellar media showing that the reactions involved are gas-phase ones. We show that the abundances of these species are controlled by kinetic rather than thermodynamic effects.

  14. Myostatin Stimulates, Not Inihibits, C2C12 Myoblast Proliferation

    Rodgers, Buel D.; Wiedeback, Benjamin D.; Hoversten, Knut E.; Jackson, Melissa F; Walker, Ryan G.; Thompson, Thomas B.

    2014-01-01

    The immortal C2C12 cell line originates from dystrophic mouse thigh muscle and has been used to study the endocrine control of muscle cell growth, development, and function, including those actions regulated by myostatin. Previous studies suggest that high concentrations of recombinant myostatin generated in bacteria inhibit C2C12 proliferation and differentiation. Recombinant myostatin generated in eukaryotic systems similarly inhibits the proliferation of primary myosatellite cells, but con...

  15. The interstellar chemistry of H2C3O isomers

    Loison, Jean-Christophe; Agúndez, Marcelino; Marcelino, Núria; Wakelam, Valentine; Hickson, Kevin M.; Cernicharo, José; Gerin, Maryvonne; Roueff, Evelyne; Guélin, Michel

    2016-01-01

    We present the detection of two H2C3O isomers, propynal and cyclopropenone, toward various starless cores and molecular clouds, together with upper limits for the third isomer propadienone. We review the processes controlling the abundances of H2C3O isomers in interstellar media showing that the reactions involved are gas-phase ones. We show that the abundances of these species are controlled by kinetic rather than thermodynamic effects. PMID:27013768

  16. The interstellar chemistry of H2C3O isomers

    Loison, Jean-Christophe; Marcelino, Núria; Wakelam, Valentine; Hickson, Kevin M; Cernicharo, José; Gerin, Maryvonne; Roueff, Evelyne; Guélin, Michel

    2015-01-01

    We present the detection of two H2C3O isomers, propynal and cyclopropenone, toward various starless cores and molecular clouds, together with upper limits for the third isomer propadienone. We review the processes controlling the abundances of H2C3O isomers in interstellar media showing that the reactions involved are gas-phase ones. We show that the abundances of these species are controlled by kinetic rather than thermodynamic effects.

  17. Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A

    Benoit, Roger M.; Frey, Daniel; Hilbert, Manuel; Kevenaar, Josta T.; Wieser, Mara M.; Stirnimann, Christian U.; McMillan, David; Ceska, Tom; Lebon, Florence; Jaussi, Rolf; Steinmetz, Michel O.; Schertler, Gebhard F. X.; Hoogenraad, Casper C.; Capitani, Guido; Kammerer, Richard A.

    2014-01-01

    Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral β-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open β-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties.

  18. Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis.

    Lin, Jieru E; Colon-Gonzalez, Francheska; Blomain, Erik; Kim, Gilbert W; Aing, Amanda; Stoecker, Brian; Rock, Justin; Snook, Adam E; Zhan, Tingting; Hyslop, Terry M; Tomczak, Michal; Blumberg, Richard S; Waldman, Scott A

    2016-01-15

    Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide. PMID:26773096

  19. Implementation of I 2C Master Bus Protocol on FPGA

    Regu Archana

    2014-10-01

    Full Text Available The focus of this paper is on I 2C (Inter-Integrated Circuit protocol interface between Master Bus protocol and slave. Here we are interfacing between micro-controller and DS1307. I 2C bus protocol sends 8 bit data from micro-controller to DS1307. This module was designed in VHDL and simulated and synthesized using Xilinx ISE Design Suite 14.2. I 2C and optimized for area and power. This concept is widely applicable from any high speed device or low speed device to any low speed device or high speed device. This module acts as a slave for the DS1307 at the same time acts like a master for the micro-controller device which can be considered as a slave. . It can be used to interface low speed peripherals like motherboard, embedded system, mobile phones, set top boxes, DVD, PDA’s or other electronic devices.

  20. Risk Analysis and Consumer Protection in B2C Transactions

    YANG Jian-zheng; SHI Qi-liang; Gary Millar; Ruhul A. Sarker

    2005-01-01

    Recent studies have shown that the perceived lack of security is a major obstacle to the wider acceptance of e-commerce. To overcome this barrier, businesses need to implement comprehensive consumer protection systems that protect consumers during every stage of the purchasing process. This paper used the consumer behaviour model as the basis for analysing risks in Bussiness-to-Consumer (B2C) transactions. Four categories of risks were identified: information, agreement, payment and delivery risk. By combining these risk categories with the three dimensions of management, technology and legislation, a comprehensive B2C consumer protection framework is developed.

  1. Thermoelectric performance of functionalized Sc 2 C MXenes

    Kumar, S.

    2016-07-05

    Functionalization of the MXene Sc2C, which has the rare property to realize semiconducting states for various functionalizations including O, F, and OH, is studied with respect to the electronic and thermal behavior. The lowest lattice thermal conductivity is obtained for OH functionalization and an additional 30% decrease can be achieved by confining the phonon mean free path to 100 nm. Despite a relatively low Seebeck coefficient, Sc2C(OH)2 is a candidate for intermediate-temperature thermoelectric applications due to compensation by a high electrical conductivity and very low lattice thermal conductivity.

  2. Cobalt triggers necrotic cell death and atrophy in skeletal C2C12 myotubes

    Severe poisoning has recently been diagnosed in humans having hip implants composed of cobalt–chrome alloys due to the release of particulate wear debris on polyethylene and ceramic implants which stimulates macrophagic infiltration and destroys bone and soft tissue, leading to neurological, sensorial and muscular impairments. Consistent with this premise, in this study, we focused on the mechanisms underlying the toxicity of Co(II) ions on skeletal muscle using mouse skeletal C2C12 myotubes as an in vitro model. As detected using propidium iodide incorporation, increasing CoCl2 doses (from 5 to 200 μM) affected the viability of C2C12 myotubes, mainly by cell necrosis, which was attenuated by necrostatin-1, an inhibitor of the necroptotic branch of the death domain receptor signaling pathway. On the other hand, apoptosis was hardly detectable as supported by the lack of caspase-3 and -8 activation, the latter resulting in only faint activation after exposure to higher CoCl2 doses for prolonged time points. Furthermore, CoCl2 treatment resulted in atrophy of the C2C12 myotubes which was characterized by the increased expression of HSP25 and GRP94 stress proteins and other typical 'pro-atrophic molecular hallmarks, such as early activation of the NF-kB pathway and down-regulation of AKT phosphorylation, followed by the activation of the proteasome and autophagy systems. Overall, these results suggested that cobalt may impact skeletal muscle homeostasis as an inducer of cell necrosis and myofiber atrophy. - Highlights: • The effects of cobalt on muscle myofibers in vitro were investigated. • Cobalt treatment mainly causes cell necrosis in skeletal C2C12 myotubes. • Cobalt impacts the PI3K/AKT and NFkB pathways and induces cell stress markers. • Cobalt induces atrophy of C2C12 myotubes through the activation of proteasome and autophagy systems. • Co treatment triggers NF-kB and PI3K/AKT pathways in C2C12 myotubes

  3. Cobalt triggers necrotic cell death and atrophy in skeletal C2C12 myotubes

    Rovetta, Francesca [Unit of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, Brescia I-25123 (Italy); Interuniversity Institute of Myology (IIM) (Italy); Stacchiotti, Alessandra [Institute of Human Anatomy, Department of Clinical and Experimental Sciences, University of Brescia, Brescia I-25123 (Italy); Faggi, Fiorella [Unit of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, Brescia I-25123 (Italy); Interuniversity Institute of Myology (IIM) (Italy); Catalani, Simona; Apostoli, Pietro [Unit of Occupational Health and Industrial Hygiene, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia I-25123 (Italy); Fanzani, Alessandro, E-mail: fanzani@med.unibs.it [Unit of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, Brescia I-25123 (Italy); Interuniversity Institute of Myology (IIM) (Italy); Aleo, Maria Francesca, E-mail: aleo@med.unibs.it [Unit of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, Brescia I-25123 (Italy); Interuniversity Institute of Myology (IIM) (Italy)

    2013-09-01

    Severe poisoning has recently been diagnosed in humans having hip implants composed of cobalt–chrome alloys due to the release of particulate wear debris on polyethylene and ceramic implants which stimulates macrophagic infiltration and destroys bone and soft tissue, leading to neurological, sensorial and muscular impairments. Consistent with this premise, in this study, we focused on the mechanisms underlying the toxicity of Co(II) ions on skeletal muscle using mouse skeletal C2C12 myotubes as an in vitro model. As detected using propidium iodide incorporation, increasing CoCl{sub 2} doses (from 5 to 200 μM) affected the viability of C2C12 myotubes, mainly by cell necrosis, which was attenuated by necrostatin-1, an inhibitor of the necroptotic branch of the death domain receptor signaling pathway. On the other hand, apoptosis was hardly detectable as supported by the lack of caspase-3 and -8 activation, the latter resulting in only faint activation after exposure to higher CoCl{sub 2} doses for prolonged time points. Furthermore, CoCl{sub 2} treatment resulted in atrophy of the C2C12 myotubes which was characterized by the increased expression of HSP25 and GRP94 stress proteins and other typical 'pro-atrophic molecular hallmarks, such as early activation of the NF-kB pathway and down-regulation of AKT phosphorylation, followed by the activation of the proteasome and autophagy systems. Overall, these results suggested that cobalt may impact skeletal muscle homeostasis as an inducer of cell necrosis and myofiber atrophy. - Highlights: • The effects of cobalt on muscle myofibers in vitro were investigated. • Cobalt treatment mainly causes cell necrosis in skeletal C2C12 myotubes. • Cobalt impacts the PI3K/AKT and NFkB pathways and induces cell stress markers. • Cobalt induces atrophy of C2C12 myotubes through the activation of proteasome and autophagy systems. • Co treatment triggers NF-kB and PI3K/AKT pathways in C2C12 myotubes.

  4. SL(2,C) Exterior forms and quantum gravity

    Baaklini, N.S.

    1979-01-15

    On the basis of a formal generalization of the functional integral to the space of SL(2,C) exterior forms, I obtain gravity as an exact effective theory, after integrating over fundamental spin-1/2 and spin-3/2 fields. The same formalism is suggested for a new frame-independent formulation of quantum gravity.

  5. Morphisms from P2 to Gr(2,C4)

    Mazouni, A El; Nagaraj, D S

    2009-01-01

    In this note we study morphisms from P2 to Gr(2,C4) from the point of view of the cohomology class they represent in the Grassmannian. This leads to some new result about projection of d-uple imbedding of P2 to P5.

  6. LM-2C Sent Yaogan 13 into Space

    2011-01-01

    The Yaogan 13 remote sensing satellite was launched into orbit from the Taiyuan Satellite Launch Center on November 30 on a LM-2C launch vehicle.Developed by SAST,the satellite will be used for scientific experiments,land survey,crop yield assessment and disaster monitoring.

  7. Main: 1I2C [RPSD[Archive

    Full Text Available Molecule: Sulfolipid Biosynthesis Protein Sqd1; Chain: A; Engineered: Yes; Mutation: Yes Biosynthetic Protei... Formation Of The Sulfonic Acid Product In The Crystalline State. To Be Published Sdr, Short-Chain Dehydroge...IHDRISRWKALTGKSIELYVGDICDFEFLAESFKSFEPDSVVHFGEQRSAPYSMIDRSRAVYTQHNNVIGTLNVLFAIKEFGEECHLVKLGTMGEYGTPNIDIEEGYI...FCVQAAVGHPLTVYGKGGQTRGYLDIRDTVQCVEIAIANPAKAGEFRVFNQFTEQFSVNELASLVTKAGSKLGLDVKKMTVPNPRVEAEEHYYNAKHTKLMELGLEPHYLSDSLLDSLLNFAVQFKDRVDTKQIMPSVSWKKIGVKTKSMTT arabi_1I2C.jpg ...

  8. Studies on CYP2C8-mediated drug interactions

    Tornio, Aleksi

    2008-01-01

    Useiden lÀÀkkeiden yhtÀaikainen kÀyttö on nykyÀÀn hyvin yleistÀ, mikÀ lisÀÀ lÀÀkeaineiden haitallisten yhteisvaikutusten riskiÀ. LÀÀkeaineiden poistumisessa elimistöstÀ ovat tÀrkeÀssÀ osassa niitÀ hajottavat (metaboloivat) maksan sytokromi P450 (CYP) entsyymit. Vasta aivan viime vuosina on havaittu, ettÀ CYP2C8-entsyymillÀ voi olla tÀrkeÀ merkitys mm. lÀÀkeaineyhteisvaikutuksissa. ErÀÀt lÀÀkeaineet voivat estÀÀ (inhiboida) CYP2C8-entsyymin kautta tapahtuvaa m...

  9. Online Trading C2C Operators Fight for Number One

    DAVID HENDRICKSON

    2006-01-01

    @@ Whether shopping casually or searching for some obscure, hard to find item, more and more Chinese are logging online and turning to customer-to-customer (C2C) network operators for their trading needs rather than bother with the hassles of conventional buying and selling. Proof is in the numbers. A leading technology, new media, and telecom watchdog, Analysys International reports that China's C2C market users more than doubled in 2005 to 37.87 million, while the sector's total transaction value increased from 4.16 billion yuan in 2004, to 13.9billion yuan (US$1.74 billion). Supplanted by a web surfing pool of 100 million and counting, they are trends that Analysys and other industry groups expect will continue in China for some time, fundamentally transforming how the country's independent traders do business.

  10. Magnetic ordering in Ho2Fe2Si2C

    We have used neutron diffraction and 57Fe Mössbauer spectroscopy, complemented by magnetisation and specific heat measurements, to examine the magnetic ordering of Ho2Fe2Si2C. We have established that Ho2Fe2Si2C orders antiferromagnetically below TN = 16(1) K with a magnetic structure involving ordering of the Ho sublattice along the b-axis with a propagation vector k=[0 0 1/2 ]. 57Fe Mössbauer spectra collected below TN show no evidence of a magnetic splitting, demonstrating the absence of long range magnetic ordering of the Fe sublattice. A small line broadening is observed in the 57Fe spectra below TN, which is due to a transferred hyperfine field—estimated to be around 0.3 T at 10 K—from the Ho sublattice

  11. Tsh receptor

    Frauman, Albert

    2013-01-01

    The TSH receptor is a member of the G protein-coupled receptor(GPCR)family. It is one of the glycoprotein hormone receptors, which also includes the FSH and LH/CG receptors. The TSH receptor mediates the action of the pituitary-derived glycoprotein, TSH (thyroid stimulating hormone, thyrotropin or thyrotrophin). TSH binds to the TSH receptor which is located on thyroid follicular cells (but is also expressed in extrathyroidal sites). Glycosylation of the TSH receptor occurs, as does cleavage ...

  12. Identification and mechanism of ABA receptor antagonism

    Melcher, Karsten; Xu, Yong; Ng, Ley-Moy; Zhou, X. Edward; Soon, Fen-Fen; Chinnusamy, Viswanathan; Suino-Powell, Kelly M; Kovach, Amanda; Tham, Fook S.; Cutler, Sean R.; Li, Jun; Yong, Eu-Leong; Zhu, Jian-Kang; Xu, H. Eric (NU Sinapore); (Van Andel); (UCR)

    2010-11-11

    The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands.

  13. Novel ultra-incompressible phases of Ru2C

    The crystal structures of Ru2C were extensively investigated using the structure searching method coupled with first-principles calculations. In contrast to the previously proposed P-3m1 phase, two energetically more favorable structures with space groups P-31m and P63/mmc were found, which are stable at pressure ranges of 0–32 GPa and 32–50 GPa, respectively. The dynamical stabilities of both phases at ambient and high pressures are confirmed by the phonon dispersions. Further calculations indicate that the two new predicted phases are ultra-incompressible metals due to a strong covalent Ru–C bond. (paper)

  14. Global structure search and physical properties of Os2C

    Hong, Feng; Lu, Jian; Gao, Heng; Ren, Wei; Xu, Run; Xu, Fei; Ma, Zhongquan; Yan, Yanfa

    2016-09-01

    The crystal structures of Os2C were extensively investigated using the structure search method from the first-principles calculations. In contrast to the P6 3 /mmc phase previously proposed as the ground state at ambient pressure, an energetically favorable structure with space group P-6m2 was found more stable at ambient condition. The structural stabilities of the new phase are confirmed by the phonon dispersion and elastic constants. Further calculations indicate that the newly predicted P-6m2 phase is ultra-incompressible with a high bulk modulus of 387 GPa and has a larger ideal shear strength than the P6 3 /mmc phase.

  15. Valence fluctuation in CeMo2Si2C

    Highlights: •Evidence for valence fluctuation of Ce ions. •XAS provides average formal LIII valence of Ce. •Kadowaki Woods ratio and Sommerfeld Wilson ratio indicate Fermi-liquid behavior. •DFT calculations reveal strong hybridization between Ce 4f and Mo 4d states. -- Abstract: We report on the valence fluctuation of Ce in CeMo2Si2C as studied by means of magnetic susceptibility χ(T), specific heat C(T), electrical resistivity ρ(T) and X-ray absorption spectroscopy. Powder X-ray diffraction revealed that CeMo2Si2C crystallizes in CeCr2Si2C-type layered tetragonal crystal structure (space group P4/mmm). The unit cell volume of CeMo2Si2C deviates from the expected lanthanide contraction, indicating non-trivalent state of Ce ions in this compound. The observed weak temperature dependence of the magnetic susceptibility and its low value indicate that Ce ions are in valence fluctuating state. The formal LIII Ce valence in CeMo2Si2C〈ν∼〉=3.14 as determined from X-ray absorption spectroscopy measurement is well below the value 〈ν∼〉≃3.4 in tetravalent Ce compound CeO2. The temperature dependence of specific heat does not show any anomaly down to 1.8 K which rules out any magnetic ordering in the system. The Sommerfeld coefficient obtained from the specific heat data is γ = 23.4 mJ/mol K2. The electrical resistivity follows the T2 behavior in the low temperature range below 35 K confirming a Fermi liquid behavior. Accordingly both the Kadowaki Woods ratio A/γ2 and the Sommerfeld Wilson ratio χ(0)/γ are in the range expected for Fermi-liquid systems. In order to get some information on the electronic states, we calculated the band structure within the density functional theory, eventhough this approach is not able to treat 4f electrons accurately. The non-f electron states crossing the Fermi level have mostly Mo 4d character. They provide the states with which the 4f sates are strongly hybridized, leading to the intermediate valent state

  16. Particle Classification and Dynamics in GL(2,C) Gravity

    Stern, A

    2009-01-01

    A relatively simple approach to noncommutative gravity utilizes the gauge theory formulation of general relativity and involves replacing the Lorentz gauge group by a larger group. This results in additional field degrees of freedom which either must be constrained to vanish in a nontrivial way, or require physical interpretation. With the latter in mind, we examine the coupling of the additional fields to point particles. Nonstandard particle degrees of freedom should be introduced in order to write down the most general coupling. The example we study is the $GL(2,C)$ central extension of gravity given by Chamseddine, which contains two U(1) gauge fields, and a complex vierbein matrix, along with the usual spin connections. For the general coupling one should then attach two U(1) charges and a complex momentum vector to the particle, along with the spin. The momenta span orbits in a four-dimensional complex vector space, and are classified by $GL(2,C)$ invariants and by their little groups. In addition to or...

  17. Particle classification and dynamics in GL(2,C) gravity

    A relatively simple approach to noncommutative gravity utilizes the gauge theory formulation of general relativity and involves replacing the Lorentz gauge group by a larger group. This results in additional field degrees of freedom which either must be constrained to vanish in a nontrivial way or require physical interpretation. With the latter in mind, we examine the coupling of the additional fields to point particles. Nonstandard particle degrees of freedom should be introduced in order to write down the most general coupling. The example we study is the GL(2,C) central extension of gravity given by Chamseddine, which contains two U(1) gauge fields and a complex vierbein matrix, along with the usual spin connections. For the general coupling one should then attach two U(1) charges and a complex momentum vector to the particle, along with the spin. The momenta span orbits in a four-dimensional complex vector space and are classified by GL(2,C) invariants and by their little groups. In addition to orbits associated with standard massive and massless particles, a number of novel orbits can be identified. We write down a general action principle for particles associated with any nontrivial orbit and show that it leads to corrections to geodesic motion. We also examine the classical and quantum theory of the particle in flat space-time.

  18. NCEP/DOE Reanalysis II in HDF-EOS5, for GSSTF2c, 1x1 deg Daily grid V2c

    National Aeronautics and Space Administration — These data are the Goddard Satellite-based Surface Turbulent Fluxes Version-2c (GSSTF2c) Dataset recently produced through a MEaSURES funded project led by Dr....

  19. DECOVALEX II PROJECT Technical Report - Task 2C

    The DECOVALEX II project is an international co-operative research project supported by a number of national radioactive waste management organizations of different countries. The project studied four tasks: Task 1: numerical simulation of the RCF3 pump test at Sellafield, UK; Task 2: numerical simulation of the in situ T-H-M experiment at Kamaishi Mine, Japan; Task 3: monitoring of current development in rock fracture research; and Task 4: report on treatment of T-H-M processes in Performance Assessment works for nuclear waste repositories. The project started in 1995 and is scheduled to be finalised in March, 1999. This report concerns the Task 2 of the DECOVALEX H project. Task 2 of the DECOVALEX II project is the numerical modelling of the in-situ T-H-M experiment of a fractured rock - buffer - heater system at Kamaishi Mine, Japan. The experiment was carried out inside a test pit drilled in the floor of a 5 x 7 m alcove excavated near an existing drift at the 550 m level. The test pit has a circular cross section of diameter 1.7 m and a depth of 5 m, filled with bentonite which contains an electric heater. Four research teams studied Task 2 with different computational models. The task is divided into three sub-tasks: Task 2A, Task 2B and Task 2C. Task 2A was defined as a blind prediction to the coupled hydro-mechanical behaviour of the fractured rocks due to the excavation of the test pit. The calibration of the numerical models against measured results of pore pressures, flow rates and rock deformation before filling up of the test pit formed Task 2B. These two sub-tasks were performed to establish well calibrated fields of hydraulic conductivity and mechanical deformability of the fractured rocks at the test site. They were necessary for further simulations on interactions between the rock and buffer materials during heating experiments, as required for Task 2C, with a higher level of confidence on rock mass models. Presented in this report is the

  20. Up-Regulation of CYP2C19 Expression by BuChang NaoXinTong via PXR Activation in HepG2 Cells

    Wu, Xiao-Ying; Wang, Huan; Qu, Qiang; Tan, Shen-Lan; Ruan, Jun-Shan; Qu, Jian; Chen, Hui

    2016-01-01

    Background Cytochrome P450 2C19 (CYP2C19) is an important drug-metabolizing enzyme (DME), which is responsible for the biotransformation of several kinds of drugs such as proton pump inhibitors, platelet aggregation inhibitors and antidepressants. Previous studies showed that Buchang NaoXinTong capsules (NXT) increased the CYP2C19 metabolic activity in vitro and enhanced the antiplatelet effect of clopidogrel in vivo. However, the underlying molecular mechanism remained unclear. In the present study, we examined whether Pregnane X receptor (PXR) plays a role in NXT-mediated regulation of CYP2C19 expression. Methods We applied luciferase assays, real-time quantitative PCR (qPCR), Western blotting and cell-based analysis of metabolic activity experiments to investigate the NXT regulatory effects on the CYP2C19 promoter activity, the mRNA/ protein expression and the metabolic activity. Results Our results demonstrated that NXT significantly increased the CYP2C19 promoter activity when co-transfected with PXR in HepG2 cells. Mutations in PXR responsive element abolished the NXT inductive effects on the CYP2C19 promoter transcription. Additionally, NXT incubation (150 and 250μg/mL) also markedly up-regulated endogenous CYP2C19 mRNA and protein levels in PXR-transfected HepG2 cells. Correspondingly, NXT leaded to a significant enhancement of the CYP2C19 catalytic activity in PXR-transfected HepG2 cells. Conclusion In summary, this is the first study to suggest that NXT could induce CYP2C19 expression via PXR activation. PMID:27467078

  1. The strong selective sweep candidate gene ADRA2C does not explain domestication related changes in the stress response of chickens.

    Magnus Elfwing

    Full Text Available Analysis of selective sweeps to pinpoint causative genomic regions involved in chicken domestication has revealed a strong selective sweep on chromosome 4 in layer chickens. The autoregulatory α-adrenergic receptor 2C (ADRA2C gene is the closest to the selective sweep and was proposed as an important gene in the domestication of layer chickens. The ADRA2C promoter region was also hypermethylated in comparison to the non-selected ancestor of all domesticated chicken breeds, the Red Junglefowl, further supporting its relevance. In mice the receptor is involved in the fight-or-flight response as it modulates epinephrine release from the adrenals. To investigate the involvement of ADRA2C in chicken domestication, we measured gene expression in the adrenals and radiolabeled receptor ligand in three brain regions comparing the domestic White Leghorn strain with the wild ancestor Red Junglefowl. In adrenals ADRA2C was twofold greater expressed than the related receptor gene ADRA2A, indicating that ADRA2C is the predominant modulator of epinephrine release but no strain differences were measured. In hypothalamus and amygdala, regions associated with the stress response, and in striatum, receptor binding pIC50 values ranged between 8.1-8.4, and the level was not influenced by the genotyped allele. Because chicken strains differ in morphology, physiology and behavior, differences attributed to a single gene may be lost in the noise caused by the heterogeneous genetic background. Therefore an F10 advanced intercross strain between White Leghorn and Red Junglefowl was used to investigate effects of ADRA2C alleles on fear related behaviors and fecundity. We did not find compelling genotype effects in open field, tonic immobility, aerial predator, associative learning or fecundity. Therefore we conclude that ADRA2C is probably not involved in the domestication of the stress response in chicken, and the strong selective sweep is probably caused by selection

  2. Vortex lattice transitions in YNi2B2C

    S J Levett; C D Dewhurst; D McK Paul

    2002-05-01

    We have performed extensive small-angle neutron scattering (SANS) diffraction studies of the vortex lattice in single crystal YNi2B2C for $B||c$. High-resolution SANS, combined with a field-oscillation vortex lattice preparation technique, allows us to separate Bragg scattered intensities from two orthogonal domains and accurately determine the unit cell angle, . The data suggest that upon increasing field there is a finite transition width where both low- and high-field distorted hexagonal vortex lattice phases, mutually rotated by 45°, coexist. The smooth variation of diffracted intensity from each phase through the transition corresponds to a redistribution of populations between the two types of domains.

  3. A rare Cervical Nerve Root, C2-C3 Schwannoma

    Nilesh Chordia

    2014-04-01

    Full Text Available Schwannomas, neurilemmomas or neurinomas are benign nerve sheath tumors deriving from Schwann cells that occur in the head and neck region in 25-45% of cases 1 .About 10% of schwannoma that occur in the head and neck region generally originate from the vagus or sympathetic nervous system, those arising from C2 nerve root are extremely rare. 2 Preoperative imaging studies such as magnetic resonance imaging (MRI and computed tomography (CT are used to distinguish its location and origin. The treatment of schwannoma is surgical resection, with several surgical modalities have been introduced to preserve the neurological function. We present a rare case of Cervical nerve (C2-C3 root schwannoma of 70 years old male who presented with lateral neck swelling with no neurological deficit ,swelling which also had intervertebral part was removed successfully through neck incision with no post-operative neurological symptoms

  4. Preparation and characterization of Pt-CeO2/C and Pt-TiO2/C electrocatalysts with improved electrocatalytic activity for methanol oxidation

    Hameed, R. M. Abdel; Amin, R. S.; El-Khatib, K. M.; Fetohi, Amani E.

    2016-03-01

    Pt-TiO2/C and Pt-CeO2/C electrocatalysts were synthesized by solid state reaction of TiO2/C and CeO2/C powders using intermittent microwave heating, followed by chemical reduction of platinum ions using mixed reducing agents of ethylene glycol and sodium borohydride. The crystal structure, surface morphology and chemical composition of prepared electrocatalysts were investigated using X-ray diffraction (XRD), transmission electron microscopy (TEM) and energy dispersive X-ray analysis (EDX). The phase angle values of different Pt diffraction planes in Pt-TiO2/C and Pt-CeO2/C were shifted in the positive direction relative to those in Pt/C. Pt particles with diameter values of 3.06 and 2.78 nm were formed in Pt-TiO2/C and Pt-CeO2/C, respectively. The electrochemical performance of prepared electrocatalysts was examined using cyclic voltammetry, chronoamperometry and electrochemical impedance spectroscopy. Pt-CeO2/C showed an enhanced oxidation current density when compared to Pt/C. Long time oxidation test at Pt-TiO2/C and Pt-CeO2/C revealed their improved stability. Lower charge transfer resistance values were estimated at Pt-metal oxide/C electrocatalysts.

  5. Structural and functional insights into CYP2C8.3:A genetic polymorph of cytochrome P450 2C8

    2010-01-01

    The cytochrome P450 (CYP) superfamily plays a key role in the oxidative metabolism of a wide range of exogenous chemicals. CYP2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel in the human liver, and carries out the oxidative metabolism of at least 5% of clinical drugs. Polymorphisms in CYP2C8 have been closely implicated in individualized medication. CYP2C8.3, a common polymorph of CYP2C8 with dual amino acid substitutions R139K and K399R, is found primarily in Caucasians. In this study, CYP2C8.3 and its wild type (WT) CYP2C8 were expressed in E. coli, and their purified proteins were characterized by UV-visible spectroscopy, mass spectrometry, and circular dichroism. Their thermal stability, substrate binding ability, and metabolic activity against paclitaxel were investigated. The electron transfer kinetics during paclitaxel metabolism by WT CYP2C8 or CYP2C8.3 was studied by stopped-flow kinetics. The results revealed that mutations in CYP2C8.3 did not greatly influence the heme active site or protein thermal stability and paclitaxel binding ability, but the metabolic activity against paclitaxel was significantly depressed to just 11% of that of WT CYP2C8. Electron transfer from CYP reductase to CYP2C8.3 was found to be significantly slower than that to WT CYP2C8 during catalysis, and this might be the main reason for the depressed metabolic activity. Since the polymorph CYP2C8.3 is defective in catalyzing substrates of CYP2C8 in vitro, it might be expected to have important clinical and pathophysiological consequences in homozygous individuals, and this study provides valuable information in this aspect.

  6. UBE2C is a marker of unfavorable prognosis in bladder cancer after radical cystectomy

    Morikawa, Teppei; Kawai, Taketo; Abe, Hiroyuki; Kume, Haruki; Homma, Yukio; Fukayama, Masashi

    2013-01-01

    It has been suggested that ubiquitin-conjugating enzyme E2C (UBE2C, also known as UBCH10) represents a promising cancer biomarker. However, the clinicopathological or prognostic significance as well as the functions of UBE2C in bladder cancer are largely unknown. To investigate the significance of UBE2C expression in bladder cancer, immunohistochemical analysis was performed using a tissue microarray. UBE2C positivity was observed in 51 of 82 (62%) bladder urothelial carcinoma cases treated w...

  7. C-2-C market relations and word of mouth

    Grubor Aleksandar

    2015-01-01

    Full Text Available Most market research focuses on business-to-business and business- to-consumer interactions to explain the structure and dynamics of the market. Meanwhile, negligible effort has been invested in researching consumer-to-consumer interaction and its impact on companies’ behaviour and purchase decision-making, which determines business performance. The greatest challenge for marketers at the beginning of the 21st century is this third relationship dimension, consumer-to-consumer interaction: how consumers influence each other’s attitudes, expectations, perceptions, preferences, satisfaction, loyalty, and purchasing decisions, and, importantly, the possibility of incorporating consumers into businesses’ marketing programmes. Despite the existence of a multitude of media and different forms of communication between businesses and the market, such as newspapers, periodicals, billboards, television etc., a considerable portion of information is communicated to consumers informally, mostly in the form of word-of-mouth. The information received by consumers through this communication form - from family and similar individuals -is very often accepted as more reliable and certain than information transmitted through formal communication channels. What is often neglected when studying the phenomenon of word-of-mouth communication is the fact that its efficiency and effect also depend on the type and character of the interaction between the consumers themselves. This paper aims to investigate the extent to which the nature of customer to-customer (C2C interaction influences the effect of word-of-mouth communication.

  8. Phonon linewidths in YNi2B2C

    L Pintschovius; F Weber; W Reichardt; A Kreyssig; R Heid; D Reznik; O Stockert; K Hradil

    2008-10-01

    Phonons in a metal interact with conduction electrons which give rise to a finite linewidth. In the normal state, this leads to a Lorentzian shape of the phonon line. Density functional theory is able to predict the phonon linewidths as a function of wave vector for each branch of the phonon dispersion. An experimental verification of such predictions is feasible only for compounds with very strong electron–phonon coupling. YN2B2C was chosen as a test example because it is a conventional superconductor with a fairly high c (15.2 K). Inelastic neutron scattering experiments did largely confirm the theoretical predictions. Moreover, they revealed a strong temperature dependence of the linewidths of some phonons with particularly strong electron–phonon coupling which can as yet only qualitatively be accounted for by theory. For such phonons, marked changes of the phonon frequencies and linewidths were observed from room temperature down to 15 K. Further changes were observed on entering into the superconducting state. These changes can, however, not be described simply by a change of the phonon linewidth.

  9. Basic Data Report for Drillhole SNL-2 (C-2948)

    Powers, Dennis W. [Washington Regulatory and Environmental Services (United States)

    2005-01-19

    SNL-2 was drilled in the northwest quarter of Section 12, T22S, R30E, in eastern Eddy County, New Mexico (Figure 2-1). It is located 574 ft from the north line (fnl) and 859 ft from the west line (fwl) of the section (Figure 2-2). This location places the drillhole east of the Livingston Ridge escarpment among oil wells of the Cabin Lake field. SNL-2 will be used to test hydraulic properties and to monitor ground water levels of the Culebra Dolomite Member of the Permian Rustler Formation. SNL-2 was permitted by the New Mexico State Engineer as C-2948. [Official correspondence regarding permitting and regulatory information must reference this permit number.] In the plan describing the integrated groundwater hydrology program (Sandia National Laboratories, 2003), SNL-2 is also codesignated WTS-1 because the location also satisfies needs for long-term monitoring of water quality and movement in the Culebra Dolomite for RCRA permitting; this program is under the management of Washington TRU Solutions LLC (WTS). In the event that additional wells are established on the SNL-2 drillpad to monitor other hydrological units (e.g., the Magenta Dolomite Member of the Permian Rustler Formation), the current drillhole will likely be referred to as SNL-2C because it is completed in the Culebra. Most drillholes at WIPP have been described after completion to provide an account of the geology, hydrology, or other basic data acquired during drilling and immediate completion of the drillhole. In addition, the basic data report provides an account of the drilling procedures and activities that may be helpful to later interpretations of data or for further work in the drillhole, including test activities and eventual plugging and abandoning activities. The basic data report also provides a convenient means of reporting information about administrative activities necessary to drill the hole.

  10. σ1 Receptor Modulation of G-Protein-Coupled Receptor Signaling: Potentiation of Opioid Transduction Independent from Receptor Binding

    Kim, Felix J.; Kovalyshyn, Ivanka; Burgman, Maxim; Neilan, Claire; Chien, Chih-Cheng

    2010-01-01

    σ Ligands modulate opioid actions in vivo, with agonists diminishing morphine analgesia and antagonists enhancing the response. Using human BE(2)-C neuroblastoma cells that natively express opioid receptors and human embryonic kidney (HEK) cells transfected with a cloned μ opioid receptor, we now demonstrate a similar modulation of opioid function, as assessed by guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding, by σ1 receptors. σ Ligands do not compete opioid receptor binding. Administered alone, neither σ agonists nor antagonists significantly stimulated [35S]GTPγS binding. Yet σ receptor selective antagonists, but not agonists, shifted the EC50 of opioid-induced stimulation of [35S]GTPγS binding by 3- to 10-fold to the left. This enhanced potency was seen without a change in the efficacy of the opioid, as assessed by the maximal stimulation of [35S]GTPγS binding. σ1 Receptors physically associate with μ opioid receptors, as shown by coimmunoprecipitation studies in transfected HEK cells, implying a direct interaction between the proteins. Thus, σ receptors modulate opioid transduction without influencing opioid receptor binding. RNA interference knockdown of σ1 in BE(2)-C cells also potentiated μ opioid-induced stimulation of [35S]GTPγS binding. These modulatory actions are not limited to μ and δ opioid receptors. In mouse brain membrane preparations, σ1-selective antagonists also potentiated both opioid receptor and muscarinic acetylcholine receptor-mediated stimulation of [35S]GTPγS binding, suggesting a broader role for σ receptors in modulating G-protein-coupled receptor signaling. PMID:20089882

  11. Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding.

    Kim, Felix J; Kovalyshyn, Ivanka; Burgman, Maxim; Neilan, Claire; Chien, Chih-Cheng; Pasternak, Gavril W

    2010-04-01

    sigma Ligands modulate opioid actions in vivo, with agonists diminishing morphine analgesia and antagonists enhancing the response. Using human BE(2)-C neuroblastoma cells that natively express opioid receptors and human embryonic kidney (HEK) cells transfected with a cloned mu opioid receptor, we now demonstrate a similar modulation of opioid function, as assessed by guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP gamma S) binding, by sigma(1) receptors. sigma Ligands do not compete opioid receptor binding. Administered alone, neither sigma agonists nor antagonists significantly stimulated [(35)S]GTP gamma S binding. Yet sigma receptor selective antagonists, but not agonists, shifted the EC(50) of opioid-induced stimulation of [(35)S]GTP gamma S binding by 3- to 10-fold to the left. This enhanced potency was seen without a change in the efficacy of the opioid, as assessed by the maximal stimulation of [(35)S]GTP gamma S binding. sigma(1) Receptors physically associate with mu opioid receptors, as shown by coimmunoprecipitation studies in transfected HEK cells, implying a direct interaction between the proteins. Thus, sigma receptors modulate opioid transduction without influencing opioid receptor binding. RNA interference knockdown of sigma(1) in BE(2)-C cells also potentiated mu opioid-induced stimulation of [(35)S]GTP gamma S binding. These modulatory actions are not limited to mu and delta opioid receptors. In mouse brain membrane preparations, sigma(1)-selective antagonists also potentiated both opioid receptor and muscarinic acetylcholine receptor-mediated stimulation of [(35)S]GTP gamma S binding, suggesting a broader role for sigma receptors in modulating G-protein-coupled receptor signaling. PMID:20089882

  12. 23. Establishment of two transgenic cells stable expression of human cytochrome P450 2C

    2001-01-01

    AIM: To clone the human cytochrome P450 2C9 (CYP2C9) and CYP2C18 cDNA and establish two transgenic CHL cell line stable expressing human CYP2C9 and CYP2C18. METHODS:Extracting total RNA from human liver tissue, the human CYP2C9 and CYP2C18 cDNA was amplified with reverse transcription polymerase chain reaction (RT-PCR), and cloned into cloning vector pGEM-T. The cDNA segment was identified by DNA sequencing and subcloned into a mammalian expression vector pREP9. Two transgenic cell line were established by transfecting the recombinant vectors of pREP9-CYP2C9 and pREP9-CYP2C18 to Chinese hamster lung cell CHL. The enzyme activity of CYP2C9 and CYP2C18 catalyze tolbutamide to 4-hydroxy tolbutamide in S9 protein of the cells were determinated by HPLC. RESULTS: The sequence of the two cDNA segments cloned, which were 1540 bp and 1671 bp in length, were identical to those reported by Romkes et al(GenBank accession number: M61855, M61856, J05326) in coding amino acids. The S9 fraction of the established cell lines can metabolize tolbutamide to 4-hydroxy tolbutamide, the tolbutamide-4-hydroxylase activity was found to be 0.465±0.109 and 0.509±0.052 nmol*min-1*(mg S9 protein)-1 (n=3), but was not detectable in parental CHL cell. CONCLUSION: The cDNA of CYP2C9 and CYP2C18 were successfolly cloned and cell lines of CHL-CYP2C9 and CHL-CYP2C18 which efficiently expressed the protein of CYP2C9 and CYP2C18 were established.

  13. Isolation and Crystallographic Characterization of La2C2@Cs(574)-C102 and La2C2@C2(816)-C104: Evidence for the Top-Down Formation Mechanism of Fullerenes.

    Cai, Wenting; Li, Fang-Fang; Bao, Lipiao; Xie, Yunpeng; Lu, Xing

    2016-05-25

    Tubular higher fullerenes are prototypes of finite-length end-capped carbon nanotubes (CNTs) whose structures can be accurately characterized by single-crystal X-ray diffraction crystallography. We present here the isolation and crystallographic characterization of two unprecedented higher fullerenes stabilized by the encapsulation of a La2C2 cluster, namely, La2C2@Cs(574)-C102, which has a perfect tubular cage corresponding to a short (10, 0) zigzag carbon nanotube, and La2C2@C2(816)-C104 which has a defective cage with a pyracylene motif inserting into the cage waist. Both cages provide sufficient spaces for the large La2C2 cluster to adopt a stretched and nearly planar configuration, departing from the common butterfly-like configuration which has been frequently observed in midsized carbide metallofullerenes (e.g., Sc2C2@C80-84), to achieve strong metal-cage interactions. More meaningfully, our crystallographic results demonstrate that the defective cage of C2(816)-C104 is a starting point to form the other three tubular cages known so far, i.e., D5(450)-C100, Cs(574)-C102, and D3d(822)-C104, presenting evidence for the top-down formation mechanism of fullerenes. The fact that only the large La2C2 cluster has been found in giant fullerene cages (C>100) and the small clusters M2C2 (M = Sc, Y, Er, etc.) are present in midsized fullerenes (C80-C86) indicates that geometrical matching between the cluster and the cage, which ensures strong metal-cage interactions, is an important factor controlling the stability of the resultant metallofullerenes, in addition to charge transfer. PMID:27157415

  14. Surface Turbulent Fluxes, 1x1 deg Daily Grid, Satellite F13 V2c

    National Aeronautics and Space Administration — These data are part of the Goddard Satellite-based Surface Turbulent Fluxes Version-2c (GSSTF 2c) Dataset recently produced through a MEaSURES funded project led by...

  15. Surface Turbulent Fluxes, 1x1 deg Daily Grid, Satellite F11 V2c

    National Aeronautics and Space Administration — These data are part of the Goddard Satellite-based Surface Turbulent Fluxes Version-2c (GSSTF 2c) Dataset recently produced through a MEaSURES funded project led by...

  16. Surface Turbulent Fluxes, 1x1 deg Daily Grid, Satellite F15 V2c

    National Aeronautics and Space Administration — These data are part of the Goddard Satellite-based Surface Turbulent Fluxes Version-2c (GSSTF 2c) Dataset recently produced through a MEaSURES funded project led by...

  17. Surface Turbulent Fluxes, 1x1 deg Daily Grid, Satellite F10 V2c

    National Aeronautics and Space Administration — These data are part of the Goddard Satellite-based Surface Turbulent Fluxes Version-2c (GSSTF 2c) Dataset recently produced through a MEaSURES funded project led by...

  18. Surface Turbulent Fluxes, 1x1 deg Daily Grid, Satellite F08 V2c

    National Aeronautics and Space Administration — These data are part of the Goddard Satellite-based Surface Turbulent Fluxes Version-2c (GSSTF 2c) Dataset recently produced through a MEaSURES funded project led by...

  19. Superconductivity in the W-Tc and W2C-Tc systems

    A series of compositions in the W-Tc, W2C-Re and W2C-Tc systems were prepared and examined for superconductivity. The crystal structure, lattice parameters and superconducting transition temperatures of the W2C-Tc are reported for the first time. Similar measurements were made on the W-Tc and W2C-Re systems and the results compared with previous published results for these systems. 7 refs., 2 figs., 2 tabs

  20. The CYP2C8 inhibitor gemfibrozil does not affect the pharmacokinetics of zafirlukast

    Karonen, Tiina; Neuvonen, Pertti J; Backman, Janne T.

    2010-01-01

    Abstract Purpose Gemfibrozil, a strong inhibitor of cytochrome P450 (CYP) 2C8 in vivo, was recently found to markedly increase the plasma concentrations of montelukast in humans. Like montelukast, zafirlukast is a substrate of CYP2C9 and CYP3A4 and a potent inhibitor of CYP2C8 in vitro. To investigate the contribution of CYP2C8 to the metabolism of zafirlukast in vivo, we studied the effect of gemfibrozil on the pharmacokinetics of zafirlukast. ...

  1. Docosahexaenoyl ethanolamide improves glucose uptake and alters endocannabinoid system gene expression in proliferating and differentiating C2C12 myoblasts

    BruceAlanWatkins

    2014-03-01

    Full Text Available Skeletal muscle is a major storage site for glycogen and a focus for understanding insulin resistance and type-2-diabetes. New evidence indicates that overactivation of the peripheral endocannabinoid system (ECS in skeletal muscle diminishes insulin sensitivity. Specific n-6 and n-3 polyunsaturated fatty acids (PUFA are precursors for the biosynthesis of ligands that bind to and activate the cannabinoid receptors. The function of the ECS and action of PUFA in skeletal muscle glucose uptake was investigated in proliferating and differentiated C2C12 myoblasts treated with either 25µM of arachidonate (AA or docosahexaenoate (DHA, 25µM of EC [anandamide (AEA, 2-arachidonoylglycerol (2-AG, docosahexaenoylethanolamide (DHEA], 1µM of CB1 antagonist NESS0327, and CB2 antagonist AM630. Compared to the BSA vehicle control cell cultures in both proliferating and differentiated myoblasts those treated with DHEA, the EC derived from the n-3 PUFA DHA, had higher 24 h glucose uptake, while AEA and 2-AG, the EC derived from the n-6 PUFA AA, had lower basal glucose uptake. Adenylyl cyclase mRNA was higher in myoblasts treated with DHA in both proliferating and differentiated states while those treated with AEA or 2-AG were lower compared to the control cell cultures. Western blot and qPCR analysis showed higher expression of the cannabinoid receptors in differentiated myoblasts treated with DHA while the opposite was observed with AA. These findings indicate a compensatory effect of DHA and DHEA compared to AA-derived ligands on the ECS and associated ECS gene expression and higher glucose uptake in myoblasts.Key Words: endocannabinoid system •C2C12 myoblasts cannabinoid receptors glucose uptake gene expression DHEA • polyunsaturated fatty acids

  2. Vortex phase diagram studies in the weakly pinned single crystals of YNi2B2C and LuNi2B2C

    D Jaiswal-Nagar; D Pal; M R Eskildsen; P C Canfield; H Takeya; S Ramakrishnan; A K Grover

    2006-01-01

    We present a study of magnetization measurements performed on the single crystals of YNi2B2C and LuNi2B2C. For both the compounds, we find flux jumps in magnetisation values in the respective field regions, where the structural transitions in the flux line lattice symmetry have been reported in these systems via the small angle neutron scattering experiments. The magnetisation hysteresis loops and the AC susceptibility measurements show pronounced peak effect as well as second magnetisation peak anomaly for both YNi2B2C and LuNi2B2C. Based on these results, a vortex phase diagram has been constructed for YNi2B2C for $H \\Arrowvert c$ depicting different glassy phases of the vortex matter.

  3. File list: Oth.Brs.50.TFAP2C.AllCell [Chip-atlas[Archive

    Full Text Available Oth.Brs.50.TFAP2C.AllCell hg19 TFs and others TFAP2C Breast SRX128102,SRX128099,SRX...128100,SRX018833,SRX128101,SRX028632,SRX028633,SRX673728,SRX673727 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.50.TFAP2C.AllCell.bed ...

  4. Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2+ stores

    Behne, M J; Tu, Chia-Ling L; Aronchik, I; Epstein, E; Bench, G.; Bikle, D D; Pozzan, T; Mauro, T.M.

    2003-01-01

    Hailey-Hailey disease (MIM16960) is a blistering skin disease caused by mutations in the Ca2+ ATPase ATP2C1. We found that the abnormal Ca2+ signaling seen in Hailey-Hailey disease keratinocytes correlates with decreased protein levels of ATP2C1. Human ATP2C1 protein approximated 115 kDa in size. The ATP2C1 is localized to the Golgi apparatus in human keratinocytes, similar to its localization in yeast and Caenorhabditis elegans. To test whether the ATP2C1 controls Golgi Ca2+ stores, we measu...

  5. First detection of canine parvovirus type 2c in Brazil Detecção de parvovírus canino tipo 2c no Brasil

    André Felipe Streck; Carine Kunzler de Souza; Karla Rathje Gonçalves; Luciana Zang; Luciane Dubina Pinto; Cláudio Wageck Canal

    2009-01-01

    The presence of canine parvovirus type 2 (CPV-2), 2a and 2b has been described in Brazil, however, the type 2c had not been reported until now. In the current study, seven out of nine samples from dogs with diarrhea were characterized as CPV-2c, indicating that this virus is already circulating in the Brazilian canine population.No Brasil, a presença do parvovírus canino do tipo 2 (CPV-2), 2a e 2b já havia sido descrita, contudo, ainda não havia sido verificada a presença do tipo 2c. No prese...

  6. Enzyme activity analysis of CYP2C18 with exon 5 skipped

    Jian ZHU-GE; Ying-nian YU

    2004-01-01

    AIM: To study the enzyme activity of CYP2C18 variant with exon 5 skipped. METHODS: A full length CYP2C18 cDNA X1 and an exon 5 skipped variant CYP2C18 X2 were separately subcloned into mammalian expression vector pREP9 to transfect HepG2 cells. The expression of CYP2C 18 mRNA in transgenic cells and human liver tissues were determined by RT-PCR. The enzyme activity of CYP2C18 to oxidate tolbutamide in postmitochondrial supernate (S9) fraction was determined by HPLC. The cytotoxicity of ifosfamide to transgenic cells was evaluated by MTT test. RESULTS: HepG2-CYP2C18 X1 cells showed strong expression of the full length CYP2C18 mRNA.On the other hand, HepG2-CYP2C 18 X2 cells had only infinitesimal expression of the exon-skipped CYP2C 18 as well as the full length CYP2C 18, while non-transfected HepG2 cell only demonstrated an infinitesimal expression of the full length CYP2C 18. The expression of CYP2C 18 exons 2 to 7 was also analyzed by RT-PCR in 7 extratumoral liver tissues. Among them, 3 samples expressed only wild type mRNA, whereas 4 samples expressed both wild type and alternative splicing products. The tolbutamide hydroxylase activity of CYP2C 18 was tested, and it was shown that HepG2-2C18 X1 cells had higher enzyme activity than those of HepG2-2C18 X2 and HepG2 cells. The relative survival of HepG2-CYP2C 18 X1 cells was lower than that of HepG2 cells with 1, 2, and 4 mmol/L ifosfamide treatments. In contrast, the relative survival of HepG2-CYP2C 18 X2 cell was the same as that of HepG2 cell in 0.5 and 1 mmol/L of ifosfamide, but lower than that of HepG2 cell in 2 and 4 mmol/L of ifosfamide. CONCLUSION:CYP2C 18 X 1 could metabolize tolbutamide and ifosfamide efficiently. The exon 5-skipped CYP2C 18 X2 could not metabolize tolbutamide, and could not metabolize ifosfamide effectively at low concentrations.

  7. Different effects of proton pump inhibitors and famotidine on the clopidogrel metabolic activation by recombinant CYP2B6, CYP2C19 and CYP3A4.

    Ohbuchi, Masato; Noguchi, Kiyoshi; Kawamura, Akio; Usui, Takashi

    2012-07-01

    Inhibitory potential of proton pump inhibitors (PPIs) and famotidine, an H(2) receptor antagonist, on the metabolic activation of clopidogrel was evaluated using recombinant CYP2B6, CYP2C19 and CYP3A4. Formation of the active metabolite from an intermediate metabolite, 2-oxo-clopidogrel, was investigated by liquid chromatography-tandem mass spectrometry and three peaks corresponding to the pharmacologically active metabolite and its stereoisomers were detected. Omeprazole potently inhibited clopidogrel activation by CYP2C19 with an IC(50) of 12.8 μmol/L and more weakly inhibited that by CYP2B6 and CYP3A4. IC(50) of omeprazole for CYP2C19 and CYP3A4 was decreased about two- and three-fold, respectively, by 30-min preincubation with NADPH. Lansoprazole, esomeprazole, pantoprazole, rabeprazole and rabeprazole thioether, a major metabolite, also inhibited metabolic activation by CYP2C19, with an IC(50) of 4.3, 8.9, 48.3, 36.2 and 30.5 μmol/L, respectively. In contrast, famotidine showed no more than 20% inhibition of clopidogrel activation by CYP2B6, CYP2C19 and CYP3A4 at up to 100 μmol/L and had no time-dependent CYP2C19 and CYP3A4 inhibition. These results provide direct evidence that PPIs inhibit clopidogrel metabolic activation and suggest that CYP2C19 inhibition is the main cause of drug-drug interaction between clopidogrel and omeprazole. Famotidine is considered as a safe anti-acid agent for patients taking clopidogrel. PMID:22313038

  8. First detection of canine parvovirus type 2c in Brazil Detecção de parvovírus canino tipo 2c no Brasil

    André Felipe Streck

    2009-09-01

    Full Text Available The presence of canine parvovirus type 2 (CPV-2, 2a and 2b has been described in Brazil, however, the type 2c had not been reported until now. In the current study, seven out of nine samples from dogs with diarrhea were characterized as CPV-2c, indicating that this virus is already circulating in the Brazilian canine population.No Brasil, a presença do parvovírus canino do tipo 2 (CPV-2, 2a e 2b já havia sido descrita, contudo, ainda não havia sido verificada a presença do tipo 2c. No presente trabalho, sete de nove amostras de cães com diarréia foram caracterizadas como CPV-2c, indicando que este vírus já está circulando na população canina no Brasil.

  9. Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions.

    Backman, Janne T; Filppula, Anne M; Niemi, Mikko; Neuvonen, Pertti J

    2016-01-01

    During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing. Similarly, many drugs have been identified as CYP2C8 inhibitors or inducers. In vivo, already a small dose of gemfibrozil, i.e., 10% of its therapeutic dose, is a strong, irreversible inhibitor of CYP2C8. Interestingly, recent findings indicate that the acyl-β-glucuronides of gemfibrozil and clopidogrel cause metabolism-dependent inactivation of CYP2C8, leading to a strong potential for drug interactions. Also several other glucuronide metabolites interact with CYP2C8 as substrates or inhibitors, suggesting that an interplay between CYP2C8 and glucuronides is common. Lack of fully selective and safe probe substrates, inhibitors, and inducers challenges execution and interpretation of drug-drug interaction studies in humans. Apart from drug-drug interactions, some CYP2C8 genetic variants are associated with altered CYP2C8 activity and exhibit significant interethnic frequency differences. Herein, we review the current knowledge on substrates, inhibitors, inducers, and pharmacogenetics of CYP2C8, as well as its role in clinically relevant drug interactions. In addition, implications for selection of CYP2C8 marker and perpetrator drugs to investigate CYP2C8-mediated drug metabolism and interactions in preclinical and clinical studies are discussed. PMID:26721703

  10. Platinum deposited on TiO2-C and SnO2-C composites for methanol oxidation and oxygen reduction

    Highlights: • The activity of Pt/SnO2-C and Pt/TiO2-C for the MOR was evaluated. • The effect of different oxide on the methanol tolerance was determinate. • Chronoamperometry results confirm the Pt/SnO2-C catalyst stability. • The role of SnO2 can be addressed as co-catalyst of Pt for MOR and ORR. - Abstract: Electrocatalytic activities and stabilities of Pt supported on SnO2-carbon and TiO2-carbon as electrocatalysts were examined for methanol oxidation and oxygen reduction reactions. The Pt/oxide-C catalysts were synthesized by photo-deposition method at RT. The samples prepared were characterized by X-ray diffraction, TEM analysis, cyclic and lineal voltammetry, CO stripping and chronoamperometry techniques. Electrochemical activities of Pt/oxide-C for methanol oxidation reaction (MOR) and methanol tolerance for oxygen reduction were compared with those of Pt/C (Pt-Etek). The MOR activity of Pt/SnO2-C was enhanced over those of the Pt/TiO2-C and Pt/C at different concentrations due to the small platinum particles size. Pt-Sn interaction produce changes in the platinum electronic properties that improve the electrochemical activity towards the methanol oxidation and stability to the methanol presence. The SnO2-C composite appear to be a promising support material that promote electrochemical reactions and stabilize catalytic particles in direct alcohol fuel cells

  11. Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate

    Banerjee, Sarmistha; Das, Rajat Kumar; Giffear, Kelly A.; Shapiro, Bernard H., E-mail: shapirob@vet.upenn.edu

    2015-04-01

    Perinatal exposure of rats and mice to the typically reported 4 mg/g bd wt dose of monosodium glutamate (MSG) results in a complete block in GH secretion as well as obesity, growth retardation and a profound suppression of several cytochrome P450s, including CYP2C11, the predominant male-specific isoform — all irreversible effects. In contrast, we have found that a lower dose of the food additive, 2 mg/g bd wt on alternate days for the first 9 days of life results in a transient neonatal depletion of plasma GH, a subsequent permanent overexpression of CYP2C11 as well as subnormal (mini) GH pulse amplitudes in an otherwise normal adult masculine episodic GH profile. The overexpressed CYP2C11 was characterized by a 250% increase in mRNA, but only a 40 to 50% increase in CYP2C11 protein and its catalytic activity. Using freshly isolated hepatocytes as well as primary cultures exposed to the masculine-like episodic GH profile, we observed normal induction, activation, nuclear translocation and binding to the CYP2C11 promoter of the GH-dependent signal transducers required for CYP2C11 transcription. The disproportionately lower expression levels of CYP2C11 protein were associated with dramatically high expression levels of an aberrant, presumably nontranslated CYP2C11 mRNA, a 200% increase in CYP2C11 ubiquitination and a 70–80% decline in miRNAs associated, at normal levels, with a suppression of CYP2C expression. Whereas the GH-responsiveness of CYP2C7 and CYP2C6 as well as albumin was normal in the MSG-derived hepatocytes, the abnormal expression of CYP2C11 was permanent and irreversible. - Highlights: • A “low” neonatal dose of MSG causes an immediate but transient growth hormone depletion. • Adult circulating growth hormone contains mini pulses in an otherwise male profile. • CYP2C11 is permanently overexpressed > 250%; CYP2C6, 2C7 and albumin remain normal. • The bulk of the overexpressed CYP2C11 mRNA consists of an intron-retained form. • SOCS2

  12. Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate

    Perinatal exposure of rats and mice to the typically reported 4 mg/g bd wt dose of monosodium glutamate (MSG) results in a complete block in GH secretion as well as obesity, growth retardation and a profound suppression of several cytochrome P450s, including CYP2C11, the predominant male-specific isoform — all irreversible effects. In contrast, we have found that a lower dose of the food additive, 2 mg/g bd wt on alternate days for the first 9 days of life results in a transient neonatal depletion of plasma GH, a subsequent permanent overexpression of CYP2C11 as well as subnormal (mini) GH pulse amplitudes in an otherwise normal adult masculine episodic GH profile. The overexpressed CYP2C11 was characterized by a 250% increase in mRNA, but only a 40 to 50% increase in CYP2C11 protein and its catalytic activity. Using freshly isolated hepatocytes as well as primary cultures exposed to the masculine-like episodic GH profile, we observed normal induction, activation, nuclear translocation and binding to the CYP2C11 promoter of the GH-dependent signal transducers required for CYP2C11 transcription. The disproportionately lower expression levels of CYP2C11 protein were associated with dramatically high expression levels of an aberrant, presumably nontranslated CYP2C11 mRNA, a 200% increase in CYP2C11 ubiquitination and a 70–80% decline in miRNAs associated, at normal levels, with a suppression of CYP2C expression. Whereas the GH-responsiveness of CYP2C7 and CYP2C6 as well as albumin was normal in the MSG-derived hepatocytes, the abnormal expression of CYP2C11 was permanent and irreversible. - Highlights: • A “low” neonatal dose of MSG causes an immediate but transient growth hormone depletion. • Adult circulating growth hormone contains mini pulses in an otherwise male profile. • CYP2C11 is permanently overexpressed > 250%; CYP2C6, 2C7 and albumin remain normal. • The bulk of the overexpressed CYP2C11 mRNA consists of an intron-retained form. • SOCS2

  13. Conessine Interferes with Oxidative Stress-Induced C2C12 Myoblast Cell Death through Inhibition of Autophagic Flux.

    Hyunju Kim

    Full Text Available Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2 result in muscle cell death by inducing excessive autophagic flux. Treatment with conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux.

  14. Conessine Interferes with Oxidative Stress-Induced C2C12 Myoblast Cell Death through Inhibition of Autophagic Flux

    Kim, Hyunju; Lee, Kang Il; Jang, Minsu; Namkoong, Sim; Park, Rackhyun; Ju, Hyunwoo; Choi, Inho; Oh, Won Keun

    2016-01-01

    Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2) result in muscle cell death by inducing excessive autophagic flux. Treatment with conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux. PMID:27257813

  15. File list: Oth.ALL.05.TFAP2C.AllCell [Chip-atlas[Archive

    Full Text Available Oth.ALL.05.TFAP2C.AllCell hg19 TFs and others TFAP2C All cell types SRX673727,SRX67...3728,SRX150450,SRX190406,SRX018833,SRX128099,SRX128102,SRX028632,SRX128100,SRX028633,SRX128101 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.05.TFAP2C.AllCell.bed ...

  16. Relation between CYP2C19 phenotype and genotype in a group of Brazilian volunteers

    Rafael Linden; Ana Luiza Ziulkoski; Paula Tonello; Maína Wingert; André Arigony Souto

    2009-01-01

    The CYP2C19 gene presents polymorphism affecting the pharmacokinetics of several drugs of clinical importance. The purpose of this study was to investigate the correlation between CYP2C19 genotype and metabolic phenotype in a group of 38 Brazilian volunteers, evaluating the phenotype prediction capacity of the genotyping procedure. For CYP2C19 phenotyping, omeprazole was used as the probe drug, using the hydroxylation metabolic ratio as the phenotypic indicator. Venous blood samples were draw...

  17. Lipoic Acid Exerts Antioxidant and Anti-inflammatory Effects in Response to Heat Shock in C2C12 Myotubes.

    Lee, Cheng-Tse; Chang, Li-Ching; Wu, Pei-Fung

    2016-06-01

    This study explored that lipoic acid treatment for 24 h significantly upregulated and promoted heat shock-induced catalase expression and downregulated GPx1 messenger RNA (mRNA) expression, indicating that lipoic acid exhibits antioxidant activity in the decomposition of hydrogen peroxide by upregulating catalase expression. Moreover, lipoic acid treatment for 3 h increased and promoted heat shock-induced interleukin (IL)-6 mRNA and protein levels and that for 24 h downregulated IL-6 mRNA expression, suggesting a dual effect of lipoic acid on IL-6 regulation. Lipoic acid alone failed to increase or reduce tumor necrosis factor (TNF)-α mRNA and protein levels, whereas heat shock alone downregulated TNF-α mRNA and protein expression. These data suggest that lipoic acid does not have a proinflammatory role and that heat shock acts as an anti-inflammatory agent by downregulating TNF-α expression in C2C12 myotubes. Moreover, lipoic acid or heat shock alone upregulated the IL-6 receptor (IL-6R-α) and glycoprotein 130 (gp130) mRNA expression followed by IL-6 expression; these data indicate that the regulation of lipoic acid or heat shock is mediated by IL-6R signaling, thus suggesting that C2C12 myotubes possesses a mechanism for regulating IL-6R and gp130 expression following lipoic acid treatment or heat shock. PMID:27086282

  18. MEF2C and EBF1 Co-regulate B Cell-Specific Transcription.

    Kong, Nikki R; Davis, Matthew; Chai, Li; Winoto, Astar; Tjian, Robert

    2016-02-01

    Hematopoietic stem cells are capable of self-renewal or differentiation along three main lineages: myeloid, erythroid, and lymphoid. One of the earliest lineage decisions for blood progenitor cells is whether to adopt the lymphoid or myeloid fate. Previous work had shown that myocyte enhancer factor 2C (MEF2C) is indispensable for the lymphoid fate decision, yet the specific mechanism of action remained unclear. Here, we have identified early B cell factor-1 (EBF1) as a co-regulator of gene expression with MEF2C. A genome-wide survey of MEF2C and EBF1 binding sites identified a subset of B cell-specific genes that they target. We also determined that the p38 MAPK pathway activates MEF2C to drive B cell differentiation. Mef2c knockout mice showed reduced B lymphoid-specific gene expression as well as increased myeloid gene expression, consistent with MEF2C's role as a lineage fate regulator. This is further supported by interaction between MEF2C and the histone deacetylase, HDAC7, revealing a likely mechanism to repress the myeloid transcription program. This study thus elucidates both activation and repression mechanisms, identifies regulatory partners, and downstream targets by which MEF2C regulates lymphoid-specific differentiation. PMID:26900922

  19. Genotype and allele frequency of CYP2C19*17 in a healthy Iranian population

    Payan, Maryam; Tajik, Nader; Rouini, Mohammad Reza; Ghahremani, Mohammad Hossein

    2015-01-01

    Background: Cytochrome P450 2C19 (CYP2C19) is important in metabolism of wide range of drugs. CYP2C19*17 is a novel variant allele which increases gene transcription and therefore results in ultra-rapid metabolizer phenotype (URM). Distribution of this variant allele has not been well studied worldwide. The aim of present study was to investigate allele and genotype frequencies of CYP2C19*17 in a healthy Iranian population and compare them with other ethnic groups. Methods: One hundred eighty...

  20. Review of magnetic features observed in (A,A')Ni2B2C solid solutions

    The nickel-borocarbides ANi2B2C [A=Y, Ln (lanthanide), An(actinide)], crystallizing in the body-centred tetragonal LuNi2B2C-type structure, are classified according to the existence or coexistence of superconducting and antiferromagnetic states (AF). The magnetic features observed in polycrystalline (A,A')Ni2B2C solid solutions, adopting the same crystal structure, are reviewed and discussed. Published data on the magnetism in (A,Ln)Ni2B2C systems (ANi2B2C nonmagnetic, A=Y,La,Lu) indicate a gradual rise in the threshold content, x(m), in (Y1-xLnx)Ni2B2C (Ln=Gd,Tb,Dy,Ho,Er) for the establishment of AF states. (A,A')Ni2B2C systems with magnetic end compounds show gradual variation in magnetic features when A and A' are both heavy Ln. The behaviour of (A,A')Ni2B2C systems of light A (Pr or U) and heavy A' (Dy or Tm) depends on the magnetic structures of the end compounds. In intermediate compositions, incomplete moment compensation in (Pr,Dy)Ni2B2C decreases TN, while different moment directions in the end compounds in (U,Dy)Ni2B2C lead to a directional frustration of ordered moments. Such a frustration in (U,Tm)Ni2B2C is related to different magnetic structures of the end compounds

  1. CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation

    Carlos Alexandre Twardowschy

    2011-04-01

    Full Text Available OBJECTIVE: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect therapeutic outcome during treatment. The distribution of variant CYP2C9 alleles and prevalence of phenytoin adverse reactions were hereby investigated in a population of patients diagnosed with epilepsy. METHOD: Allele-specific PCR analysis was carried out in order to determine frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 100 epileptic patients. We also analyzed the frequency of phenytoin adverse reactions among those different genotypes groups. The data was presented as mean±standard deviation. RESULTS: The mean age at enrollment was 39.6±10.3 years (range, 17-72 years and duration of epilepsy was 26.5±11.9 years (range 3-48 years. The mean age at epilepsy onset was 13.1±12.4 years (range, 1 month-62 years. Frequencies of CYP2C9*1 (84%, CYP2C9*2 (9% and CYP2C9*3 (7% were similar to other published reports. Phenytoin adverse reactions were usually mild and occurred in 15% patients, without correlation with the CYP2C9 polymorphism (p=0.34. CONCLUSION: Our findings indicate an overall similar distribution of the CYP2C9 alleles in a population of patients diagnosed with epilepsy in the South of Brazil, compared to other samples. This sample of phenytoin users showed no drug related adverse reactions and CYP2C9 allele type correlation. The role of CYP2C9 polymorphism influence on phenytoin adverse reaction remains to be determined since some literature evidence and our data found negative results.

  2. Hall effect in LuNi2B2C and YNi2B2C borocarbides in normal and superconducting mixed states

    It was shown that the Hall resistivity ρxy for LuNi2B2C and YNi2B2C is negative in the normal and mixed states and has no sign reversal below Tc. In the mixed state the scaling relation ρxy approximately ρxxβ (ρxx is the longitudinal resistivity) was found for both compounds with β ∼ 2.0. In the normal state a distinct nonlinearity in the ρxy(H) dependence, accompanied by a large magnetoresistance, was found below 40 K only for LuNi2B2C. The difference in the behavior of Lu- and Y-based borocarbides seems to be connected with the difference in the Fermi surfaces of these compounds

  3. Molecular pharmacology of human NMDA receptors

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard;

    2012-01-01

    current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side......-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest that the...... binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human...

  4. Structural and electronic studies of metal carbide clusterfullerene Sc2C2@Cs-C72

    Feng, Yongqiang; Wang, Taishan; Wu, Jingyi; Feng, Lai; Xiang, Junfeng; Ma, Yihan; Zhang, Zhuxia; Jiang, Li; Shu, Chunying; Wang, Chunru

    2013-07-01

    We present a metal carbide clusterfullerene Sc2C2@Cs(10528)-C72, whose structure has been baffling for many years. A motional endohedral Sc2C2 cluster, special molecule geometry and electronic structure were found in Sc2C2@Cs(10528)-C72. The paramagnetic Sc2C2@Cs-C72 anion radical was successfully prepared by a chemical reduction method and hyperfine couplings in the ESR spectrum were observed.We present a metal carbide clusterfullerene Sc2C2@Cs(10528)-C72, whose structure has been baffling for many years. A motional endohedral Sc2C2 cluster, special molecule geometry and electronic structure were found in Sc2C2@Cs(10528)-C72. The paramagnetic Sc2C2@Cs-C72 anion radical was successfully prepared by a chemical reduction method and hyperfine couplings in the ESR spectrum were observed. Electronic supplementary information (ESI) available: Experimental details, HPLC chromatogram, and DFT calculations. CCDC 917712. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3nr01739g

  5. The transcription factor MEF2C negatively controls angiogenic sprouting of endothelial cells depending on oxygen.

    Caterina Sturtzel

    Full Text Available The MADS box transcription factor MEF2C has been detected by us to be upregulated by the angiogenic factors VEGF-A and bFGF in endothelial cells. We have here investigated its potential role for angiogenesis. MEF2C was surprisingly found to strongly inhibit angiogenic sprouting, whereas a dominant negative mutant rather induced sprouting. The factor mainly affected migratory processes of endothelial cells, but not proliferation. In gene profiling experiments we delineated the alpha-2-macroglobulin gene to be highly upregulated by MEF2C. Further data confirmed that MEF2C in endothelial cells indeed induces alpha-2-macroglobulin mRNA as well as the secretion of alpha-2-macroglobulin and that conditioned supernatants of cells overexpressing MEF2C inhibit sprouting. Alpha-2-macroglobulin mediates, at least to a large extent, the inhibitory effects of MEF2C as is shown by knockdown of alpha-2-macroglobulin mRNA by lentiviral shRNA expression which reduces the inhibitory effect. However, under hypoxic conditions the VEGF-A/bFGF-mediated upregulation of MEF2C is reduced and the production of alpha-2-macroglobulin largely abolished. Taken together, this suggests that the MEF2C/alpha-2-macroglobulin axis functions in endothelial cells as a negative feed-back mechanism that adapts sprouting activity to the oxygen concentration thus diminishing inappropriate and excess angiogenesis.

  6. Conservation laws in the SLsub(2,C) gauge theory of gravitation

    A one-parameter family of new Lagrangian densities for the SLsub(2,C) gauge theory of gravitation is proposed. The relation between the laws of conservation and the SLsub(2,C) symmetry of general relativity through the Noether theorem is investigated

  7. 40 CFR Table 2c to Subpart E of... - Reactivity Factors for Aromatic Hydrocarbon Solvent Mixtures

    2010-07-01

    ... 40 Protection of Environment 5 2010-07-01 2010-07-01 false Reactivity Factors for Aromatic Hydrocarbon Solvent Mixtures 2C Table 2C to Subpart E of Part 59 Protection of Environment ENVIRONMENTAL... Hydrocarbon Solvent Mixtures Bin Boiling range (degrees F) Criteria Reactivityfactor 21 280-290...

  8. Acute Effects of the Novel Psychoactive Drug 2C-B on Emotions

    González, Débora; Torrens, Marta; Farré, Magí

    2015-01-01

    Background. 2C-B (Nexus) is one of the most widespread novel psychoactive substances. There is limited information about its pharmacological properties, and few studies in humans concern its acute and chronic effects. 2C-B has been classified as a stimulant, hallucinogen, entactogen, and/or empathogen. Objectives. To evaluate the emotional, subjective, and cardiovascular effects of 2C-B. Methods. Twenty healthy recreational 2C-B users (12 women) self-administered a 20 mg dose of 2C-B. Evaluations included emotional (IAPS, FERT, and speech), subjective (visual analog scales, ARCI, VESSPA, HRS, and POMS questionnaires), and cardiovascular effects (blood pressure and heart rate). Results. Positive subjective effects predominated with a reduction of anger under the influence of 2C-B. It did, however, increase reactivity to negative emotional stimuli and decrease the ability to recognize expressions of happiness. Augmented emotionality in speech could be appreciated by others. 2C-B induced euphoria and well-being, changes in perceptions, and slight hallucinogenic states. Mild sympathetic actions were observed. Conclusions. The specific profile that 2C-B exerts on emotions suggests its classification as an entactogen with psychedelic properties. PMID:26543863

  9. Crystal Structures and Mechanical Properties of Ca2C at High Pressure

    Qun Wei

    2016-07-01

    Full Text Available Recently, a new high-pressure semiconductor phase of Ca2C (space group Pnma was successfully synthesized, it has a low-pressure metallic phase (space group C2/m. In this paper, a systematic investigation of the pressure-induced phase transition of Ca2C is studied on the basis of first-principles calculations. The calculated enthalpy reveals that the phase transition which transforms from C2/m-Ca2C to Pnma-Ca2C occurs at 7.8 GPa, and it is a first-order phase transition with a volume drop of 26.7%. The calculated elastic constants show that C2/m-Ca2C is mechanically unstable above 6.4 GPa, indicating that the structural phase transition is due to mechanical instability. Both of the two phases exhibit the elastic anisotropy. The semiconductivity of Pnma-Ca2C and the metallicity of C2/m-Ca2C have been demonstrated by the electronic band structure calculations. The quasi-direct band gap of Pnma-Ca2C at 0 GPa is 0.86 eV. Furthermore, the detailed analysis of the total and partial density of states is performed to show the specific contribution to the Fermi level.

  10. Conceptualizing B2C Businesses as a New Category of Services

    Anil Pandya; Nikhilesh Dholakia

    2005-01-01

    Conceptualizing B2C businesses as an innovative class of technology-infused services yields insights into the factors that may lead to success or failure of such businesses. Drawing from services’ marketing literature and recent thinking on Internet service metrics, this paper presents a framework for analyzing B2C businesses.

  11. Hydrogenation of Benzene over Mo2C/Al2O3 Catalyst

    Zhang Jing; Wu Weicheng

    2008-01-01

    The process of benzene hydrogenation over Mo2C catalyst has been studied.Mo2C was the active phase in benzene hydrogenation.The major problem with the metal carbides was their poor stability due to deactivation by carbon deposition.

  12. Synthesis of two-dimensional molybdenum carbide, Mo2C, from the gallium based atomic laminate Mo2Ga2C

    We report on the synthesis of a two-dimensional transition metal carbide, Mo2C, (MXene) obtained by immersing Mo2Ga2C thin films in hydrofluoric acid. Experimental evidences for neither synthesis of a Mo-based MXene nor selective etching of Ga from an atomic nanolaminate have previously been presented. MXene formation is verified through X-ray diffraction, transmission electron microscopy, and energy dispersive X-ray spectroscopy. This discovery unlocks new potential applications for Mo-based MXenes in a host of applications, from thermoelectrics to catalysis and energy storage

  13. Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms.

    Dorado, P; López-Torres, E; Peñas-Lledó, E M; Martínez-Antón, J; Llerena, A

    2013-08-01

    Pharmacogenetic studies have shown that genetic defects in drug-metabolizing enzymes encoded by CYP2C9, CYP2C19 genes and by the transporter ABCB1 gene can influence phenytoin (PTH) plasma levels and toxicity. The patient reported here is a 2-year-old girl with a medical history of cryptogenic (probably symptomatic) epilepsy, who had her first focal seizure with secondary generalization at 13 months of age. She initially received oral valproate treatment and three months later, she was prescribed an oral oxcarbazepine treatment. At 20 months of age, she was admitted to the Emergency Department because of generalized convulsive Status Epilepticus needing to be immediately treated with rectal diazepam (0.5 mg kg(-1)), intravenous diazepam (0.3 mg kg(-1)), and intravenous phenytoin with an initial-loading dose of 15 mg kg(-1). However, two hours after the initial-loading dose of PTH, the patient developed dizziness, nystagmus, ataxia and excessive sedation. Other potential causes of PTH toxicity were excluded such as drug interactions, decreased albumin or lab error. Therefore, to explain the neurological toxicity, PTH plasma levels and CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms were analyzed. Initial plasma PTH levels were higher than expected (69 mg l(-1); normal range: 10-20 mg l(-1)), and the patient was homozygous for the CYP2C9*2 allele, heterozygous for the CYP2C19*4 allele and homozygous for the 3435C and 1236C ABCB1 alleles. Present findings support the previously established relationship between CYP2C9 and CYP2C19 genetic polymorphisms and the increased risk to develop PTH toxicity owing to high plasma concentrations. Nevertheless, although the association of these genes with PTH-induced adverse effects has been well-documented in adult populations, this is the first report examining the influence of these genetic polymorphisms on PTH plasma levels and toxicity in a pediatric patient. PMID:22641027

  14. Relative Copy Number Variations of CYP2C19 in South Indian Population

    Anichavezhi Devendran

    2012-01-01

    Full Text Available CYP2C19 is a polymorphic enzyme involved in the metabolism of clinically important drugs. Genotype-phenotype association studies of CYP2C19 have reported wide ranges in the metabolic ratios of its substrates. These discrepancies could be attributed to the variations in the promoter region and this aspect has been reported recently. The observations in the recent reports on the influence of promoter region variants on the metabolism of CYP2C19 substrates might also have been influenced by the copy number variations of CYP2C19. In this paper, we describe copy number variations of CYP2C19 using real-time polymerase chain reaction by comparative Ct method. No copy number variations were observed in the south Indian population indicating the observed discrepancies in genotype-phenotype association studies might be due to the regulatory region polymorphisms as reported earlier.

  15. Splicing factors control C. elegans behavioural learning in a single neuron by producing DAF-2c receptor

    Tomioka, Masahiro; Naito, Yasuki; Kuroyanagi, Hidehito; Iino, Yuichi

    2016-01-01

    UTokyo Research掲載「飢餓の記憶の形成に必要な分子が作られるしくみ」 URI: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/production-of-a-molecule-for-memory-of-salt-concentration.html

  16. One-Pot N2C/C2C/N2N Ligation To Trap Weak Protein-Protein Interactions.

    Zhao, Lei; Ehrt, Christiane; Koch, Oliver; Wu, Yao-Wen

    2016-07-01

    Weak transient protein-protein interactions (PPIs) play an essential role in cellular dynamics. However, it is challenging to obtain weak protein complexes owing to their short lifetime. Herein we present a general and facile method for trapping weak PPIs in an unbiased manner using proximity-induced ligations. To expand the chemical ligation spectrum, we developed novel N2N (N-terminus to N-terminus) and C2C (C-terminus to C-terminus) ligation approaches. By using N2C (N-terminus to C-terminus), N2N, and C2C ligations in one pot, the interacting proteins were linked. The weak Ypt1:GDI interaction drove C2C ligation with t1/2 of 4.8 min and near quantitative conversion. The Ypt1-GDI conjugate revealed that binding of Ypt1 G-domain causes opening of the lipid-binding site of GDI, which can accommodate one prenyl group, giving insights into Rab membrane recycling. Moreover, we used this strategy to trap the KRas homodimer, which plays an important role in Ras signaling. PMID:27213482

  17. Role of cytochrome P450 2C8*3 (CYP2C8*3) in paclitaxel metabolism and paclitaxel-induced neurotoxicity

    Lee, Mi-Young; Apellániz-Ruiz, María; Johansson, Inger;

    2015-01-01

    AIM: The CYP2C8*3 allele has been suggested as a risk factor for paclitaxel-induced neuropathy but the data hitherto published are conflicting. MATERIALS & METHODS: In total 435 patients were investigated with respect to maximum neuropathy grade and accumulated paclitaxel dose. The enzymatic prop...

  18. Identification and mechanism of ABA receptor antagonism

    Melcher, Karsten

    2010-08-22

    The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands. © 2010 Nature America, Inc. All rights reserved.

  19. Lipoxin Receptors

    Mario Romano

    2007-01-01

    Full Text Available Lipoxins (LXs represent a class of arachidonic acid (AA metabolites that carry potent immunoregulatory and anti-inflammatory properties, LXA4 and LXB4 being the main components of this series. LXs are generated by cooperation between 5-lipoxygenase (LO and 12- or 15-LO during cell-cell interactions or by single cell types. LX epimers at carbon 15, the 15-epi-LXs, are formed by aspirin-acetylated cyclooxygenase-2 (COX-2 in cooperation with 5-LO. 15-epi-LXA4 is also termed aspirin-triggered LX (ATL. In vivo studies with stable LX and ATL analogs have established that these eicosanoids possess potent anti-inflammatory activities. A LXA4 receptor has been cloned. It belongs to the family of chemotactic receptors and clusters with formyl peptide receptors on chromosome 19. Therefore, it was initially denominated formyl peptide receptor like 1 (FPRL1. This receptor binds with high affinity and stereoselectivity LXA4 and ATL. It also recognizes a variety of peptides, synthetic, endogenously generated, or disease associated, but with lower affinity compared to LXA4. For this reason, this receptor has been renamed ALX. This review summarizes the current knowledge on ALX expression, signaling, and potential pathophysiological role. The involvement of additional recognition sites in LX bioactions is also discussed.

  20. CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin.

    Bland, Tina M; Haining, Robert L; Tracy, Timothy S; Callery, Patrick S

    2005-10-01

    Delta9-tetrahydrocannabinol (delta9-THC), the primary psychoactive constituent of marijuana, is subject to first pass hepatic metabolism primarily by hydroxylation to yield active and inactive oxygenated products. The primary metabolite is formed via oxidation of the allylic methyl group to yield 11-hydroxy-delta9-THC, which is oxidized further to 11-nor-9-carboxy-delta9-THC. The hydroxylation is thought to be mediated by CYP2C9. The present study was designed to address the kinetics and pharmacogenetics of CYP2C-mediated metabolism of (delta9)-THC by studying its metabolism in human liver microsomes and expressed enzymes. Expressed CYP2C9.1 exhibited high affinity for the hydroxylation of delta9-THC (apparent Km, 2 microM), similar to that observed in human liver microsomes (apparent Km 0.8 microM). In contrast, the calculated intrinsic clearance (apparent Vm/Km) for CYP2C9.2 and CYP2C9.3 was approximately 30% that of the wild type, CYP2C9.1. Given the high affinity of CYP2C9 for the hydroxylation of delta9-THC, we evaluated the potential for an interaction between delta9-THC, 11-hydroxy-delta9-THC, or 11-nor-9-carboxy-delta9-THC and the CYP2C9 substrate, phenytoin. Surprisingly, delta9-THC increased the rate of phenytoin hydroxylation in human liver microsomes and expressed CYP2C9 enzyme. Similar increases in rate were observed with co-incubation of 11-hydroxy-delta9-THC and 11-nor-9-carboxy-delta9-THC with phenytoin. These in vitro data suggest the potential for an interaction from the concomitant administration of delta9-THC and phenytoin that could result in decreased phenytoin concentrations in vivo. PMID:16112652

  1. Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism

    Shi, Hui-Yan; Yan, Jin; Zhu, Wen-hui; Yang, Guo-Ping; Tan, Zhi-rong; Wu, Wei-Hua; Zhou, Gan; Chen, Xiao-Ping; Ouyang, Dong-Sheng

    2010-01-01

    Purpose To assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects. Methods A single-center, open, crossover clinical study with two treatment phases was carried out. Eighteen healthy male volunteers, including 6 CYP2C19 homozygous extensive metabolizers (EMs, *1/*1), 6 heterozygous EMs (HEMs, *1/*2 or *1/*3), and 6 CYP2C19 poor metabolizers (PMs, *2/*2 or *2/*3), were enrolled in this study. A sing...

  2. Structural properties of the sesquicarbide superconductor La2C3 at high pressure

    X Wang; Loa, I.; Syassen, K.; Kremer, R. K.; Simon, A; Hanfland, M; Ahn, K.

    2005-01-01

    The effect of pressure on the structural properties of lanthanum sesquicarbide La2C3 (T_c = 13 K) has been investigated at room temperature by angle-dispersive powder x-ray diffraction in a diamond anvil cell. The compound remains in the cubic Pu2C3-type structure at pressures up to at least 30 GPa. The corresponding equation of state parameters are reported and discussed in terms of phase stability of La2C3. Pressure-volume data of the impurity phase LaC2 are reported also for pressures up t...

  3. The b2c e-commerce landscape of the Dutch retail sector

    Weltevreden, Jesse; De Kruijf, Karlijn; Atzema, Oedzge; Frenken, Koen; van Oort, Frank

    2005-01-01

    Business-to-consumer (b2c) e-commerce can be regarded as a disruptive process innovation that can make existing business models obsolete. B2c e-commerce provides retailers the possibility of a new service concept, new client interface and even delivery system. The history of retailing is replete of such innovations, like the introduction of department stores, mail order etcetera. It is only recently that researchers from various disciplines are examining the way retailers respond to b2c e-com...

  4. NCoR1 Mediates Papillomavirus E8^E2C Transcriptional Repression▿ †

    Powell, Maria L.C.; Smith, Jennifer A.; Sowa, Mathew E.; Harper, J. Wade; Iftner, Thomas; Stubenrauch, Frank; Howley, Peter M.

    2010-01-01

    The papillomavirus E2 open reading frame encodes the full-length E2 protein as well as an alternatively spliced product called E8^E2C. E8^E2C has been best studied for the high-risk human papillomaviruses, where it has been shown to regulate viral genome levels and, like the full-length E2 protein, to repress transcription from the viral promoter that directs the expression of the viral E6 and E7 oncogenes. The repression function of E8^E2C is dependent on the 12-amino-acid N-terminal sequenc...

  5. Tumor Radiation Therapy Creates Therapeutic Vaccine Responses to the Colorectal Cancer Antigen GUCY2C

    Witek, Matthew [Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Blomain, Erik S.; Magee, Michael S.; Xiang, Bo; Waldman, Scott A. [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Snook, Adam E., E-mail: adam.snook@jefferson.edu [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2014-04-01

    Purpose: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. Methods and Materials: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses were assessed by tumor size and incidence. Results: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P<.05), tumor eradication was maximized (P<.01), and tumor volumes were minimized (P<.001) in mice whose tumors were irradiated before, compared with after, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. The antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT showed long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells. Conclusions: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance

  6. Equilibrium Structures and Isomerization Reactions of the Unsaturated Germylenoid H2C=GeLiF

    LI Wen-Zuo; CHENG Jian-Bo; GONG Bao-An; XIAO Cui-Ping

    2007-01-01

    The unsaturated germylenoid H2C=GeLiF has been studied by using DFT method at the B3LYP/6-311+G (d, p) level. Geometry optimization calculations indicate that H2C=GeLiF has three equilibrium configurations, in which the p-complex is the lowest in energy and the most stable structure. Two transition states for isomerization reactions of H2C=GeLiF are located and the energy barriers are calculated. For the most stable one, vibrational frequencies and infrared intensities have been predicted.

  7. ABA Inducible Rice Protein Phosphatase 2C Confers ABA Insensitivity and Abiotic Stress Tolerance in Arabidopsis

    Singh, Amarjeet; Jha, Saroj K.; Bagri, Jayram; Pandey, Girdhar K.

    2015-01-01

    Arabidopsis PP2C belonging to group A have been extensively worked out and known to negatively regulate ABA signaling. However, rice (Oryza sativa) orthologs of Arabidopsis group A PP2C are scarcely characterized functionally. We have identified a group A PP2C from rice (OsPP108), which is highly inducible under ABA, salt and drought stresses and localized predominantly in the nucleus. Genetic analysis revealed that Arabidopsis plants overexpressing OsPP108 are highly insensitive to ABA and t...

  8. Investigating affordances of virtual worlds for real world B2C e-commerce

    Tran, Minh; Minocha, Shailey; Roberts, Dave; Laing, Angus; Langdridge, Darren

    2011-01-01

    Virtual worlds are three-dimensional (3D) online persistent multi-user environments where users interact through avatars. The literature suggests that virtual worlds can facilitate real world business-to-consumer (B2C) e-commerce. However, few real world businesses have adopted virtual worlds for B2C e-commerce. In this paper, we present results from interviews with consumers in a virtual world to investigate how virtual worlds can support B2C e-commerce. A thematic analysis of the data was c...

  9. Competition in B2C eCommerce: Analytical Issues and Empirical Evidence

    Schmitz, Stefan W.; Michael Latzer

    2002-01-01

    This paper questions the widely held view that B2C eCommerce markets are characterised by a high intensity of competition, using a mixture of theoretical arguments and empirical evidence. We discuss two hypothesis and survey empirical studies which test them. We argue that the goods sold in B2C eCommerce have to be interpreted as heterogeneous “composite goods”, that market transparency in B2C eCommerce is lower than widely assumed, and that high endogenous sunk costs limit the intensity of c...

  10. B2C eCommerce Strategy and Market Structure: The Survey Based Approach

    Sint, Peter Paul; Schmitz, Stefan W.

    2003-01-01

    This paper follows two objectives: (i) It demonstrates the merits of the survey based approach to B2C eCommerce characteristics and company strategy, and (ii) it presents empirical evidence of the crucial importance of size and marketing investment in B2C eCommerce markets. It presents econometric estimates of the effects of company characteristics and company strategies on the performance of Viennese B2C eCommerce companies in 2001. We provide econometric analysis of three dependent variable...

  11. A Multi-attribute Model to Compute Review’s Value in C2C

    Leiyue Yao

    2014-11-01

    Full Text Available The valuable review can help consumers to make decisions in C2C e-commerce. Due to the subjectivity of review, instability of product features, and cheat behavior in C2C, the main work in this paper is to design a multi-attribute model for the assessment of review’s value based on the review’s content, reliability, timeliness. The preliminary experiments show that the proposed way can filter informative review effectively than a quality assessment approach constructed based on user-generated helpful votes, and can resist the fraud review in C2C e-commerce.

  12. Tumor Radiation Therapy Creates Therapeutic Vaccine Responses to the Colorectal Cancer Antigen GUCY2C

    Purpose: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. Methods and Materials: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses were assessed by tumor size and incidence. Results: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P<.05), tumor eradication was maximized (P<.01), and tumor volumes were minimized (P<.001) in mice whose tumors were irradiated before, compared with after, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. The antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT showed long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells. Conclusions: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance

  13. Correlative Analysis of [Ca2+]C and Apical Secretion during Pollen Tube Growth and Reorientation

    Coelho, Pedro Castanho; Malhó, Rui

    2006-01-01

    The maintenance of a cytosolic free calcium gradient (Ca2+]c) and vesicle secretion in the apex of pollen tubes is essential for growth. It has been postulated that high [Ca2+]c levels promote and confine vesicle fusion with the apical plasma membrane and in this study we performed a correlative analysis of both events using specific fluorescent dyes and confocal scanning microscopy. [Ca2+]c was imaged with Calcium Green-1 10 kDa dextran (CG-1) while secretory events were followed with FM1–43...

  14. Anomalous magnetic susceptibility of antiferromagnetic TbB2C2

    We measured the magnetic susceptibilities of TbB2C2 under fields along the , and directions. The susceptibilities below TN exhibit clear twofold symmetry in the (0 0 1) plane. No spontaneous magnetization in TbB2C2 indicates that this anisotropy in the tetragonal basal plane reflects parallel and perpendicular susceptibilities of an antiferromagnet. The susceptibilities of the and [1 1 0] directions show no cusp-like anomaly but anomalous upturns below TN with decreasing temperature, though TbB2C2 is confirmed to be an antiferromagnet. (author)

  15. Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52,000 individuals

    Kaur-Knudsen, D; Bojesen, S E; Nordestgaard, B G

    2009-01-01

    Cytochrome P450 2C9 (CYP2C9) enzymes metabolize warfarin and arachidonic acid. We hypothesized that the CYP2C9(*)2 (rs.1799853) and CYP2C9(*)3 (rs.1057910) polymorphisms with decreased enzyme activity affect risk of subclinical atherosclerosis (reduced ankle brachial index and increased C-reactiv...

  16. Possible coexistence of superconductivity and magnetic order in NdPt2B2C

    S K Dhar; A D Chinchure; E Alleno; C Godart; L C Gupta; R Nagarajan

    2002-05-01

    Coexistence of superconductivity and magnetic order has been one of the exciting aspects of the quaternary borocarbide superconductors. So far, RNi2B2C (R=Tm, Er, Ho and Dy) are the only known magnetic superconductors in this family. Here, we present our resistivity, magnetization and heat capacity studies on NdPt2B2C (nominal composition, NdPt1.5Au0.6B2C and NdPt2.1B2.4C1.2). We find superconductivity in both samples with c,onset∼ 3 K. Bulk magnetic order is found to occur below 1.7 K. We suggest that NdPt2B2C is a possible magnetic superconductor.

  17. An Implementation of I2C using VHDL for DATA surveillance

    Arvind Sahu,

    2011-05-01

    Full Text Available Once the I2C protocol designed for data surveillance system, It is easy to communicate devices with each other without data loss, as well as a excellent speed is being developed with I2C as compare toany other communication methodology. The main purpose of this technique is not only to communicate the devices but keep in touch with every operation which can be performing by with the help of thisprotocol. Because of I2C only uses two wires for communication. It is lightweight, economical, and omnipresent. The design is use in surveillance system to make overall system more efficient and accurate, with the use of I2C data transmit rate get also increased. This design method was design in VHDL, implementation in FPGA and applied in OV7620 single-chip CMOS VGA color digital camera.

  18. Magnetic structures in RNi2B2C (R = Ho, Er) superconductors

    Single crystal neutron diffraction techniques have been employed to study the evolution of magnetic structures in RNi2B2C compounds in an attempt to understand the relationship between magnetic ordering and superconductivity in several members of this series. For HoNi2B2C, below the superconducting transition (Tc = 8 K), an incommensurate magnetic structure characterized by two wave vectors (0.585 a* and 0.915 c*) is found in a narrow temperature range between 4.7 K and 6 K. This is the same temperature range where bulk measurements find a deep minimum in the upper critical field, Hc2. Below 4.7 K, HoNi2B2C is a simple collinear antiferromagnet. ErNi2B2C (Tc = 11 K) orders in an incommensurate modulated antiferromagnetic state characterized by an ordering wave vector 0.553 a* below 7 K, which coexists with superconductivity

  19. Surface Turbulent Fluxes, 1x1 deg Yearly Climatology, Set1 and NCEP V2c

    National Aeronautics and Space Administration — These data are the Goddard Satellite-based Surface Turbulent Fluxes Version-2c Dataset recently produced through a MEaSURES funded project led by Dr. Chung-Lin Shie...

  20. Surface Turbulent Fluxes, 1x1 deg Seasonal Climatology, Set1 and NCEP V2c

    National Aeronautics and Space Administration — These data are the Goddard Satellite-based Surface Turbulent Fluxes Version-2c Dataset recently produced through a MEaSUREs funded project led by Dr. Chung-Lin Shie...

  1. Engineering Macaca fascicularis cytochrome P450 2C20 to reduce animal testing for new drugs.

    Rua, Francesco; Sadeghi, Sheila J; Castrignanò, Silvia; Di Nardo, Giovanna; Gilardi, Gianfranco

    2012-12-01

    In order to develop in vitro methods as an alternative to P450 animal testing in the drug discovery process, two main requisites are necessary: 1) gathering of data on animal homologues of the human P450 enzymes, currently very limited, and 2) bypassing the requirement for both the P450 reductase and the expensive cofactor NADPH. In this work, P450 2C20 from Macaca fascicularis, homologue of the human P450 2C8 has been taken as a model system to develop such an alternative in vitro method by two different approaches. In the first approach called "molecular Lego", a soluble self-sufficient chimera was generated by fusing the P450 2C20 domain with the reductase domain of cytochrome P450 BM3 from Bacillus megaterium (P450 2C20/BMR). In the second approach, the need for the redox partner and also NADPH were both obviated by the direct immobilization of the P450 2C20 on glassy carbon and gold electrodes. Both systems were then compared to those obtained from the reconstituted P450 2C20 monooxygenase in presence of the human P450 reductase and NADPH using paclitaxel and amodiaquine, two typical drug substrates of the human P450 2C8. The K(M) values calculated for the 2C20 and 2C20/BMR in solution and for 2C20 immobilized on electrodes modified with gold nanoparticles were 1.9 ± 0.2, 5.9 ± 2.3, 3.0 ± 0.5 μM for paclitaxel and 1.2 ± 0.2, 1.6±0.2 and 1.4 ± 0.2 μM for amodiaquine, respectively. The data obtained not only show that the engineering of M. fascicularis did not affect its catalytic properties but also are consistent with K(M) values measured for the microsomal human P450 2C8 and therefore show the feasibility of developing alternative in vitro animal tests. PMID:22819650

  2. Effects of myostatin propeptide gene tranfection on glucose metabolism in cultured C2C12 cells

    张莎莎

    2014-01-01

    Objective To investigate the effects of recombinant adeno-associated virus-mediated myostatin propeptide(MPRO)on uptake and oxidation of glucose,and glycogen synthesis in C2C12 myotubes,as well as the associated molecular mechanism.Methods Mature C2C12myotubes were assigned to the following 6 groups:control,insulin,green fluorescent protein(GFP),insulin+

  3. An ANFIS-based on B2C electronic commerce transaction

    The purpose of this study is to use an adaptive-network-based fuzzy inference system to model a fuzzy logic-based system (FIS) for supporting decision-making process in B2C electronic commerce transaction. Firstly we introduce FIS in B2C electronic commerce transaction and ANFIS. Then we use ANFIS to model FIS with different membership functions(MF). Lastly we give a conclusion

  4. YNi2B2C: possible anisotropic pressure dependence of the superconducting transition temperature

    The effect of chemical pressure on the superconductivity of the (Y1-xLax)Ni2B2C system was studied. The results give an indication that the experimentally observed hydrostatic pressure for YNi2B2C is possibly a consequence of the balance between positive in-plane and negative out-of-plane uniaxial pressure derivatives. It is suggested that c-uniaxial pressure is detrimental for superconductivity in this system. (author)

  5. A core level spectroscopic study on RNi2B2C (R=Y,Er) borocarbides

    Polycrystalline samples of YNi2B2C and magnetic ErNi2B2C were prepared by arc-melting technique with a Tc ∼ 15 K. Core level spectroscopic studies have been performed in order to see the valence of Y, Er and Ni. The results show that Ni and Er exists in 2+ valence state and Y exists in 3+ valence state. (author)

  6. Growth and study of LuNi2B2C single crystals

    Rare earth-nickel-borocarbides have attracted much interest in the last years because the compounds show the interplay of superconductivity and magnetic ordering. LuNi2B2C can be considered as non-magnetic reference system of such magnetic borocarbides as HoNi2B2C in which superconducting and antiferromagnetic ordering temperatures, Tc and TN, are similar. So far, LuNi2B2C crystals were only prepared by a flux method. For growing larger crystals we used an optical floating zone (FZ) technique, which already was successful in crystal growth of other RNi2B2C (R = Y,Tb,Ho,Tm,Er) compounds. In the case of LuNi2B2C, the primary crystallization field is far from the stoichiometric composition, and adjacent to the properitectic LuB2C2 phase field an extended region of LuNiBC occurs. Systematic studies of polycrystalline samples revealed that samples with nominal compositions LuNi5B3.5C and LuNi5B3C0.5 are free of the properitectic LuB2C2 and LuNiBC phases. Thus in the FZ crystal growth experiments we used a molten zone which corresponds to these compositions. From the grown LuNi2B2C rods single crystalline pieces have been prepared to investigate Fermi surface peculiarities by magneto-resistance measurements and to study the electronic band structure

  7. An ANFIS-based on B2C electronic commerce transaction

    Lin, Juan; Liu, Chenlian; Guo, Yongning

    2014-10-01

    The purpose of this study is to use an adaptive-network-based fuzzy inference system to model a fuzzy logic-based system (FIS) for supporting decision-making process in B2C electronic commerce transaction. Firstly we introduce FIS in B2C electronic commerce transaction and ANFIS. Then we use ANFIS to model FIS with different membership functions(MF). Lastly we give a conclusion.

  8. An ANFIS-based on B2C electronic commerce transaction

    Lin, Juan, E-mail: linjuanliucaihong@qq.com [Department of Mathematics and Computer Science, Fuqing Branch of Fujian Normal University, Fuqing 350300 (China); Liu, Chenlian, E-mail: chenglian.liu@gmail.com [School of Mathematics and Computer Science, Long Yan University, Longyan 364012 (China); Guo, Yongning, E-mail: guoyn@163.com [Fuqing Branch of Fujian Normal University, Fuqing 350300 (China)

    2014-10-06

    The purpose of this study is to use an adaptive-network-based fuzzy inference system to model a fuzzy logic-based system (FIS) for supporting decision-making process in B2C electronic commerce transaction. Firstly we introduce FIS in B2C electronic commerce transaction and ANFIS. Then we use ANFIS to model FIS with different membership functions(MF). Lastly we give a conclusion.

  9. Dehydroepiandrosterone activates AMP kinase and regulates GLUT4 and PGC-1α expression in C2C12 myotubes

    Yokokawa, Takumi [Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto (Japan); Sato, Koji [Graduate School of Sport & Health Science, Ritsumeikan University, Shiga (Japan); Iwanaka, Nobumasa [The Graduate School of Science and Engineering, Ritsumeikan University, Shiga (Japan); Honda, Hiroki [Graduate School of Sport & Health Science, Ritsumeikan University, Shiga (Japan); Higashida, Kazuhiko [Faculty of Sport Science, Waseda University, Saitama (Japan); Iemitsu, Motoyuki [Graduate School of Sport & Health Science, Ritsumeikan University, Shiga (Japan); Hayashi, Tatsuya [Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto (Japan); Hashimoto, Takeshi, E-mail: thashimo@fc.ritsumei.ac.jp [Graduate School of Sport & Health Science, Ritsumeikan University, Shiga (Japan)

    2015-07-17

    Exercise and caloric restriction (CR) have been reported to have anti-ageing, anti-obesity, and health-promoting effects. Both interventions increase the level of dehydroepiandrosterone (DHEA) in muscle and blood, suggesting that DHEA might partially mediate these effects. In addition, it is thought that either 5′-adenosine monophosphate-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mediates the beneficial effects of exercise and CR. However, the effects of DHEA on AMPK activity and PGC-1α expression remain unclear. Therefore, we explored whether DHEA in myotubes acts as an activator of AMPK and increases PGC-1α. DHEA exposure increased glucose uptake but not the phosphorylation levels of Akt and PKCζ/λ in C2C12 myotubes. In contrast, the phosphorylation levels of AMPK were elevated by DHEA exposure. Finally, we found that DHEA induced the expression of the genes PGC-1α and GLUT4. Our current results might reveal a previously unrecognized physiological role of DHEA; the activation of AMPK and the induction of PGC-1α by DHEA might mediate its anti-obesity and health-promoting effects in living organisms. - Highlights: • We assessed whether dehydroepiandrosterone (DHEA) activates AMPK and PGC-1α. • DHEA exposure increased glucose uptake in C2C12 myotubes. • The phosphorylation levels of AMPK were elevated by DHEA exposure. • DHEA induced the expression of the genes PGC-1α and GLUT4. • AMPK might mediate the anti-obesity and health-promoting effects of DHEA.

  10. Dehydroepiandrosterone activates AMP kinase and regulates GLUT4 and PGC-1α expression in C2C12 myotubes

    Exercise and caloric restriction (CR) have been reported to have anti-ageing, anti-obesity, and health-promoting effects. Both interventions increase the level of dehydroepiandrosterone (DHEA) in muscle and blood, suggesting that DHEA might partially mediate these effects. In addition, it is thought that either 5′-adenosine monophosphate-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mediates the beneficial effects of exercise and CR. However, the effects of DHEA on AMPK activity and PGC-1α expression remain unclear. Therefore, we explored whether DHEA in myotubes acts as an activator of AMPK and increases PGC-1α. DHEA exposure increased glucose uptake but not the phosphorylation levels of Akt and PKCζ/λ in C2C12 myotubes. In contrast, the phosphorylation levels of AMPK were elevated by DHEA exposure. Finally, we found that DHEA induced the expression of the genes PGC-1α and GLUT4. Our current results might reveal a previously unrecognized physiological role of DHEA; the activation of AMPK and the induction of PGC-1α by DHEA might mediate its anti-obesity and health-promoting effects in living organisms. - Highlights: • We assessed whether dehydroepiandrosterone (DHEA) activates AMPK and PGC-1α. • DHEA exposure increased glucose uptake in C2C12 myotubes. • The phosphorylation levels of AMPK were elevated by DHEA exposure. • DHEA induced the expression of the genes PGC-1α and GLUT4. • AMPK might mediate the anti-obesity and health-promoting effects of DHEA

  11. Selective deoxygenation of aldehydes and alcohols on molybdenum carbide (Mo{sub 2}C) surfaces

    Xiong, Ke [Catalysis Center for Energy Innovation, Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716 (United States); Yu, Weiting [Chemical Engineering, Columbia University, New York, NY 10027 (United States); Chen, Jingguang G., E-mail: jgchen@columbia.edu [Chemical Engineering, Columbia University, New York, NY 10027 (United States)

    2014-12-30

    Highlights: • Mo{sub 2}C surface can deoxygenate propanal and 1-propanol to produce propene through a similar intermediate (propoxide or η{sup 2}(C,O)-propanal). • Mo{sub 2}C surface can deoxygenate furfural and furfuryl alcohol to make 2-methylfuran through a 2-methylfuran-like intermediate. • The presence of furan ring modifies the selectivity between deoxygenation and hydrogenation/dehydrogenation pathways. - Abstract: The selective deoxygenation of aldehydes and alcohols without cleaving the C-C bond is crucial for upgrading bio-oil and other biomass-derived molecules to useful fuels and chemicals. In this work, propanal, 1-propanol, furfural and furfuryl alcohol were selected as probe molecules to study the deoxygenation of aldehydes and alcohols on molybdenum carbide (Mo{sub 2}C) prepared over a Mo(1 1 0) surface. The reaction pathways were investigated using temperature programmed desorption (TPD) and high resolution electron energy loss spectroscopy (HREELS). The deoxygenation of propanal and 1-propanol went through a similar intermediate (propoxide or η{sup 2}(C,O)-propanal) to produce propene. The deoxygenation of furfural and furfuryl alcohol produced a surface intermediate similar to adsorbed 2-methylfuran. The comparison of these results revealed the promising deoxygenation performance of Mo{sub 2}C, as well as the effect of the furan ring on the selective deoxygenation of the C=O and C-OH bonds.

  12. The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

    Munoz, Juan Pablo; Collao, Andres; Chiong, Mario; Maldonado, Carola; Adasme, Tatiana; Carrasco, Loreto; Ocaranza, Paula; Bravo, Roberto; Gonzalez, Leticia; Diaz-Araya, Guillermo [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Facultad de Ciencias Quimicas y Farmaceuticas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Hidalgo, Cecilia [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Lavandero, Sergio, E-mail: slavander@uchile.cl [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Facultad de Ciencias Quimicas y Farmaceuticas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile)

    2009-10-09

    Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-induced MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal {alpha}-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.

  13. ASIC Implementation of I2C Master Bus Controller Firm IP Core

    S Sindhu

    2015-08-01

    Full Text Available ASIC Implementation of I2C Master bus controller with design of Firm IP core has been proposed in this paper. I2C is one the most prominent protocol used in on chip communication among sub-systems. The generic design of I2C master controller has ample of features to incorporate vast varieties of application and I2C standards. The generic design is slow, congested and require high power. It’s rare to utilize all the features of generic design fully in a single particular application or system. Hence, a modified ASIC design with specific less features but with better timing, low power requirement and less area overhead, has been proposed in this paper. This design is specifically apt for digital systems which have serial bus interface requirement for on board communication. Moreover, the Firm IP core of I2C Master Controller has been designed for ASIC, which makes the design highly portable on any ASIC chips or SOC designs. The firm IPs is best in terms of flexibility and more predictable than commonly found soft IPs. The entire custom ASIC implementation of proposed design has been done in Cadence Tool chain with 45nm technology using standard cell library. A thorough comparison has been done between generic open sourced RTL design of I2C Controller obtained from Opencores.org and our proposed design.

  14. Selective deoxygenation of aldehydes and alcohols on molybdenum carbide (Mo2C) surfaces

    Highlights: • Mo2C surface can deoxygenate propanal and 1-propanol to produce propene through a similar intermediate (propoxide or η2(C,O)-propanal). • Mo2C surface can deoxygenate furfural and furfuryl alcohol to make 2-methylfuran through a 2-methylfuran-like intermediate. • The presence of furan ring modifies the selectivity between deoxygenation and hydrogenation/dehydrogenation pathways. - Abstract: The selective deoxygenation of aldehydes and alcohols without cleaving the C-C bond is crucial for upgrading bio-oil and other biomass-derived molecules to useful fuels and chemicals. In this work, propanal, 1-propanol, furfural and furfuryl alcohol were selected as probe molecules to study the deoxygenation of aldehydes and alcohols on molybdenum carbide (Mo2C) prepared over a Mo(1 1 0) surface. The reaction pathways were investigated using temperature programmed desorption (TPD) and high resolution electron energy loss spectroscopy (HREELS). The deoxygenation of propanal and 1-propanol went through a similar intermediate (propoxide or η2(C,O)-propanal) to produce propene. The deoxygenation of furfural and furfuryl alcohol produced a surface intermediate similar to adsorbed 2-methylfuran. The comparison of these results revealed the promising deoxygenation performance of Mo2C, as well as the effect of the furan ring on the selective deoxygenation of the C=O and C-OH bonds

  15. Neutron diffraction studies of magnetic ordering in superconducting ErNi2B2C and TmNi2B2C in an applied magnetic field

    The field-induced magnetic structures of ErNi2B2C and TmNi2B2C in are especially interesting because the field suppresses the superconducting order parameter and therefore the magnetic properties can be studied while varying the strength of superconductivity. ErNi2B2C: For magnetic fields along all three symmetry directions, the observed magnetic structures have a period corresponding to the Fermi surface nesting structure. The phase diagrams present all the observed magnetic structures. Two results remain unresolved: 1. When applying the magnetic field along [010], the minority domain (QNB = (0,Q,0) with moments perpendicular to the field) shows no signs of hysteresis. I expected it to be a meta-stable state, which would be gradually suppressed by a magnetic field, and when decreasing the field it would not reappear until some small field of approximately 0.1 T. 2. When the field is applied along [110], the magnetic structure rotates a small angle of 0.5 degrees away from the symmetry direction. TmNi2B2C: A magnetic field applied in the [100] direction suppresses the zero field magnetic structure QF = (0.094,0.094,0) (TN = 1.6 K), in favor of the Fermi surface nesting structure QN = (0.483,0,0). The appearance of the QN phase was initially believed to be caused by the suppression of superconductivity. This suppression should make it favorable to create a magnetic order with a Q-vector determined by the maximum in the magnetic susceptibility at the Fermi surface nesting vector QN. The phase diagram for the magnetic structures is presented, however several properties of the QN magnetic structure cannot be explained within any known models. Quadrupolar ordering is suggested as a possible candidate for explaining these features of the QN structure. (au)

  16. Optical and structural characterization of the Co/Mo2C/Y system

    Highlights: • Co/Mo2C/Y and Co/Y/Mo2C multilayers are deposited by dc magnetic sputtering. • We characterize the optical properties of both multilayers upon annealing. • Co layers are strong mixed with others layer in all the samples. • Tri-layer and four-layer models are proposed to fit the EUV reflectivity data. - Abstract: We study the thermal behaviour of a tri-layer multilayer, designed by inserting a third material, yttrium, into the previously studied Co/Mo2C system. The system is designed to work at near-normal incidence at the wavelength of 14.1 nm. The theoretical reflectivity of Co-based multilayer (Co/Mo2C/Y system) is improved up to 54% after the addition of yttrium. Two types of multilayers with different orders of yttrium layer are deposited: Co/Mo2C/Y and Co/Y/Mo2C. The samples are annealed up to 600 °C. The multilayers were characterized using hard x-ray and extreme ultraviolet reflectivity, nuclear magnetic resonance (NMR) spectroscopy and x-ray diffraction (XRD). The results show that the reflectivity of the Co/Mo2C/Y multilayer is 27.5% at near normal incidence around 14.6 nm for as-deposited sample, and then it decreases gradually after annealing up to 600 °C. A significant period compression is observed from 300 °C annealing and above. The Co/Y/Mo2C multilayer shows low reflectivity, less than 2.5%. NMR spectra reveal that the pure Co layers are completely mixed with other elements since there is no signal from ferromagnetic Co in the annealing samples of the Co/Mo2C/Y multilayer and all Co/Y/Mo2C samples. Based on the NMR and XRD results, we fit the EUV data for both multilayers with two different models in one period taking into account the formation of the interfacial compounds

  17. Convergence on a Distinctive Assembly Mechanism by Unrelated Families of Activating Immune Receptors

    Feng, Jianwen; Garrity, David; Call, Matthew E.; Moffett, Howell; Wucherpfennig, Kai W.

    2005-01-01

    Activating receptors in cells of hematopoetic origin include members of two unrelated protein families, the immunoglobulin (Ig) and C type lectins, which differ even in the orientation of the transmembrane (TM) domains. We examined assembly of four receptors with diverse function: the NK receptors KIR2DS and NKG2C/CD94, the Fc receptor for IgA, and the GPVI collagen receptor. For each of the four different receptors studied here, assembly results in the formation of a three-helix interface in...

  18. Cytochrome P450 2C epoxygenases mediate photochemical stress-induced death of photoreceptors.

    Chang, Qing; Berdyshev, Evgeny; Cao, Dingcai; Bogaard, Joseph D; White, Jerry J; Chen, Siquan; Shah, Ravi; Mu, Wenbo; Grantner, Rita; Bettis, Sam; Grassi, Michael A

    2014-03-21

    Degenerative loss of photoreceptors occurs in inherited and age-related retinal degenerative diseases. A chemical screen facilitates development of new testing routes for neuroprotection and mechanistic investigation. Herein, we conducted a mouse-derived photoreceptor (661W cell)-based high throughput screen of the Food and Drug Administration-approved Prestwick drug library to identify putative cytoprotective compounds against light-induced, synthetic visual chromophore-precipitated cell death. Different classes of hit compounds were identified, some of which target known genes or pathways pathologically associated with retinitis pigmentosa. Sulfaphenazole (SFZ), a selective inhibitor of human cytochrome P450 (CYP) 2C9 isozyme, was identified as a novel and leading cytoprotective compound. Expression of CYP2C proteins was induced by light. Gene-targeted knockdown of CYP2C55, the homologous gene of CYP2C9, demonstrated viability rescue to light-induced cell death, whereas stable expression of functional CYP2C9-GFP fusion protein further exacerbated light-induced cell death. Mechanistically, SFZ inhibited light-induced necrosis and mitochondrial stress-initiated apoptosis. Light elicited calcium influx, which was mitigated by SFZ. Light provoked the release of arachidonic acid from membrane phospholipids and production of non-epoxyeicosatrienoic acid metabolites. Administration of SFZ further stimulated the production of non-epoxyeicosatrienoic acid metabolites, suggesting a metabolic shift of arachidonic acid under inhibition of the CYP2C pathway. Together, our findings indicate that CYP2C genes play a direct causative role in photochemical stress-induced death of photoreceptors and suggest that the CYP monooxygenase system is a risk factor for retinal photodamage, especially in individuals with Stargardt disease and age-related macular degeneration that deposit condensation products of retinoids. PMID:24519941

  19. Glutamate receptors

    Kristensen, Anders S; Geballe, Matthew T; Snyder, James P;

    2006-01-01

    Fast excitatory synaptic transmission in the CNS relies almost entirely on the neurotransmitter glutamate and its family of ion channel receptors. An appreciation of the coupling between agonist binding and channel opening has advanced rapidly during the past five years, largely as a result of ne...

  20. Somatostatin receptors

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette;

    2003-01-01

    In 1972, Brazeau et al. isolated somatostatin (somatotropin release-inhibiting factor, SRIF), a cyclic polypeptide with two biologically active isoforms (SRIF-14 and SRIF-28). This event prompted the successful quest for SRIF receptors. Then, nearly a quarter of a century later, it was announced...

  1. Clinical application of CYP2C19 pharmacogenetics toward more personalized medicine

    Su-Jun eLee

    2013-02-01

    Full Text Available More than 30 years of genetic research on the CYP2C19 gene alone has identified approximately 2,000 reference single nucleotide polymorphisms (rsSNPs containing 28 registered alleles in the P450 Allele Nomenclature Committee and the number continues to increase. However, knowledge of CYP2C19 SNPs remains limited with respect to biological functions. Functional information on the variant is essential for justifying its clinical use. Only common variants (minor allele frequency >5% that represent CYP2C19*2, *3, *17, and others have been mostly studied. Discovery of new genetic variants is outstripping the generation of knowledge on the biological meanings of existing variants. Alternative strategies may be needed to fill this gap. The present study summarizes up-to-date knowledge on functional CYP2C19 variants discovered in phenotyped humans studied at the molecular level in vitro. Understanding the functional meanings of CYP2C19 variants is an essential step toward shifting the current medical paradigm to highly personalized therapeutic regimens.

  2. Genetic polymorphisms analysis of drug-metabolizing enzyme CYP2C9 in the Uyghur population.

    Jin, Tianbo; Xun, Xiaojie; Du, Shuli; Geng, Tingting; Wang, Hong; Feng, Tian; Chen, Chen; Yuan, Dongya; Kang, Longli

    2016-08-01

    Genetic variations in cytochrome P450 2C9 are known to contribute to interindividual and interethnic variability in response to clinical drugs, but little is known about the genetic variation of CYP2C9 in the Uyghur population. We directly sequenced the whole CYP2C9 gene in 96 unrelated, healthy Uyghur from Xinjiang Uygur Autonomous Region of China and screened for genetic variants in the promoter, exons, introns and 3'-UTR. Thirty five previously reported alleles and six genotypes were detected in this study. The allele frequencies of CYP2C9*1, *2, *11, *12, *29 and *33 were 89.58, 7.81, 0.52, 0.52, 1.04 and 0.52%, respectively. We detected one non-synonymous novel variant at position 329 from Arg to Cys and this mutation is predicted to be intolerant by SIFT. Our results provide basic information about CYP2C9 alleles in Uyghur, which may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group. PMID:26610168

  3. Sedative-Hypnotic and Receptor Binding Studies of Fermented Marine Organisms.

    Joung, Hye-Young; Kang, Young Mi; Lee, Bae-Jin; Chung, Sun Yong; Kim, Kyung-Soo; Shim, Insop

    2015-09-01

    This study was performed to investigate the sedative-hypnotic activity of γ-aminobutyric acid (GABA)-enriched fermented marine organisms (FMO), including sea tangle (FST) and oyster (FO) by Lactobacillus brevis BJ20 (L. brevis BJ20). FST and FO were tested for their binding activity of the GABAA-benzodiazepine and 5-HT2C receptors, which are well-known molecular targets for sleep aids. We also measured the sleep latency and sleep duration during pentobarbital-induced sleep in mice after oral administration of FST and FO. In GABAA and 5-HT2C receptor binding assays, FST displayed an effective concentration-dependent binding affinity to GABAA receptor, similar to the binding affinity to 5-HT2C receptor. FO exhibited higher affinity to 5-HT2C receptor, compared with the GABAA receptor. The oral administration of FST and FO produced a dose-dependent decrease in sleep latency and increase in sleep duration in pentobarbital-induced hypnosis. The data demonstrate that FST and FO possess sedative-hypnotic activity possibly by modulating GABAA and 5-HT2C receptors. We propose that FST and FO might be effective agents for treatment of insomnia. PMID:26336589

  4. Empirical Study of Consumers' Purchase Intentions in C2C Electronic Commerce

    HE Dehua; LU Yaobin; ZHOU Deyi

    2008-01-01

    Electronic commerce is becoming increasingly important in business, but lack of intention to purchase has become a main barrier in the development of electronic commerce. Thus, effective measures are needed to promote consumers' intentions to purchase in online consumer to consumer (C2C) stores. This paper postulates that five factors, the perceived ease of use of the website, perceived usefulness of the website, vendor competence, introduction and recommendations of third parties, and vendors' attitude toward customers, influence consumers' intentions to purchase in online C2C stores and this intention directly leads to their action to purchase from online C2C stores. The structural equation modeling (SEM) method was used to analyze empirical data, supporting these hypotheses except for the effect of vendor competence.

  5. CO Hydrogenation over Transition Metals (Fe, Co, or Ni Modified K/Mo2C Catalysts

    Minglin Xiang

    2013-01-01

    Full Text Available Transition metals (Fe, Co, or Ni modified K/Mo2C catalysts were prepared and investigated as catalysts for CO hydrogenation. The addition of Fe, Co, or Ni to K/Mo2C catalyst led to a sharp increase in both the activity and selectivity of C2+OH, but the promotion effects were quite different and followed the sequence: Ni > Co > Fe for the activity and Fe > Co > Ni for the alcohol selectivity. For the products distributions, it also displayed some differences; Co promoter showed much higher C5+ hydrocarbon selectivity than Fe or Ni promoter, but Fe or Co promoter gave lower methane selectivity than Ni promoter, and Fe promoter showed the highest C2=-C4= selectivity.

  6. Molecular mechanisms of genetic variation and transcriptional regulation of CYP2C19

    Nuala Ann Helsby

    2012-10-01

    Full Text Available Inherited variation in the function of the drug metabolising enzyme CYP2C19 was first observed 40 years ago. The SNP variants which underpin loss of CYP2C19 function have been elucidated and extensively studied in healthy populations. However, there has been relatively meagre translation of this information into the clinic. The presence of genotype-phenotype discordance in certain patients suggests that changes in the regulation of this gene, as well as loss of function SNPs, could play a role in deficient activity of this enzyme. Knowledge of the molecular mechanisms which control transcription of this gene, reviewed in this article, may aid the challenge of delivering CYP2C19 pharmacogenetics into clinical use.

  7. Prenatal detection of 5q14.3 duplication including MEF2C and brain phenotype.

    Cesaretti, Claudia; Spaccini, Luigina; Righini, Andrea; Parazzini, Cecilia; Conte, Giorgio; Crosti, Francesca; Redaelli, Serena; Bulfamante, Gaetano; Avagliano, Laura; Rustico, Mariangela

    2016-05-01

    The 5q14.3 duplication is a rare condition comprising speech and developmental delay, microcephaly, and mild ventriculomegaly. The region 5q14.3 contains several genes but the predominant role for the onset of the neurodevelopmental phenotype has been attributed to MEF2C. We describe the prenatal identification of 5q14.3 duplication, including MEF2C, in a monochorionic twin pregnancy with corpus callosum anomalies, confirmed by autopsy. To the best of our knowledge, this cerebral finding has been observed for the first time in 5q14.3 duplication patients, possibly widening the neurological picture of this scarcely known syndrome. A pathogenetic role of MEF2C overexpression in brain development may be assumed, but further studies are needed. © 2016 Wiley Periodicals, Inc. PMID:26864752

  8. Design, drilling, and construction of well RRL-2B, and piezometer nest RRL-2C

    This document describes the design, drilling and construction of the well RRL-2B and piezometer nest RRL-2C at the RRL-2 location. Well RRL-2B will act as the discharge well for performing large-scale hydraulic tests in units of the Grande Ronde Basalt. Piezometer nest RRL-2C will act as the primary observation points in the vicinity of the RRL-2 location. Water levels will also be measured in RRL-2C as part of the piezometer baseline monitoring program. Well RRL-2B is completed as a 12.25-in. (31.12-cm) open hole at the interim depth of 2858 ft (871.1 m). On completion of testing the Rocky Coulee flow top, the well will be deepened to the next horizon for testing. 33 refs., 25 figs., 4 tabs

  9. Vibrational structure of C 84 and Sc 2@C 84 analyzed by IR spectroscopy

    Hulman, M.; Pichler, T.; Kuzmany, H.; Zerbetto, F.; Yamamoto, E.; Shinohara, H. N.

    1997-06-01

    The isomer III of Sc 2@C 84 was separated by multi-cycle HPLC purification. We present temperature dependent IR absorption measurements of Sc 2@C 84 which have been performed between 50 and 300 K and between 400 and 5000 cm -1, respectively. The vibrational structure of the endohedral compound is compared to the structure of unfilled C 84. We find a strong overall broadening of the vibrational modes in Sc 2@C 84. Also some of the vibrational absorption lines are strongly enhanced if compared to the spectrum for the empty cage. With decreasing temperature, a dramatic narrowing of the lines in the spectral range between 700 and 800 cm -1 is observed.

  10. Spectroscopic Properties of Non-glycosilated Functional Unit KLH2-c of Keyhole Limpet Hemocyanin

    Aleksander Dolashki

    2005-12-01

    Full Text Available The functional unit KLH2-c, isolated from the structural subunit KLH2 of keyhole limpet Megathura crenulata hemocyanin, was studied to explain the effect of the oligosaccharide component for the conformational stability of the protein. The properties of this FU were characterized by fluorescence spectroscopy, combined with fluorescence quenching studies, using acrylamide, caesium chloride and potassium iodide as tryptophan quenchers. Using circular dichroism and fluorescence spectroscopy, the thermostability of the non-glycosylated FU KLH2-c was studied in comparison to the glycosylated native molecule, the structural subunits KLH1, KLH2 and the FU RvH1-a of Rapana venosa Hc. The melting Tm (45°C as well as the critical temperatures Tc (46 were found to be less for KLH2-c compared to the glycosylated forms which could be explained to be caused by the presence of oligosaccharide side chains and aggregation effects.