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


    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.

  2. Therapeutic Potential of 5-HT2C Receptor Ligands

    Nanna H. Jensen


    Full Text Available Serotonin 2C receptors are G protein-coupled receptors expressed by GABAergic, glutamatergic, and dopaminergic neurons. Anatomically, they are present in various brain regions, including cortical areas, hippocampus, ventral midbrain, striatum, nucleus accumbens, hypothalamus, and amygdala. A large body of evidence supports a critical role of serotonin 2C receptors in mediating the interaction between serotonergic and dopaminergic systems, which is at the basis of their proposed involvement in the regulation of mood, affective behavior, and memory. In addition, their expression in specific neuronal populations in the hypothalamus would be critical for their role in the regulation of feeding behavior. Modulation of these receptors has therefore been proposed to be of interest in the search for novel pharmacological strategies for the treatment of various pathological conditions, including schizophrenia and mood disorders, as well as obesity. More precisely, blockade of serotonin 2C receptors has been suggested to provide antidepressant and anxiolytic benefit, while stimulation of these receptors may offer therapeutic benefit for the treatment of psychotic symptoms in schizophrenia and obesity. In addition, modulation of serotonin 2C receptors may offer cognitive-enhancing potential, albeit still a matter of debate. In the present review, the most compelling evidence from the literature is presented and tentative hypotheses with respect to existing controversies are outlined.

  3. 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...

  4. Impact of RNA editing on functions of the serotonin 2C receptor in vivo

    Uade B Olaghere Da Silva


    Full Text Available Transcripts encoding 5-HT2C receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5-HT2C-VGV, exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5-HT2C-VGV receptors in brain to determine the in vivo consequences of altered editing. Using mice solely expressing the 5-HT2C-VGV receptor (VGV/Y, we demonstrate reduced G-protein coupling efficiency and high-affinity agonist binding of brain 5-HT2C-VGV receptors. However, enhanced behavioral sensitivity to a 5-HT2C receptor agonist was also seen in mice expressing 5-HT2C-VGV receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5-HT2C-VGV receptors had greater sensitivity to a 5-HT2C inverse agonist/antagonist enhancement of dopamine turnover relative to wild-type mice. These behavioral and biochemical results are most likely explained by increases in 5-HT2C receptor binding sites in the brains of mice solely expressing -5HT2C-VGV receptors. We conclude that 5-HT2C-VGV receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5HT2C receptor binding site density in mice solely expressing the VGV isoform. These findings suggest that RNA editing may regulate the density of 5-HT2C receptor binding sites in brain. We further caution that the pattern of 5-HT2C receptor RNA isoforms may not reflect the pattern of protein isoforms, and hence the inferred overall function of the receptor.

  5. Dynamic 5-HT2C receptor editing in a mouse model of obesity.

    Harriët Schellekens

    Full Text Available The central serotonergic signalling system has been shown to play an important role in appetite control and the regulation of food intake. Serotonin exerts its anorectic effects mainly through the 5-HT(1B, 5-HT(2C and 5-HT(6 receptors and these are therefore receiving increasing attention as principal pharmacotherapeutic targets for the treatment of obesity. The 5-HT(2C receptor has the distinctive ability to be modified by posttranscriptional RNA editing on 5 nucleotide positions (A, B, C, D, E, having an overall decreased receptor function. Recently, it has been shown that feeding behaviour and fat mass are altered when the 5-HT(2C receptor RNA is fully edited, suggesting a potential role for 5-HT(2C editing in obesity. The present studies investigate the expression of serotonin receptors involved in central regulation of food intake, appetite and energy expenditure, with particular focus on the level of 5-HT(2C receptor editing. Using a leptin-deficient mouse model of obesity (ob/ob, we show increased hypothalamic 5-HT(1A receptor expression as well as increased hippocampal 5-HT(1A, 5-HT(1B, and 5-HT(6 receptor mRNA expression in obese mice compared to lean control mice. An increase in full-length 5-HT(2C expression, depending on time of day, as well as differences in 5-HT(2C receptor editing were found, independent of changes in total 5-HT(2C receptor mRNA expression. This suggests that a dynamic regulation exists of the appetite-suppressing effects of the 5-HT(2C receptor in both the hypothalamus and the hippocampus in the ob/ob mice model of obesity. The differential 5-HT(1A, 5-HT(1B and 5-HT(6 receptor expression and altered 5-HT(2C receptor editing profile reported here is poised to have important consequences for the development of novel anti-obesity therapies.

  6. Estradiol increases the anorexia associated with increased 5-HT2C receptor activation in ovariectomized rats

    Rivera, Heidi M.; Santollo, Jessica; Nikonova, Larissa V.; Eckel, Lisa A.


    Estradiol’s inhibitory effect on food intake is mediated, in part, by its ability to increase the activity of meal-related signals, including serotonin (5-HT), which hasten satiation. The important role that postsynaptic 5-HT2C receptors play in mediating 5-HT’s anorexigenic effect prompted us to investigate whether a regimen of acute estradiol treatment increases the anorexia associated with increased 5-HT2C receptor activation in ovariectomized (OVX) rats. We demonstrated that intraperitone...

  7. Synergistic Impairment of Glucose Homeostasis in ob/ob Mice Lacking Functional Serotonin 2C Receptors

    Wade, Jennifer M.; Juneja, Punita; Mackay, Adrienne W.; Graham, James; Havel, Peter J.; Tecott, Laurence H.; Goulding, Evan H.


    To investigate how serotonin and leptin interact in the regulation of energy balance and glucose homeostasis, we generated a genetic mouse model, the OB2C mouse, which lacks functional serotonin 2C receptors and the adipocyte hormone leptin. The OB2C mice exhibited a dramatic diabetes phenotype, evidenced by a synergistic increase in serum glucose levels and water intake. The severity of the animals’ diabetes phenotype would not have been predicted from the phenotypic characterization of mice...

  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.


    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. Oligonucleotide-induced alternative splicing of serotonin 2C receptor reduces food intake.

    Zhang, Zhaiyi; Shen, Manli; Gresch, Paul J; Ghamari-Langroudi, Masoud; Rabchevsky, Alexander G; Emeson, Ronald B; Stamm, Stefan


    The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre-mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full-length receptor in intracellular membranes. We developed an oligonucleotide that promotes exon inclusion, which increases the ratio of the full-length to truncated receptor protein. Decreasing the amount of truncated receptor results in the accumulation of full-length, constitutively active receptor at the cell surface. After injection into the third ventricle of mice, the oligonucleotide accumulates in the arcuate nucleus, where it changes alternative splicing of the serotonin 2C receptor and increases pro-opiomelanocortin expression. Oligonucleotide injection reduced food intake in both wild-type and ob/ob mice. Unexpectedly, the oligonucleotide crossed the blood-brain barrier and its systemic delivery reduced food intake in wild-type mice. The physiological effect of the oligonucleotide suggests that a truncated splice variant regulates the activity of the serotonin 2C receptor, indicating that therapies aimed to change pre-mRNA processing could be useful to treat hyperphagia, characteristic for disorders like Prader-Willi syndrome.

  10. Decreased serotonin2C receptor responses in male patients with schizophrenia.

    Lee, Myung Ae; Jayathilake, Karuna; Sim, Min Young; Meltzer, Herbert Y


    Serotonin (5-HT)2C receptors in brain affect psychosis, reward, substance abuse, anxiety, other behaviors, appetite, body temperature, and other physiological measures. They also have been implicated in antipsychotic drug efficacy and side effects. We previously reported that the hyperthermia following administration of MK-212, a predominantly 5-HT(2C) receptor agonist, was diminished in a small sample of patients with schizophrenia (SCH), suggesting decreased 5-HT(2C) receptor responsiveness. We have now studied the responses to oral MK-212 and placebo in a larger sample of unmedicated male SCH (n = 69) and normal controls (CON) (n = 33), and assessed the influence of comorbid substance abuse (SA) on oral body temperature, behavioral responses, etc. The placebo-adjusted oral body temperature response to MK-212 was significantly lower in SCH compared to CON and not significantly different between the SCH with or without SA. Some behavioral responses to MK-212, e.g. self-rated feelings of increased anxiety, depression and decreased calmness, or good overall feeling, were significantly lower in the SCH patients compared to CON. These results add to the evidence for diminished 5-HT(2C) receptor responsiveness in SCH patients compared to CON and are consistent with reported association of HTR(2C) polymorphisms, leading to decreased expression or function of the HTR(2C) in patients with SCH.

  11. Estradiol increases the anorexia associated with increased 5-HT(2C) receptor activation in ovariectomized rats.

    Rivera, Heidi M; Santollo, Jessica; Nikonova, Larissa V; Eckel, Lisa A


    Estradiol's inhibitory effect on food intake is mediated, in part, by its ability to increase the activity of meal-related signals, including serotonin (5-HT), which hastens satiation. The important role that postsynaptic 5-HT(2C) receptors play in mediating 5-HT's anorexigenic effect prompted us to investigate whether a regimen of acute estradiol treatment increases the anorexia associated with increased 5-HT(2C) receptor activation in ovariectomized (OVX) rats. We demonstrated that intraperitoneal and intracerebroventricular (i.c.v.) administration of low doses of the 5-HT(2C) receptor agonist meta-chlorophenylpiperazine (mCPP) decreased 1-h dark-phase food intake in estradiol-treated, but not oil-treated, OVX rats. During a longer feeding test, we demonstrated that i.c.v. administration of mCPP decreased 22-h food intake in oil-treated and, to a greater extent, estradiol-treated OVX rats. In a second study, we demonstrated that estradiol increased 5-HT(2C) receptor protein content in the caudal brainstem, but not hypothalamus, of OVX rats. We conclude that a physiologically-relevant regimen of acute estradiol treatment increases sensitivity to mCPP's anorexigenic effect. Our demonstration that this same regimen of estradiol treatment increases 5-HT(2C) receptor protein content in the caudal hindbrain of OVX rats provides a possible mechanism to explain our behavioral findings.

  12. Functional aspects of dexamethasone upregulated nicotinic acetylcholine receptors in C2C12 myotubes

    Maestrone, E; Lagostena, L; Henning, RH; DenHertog, A; Nobile, M


    Three days of treatment with the glucocorticoid dexamethasone (1 nM-mu M) induced a concentration-dependent up-regulation of muscle nicotinic acetylcholine receptor (nAChR) in C2C12 mouse myotubes (EC(50)=10+/-7.3 nM), as assessed by [H-3]alpha-BuTx binding. The maximum increase in binding amounted

  13. Evidence that the anorexia induced by lipopolysaccharide is mediated by the 5-HT2C receptor.

    von Meyenburg, Claudia; Langhans, Wolfgang; Hrupka, Brian J


    Rats consistently reduce their food intake following injections of bacterial lipopolysaccharides (LPS). Because inhibition of serotonergic (5-HT) activity by 8-OH-DPAT (5-HT(1A) activation) attenuates LPS-induced anorexia, we conducted a series of studies to examine whether other 5-HT-receptors are involved in the mediation of peripheral LPS-induced anorexia. In all experiments, rats were injected with LPS (100 microg/kg body weight [BW] ip) at lights out (hour 0). Antagonists were administered peripherally at hour 4, shortly after the onset of anorexia, which presumably follows the enhanced cytokine production after LPS. Food intake was then recorded during the subsequent 2 h or longer. 5-HT receptor antagonists cyanopindolol and SB 224289 (5-HT(1B)), ketanserin (5-HT(2A)), RS-102221 (5-HT(2C)), and metoclopramide (5-HT(3)) failed to attenuate LPS-induced anorexia. In contrast, both ritanserin (5-HT(2A/C)-receptor antagonist) (0.5 mg/kg BW) and SB 242084 (5-HT(2C)) (0.3 mg/kg BW) attenuated LPS-induced anorexia at doses that did not alter food intake in non-LPS-treated rats (all Panorexia following peripheral LPS administration is mediated through an enhanced 5-HT-ergic activity and the 5-HT(2C) receptor.

  14. 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


    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.

  15. Multiple interactions between the alpha2C- and beta1-adrenergic receptors influence heart failure survival

    Case Karen L


    Full Text Available Abstract Background Persistent stimulation of cardiac β1-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the α2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (ADRB1 and ADRA2C, respectively on the risk of death/transplant in heart failure patients. Methods Sixteen sequence variations in ADRA2C and 17 sequence variations in ADRB1 were genotyped in a longitudinal study of 655 white heart failure patients. Eleven sequence variations in each gene were polymorphic in the heart failure cohort. Cox proportional hazards modeling was used to identify polymorphisms and potential intra- or intergenic interactions that influenced risk of death or cardiac transplant. A leave-one-out cross-validation method was utilized for internal validation. Results Three polymorphisms in ADRA2C and five polymorphisms in ADRB1 were involved in eight cross-validated epistatic interactions identifying several two-locus genotype classes with significant relative risks ranging from 3.02 to 9.23. There was no evidence of intragenic epistasis. Combining high risk genotype classes across epistatic pairs to take into account linkage disequilibrium, the relative risk of death or transplant was 3.35 (1.82, 6.18 relative to all other genotype classes. Conclusion Multiple polymorphisms act synergistically between the ADRA2C and ADRB1 genes to increase risk of death or cardiac transplant in heart failure patients.

  16. Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4-iodoamphetamine elicited head-twitch response model.

    Canal, Clinton E; Booth, Raymond G; Morgan, Drake


    There are seemingly conflicting data in the literature regarding the role of serotonin (5-HT) 5-HT2C receptors in the mouse head-twitch response (HTR) elicited by the hallucinogenic 5-HT2A/2B/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Namely, both 5-HT2C receptor agonists and antagonists, regarding 5-HT2C receptor-mediated Gq-phospholipase C (PLC) signaling, reportedly attenuate the HTR response. The present experiments tested the hypothesis that both classes of 5-HT2C receptor compounds could attenuate the DOI-elicited-HTR in a single strain of mice, C57Bl/6J. The expected results were considered in accordance with ligand functional selectivity. Commercially-available 5-HT2C agonists (CP 809101, Ro 60-0175, WAY 161503, mCPP, and 1-methylpsilocin), novel 4-phenyl-2-N,N-dimethyl-aminotetralin (PAT)-type 5-HT2C agonists (with 5-HT2A/2B antagonist activity), and antagonists selective for 5-HT2A (M100907), 5-HT2C (SB-242084), and 5-HT2B/2C (SB-206553) receptors attenuated the DOI-elicited-HTR. In contrast, there were differential effects on locomotion across classes of compounds. The 5-HT2C agonists and M100907 decreased locomotion, SB-242084 increased locomotion, SB-206553 resulted in dose-dependent biphasic effects on locomotion, and the PATs did not alter locomotion. In vitro molecular pharmacology studies showed that 5-HT2C agonists potent for attenuating the DOI-elicited-HTR also reduced the efficacy of DOI to activate mouse 5-HT2C receptor-mediated PLC signaling in HEK cells. Although there were differences in affinities of a few compounds at mouse compared to human 5-HT2A or 5-HT2C receptors, all compounds tested retained their selectivity for either receptor, regardless of receptor species. Results indicate that 5-HT2C receptor agonists and antagonists attenuate the DOI-elicited-HTR in C57Bl/6J mice, and suggest that structurally diverse 5-HT2C ligands result in different 5-HT2C receptor signaling outcomes compared to DOI.

  17. Medial parabrachial nucleus neurons modulate d-fenfluramine-induced anorexia through 5HT2C receptors.

    Trifunovic, Radmila; Reilly, Steve


    We previously reported that lesions of the medial parabrachial nucleus (PBN) enhanced d-fenfluramine (DFEN)-induced anorexia; a finding that suggests these lesions may potentiate the release of serotonin (5HT) or increase the postsynaptic action of 5HT. In the present study, we used SB 206553 (a 5HT2B/2C receptor antagonist) or m-CPP (a 5HT2C/1B receptor agonist) in a standard behavioral procedure (deprivation-induced feeding) to further explore the role of the medial PBN in drug-induced anorexia. In Experiment 1, DFEN (0 or 1.0 mg/kg) was given alone or in combination with SB 206553 (2.0 or 5.0 mg/kg). In Experiment 2, we investigated the food-suppressive effects of m-CPP (0.5, 1.0 or 2.0 mg/kg). The results of Experiment 1 show that SB 206553, while having no influence on the performance of control subjects, attenuated (2.0 mg/kg) or abolished (5 mg/kg) the potentiating effect of the lesions on DFEN-induced anorexia. In Experiment 2, m-CPP induced a suppression of food intake in nonlesioned animals that was significantly potentiated in rats with medial PBN lesions. These results are consistent with the hypothesis that medial PBN neurons mediate anorexia through 5HT2C receptors.

  18. 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


    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

  19. 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


    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

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

    Brandl EJ


    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

  1. Lorcaserin: a selective serotonin receptor (5-HT2C agonist for the treatment of obesity

    Bhaven C. Kataria


    Full Text Available Lorcaserin is a selective serotonin receptor (5-HT2C agonist that recently received the U.S. Food and Drug Administration (FDA approval for chronic weight management. The efficacy of this drug in reducing body weight and improving metabolic parameters of obese patients has been demonstrated in three phase-3 clinical trials. The available evidence indicates that this drug does not show heart valve abnormalities, and the treatment improves the risk factors for type 2 diabetes and cardiovascular diseases. However, the drug's manufacturer will be required to conduct postmarketing studies, including a long-term cardiovascular outcomes trial to assess the effect of Lorcaserin on the risk for major adverse cardiac events such as heart attack and stroke. [Int J Basic Clin Pharmacol 2012; 1(1.000: 45-47

  2. Agonist-directed signaling of serotonin 5-HT2C receptors: differences between serotonin and lysergic acid diethylamide (LSD).

    Backstrom, J R; Chang, M S; Chu, H; Niswender, C M; Sanders-Bush, E


    For more than 40 years the hallucinogen lysergic acid diethylamide (LSD) has been known to modify serotonin neurotransmission. With the advent of molecular and cellular techniques, we are beginning to understand the complexity of LSD's actions at the serotonin 5-HT2 family of receptors. Here, we discuss evidence that signaling of LSD at 5-HT2C receptors differs from the endogenous agonist serotonin. In addition, RNA editing of the 5-HT2C receptor dramatically alters the ability of LSD to stimulate phosphatidylinositol signaling. These findings provide a unique opportunity to understand the mechanism(s) of partial agonism.

  3. Receptor reserve analysis of the human alpha(2C)-adrenoceptor using.

    Umland, S P; Wan, Y; Shah, H; Billah, M; Egan, R W; Hey, J A


    Here we determine for norepinephrine, (5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline) (UK14,304), 5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride (BHT-920), (2-[3-hydroxy-2,6-dimethyl-4-t-butylbenzyl]-2-imidazoline) (oxymetazoline), and ((R)-3-Hydroxy-alpha-[(methylamino)methyl]-benzenemethanol hydrochloride) (phenylephrine), affinities using a radiolabeled agonist and antagonist, and potency and efficacy values in membrane [(35)S]guanosine-5'-O-(3-thiotriphosphate) ([(35)S]GTP gamma S) binding and cAMP cellular inhibition assays, in Chinese hamster ovary cells (CHO-K1) expressing the human alpha(2c)-adrenoceptor. These cells express a high ratio of receptor to G-protein because each agonist, but not several antagonists, displaced [(3)H]UK14,304 with higher affinity than [(3)H]rauwolscine. The rank order of potency of high affinity K(i) and EC(50) in both functional assays was norepinephrine > or =UK14,304>BHT-920>oxymetazoline>phenylephrine. The receptor reserve of G-protein activation and cAMP responses was measured with the irreversible antagonist, benextramine; K(A) values of norepinephrine or UK14,304 were similar (289, 271 or 150, 163 nM, respectively). A 20-fold greater receptor occupancy was required for agonist-induced half-maximal [(35)S]GTP gamma S binding compared to cAMP inhibition, indicating significant signal amplification in cells. Therefore, the G-protein activation assay is better at distinguishing full and partial agonists.

  4. 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


    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.

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

    Katarina eLichnerova


    Full Text Available N-methyl-D-aspartate (NMDA receptors mediate fast excitatory synaptic transmission in the mammalian central nervous system. The activation of NMDA receptors plays a key role in brain development, synaptic plasticity, and memory formation, and is a major contributor to many neuropsychiatric disorders. Here, we investigated the mechanisms that underlie the trafficking of GluN1/GluN2C receptors. Using an approach combining molecular biology, microscopy, and electrophysiology in mammalian cell lines and cultured cerebellar granule cells, we found that the surface delivery of GluN2C-containing receptors is reduced compared to GluN2A- and GluN2B-containing receptors. Furthermore, we identified three distinct regions within the N-terminus, M3 transmembrane domain, and C-terminus of GluN2C subunits that are required for proper intracellular processing and surface delivery of NMDA receptors. These results shed new light on the regulation of NMDA receptor trafficking, and these findings can be exploited to develop new strategies for treating some forms of neuropsychiatric disorders.

  6. Evaluation of the abuse potential of lorcaserin, a serotonin 2C (5-HT2C) receptor agonist, in recreational polydrug users.

    Shram, M J; Schoedel, K A; Bartlett, C; Shazer, R L; Anderson, C M; Sellers, E M


    Lorcaserin is a selective and potent serotonin 2C receptor subtype (5-HT(2C)) agonist under development for the treatment of obesity. This study assessed the drug's abuse potential on the basis of its pharmacological profile. For this purpose, a double-blind, double-dummy, placebo-controlled, randomized seven-way crossover study with single oral doses of lorcaserin (20, 40, and 60 mg), zolpidem (15 and 30 mg), ketamine (100 mg), and placebo was conducted in recreational polydrug users (N = 35). Subjective and objective measures were assessed up to 24 h after the dose. We found that zolpidem and ketamine had significantly higher peak scores relative to placebo on the primary measures as well as on most of the secondary measures. The subjective effects of a 20-mg dose of lorcaserin were similar to those of placebo, whereas supratherapeutic doses of lorcaserin were associated with significant levels of dislike by users as compared with placebo, zolpidem, and ketamine. Perceptual effects were minimal after administration of lorcaserin and significantly lower than after administration of either ketamine or zolpidem. The findings suggest that, at supratherapeutic doses, lorcaserin is associated with distinct, primarily negative, subjective effects and has low abuse potential.

  7. Peroxisome proliferator-activated receptor alpha, PPARα, directly regulates transcription of cytochrome P450 CYP2C8.

    Thomas, Maria; Winter, Stefan; Klumpp, Britta; Turpeinen, Miia; Klein, Kathrin; Schwab, Matthias; Zanger, Ulrich M


    The cytochrome P450, CYP2C8, metabolizes more than 60 clinically used drugs as well as endogenous substances including retinoic acid and arachidonic acid. However, predictive factors for interindividual variability in the efficacy and toxicity of CYP2C8 drug substrates are essentially lacking. Recently we demonstrated that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor primarily involved in control of lipid and energy homeostasis directly regulates the transcription of CYP3A4. Here we investigated the potential regulation of CYP2C8 by PPARα. Two linked intronic SNPs in PPARα (rs4253728, rs4823613) previously associated with hepatic CYP3A4 status showed significant association with CYP2C8 protein level in human liver samples (N = 150). Furthermore, siRNA-mediated knock-down of PPARα in HepaRG human hepatocyte cells resulted in up to ∼60 and ∼50% downregulation of CYP2C8 mRNA and activity, while treatment with the PPARα agonist WY14,643 lead to an induction by >150 and >100%, respectively. Using chromatin immunoprecipitation scanning assay we identified a specific upstream gene region that is occupied in vivo by PPARα. Electromobility shift assay demonstrated direct binding of PPARα to a DR-1 motif located at positions -2762/-2775 bp upstream of the CYP2C8 transcription start site. We further validated the functional activity of this element using luciferase reporter gene assays in HuH7 cells. Moreover, based on our previous studies we demonstrated that WNT/β-catenin acts as a functional inhibitor of PPARα-mediated inducibility of CYP2C8 expression. In conclusion, our data suggest direct involvement of PPARα in both constitutive and inducible regulation of CYP2C8 expression in human liver, which is further modulated by WNT/β-catenin pathway. PPARA gene polymorphism could have a modest influence on CYP2C8 phenotype.

  8. Peroxisome proliferator-activated receptor alpha, PPARα, directly regulates transcription of cytochrome P450 CYP2C8

    Maria eThomas


    Full Text Available The cytochrome P450, CYP2C8, metabolises more than 60 clinically used drugs as well as endogenous substances including retinoic acid and arachidonic acid. However predictive factors for interindividual variability in the efficacy and toxicity of CYP2C8 drug substrates are essentially lacking. Recently we demonstrated that peroxisome proliferator-activated receptor alpha (PPARα, a nuclear receptor primarily involved in control of lipid and energy homeostasis directly regulates the transcription of CYP3A4. Here we investigated the potential regulation of CYP2C8 by PPARα. Two linked intronic SNPs in PPARα (rs4253728, rs4823613 previously associated with hepatic CYP3A4 status showed significant association with CYP2C8 protein level in human liver samples (N=150. Furthermore, siRNA-mediated knock-down of PPARα in HepaRG human hepatocyte cells resulted in up to ~60% and ~50% downregulation of CYP2C8 mRNA and activity, while treatment with the PPARα agonist WY14,643 lead to an induction by >150% and >100%, respectively. Using chromatin immunoprecipitation scanning assay we identified a specific upstream gene region that is occupied in vivo by PPARα. Electromobility shift assay demonstrated direct binding of PPARα to a DR-1 motif located at positions -2762/-2775bp upstream of the CYP2C8 transcription start site. We further validated the functional activity of this element using luciferase reporter gene assays in HuH7 cells. Moreover, based on our previous studies we demonstrated that WNT/β-catenin acts as a functional inhibitor of PPARα-mediated inducibility of CYP2C8 expression. In conclusion, our data suggest direct involvement of PPARα in both constitutive and inducible regulation of CYP2C8 expression in human liver, which is further modulated by WNT/ β-catenin pathway. PPARA gene polymorphism could have a modest influence on CYP2C8 phenotype.

  9. Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels

    Serotonin 2C receptors (5-HT2CRs) expressed by pro-opiomelanocortin (POMC) neurons of hypothalamic arcuate nucleus regulate food intake, energy homeostasis ,and glucose metabolism. However, the cellular mechanisms underlying the effects of 5-HT to regulate POMC neuronal activity via 5-HT2CRs have no...

  10. Role of melatonin, serotonin 2B, and serotonin 2C receptors in modulating the firing activity of rat dopamine neurons.

    Chenu, Franck; Shim, Stacey; El Mansari, Mostafa; Blier, Pierre


    Melatonin has been widely used for the management of insomnia, but is devoid of antidepressant effect in the clinic. In contrast, agomelatine which is a potent melatonin receptor agonist is an effective antidepressant. It is, however, a potent serotonin 2B (5-HT(2B)) and serotonin 2C (5-HT(2C)) receptor antagonist as well. The present study was aimed at investigating the in vivo effects of repeated administration of melatonin (40 mg/kg/day), the 5-HT(2C) receptor antagonist SB 242084 (0.5 mg/kg/day), the selective 5-HT(2B) receptor antagonist LY 266097 (0.6 mg/kg/day) and their combination on ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) serotonin (5-HT) firing activity. Administration of melatonin twice daily increased the number of spontaneously active DA neurons but left the firing of NE neurons unaltered. Long-term administration of melatonin and SB 242084, by themselves, had no effect on the firing rate and burst parameters of 5-HT and DA neurons. Their combination, however, enhanced only the number of spontaneously active DA neurons, while leaving the firing of 5-HT neurons unchanged. The addition of LY 266097, which by itself is devoid of effect, to the previous regimen increased for DA neurons the number of bursts per minute and the percentage of spikes occurring in bursts. In conclusion, the combination of melatonin receptor activation as well as 5-HT(2C) receptor blockade resulted in a disinhibition of DA neurons. When 5-HT(2B) receptors were also blocked, the firing and the bursting activity of DA neurons were both enhanced, thus reproducing the effect of agomelatine.

  11. Development of an improved IP(1) assay for the characterization of 5-HT(2C) receptor ligands.

    Zhang, Jean Y; Kowal, Dianne M; Nawoschik, Stanley P; Dunlop, John; Pausch, Mark H; Peri, Ravikumar


    The 5-hydroxytryptamine 2C (5-HT(2C)) receptor is a member of the serotonin 5-HT(2) subfamily of G-protein-coupled receptors signaling predominantly via the phospholipase C (PLC) pathway. Stimulation of phosphoinositide (PI) hydrolysis upon 5-HT(2C) receptor activation is traditionally assessed by measuring inositol monophosphate (IP(1)) using time-consuming and labor-intensive anion exchange radioactive assays. In this study, we have developed and optimized a cellular IP(1) assay using homogeneous time-resolved fluorescence (HTRF), a fluorescence resonance energy transfer (FRET)-based technology (Cisbio; Gif sur Yvette, France). The measurement is simple to carry out without the cumbersome steps associated with radioactive assays and may therefore be used as an alternative tool to evaluate PI hydrolysis activated by 5-HT(2C) agonists. In Chinese hamster ovary (CHO) cells stably expressing 5-HT(2C) receptors, characterization of 5-HT(2C) agonists with the HTRF platform revealed a rank order of potency (EC(50), nM) comparable to that from intracellular calcium mobilization studies measured by the fluorometric imaging plate reader (FLIPR). A similar rank order of potency was seen with conventional radioactive PI assay with the exception of 5-HT. Lastly, the new assay data correlated better with agonist-induced calcium responses in FLIPR (R(2) = 0.78) than with values determined by radioactive IP(1) method (R(2) = 0.64). Our study shows that the HTRF FRET-based assay detects IP(1) with good sensitivity and may be streamlined for high-throughput (HTS) applications.

  12. Urocortin1-induced anorexia is regulated by activation of the serotonin 2C receptor in the brain.

    Harada, Yumi; Takayama, Kiyoshige; Ro, Shoki; Ochiai, Mitsuko; Noguchi, Masamichi; Iizuka, Seiichi; Hattori, Tomohisa; Yakabi, Koji


    This study was conducted to determine the mechanisms by which serotonin (5-hydroxytryptamine, 5-HT) receptors are involved in the suppression of food intake in a rat stress model and to observe the degree of activation in the areas of the brain involved in feeding. In the stress model, male Sprague-Dawley rats (8 weeks old) were given intracerebroventricular injections of urocortin (UCN) 1. To determine the role of the 5-HT2c receptor (5-HT2cR) in the decreased food intake in UCN1-treated rats, specific 5-HT2cR or 5-HT2b receptor (5-HT2bR) antagonists were administered. Food intake was markedly reduced in UCN1-injected rats compared with phosphate buffered saline treated control rats. Intraperitoneal administration of a 5-HT2cR antagonist, but not a 5-HT2bR antagonist, significantly inhibited the decreased food intake. To assess the involvement of neural activation, we tracked the expression of c-fos mRNA as a neuronal activation marker. Expression of the c-fos mRNA in the arcuate nucleus, ventromedial hypothalamic nucleus (VMH) and rostral ventrolateral medulla (RVLM) in UNC1-injected rats showed significantly higher expression than in the PBS-injected rats. Increased c-fos mRNA was also observed in the paraventricular nucleus (PVN), the nucleus of the solitary tract (NTS), and the amygdala (AMG) after injection of UCN1. Increased 5-HT2cR protein expression was also observed in several areas. However, increased coexpression of 5-HT2cR and c-fos was observed in the PVN, VMH, NTS, RVLM and AMG. Whereas, pro-opiomelanocortin mRNA expression was not changed. In an UNC1-induced stress model, 5-HT2cR expression and activation was found in brain areas involved in feeding control.

  13. Involvement of 5-HT(2A/2B/2C) receptors on memory formation: simple agonism, antagonism, or inverse agonism?

    Meneses, Alfredo


    1. The 5-HT2 receptors subdivision into the 5-HT(2A/2B/2C) subtypes along with the advent of the selective antagonists has allowed a more detailed investigation on the role and therapeutic significance of these subtypes in cognitive functions. The present study further analyzed the 5-HT2 receptors role on memory consolidation. 2. The SB-200646 (a selective 5-HT(2B/2C) receptor antagonist) and LY215840 (a nonselective 5-HT(2/7) receptor antagonist) posttraining administration had no effect on an autoshaped memory consolidation. However, both drugs significantly and differentially antagonized the memory impairments induced by 1-(3-chlorophenyl)piperazine (mCPP), 1-naphtyl-piperazine (1-NP), mesulergine, or N-(3-trifluoromethylphenyl) piperazine (TFMPP). 3. In contrast, SB-200646 failed to modify the facilitatory procognitive effect produced by (+/-)-2.5-dimethoxy-4-iodoamphetamine (DOI) or ketanserin, which were sensitive to MDL100907 (a selective 5-HT2A receptor antagonist) and to a LY215840 high dose. 4. Finally, SB-200646 reversed the learning deficit induced by dizocilpine, but not that by scopolamine: while SB-200646 and MDL100907 coadministration reversed memory deficits induced by both drugs. 5. It is suggested that 5-HT(2B/2C) receptors might be involved on memory formation probably mediating a suppressive or constraining action. Whether the drug-induced memory impairments in this study are explained by simple agonism, antagonism, or inverse agonism at 5-HT2 receptors remains unclear at this time. 6. Notably, the 5-HT2 receptor subtypes blockade may provide some benefit to reverse poor memory consolidation conditions associated with decreasedcholinergic, glutamatergic, and/or serotonergic neurotransmission.

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

    Quilter Claire R


    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.

  15. Efectos de antagonistas selectivos y no selectivos a receptores 5-HT2C sobre la estructura de la conducta alimentaria en ratas

    Juan Manuel Mancilla-Díaz; Rodrigo Erick Escartín-Pérez; Verónica Elsa López-Alonso; Melissa Rito-Domingo


    Se ha establecido que los receptores 5-HT2C están involucrados en la ingesta de alimentos. Sin embargo, el rol de antagonistas selectivos y no selectivos a receptores 5-HT2C aún no es claro. En el presente estudio se examinó el efecto de la serotonina (5-HT) sobre los patrones conductuales de alimentación de ratas pretratadas con RS-102221 (antagonista selectivo a receptores 5-HT2C) o ciproheptadina (antagonista a receptores 5-HT2C/2A). Los fármacos fueron administrados dentro del núcleo para...

  16. Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca(2+)-activated chloride channels.

    Salzer, Isabella; Gantumur, Enkhbileg; Yousuf, Arsalan; Boehm, Stefan


    Serotonin (5HT) is a constituent of the so-called "inflammatory soup" that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na(+) channels or Kv7 K(+) channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl(-) currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca(2+)-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.

  17. [Association between serotonin receptor 2C gene Cys23Ser polymorphism and social behavior in schizophrenia patients and healthy individuals].

    Alfimova, M V; Golimbet, V E; Korovaitseva, G I; Abramova, L I; Kaleda, V G


    The purpose of this work was to search for associations between the serotonin receptor 2C gene (HTR2C) and the peculiarities of social behavior and social cognition in schizophrenia. To do this, patients with schizophrenia spectrum disorders and healthy control subjects were genotyped for the Cys23Ser HTR2C marker and underwent psychological examination, including assessment of Machiavellianism, recognition of emotions in facial expression, and theory of mind. In addition, we estimated the trait anxiety level as a potential factor affecting the relationship between the gene HTR2C and social behavior. We found a significant association between the Ser allele and a reduction of estimates on the Mach-LV Machiavellianism scale in the total sample of patients (n = 182) and control subjects (n = 189), which did not reach the confidence level in either of the groups. A tendency towards a HTR2C gene influence on the trait anxiety level was also revealed. The association between HTR2C and Machiavellianism was retained if the anxiety level was taken into account. The results suggest a pleiotropic effect of HTR2Con anxiety and Machiavellianism.

  18. Inhibition of serotonin transporters by cocaine and meprylcaine through 5-TH2C receptor stimulation facilitates their seizure activities.

    Morita, Katsuya; Hamamoto, Masahiro; Arai, Shigeaki; Kitayama, Shigeo; Irifune, Masahiro; Kawahara, Michio; Kihira, Kenji; Dohi, Toshihiro


    The present study examined whether the inhibition of serotonin transporters (SERT) contributes to cocaine- and other local anesthetics-induced convulsions, and which subtypes of 5-HT receptor are involved in the convulsions. For this purpose, cocaine, meprylcaine and lidocaine, all of which have different effects on SERT, were used as convulsants and the effects of serotonin reuptake inhibitors (SSRIs), specific agonists and antagonists for 5-HT receptor subtypes were evaluated in mice. Administration of SSRI, zimelidine, citalopram and fluoxetine, 5-HT(2A,2C) receptor agonist, R(-)-DOI and the 5-HT2C receptor agonists, mCPP, and MK212 resulted in a marked increase in incidence of convulsions and a reduction in the threshold of lidocaine-induced convulsions, while the 5-HT2B receptor agonist, BW723C86, had little influence. On the other hand, SSRI did not affect the measured parameters in meprylcaine- and cocaine-induced convulsions. R(-)-DOI, mCPP, and MK212 reduced the threshold of meprylcaine or cocaine with less extent than the reduction of lidocaine threshold. Incidence of cocaine- and meprylcaine-induced convulsions was significantly reduced by 5-HT(2A,2B,2C) antagonist, LY-53857, and 5-HT2C antagonist, RS 102221. The threshold of cocaine and meprylcaine was significantly increased by both antagonists. 5-HT2A antagonists MDL 11,939 and ketanserin, and 5-HT2B antagonist SB 204741 except at high doses had little effect on cocaine- and meprylcaine-induced convulsions. None of these antagonists altered the parameters of lidocaine-induced convulsions. Pretreatment with fluoxetine but not citalopram increased the plasma concentration of lidocaine. These results suggest that the increase of serotonergic neuronal activity through 5-HT2C receptor stimulation was responsible for increased activity of local anesthetics-induced convulsions and support the involvement of this mechanism in cocaine- and meprylcaine- but not in lidocaine-induced convulsions through their

  19. Genetic and pharmacological evidence that 5-HT2C receptor activation, but not inhibition, affects motivation to feed under a progressive ratio schedule of reinforcement.

    Fletcher, Paul J; Sinyard, Judy; Higgins, Guy A


    Previous work showed that 5-HT(2C) receptor agonists reduce cocaine self-administration on a progressive ratio (PR) schedule of reinforcement, whereas a 5-HT(2C) receptor antagonist enhances responding for cocaine. The present experiments examined the effects of Ro60-0175 (5-HT(2C) agonist) and SB242084 (5-HT(2C) receptor antagonist) in rats on responding for food on a PR schedule; responding was also determined in mice lacking functional 5-HT(2C) receptors. In food-restricted rats, lever pressing reinforced by regular food pellets or sucrose pellets was reduced by Ro60-0175. This effect was blocked by SB242084, and was absent in mice lacking functional 5-HT(2C) receptors. A number of studies examined the effects of SB242084 on responding for food under a variety of conditions. These included manipulation of food type (regular pellets versus sucrose pellets), nutritional status of the animals (food restriction versus no restriction), and rate of progression of the increase in ratio requirements on the PR schedule. In all cases there was no evidence of enhanced responding for food by SB242084. Mice lacking functional 5-HT(2C) receptors did not differ from wildtype mice in responding for food in either food-restricted or non-restricted states. The effects of Ro60-0175 are consistent with its effects on food consumption and motivation to self-administer cocaine. Unlike their effects on cocaine self-administration, pharmacological blockade of 5-HT(2C) receptors, and genetic disruption of 5-HT(2C) receptor function do not alter the motivation to respond for food. Because the 5-HT(2C) receptor exerts a modulatory effect on dopamine function, the differential effects of reduced 5-HT(2C) receptor mediated transmission on responding for food versus cocaine may relate to a differential role of this neurotransmitter in mediating these two behaviours.

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

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


    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 pol

  1. Responsiveness of 5-HT2C receptors in repeatedly diazepam-injected rats: a behavioral and neurochemical study.

    Khan, Asma; Haleem, Darakhshan J


    The role of 5-hydroxytryptamine (serotonin; 5-HT)2C receptors in anxiety and the anxiolytic effects of drugs is well documented. In view of the withdrawal anxiety associated with repeated diazepam intake, the present study concerns the efficacy of 5-HT2C receptors in rats treated with diazepam. Results show that diazepam injections at a dose of 2 mg/kg daily for two weeks increased weekly food intake and growth rate. Anxiolytic effects of the drug monitored in a light/dark activity box were not significant after single administration. One week and two weeks of administration elicited anxiolytic effects, which were smaller after two weeks of administration as compared to one week, suggesting the development of tolerance to the anxiolytic profile of diazepam. Moreover, three days' withdrawal from repeated administration elicited anxiogenic behavior in the light/dark activity box. The behavioral and neurochemical effects of 1-(m-chlorophenyl)piperazine (m-CPP) (3 mg/kg), a 5-HT2C agonist, were monitored following withdrawal (three days) from two weeks of diazepam administration. Results showed that hypophagic as well as anxiogenic-like effects of m-CPP were not different from repeated saline or repeated diazepam-injected animals. Administration of m-CPP increased 5-HT metabolism in repeated saline as well as repeated diazepam-injected animals. However, m-CPP-induced increases in 5-HT metabolism were greater in repeated diazepam-injected animals. Results are discussed in the context of the role of 5-HT2C receptors in the precipitation of withdrawal anxiety.

  2. 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


    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.

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

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


    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 restricted to specific neuron types, including ASER, and is controlled by a combinatorial action of evolutionarily conserved alternative splicing factors, RBFOX, CELF and PTB families of proteins. Mutations of these factors cause a learning defect, and this defect is relieved by DAF-2c (exon 11.5+) isoform expression only in a single neuron ASER. Our results provide evidence that alternative splicing regulation of a single critical gene in a single critical neuron is essential for learning ability in an organism. PMID:27198602

  4. Role of the intracellular domain of the human type I interferon receptor 2 chain (IFNAR2c) in interferon signaling. Expression of IFNAR2c truncation mutants in U5A cells.

    Russell-Harde, D; Wagner, T C; Rani, M R; Vogel, D; Colamonici, O; Ransohoff, R M; Majchrzak, B; Fish, E; Perez, H D; Croze, E


    A human cell line (U5A) lacking the type I interferon (IFN) receptor chain 2 (IFNAR2c) was used to determine the role of the IFNAR2c cytoplasmic domain in regulating IFN-dependent STAT activation, interferon-stimulated gene factor 3 (ISGF3) and c-sis-inducible factor (SIF) complex formation, gene expression, and antiproliferative effects. A panel of U5A cells expressing truncation mutants of IFNAR2c on their cell surface were generated for study. Janus kinase (JAK) activation was detected in all mutant cell lines; however, STAT1 and STAT2 activation was observed only in U5A cells expressing full-length IFNAR2c and IFNAR2c truncated at residue 462 (R2.462). IFNAR2c mutants truncated at residues 417 (R2. 417) and 346 (R2.346) or IFNAR2c mutant lacking tyrosine residues in its cytoplasmic domain (R2.Y-F) render the receptor inactive. A similar pattern was observed for IFN-inducible STAT activation, STAT complex formation, and STAT-DNA binding. Consistent with these data, IFN-inducible gene expression was ablated in U5A, R2.Y-F, R2.417, and R2.346 cell lines. The implications are that tyrosine phosphorylation and the 462-417 region of IFNAR2c are independently obligatory for receptor activation. In addition, the distal 53 amino acids of the intracellular domain of IFNAR2c are not required for IFN-receptor mediated STAT activation, ISFG3 or SIF complex formation, induction of gene expression, and inhibition of thymidine incorporation. These data demonstrate for the first time that both tyrosine phosphorylation and a specific domain of IFNAR2c are required in human cells for IFN-dependent coupling of JAK activation to STAT phosphorylation, gene induction, and antiproliferative effects. In addition, human and murine cells appear to require different regions of the cytoplasmic domain of IFNAR2c for regulation of IFN responses.

  5. A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment.

    Palacios, Jose M; Pazos, Angel; Hoyer, Daniel


    This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5-HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [(3)H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [(3)H]mesulergine-labelling to the rat choroid plexus. [(3)H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5-HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5-HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking

  6. Dopamine-induced hypophagia is mediated by D1 and 5HT-2c receptors in chicken.

    Zendehdel, Morteza; Hasani, Keyvan; Babapour, Vahab; Mortezaei, Sepideh Seyedali; Khoshbakht, Yalda; Hassanpour, Shahin


    The present study was designed to examine the effects of intracerebroventricular (ICV) injection of Dopamine (10, 20 and 40 nmol), L-DOPA (dopamine precursor; 62.5, 125 and 250 nmol), 6-OHDA (dopamine inhibitor; 75, 150 and 300 nmol), SCH 23390 (D1 antagonist; 2.5, 5 and 10 nmol), AMI-193 (D2 antagonist; 2.5, 5 and 10 nmol), NGB2904 (D3 antagonist; 3.2, 6.4 and 12.8 nmol), L-741 T742 (D4 antagonist;1.5, 3 and 6 nmol) on food intake in FD3 chickens. At following, birds were ICV injected using 8-OH-DPAT (5-HT1A agonist; 15.25 nmol) and SB242084 (5-HT2C antagonist;1.5 μg) prior dopamine (40 nmol) injection. Cumulative food intake was determined until 3 h post-injection. According to the results, dopamine significantly decreased food intake in chickens (p dopamine on food intake was decreased by SCH 23390 pretreatment (P dopamine. In addition, hypophagic effect of dopamine was attenuated by SB242084 (P dopamine decrease food intake via D1 receptor and there is an interaction between dopaminergic and serotonergic systems via 5-HT2C receptor in chickens.

  7. Delineation of the complement receptor type 2-C3d complex by site-directed mutagenesis and molecular docking.

    Shaw, Craig D; Storek, Michael J; Young, Kendra A; Kovacs, James M; Thurman, Joshua M; Holers, V Michael; Hannan, Jonathan P


    The interactions between the complement receptor type 2 (CR2) and the C3 complement fragments C3d, C3dg, and iC3b are essential for the initiation of a normal immune response. A crystal-derived structure of the two N-terminal short consensus repeat (SCR1-2) domains of CR2 in complex with C3d has previously been elucidated. However, a number of biochemical and biophysical studies targeting both CR2 and C3d appear to be in conflict with these structural data. Previous mutagenesis and heteronuclear NMR spectroscopy studies directed toward the C3d-binding site on CR2 have indicated that the CR2-C3d cocrystal structure may represent an encounter/intermediate or nonphysiological complex. With regard to the CR2-binding site on C3d, mutagenesis studies by Isenman and coworkers [Isenman, D. E., Leung, E., Mackay, J. D., Bagby, S. & van den Elsen, J. M. H. (2010). Mutational analyses reveal that the staphylococcal immune evasion molecule Sbi and complement receptor 2 (CR2) share overlapping contact residues on C3d: Implications for the controversy regarding the CR2/C3d cocrystal structure. J. Immunol. 184, 1946-1955] have implicated an electronegative "concave" surface on C3d in the binding process. This surface is discrete from the CR2-C3d interface identified in the crystal structure. We generated a total of 18 mutations targeting the two (X-ray crystallographic- and mutagenesis-based) proposed CR2 SCR1-2 binding sites on C3d. Using ELISA analyses, we were able to assess binding of mutant forms of C3d to CR2. Mutations directed toward the concave surface of C3d result in substantially compromised CR2 binding. By contrast, targeting the CR2-C3d interface identified in the cocrystal structure and the surrounding area results in significantly lower levels of disruption in binding. Molecular modeling approaches used to investigate disparities between the biochemical data and the X-ray structure of the CR2-C3d cocrystal result in highest-scoring solutions in which CR2 SCR1-2 is

  8. Chronic escitalopram treatment caused dissociative adaptation in serotonin (5-HT) 2C receptor antagonist-induced effects in REM sleep, wake and theta wave activity.

    Kostyalik, Diána; Kátai, Zita; Vas, Szilvia; Pap, Dorottya; Petschner, Péter; Molnár, Eszter; Gyertyán, István; Kalmár, Lajos; Tóthfalusi, László; Bagdy, Gyorgy


    Several multi-target drugs used in treating psychiatric disorders, such as antidepressants (e.g. agomelatine, trazodone, nefazodone, amitriptyline, mirtazapine, mianserin, fluoxetine) or most atypical antipsychotics, have 5-hydroxytryptamine 2C (5-HT2C) receptor-blocking property. Adaptive changes in 5-HT2C receptor-mediated functions are suggested to contribute to therapeutic effects of selective serotonin reuptake inhibitor (SSRI) antidepressants after weeks of treatment, at least in part. Beyond the mediation of anxiety and other functions, 5-HT2C receptors are involved in sleep regulation. Anxiety-related adaptive changes caused by antidepressants have been studied extensively, although sleep- and electroencephalography (EEG)-related functional studies are still lacking. The aim of this study was to investigate the effects of chronic SSRI treatment on 5-HT2C receptor antagonist-induced functions in different vigilance stages and on quantitative EEG (Q-EEG) spectra. Rats were treated with a single dose of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg, i.p.) or vehicle at the beginning of passive phase following a 20-day-long SSRI (escitalopram; 10 mg/kg/day, osmotic minipump) or VEHICLE pretreatment. Fronto-parietal electroencephalogram, electromyogram and motility were recorded during the first 3 h of passive phase. We found that the chronic escitalopram pretreatment attenuated the SB-242084-caused suppression in rapid eye movement sleep (REMS). On the contrary, the 5-HT2C receptor antagonist-induced elevations in passive wake and theta (5-9 Hz) power density during active wake and REMS were not affected by the SSRI. In conclusion, attenuation in certain, but not all vigilance- and Q-EEG-related functions induced by the 5-HT2C receptor antagonist, suggests dissociation in 5-HT2C receptor adaptation.

  9. Evidence for a role of 5-HT2C receptors in the motor aspects of performance, but not the efficacy of food reinforcers, in a progressive ratio schedule

    Bezzina, G.; Body, S.; Cheung, T.H.; Hampson, C.L.; Bradshaw, C.M.; Glennon, J.C.; Szabadi, E.


    RATIONALE: 5-Hydroxytryptamine2C (5-HT2C) receptor agonists reduce the breakpoint in progressive ratio schedules of reinforcement, an effect that has been attributed to a decrease of the efficacy of positive reinforcers. However, a reduction of the breakpoint may also reflect motor impairment. Mathe

  10. Serotonin increases ERK1/2 phosphorylation in astrocytes by stimulation of 5-HT2B and 5-HT2C receptors.

    Li, Baoman; Zhang, Shiquen; Li, Min; Hertz, Leif; Peng, Liang


    We have previously shown that fluoxetine causes ERK(1/2) phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5-HT(2B) receptors (Li et al., 2008b). This raises the question whether this is also the case for serotonin (5-HT) itself. In the present study serotonin was found to induce ERK(1/2) phosphorylation by stimulation of 5-HT(2B) receptors with high affinity (EC(50): 20-30 pM), and by stimulation of 5-HT(2C) receptor with low affinity (EC(50): 1 microM or higher). ERK(1/2) phosphorylation induced by stimulation of either 5-HT(2B) or 5-HT(2C) receptors was mediated by epidermal growth factor (EGF) receptor transactivation (Peng et al., this issue), shown by the inhibitory effect of AG1478, an inhibitor of the EGF receptor tyrosine kinase, and GM6001, an inhibitor of Zn-dependent metalloproteinases, and thus of 5-HT(2B) receptor-mediated EGF receptor agonist release. It is discussed that the high potency of the 5-HT(2B)-mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5-HT(2B) receptors and with observations of low extracellular concentrations of serotonin in brain, which would allow a demonstrated moderate and modality-dependent increase in specific brain areas to activate 5-HT(2B) receptors. In contrast the relevance of the observed 5-HT(2C) receptors on astrocytes is questioned.

  11. Role of 5-HT1B, 5-HT2A and 5-HT2C receptors in learning.

    Meneses, A; Hong, E


    The effects of post-training (i.p.) injection of TFMPP, mCPP, DOI or 1-NP in the autoshaping learning task was explored. Furthermore, the post-training effects of these agonists after treatment with the antagonists (+/-)-pindolol, (+/-)-propranolol, NAN-190, ketanserin, ritanserin, mesulergine, MDL-72222 or p-chloroamphetamine (5-HT depleter) were studied. Rats were individually trained with a lever-press response (conditioned response; CR) on the autoshaping task and tested 24 h later. The results showed that the injection of TFMPP (1-10 mg/kg), mCPP (1-10 mg/kg), 1-NP (0.1-1.0 mg/kg) or mesulergine (0.4 mg/kg) decreased the rate of CR, while DOI (0.01-0.1 mg/kg) and ritanserin (0.5 mg/kg) and ketanserin (0.001-0.1 mg/kg) increased it. However, the effect induced by TFMPP was reversed by (+/-)-pindolol, ketanserin, ritanserin and PCA; the mCPP-induced effect was antagonized by (+/-)-propranolol, ketanserin, ritanserin and MDL-72222; and the effect produced by 1-NP was reversed by ketanserin, ritanserin and PCA. In addition, the increment in CR provoked by DOI was enhanced by ketanserin, and reversed by ritanserin, mesulergine and PCA. These findings suggest that TFMPP, 1-NP and DOI exerted their effects via stimulation of presynaptic 5-HT receptors. The effects of mCPP most probably reflect activation of postsynaptic receptors. The present data suggest that both 5-HT1B and 5-HT2A-2C receptors play a significant role in the consolidation of learning.

  12. Weight Loss After RYGB Is Independent of and Complementary to Serotonin 2C Receptor Signaling in Male Mice

    Carmody, Jill S.; Ahmad, Nadia N.; Machineni, Sriram; Lajoie, Scott


    Roux-en-Y gastric bypass (RYGB) typically leads to substantial, long-term weight loss (WL) and diabetes remission, although there is a wide variation in response to RYGB among individual patients. Defining the pathways through which RYGB works should aid in the development of less invasive anti-obesity treatments, whereas identifying weight-regulatory pathways unengaged by RYGB could facilitate the development of therapies that complement the beneficial effects of surgery. Activation of serotonin 2C receptors (5-HT2CR) by serotonergic drugs causes WL in humans and animal models. 5-HT2CR are located on neurons that activate the melanocortin-4 receptors, which are essential for WL after RYGB. We therefore sought to determine whether 5-HT2CR signaling is also essential for metabolic effects of RYGB or whether it is a potentially complementary pathway, the activation of which could extend the benefits of RYGB. Diet-induced obese male mice deficient for the 5-HT2CR and their wild-type littermates underwent RYGB or sham operation. Both groups lost similar amounts of weight after RYGB, demonstrating that the improved metabolic phenotype after RYGB is 5-HT2CR independent. Consistent with this hypothesis, wild-type RYGB-treated mice lost additional weight after the administration of the serotonergic drugs fenfluramine and meta-chlorophenylpiperazine but not the nonserotonergic agent topiramate. The fact that RYGB does not depend on 5-HT2CR signaling suggests that there are important WL mechanisms not fully engaged by surgery that could potentially be harnessed for medical treatment. These results suggest a rational basis for designing medical-surgical combination therapies to optimize clinical outcomes by exploiting complementary physiological mechanisms of action. PMID:26066076

  13. Enhanced food anticipatory activity associated with enhanced activation of extrahypothalamic neural pathways in serotonin2C receptor null mutant mice.

    Jennifer L Hsu

    Full Text Available 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 enhanced food anticipatory activity compared to wild-type littermates, without phenotypic differences in the impact of restricted feeding on food consumption, body weight loss, or blood glucose levels. Moreover, we show that the enhanced food anticipatory activity in 5-HT2CR null mutant mice develops independent of external light cues and persists during two days of total food deprivation, indicating that food anticipatory activity in 5-HT2CR null mutant mice reflects the locomotor output of a food-entrainable oscillator. Whereas restricted feeding induces c-fos expression to a similar extent in hypothalamic nuclei of wild-type and null mutant animals, it produces enhanced expression in the nucleus accumbens and other extrahypothalamic regions of null mutant mice relative to wild-type subjects. These data suggest that 5-HT2CRs gate food anticipatory activity through mechanisms involving extrahypothalamic neural pathways.

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

    Paddy KC Janssen


    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.

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

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


    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-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.

  16. Distribution of serotonin 2A and 2C receptor mRNA expression in the cervical ventral horn and phrenic motoneurons following spinal cord hemisection.

    Basura, G J; Zhou, S Y; Walker, P D; Goshgarian, H G


    Cervical spinal cord injury leads to a disruption of bulbospinal innervation from medullary respiratory centers to phrenic motoneurons. Animal models utilizing cervical hemisection result in inhibition of ipsilateral phrenic nerve activity, leading to paralysis of the hemidiaphragm. We have previously demonstrated a role for serotonin (5-HT) as one potential modulator of respiratory recovery following cervical hemisection, a mechanism that likely occurs via 5-HT2A and/or 5-HT2C receptors. The present study was designed to specifically examine if 5-HT2A and/or 5-HT2C receptors are colocalized with phrenic motoneurons in both intact and spinal-hemisected rats. Adult female rats (250-350 g; n = 6 per group) received a left cervical (C2) hemisection and were injected with the fluorescent retrograde neuronal tracer Fluorogold into the left hemidiaphragm. Twenty-four hours later, animals were killed and spinal cords processed for in situ hybridization and immunohistochemistry. Using (35)S-labeled cRNA probes, cervical spinal cords were probed for 5-HT2A and 5-HT2C receptor mRNA expression and double-labeled using an antibody to Fluorogold to detect phrenic motoneurons. Expression of both 5-HT2A and 5-HT2C receptor mRNA was detected in motoneurons of the cervical ventral horn. Despite positive expression of both 5-HT2A and 5-HT2C receptor mRNA-hybridization signal over phrenic motoneurons, only 5-HT2A silver grains achieved a signal-to-noise ratio representative of colocalization. 5-HT2A mRNA levels in identified phrenic motoneurons were not significantly altered following cervical hemisection compared to sham-operated controls. Selective colocalization of 5-HT2A receptor mRNA with phrenic motoneurons may have implications for recently observed 5-HT2A receptor-mediated regulation of respiratory activity and/or recovery in both intact and injury-compromised states.

  17. Expression of hippocampal serotonin receptors 5-HT2C and 5-HT5A in a rat model of diet-induced obesity supplemented with tryptophan.

    Lopez-Esparza, Sarahi; Berumen, Laura C; Padilla, Karla; Miledi, Ricardo; García-Alcocer, Guadalupe


    Food intake regulation is a complex mechanism that involves endogenous substances and central nervous system structures like hypothalamus or even hippocampus. The neurotransmitter serotonin is distinguished as food intake mediator; within its multiples receptors, the 5-HT2C type is characterized by its inhibitory appetite action but there is no information about 5-HT5A receptors involvement in obesity disease. It is also unknown if there are any changes in the receptors expression in rats hippocampus with induced obesity during development through a high energy diet (HED) supplemented with tryptophan (W). To appreciate the receptors expression pattern in the hippocampus, obesity was induced to young Sprague Dawley rats through a HED and supplemented with W. Immunocytochemical and western blot techniques were used to study the receptor distribution and quantify the protein expression. The rats with HED diet developed obesity until week 13 of treatment. The 5-HT2C receptor expression decreased in CA1, CA2, CA3 and DG of HED group; and also in CA2, CA3 and DG for HEDW group. The 5-HT5A receptor expression only decreased in DG for HED group. Variations of the two serotonin receptors subtypes support their potential role in obesity.

  18. The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease

    Kordelas, Lambros; Steckel, Nina-Kristin; Horn, Peter A.; Beelen, Dietrich W.; Rebmann, Vera


    Natural killer (NK) cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT), alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E). Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD). Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention. PMID:27801784

  19. S32006, a novel 5-HT(2C) receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models

    Dekeyne, Anne; la Cour, Clotilde Mannoury; Gobert, Alain; Brocco, Mauricette; Lejeune, Francoise; Serres, Florence; Sharp, Trevor; Daszuta, Annie; Soumier, Amelie; Papp, Mariusz; Rivet, Jean-Michel; Flik, Gunnar; Cremers, Thomas I.; Muller, Olivier; Lavielle, Gilbert; Millan, Mark J.


    Rationale Serotonin (5-HT)(2C) receptors are implicated in the control of mood, and their blockade is of potential interest for the management of anxiodepressive states. Objectives Herein, we characterized the in vitro and in vivo pharmacological profile of the novel benzourea derivative, S32006. Ma

  20. Limited participation of 5-HT1A and 5-HT2A/2C receptors in the clozapine-induced Fos-protein expression in rat forebrain regions

    Sebens, JB; Kuipers, SD; Koch, T; Ter Horst, GJ; Korf, J


    Through the development of tolerance following long-term clozapine treatment, we investigated whether 5-HT1A and 5-HT2A/2C receptors participate in the clozapine-induced Fos-protein expression in the rat forebrain. Tolerance exists when the acutely increased Fos responses to a challenge dose of the

  1. The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease

    Lambros Kordelas


    Full Text Available Natural killer (NK cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT, alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E. Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD. Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention.

  2. The role of RNA editing of the serotonin 2C receptor in a rat model of oro-facial neuropathic pain.

    Nakae, Aya; Nakai, Kunihiro; Tanaka, Tatsuya; Hagihira, Saotoshi; Shibata, Masahiko; Ueda, Koichi; Masimo, Takashi


    We examined whether infraorbital nerve injury affected the RNA editing efficiency of the serotonin (5HT) 2C receptor in the cervical spinal cord, in association with increased pain thresholds, and whether a 5HT reuptake inhibitor (fluvoxamine; Depromel, Meiji Seika, Tokyo, Japan) altered this editing. Accordingly, we injured rats with an infraorbital nerve loose ligation and examined the pain thresholds, mRNA and mRNA editing of the 5HT2C receptor. We evaluated changes in mRNA editing and 5HT2C mRNA expression using cloning along with sequence analysis and quantitative reverse transcription-polymerase chain reaction to compare samples taken at post-injury day 28 from spinal cord sites, including the trigeminal nucleus caudalis, in naive, sham and injured rats (groups of each type had also received fluvoxamine). 5HT2C receptor expression was maintained post-injury. The RNA editing efficiency was statistically significantly lower at molecular sites A and B in ipsilateral spinal cord samples from injured rats than in bilateral samples from naive and sham rats, and in contralateral samples from injured rats. After injury, the proportional presence of two receptor isoforms changed, i.e. statistically significantly less VNV and significantly more INV and ISV. The proportions reverted after fluvoxamine administration. The post-injury change might be evidence of a functional adaptation mechanism that increases the expression of 5HT2C mRNA isoforms that encode receptors that are more sensitive to 5HT. This would activate the brainstem-spinal descending 5HT systems and, in effect, suppress nociceptive signals from primary afferent neurons to the spinal trigeminal nucleus caudalis.

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

    Nonogaki, Katsunori, E-mail: [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)


    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.

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

    Tsukahara, Tamotsu, E-mail: [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)


    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. 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.


    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.

  6. 5-HT2A/5-HT2C receptor pharmacology and intrinsic clearance of N-benzylphenethylamines modified at the primary site of metabolism

    Leth-Petersen, Sebastian; Petersen, Ida Nymann; Jensen, Anders A


    The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability and 5-HT2A/5-HT2C receptor profile of novel analogs of 25B-NBOMe modified at the primary site of metabolism. Although...... microsomal stability could be increased while maintaining potent 5-HT2 receptor agonist properties, all analogs had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism....

  7. 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


    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

  8. 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


    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......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...

  9. m-CPP, a 5-HT2C receptor agonist that modifies the perfusion pressure of the hindquarter vascular bed of anesthetized rat.

    Calama, E; Morán, A; Ortiz de Urbina, A V; Martín, M L; San Román, L


    In the present work we studied the actions of the intra-arterial administration of meta-chlorophenylpiperazine (m-CPP - a 5-HT(2C) receptor agonist) in the hindquarters of the anesthetized rat. The lowest doses used (0.001, 0.01, 0.1, 0.25 and 0.5 microg/kg) induced vasodilatation whereas the highest doses produced vasoconstriction (1, 6.25, 12.5 and 25 microg/kg). Both vasodilatation and vasoconstriction were inhibited by the 5-HT(1,2 )receptor antagonist methiothepin, whereas the 5-HT(2 )receptor antagonist ritanserin blocked only the vasoconstrictor responses. 1-[4-(1-Adamantanecarboxamido)butyl]-4-(2-methoxyphenyl)piperazine (a 5-HT(1A) receptor antagonist) and ICI 118,551 (a beta(2)-receptor antagonist) failed to modify the vasodilator responses of m-CPP. Both BRL 15572 (a 5-HT(1D) receptor antagonist) and GR 55562 (a 5-HT(1B) receptor antagonist) only partially inhibited this action. Our data reveal that m-CPP induces the 5-HT(1 )and/or non-specific vasodilator effect and 5-HT(2) vasoconstrictor effects in the hindquarter vascular bed of the rat.

  10. Meta-chlorophenylpiperazine induced changes in locomotor activity are mediated by 5-HT1 as well as 5-HT2C receptors in mice.

    Gleason, S D; Shannon, H E


    1-(Meta-chloro)phenylpiperazine (m-CPP) is a 5-HT receptor agonist which has been purported to be relatively selective for the 5-HT2C receptor. In particular, the hypolocomotion produced by m-CPP has been suggested to be mediated by 5-HT2C receptors. m-CPP binds with high affinity to 5-HT1 as well as 5-HT2 receptors, thus effects of m-CPP on locomotor activity may be due to the physiologic summation of the actions of m-CPP at 5-HT1 as well as 5-HT2 receptors. The present study investigated the effects of m-CPP alone and in the presence of the 5-HT2 receptor antagonist 6-methyl-1-(-methyethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate (LY53857), the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2pyridinyl)c yclohexanecarboxamide trihydrochloride (WAY 100,635), and the 5-HT(1B/1D) receptor antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-corbox ylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]amide (GR 127935) on locomotor activity. Administration of m-CPP alone (0.3-10 mg/kg) produced a dose-related decrease in locomotor activity. The 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) in combination with m-CPP produced a slight leftward shift of the dose-response curve of m-CPP. The 5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg) in combination with m-CPP did not alter the m-CPP dose-response curve. The non-selective 5-HT2 receptor antagonist LY53857 (1.0 mg/kg) in combination with m-CPP unmasked a hyperlocomotion produced by m-CPP. Furthermore, the hyperlocomotion produced by m-CPP in the presence of LY53857 (1.0 mg/kg) was blocked by both the 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) and the 5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg). The present results demonstrate that the hyperlocomotion seen with the combination of m-CPP and LY53857 is mediated by 5-HT1 receptors. Taken together the data indicate that m-CPP affects locomotor activity by the

  11. 5-Hydroxytryptamine potentiates neurogenic contractions of rat isolated urinary bladder through both 5-HT(7) and 5-HT(2C) receptors.

    Rekik, Moèz; Lluel, Philippe; Palea, Stefano


    Serotonin (5-HT) enhances the neurogenic contractile response induced by electrical field stimulation (EFS) in the rat isolated urinary bladder. The aim of this study was to functionally characterize the receptors involved in this effect by using a range of 5-HT receptor subtype selective agonists and antagonists. 5-HT produced a concentration-dependent potentiation of contractile responses to EFS with a pEC(50) value of 6.86±0.24. SB-269970 (0.01, 0.1 and 1μM), a selective 5-HT(7) receptor antagonist, caused a concentration-dependent rightward shift of the 5-HT-induced response. The pA(2) value was 8.16 with a slope of 0.46±0.08. Neither ketanserine nor SB-204741, 5-HT(2A) and 5-HT(2B) receptors antagonists, respectively, affected the concentration-response curve to 5-HT. However, 5-HT response was antagonized by the selective 5-HT(2C) receptor antagonist SB-242084 (0.1 and 1μM). In the presence of 1μM of both antagonists SB-269970 and SB-242084, 5-HT response was almost fully inhibited. 5-CT, a 5-HT(7) receptor agonist, induced a biphasic concentration-dependent potentiation of neurogenic contractions. SB-269970 concentration-dependently antagonized the first phase of 5-CT response with a pA(2) value of 8.77 and a slope not significantly different from unity (0.91±0.11) that suggests a competitive antagonism. WAY-161503, a 5-HT(2C) receptor agonist (0.01-10μM), induced a concentration-dependent potentiation of contractile response to EFS while DOI (a selective 5-HT(2A) agonist) had no effect. SB-242084 (0.1 and 1μM) antagonized the effect of WAY-161503 in a concentration-dependent manner. The current results demonstrate that 5-HT potentiates neurogenic contractions of rat isolated detrusor muscle through both 5-HT(7) and 5-HT(2c) receptors.

  12. Activation of 5-HT(2C) receptors in the dorsal periaqueductal gray increases antinociception in mice exposed to the elevated plus-maze.

    Baptista, Daniela; Nunes-de-Souza, Ricardo Luiz; Canto-de-Souza, Azair


    Several findings have pointed to the role of the dorsal periaqueductal gray (dPAG) serotonin 5-HT(1A) and 5-HT(2A-C) receptor subtypes in the modulation of defensive behavior in animals exposed to the elevated plus-maze (EPM). Besides displaying anxiety-like behavior, rodents also exhibit antinociception in the EPM. This study investigated the effects of intra-dPAG injections of 5-HT(1A) and 5-HT(2B/2C) receptor ligands on EPM-induced antinociception in mice. Male Swiss mice received 0.1 μl intra-dPAG injections of vehicle, 5.6 and 10 nmol of 8-OHDPAT, a 5-HT(1A) receptor agonist (Experiment 1), or 0.01, 0.03 and 0.1 nmol of mCPP, a 5-HT(2B/2C) receptor agonist (Experiment 2). Five minutes later, each mouse received an intraperitoneal injection of 0.6% acetic acid (0.1 ml/10 g body weight; nociceptive stimulus) and was individually confined in the open (OA) or enclosed (EA) arms of the EPM for 5 min, during which the number of abdominal writhes induced by the acetic acid was recorded. While intra-dPAG injection of 8-OHDPAT did not change open-arm antinociception (OAA), mCPP (0.01 nmol) enhanced it. Combined injections of ketanserin (10 nmol/0.1 μl), a 5-HT(2A/2C) receptor antagonist, and 0.01 nmol of mCPP (Experiment 3), selectively and completely blocked the OAA enhancement induced by mCPP. Although intra-dPAG injection of mCPP (0.01 nmol) also produced antinociception in EA-confined mice (Experiment 2), this effect was not confirmed in Experiment 3. Moreover, no other compound changed the nociceptive response in EA-confined animals. These results suggest that the 5-HT(2C) receptors located within the PAG play a role in this type of environmentally induced pain inhibition in mice.

  13. Serotonin 2A and 2C receptor biosynthesis in the rodent striatum during postnatal development: mRNA expression and functional linkage to neuropeptide gene regulation.

    Basura, G J; Walker, P D


    The present study was designed to determine if there are region-specific differences in serotonin (5-HT) neurotransmission and 5-HT receptor expression that may limit the stimulatory effects of the 5-HT releaser p-chloroamphetamine (pCA) on striatal neuropeptide gene expression to the posterior striatum (P-STR) during postnatal maturation. Sprague-Dawley rat brains from postnatal days (PND) 1-35 were processed for 5-HT(2A) and 5-HT(2C) receptor mRNA expression by in situ hybridization and monoamine analysis by HPLC. Within the P-STR, 5-HT(2A) receptor mRNA expression reached young adult (PND 35) levels by PND 3, while levels in the A-STR were significantly less (range: 1.43 +/- 0.219-6. 36 +/- 0.478) than P-STR (5.36 +/- 0.854-12.11 +/- 1.08) at each respective age throughout the time course. 5-HT(2C) receptor mRNA expression reached young adult levels at PND 7 in the A-STR and by PND 3 in the P-STR. At each PND age 5-HT(2C) receptor mRNA levels within the P-STR were significantly less (6.23 +/- 1.02-12.32 +/- 0.427) than the A-STR (7.31 +/- 1.65-26.84 +/- 2.24). 5-HT content increased across the developmental time course within the P-STR (5.01 +/- 0.327-15.7 +/- 1.03 ng/mg protein) and A-STR (2.97 +/- 0. 223-11.2 +/- 0.701 ng/mg protein). Four hours following injection (i. p.) of pCA (10 mg/kg), preprotachykinin (PPT) mRNA levels increased 89% in the P-STR but not the anterior (A-STR) striatum of the 3-week-old rat, which were prevented by preinjection (30 min, i.p.) of the 5-HT(2) receptor antagonist ritanserin (1 mg/kg). Together, these data suggest that faster maturity of 5-HT(2A) receptor expression in the P-STR may be sufficient to convey the region-specific acute stimulatory effects of pCA on PPT mRNA transcription in the developing rodent striatum. These results provide further evidence that the influence of 5-HT on neuropeptide gene expression is far stronger in caudal vs. rostral striatal regions during postnatal development.

  14. Pregnane X receptors regulate CYP2C8 and P-glycoprotein to impact on the resistance of NSCLC cells to Taxol.

    Chen, Yan; Huang, Wandan; Chen, Feiyu; Hu, Guoping; Li, Fenglei; Li, Jianhua; Xuan, Aiguo


    Cytochrome P450 2C8 (CYP2C8) is one of the enzymes that primarily participate in producing metabolisms of medications and P-glycoprotein (P-gp) has been regarded as one of the important molecules in chemotherapeutically induced multidrug resistance (MDR). In addition, the pregnane X receptor (PXR) is involved in regulating both CYP2C8 and P-gp. We aim to research the effect of PXR on Taxol-resistant non-small-cell lung cancer (NSCLC cells) via regulating CYP2C8 and P-gp. NSCLC cells were treated with SR12813, LY335979, or PXR siRNA. Cell counting kit (CCK-8) assay was used to detect cell vitality. Colony formation assay was used to observe cell proliferation. Western blotting, real-time polymerase chain reaction (RT-PCR), and immunofluorescence staining were conducted to analyze the expressions of PXR, CYP2C8, and P-gp. Taxol and its metabolic products were detected by high-performance liquid chromatography (HPLC). The expression of PXR in A549 cell line was higher than that in other cell lines. The accumulation of PXR was observed in the nucleus after cells were treated with SR12813. Besides, SR12813 induced higher expressions of CYP2C8 and P-gp proteins. We also discovered that pretreatment with SR12813 reversed the inhibition of cell viability and proliferation after the Taxol treatment in comparison to the SR12813 untreated group. Furthermore, the hydroxylation products of Taxol analyzed by HPLC were increased in comparison to the SR12813 untreated group, indicating that high expressions of CYP2C8 and P-gp enhanced the resistance of A549 cells to Taxol. For cells treated with PXR siRNA, cell viability, cell proliferation, and Taxol metabolites were significantly reduced after the Taxol treatment in comparison to the siRNA-negative group. The cell viability, cell proliferation, and Taxol metabolites were regulated by the expressions of PXR, P-gp, and CYP2C8. That is, PXR expression has an important effect on the resistance of NSCLC cells to Taxol via

  15. 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


    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.

  16. Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow.

    Devroye, Céline; Cathala, Adeline; Maitre, Marlène; Piazza, Pier Vincenzo; Abrous, Djoher Nora; Revest, Jean-Michel; Spampinato, Umberto


    The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.

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

    Sofia I I Kring

    Full Text Available 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 genes with obesity and metabolic traits. METHODOLOGY/PRINCIPAL FINDINGS: In a population of 166 200 young men examined at the draft boards, obese men (n = 726, BMI> or =31.0 kg/m(2 and a randomly selected group (n = 831 were re-examined at two surveys at mean ages 46 and 49 years (S-46, S-49. Anthropometric, physiological and biochemical measures were available. Logistic regression analyses were used to assess age-adjusted odds ratios. No significant associations were observed of 5HT2A rs6311, 5HT2C rs3813929 and COMT rs4680 with obesity, except that COMT rs4680 GG-genotype was associated with fat-BMI (OR = 1.08, CI = 1.01-1.16. The SNPs were associated with a number of physiological variables; most importantly 5HT2C rs3813929 T-allele was associated with glucose (OR = 4.56, CI = 1.13-18.4 and acute insulin response (OR = 0.65, CI = 0.44-0.94 in S-49. COMT rs4680 GG-genotype was associated with glucose (OR = 1.04, CI = 1.00-1.09. Except for an association between 5HT2A rs6311 and total-cholesterol at both surveys, significant in S-46 (OR = 2.66, CI = 1.11-6.40, no significant associations were observed for the other phenotypes. Significant associations were obtained when combined genotype of 5HT2C rs3813929 and COMT rs4680 were examined in relation to BMI (OR = 1.12, CI = 1.03-1.21, fat-BMI (OR = 1.22, CI = 1.08-1.38, waist (OR = 1.13, CI = 1.04-1.22, and cholesterol (OR = 5.60, CI = 0.99-31.4. Analyses of impaired glucose tolerance (IGT and type 2 diabetes (T2D revealed, a 12.3% increased frequency of 5HT2C rs3813929 T-allele and an 11.6% increased frequency of COMT rs4680 GG-genotype in individuals with IGT or T2D (chi(2, p = 0.05 and p = 0

  18. Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons

    Roepke, T. A.; Smith, A W; Rønnekleiv, O. K.; Kelly, M. J.


    Hypothalamic proopiomelanocortin (POMC) neurons are controlled by many central signals, including serotonin. Serotonin increases POMC activity and reduces feeding behavior via serotonion [5-hydroxytryptamine (5-HT)] receptors by modulating K+ currents. A potential K+ current is the M-current, a noninactivating, subthreshold outward K+ current. Previously, we found that M-current activity was highly reduced in fasted vs. fed states in neuropeptide Y neurons. Because POMC neurons also respond t...

  19. Prelimbic cortex 5-HT1A and 5-HT2C receptors are involved in the hypophagic effects caused by fluoxetine in fasted rats.

    Stanquini, Laura A; Resstel, Leonardo B M; Corrêa, Fernando M A; Joca, Sâmia R L; Scopinho, América A


    The regulation of food intake involves a complex interplay between the central nervous system and the activity of organs involved in energy homeostasis. Besides the hypothalamus, recognized as the center of this regulation, other structures are involved, especially limbic regions such as the ventral medial prefrontal cortex (vMPFC). Monoamines, such as serotonin (5-HT), play an important role in appetite regulation. However, the effect in the vMPFC of the selective serotonin reuptake inhibitor (SSRI), fluoxetine, on food intake has not been studied. The aim of the present study was to study the effects on food intake of fed and fasted rats evoked by fluoxetine injection into the prelimbic cortex (PL), a sub-region of the vMPFC, or given systemically, and which 5-HT receptors in the PL are involved in fluoxetine responses. Fluoxetine was injected into the PL or given systemically in male Wistar rats. Independent groups of rats were pretreated with intra-PL antagonists of 5-HT receptors: 5-HT1A (WAY100635), 5-HT2C (SB242084) or 5-HT1B (SB216641). Fluoxetine (0.1; 1; 3; 10nmol/200nL) injected into the PL induced a dose-dependent hypophagic effect in fasted rats. This effect was reversed by prior local treatment with WAY100635 (1; 10nmol) or SB242084 (1; 10nmol), but not with SB216641 (0.2; 2.5; 10nmol). Systemic fluoxetine induced a hypophagic effect, which was blocked by intra-PL 5-HT2C antagonist (10nmol) administration. Our findings suggest that PL 5-HT neurotransmission modulates the central control of food intake and 5-HT1A and 5-HT2C receptors in the PL could be potential targets for the action of fluoxetine.

  20. The inhibitory effect of combination treatment with leptin and cannabinoid CB1 receptor agonist on food intake and body weight gain is mediated by serotonin 1B and 2C receptors.

    Wierucka-Rybak, M; Wolak, M; Juszczak, M; Drobnik, J; Bojanowska, E


    Previous studies reported that the co-injection of leptin and cannabinoid CB1 receptor antagonists reduces food intake and body weight in rats, and this effect is more profound than that induced by these compounds individually. Additionally, serotonin mediates the effects of numerous anorectic drugs. To investigate whether serotonin interacts with leptin and endocannabinoids to affect food intake and body weight, we administered 5-hydroxytryptamine(HT)1B and 5-hydroxytryptamine(HT)2C serotonin receptor antagonists (3 mg/kg GR 127935 and 0.5 mg/kg SB 242084, respectively) to male Wistar rats treated simultaneously with leptin (100 μg/kg) and the CB1 receptor inverse agonist AM 251 (1 mg/kg) for 3 days. In accordance with previous findings, the co-injection of leptin and AM 251, but not the individual injection of each drug, resulted in a significant decrease in food intake and body weight gain. Blockade of the 5-HT1B and 5-HT2C receptors completely abolished the leptin- and AM 251-induced anorectic and body-weight-reducing effects. These results suggest that serotonin mediates the leptin- and AM 251-dependent regulation of feeding behavior in rats via the 5-HT1B and 5-HT2C receptors.

  1. Evidence for a role of the 5-HT2C receptor in central lipopolysaccharide-, interleukin-1 beta-, and leptin-induced anorexia.

    von Meyenburg, Claudia; Langhans, Wolfgang; Hrupka, Brian J


    We examined the role of serotonin (5-HT) and the 5-HT(1A) and 5-HT(2C) receptors in the anorectic effects of centrally administered lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), and leptin. Food intake was measured in rats after intracerebroventricular (ICV) injections of LPS (20 ng), IL-1 beta (10 ng), or leptin (1 microg) at lights out, followed by intraperitoneal (IP) injections of either the 5-HT(1A) autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) (125 microg/kg) or the 5-HT(2C) receptor antagonist SB 242084 (0.3 mg/kg) at the onset of anorexia. SB 242084 significantly attenuated the food intake reduction caused by all compounds (all Panorexia (Panorexia. Rats were injected intraperitoneally with either LPS (100 microg/kg) or IL-1 beta (2 microg/kg) at lights out, and 8-OH-DPAT (4 nmol) was administered directly into the median raphe nucleus at the onset of anorexia. Median raphe injections of 8-OH-DPAT significantly attenuated both IL-1 beta- and LPS-induced anorexia (both Panorexia. Our results also suggest that the midbrain raphe nuclei play a role in mediating the anorectic response to peripheral LPS and IL-1 beta.

  2. Transcriptional Regulation of CYP3A4/2B6/2C9 Mediated via Nuclear Receptor PXR by Helicid and Its Metabolites

    Qun Chen


    Full Text Available Objective. This study aims at establishing and validating an in vitro system to screen drug inducers of CYPs mediated via hPXR, as well as studying transcriptional regulation of CYPs mediated via hPXR by helicid and its two metabolites. Methods. Cloning the nuclear receptor hPXR and the promoters of CYP3A4, CYP2B6, CYP2C9, and inserting the trans-element to the upstream of firefly luciferase reporter gene of the pGL4.17 vectors, then cotransfecting the report vectors and hPXR expression plasmid to HepG2 cell line. After 24 hours, the transfected cells were treated with helicid (0.004, 0.04, and 0.4 μmol/L and its metabolite I and metabolite II (0.0004, 0.004, and 0.04 μmol/L for 48 h, while rifampin (10 μmol/L was included as the positive control and 0.1% DMSO as the negative control group. Cells were lysized and luciferase activity was determined using a dual luciferase reporter assay kit. Results. Helicid and its metabolites did not significantly increase promoter activities of CYP3A4, CYP2B6, and CYP2C9 in HepG2 cells transfected with PXR expression plasmid (P>0.05. Conclusion. PXR-expressed CYP3A4, CYP2B6, and CYP2C9 dual luciferase reporter gene platforms were successfully established, and helicid and its metabolites I, II do not significantly induce the transcription of CYP3A4, CYP2B6, and CYP2C9.

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

    V. Baptista


    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.

  4. 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.


    ABSTRACT 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. PMID:26769798

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

    Malgorzata S. Martin-Gronert


    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.

  6. The role of dopamine D-3, 5-HT2(A) and 5-HT2(C) receptor variants as pharmacogenetic determinants in tardive dyskinesia in African-Caribbean patients under chronic antipsychotic treatment Curacao extrapyramidal syndromes study IX

    Wilffert, B.; Al Hadithy, A. F. Y.; Sing, V. J.; Matroos, G.; Hoek, H. W.; van Os, J.; Bruggeman, R.; Brouwers, J. R. B. J.; van Harten, P. N.


    Tardive dyskinesia (TD) is associated with polymorphisms of the dopamine D-3, serotonin 2A and 2C receptors (DRD3, HTR2A and HTR2C, respectively). This study investigated the possible relationship between TD and the polymorphisms Ser9Gly (DRD3), 102T>C (HTR2A), -1438G>A(HTR2A) and Cys23Ser (HTR2C) i

  7. The role of dopamine D3, 5-HT2A and 5-HT2C receptor variants as pharmacogenetic determinants in tardive dyskinesia in African-Caribbean patients under chronic antipsychotic treatment

    Wilffert, B.; Al Hadithy, A.F.; Sing, V.J.; Matroos, G.; Hoek, H.W.; van Os, J.; Bruggeman, R.; Brouwers, J.R.; van Harten, P.N.


    Abstract Tardive dyskinesia (TD) is associated with polymorphisms of the dopamine D3, serotonin 2A and 2C receptors (DRD3, HTR2A and HTR2C, respectively). This study investigated the possible relationship between TD and the polymorphisms Ser9Gly (DRD3), 102T>C (HTR2A), -1438G>A(HTR2A) and Cys23Ser (

  8. 5-HT7 receptor signaling: improved therapeutic strategy in gut disorders

    Janice J Kim


    Full Text Available Serotonin (5-hydroxytrytamine; 5-HT is most commonly known for its role as a neurotransmitter in the central nervous system. However, the majority of the body’s 5-HT is produced in the gut by enterochromaffin (EC cells. Alterations in 5-HT signaling have been associated with various gut disorders including inflammatory bowel disease (IBD, irritable bowel syndrome (IBS and enteric infections. Recently, our studies have identified a key role for 5-HT in the pathogenesis of experimental colitis. 5-HT7 receptors are expressed in the gut and very recently, we have shown evidence of 5-HT7 receptor expression on intestinal immune cells and demonstrated a key role for 5-HT7 receptors in generation of experimental colitis. This review summarizes the key findings of these studies and provides a comprehensive overview of our current knowledge of the 5-HT7 receptor in terms of its pathophysiological relevance and therapeutic potential in intestinal inflammatory conditions, such as IBD.

  9. Effects of a Cannabinoid1 receptor antagonist and Serotonin2C receptor agonist alone and in combination on motivation for palatable food: a dose-addition analysis study in mice.

    Ward, Sara Jane; Lefever, Timothy W; Jackson, Cavario; Tallarida, Ronald J; Walker, Ellen A


    The cannabinoid and serotonin systems modulate feeding behavior in humans and laboratory animals. The present study assessed whether a cannabinoid (CB)(1) receptor antagonist and a serotonin (5-HT)(2C) receptor agonist alone and in combination attenuate motivation for the liquid nutritional drink Ensure as measured by a progressive ratio (PR) schedule of reinforcement in male C57BL/6 mice. Pretreatment (15 min i.p.) with either the CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) (SR; Rimonabant or Acomplia) or the 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP) dose-dependently decreased the maximum ratio completed under the PR schedule (break point) in mice. ED(25) values for SR and mCPP to decrease break point were determined, and the relative potency of each drug alone was quantified. Fixed dose-ratio pairs of SR/mCPP based on their relative potency were then administered. Dose-addition analysis comparing the experimentally determined potency for SR/mCPP combinations with their predicted additive potency revealed that SR/mCPP combinations in 1:1 and 2:1 ratios based on relative potency produced significant synergistic attenuation of break point for Ensure. The ED(25) values for decreasing break point were consistently lower than ED(25) values for decreasing response rate, and synergistic effects of SR/mCPP combinations on break point were seen independent of synergistic effects on response rate. These results indicate that cannabinoid CB(1) and serotonin 5-HT(2C) receptors are involved in motivated feeding behavior in mice and that these compounds can synergistically modulate motivation for palatable food with the synergy dependent upon the ratio of SR/mCPP in the combination.

  10. EPO-receptor is present in mouse C2C12 and human primary skeletal muscle cells but EPO does not influence myogenesis.

    Lamon, Séverine; Zacharewicz, Evelyn; Stephens, Andrew N; Russell, Aaron P


    Abstract The role and regulation of the pleiotropic cytokine erythropoietin (EPO) in skeletal muscle are controversial. EPO exerts its effects by binding its specific receptor (EPO-R), which activates intracellular signaling and gene transcription in response to internal and external stress signals. EPO is suggested to play a direct role in myogenesis via the EPO-R, but several studies have questioned the effect of EPO treatment in muscle in vitro and in vivo. The lack of certainty surrounding the use of nonspecific EPO-R antibodies contributes to the ambiguity of the field. Our study demonstrates that the EPO-R gene and protein are expressed at each stage of mouse C2C12 and human skeletal muscle cell proliferation and differentiation and validates a specific antibody for the detection of the EPO-R protein. However, in our experimental conditions, EPO treatment had no effect on mouse C2C12 and human muscle cell proliferation, differentiation, protein synthesis or EPO-R expression. While an increase in Akt and MAPK phosphorylation was observed, we demonstrate that this effect resulted from the stress caused by changing medium and not from EPO treatment. We therefore suggest that skeletal muscle EPO-R might be present in a nonfunctional form, or too lowly expressed to play a role in muscle cell function.

  11. 5-HT_(2c)受体基因Cys23Ser多态性与偏头痛关系的临床研究%SEROTONIN 2C RECEPTOR GENE Cys23Ser POLYMORPHISM AND MIGRAINE

    刘艳; 于生元



  12. 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.

  13. Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways

    Racagni Giorgio


    Full Text Available Abstract Background Agomelatine is a melatonergic receptor agonist and a 5HT2C receptor antagonist that has shown antidepressant efficacy. In order to analyze separately the effect of the two receptorial components, rats were chronically treated with agomelatine, melatonin (endogenous melatonergic agonist, or S32006 (5-HT2C antagonist, and then subjected to acute footshock-stress. Results Only chronic agomelatine, but not melatonin or S32006, completely prevented the stress-induced increase of glutamate release in the rat prefrontal/frontal cortex. Conclusions These results suggest a potential synergy between melatonergic and serotonergic pathways in the action of agomelatine.

  14. 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


    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 serotonin.......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...

  15. Food intake inhibition in rainbow trout induced by activation of serotonin 5-HT2C receptors is associated with increases in POMC, CART and CRF mRNA abundance in hypothalamus.

    Pérez-Maceira, Jorge J; Otero-Rodiño, Cristina; Mancebo, María J; Soengas, José L; Aldegunde, Manuel


    In rainbow trout, the food intake inhibition induced by serotonin occurs through 5-HT2C and 5-HT1A receptors, though the mechanisms involved are still unknown. Therefore, we assessed if a direct stimulation of 5-HT2C and 5-HT1A serotonin receptors (resulting in decreased food intake in rainbow trout), affects gene expression of neuropeptides involved in the control of food intake, such as pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), corticotrophin releasing factor (CRF), and agouti-related peptide (AgRP). In a first set of experiments, the injection of the 5-HT2C receptor agonists MK212 (60 μg kg(-1) icv) and WAY 161503 (1 mg kg(-1) ip), and of the 5-HT1A receptor agonist 8-OH-DPAT (1 mg kg(-1) ip and 30 μg kg(-1) icv) induced food intake inhibition. In a second set of experiments, we observed that the injection of MK212 or WAY 161503 (1 and 3 mg kg(-1)) significantly increased hypothalamic POMC mRNA abundance. CART mRNA abundance in hypothalamus was enhanced by treatment with MK212 and unaffected by WAY 161503. The administration of the 5-HT1A receptor agonist 8-OH-DPAT did not induce any significant variation in the hypothalamic POMC or CART mRNA levels. CRF mRNA abundance was only affected by MK212 that increased hypothalamic values. Finally, hypothalamic AgRP mRNA abundance was only evaluated with the agonist 5-HT2C MK212 resulting in no significant effects. The results show that the reduction in food intake mediated by 5-HT2C receptors is associated with increases in hypothalamic POMC, CART and CRF mRNA abundance.

  16. Pannexin Channels Mediate the Acquisition of Myogenic Commitment in C2C12 Reserve Cells Promoted by P2 Receptor Activation

    Manuel Antonio Riquelme


    Full Text Available The acquisition of myoblast commitment to the myogenic linage requires rises in intracellular free Ca2+ concentration ([Ca2+]i. Putative cell membrane pathways involved in these [Ca2+]i increments are P2 receptors (P2Rs as well as connexin (Cx and/or pannexin (Panx hemichannels and channels (Cx HChs and Panx Chs, respectively, which are known to permeate Ca2+. Reserve cells (RCs are uncommitted myoblasts obtained from differentiated C2C12 cell cultures, which acquire commitment upon replating. Regarding these cells, we found that extracellular ATP increases the [Ca2+]i via P2Rs. Moreover, ATP increases the plasma membrane permeability to small molecules and a non-selective membrane current, both of which were inhibited by Cx HCh/Panx1Ch blockers. However, RCs exposed to divalent cation-free saline solution, which is known to activate Cx HChs (but not Panx Chs, did not enhance membrane permeability, thus ruling out the possible involvement of Cx HChs. Moreover, ATP-induced membrane permeability was inhibited with blockers of P2Rs that activate Panx Chs. In addition, exogenous ATP induced the expression of myogenic commitment and increased MyoD levels, which was prevented by the inhibition of P2Rs or knockdown of Panx1 Chs. Similarly, increases in MyoD levels induced by ATP released by RCs were inhibited by Panx Ch/Cx HCh blockers. Myogenic commitment acquisition thus requires a feed-forward mechanism mediated by extracellular ATP, P2Rs and Panx Chs.

  17. Activation of serotonin 5-HT2C 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.


    Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and social 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-HT2C receptor (5-HT2CR) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT2CR agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT2CR 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-HT2CR 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-HT2CR antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT2CR protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT2CR can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT2CR may represent a new avenue for the treatment of opioid addiction. PMID:26432939

  18. Serotonin-2C receptors in the basolateral nucleus of the amygdala mediate the anxiogenic effect of acute imipramine and fluoxetine administration.

    Vicente, Maria Adrielle; Zangrossi, Helio


    A growing body of evidence indicates that facilitation of serotonin-2C receptor (5-HT2CR)-mediated neurotransmission in the basolateral nucleus of the amygdala (BLA) is involved in anxiety generation. We investigated here whether BLA 5-HT2CRs exert a differential role in the regulation of defensive behaviours related to generalized anxiety (inhibitory avoidance) and panic (escape) disorders. We also evaluated whether activation of BLA 5-HT2CRs accounts for the anxiogenic effect caused by acute systemic administration of the antidepressants imipramine and fluoxetine. Male Wistar rats were tested in the elevated T-maze after intra-BLA injection of the endogenous agonist 5-HT, the 5-HT2CR agonist MK-212 or the 5-HT2CR antagonist SB-242084. This test allows the measurement of inhibitory avoidance acquisition and escape expression. We also investigated whether intra-BLA administration of SB-242084 interferes with the acute anxiogenic effect caused by imipramine and fluoxetine in the Vogel conflict test, and imipramine in the elevated T-maze. While intra-BLA administration of 5-HT and MK-212 facilitated inhibitory avoidance acquisition, suggesting an anxiogenic effect, SB-242084 had the opposite effect. None of these drugs affected escape performance. Intra-BLA injection of a sub-effective dose of SB-242084 fully blocked the anxiogenic effect caused either by the local microinjection of 5-HT or the systemic administration of imipramine and fluoxetine. Our findings indicate that 5-HT2CRs in BLA are selectively involved in the regulation of defensive behaviours associated with generalized anxiety, but not panic. The results also provide the first direct evidence that activation of BLA 5-HT2CRs accounts for the short-term aversive effect of antidepressants.

  19. The contribution of serotonin 5-HT2C and melanocortin-4 receptors to the satiety signaling of glucagon-like peptide 1 and liraglutide, a glucagon-like peptide 1 receptor agonist, in mice.

    Nonogaki, Katsunori; Suzuki, Marina; Sanuki, Marin; Wakameda, Mamoru; Tamari, Tomohiro


    Glucagon-like peptide 1 (GLP-1), an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L-cells, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, induce satiety. The serotonin 5-HT2C receptor (5-HT2CR) and melanoroctin-4 receptor (MC4R) are involved in the regulation of food intake. Here we show that systemic administration of GLP-1 (50 and 200μg/kg)-induced anorexia was blunted in mice with a 5HT2CR null mutation, and was attenuated in mice with a heterozygous MC4R mutation. On the other hand, systemic administration of liraglutide (50 and 100μg/kg) suppressed food intake in mice lacking 5-HT2CR, mice with a heterozygous mutation of MC4R and wild-type mice matched for age. Moreover, once-daily consecutive intraperitoneal administration of liraglutide (100μg/kg) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of MC4R as well as wild-type mice. These findings suggest that GLP-1 and liraglutide induce anorexia via different central pathways.

  20. 5-HT2C receptors in the basolateral amygdala and dorsal striatum are a novel target for the anxiolytic and antidepressant effects of exercise.

    Benjamin N Greenwood

    Full Text Available Physical activity reduces the incidence and severity of psychiatric disorders such as anxiety and depression. Similarly, voluntary wheel running produces anxiolytic- and antidepressant-like effects in rodent models. The specific neurobiological mechanisms underlying the beneficial properties of exercise, however, remain unclear. One relevant pharmacological target in the treatment of psychiatric disorders is the 5-HT(2C receptor (5-HT(2CR. Consistent with data demonstrating the anxiogenic consequences of 5-HT(2CR activation in humans and rodents, we have previously reported that site-specific administration of the selective 5-HT(2CR agonist CP-809101 in the lateral/basolateral amygdala (BLA increases shock-elicited fear while administration of CP-809101 in the dorsal striatum (DS interferes with shuttle box escape learning. These findings suggest that activation of 5-HT(2CR in discrete brain regions contributes to specific anxiety- and depression-like behaviors and may indicate potential brain sites involved in the anxiolytic and antidepressant effects of exercise. The current studies tested the hypothesis that voluntary wheel running reduces the behavioral consequences of 5-HT(2CR activation in the BLA and DS, specifically enhanced shock-elicited fear and interference with shuttle box escape learning. After 6 weeks of voluntary wheel running or sedentary conditions, the selective 5-HT(2CR agonist CP-809101 was microinjected into either the BLA or the DS of adult Fischer 344 rats, and shock-elicited fear and shuttle box escape learning was assessed. Additionally, in-situ hybridization was used to determine if 6 weeks of voluntary exercise changed levels of 5-HT(2CR mRNA. We found that voluntary wheel running reduced the behavioral effects of CP-809101 and reduced levels of 5-HT(2CR mRNA in both the BLA and the DS. The current data indicate that expression of 5-HT(2CR mRNA in discrete brain sites is sensitive to physical activity status of the

  1. Expression of mRNAs encoding for 5-HT2C,5-HT3,5-HT6 and 5-HT7 receptor subtypes in rat spinal cord%大鼠脊髓内5-HT2C,5-HT3,5-HT6和5-HT7受体亚型mRNAs的表达

    武胜昔; 王亚云; 刘翔宇; 王文; 李云庆


    Objective:To examine the expression of mRNAs encoding for serotonin (5-HT) 5-HT2c, 5-HT3, 5-HT6and 5-HT7 receptor subtypes within different segments of the rat spinal cord. Methods: Reverse transcriptase-polymerasechain reaction (RT-PCR) technique was used. Results: Strong expression of 5-HT2C receptor mRNA was observed inboth dorsal horn (DH) and ventral horn (VH) of the cervical, thoracic, lumbar and sacral segments of the spinal cord.The 5-HT3 receptor mRNA was present at high expression level in the DH and at slightly lower expression level in the Vhof all spinal cord segments. In contrast, the VH generally contained higher expression level of 5-HT6 receptor subtype mR-NA when compared to the DH. Similar to 5-HT3 receptor, the 5-HT7 receptor mRNA was also found at high expressionlevel in the DH. The differences in the expression level among these 5-HT receptor subtypes at the same level of the spinalcord or the same receptor subtype in different segments of the spinal cord were also observed. Conclusion: Four serotoninreceptor subtypes show a distinct expression pattern in the spinal cord. The present results indicate that these 5-HT recep-tor subtypes might have different physiological roles at the spinal level and provide further evidence for 5-HT receptor un-derlying the mechanism of nociception and movement.%目的:观察5-HT2C,5-HT3,5-HT6和5-HT7受体亚型mRNAs在大鼠脊髓不同节段的表达.方法:反转录PCR方法.结果:5-HT2C受体亚型mRNA在颈、胸、腰、骶段脊髓的背角(DH)和前角(VH)均有较强的表达;5-HT3受体mRNA在各节段脊髓DH的表达水平较高,而在VH则较低;与5-HT3受体亚型相反,5-HT6受体亚型mR-NA在脊髓VH的表达水平高于DH;5-HT7受体mRNA在脊髓的表达则与5-HT3受体相似,在各节段的DH均有较高水平的表达.不同的受体亚型在脊髓同一节段以及同一受体亚型在不同脊髓节段的表达水平存在差异.结论:本研究结果表明,上述四种5-HT受体亚

  2. The role of dopamine D3, 5-HT2A and 5-HT2C receptor variants as pharmacogenetic determinants in tardive dyskinesia in African-Caribbean patients under chronic antipsychotic treatment: Curacao extrapyramidal syndromes study IX.

    Wilffert, B; Al Hadithy, A F Y; Sing, V J; Matroos, G; Hoek, H W; van Os, J; Bruggeman, R; Brouwers, J R B J; van Harten, P N


    Tardive dyskinesia (TD) is associated with polymorphisms of the dopamine D(3), serotonin 2A and 2C receptors (DRD3, HTR2A and HTR2C, respectively). This study investigated the possible relationship between TD and the polymorphisms Ser9Gly (DRD3), 102T>C (HTR2A), -1438G>A(HTR2A) and Cys23Ser (HTR2C) in African-Caribbean inpatients. One hundred and twenty-six patients under chronic antipsychotic treatment were genotyped. The assessment of TD was carried out with the abnormal involuntary movement scale (AIMS). The relationships between the carriership of the least frequent alleles and the respective orofaciolingual dyskinesia (TDof) (sum of the items 1-4 of the AIMS), limb-truncal dyskinesia (TDlt) (sum of items 5-7 of the AIMS) and TD (sum of items 1-7 of the AIMS) were analyzed with ANCOVA, comparing means with age as a covariate and stratification for carriers and non-carriers of the mutations. In addition, we conducted pre-planned t-tests to compare AIMS values of carriers of the combinations of alleles versus the corresponding non-carriers. In the study population, females with 9Ser carriership exhibited higher AIMS values than non-carriers. Male subjects with 9Ser carriership in combination with 23Ser or -1438A carriership exhibited higher AIMS values. In male patients also, the combination of 23Ser and -1438A carriership increased TD. The study clearly shows that the African-Caribbean population differs from the Caucasian population with regard to the association of TD with the polymorphisms studied and suggests that the association of TD with the studied polymorphisms of the 5-HT(2C) and probably of the 5-HT(2A) receptor are the result of a changed susceptibility of the patients, independent of the action of the antipsychotics on these receptors.

  3. Involvement of ERK1/2, cPLA2 and NF-κB in microglia suppression by cannabinoid receptor agonists and antagonists.

    Ribeiro, Rachel; Wen, Jie; Li, Shihe; Zhang, Yumin


    Cannabinoids have been consistently shown to suppress microglia activation and the release of cytotoxic factors including nitric oxide, superoxide and proinflammatory cytokines. However, the underlying molecular mechanisms and whether the action of cannabinoids is coupled to the activation of cannabinoid type 1 (CB1) and type 2 (CB2) receptors are still poorly defined. In this study we observed that the CB1 and CB2 receptor non-selective or selective agonists dramatically attenuate iNOS induction and ROS generation in LPS-activated microglia. These effects are due to their reduction of phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), cytosolic phospholipase A (cPLA) and activation of NF-κB. Surprisingly, instead of reversing the effect of the respective CB1 and CB2 receptor agonists, the antagonists also suppress iNOS induction and ROS generation in activated microglia by similar mechanisms. Taken together, these results indicate that both cannabinoid receptor agonists and antagonists might suppress microglia activation by CB1 and CB2 receptor independent mechanisms, and provide a new insight into the mechanisms of microglia inhibition by cannabinoids.

  4. Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory.

    Meneses, Alfredo


    In order to determine whether short- (STM) and long-term memory (LTM) function in serial or parallel manner, serotonin (5-hydroxtryptamine, 5-HT) receptor agonists were tested in autoshaping task. Results show that control-vehicle animals were modestly but significantly mastering the autoshaping task as illustrated by memory scores between STM and LTM. Thus, post-training administration of 8-OHDPAT (agonist for 5-HT(1A/7) receptors) only at 0.250 and 0.500 mg/kg impaired both STM and LTM. CGS12066 (agonist for 5-HT(1B)) produced biphasic affects, at 5.0 mg/kg impaired STM but at 1.0 and 10.0 mg/kg, respectively, improved or impaired LTM. DOI (agonist for 5-HT(2A/2C) receptors) dose-dependently impaired STM and, at 10.0 mg/kg only impaired LTM. Both, STM and LTM were impaired by either mCPP (mainly agonist for 5-HT(2C) receptors) or mesulergine (mainly antagonist for 5-HT(2C) receptors) lower dose. The 5-HT(3) agonist mCPBG at 1.0 impaired STM and its higher dose impaired both STM and LTM. RS67333 (partial agonist for 5-HT(4) receptors), at 5.0 and 10.0 mg/kg facilitated both STM and LTM. The higher dose of fluoxetine (a 5-HT uptake inhibitor) improved both STM and LTM. Using as head-pokes during CS as an indirect measure of food-intake showed that of 30 memory changes, 21 of these were unrelated to the former. While some STM or LTM impairments can be attributed to decrements in food-intake, but not memory changes (either increase or decreases) produced by 8-OHDPAT, CGS12066, RS67333 or fluoxetine. Except for animals treated with DOI, mCPBG or fluoxetine, other groups treated with 5-HT agonists 6 h following autoshaping training showed similar LTM and unmodified CS-head-pokes scores.

  5. Strain-dependent effects of diazepam and the 5-HT2B/2C receptor antagonist SB 206553 in spontaneously hypertensive and Lewis rats tested in the elevated plus-maze

    Takahashi R.N.


    Full Text Available The 5-HT2B/2C receptor antagonist SB 206553 exerts anxiolytic effects in rat models of anxiety. However, these effects have been reported for standard rat strains, thus raising the issue of SB 206553 effects in rat strains displaying different levels of anxiety. Herein, the effects of SB 206553 in a 5-min elevated plus-maze test of anxiety were compared to those of the reference anxiolytic, diazepam, in two rat strains respectively displaying high (Lewis rats and low (spontaneously hypertensive rats, SHR anxiety. Diazepam (0.37, 0.75, or 1.5 mg/kg; 30 min before testing increased in a dose-dependent manner the behavioral measures in SHR, but not in Lewis rats. On the other hand, SB 206553 (1.25, 2.5, or 5 mg/kg; 30 min before testing failed to alter the anxiety parameters in both strains, whereas it increased closed arm entries in Lewis rats, suggesting that it elicited hyperactivity in the latter strain. Accordingly, the hypolocomotor effect of the nonselective 5-HT2B/2C receptor agonist m-chlorophenylpiperazine (1.5 mg/kg ip 20 min before a 15-min exposure to an activity cage was prevented by the 1.25 and 2.5 mg/kg doses of SB 206553 in Lewis rats and SHR, respectively. Compared with SHR, Lewis rats may display a lower response to benzodiazepine-mediated effects and a more efficient control of locomotor activity by 5-HT2B/2C receptors.

  6. Prophylactic Melatonin Attenuates Isoflurane-Induced Cognitive Impairment in Aged Rats through Hippocampal Melatonin Receptor 2 - cAMP Response Element Binding Signalling.

    Liu, Yajie; Ni, Cheng; Li, Zhengqian; Yang, Ning; Zhou, Yang; Rong, Xiaoying; Qian, Min; Chui, Dehua; Guo, Xiangyang


    Melatonin exerts many physiological effects via melatonin receptors, among which the melatonin-2 receptor (MT2 ) plays a critical role in circadian rhythm disorders, Alzheimer's disease and other neurological disorders. A melatonin replacement strategy has been tested previously, and MT2 was a critical target during the process. cAMP response element binding (CREB) is an essential transcription factor for memory formation and could be involved in MT2 signalling. Therefore, the present study was designed to investigate the effects of prophylactic melatonin on inhaled anaesthetic isoflurane-induced cognitive impairment, and to determine whether the protective effects of melatonin are dependent on MT2 and downstream CREB signalling in the hippocampus of aged rats. The results showed that prophylactic melatonin attenuated isoflurane-induced decreases in plasma/hippocampal melatonin levels and cognitive impairment in aged rats. Furthermore, 4P-PDOT, a selective MT2 antagonist, blocked the protective effects of melatonin on isoflurane-induced decreases in both hippocampal MT2 expression and downstream CREB phosphorylation. And 4P-PDOT blocked the attenuation of melatonin on isoflurane-induced memory impairment. Collectively, the results suggest that the protective effects of prophylactic melatonin are dependent on hippocampal MT2 -CREB signalling, which could be a potential therapeutic target for anaesthetic-induced cognitive impairment.

  7. Association between peroxisome proliferator-activated receptor-γcoactivator-1α gene polymorphisms and type 2 diabetes in southern Chinese population: role of altered interaction with myocyte enhancer factor 2C

    ZHANG Shao-ling; LU Wen-sheng; YAN Li; WU Mu-chao; XU Ming-tong; CHEN Li-hong; CHENG Hua


    Background Some single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-Y coactivator (PGC)-1α gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1a and type 2 diabetes in the southern Chinese population and to determine whether the common variants: Gly482Ser and Thr394Thr, in the PGC-1α gene have any impacts on interaction with myocyte enhancer factor (MEF) 2C.Methods The SNPs in all exons of the PGC-1α gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Thereafter, 263 type 2diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C.Results Three frequent SNPs (Thr394Thr, Gly482Ser and Thr528Thr) were found in exons of the PGC-1α gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls (40.1% vs 29.3%, P<0.01). Even in controls, the 482Ser(A) carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly(G) carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr (A) had a synergic effect on the interaction between

  8. Extending David Horrobin's membrane phospholipid theory of schizophrenia: overactivity of cytosolic phospholipase A(2) in the brain is caused by overdrive of coupled serotonergic 5HT(2A/2C) receptors in response to stress.

    Eggers, Arnold E


    David Horrobin's membrane phospholipid theory of schizophrenia has held up well over time because his therapeutic prediction that dietary supplementation with eicosapentaenoic acid (EPA) would have a therapeutic effect has been partially verified and undergoes continued testing. In the final version of his theory, he hypothesized that there was hyperactivity of phosphoslipase A(2) (PLA(2)) or a related enzyme but did not explain how the hyperactivity came about. It is known that serotonergic 5HT(2A/2C) receptors are coupled to PLA(2), which hydrolyzes both arachidonic acid (AA) and EPA from diacylglycerides at the sn-2 position. In this paper, Horrobin's theory is combined with a previously published theory of chronic stress in which it was hypothesized that a disinhibited dorsal raphe nucleus, the principal nucleus of the serotonergic system, can organize the neuropathology of diseases such as migraine, hypertension, and the metabolic syndrome. The new or combined theory is that schizophrenia is a disease of chronic stress in which a disinhibited DRN causes widespread serotonergic overdrive in the cerebral cortex. This in turn causes overdrive of cPLA(2) and both central and peripheral depletion of AA and EPA. Because EPA is present in smaller amounts, it falls below threshold for maintaining an intracellular balance between AA-derived and EPA-derived second messenger cascades, which leads to abnormal patterns of neuronal firing. There are two causes of neuronal dysfunction: the disinhibited DRN and EPA depletion. Schizophrenia is statistically associated with metabolic syndrome, hypertension, and migraine because they form a cluster of diseases with similar pathophysiology. The theory provides an explanation for both the central and peripheral phospholipid abnormalities in schizophrenia. It also explains the role of stress in schizophrenia, elevated serum PLA(2) activity in schizophrenia, the relationship between untreated schizophrenia and metabolic syndrome

  9. 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


    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.

  10. 5-HT7 receptor signaling: improved therapeutic strategy in gut disorders

    Janice J Kim; Khan, Waliul I.


    Serotonin (5-hydroxytrytamine; 5-HT) is most commonly known for its role as a neurotransmitter in the central nervous system. However, the majority of the body’s 5-HT is produced in the gut by enterochromaffin (EC) cells. Alterations in 5-HT signaling have been associated with various gut disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and enteric infections. Recently, our studies have identified a key role for 5-HT in the pathogenesis of experimental coli...

  11. 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


    a more meaningful assessment of available receptors than antagonist radioligands. In the current study we characterized [(11)C]Cimbi-36 receptor binding in the primate brain. On five experimental days, a total of 14 PET measurements were conducted in three female rhesus monkeys. On each day, PET...

  12. 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


    and pharmacological characterization of a series of N- and O-substituted THAZ analogues. The analogues N-Bn-THAZ (3d) and O-Bn-THAZ (4d) were found to be potent agonists of the human 5-HT2A and 5-HT2C receptors. Judging from an elaborate pharmacological profiling at numerous other CNS targets, the 3d analogue appears...... 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...

  13. 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


    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.

  14. 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.


    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

  15. Ti2C80 is more likely a titanium carbide endohedral metallofullerene (Ti2C2)@C78.

    Tan, Kai; Lu, Xin


    We show by means of density functional calculations that the previously synthesized metallofullerene Ti2C80 does not take the form of Ti2@C80, but is a titanium carbide endohedral metallofullerene, Ti2C2@C78, that has a C78(6-)(D3h) cage which follows faithfully the stable closed-shell electronic rule.

  16. 5-Hydroxytryptamine2A/2C receptors of nucleus raphe magnus and gigantocellularis/paragigantocellularis pars α reticular nuclei modulate the unconditioned fear-induced antinociception evoked by electrical stimulation of deep layers of the superior colliculus and dorsal periaqueductal grey matter.

    de Oliveira, Ricardo; de Oliveira, Rithiele Cristina; Falconi-Sobrinho, Luiz Luciano; da Silva Soares, Raimundo; Coimbra, Norberto Cysne


    The electrical stimulation of the dorsolateral columns of the periaquedutal grey matter (dlPAG) or deep layers of the superior colliculus (dlSC) evokes defensive behaviours followed by an antinociceptive response. Monoaminergic brainstem reticular nuclei are suggested to comprise the endogenous pain modulatory system. The aim of the present work was to investigate the role played by 5-HT2 subfamily of serotonergic receptors of the nucleus raphe magnus (NRM) and the gigantocellularis/paragigantocellularis pars α reticular nuclei (Gi/PGiα) in the elaboration of instinctive fear-induced antinociception elicited by electrical stimulation of dlPAG or of dlSC. The nociceptive thresholds were measured by the tail-flick test in Wistar rats. The 5-HT2A/2C-serotonergic receptors antagonist ritanserin was microinjected at different concentrations (0.05, 0.5 and 5.0μg/0.2μL) either in Gi/PGiα or in NRM. The blockade of 5-HT2 receptors in both Gi/PGiα and NRM decreased the innate fear-induced antinociception elicited by electrical stimulation of the dlSC or the dlPAG. These findings indicate that serotonin is involved in the hypo-algesia induced by unconditioned fear-induced behavioural responses and the 5-HT2A/2C-serotonergic receptor subfamily in neurons situated in the Gi/PGiα complex and NRM are critically recruited in pain modulation during the panic-like emotional behaviour.

  17. 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)


    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.

  18. A Cistanches Herba Fraction/β-Sitosterol Causes a Redox-Sensitive Induction of Mitochondrial Uncoupling and Activation of Adenosine Monophosphate-Dependent Protein Kinase/Peroxisome Proliferator-Activated Receptor γ Coactivator-1 in C2C12 Myotubes: A Possible Mechanism Underlying the Weight Reduction Effect

    Hoi Shan Wong


    Full Text Available Previous studies have demonstrated that HCF1, a semipurified fraction of Cistanches Herba, causes weight reduction in normal diet- and high fat diet-fed mice. The weight reduction was associated with the induction of mitochondrial uncoupling and changes in metabolic enzyme activities in mouse skeletal muscle. To further investigate the biochemical mechanism underlying the HCF1-induced weight reduction, the effect of HCF1 and its active component, β-sitosterol (BSS, on C2C12 myotubes was examined. Incubation with HCF1/BSS caused a transient increase in mitochondrial membrane potential (MMP, possibly by fluidizing the mitochondrial inner membrane. The increase in MMP was paralleled to an increase in mitochondrial reactive oxygen species (ROS production. Mitochondrial ROS, in turn, triggered a redox-sensitive induction of mitochondrial uncoupling by uncoupling protein 3 (UCP3. Biochemical analysis indicated that HCF1 was capable of activating an adenosine monophosphate-dependent protein kinase/peroxisome proliferator-activated receptor γ coactivator-1 pathway and thereby increased the expression of cytochrome c oxidase and UCP3. Animal studies using mitochondrial recoupler also confirmed the role of mitochondrial uncoupling in the HCF1-induced weight reduction. In conclusion, a HCF1/BSS causes the redox-sensitive induction of mitochondrial uncoupling and activation of AMPK/PGC-1 in C2C12 myotubes, with resultant reductions in body weight and adiposity by increased energy consumption.

  19. 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


    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.

  20. 传统抗精神病药物所致迟发性运动障碍的药理遗传学初步研究%Pharmacogenetic assessment of antipsychotic-induced tardive dyskinesia: contribution of 5-hydroxytryptamine 2C receptor gene and of a combination of dopamine D3 variant allele (Gly) and MnSOD wild allele (Val)

    张珺; 侯钢; 张晓斌; 姚辉; 沙维伟; 张心保


    目的进一步探讨多巴胺D2、D3受体(dopamine D2,D3 receptor, DRD2,DRD3)功能基因多态性与迟发性运动障碍(tardive dyskinesia, TD)的相关性及各候选基因,同时包括五羟色胺2C受体(5-hydroxytryptamine 2C receptor, HTR2C)和锰超氧化物歧化酶(manganese superoxide dismutase, MnSOD)基因的相互作用对TD发生的影响.方法使用异常不自主运动量表(abnormal involuntary movement scale, AIMS)评定精神分裂症(schizophrenia, SCH)患者有无TD及其严重程度,并采用简明精神病评定量表评定患者精神症状;应用聚合酶链反应-限制性片段长度多态性技术分析TD组和非TD组各候选基因等位基因和(或)基因型分布频率及其结合分布频率,并分析对AIMS总分值的影响.结果各候选基因在SCH患者组以及TD和非TD组基因型分布均符合Hardy-Weinberg平衡定律;TD组HTR2C基因-697C(突变型)等位基因频率高于非TD组,差异有显著性(P0.05);仅DRD3突变型(Gly)和MnSOD野生型(Val)结合分布频率高于其它结合型,差异有显著性(P0.05).结论 HTR2C基因启动区-697G→C单碱基置换可能是中国汉族男性SCH患者TD发生的易感因素;而SCH患者若同时携带DRD3基因9Gly突变型和MnSOD基因-9Val 野生型等位基因可能增加了TD的易感性.

  1. 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


    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.




    1 The presence of a nucleotide receptor and a discrete ATP-sensitive receptor on C2C12 myotubes has been shown by electrophysiological experiments. In this study, the ATP-sensitive receptors of C2C12 myotubes were further characterized by measuring the formation of inositol(1,4,5)trisphosphate (Ins(

  3. Investigation of the CYP2C9 induction profile in human hepatocytes by combining experimental and modelling approaches.

    Belic, Ales; Temesvári, Manna; Kohalmy, Krisztina; Vrzal, Radim; Dvorak, Zdenek; Rozman, Damjana; Monostory, Katalin


    The goal of the present review is to characterise the induction profile of CYP2C9, a member of the cytochrome P450 superfamily. Since the mechanism of CYP2C9 induction is fairly complex, with parallel processes triggered by various inducers, an evaluation of the experimental results is often a great challenge. At least three nuclear receptors, the glucocrticoid receptor (GR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), are known to mediate the CYP2C9 gene induction in man. However, mathematical modelling and simulation can provide an appropriate tool for the interpretation of CYP2C9 regulatory mechanisms. As an example, we present modelling and simulation approaches of the CYP2C9 gene expression in human hepatocytes treated with well-known CYP2C9 inducers: the steroid hormone precursor dehydroepiandrosterone (DHEA) and the synthetic glucocorticoid dexamethasone (DXM). The results of the analysis suggest that in addition to the potent function of GR and the further involvement of PXR and CAR activated by DXM or DHEA, an additional factor might play a role in CYP2C9 regulation by DHEA. The novel potential candidate for DHEA action in CYP2C9 induction is likely to be the estrogen receptor. Additionally, the balance of DHEA sulphation-desulphation processes should also be considered in any description of DHEA-induced CYP2C9 profiles.

  4. 5-HT2C受体亚型参与易化大鼠内嗅区-海马通路的突触传递:平面微电极阵列记录技术研究%Facilitation of synaptic transmission and connections of entorhinal-hippocampal pathway by 5-HT2C receptor subtype: multi-electrode array recordings

    许燕; 金建慧; 王燕; 王蕊蕊; 李震; 陈军


    Using 64-channels (8 × 8) multi-electrode array technique (MED-64 system), the modulatory actions of 5-hydroxytryptam-ine (5-HT) 2C receptor subtype on the entorhinal (EC)-hippocampal synaptic transmission and connections were studied. One of freshly dissociated acute hippocampal slices of rats which was placed on the MED-64 probe, was subject to constant perfusion with oxygenated artificial cerebrospinal fluid (ACSF, 95% O2 and 5% CO2). Two hours after ACSF incubation, simultaneous multi-site electrophysiological recordings were performed. One electrode was selected to be used for perforant path (PP) stimulation, and the remaining 63 electrodes were used for recordings of network field excitatory postsynaptic potentials (fEPSPs) within both CA1 and dentate gyms (DG) that have been previously proved to be mediated by glutamate non-NMDA receptors. After stability of network fEPSPs was achieved, (±)-l(2, 5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, an agonist of 5-HT2C receptor subtype), or SB242084 (6-Chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-lH-indole-l-carboxyamide dihy-drochloride hydrate) (a selective antagonist of 5-HT2C receptor subtype) was applied for 10 min perfusion, respectively. Two-dimensional current source density (2D-CSD) analysis was also transformed by bilinear interpolation at each point of the 64 electrodes for spatial imaging of the fEPSP network responses. Based upon the polarities of fEPSP and 2D-CSD imaging, it was clearly shown that synaptic activations were evoked to occur within the molecular layer of DG and pyramidal cell layer of CA1 by the PP stimulation in which negative-going field potentials and current sink (blue) could be recorded. While, positive-going field potentials and current source (yellow) were mainly localized within the granule cell layer and hilus of DG and alveus of CA1, reflecting spread of electrical signals derived from depolarized region toward CA3 area or subiculum

  5. receptores

    Salete Regina Daronco Benetti


    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”.

  6. LM-2C Series Launch Vehicles



    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.

  7. Histamine H3 receptor inhibited electrically evoked cytoplasmic calcium in differentiated skeletal C2C12 myoblasts%组胺 H3受体降低电激发收缩的小鼠成肌细胞胞浆中钙离子浓度

    齐麟; 冯晓; 陈燕; 薛瑞; 张凤; 王素云; 孙素珂; 建国


    目的:探讨组胺H3受体(H3R)在小鼠成肌细胞C2C12成肌分化过程及分化后的横纹肌细胞中的表达和可能发挥的作用。方法:诱导C2C12细胞成肌分化,测量H3R和分化晚期标志物肌球蛋白重链mRNA和蛋白的表达;分化过程中加入H3R拮抗剂ciproxifan,测量分化早期标志物desmin、中期标志物myogenin和肌球蛋白重链mRNA的表达。 Fluo-4结合剂标记分化后的横纹肌胞内钙离子,测量双极交流电200 mA刺激下,H3R激动剂甲基组胺(RMeHA)对胞浆中钙离子浓度的影响。结果:H3R和肌球蛋白重链在成肌分化过程中表达量逐渐增加。 Ciproxifan在成肌分化过程中对3种分化标志物mRNA的表达与对照组相比无差异( P>0.05)。 RMeHA在浓度10 nmol/L~100μmol/L刺激细胞5~20 min,可呈钟形降低因交流电引起的肌浆钙离子浓度的升高( P<0.05),其中RMeHA 100 nmol/L在10 min和20 min对电刺激细胞中Ca2+的抑制百分率最高。相同浓度的RMeHA在20 min和10 min时对Ca2+的抑制率比其在5 min时高(P<0.05)。结论:H3R可能在成肌分化过程中的作用不大,而在分化成熟细胞中可以降低电刺激引起的胞浆钙离子浓度的升高。%AIM:To explore the expression and possible function of histamine H3 receptor (H3R) in striated myogenesis and the differentiated C2C12 cells.METHODS: H3R and myogenesis late marker myosin heavy chain (MHC) were detected at mRNA and protein levels during C2C12 myogenesis.H3R antagonist ciproxifan was added and the expression of the myogenesis early marker desmin, intermediate markers myogenin and MHC was detected.Differentia-ted myoblasts were loaded with Fluo-4 calcium indicator dye and the effect of R-( a)-methylhistamine ( RMeHA) on the cy-toplasmic calcium concentration was determined under the 200 mA electrical stimulation.RESULTS: The expression of H3R and MHC was increased during myogenesis

  8. Far infrared transmittance of Sc2@C84 and Er2@C82

    Grannan, S.M.; Birmingham, J.T.; Richards, P.L.; Bethune, D.S.; Vries, M.S. de; Loosdrecht, P.H.M. van; Dorn, H.C.; Burbank, P.; Bailey, J.; Stevenson, S.


    We have measured the far infrared transmittance of Sc2@C84 and Er2@C82 at 1.5 K between 30 and 200 cm-1. Both materials are observed to have a large primary absorption feature centered at 95 cm-1 with a width of approximately 50 cm-1, as well as a number of secondary absorption features which are di

  9. Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

    Jukić, M M; Opel, N; Ström, J; Carrillo-Roa, T; Miksys, S; Novalen, M; Renblom, A; Sim, S C; Peñas-Lledó, E M; Courtet, P; Llerena, A; Baune, B T; de Quervain, D J; Papassotiropoulos, A; Tyndale, R F; Binder, E B; Dannlowski, U; Ingelman-Sundberg, M


    The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3β phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.Molecular Psychiatry advance online publication, 29 November 2016; doi:10.1038/mp.2016.204.

  10. SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist.

    Sard, Howard; Kumaran, Govindaraj; Morency, Cynthia; Roth, Bryan L; Toth, Beth Ann; He, Ping; Shuster, Louis


    An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT(2C) receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive-compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT(2C) agonists with applications for drug discovery.

  11. Surface reconstruction of W2C(0001)

    Aizawa, Takashi; Hishita, Shunichi; Tanaka, Takaho; Otani, Shigeki


    A single crystal surface of ditungsten carbide, W2C(0001) was investigated using low-energy (LEED) and high-energy electron diffraction, Auger electron spectroscopy, x-ray photoelectron spectroscopy (XPS), and high-resolution electron energy loss spectroscopy (HREELS). A new reconstruction, \\sqrt {13} \\times \\sqrt {13} {R}+/- 13.9^{\\circ } , was found as a clean surface structure after annealing the W2C at > 1900 K. The surface carbon content is shown as larger than that in the bulk. Our preliminary results showed that the same structure is realized also on WC(0001). The same surface periodicity is described for an Mo2C(0001) LEED pattern in the literature. This reconstruction phase is presumably common on the (0001) surface of hexagonal group-6 transition-metal carbides. In the off-specular HREELS, an atomic vibration of 44.8 meV (361 cm - 1) appeared within the gap energy region of the bulk phonon bands, which was assigned to a surface carbon vibration perpendicular to the surface. One possible explanation of the low vibrational frequency is very low adsorption height of the surface carbon atoms.

  12. Interferon signaling is dependent on specific tyrosines located within the intracellular domain of IFNAR2c. Expression of IFNAR2c tyrosine mutants in U5A cells.

    Wagner, T Charis; Velichko, Sharlene; Vogel, David; Rani, M R Sandhya; Leung, Stewart; Ransohoff, Richard M; Stark, George R; Perez, H Daniel; Croze, Ed


    Type I interferons (IFNs) are cytokines that play a central role in mediating antiviral, antiproliferative, and immunomodulatory activities in virtually all cells. These activities are entirely dependent on the interaction of IFNs with their particular cell surface receptor. In this report, we identify two specific tyrosine residues located within the cytoplasmic domain of IFNAR2c that are obligatory for IFN-dependent signaling. Various IFNAR2c tyrosine mutants were expressed in a human lung fibroscarcoma cell line lacking IFNAR2c (U5A). Stable clones expressing these mutants were analyzed for their ability to induce STAT1 and STAT2 activation, ISGF3 transcriptional complex formation, gene expression, and cell growth regulation in response to stimulation with type I IFNs. The replacement of all seven cytoplasmic tyrosine residues of IFNAR2c with phenylalanine resulted in a receptor unable to respond to IFN stimulation. Substitution of single tyrosines at amino acid residue 269, 316, 318, 337, or 512 with phenylalanine had no effect on IFN-dependent signaling, suggesting that no single tyrosine is essential for IFN receptor-mediated signaling. In addition, IFNAR2c retaining five proximal tyrosines residues (269, 306, 316, 318, and 337) or either two distal tyrosine residues (411 or 512) continued to be responsive to IFN stimulation. Surprisingly, the presence of only a single tyrosine at either position 337 or 512 was sufficient to restore a complete IFN response. These results indicate that IFN-dependent signaling proceeds through the redundant usage of two tyrosine residues in the cytoplasmic domain of IFNAR2c.

  13. Association between HTR2C polymorphisms and the metabolic syndrome in patients using antipsychotics : a replication study

    Risselada, A.; Vehof, J.; Bruggeman, R.; Wilffert, B.; Cohen, D.; Al Hadithy, A. F.; Arends, J.; Mulder, H.


    Background: In two previous studies we investigated the possible association between the rs1414334 C/G and 759 C/T polymorphisms in the gene that encodes the 5HT2c receptor (HTR2c) and prevalence of the metabolic syndrome in a schizophrenic population [1,2]. In both studies we found an association b

  14. Association between HTR2C polymorphisms and the metabolic syndrome in patients using antipsychotics: A replication study

    Risselada, A.; Vehof, J.; Bruggeman, R.; Wilffert, B.; Cohen, D.; Al Hadithy, A.F.; Arends, J.; Mulder, H.


    Background: In two previous studies we investigated the possible association between the rs1414334 C/G and 759 C/T polymorphisms in the gene that encodes the 5HT2c receptor (HTR2c) and prevalence of the metabolic syndrome in a schizophrenic population [1,2]. In both studies we found an association b

  15. Association between HTR2C gene polymorphisms and the metabolic syndrome in patients Using Antipsychotics: A Replication Study

    Risselada, Arne; Vehof, Jelle; Bruggeman, Richard; Wilffert, Bob; Cohen, Dan; Al Hadithy, Asmar; Arends, Johan; Mulder, Hans


    Background: In two previous studies we investigated the association between the rs1414334 C/G and 759 C/T polymorphisms in the HTR2C gene, coding for the 5HT2c-receptor, and prevalence of the metabolic syndrome in a schizophrenic population. In both studies we found an association between the varian

  16. Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis

    Yan Gong


    Full Text Available Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPARα agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP2C with higher affinity than to PPARα. CYP2C metabolizes ω-3 long-chain polyunsaturated fatty acids (LCPUFAs. While ω-3 LCPUFA products from other metabolizing pathways decrease retinal and choroidal neovascularization, CYP2C products of both ω-3 and ω-6 LCPUFAs promote angiogenesis. We hypothesized that fenofibrate inhibits retinopathy by reducing CYP2C ω-3 LCPUFA (and ω-6 LCPUFA pro-angiogenic metabolites. Fenofibrate reduced retinal and choroidal neovascularization in PPARα-/-mice and augmented ω-3 LCPUFA protection via CYP2C inhibition. Fenofibrate suppressed retinal and choroidal neovascularization in mice overexpressing human CYP2C8 in endothelial cells and reduced plasma levels of the pro-angiogenic ω-3 LCPUFA CYP2C8 product, 19,20-epoxydocosapentaenoic acid. 19,20-epoxydocosapentaenoic acid reversed fenofibrate-induced suppression of angiogenesis ex vivo and suppression of endothelial cell functions in vitro. In summary fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition as well as by acting as an agonist of PPARα. Fenofibrate augmented the overall protective effects of ω-3 LCPUFAs on neovascular eye diseases.

  17. TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling.

    Woodfield, George W; Horan, Annamarie D; Chen, Yizhen; Weigel, Ronald J


    Breast cancers expressing estrogen receptor-alpha (ERalpha) are associated with a favorable biology and are more likely to respond to hormonal therapy. In addition to ERalpha, other pathways of estrogen response have been identified including ERbeta and GPR30, a membrane receptor for estrogen, and the key mechanisms regulating expression of ERs and hormone response remain controversial. Herein, we show that TFAP2C is the key regulator of hormone responsiveness in breast carcinoma cells through the control of multiple pathways of estrogen signaling. TFAP2C regulates the expression of ERalpha directly by binding to the ERalpha promoter and indirectly via regulation of FoxM1. In so doing, TFAP2C controls the expression of ERalpha target genes, including pS2, MYB, and RERG. Furthermore, TFAP2C controlled the expression of GPR30. In distinct contrast, TFAP2A, a related factor expressed in breast cancer, was not involved in estrogen-mediated pathways but regulated expression of genes controlling cell cycle arrest and apoptosis including p21(CIP1) and IGFBP-3. Knockdown of TFAP2C abrogated the mitogenic response to estrogen exposure and decreased hormone-responsive tumor growth of breast cancer xenografts. We conclude that TFAP2C is a central control gene of hormone response and is a novel therapeutic target in the design of new drug treatments for breast cancer.

  18. Isolation and characterization of canine parvovirus type 2C (CPV-2C) from symptomatic puppies.

    Puentes, R; Eliopulos, N; Pérez, R; Franco, G; Sosa, K; Bianchi, P; Furtado, A; Hübner, S O; Esteves, P A


    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.

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

    R Puentes


    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.

  20. Analysis list: Tfap2c [Chip-atlas[Archive

    Full Text Available Tfap2c Breast,Pluripotent stem cell + mm9,

  1. Submillimeter spectroscopy of H$_2$C$^{17}$O and a revisit of the rotational spectra of H$_2$C$^{18}$O and H$_2$C$^{16}$O

    Müller, Holger S P


    The rotational spectrum of the formaldehyde isotopologue H2C(17)O was investigated between 0.56 and 1.50 THz using a sample of natural isotopic composition. In addition, transition frequencies were determined for H2C(18)O and H2C(16)O between 1.37 and 1.50 THz. The data were combined with critically evaluated literature data to derive improved sets of spectroscopic parameters which include (17)O or H nuclear hyperfine structure parameters.

  2. GUCY2C: at the intersection of obesity and cancer

    Kim, Gilbert W.; Lin, Jieru E.; Waldman, Scott A.


    Guanylyl cyclase C (GUCY2C) has canonical centrality in defense of key intestinal homeostatic mechanisms, encompassing fluid and electrolyte balance, epithelial dynamics, antitumorigenesis, and intestinal barrier function. Recent discoveries expand the homeostatic role of GUCY2C to reveal a novel gut-brain endocrine axis regulating appetite, anchored by hypothalamic GUCY2C which is responsive to intestine-derived uroguanylin. Thus, GUCY2C may represent a new target for anti-obesity pharmacoth...

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

    Full Text Available TFAP2C Breast,Epidermis,Uterus + hg19,, http://dbarchive.biosciencedb

  4. 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


    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.

  5. Molecular dynamic simulation of the self-assembly of DAP12-NKG2C activating immunoreceptor complex.

    Peng Wei

    Full Text Available The DAP12-NKG2C activating immunoreceptor complex is one of the multisubunit transmembrane protein complexes in which ligand-binding receptor chains assemble with dimeric signal-transducing modules through non-covalent associations in their transmembrane (TM domains. In this work, both coarse grained and atomistic molecular dynamic simulation methods were applied to investigate the self-assembly dynamics of the transmembrane domains of the DAP12-NKG2C activating immunoreceptor complex. Through simulating the dynamics of DAP12-NKG2C TM heterotrimer and point mutations, we demonstrated that a five-polar-residue motif including: 2 Asps and 2 Thrs in DAP12 dimer, as well as 1 Lys in NKG2C TM plays an important role in the assembly structure of the DAP12-NKG2C TM heterotrimer. Furthermore, we provided clear evidences to exclude the possibility that another NKG2C could stably associate with the DAP12-NKG2C heterotrimer. Based on the simulation results, we proposed a revised model for the self-assembly of DAP12-NKG2C activating immunoreceptor complex, along with a plausible explanation for the association of only one NKG2C with a DAP12 dimer.

  6. Main: 1I2C [RPSD[Archive

    Full Text Available 1I2C シロイヌナズナ Arabidopsis Arabidopsis thaliana (L.) Heynh. Udp-Sulfoquinovose Syntha... AAM47379.1; -.|PIR; T05311; T05311.|PDB; 1I24; X-ray; A=74-477.|PDB; 1I2B; X-ray; A=74-477.|PDB; 1I2C; X-ra...FCVQAAVGHPLTVYGKGGQTRGYLDIRDTVQCVEIAIANPAKAGEFRVFNQFTEQFSVNELASLVTKAGSKLGLDVKKMTVPNPRVEAEEHYYNAKHTKLMELGLEPHYLSDSLLDSLLNFAVQFKDRVDTKQIMPSVSWKKIGVKTKSMTT arabi_1I2C.jpg ...

  7. 5-羟色胺2C受体基因启动子区多态性与迟发性运动障碍的关联分析%Association of a polymorphism in the promoter region of the serotonin 2C receptor gene with tardive dyskinesia in schizophrenic patients

    张晓斌; 张志珺; 侯钢; 姚辉; 沙维伟; 张心保


    目的探讨5-羟色胺2C(5-HT2C)受体基因启动区-759C/T和-697G/C单碱基置换多态性与精神分裂症伴迟发性运动障碍(TD)的相关性.方法先用异常不自主运动量表(AIMS)评定精神分裂症男性患者有无TD及其严重程度,再对42例符合TD(AIMS总分≥3分)者和与TD组严格相匹配的50例非TD者,采用简明精神病评定量表(BPRS)评定精神症状,并应用聚合酶链反应-限制性片段长度多态性方法分析5-HT2C受体基因的分布频率.结果 (1)TD组的-697C(突变型)半合子型频率(38%)高于非TD组(18%;χ2=4.7,P=0.03,OR=2.8).TD组-759T(突变型)半合子型频率和-759T/-697C突变型单倍体频率虽高于非TD组,但差异均无显著性(χ2值分别为2.9和4.9,P=0.09).(2)TD组的AIMS和BPRS评分分别为(6.5±1.8)分和(51.2±7.8)分,非TD组分别为0分和(50.0±7.3)分,差异无显著性(P>0.05).结论 5-HT2C受体基因启动控制区的-697G/T单碱基置换突变可能是精神分裂症患者发生TD的易感因素之一.

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

    Hansen, Martin; Phonekeo, Karina; Paine, James S;


    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 series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having......) for the 5-HT2A receptor in the binding assays although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor....

  10. Menthol reduces the anticoagulant effect of warfarin by inducing cytochrome P450 2C expression.

    Hoshino, Motohiro; Ikarashi, Nobutomo; Tsukui, Makoto; Kurokawa, Asako; Naito, Rina; Suzuki, Midori; Yokobori, Kohsuke; Ochiai, Takumi; Ishii, Makoto; Kusunoki, Yoshiki; Kon, Risako; Ochiai, Wataru; Wakui, Nobuyuki; Machida, Yoshiaki; Sugiyama, Kiyoshi


    Recently, it was reported that the anticoagulant effect of warfarin was reduced when patients receiving warfarin also took menthol. The purpose of this study is to reveal the mechanism of this reduced anticoagulant effect of warfarin from the pharmacokinetic point of view. Warfarin was orally administered to mice 24h after the administration of menthol for 2 days, and the plasma warfarin concentration was measured. In the menthol administration group, the area under the blood concentration time curve of warfarin was decreased by approximately 25%, while total clearance was increased to 1.3-fold compared to the control group. The hepatic cytochrome P450 (CYP) 2C protein expression level in the menthol administration group was significantly increased compared to that in the control group. An increase in the nuclear translocation of constitutive androstane receptor (CAR) was also observed. The addition of menthol to human hepatic cells, HepaRG cells, caused an increase in the mRNA expression level of CYP2C9. The results of this study revealed that menthol causes an increase in CYP2C expression levels in the liver, which leads to an enhancement of warfarin metabolism, resulting in a decreased anticoagulant effect of warfarin. It was also suggested that menthol acted directly on the liver and increased the expression level of CYP2C by enhancing the nuclear translocation of CAR.

  11. Robotic Range Clearance Competition (R2C2)


    as a dry run for the actual competition, scheduled to be held in 2011, and as a way to validate the competition scoring. Figure 1. Map of... rework or brainstorm solutions to non-functioning equipment. If it is determined by an R2C2 observer that continual effort is not being made the...R2C2 judge and will be filmed for reference. C. According to the professional judgment of a R2C2 robotics expert (judge), the Level of Human

  12. Dephosphorylation of Centrins by Protein Phosphatase 2C and

    Marie-Christin Thissen


    Full Text Available In the present study, we identified protein phosphatases dephosphorylating centrins previously phosphorylated by protein kinase CK2. The following phosphatases known to be present in the retina were tested: PP1, PP2A, PP2B, PP2C, PP5, and alkaline phosphatase. PP2C and were capable of dephosphorylating P-Thr138-centrin1 most efficiently. PP2C was inactive and the other retinal phosphatases also had much less or no effect. Similar results were observed for centrins 2 and 4. Centrin3 was not a substrate for CK2. The results suggest PP2C and to play a significant role in regulating the phosphorylation status of centrins in vivo.

  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


    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

  14. Evaluation of P2-C2 bias estimation

    Santos, M. C.; van der Bree, R.; van der Marel, H.; Verhagen, S.; Garcia, C. A.


    The availability of the second civilian code C2 created a new issue to be considered: the bias relating P2 and C2 signals. Such an issue is important when merging C2-capable and legacy receivers and when processing data collected by a C2-capable receiver with satellite clock values generated using a legacy receiver network. The P2-C2 bias is essentially a consequence from the fact that receiver and satellite hardware delays for C2 measurements may not be necessarily the same of those for P2. Knowing this bias makes possible the use of C2 as an observable for positioning using IGS clock products. We are using the PPP-based approach for P2-C2 bias estimation developed at the University of New Brunswick. For that purpose, we use GAPS, the GPS Analysis and Positioning Software. We also determine P2-C2 bias directly from the code observations. This poster presents and discusses the evaluation of P2-C2 values estimated from a sub-set of the IGS L2C Test Network. The values are applied to observations collected by C2-capable receivers in the point positioning mode. Coordinate repeatability indicate an improvement of up to 50% when using the P2-C2 bias.

  15. Character algebras of decorated SL_2(C)-local systems

    Muller, Greg


    Let S be a path-connected, locally-compact CW-complex, and let M be a subcomplex with finitely-many components. A `decorated SL_2(C)-local system' is an SL_2(C)-local system on S, together with a choice of `decoration' at each component of M (a section of the stalk of an associated vector bundle). We study the (decorated SL_2(C)-)character algebra of (S,M), those functions on the space of decorated SL_2(C)-local systems on (S,M) which are regular with respect to the monodromy. The character algebra is presented explicitly. The character algebra is then shown to correspond to the algebra spanned by collections of oriented curves in S modulo simple graphical rules. As an intermediate step, we obtain an invariant-theory result of independent interest: a presentation of the algebra of SL_2(C)-invariant functions on End(V)^m + V^n, where V is the tautological representation of SL_2(C).

  16. The GSTM2 C-Terminal Domain Depresses Contractility and Ca2+ Transients in Neonatal Rat Ventricular Cardiomyocytes

    Hewawasam, Ruwani P.; Liu, Dan; Casarotto, Marco G.; Board, Philip G.; Dulhunty, Angela F.


    The cardiac ryanodine receptor (RyR2) is an intracellular ion channel that regulates Ca2+ release from the sarcoplasmic reticulum (SR) during excitation–contraction coupling in the heart. The glutathione transferases (GSTs) are a family of phase II detoxification enzymes with additional functions including the selective inhibition of RyR2, with therapeutic implications. The C-terminal half of GSTM2 (GSTM2C) is essential for RyR2 inhibition, and mutations F157A and Y160A within GSTM2C prevent the inhibitory action. Our objective in this investigation was to determine whether GSTM2C can enter cultured rat neonatal ventricular cardiomyocytes and influence contractility. We show that oregon green-tagged GSTM2C (at 1 μM) is internalized into the myocytes and it reduces spontaneous contraction frequency and myocyte shortening. Field stimulation of myocytes evoked contraction in the same percentage of myocytes treated either with media alone or media plus 15 μM GSTM2C. Myocyte shortening during contraction was significantly reduced by exposure to 15 μM GSTM2C, but not 5 and 10 μM GSTM2C and was unaffected by exposure to 15 μM of the mutants Y160A or F157A. The amplitude of the Ca2+ transient in the 15 μM GSTM2C - treated myocytes was significantly decreased, the rise time was significantly longer and the decay time was significantly shorter than in control myocytes. The Ca2+ transient was not altered by exposure to Y160A or F157A. The results are consistent with GSTM2C entering the myocytes and inhibiting RyR2, in a manner that indicates a possible therapeutic potential for treatment of arrhythmia in the neonatal heart. PMID:27612301

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

    Regu Archana


    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.

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

    Elfwing, Magnus; Fallahshahroudi, Amir; Lindgren, Isa; Jensen, Per; Altimiras, Jordi


    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 of some unknown

  19. Insights into the influence of 5-HT2c aminoacidic variants with the inhibitory action of serotonin inverse agonists and antagonists.

    Galeazzi, Roberta; Massaccesi, Luca; Piva, Francesco; Principato, Giovanni; Laudadio, Emilioano


    Specific modulation of serotonin 5-HT(2C) G protein-coupled receptors may be therapeutic for obesity and neuropsychiatric disorders. The different efficacy of drugs targeting these receptors are due to the presence of genetic variants in population and this variability is still hard to predict. Therefore, in order to administer the more suitable drug, taking into account patient genotype, it is necessary to know the molecular effects of its gene nucleotide variations. In this work, starting from an accurate 3D model of 5-HT(2C), we focus on the prediction of the possible effect of some single nucleotide polymorphisms (SNPs) producing amino acidic changes in proximity of the 5-HT(2C) ligand binding site. Particularly we chose a set of 5-HT(2C) inverse agonists and antagonists which have high inhibitory activity. After prediction of the structures of the receptor-ligand complexes using molecular docking tools, we performed full atom molecular dynamics simulations in explicit lipid bilayer monitoring the interactions between ligands and trans-membrane helices of the receptor, trying to infer relations with their biological activity. Serotonin, as the natural ligand was chosen as reference compound to advance a hypothesis able to explain the receptor inhibition mechanism. Indeed we observed a different behavior between the antagonists and inverse agonist with respect to serotonin or unbounded receptor, which could be responsible, even if not directly, of receptor's inactivation. Furthermore, we analyzed five aminoacidic variants of 5HT(2C) receptor observing alterations in the interactions between ligands and receptor which give rise to changes of free energy values for every complex considered.

  20. Risk Analysis and Consumer Protection in B2C Transactions

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


    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.


    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. Proteasome inhibition compromises direct retention of cytochrome P450 2C2 in the endoplasmic reticulum.

    Szczesna-Skorupa, Elzbieta; Kemper, Byron


    To determine whether protein degradation plays a role in the endoplasmic reticulum (ER) retention of cytochromes P450, the effects of proteasomal inhibitors on the expression and distribution of green fluorescent protein chimeras of CYP2C2 and related proteins was examined. In transfected cells, expression levels of chimeras of full-length CYP2C2 and its cytosolic domain, but not its N-terminal transmembrane sequence, were increased by proteasomal inhibition. Redistribution of all three chimeras from the reticular ER into a perinuclear compartment and, in a subset of cells, also to the cell surface was observed after proteasomal inhibition. Redistribution was blocked by the microtubular inhibitor, nocodazole, suggesting that redistribution to the cell surface followed the conventional vesicular transport pathway. Similar redistributions were detected for BAP31, a CYP2C2 binding chaperone; CYP2E1 and CYP3A4, which are also degraded by the proteasomal pathway; and for cytochrome P450 reductase, which does not undergo proteasomal degradation; but not for the ER membrane proteins, sec61 and calnexin. Redistribution does not result from saturation of an ER retention "receptor" since in some cases protein levels were unaffected. Proteasomal inhibition may, therefore, alter ER retention by affecting a protein critical for ER retention, either directly, or indirectly by affecting the composition of the ER membranes.

  3. Recombinant myostatin reduces highly expressed microRNAs in differentiating C2C12 cells

    Zachary A. Graham


    Full Text Available Myostatin is small glycopeptide that is produced and secreted by skeletal muscle. It is a potent negative regulator of muscle growth that has been associated with conditions of frailty. In C2C12 cells, myostatin limits cell differentiation. Myostatin acts through activin receptor IIB, activin receptor-like kinase (ALK and Smad transcription factors. microRNAs (miRNA are short, 22 base pair nucleotides that bind to the 3′ UTR of target mRNA to repress translation or reduce mRNA stability. In the present study, expression in differentiating C2C12 cells of the myomiRs miR-1 and 133a were down-regulated following treatment with 1 µg of recombinant myostatin at 1 d post-induction of differentiation while all myomiRs (miR-1, 133a/b and 206 were upregulated by SB431542, a potent ALK4/5/7 inhibitor which reduces Smad2 signaling, at 1 d and all, with the exception of miR-206, were upregulated by SB431542 at 3 d. The expression of the muscle-enriched miR-486 was greater following treatment with SB431542 but not altered by myostatin. Other highly expressed miRNAs in skeletal muscle, miR-23a/b and 145, were altered only at 1 d post-induction of differentiation. miR-27b responded differently to treatments at 1 d, where it was upregulated, as compared to 3 d, where it was downregulated. Neither myostatin nor SB431542 altered cell size or cell morphology. The data indicate that myostatin represses myomiR expression in differentiating C2C12 cells and that inhibition of Smad signaling with SB431542 can result in large changes in highly expressed miRNAs in differentiating myoblasts.

  4. Units in Z_2(C_2 × D_infinity

    Kanchan Joshi


    Full Text Available In this paper we consider the group algebra R(C_2 ×D_infinity. It is shown that R(C_2 ×D_infinity can be represented by a 4 × 4 block circulant matrix. It is also shown that U(Z_2(C_2 × D_infinity isinfinitely generated

  5. E-2C Loads Calibration in DFRC Flight Loads Lab

    Schuster, Lawrence S.


    Objectives: a) Safely and efficiently perform structural load tests on NAVAIR E-2C aircraft to calibrate strain gage instrumentation installed by NAVAIR; b) Collect load test data and derive loads equations for use in NAVAIR flight tests; and c) Assist flight test team with use of loads equations measurements at PAX River.

  6. Theoretical Investigations of La2C2 Cluster

    武志坚; 周誓红; 张思远


    Possible structures of La2C2 were studied and proposed by use of density functional theory. All proposed isomers are planar. The results indicate that the structure with the lowest symmetry (C1) is the most stable. Linear isomers are not favored.

  7. LM-2C Sent Yaogan 13 into Space


    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.

  8. High-throughput screening assays for the assessment of CYP2C9*1, CYP2C9*2, and CYP2C9*3 metabolism using fluorogenic Vivid substrates.

    Marks, Bryan D; Thompson, David V; Goossens, Tony A; Trubetskoy, Olga V


    CYP2C9 is a genetically polymorphic human cytochrome P450 isozyme involved in the oxidative metabolism of many drugs, including nonsteroidal anti-inflammatory compounds. Individuals genotyped heterozygous or homozygous for CYP2C9 allelic variants have demonstrated altered metabolism of some drugs primarily metabolized by CYP2C9. The ability to expand screening of CYP2C9 allelic variants to a larger set of drugs and pharmaceutical agents would contribute to a better understanding of the significance of CYP2C9 polymorphisms in the population and to predictions of possible outcomes. The authors report the development of an in vitro fluorescence-based assay employing recombinant CYP2C9 variants (CYP2C9*1, CYP2C9*2, and CYP2C9*3) and fluorogenic Vivid(R) CYP2C9 substrates to explore the effects of CYP2C9 polymorphisms on drug metabolism, using drugs primarily metabolized by CYP2C9. Several chemically diverse fluorogenic substrates (Vivid(R) CYP2C9 blue, green, and red substrates) were used as prototypic probes to obtain in vitro CYP2C9 metabolic rates and kinetic parameters, such as apparent K(m), V(max), and V(max)/K(m) ratios for each allelic variant. In addition, a diverse panel of drugs was screened as assay modifiers with CYP2C9*1, CYP2C9*2, CYP2C9*3, and the fluorogenic Vivid(R) CYP2C9 substrates. The inhibitory potential of this large group of chemically diverse drugs and compounds has been assessed on the basis of their ability to compete with Vivid(R) CYP2C9 substrates in fluorescent reporter assays, thus providing a sensitive and quick assessment of polymorphism-dependent changes in CYP2C9 metabolism.

  9. 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: [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: [Unit of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, Brescia I-25123 (Italy); Interuniversity Institute of Myology (IIM) (Italy)


    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.

  10. Liver-specific cytochrome P450 CYP2C22 is a direct target of retinoic acid and a retinoic acid-metabolizing enzyme in rat liver.

    Qian, Linxi; Zolfaghari, Reza; Ross, A Catharine


    Several cytochrome P450 (CYP) enzymes catalyze the C4-hydroxylation of retinoic acid (RA), a potent inducer of cell differentiation and an agent in the treatment of several diseases. Here, we have characterized CYP2C22, a member of the rat CYP2C family with homology to human CYP2C8 and CYP2C9. CYP2C22 was expressed nearly exclusively in hepatocytes, where it was one of the more abundant mRNAs transcripts. In H-4-II-E rat hepatoma cells, CYP2C22 mRNA was upregulated by all-trans (at)-RA, and Am580, a nonmetabolizable analog of at-RA. In comparison, in primary human hepatocytes, at-RA increased CYP2C9 but not CYP2C8 mRNA. Analysis of the CYP2C22 promoter region revealed a RA response element (5'-GGTTCA-(n)5-AGGTCA-3') in the distal flanking region, which bound the nuclear hormone receptors RAR and RXR and which was required for transcriptional activation response of this promoter to RA in CYP2C22-luciferase-transfected RA-treated HepG2 cells. The cDNA-expressed CYP2C22 protein metabolized [3H]at-RA to more polar metabolites. While long-chain polyunsaturated fatty acids competed, 9-cis-RA was a stronger competitor. Our studies demonstrate that CYP2C22 is a high-abundance, retinoid-inducible, hepatic P450 with the potential to metabolize at-RA, providing additional insight into the role of the CYP2C gene family in retinoid homeostasis.

  11. Influence of serotonergic transmission and postsynaptic 5-HT2C action on the feeding behavior of Coturnix japonica (Galliformes: Aves

    P. L. Cedraz-Mercez

    Full Text Available We investigated the role of 5-HT2C receptors and serotonergic transmission in the feeding behavior control of quails. Administration of serotonin releaser, fenfluramine (FEN and 5-HT2C agonists, mCPP and MK212, 1.0 and 3.3 mg/Kg induced significant inhibition of food intake in previously fasted fowls (0.71 ± 0.18 g and 0.47 ± 0.2 g; 0.49 ± 0.22 g and 0.48 ± 0.29 g; 0.82 ± 0.13 g and 0.71 ± 0.16 g, respectively. Control groups ranged from 2.89 ± 0.21 g to 2.97 ± 0.22 g, 60 min after reintroduction of food, P < 0.0001. Similar results were obtained with normally fed quails. Both serotonin releaser and 5-HT2C agonists, in a 3.3 mg/Kg dose, induced hypophagy (FEN, 0.78 ± 0.08 g; mCPP, 0.89 ± 0.07 g; MK212, 1.25 ± 0.17 g vs. controls, 2.05 ± 0.12 g, 120 min after food was presented, P < 0.0001 to P < 0.01. Previous administration of 5-HT2C antagonist, LY53857 (5.0 mg/Kg blocked the hypophagic response induced by 5-HT2C agonists 60 min after food was reintroduced. Current data show a modulatory role of serotonin release and postsynaptic 5-HT2C receptors in the feeding behavior of quails.

  12. Predicting drug metabolism by cytochrome P450 2C9

    Rydberg, Patrik; Olsen, Lars


    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...... isoforms are discussed through structural knowledge from the X-ray crystal structures and trends in experimental data. The final model was validated on an independent test set, resulting in an area under the curve value of 0.92, and a site of metabolism was found among the top two ranked atoms for 77...

  13. Online Trading C2C Operators Fight for Number One



    @@ 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.

  14. Field emission from Mo2C coated carbon nanosheets

    Bagge-Hansen, M.; Outlaw, R. A.; Miraldo, P.; Zhu, M. Y.; Hou, K.; Theodore, N. D.; Zhao, X.; Manos, D. M.


    Carbon nanosheets have recently evolved into useful edge emitters with high emission current densities, low threshold electric fields, and long lifetimes. In addition to further improvement in these characteristics, good stability and repeatability are also essential for these materials to be suitable for high vacuum applications such as microwave tubes and flat panel displays. Since the work function of graphite, carbon nanotubes, and amorphous carbon is relatively high, 4.6-4.8eV, selective thin film coatings may offer significant advantages. Carbides are a good film choice for their corrosive resistance, chemical stability, and substantially lower work function. Approximately 3 ML (monolayer) (˜1nm) of molybdenum were deposited on carbon nanosheets by physical vapor deposition and the carbide (Mo2C) formed by heating to >200°C at 1×10-8Torr. The carbide stoichiometry was confirmed in situ by the characteristic Auger triple peak at 272eV. A stoichiometric Mo2C calibration sample was used to acquire the Auger electron spectroscopy asymmetric ratio of 0.7 and this was used to determine the carbide growth as a function of temperature (from room temperature to 1000°C). Field emission currents of up to 400μA were compared with uncoated CNS at a given electric field. The Mo2C/CNS cathodes were shown to have greater than a factor of 100 increase in current and greater than 2V/μm decrease in threshold. The Fowler-Nordheim plots were exceptionally linear and quite repeatable (correlation coefficient R2=0.999+). Using the slope and vertical intercept, an emission area for the 0.07cm2 Mo2C/CNS dot sample was determined to be ˜3×10-9cm2 and the field enhancement factor was found to be β ˜530.

  15. Optical characterization of polished Mo2C foil.

    Grimes, Jacob; Geerts, W.; Bandyopadhyay, A.; Gutierrez; Radican, K.; Rivera, N.; Holland, P.; Givens, J.; Oyama, Ted


    Mo_2C has been in use by industry for a number of years, however its optical properties are previously uncharacterized with no reports of experimentally obtained values for the refraction index(n) and extinction coefficient(k). Toward the goal of identifying the values for these properties several tests are performed on a Molybdenum foil carburized in a stream of 20 molar CH4 in H2 at 1373K. The surface of the sample is polished to an optically flat finish using several diamond disks in an Allied High Tech polisher. X-ray data shows that the remaining surface material is Mo_2C. Ψ and Δ are measured with a Variable Angle Spectroscopic Ellipsometer from 190 to 1700nm. Then n, k, and reflectance are calculated using FilmWizard. The spectra for refraction, extinction, and reflectance of Mo_2C differ greatly from those reported for Mo. Generally they exhibit a quasi-linear character increasing with wavelength with structures in the red and blue parts of the spectra.

  16. Similar substrate specificity of cynomolgus monkey cytochrome P450 2C19 to reported human P450 2C counterpart enzymes by evaluation of 89 drug clearances.

    Hosaka, Shinya; Murayama, Norie; Satsukawa, Masahiro; Uehara, Shotaro; Shimizu, Makiko; Iwasaki, Kazuhide; Iwano, Shunsuke; Uno, Yasuhiro; Yamazaki, Hiroshi


    Cynomolgus monkeys are used widely in preclinical studies as non-human primate species. The amino acid sequence of cynomolgus monkey cytochrome P450 (P450 or CYP) 2C19 is reportedly highly correlated to that of human CYP2C19 (92%) and CYP2C9 (93%). In the present study, 89 commercially available compounds were screened to find potential substrates for cynomolgus monkey CYP2C19. Of 89 drugs, 34 were metabolically depleted by cynomolgus monkey CYP2C19 with relatively high rates. Among them, 30 compounds have been reported as substrates or inhibitors of, either or both, human CYP2C19 and CYP2C9. Several compounds, including loratadine, showed high selectivity to cynomolgus monkey CYP2C19, and all of these have been reported as human CYP2C19 and/or CYP2C9 substrates. In addition, cynomolgus monkey CYP2C19 formed the same loratadine metabolite as human CYP2C19, descarboethoxyloratadine. These results suggest that cynomolgus monkey CYP2C19 is generally similar to human CYP2C19 and CYP2C9 in its substrate recognition functionality.

  17. Global structure search and physical properties of Os2C

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


    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.

  18. Interactions between CYP2C9 and CYP2C19 in reconstituted binary systems influence their catalytic activity: possible rationale for the inability of CYP2C19 to catalyze methoxychlor demethylation in human liver microsomes.

    Hazai, Eszter; Kupfer, David


    Previous studies in our laboratory showed that among cDNA-expressed human cytochrome P450 (P450) supersomes, CYP2C19 was the most active in methoxychlor-O-demethylation. However, based on the lack of inhibition of methoxychlor-O-demethylation by monoclonal anti-CYP2C19 antibodies in human liver microsomes (HLM), CYP2C19 did not seem to catalyze that reaction in HLM. By contrast, CYP2C9, much less active than CYP2C19 in supersomes, was the most active in HLM. The current study examines whether the lack of methoxychlor-O-demethylation by CYP2C19 in HLM was due to CYP2C19 exhibiting inferior competition for the NADPH-cytochrome P450 reductase (CPR) versus CYP2C9 and explores the interactions between CYP2C9 and CYP2C19 in a singular and binary complex of a reconstituted system. When reconstituted with CPR, cytochrome b(5), and lipid, purified CYP2C19 and CYP2C9 catalyzed methoxychlor-O-demethylation. However, whereas equimolar CPR to CYP2C9 supported maximal rates of methoxychlor demethylation and diclofenac hydroxylation, the rate of methoxychlor demethylation by CYP2C19 was not fully saturated, even with a 9-fold molar excess of CPR over CYP2C19. This behavior of CYP2C19 was also observed with S-mephenytoin as the substrate. When a binary reconstitution system was prepared by mixing CYP2C9 and CYP2C19 enzymes, methoxychlor-O-demethylation and S-mephenytoin hydroxylation by CYP2C19 were dramatically inhibited. Inhibition depended on the amount of CPR and substrate used. By contrast, in the incubation containing CYP2C9, diclofenac hydroxylation was activated by the presence of CYP2C19. These results show that interactions among P450 enzymes can modulate their catalytic rates, which depend on the substrate undergoing metabolism.

  19. The 2 C scenario - A sustainable world energy perspective

    Krewitt, Wolfram; Simon, Sonja [German Aerospace Center (DLR), Institute of Technical Thermodynamics, Department of Systems Analysis and Technology Assessment, Pfaffenwaldring 38-40, 70565 Stuttgart (Germany); Graus, Wina [Ecofys, Kanaalweg 16G, 3526 KL Utrecht (Netherlands); Teske, Sven [Greenpeace International, Ottho Heldringstraat 5, 1066 AZ Amsterdam (Netherlands); Zervos, Arthouros; Schaefer, Oliver [European Renewable Energy Council, 63-65, rue d' Arlon, 1040 Brussels (Belgium)


    A target-oriented scenario of future energy demand and supply is developed in a backcasting process. The main target is to reduce global CO{sub 2} emissions to around 10 Gt/a in 2050, thus limiting global average temperature increase to 2 C and preventing dangerous anthropogenic interference with the climate system. A 10-region energy system model is used for simulating global energy supply strategies. A review of sector and region-specific energy efficiency measures resulted in the specification of a global energy demand scenario incorporating strong energy efficiency measures. The corresponding supply scenario has been developed in an iterative process in close cooperation with stakeholders and regional counterparts from academia, NGOs and the renewable energy industry. The 2 C scenario shows that renewable energy could provide as much as half of the world's energy needs by 2050. Developing countries can virtually stabilise their CO{sub 2} emissions, while at the same time increasing energy consumption through economic growth. OECD countries will be able to reduce their emissions by up to 80%. (author)

  20. 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....

  1. Novel Marmoset Cytochrome P450 2C19 in Livers Efficiently Metabolizes Human P450 2C9 and 2C19 Substrates, S-Warfarin, Tolbutamide, Flurbiprofen, and Omeprazole.

    Uehara, Shotaro; Uno, Yasuhiro; Inoue, Takashi; Kawano, Mirai; Shimizu, Makiko; Toda, Akiko; Utoh, Masahiro; Sasaki, Erika; Yamazaki, Hiroshi


    The common marmoset (Callithrix jacchus), a small New World monkey, has the potential for use in human drug development due to its evolutionary closeness to humans. Four novel cDNAs, encoding cytochrome P450 (P450) 2C18, 2C19, 2C58, and 2C76, were cloned from marmoset livers to characterize P450 2C molecular properties, including previously reported P450 2C8. The deduced amino acid sequence showed high sequence identities (>86%) with those of human P450 2Cs, except for marmoset P450 2C76, which has a low sequence identity (∼70%) with any human P450 2Cs. Phylogenetic analysis showed that marmoset P450 2Cs were more closely clustered with those of humans and macaques than other species investigated. Quantitative polymerase chain reaction analysis showed that all of the marmoset P450 2C mRNAs were predominantly expressed in liver as opposed to the other tissues tested. Marmoset P450 2C proteins were detected in liver by immunoblotting using antibodies against human P450 2Cs. Among marmoset P450 2Cs heterologously expressed in Escherichia coli, marmoset P450 2C19 efficiently catalyzed human P450 2C substrates, S-warfarin, diclofenac, tolbutamide, flurbiprofen, and omeprazole. Marmoset P450 2C19 had high Vmax and low Km values for S-warfarin 7-hydroxylation that were comparable to those in human liver microsomes, indicating warfarin stereoselectivity similar to findings in humans. Faster in vivo S-warfarin clearance than R-warfarin after intravenous administration of racemic warfarin (0.2 mg/kg) to marmosets was consistent with the in vitro kinetic parameters. These results indicated that marmoset P450 2C enzymes had functional characteristics similar to those of humans, and that P450 2C-dependent metabolic properties are likewise similar between marmosets and humans.

  2. Inhibitory effects of curcumin on activity of cytochrome P450 2C9 enzyme in human and 2C11 in rat liver microsomes.

    Wang, Zhe; Sun, Wei; Huang, Cheng-Ke; Wang, Li; Xia, Meng-Ming; Cui, Xiao; Hu, Guo-Xin; Wang, Zeng-Shou


    Cytochrome P450 2C9 (CYP2C9), one of the most important phase I drug metabolizing enzymes, could catalyze the reactions that convert diclofenanc into diclofenac 4'-hydroxylation. Evaluation of the inhibitory effects of compounds on CYP2C9 is clinically important because inhibition of CYP2C9 could result in serious drug-drug interactions. The objective of this work was to investigate the effects of curcumin on CYP2C9 in human and cytochrome P450 2C11 (CYP2C11) in rat liver microsomes. The results showed that curcumin inhibited CYP2C9 activity (10 µmol L(-1) diclofenac) with half-maximal inhibition or a half-maximal inhibitory concentration (IC50) of 15.25 µmol L(-1) and Ki = 4.473 µmol L(-1) in human liver microsomes. Curcumin's mode of action on CYP2C9 activity was noncompetitive for the substrate diclofenanc and uncompetitive for the cofactor NADPH. In contrast to its potent inhibition of CYP2C9 in human, diclofenanc had lesser effects on CYP2C11 in rat, with an IC50 ≥100 µmol L(-1). The observations imply that curcumin has the inhibitory effects on CYP2C9 activity in human. These in vitro findings suggest that more attention should be paid to special clinical caution when intake of curcumin combined with other drugs in treatment.

  3. Exactly solvable models of scattering with SL(2, C) symmetry

    Levay, P. [School of Physics, University of Melbourne, Parkville (Australia); Department of Theoretical Physics, Institute of Physics, Technical University, Budapest (Hungary)


    Using the theory of induced representations two exactly solvable models of non-relativistic scattering with SL(2, C) symmetry are presented. The first describes the scattering of a charged particle moving on the Poincare upper half space H under the influence of an SU(2) non-Abelian gauge potential with isospin s. The second deals with a one-dimensional coupled-channel scattering problem for a charged particle in a matrix-valued scalar potential containing Morse-like interaction terms. The coupled channel wavefunctions and the corresponding scattering matrices are calculated. A detailed description of the underlying geometric structures is also given and a generalization for restricting the motion to fundamental domains of H (three manifolds of constant negative sectional curvature) is outlined. Such models provide an interesting generalization to the known ones of multichannel scattering, quantum chaos and chaotic cosmology. (author)

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

    Nilesh Chordia


    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

  5. Vortex lattice transitions in YNi2B2C

    S J Levett; C D Dewhurst; D McK Paul


    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.

  6. Preparation and characterization of Pt–CeO{sub 2}/C and Pt–TiO{sub 2}/C electrocatalysts with improved electrocatalytic activity for methanol oxidation

    Hameed, R.M. Abdel [Chemistry Department, Faculty of Science, Cairo University, Giza (Egypt); Amin, R.S. [Chemical Engineering Department, National Research Center, Dokki, Giza (Egypt); El-Khatib, K.M., E-mail: [Chemical Engineering Department, National Research Center, Dokki, Giza (Egypt); Fetohi, Amani E. [Chemical Engineering Department, National Research Center, Dokki, Giza (Egypt)


    Graphical abstract: - Highlights: • Adding TiO{sub 2} or CeO{sub 2} to Pt/C reduced its Pt particle size. • Methanol oxidation current density decreased as Pt–CeO{sub 2}/C > Pt–TiO{sub 2}/C > Pt/C. • Decreased R{sub ct} values were observed at Pt–TiO{sub 2}/C and Pt–CeO{sub 2}/C. - Abstract: Pt–TiO{sub 2}/C and Pt–CeO{sub 2}/C electrocatalysts were synthesized by solid state reaction of TiO{sub 2}/C and CeO{sub 2}/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–TiO{sub 2}/C and Pt–CeO{sub 2}/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–TiO{sub 2}/C and Pt–CeO{sub 2}/C, respectively. The electrochemical performance of prepared electrocatalysts was examined using cyclic voltammetry, chronoamperometry and electrochemical impedance spectroscopy. Pt–CeO{sub 2}/C showed an enhanced oxidation current density when compared to Pt/C. Long time oxidation test at Pt–TiO{sub 2}/C and Pt–CeO{sub 2}/C revealed their improved stability. Lower charge transfer resistance values were estimated at Pt–metal oxide/C electrocatalysts.

  7. Study on Cytochrome P450 2C19 (CYP2C19) Genetic Polymorphism in Qinghai Sala Population%青海撒拉族人群CYP2C19基因多态性研究

    李永芳; 杨梅; 寇毅英


    目的 调查青海撒拉族健康人群中CYP2C19基因型及等位基因的分布特征.方法 采用聚合酶链式反应与限制性内切酶片段长度多态性技术(PCR-RFLP),对99例健康撒拉族人群CYP2C19基因多态性进行分析.结果 撒拉族人群的CYP2C19*1、CYP2C19*2和CYP2C19*3 3种等位基因的发生频率分别为56.6%、29.8%和13.6%;CYP2C19*1/*1、CYP2C19* 1/*2、CYP2C19*1/*3、CYP2C19* 2/*2和CYP2C19*2/*3基因型出现频率分别为30.3%、36.4%、16.2%、6.1%和11.1%,CYP2C19* 3/*3的纯合子基因型在本试验中未发现.结论 青海撒拉族人群CYP2C19基因分布明显不同于维族、黎族、傣族、白族、畲族、回族和爱尔兰人,而相似于土族、独龙族、苗族、藏族和汉族.%OBJECTIVE To identify the genotype and allele distribution feature of cytochrome P450 2C19(CYP2C19)in Qinghai Sala population. METHODS The CYP2C19 genotypes of 99 healthy Sala population were detected by polymerase chain reaction-restriction fragment length polymorphism ( PCR-RFLP) technology. RESULTS In Qinghai Sala population, CYP2C19 * 1, CYP2C19 * 2 and CYP2C19 * 3 allele frequencies were 56. 6% ,29. 8% and 13. 6% , respectively; CYP2C19 * 1/ * 1, CYP2C19 * 1/ * 2, CYP2C19 * 1/ * 3, CYP2C19 * 2/ * 2 and CYP2C19 * 2/ * 3 genotype frequencies were 30. 3% , 36.4% , 16. 2% , 6. 1 % and 11. 1 % , respectively ;CYP2C19 * 3 / * 3 homozygous genotype was not found in this study. CONCLUSION The genotype distribution of CYP2C19 in Qinghai Sala population is significantly different to Uigu,Lj,Bai,Dai,She,Hui and Iran population,but similar to Tu.Dulong, Miao, Zang and Han population.

  8. 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.


    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.

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


    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.

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

    Grubor Aleksandar


    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.

  11. Phonon linewidths in YNi2B2C

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


    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.

  12. Enumeration of NKG2C+ natural killer cells early following allogeneic stem cell transplant recipients does not allow prediction of the occurrence of cytomegalovirus DNAemia.

    Giménez, Estela; Solano, Carlos; Amat, Paula; de la Cámara, Rafael; Nieto, José; López, Javier; Garcia-Noblejas, Ana; Navarro, David


    The role of Natural killer (NK) cells in the control of cytomegalovirus (CMV) infection in allogeneic stem cell transplant recipients has not been precisely characterized. The current study is aimed at investigating the potential role of NK cells expressing the activating receptor NKG2C in affording protection against the development of CMV DNAemia in patients exhibiting detectable CMV-specific CD8(+) T-cell responses early following transplantation. A total of 61 nonconsecutive patients were included in the study. Peripheral levels of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK cells and CMV pp65/IE-1-specific IFN-γ-producing CD8(+) T-cells were enumerated by flow cytometry at days +30 and +60 after transplant. Neither the absolute number of NKG2C(+) NK cells, nor that of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK-cell subsets at day 30 differed significantly between patients with or without subsequent CMV DNAemia. No significant correlation was found between levels of both NKG2C(+) NK-cell populations and the peak CMV DNA load within subsequent episodes of CMV DNAemia. The data indicate that enumeration of NKG2C(+) NK cells early after transplant is unlikely to be helpful in identifying those patients at highest risk of developing CMV DNAemia. Moreover, the data do not support a direct implication of NKG2C(+) NK cells in preventing the development of CMV DNAemia.

  13. Establishment of a transgenic cell line stably expressing human cytochrome P450 2C18 and identification of a CYP2C18 clone with exon 5 missing

    Jian Zhu-Ge; Ying-Nian Yu; Yu-Li Qian; Xin Li


    AIM: The human cytochrome P-450 2C18(CYP2C18) hasbeen characterized. However, the protein has not beenpurified from liver and very little is known regarding thespecific substrate of CYP2C18. In order to study its enzymaticactivity for drug metabolism, the CYP2C18cDNA was clonedand a stable CHL cell line expressing recombinant CYP 2C18was established.METHODS: The human CYP2C18cDNA was amplified withreverse transcription-polymerase chain reaction (RT-PCR)from total RNAs extracted from human liver and cloned intopGEM-T vector. The cDNA segment was identified by DNAsequencing and subcloned into a mammalian expressionvector pREP9. A transgenic cell line was established bytransfecting the recombinant plasmid of pREPg-CYP2C18toChinese hamster lung (CHL) cell. The enzyme activity ofCYP2C18 catalyzing oxidation of tolbutamide tohydroxytolbutamide in postmitochondrial supernant(Sg)fraction of the cell was determined by high performanceliquid chromatography(HPLC).RESULTS: The amino acid sequence predicted from thecloned cDNA segment was identical to that of reported byRomkes et al(GenBank accession number: M61856,J05326).The S9 fraction of the established cell line metabolizestolbutamide to hydroxytolbutamide. Tolbutamide hydroxylaseactivity was found to be 0.509±0.052 μmol.min-1.g-1 S9protein or 8.82±0.90 mol.min-1.mol-1 CYP, but wasundetectable in parental CHL cell. In addition, we haveidentified a CYP2C18cDNA clone with exon 5 missing.CONCLUSION: The cDNA of human CYP2C18 wassuccessfully cloned and a cell line, CHL-CYP2C18, efficientlyexpressing the protein of CYP2C18, was established. Aspliced variant of CYP2C18 with exon 5 missing was identifiedin the cloning process.

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

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


    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.

  15. Facile fabrication of transparent TiO2-C@TiO2-C free-standing film for visible-light photocatalytic application

    Hu, Luyang; Zhang, Yumin; Zhang, Shanmei; Li, Benxia


    A transparent TiO2-C@TiO2-C free-standing film has been synthesized by two-step hydrothermal method and subsequent thermal annealing. The chemical composition and morphological features of the TiO2-C@TiO2-C film are characterized using X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy and N2 adsorption-desorption measurement. The results indicate that the flower-like micro/nanostructure TiO2-C particle layers are intimately inhered to porous TiO2-C fibers. The fibers in film are interconnected each other to form a three-dimensional reticulate microstructure, and exhibit intense visible light absorption and high adsorptivity of dye molecules. The interaction between TiO2 and its surface carbon layer in TiO2-C particle promotes the generation of Ti-O-C bonds, which leads to effective charge transfer. Under visible-light irradiation, TiO2-C@TiO2-C film presents enhanced photocatalytic activity for degradation of methylene blue. This work may provide a new viewpoint for designing transparent photocatalytic film for promising applications in heterogeneous photocatalysis.

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


    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.

  17. The Roots of Atractylodes macrocephala Koidzumi Enhanced Glucose and Lipid Metabolism in C2C12 Myotubes via Mitochondrial Regulation

    Mi Young Song


    Full Text Available The root of Atractylodes macrocephala Koidzumi (Atractylodis Rhizoma Alba, ARA is a Traditional Korean Medicine and has been commonly used for weight control. Mitochondrial dysfunction appears to be a key contributor to insulin resistance, and therefore mitochondrial targeting drugs represent an important potential strategy for the treatment of insulin resistance and obesity. In this study, the authors investigated the regulatory effects of ARA on mitochondrial function with respect to the stimulation of glucose and lipid metabolism in C2C12 myotubes. After differentiating C2C12 myotubes, cells were treated with or without different concentrations (0.2, 0.5, and 1.0 mg/mL of ARA extract. ARA extract significantly increased the expression of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC1α and the downregulations of its targets, nuclear respiratory factor-1 (NRF-1, transcription factor A (TFAM, and total ATP content in C2C12 myotubes. ARA extract also increased the expressions of PGC1α activator and of the metabolic sensors, AMP-activated protein kinase (AMPK, and acetyl-CoA carboxylase and sirtuin (SIRT 1. Furthermore, it significantly increased glucose uptake by enhancing glucose consumption and subsequently decreased FFA contents and increased carnitine palmitoyltransferase (CPT 1b expression. Our study indicates that ARA has a potential for stimulating mitochondrial function and energy metabolism in muscle.

  18. Frequencies of two CYP2C19 defective alleles (CYP2C19*2, and *3 among Iranian population in Mazandaran Province

    Naghi Shahabi-Majd


    Conclusion: The result of the present study showed that the two inactive alleles of CYP2C19 accounted for 9.0% of CYP2C19 alleles in our sample versus 8.8 - 40.1% reported in other populations. The frequencies of the studied alleles resulted significant differences between our sample and African and Eastern Asian populations.

  19. Session 6: Decomposition of NO over {beta}-Mo{sub 2}C and {beta}-Mo{sub 2}C/Al{sub 2}O{sub 3} catalysts

    Shengfu, Ji; Chengyue, Li [Beijing University of Chemical Technology, Key Lab. of Science and Technology of Controllable Chemical Reactions, Ministry of Education (China); Shengfu, Ji; Jiaxin, Wang; Jian, Yang; Shuben, Li [State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou (China)


    In this study, for the first time it has been found that the the bulk {beta}-Mo{sub 2}C and an alumina-supported {beta}-Mo{sub 2}C catalysts are very active for the direct NO decomposition at low temperature. The obtained experimental results are presented. (authors)

  20. Synthesis of furo[3,2-c ]- and pyrano[ 3,2-c ] quinolines by lanthanide triflate catalyzed imino-Diels-Alder reaction

    MA, Yun(马云); QIAN, Chang-Tao(钱长涛); SUN, Jie(孙杰); XIE, Mei-Hua(谢美华)


    Imino Diels-Alder reaction of imines witth 2,3-dihydrofuran or 3,4-dihydro-2H-pyran proceeded smothly in the presence of a catalytic amount (0.5 mol %) of ytterbium triflate to afford furo[3,2-c]- and pyrano[3,2-c] quinolines conveniently in high yield.

  1. Enhanced tolerance to low temperature in tobacco by over-expression of a new maize protein phosphatase 2C, ZmPP2C2.

    Hu, Xiaoli; Liu, Lixia; Xiao, Beilei; Li, Dapeng; Xing, Xin; Kong, Xiangpei; Li, Dequan


    Low temperature is one of the most common environmental stresses affecting plant growth and agricultural production. Serine/threonine protein phosphatases 2C (PP2Cs) have been suggested to play an important role in stress signaling. To identify potential new member of the PP2C proteins in maize and investigate its functions for stress responses, the ZmPP2C2 gene, encoding a new PP2C protein from maize roots, was cloned by RT-PCR and RACE-PCR. Its constitutive expression in roots, stems and leaves of maize seedlings was detected by RNA gel blot, and its regulation in response to cold stress was also examined. To further evaluate its function in the cold stress response, we over-expressed the ZmPP2C2 gene in tobacco under the control of the Cauliflower Mosaic Virus (CaMV) 35S promoter, and assessed a series of physiological changes in wild type and transgenic plants under low temperatures. Compared with wild type tobacco under cold stress, plants that over-expressed ZmPP2C2 displayed higher germination speed and rate, higher antioxidant enzyme (SOD, POD, CAT) activities, with lower cold-induced electrolyte leakage and malondialdehyde (MDA) contents. These results show that over-expression of ZmPP2C2 in tobacco enhanced tolerance to cold stress, suggesting that this new gene, ZmPP2C2, may act as a positive regulator of cold resistance in plants.

  2. 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...

  3. Data of evolutionary structure change: 1ACLA-2C0QA [Confc[Archive


  4. Data of evolutionary structure change: 1ACLA-2C0QB [Confc[Archive


  5. Data of evolutionary structure change: 1ACLA-2C0PA [Confc[Archive


  6. Data of evolutionary structure change: 1ACLA-2C0PB [Confc[Archive


  7. 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...

  8. 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...

  9. 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...

  10. 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...

  11. Insulin sensitizing effects of oligomannuronate-chromium (III complexes in C2C12 skeletal muscle cells.

    Cui Hao

    Full Text Available BACKGROUND: It was known that the insulin resistance in skeletal muscle is a major pathogenic factor in diabetes mellitus. Therefore prevention of metabolic disorder caused by insulin resistance and improvement of insulin sensitivity are very important for the therapy of type 2 diabetes. In the present study, we investigated the ability of marine oligosaccharides oligomannuronate and its chromium (III complexes from brown alga to enhance insulin sensitivity in C2C12 skeletal muscle cells. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that oligomannuronate, especially its chromium (III complexes, enhanced insulin-stimulated glucose uptake and increased the mRNA expression of glucose transporter 4 (GLUT4 and insulin receptor (IR after their internalization into C2C12 skeletal muscle cells. Additionally, oligosaccharides treatment also significantly enhanced the phosphorylation of proteins involved in both AMP activated protein kinase (AMPK/acetyl-CoA carboxylase (ACC and phosphoinositide 3-kinase (PI3K/protein kinase B (Akt signaling pathways in C2C12 cells, indicating that the oligosaccharides activated both the insulin signal pathway and AMPK pathways as their mode of action. Moreover, oligosaccharides distributed to the mitochondria after internalization into C2C12 cells and increased the expression of transcriptional regulator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, carnitine palmitoyl transferase-1 (CPT-1, and phosphorylated acetyl-CoA carboxylase (p-ACC, which suggested that the actions of these oligosaccharides might be associated with mitochondria through increasing energy expenditure. All of these effects of marine oligosaccharides were comparable to that of the established anti-diabetic drug, metformin. In addition, the treatment with oligosaccharides showed less toxicity than that of metformin. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that oligomannuonate and its chromium (III complexes improved

  12. Identification of an RNA element for specific coordination of A-to-I RNA editing on HTR2C pre-mRNA.

    Fukuda, Masatora; Oyama, Yui; Nishitarumizu, Azusa; Omura, Miki; Nose, Kanako; Deshimaru, Masanobu


    Adenosine-to-Inosine (A-to-I) RNA editing is an intracellular mechanism in which inosine is specifically substituted against adenosine by the action of adenosine deaminases acting on RNA (ADARs). Serotonin 2C receptor (HTR2C) is encoded through combinatorial A-to-I RNA editing at recoding sites (A - E site) on its pre-mRNA. Although the efficiency of RNA editing at particular sites is known to be critical for modulating the serotonin signaling, the mechanistic details of site-specific editing on HTR2C pre-mRNA are not fully understood. Toward complete understanding of this mechanism, we discovered an RNA element, which coordinates site-specific RNA editing on HTR2C pre-mRNA by an in vitro editing assay and secondary structural analysis of mutant HTR2C RNA fragments. Our results showed that HTR2C pre-mRNA forms a characteristic structure, which was restricted by the internal loop and Watson-Crick base-pair interaction on site E, for intrinsic editing. We suggest that the internal loop would contribute toward adjusting the relative distance and/or geometry between the editing sites and the scaffold for ADAR.

  13. Genetic polymorphisms of CYP2C9%药物代谢酶CYP2C9基因多态性

    李树春; 王桂萍


    Human cytochrome P450 2C9 (CYP2C9) accounts for -20% of hepatic total cytochrome P450 content and metabolizes~15% clinical drugs, especially the drugs with a narrow therapeutic index. CYP2C9 is highly polymorphism. Many results have shown that the genetic polymorphisms of CYP2C9 have close relationship with drug metabolism and adverse drug reaction. According to CYP2C9 enzyme activity, CYP2C9 could be classified as extensive metabolizers, intermedia metabolizers and poor metabolizers. The relationship between genetic polymorphisms and phenotypes, have become the prevalent research topics in the area of pharmacogenetics. In this paper, we reviewed the genetic polymorphisms of CYP2C9 in four areas: the mechanism, metabolic phenotype, drug metabolism and disease susceptibility.%细胞色素氧化酶P450 2C9(CYP2C9)是人类肝脏中一类重要的药物代谢酶,负责约15%临床上常用药物(特别是一些治疗安全范围较窄的药物)的代谢.CYP2C9基因具有高度多态性,研究表明该多态性与药物代谢和药物不良反应的产生关系密切.根据CYP2C9突变基因对CYP2C9酶活性的影响结果,一般可将CYP2C9的代谢表型划分为泛代谢型、中间代谢型和弱代谢型.近年来对该基因多态性及其与表型关系的研究再次成为遗传药理学研究的热点.本文从发生机制、代谢表型、药物代谢以及疾病的易感性等四个方面对CYP2C9基因多态性进行综述.

  14. 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


    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.

  15. 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 ...

  16. Effect of CYP2C9 genetic polymorphism on the metabolism of flurbiprofen in vitro.

    Wang, Li; Bao, Shi-Hui; Pan, Pei-Pei; Xia, Meng-Ming; Chen, Meng-Chun; Liang, Bing-Qing; Dai, Da-Peng; Cai, Jian-Ping; Hu, Guo-Xin


    CYP2C9 is an important member of the cytochrome P450 enzyme superfamily, and 57 cytochrome P450 2C9 alleles have been previously reported. To examine the enzymatic activity of the CYP2C9 alleles, kinetic parameters for 4'-hydroxyflurbiprofen were determined using recombinant human P450s CYP2C9 microsomes from insect cells Sf21 carrying wild-type CYP2C9*1 and other variants. The results showed that the enzyme activity of most of the variants decreased comparing with the wild type as the previous studies reported, while the enzyme activity of some of them increased, which were not in accordance with the previous researches. Of the 36 tested CYP2C9 allelic isoforms, two variants (CYP2C9*53 and CYP2C9*56) showed a higher intrinsic clearance value than the wild-type protein, especially for CYP2C9*56, exhibited much higher intrinsic clearance (197.3%) relative to wild-type CYP2C9*1, while the remaining 33 CYP2C9 allelic isoforms exhibited significantly decreased clearance values (from 0.6 to 83.8%) compared to CYP2C9*1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP2C9 variants in the Chinese population with regard to the commonly used non-steroidal anti-inflammatory drug, flurbiprofen (FP). The results indicated that most of the tested rare alleles decreased the catalytic activity of CYP2C9 variants toward FP hydroxylation in vitro. This is the first report of all these rare alleles for FP metabolism providing fundamental data for further clinical studies on CYP2C9 alleles for FP metabolism in vivo.

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

    Jeffrey eKim


    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

  18. Reduced Toxicity of Shiga Toxin (Stx Type 2c in Mice Compared to Stx2d Is Associated with Instability of Stx2c Holotoxin

    Joshua C. Bunger


    Full Text Available Shiga toxin (Stx is an AB5 ribotoxin made by Stx-producing Escherichia coli (STEC. These organisms cause diarrhea, hemorrhagic colitis and the hemolytic uremic syndrome. STEC make two types of Stxs, Stx1 and/or Stx2. Stx2 has one prototype (a and six subtypes (b–g, but only STEC that make Stx2a, and/or Stx2c, or Stx2d are associated with severe disease. However, Stx2c is about 10-fold less toxic than Stx2d in vivo despite only two amino acid differences in the A subunit at positions 291 and 297. We made mutations at these two sites to create intermediate toxins between Stx2c and Stx2d, and determined the 50% cytotoxic dose on Vero cells before and after heat treatment, and the 50% lethal dose in mice of the toxins. We found that serine 291 was associated with increased toxicity in vivo and that either amino acid change from that in Stx2c to that in Stx2d increased heat stability. We also assessed the secondary structure of Stx2c and Stx2d by circular dichroism (CD spectroscopy. The CD studies suggest that Stx2c has a less-ordered secondary structure than Stx2d. We conclude that both amino acids at positions 291 and 297 in Stx2c contribute to its decreased stability and in vivo toxicity compared to Stx2d.

  19. Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response.

    Halberstadt, Adam L; Geyer, Mark A


    N-benzyl substitution markedly enhances the affinity of phenethylamine hallucinogens at the 5-HT(2A) receptor. N-benzyl substituted derivatives of 2,5-dimethoxy-4-iodophenethylamine (2C-I), such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) and N-(2,3-methylenedioxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBMD), have appeared recently as designer drugs, but have not been characterized behaviorally. The head twitch response (HTR) is induced by 5-HT(2A) receptor activation in rats and mice, and is widely used as a behavioral proxy for hallucinogen effects in humans. Nevertheless, it is not clear whether phenethylamine hallucinogens reliably provoke this behavior. Hence, we investigated whether 2C-I, 25I-NBOMe and 25I-NBMD induce head twitches in C57BL/6J mice. The HTR was assessed using a head-mounted magnet and a magnetometer coil. 2C-I (1-10 mg/kg SC), 25I-NBOMe (0.1-1 mg/kg SC), and 25I-NBMD (1-10 mg/kg SC) induced the HTR. 25I-NBOMe displayed 14-fold higher potency than 2C-I, and the selective 5-HT(2A) antagonist M100,907 completely blocked the HTR induced by all three compounds. These findings show that phenethylamine hallucinogens induce the HTR by activating 5-HT(2A) receptors. Our results demonstrate that 25I-NBOMe is a highly potent derivative of 2C-I, confirming previous in vitro findings that N-benzyl substitution increases 5-HT(2A) affinity. Given the high potency and ease of synthesis of N-benzylphenethylamines, it is likely that the recreational use of these hallucinogens will become more widespread in the future.

  20. Interaction of 2C T cells with a hybrid Ld molecule bearing an alpha 3 domain derived from the class IB molecule, Qa-2.

    Ungchusri, T; Kettman, J R; Forman, J


    The CD8 co-receptor interacts with nonpolymorphic residues on class I molecules. LQ3, a laboratory engineered Ld molecule bearing an alpha 3 domain derived from Q7 (Qa-2), interacts poorly with anti-Ld CD8-dependent T cells. 2C TCR transgenic mice bear a receptor specific for the p2Ca peptide bound to Ld. The authors show that although this peptide interacts with LQ3, LQ3 APC fail to activate splenic 2C CD8 T cells in vitro in the absence of IL-2, while control Ld APC do. The authors have used this receptor ligand pair to examine negative selection within the thymus of (B6 x C3H.Ld)F1 versus (B6 x C3H.LQ3)F1 radiation chimeras repopulated with 2C bone marrow cells. While positive selection occurs normally in (B6 x C3H)F1 chimeras, animals expressing either Ld or LQ3 fail to generate 2C CD8+ cells. Thus, either CD8 is not required for negative selection of this TCR or a weak interaction of CD8 with LQ3 is sufficient. TSA-1, a developmentally regulated marker, was used to follow the process of negative selection. The results show that deletion of 2C T cells does not occur until thymocytes reach the double positive (DP) stage. Furthermore, the authors noted a small population of DP TSA-1hi cells remains, while DP TSA-1int and TSA-1lo cells are absent. These data support the notion that thymocytes either reach a particular stage of development or locate in an appropriate intrathymic compartment before they undergo negative selection.

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

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


    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...

  2. Establishment of a functional cell line expressing both subunits of H1a and H2c of human hepatocyte surface molecule ASGPR.

    Hu, Bin; Yang, Yan; Liu, Jia; Ma, Zhiyong; Huang, Hongping; Liu, Shenpei; Yu, Yuan; Hao, Youhua; Wang, Baoju; Lu, Mengji; Yang, Dongliang


    To better understand the effect of a new split variant of human asialoglycoprotein receptor (ASGPR H1b) on ASGPR ligands' binding ability, we established a functional cell line which expresses ASGPR. The full lengths of ASGPRH1a and H2c fragments from human liver were amplified by reverse transcript PCR (RT-PCR) and inserted into eukaryotic expression vector pIRES2EGFP, pCDNA3.1 (Zeo+) respectively. The recombinants were co-transfected into HeLa cells. After selection by using Neocin and Zeocin, a stably transfected cell line was established, which was designated 4-1-6. The transcription and expression of ASGPRH1a and H2c in 4-1-6 were confirmed by RT-PCR, Western blotting and immunofluorescence. The endocytosis function of the artificial "ASGPR" on the surface of 4-1-6 was tested by FACS. It was found that the cell line 4-1-6 could bind ASGPR natural ligand molecular asialo-orosomucoid (ASOR). After the eukaryotic plasmid H1b/pCDNA3.1 (neo) was transfected into cell line 4-1-6, H1b did not down-regulate the ligand binding ability of ASGPR. The eukaryotic expression plasmid H1b/pcDNA3.1 (neo) and H2c/pcDNA3.1 (neo) were co-transfected transiently into Hela cell. Neither single H1b nor H1b and H2c could bind ASOR. In conclusion, a functional cell line of human asialoglycoprotein receptor (ASGPR) which expresses both H1a and H2c stably was established. The new split variant H1b has no effect on ASGPR binding to ASOR. ASGPRH1b alone can't bind to ASOR, it yet can't form functional complex with ASGPRH2c.

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

    André Felipe Streck


    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.

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

    Banerjee, Sarmistha; Das, Rajat Kumar; Giffear, Kelly A.; Shapiro, Bernard H., E-mail:


    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

  5. 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 ...

  6. Metabolism of R- and S-Warfarin by CYP2C19 into Four Hydroxywarfarins

    Kim, So-Young; Kang, Ji-Yeon; Hartman, Jessica H.; Park, Sun-Ha; Jones, Drew R.; Yun, Chul-Ho; Boysen, Gunnar; Miller, Grover P.


    Coumadin (R/S-warfarin) is a highly efficacious and widely used anticoagulant; however, its highly variable metabolism remains an important contributor to uncertainties in therapeutic responses. Pharmacogenetic studies report conflicting findings on the clinical relevance of CYP2C19. A resolution to this controversy is impeded by a lack of detail on the potential role of CYP2C19 in warfarin metabolism. Consequently, we assessed the efficiency of CYP2C19 metabolism of R- and S-warfarin and explored possible contributions in the liver using in vitro methods. Recombinant CYP2C19 metabolized R- and S-warfarin mainly to 6-, 7-, and 8-hydroxywarfarin, while 4′-hydroxywarfarin was a minor metabolite. Overall R-warfarin metabolism was slightly more efficient than that for S-warfarin. Metabolic pathways that produce R-6-, 7-, and 8-hydroxywarfarin in human liver microsomal reactions correlated strongly with CYP2C19 S-mephenytoin hydroxylase activity. Similarly, CYP1A2 activity toward phenacetin correlated with formation of R-6 and 7-hydroxywarfarin such that R-8-hydroxywarfarin seems unique to CYP2C19 and possibly a biomarker. In following, CYP2C19 likely impacts R-warfarin metabolism and patient response to therapy. Intriguingly, CYP2C19 may contribute to S-warfarin metabolism in patients, especially when CYP2C9 activity is compromised due to drug interactions or genetic polymorphisms. PMID:23331088

  7. Frequency of CYP2C9 alleles in Koreans and their effects on Iosartan pharmacokinetics

    Jung-woo BAE; Byung-sung KANG; Hye-in LEE; Yun-jeong LEE; Hyun-joo PARK; Ji-hey HA; Hee-jung SHIN; Young-hoon KIM; Han-sung NA; Myeon-woo CHUNG; Soon-young HAN; Chang-ik CHOI; Seung-hee KIM; Choon-gon JANG; Seok-yong LEE; Mi-jeong KIM; Da-hee OH; Seul-ki KEUM; Jung-in PARK; Bo-hye KIM; Hye-kyoung BANG; Sung-gon OH


    Aim:CYP2C9 enzyme metabolizes numerous clinically important drugs.The aim of this study is to investigate the frequencies of CYP2C9 genotypes and the effects of selected alleles on Iosartan pharmacokinetics in a large sample of the Korean population.Methods:The CYP2C9 gene was genotyped in 1796 healthy Korean subjects.CYP2C9 alleles (CYP2C9*1,*2,*3,and *13 alleles)were measured using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and direct sequencing assay.The enzymatic activity of each CYP2C9 genotype was evaluated using losartan as the substrate.Results:The frequencies of CYP2C9*1,*3,and *13 allele were 0.952 (95% confidence interval 0.945-0.959),0.044 (95% CI 0.037-0.051),and 0.005 (95% CI 0.003-0.007),respectively.The frequencies of the CYP2C9*1/*1,*1/*3,*1/*13,and *3/*3 genotypes were 0.904 (95% CI 0.890-0.918),0.085 (95% CI 0.072-0.098),0.009 (95% CI 0.005-0.013),and 0.001 (95% CI 0.000-0.002),respectively.In the pharmacokinetics studies,the AUC0-∞ of losartan in CYP2C9*3/*3 subject was 1.42-fold larger than that in CYP2C9*1/*1 subjects,and the AUC0-∞ of E-3174,a more active metaboiite of Iosartan,in CYP2C9*3/*3 subject was only 12% of that in CYP2C9*1/*1 subjects.Conclusion:The results confirmed the frequencies of CYP2C9 genotypes in a large cohort of Koreans,and detected the CYP2C9*3/*3 genotype.CYP2C9*3/*3 subjects metabolized much less losartan into E-3174 than CYP2C9*1/*1 subjects.

  8. 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.

  9. 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


    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

  10. Mechanical stimulation of C2C12 cells increases m-calpain expression, focal adhesion plaque protein degradation

    Grossi, Alberto; Karlsson, Anders H; Lawson, Moira Ann


    reorganization due to the activity of the ubiquitous proteolytic enzymes, calpains, has been reported. Whether there is a link between stretch- or load-induced signaling and calpain expression and activation is not known. Using a magnetic bead stimulation assay and C2C12 mouse myoblasts cell population, we have...... demonstrated that mechanical stimulation via laminin receptors leads to an increase in m-calpain expression, but no increase in the expression of other calpain isoforms. Our study revealed that after a short period of stimulation, m-calpain relocates into focal adhesion complexes and is followed by a breakdown...... of specific focal adhesion proteins previously identified as substrates for this enzyme. We show that stimulation also leads to an increase in calpain activity in these cells. These data support the pivotal role for m-calpain in the control of muscle precursor cell differentiation and thus strengthen the idea...

  11. Interaction between DRD2 C957T polymorphism and an acute psychosocial stressor on reward-related behavioral impulsivity.

    White, Melanie J; Lawford, Bruce R; Morris, C Phillip; Young, Ross McD


    The dopamine D2 receptor (DRD2) C957T polymorphism CC genotype is associated with decreased striatal binding of DRD2 and executive function and working memory impairments in healthy adults. We investigated the relationships between C957T and acute stress with behavioral phenotypes of impulsivity in 72 young adults randomly allocated to either an acute psychosocial stress or relaxation induction condition. Homozygotes for 957C showed increased reward responsiveness after stress induction. They were also quicker when making immediate choices on the delay discounting task when stressed, compared with homozygotes who were not stressed. No effects were found for response inhibition, a dimension of impulsivity not related to extrinsic rewards. These data suggest that C957T is associated with a reward-related impulsivity endophenotype in response to acute psychosocial stress. Future studies should examine whether the greater sensitivity of 957C homozygotes to the effects of stress is mediated through dopamine release.

  12. Protein O-fucosyltransferase 1 expression impacts myogenic C2C12 cell commitment via the Notch signaling pathway.

    Der Vartanian, Audrey; Audfray, Aymeric; Al Jaam, Bilal; Janot, Mathilde; Legardinier, Sébastien; Maftah, Abderrahman; Germot, Agnès


    The Notch signaling pathway plays a crucial role in skeletal muscle regeneration in mammals by controlling the transition of satellite cells from quiescence to an activated state, their proliferation, and their commitment toward myotubes or self-renewal. O-fucosylation on Notch receptor epidermal growth factor (EGF)-like repeats is catalyzed by the protein O-fucosyltransferase 1 (Pofut1) and primarily controls Notch interaction with its ligands. To approach the role of O-fucosylation in myogenesis, we analyzed a murine myoblastic C2C12 cell line downregulated for Pofut1 expression by short hairpin RNA (shRNA) inhibition during the time course of differentiation. Knockdown of Pofut1 affected the signaling pathway activation by a reduction of the amount of cleaved Notch intracellular domain and a decrease in downstream Notch target gene expression. Depletion in Pax7(+)/MyoD(-) cells and earlier myogenic program entrance were observed, leading to an increase in myotube quantity with a small number of nuclei, reflecting fusion defects. The rescue of Pofut1 expression in knockdown cells restored Notch signaling activation and a normal course in C2C12 differentiation. Our results establish the critical role of Pofut1 on Notch pathway activation during myogenic differentiation.

  13. A genetic variant of HTR2C may play a role in the manifestation of Tourette syndrome.

    Dehning, Sandra; Müller, Norbert; Matz, Judith; Bender, Andreas; Kerle, Irina; Benninghoff, Jens; Musil, Richard; Spellmann, Ilja; Bondy, Brigitta; Möller, Hans-Juergen; Riedel, Michael; Zill, Peter


    Gilles de la Tourette syndrome (GTS) (MIM 137580) is a complex neuropsychiatric disorder probably originating from a disturbed interplay of several neurotransmitter systems in the prefrontal-limbic-basal ganglia loop. Polygenetic multifactorial inheritance has been postulated; nevertheless, no confirmed susceptible genes have been identified yet. As neuroimaging studies allude to dopaminergic and serotonergic dysfunction in GTS and serotonin as an important factor for dopamine release, genotyping of common polymorphisms in the serotonergic receptor (HTR1A: C-1019G; HTR2A: T102C, His452Tyr, A-1438G; HTR2C: C-759T, G-697C) and transporter genes (SLC6A4) was carried out in 87 patients with GTS, compared with 311 matched controls. We found a nominally significant association between both polymorphisms in the HTR2C and the GTS, which was more pronounced in male patients. Analysis of the further serotonergic polymorphisms did not reveal any significant result. A modified function of these promoter polymorphisms may contribute to the complex interplay of serotonin and dopamine and then to the manifestation of GTS.

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

    Carlos Alexandre Twardowschy


    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.

  15. ABA Receptors: Past, Present and Future

    Guo, Jianjun [Harvard University; Yang, Xiaohan [ORNL; Weston, David [ORNL; Chen, Jay [ORNL


    Abscisic acid (ABA) is the key plant stress hormone. Consistent with the earlier studies in support of the presence of both membrane- and cytoplasm-localized ABA receptors, recent studies have identified multiple ABA receptors located in various subcellular locations. These include a chloroplast envelope-localized receptor (the H subunit of Chloroplast Mg2+-chelatase/ABA Receptor), two plasma membrane-localized receptors (G-protein Coupled Receptor 2 and GPCR-type G proteins), and one cytosol/nucleus-localized Pyrabactin Resistant (PYR)/PYR-Like (PYL)/Regulatory Component of ABA Receptor 1 (RCAR). Although the downstream molecular events for most of the identified ABA receptors are currently unknown, one of them, PYR/PYL/RACR was found to directly bind and regulate the activity of a long-known central regulator of ABA signaling, the A-group protein phosphatase 2C (PP2C). Together with the Sucrose Non-fermentation Kinase Subfamily 2 (SnRK2s) protein kinases, a central signaling complex (ABA-PYR-PP2Cs-SnRK2s) that is responsible for ABA signal perception and transduction is supported by abundant genetic, physiological, biochemical and structural evidence. The identification of multiple ABA receptors has advanced our understanding of ABA signal perception and transduction while adding an extra layer of complexity.

  16. Abscisic Acid Receptors: Past, Present and Future

    Jianjun Guo; Xiaohan Yang; David J. Weston; Jin-Gui Chen


    Abscisic acid (ABA) is the key plant stress hormone. Consistent with the earlier studies in support of the presence of both membrane- and cytoplasm-localized ABA receptors, recent studies have identified multiple ABA receptors located in various subcellular locations. These include a chloroplast envelope-localized receptor (the H subunit of Chloroplast Mg2+-chelatase/ABA Receptor), two plasma membrane-localized receptors (G-protein Coupled Receptor 2 and GPCR-type G proteins),and one cytosol/nucleus-localized Pyrabactin Resistant (PYR)/PYR-Like (PYL)/Regulatory Component of ABA Receptor 1 (RCAR). Although the downstream molecular events for most of the identified ABA receptors are currently unknown, one of them, PYR/PYL/RCAR was found to directly bind and regulate the activity of a long-known central regulator of ABA signaling, the A-group protein phosphatase 2C (PP2C). Together with the Sucrose Non-fermentation Kinase Subfamily 2 (SnRK2s) protein kinases, a central signaling complex (ABA-PYR-PP2Cs-SnRK2s) that is responsible for ABA signal perception and transduction is supported by abundant genetic, physiological, biochemical and structural evidence. The identification of multiple ABA receptors has advanced our understanding of ABA signal perception and transduction while adding an extra layer of complexity.

  17. First-Principle Calculations of Hardness and Melting Point of Mo2C

    X.R.Wang; M.F.Yan; H.T.Chen


    This paper has constructed two kinds of atomic and electronic models for hexagonal β-Mo2C and orthorhombic α-Mo2C.The optimized lattice parameters, elastic constant matrixes and overlap population for Mo2C crystal cells have been obtained to realize the characterization of the hardness and melting point of the two structures by the first-principles plane wave pseudo potential method based on the density functional theory. The results reveal that the calculated lattice parameters of the Mo2C crystal cells agree with the experimental and other calculated data.The calculated melting point/hardness are 2715 K/11.38 GPa for β-Mo2C and 2699 K/10.57~12.67 GPa for α-Mo2C, respectively.The calculated results from the density of states (DOS)demonstrate that the hybridization effect between Mo-3d and C-2p states in α-Mo2C crystal cell is much stronger than that in β-Mo2C one.

  18. Hydrogenation of Benzene over Mo2C/Al2O3 Catalyst

    Zhang Jing; Wu Weicheng


    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.

  19. 40 CFR Table 2c to Subpart E of... - Reactivity Factors for Aromatic Hydrocarbon Solvent Mixtures


    ... 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...

  20. 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


    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

  1. Draft genome sequence of the antagonistic rhizosphere bacterium Serratia plymuthica strain PRI-2C.

    Garbeva, P; van Elsas, J D; de Boer, W


    Serratia plymuthica strain PRI-2C is a rhizosphere bacterial strain with antagonistic activity against different plant pathogens. Here we present the 5.39-Mb (G+C content, 55.67%) draft genome sequence of S. plymuthica strain PRI-2C with the aim of providing insight into the genomic basis of its antagonistic activity.

  2. Genotype of cytochrome-450 2C9 in patients with tuberculosis

    Kresyun V.I.


    Full Text Available The aim of present work was to investigate CYP2С9 polymorphism in the south of Ukraine in TB-patients and comparing with the same data of control group by the example of Odessa region. Gene CYP2С9 polymorphism was studied with the help of PCR (polymerase chain reaction and endonuclease analysis. The blood samples were obtained from patients with new cases of pulmonary TB from Odessa regional antituberculous dispensary and healthy donors in Odessa district station of blood transfusion in the year 2010-12. According to genotype of CYP2C9 of 55 TB-patients, 67,3% persons were the carriers of homozygote wild gene CYP2C9*1/*1, 21,8 and 3,6% - heterozygote genes CYP2C9*1/*2 and CYP2C9*1/*3. Only 7,2% individuals belonged to carriers of slow metabolizers genotype - CYP2C9*2/*2, *2/*3, *3/*3. In general, the mutated alleles CYP2C9*2 and CYP2C9*3 in TB-males were observed by 1,8 times more frequently than among healthy donors of the same gender. TB-patients older than 30 years more frequently had mutated allele CYP2C9*2, almost by 3 times than individuals from control group.

  3. Data of evolutionary structure change: 1CRLA-2C0PA [Confc[Archive


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

    Qun Wei


    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.

  5. High specific surface area Mo2C nanoparticles as an efficient electrocatalyst for hydrogen evolution

    Tang, Chaoyun; Sun, Aokui; Xu, Yushuai; Wu, Zhuangzhi; Wang, Dezhi


    Mo2C nanoparticles with high specific surface area (120 m2 g-1) are successfully synthesized using a typical and low-cost monosaccharide of glucose via a facile calcination and subsequent reduction process. The HER functions of the obtained Mo2C nanoparticles are investigated and the effect of reduction time in hydrogen is also discussed. It is found that η-MoC can be obtained at 800 °C with a reduction time of 10 min, but the formation of β-Mo2C phase requires more than 20 min. Moreover, the β-Mo2C obtained with a reduction time of 20 min exhibits the best HER activity with a small Tafel slope of 55 mV dec-1 and a large current density of 60 mA cm-2 at -200 mV, which is among the best records over Mo2C-based HER catalysts.

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

    Anichavezhi Devendran


    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.

  7. Cytoprotective Effect of Hispidin against Palmitate-Induced Lipotoxicity in C2C12 Myotubes

    Jun Myoung Park


    Full Text Available It is well known that Phellinus linteus, which produces hispidin and its derivatives, possesses antioxidant activities. In this study, we investigated whether hispidin has protective effects on palmitate-induced oxidative stress in C2C12 skeletal muscle cells. Our results showed that palmitate treatment in C2C12 myotubes increased ROS generation and cell death as compared with the control. However, pretreatment of hispidin for 8 h improved the survival of C2C12 myotubes against palmitate-induced oxidative stress via inhibition of intracellular ROS production. Hispidin also inhibited palmitate-induced apoptotic nuclear condensation in C2C12 myotubes. In addition, we found that hispidin can suppress cleavage of caspase-3, expression of Bax, and NF-κB translocation. Therefore, these results suggest that hispidin is capable of protecting C2C12 myotubes against palmitate-induced oxidative stress.

  8. The alpha2C-adrenoceptor modulates GABA release in mouse striatum.

    Zhang, Weilie; Ordway, Gregory A


    The alpha(2C)-adrenoceptor occurs in high density in the striatum relative to other brain regions, but its biological role in striatal physiology is perplexing because of the paucity of noradrenergic terminals in this region. In this study, mice with a targeted inactivation of the alpha(2C)-adrenoceptor gene (alpha(2C)-KO mice), and genetically related mice (WT mice), were used to study the potential role of the striatal alpha(2C)-adrenoceptor in modulating GABA release. Perfused brain slices were pre-loaded with [(3)H]GABA and were stimulated electrically. In WT mice, the alpha(2)-adrenoceptor agonist, UK14304 (brimonidine), significantly enhanced [(3)H]GABA release from striatal slices, while the alpha(2)-adrenoceptor antagonist, RX821002, alone evoked a significant decrease in [(3)H]GABA release. In alpha(2C)-KO mice, the effect of RX821002 was absent, while UK14304 retained its ability to enhance [(3)H]GABA release. Pharmacological depletion of monoamines in WT mice also abolished the effect of RX821002 on [(3)H]GABA release. In hippocampal slices, RX821002-induced reduction in [(3)H]GABA release was present in WT and alpha(2C)-KO mice. In the presence of tetrodotoxin, RX821002 increased [(3)H]GABA release in striatal slices from both WT and alpha(2C)-KO mice. Together, these data imply that alpha(2A)- and alpha(2C)-adrenoceptors are located on different neurons in the striatum, that alpha(2C)-adrenoceptor-mediated effects on striatal GABA release are mediated by an endogenous catecholamine that could be dopamine, and that the alpha(2C)-adrenoceptor effect of RX821002 does not occur at the GABAergic terminal.

  9. Structural and functional characterization of the coxsackievirus B3 CRE(2C): role of CRE(2C) in negative- and positive-strand RNA synthesis.

    Ooij, M.J. van; Vogt, D.A.; Paul, A.; Castro, C.; Kuijpers, J.M.; Kuppeveld, F.J.M. van; Cameron, C.E.; Wimmer, E.; Andino, R.; Melchers, W.J.G.


    A stem-loop element located within the 2C-coding region of the coxsackievirus B3 (CVB3) genome has been proposed to function as a cis-acting replication element (CRE). It is shown here that disruption of this structure indeed interfered with viral RNA replication in vivo and abolished uridylylation

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

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


    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...

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

    Toft, Katrine Nørgaard

    along [110], the magnetic structure rotates a small angle of 0.5 degrees away from the symmetrydirection. 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......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 ofsuperconductivity. 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...




    En esta tesis, los receptores serotoninérgicos 5-HT2A y 5-HT2c fueron escogidos como modelos de la familia más amplia de receptores insertos en membranas y acoplados a proteínasG con el propósito de estudiar las interacciones ligando-receptor. Utilizando 183p.

  13. Spatial segregation of BMP/Smad signaling affects osteoblast differentiation in C2C12 cells.

    Eva Heining

    Full Text Available BACKGROUND: Bone morphogenetic proteins (BMPs are involved in a plethora of cellular processes in embryonic development and adult tissue homeostasis. Signaling specificity is achieved by dynamic processes involving BMP receptor oligomerization and endocytosis. This allows for spatiotemporal control of Smad dependent and non-Smad pathways. In this study, we investigate the spatiotemporal regulation within the BMP-induced Smad transcriptional pathway. METHODOLOGY/PRINCIPAL FINDINGS: Here we discriminate between Smad signaling events that are dynamin-dependent (i.e., require an intact endocytic pathway and dynamin-independent. Inhibition of dynamin-dependent endocytosis in fluorescence microscopy and fractionation studies revealed a delay in Smad1/5/8 phosphorylation and nuclear translocation after BMP-2 stimulation of C2C12 cells. Using whole genome microarray and qPCR analysis, we identified two classes of BMP-2 induced genes that are differentially affected by inhibition of endocytosis. Thus, BMP-2 induced gene expression of Id1, Id3, Dlx2 and Hey1 is endocytosis-dependent, whereas BMP-2 induced expression of Id2, Dlx3, Zbtb2 and Krt16 is endocytosis-independent. Furthermore, we demonstrate that short term inhibition of endocytosis interferes with osteoblast differentiation as measured by alkaline phosphatase (ALP production and qPCR analysis of osteoblast marker gene expression. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that dynamin-dependent endocytosis is crucial for the concise spatial activation of the BMP-2 induced signaling cascade. Inhibition of endocytic processes during BMP-2 stimulation leads to altered Smad1/5/8 signaling kinetics and results in differential target gene expression. We show that interfering with the BMP-2 induced transcriptional network by endocytosis inhibition results in an attenuation of osteoblast differentiation. This implies that selective sensitivity of gene expression to endocytosis provides an

  14. Weight Loss After RYGB Is Independent of and Complementary to Serotonin 2C Receptor Signaling in Male Mice

    Carmody, Jill S.; Ahmad, Nadia N.; Machineni, Sriram; Lajoie, Scott; Kaplan, Lee M.


    Roux-en-Y gastric bypass (RYGB) typically leads to substantial, long-term weight loss (WL) and diabetes remission, although there is a wide variation in response to RYGB among individual patients. Defining the pathways through which RYGB works should aid in the development of less invasive anti-obesity treatments, whereas identifying weight-regulatory pathways unengaged by RYGB could facilitate the development of therapies that complement the beneficial effects of surgery. Activation of serot...

  15. Somatostatin receptors

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


    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing......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...... that a neuropeptide, to be named cortistatin (CST), had been cloned, bearing strong resemblance to SRIF. Evidence of special CST receptors never emerged, however. CST rather competed with both SRIF isoforms for specific receptor binding. And binding to the known subtypes with affinities in the nanomolar range, it has...

  16. In silico description of differential enantioselectivity in methoxychlor O-demethylation by CYP2C enzymes.

    Bikádi, Zsolt; Hazai, Eszter


    Methoxychlor undergoes metabolism by cytochrome P450 (CYP) enzymes forming a chiral mono-phenolic derivative (Mono-OH-M) as main metabolite. In the current study, members of the CYP2C family were examined for their chiral preference in Mono-OH-M formation. CYP2C9 and CYP2C19 possessed high enantioselectivity favoring the formation of S-Mono-OH-M; CYP2C3 showed no enantioselectivity, whereas CYP2C5 slightly favored the formation of R-Mono-OH-M. Molecular modeling calculations were utilized in order to explain the observed differences in chiral preference of CYP2C enzymes. Molecular docking calculations could describe neither the existence of chiral preference in metabolism, nor the enantiomer which is preferentially formed. Molecular dynamic calculations were also carried out and were found to be useful for accurate description of chiral preference in biotransformation of methoxychlor by CYP2C enzymes. An in silico model capable of predicting chiral preference in cytochrome P450 enzymes in general can be developed based on the analysis of the stability and rigidity parameters of interacting partners during molecular dynamic simulation.

  17. The role of CYP2C9 genetic polymorphism in carvedilol O-desmethylation in vitro.

    Pan, Pei-Pei; Weng, Qing-Hua; Zhou, Chen-Jian; Wei, Yan-Li; Wang, Li; Dai, Da-Peng; Cai, Jian-Ping; Hu, Guo-Xin


    We aimed at investigating the role of CYP2C9 in carvedilol O-desmethylation and identifying the effect of 35 CYP2C9 allelic variants we found in Chinese Han population on the in vitro metabolism of carvedilol. Recombinant CYP2C9 and CYP2D6 microsomes of the wild type were used to test and verify the enzymes involved in carvedilol O-desmethylation. Recombinant CYP2C9 microsomes of distinguished genotypes were used to characterize the corresponding enzyme activity toward carvedilol. 2-100 μM carvedilol was incubated for 30 min at 37 °C. The products were detected using high-performance liquid chromatography. CYP2C9 plays a certain role in carvedilol metabolism. Compared with wild-type CYP2C9*1, the intrinsic clearance (V max/K m) values of all variants toward carvedilol O-desmethylation were significantly altered. The variants exhibited significantly decreased values (from 30 to 99.8 %) due to increased K m and/or decreased V max values. We conclude that recombinant system could be used to investigate the enzymes involved in drug metabolism and these findings complement the database where CYP2C9 polymorphism interacts with biotransformation of exogenous substances like drugs and toxins.

  18. MEF2C mediates the effect of microRNA-214 on inhibiting cardiomyocyte hypertrophy

    TANG Chun-mei; ZHU Jie-ning; ZHU Wen-si; LIN Qiu-xiong; HU Zhi-qin; FU Yong-heng; ZHANG Meng-zhen; SHAN Zhi-xin


    AIM:To investigate the effect of miR-214 on cardiomyocyte hypertrophy and the expression of the potential target genes . METHODS:A cell model of hypertrophy was established based on angiotensin-Ⅱ( Ang-Ⅱ)-induced neonatal mouse ventricular car-diomyocytes (NMVCs).Dual luciferase reporter assay was performed to verify the interaction between miR-214 and the 3’ UTR of MEF2C.The expression of MEF2C and hypertrophy-related genes at mRNA and protein levels was determined by RT-qPCR and Wes-tern blotting, respectively.RESULTS:The expression of ANP, ACTA1,β-MHC and miR-214 was markedly increased in Ang-Ⅱ-in-duced hypertrophic cardiomyocytes .Dual luciferase reporter assay revealed that miR-214 interacted with the 3’ UTR of MEF2C, and miR-214 was verified to inhibit MEF2C expression at the transcriptional level .The protein expression of MEF2C was markedly in-creased in the hypertrophic cardiomyocytes .Moreover, miR-214 mimic, in parallel to MEF2C siRNA, inhibited the expression of hy-pertrophy-related genes in Ang-Ⅱ-induced NMVCs.CONCLUSION:MEF2C is a target gene of miR-214, which mediates the effect of miR-214 on attenuating cardiomyocyte hypertrophy .

  19. Cytochrome P450 2C24: expression, tissue distribution, high-throughput assay, and pharmacological inhibition

    Jun Yang


    Full Text Available Cytochrome P450 (CYP-mediated epoxidation of arachidonic acid (AA contributes to important biological functions, including the pain-relieving responses produced by analgesic drugs. However, the relevant epoxygenase(s remain unidentified. Presently, we describe the tissue distribution, high-throughput assay, and pharmacological characteristics of the rat epoxygenase CYP2C24. Following cloning from male rat liver, recombinant baculovirus containing the C-terminal His-tagged cDNA was constructed and used to express the protein in Spodoptera frugiperda (Sf9 cells. Enzymatic activity was detected with membranes, NADPH regenerating system and CYP reductase, and optimized for high throughput screening by use of the Vivid Blue© BOMCC fluorescence substrate. Quantitative real-time PCR identified CYP2C24 m-RNA in liver, kidney, heart, lung, gonad and brain. Screening of CYP2C24 activity against a panel of inhibitors showed a very strong correlation with activity against the human homologue CYP2C19. In agreement with recent findings on CYP2C19, the epoxygenase blockers PPOH and MS-PPOH inhibited CYP2C24 only weakly, confirming that these drugs are not universal epoxygenase inhibitors. Finally, comparisons of the CYP2C24 inhibitor profile with anti-analgesic activity suggests that this isoform does not contribute to brain analgesic drug action. The present methods and pharmacological data will aid in study of the biological significance of this CYP isoform.

  20. Strategies for purifying variants of human rhinovirus 14 2C protein.

    Sára, Tomáš; Konrat, Robert; Skern, Tim


    The positive strand RNA genome of picornaviruses, including human rhinovirus (HRV), poliovirus (PV) and foot-and-mouth disease virus, is translated immediately into a polyprotein that is cleaved by virally encoded proteinases into 10-13 mature proteins. These include the four proteins required to assemble the viral particle as well as 3D(pol) (the viral RNA polymerase) and 2C, an ATPase and putative helicase. 2C is a protein which is responsible, together with 2B and 3A, for anchoring the replication complexes to membranous structures in the infected cell on which RNA replication takes place. Additionally, expression of 2C and its precursor 2BC in mammalian cells leads to vesicle formation observed in infected cells. 2C is encoded by all picornaviruses; nevertheless, its exact role in viral replication remains unclear. A contributing factor is the absence of structural data for this hydrophobic protein the generation of which has been hampered by an inability to produce soluble and stable material. Here, we compare 2C from several genera and show that the 2C protein has considerable heterogeneity. Using protein structure meta-analysis, we developed models of HRV14 2C that should be useful for mutational analysis. Based on these analyses, we expressed and purified two domains of HRV14 2C using three different protocols and examined the folding by thermal denaturation or (1)H NMR. Both domains were concentrated sufficiently to allow crystal screens or NMR pilot experiments to be performed. This work provides a platform to explore 2C proteins from all picornaviral genera to generate candidates for structural analysis.

  1. Growth hormone-regulated periportal expression of CYP2C7 in rat liver.

    Oinonen, T; Ronis, M; Wigell, T; Tohmo, K; Badger, T; Lindros, K O


    Most drug- and steroid-metabolizing cytochrome P450 (CYP) enzymes are expressed in the mammalian liver in a characteristic zonated pattern, with high expression in the downstream perivenous (centrilobular) region. Here, we report that CYP2C7, a member of the rat CYP2 family, is expressed preferentially in the opposite, periportal region. CYP2C7 mRNA, as detected by reverse transcription-polymerase chain reaction, was detected almost exclusively in cell lysates obtained from the periportal region, indicating a very steep acinar gradient. The amount of immunoreactive CYP2C7 protein in periportal cell lysates was also higher than in samples from the perivenous region. This gradient was reversed by hypophysectomy, which markedly and selectively reduced the periportal CYP2C7 protein content. Subsequent growth hormone infusion by osmotic minipumps restored the zonation by selectively increasing the amount of periportal CYP2C7 protein. Although hypophysectomy suppressed CYP2C7 mRNA and growth hormone counteracted it, regulation at this level did not appear to occur in a zone-specific fashion. This indicates that growth hormone-mediated zonal regulation of CYP2C7 protein has additional translational or posttranslational components. Ethanol treatment, which has been shown to affect growth hormone levels, significantly induced CYP2C7 mRNA, but not zone specifically. Our results demonstrate that growth hormone up-regulates the CYP2C7 gene by enhancing the expression of the protein specifically in the periportal liver region. Growth hormone may up-regulate other periportally expressed liver genes in a similar fashion.

  2. Electrochemical Synthesis of Mo2C Catalytical Coatings for the Water-Gas Shift Reaction

    Kuznetsov, Sergey A.; Dubrovskiy, Anton R.; Rebrov, Evgeny V.; Schouten, Jaap C.


    The electroreduction of CO32- ions on a molybdenum cathode in a NaCl-KCl-Li2CO3 melt was studied by cyclic voltammetry. The electrochemical synthesis of Mo2C on molybdenum substrates has been performed at 1123 K for 7 h with a cathodic current density of 5 mA cm-2. If molybdenum carbide is present as a thin (ca. 500 nm) film on a molybdenum substrate (Mo2C/Mo), its catalytic activity in the water gas-shift reaction is enhanced by at least an order of magnitude compared to that of the bulk Mo2C phase.

  3. Clinically significant CYP2C inhibition by noscapine but not by glucosamine.

    Rosenborg, S; Stenberg, M; Otto, S; Ostervall, J; Masquelier, M; Yue, Q-Y; Bertilsson, L; Eliasson, E


    Noscapine and glucosamine reportedly interact with warfarin. We investigated the effects of these drugs on various cytochrome P450 (CYP) activity markers. Twelve healthy subjects were phenotyped at baseline and during separate treatments with noscapine and glucosamine. Whereas glucosamine had no significant effect on CYP activity, noscapine caused marked inhibition of CYP2C9 (4.9-fold increase in urinary losartan/E3174 ratio) and CYP2C19 (3.6-fold increase in the plasma omeprazole/5-hydroxyomeprazole ratio). Noscapine-dependent inhibition of CYP2C9 may explain the interaction with warfarin.

  4. 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: [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)


    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

  5. High energy factorization predictions for the charm structure function $F_{2}^{c}$ at HERA

    Munier, S


    High energy factorization predictions for F2^c are derived using BFKL descriptions of the proton structure function F2 at HERA. The model parameters are fixed by a fit of F2 at small x. Two different approaches of the non perturbative proton input are shown to correspond to the factorization at the gluon or quark level, respectively. The predictions for F2^c are in agreement with the data within the present error bars. However, the photon wave-function formulation (factorization at quark level) predicts significantly higher F2^c than both gluon factorization and a next-leading order DGLAP model.

  6. Transcriptional regulation of SlPYL, SlPP2C, and SlSnRK2 gene families encoding ABA signal core components during tomato fruit development and drought stress.

    Sun, Liang; Wang, Yan-Ping; Chen, Pei; Ren, Jie; Ji, Kai; Li, Qian; Li, Ping; Dai, Sheng-Jie; Leng, Ping


    In order to characterize the potential transcriptional regulation of core components of abscisic acid (ABA) signal transduction in tomato fruit development and drought stress, eight SlPYL (ABA receptor), seven SlPP2C (type 2C protein phosphatase), and eight SlSnRK2 (subfamily 2 of SNF1-related kinases) full-length cDNA sequences were isolated from the tomato nucleotide database of NCBI GenBank. All SlPYL, SlPP2C, and SlSnRK2 genes obtained are homologous to Arabidopsis AtPYL, AtPP2C, and AtSnRK2 genes, respectively. Based on phylogenetic analysis, SlPYLs and SlSnRK2s were clustered into three subfamilies/subclasses, and all SlPP2Cs belonged to PP2C group A. Within the SlPYL gene family, SlPYL1, SlPYL2, SlPYL3, and SlPYL6 were the major genes involved in the regulation of fruit development. Among them, SlPYL1 and SlPYL2 were expressed at high levels throughout the process of fruit development and ripening; SlPYL3 was strongly expressed at the immature green (IM) and mature green (MG) stages, while SlPYL6 was expressed strongly at the IM and red ripe (RR) stages. Within the SlPP2C gene family, the expression of SlPP2C, SlPP2C3, and SlPP2C4 increased after the MG stage; SlPP2C1 and SlPP2C5 peaked at the B3 stage, while SlPP2C2 and SlPP2C6 changed little during fruit development. Within the SlSnRK2 gene family, the expression of SlSnRK2.2, SlSnRK2.3, SlSnRK2.4, and SlSnRK2C was higher than that of other members during fruit development. Additionally, most SlPYL genes were down-regulated, while most SlPP2C and SlSnRK2 genes were up-regulated by dehydration in tomato leaf.

  7. Mechanical Stimulation of C2C12 Cells Increases m-Calpain Expression and Activity, Focal Adhesion Plaque Degradation and Cell Fusion

    Grossi, Alberto; Lawson, Moira Ann; Karlsson, Anders H

    Abstract Mechanical Stimulation of C2C12 Cells Increases m-calpain Expression and Activity, Focal Adhesion Plaque Degradation and Cell Fusion A. Grossi, A. H. Karlsson, M. A. Lawson; Department of Dairy and Food Science, Royal Veterinary and Agricultural University, Frederiksberg C, Denmark...... to the activity of ubiquitous proteolytic enzymes known as calpains has been reported. Whether there is a link between stretch- or load induced signaling and calpain expression and activation is not known. Using a magnetic bead stimulation assay and C2C12 mouse myoblasts cell population, we have demonstrated...... that mechanical stimulation via laminin receptors leads to an increase in m-calpain expression, but no increase in the expression of other calpain isoforms. Our study revealed that after a short period of stimulation, m-calpain relocates into focal adhesion complexes and is followed by a breakdown of specific...

  8. Graphene-Based Patterning and Differentiation of C2C12 Myoblasts

    Bajaj, Piyush; Rivera, Jose A; Marchwiany, Daniel


    This study aims at generating highly aligned functional myotubes using graphene as the underlying scaffold. Graphene not only supports the growth of C2C12 muscle cells but also enhances its differentiation and leads to spontaneous patterning of myotubes....

  9. Ultra-rapid processing of refractory carbides; 20 s synthesis of molybdenum carbide, Mo2C.

    Vallance, Simon R; Kingman, Sam; Gregory, Duncan H


    The microwave synthesis of molybdenum carbide, Mo(2)C, from carbon and either molybdenum metal or the trioxide has been achieved on unprecedented timescales; Ex- and in-situ characterisation reveals key information as to how the reaction proceeds.

  10. 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...

  11. 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...

  12. Detection of ATP2C1 Gene Mutation in Familial Benign Chronic Pemphigus


    The ATP2C1 gene mutation in one case of familial benign chronic pemphigus was investigated.One patient was diagnosed as familial benign chronic pemphigus by pathology, ultrastructral examination and clinical features. Genomic DNA was extracted from blood samples. Mutation of ATP2C1 gene was detected by polymerase chain reaction (PCR) and DNA sequencing. The results showed that deletion mutation was detected in ATP2C1 gene in this patient, which was 2374delTTTG. No mutation was found in the family members and normal individuals. It was concluded that the 2374delTTTG mutation in ATP2C1 gene was the specific mutation for the clinical phenotype for this patient and was a de novo mutation.

  13. Possible coexistence of superconductivity and magnetic order in NdPt2B2C

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


    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.

  14. Northwestern Hawaiian Islands (NWHI) photo-quadrat monitoring data table : Site number MID P2c

    US Fish and Wildlife Service, Department of the Interior — This spreadsheet summarizes the number of corals photographed along a 26-meter transect line at Underwater Site P2-C at Midway Atoll in the Northwestern Hawaiian...

  15. Classification of gradient space of dimension 8 by a reducible sl(2,C)action

    YAU; Stephen; S.-T.


    This paper deals with a reducible sl(2,C)action on the formal power series ring.The purpose of this paper is to confirm a special case of the Yau conjecture:Suppose that sl(2,C)acts on the formal power series ring via(1.1).Then I(f)=(li 1 )⊕(il2 )⊕···⊕(lis)modulo some one dimensional sl(2,C)representations where(i)is an irreducible sl(2,C)representation of i dimension and{li1 ,li2 ,...,lis }{ll1,ll2,...,lr}.Unlike classical invariant theory which deals only with irreducible action and 1-dimensional representations,we treat the reducible action and higher dimensional representations successively.

  16. 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


    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.

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

    Yuan, Yanyan; Le Guen, Karine; André, Jean-Michel; Wang, Zhanshan; Zhu, Jingtao; Mény, Christian; Jonnard, Philippe


    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.

  18. M2C Precipitate in Isothermal Tempering of High Co-Ni Alloy Steel


    The ultra-strength alloy steel with high content of Co and Ni is typical tempering martensite steel, and the secondary hardening is accomplished by the precipitation of fine scale alloy carbides with black-white contrast until peak-hardening. The crystal structure of precipitates was well determined as M2C with hexagonal by micro-beam diffraction. Observing in HREM, M2C carbides were shown coherent with the ferrite matrix completely and have their own structure.

  19. Neutron scattering study of Na2C60 in the pressure-temperature plane

    Yildirim, T.; Neumann, D. A.; Trevino, S. F.; Fischer, J. E.


    Na2C60 is the only known fulleride with divalent C60 and orientational order (Pa3¯ symmetry). We investigated the phase behavior of Na2C60 for 0200 K and P>1 kbar, the structure is transformed into a low-symmetry distorted phase. Here the peaks at low Q are significantly broadened while the high Q peaks are almost completely smeared out. This transformation is reversible; releasing pressure above 200 K recovers the cubic Pa3¯ structure.

  20. An ANFIS-based on B2C electronic commerce transaction

    Lin, Juan, E-mail: [Department of Mathematics and Computer Science, Fuqing Branch of Fujian Normal University, Fuqing 350300 (China); Liu, Chenlian, E-mail: [School of Mathematics and Computer Science, Long Yan University, Longyan 364012 (China); Guo, Yongning, E-mail: [Fuqing Branch of Fujian Normal University, Fuqing 350300 (China)


    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.

  1. An ANFIS-based on B2C electronic commerce transaction

    Lin, Juan; Liu, Chenlian; Guo, Yongning


    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.

  2. A new 2D monolayer BiXene, M2C (M = Mo, Tc, Os).

    Sun, Weiwei; Li, Yunguo; Wang, Baotian; Jiang, Xue; Katsnelson, Mikhail I; Korzhavyi, Pavel; Eriksson, Olle; Di Marco, Igor


    The existence of BiXenes, a new family of 2D monolayers, is hereby predicted. Theoretically, BiXenes have 1H symmetry (P6[combining macron]m2) and can be formed from the 4d/5d binary carbides. As the name suggests, they are close relatives of MXenes, which instead have 1T symmetry (P3[combining macron]m1). The newly found BiXenes, as well as some new MXenes, are shown to have formation energies close to that of germanene, which suggests that these materials should be possible to be synthesised. Among them, we illustrate that 1H-Tc2C and 1T-Mo2C are dynamically stable at 0 K, while 1H-Mo2C, 1T-Tc2C, 1H-Os2C, and 1T-Rh2C are likely to be stabilised via strain or temperature. In addition, the nature of the chemical bonding is analysed, emphasizing that the covalency between the transition metal ions and carbon is much stronger in BiXenes than in MXenes. The emergence of BiXenes can not only open up a new era of conducting 2D monolayers, but also provide good candidates for carrier materials aimed at energy storage and spintronic devices that have already been unveiled in MXenes.

  3. Evidence for conventional superconducting behavior in noncentrosymmetric Mo3Al2C

    Bonalde, I.; Kim, H.; Prozorov, R.; Rojas, C.; Rogl, P.; Bauer, E.


    We report on measurements of the magnetic penetration depth of polycrystalline samples of nonmagnetic Mo3Al2C (Tc=9 K) without inversion symmetry. Two previous specific-heat measurements in this compound found different anomalous peaks in the low-temperature limit. One of these peaks was attributed to the superconducting transition at 3 K of the impurity phase Mo2C. We argue here that the second anomalous peak may be caused by the superconducting transition of SiC:Al at 1.45 K, another impurity phase possibly present in Mo3Al2C samples. The temperature-independent behavior of the penetration depth observed below 0.5 K is taken as firm evidence for the presence of a nodeless superconducting gap in Mo3Al2C. Numerical calculations using the BCS expression for the penetration depth give qualitative support for an isotropic energy gap in Mo3Al2C. The present results suggest that Mo3Al2C is a conventional s-wave superconductor, although two-gap or anisotropic-gap superconductivity cannot be ruled out.

  4. Nickel and potassium co-modified β-Mo2C catalyst for CO conversion

    Minglin Xiang; Juan Zou; Debao Li; Wenhuai Li; Yuhan Sun; Xichun She


    Nickel and potassium co-medified β-Mo2C catalysts were prepared and used for CO hydrogenation reaction. The major products over β-Mo2C were C1-C4 hydrocarbons, only few alcohols were obtained. Addition of potassium resulted in remarkable selectivity shift from hydrocarbons to alcohols at the expense of CO conversion over β-Mo2C. Moreover, it was found that potassium enhanced the ability of chain propagation with a higher C2+OH production. Modified by nickel, β-Mo-2C showed a relatively high CO conversion, however, the products were similar to those of pure β-Mo2C. When co-modified by nickel and potassium,β-Mo2C exhibited high activity and selectivity towards mixed alcohols synthesis, and also the whole chain propagation to produce alcohols especially for the stage of C1OH to C2OH was remarkably enhanced. It was concluded that the Ni and K had, to some extent, synergistic effect on CO conversion.

  5. 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: [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)


    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.

  6. New polymorphisms in human MEF2C gene as potential modifier of hypertrophic cardiomyopathy.

    Alonso-Montes, Cristina; Naves-Diaz, Manuel; Fernandez-Martin, Jose Luis; Rodriguez-Reguero, Julian; Moris, Cesar; Coto, Eliecer; Cannata-Andia, Jorge B; Rodriguez, Isabel


    Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomeric proteins. Its variable phenotype suggests the existence of modifier genes. Myocyte enhancer factor (MEF) 2C could be important in this process given its role as transcriptional regulator of several cardiac genes. Any variant affecting MEF2C expression and/or function may impact on hypertrophic cardiomyopathy clinical manifestations. In this candidate gene approach, we screened 209 Caucasian hypertrophic cardiomyopathy patients and 313 healthy controls for genetic variants in MEF2C gene by single-strand conformation polymorphism analysis and direct sequencing. Functional analyses were performed with transient transfections of luciferase reporter constructions. Three new variants in non-coding exon 1 were found both in patients and controls with similar frequencies. One-way ANOVA analyses showed a greater left ventricular outflow tract obstruction (p = 0.011) in patients with 10C+10C genotype of the c.-450C(8_10) variant. Moreover, one patient was heterozygous for two rare variants simultaneously. This patient presented thicker left ventricular wall than her relatives carrying the same sarcomeric mutation. In vitro assays additionally showed a slightly increased transcriptional activity for both rare MEF2C alleles. In conclusion, our data suggest that 15 bp-deletion and C-insertion in the 5'UTR region of MEF2C could affect hypertrophic cardiomyopathy, potentially by affecting expression of MEF2C and therefore, the expression of their target cardiac proteins that are implicated in the hypertrophic process.

  7. 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: [Chemical Engineering, Columbia University, New York, NY 10027 (United States)


    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.

  8. Heat and charge transport in YNi{sub 2}B{sub 2}C and HoNi{sub 2}B{sub 2}C single crystals

    Schneider, M; Gladun, A; Kreyssig, A [Institut fuer Festkoerperphysik, Technische Universitaet Dresden, D-01062 Dresden (Germany); Wosnitza, J [Hochfeld-Magnetlabor Dresden (HLD), Forschungszentrum Dresden-Rossendorf, D-01314 Dresden (Germany); Petzold, V; Rosner, H [Max-Planck-Institut fuer Chemische Physik fester Stoffe, D-01187 Dresden (Germany); Behr, G; Souptel, D; Mueller, K-H; Drechsler, S-L; Fuchs, G [Leibniz-Institut fuer Festkoerper- und Werkstoffforschung Dresden (IFW), D-01171 Dresden (Germany)], E-mail:, E-mail:


    For a systematic investigation of the heat- and charge-transport properties of YNi{sub 2}B{sub 2}C and HoNi{sub 2}B{sub 2}C, single-crystal measurements of the electrical resistivity, the thermal conductivity, and the thermoelectric power were performed on the same samples. For HoNi{sub 2}B{sub 2}C, a local maximum of the Lorenz number at 20 K is evidently connected with the occurrence of magnetic fluctuations well above the ordering temperature. For the in-plane thermal conductivity, a kink near the superconducting transition was observed, consistent with an anisotropic gap or a multiband description. For both investigated borocarbides, the electrical resistance is isotropic. In contrast, the thermal conductivity shows a pronounced anisotropy. The thermoelectric power exhibits a minor anisotropy and can be well described by electron-diffusion and phonon-drag contributions over a wide temperature range. Based on an analysis of full-potential local-orbital calculations, a strong influence of the boron z position on the thermoelectric power has been revealed.

  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: [Graduate School of Sport & Health Science, Ritsumeikan University, Shiga (Japan)


    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. Humanized monoclonal antibody 2C9-cIgG has enhanced efficacy for yellow fever prophylaxis and therapy in an immunocompetent animal model.

    Julander, Justin G; Thibodeaux, Brett A; Morrey, John D; Roehrig, John T; Blair, Carol D


    Yellow fever virus (YFV) causes significant human disease and mortality in tropical regions of South and Central America and Africa, despite the availability of an effective vaccine. No specific therapy for YF is available. We previously showed that the humanized monoclonal antibody (MAb) 2C9-cIgG provided prophylactic and therapeutic protection from mortality in interferon receptor-deficient strain AG129 mice challenged with YF 17D-204 vaccine. In this study we tested the prophylactic and therapeutic efficacy of this MAb against virulent YFV infection in an immunocompetent hamster model. Intraperitoneal (ip) administration of a single dose of MAb 2C9-cIgG 24h prior to YFV challenge resulted in significantly improved survival rates in animals treated with 380 or 38 μg of MAb compared to untreated animals. Treatment with the higher dose also resulted in significantly improved weight gain and reductions in serum alanine aminotransferase (ALT) and virus titers in serum and liver. Prophylactic treatment with 2C9-cIgG 24h prior to virus challenge prevented the development of a virus-neutralizing antibody (vnAb) response in hamsters. Administration of a single ip dose of 380 μg of 2C9-cIgG as late as 72 h post-YFV challenge also resulted in significant improvement in survival rates. Hamsters treated at 4-72 h post-virus challenge developed a robust vnAb response. Enhanced survival and improvement of various disease parameters in the hamster model when MAb 2C9-cIgG is administered up to 3 days after virus challenge demonstrate the clinical potential of specific antibody therapy for YF.

  11. Photoelectron spectroscopy of the hydroxymethoxide anion, H2C(OH)O-

    Oliveira, Allan M.; Lehman, Julia H.; McCoy, Anne B.; Lineberger, W. Carl


    We report the negative ion photoelectron spectroscopy of the hydroxymethoxide anion, H2C(OH)O-. The photoelectron spectra show that 3.49 eV photodetachment produces two distinct electronic states of the neutral hydroxymethoxy radical (H2C(OH)Oṡ). The H2C(OH)Oṡ ground state (X ˜ 2A) photoelectron spectrum exhibits a vibrational progression consisting primarily of the OCO symmetric and asymmetric stretches, the OCO bend, as well as combination bands involving these modes with other, lower frequency modes. A high-resolution photoelectron spectrum aids in the assignment of several vibrational frequencies of the neutral H2C(OH)Oṡ radical, including an experimental determination of the H2C(OH)Oṡ 2ν12 overtone of the H-OCO torsional vibration as 220(10) cm-1. The electron affinity of H2C(OH)Oṡ is determined to be 2.220(2) eV. The low-lying A ˜ 2A excited state is also observed, with a spectrum that peaks ˜0.8 eV above the X ˜ 2A state origin. The A ˜ 2A state photoelectron spectrum is a broad, partially resolved band. Quantum chemical calculations and photoelectron simulations aid in the interpretation of the photoelectron spectra. In addition, the gas phase acidity of methanediol is calculated to be 366(2) kcal mol-1, which results in an OH bond dissociation energy, D0(H2C(OH)O-H), of 104(2) kcal mol-1, using the experimentally determined electron affinity of the hydroxymethoxy radical.

  12. CYP2C19 polymorphisms in acute coronary syndrome patients undergoing clopidogrel therapy in Zhengzhou population.

    Guo, Y M; Zhao, Z C; Zhang, L; Li, H Z; Li, Z; Sun, H L


    The goal of this study was to explore the polymorphisms of CYP2C19 (CYP2C19*2, CYP2C19*3) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) on clopidogrel therapy in Zhengzhou city for guidance on clinical medication and reduction in the incidence of thromboembolic events. Two hundred and thirty-four ACS patients undergoing PCI were included in the study, including 171 males (average age = 64.13 ± 12 years) and 63 females (average age = 67.86 ± 10.20 years). Pyrosequencing analysis detected CYP2C19*2/*3 genotypes, which were divided into wild-type homozygous C/C, mutant heterozygous C/T, and mutant homozygous T/T. This study further explored the relationship between CYP2C19 polymorphisms and clopidogrel resistance in ACS patients. Gene frequencies of C/C, C/T, and T/T for CYP2C19*2 were 39.74, 50, and 10.26%, respectively, while the frequencies of C/C, C/T, and T/T for CYP2C19*3 were 94.02, 5.55, and 0.43%, respectively. According to platelet aggregation analysis, 203 cases normally responded to clopidogrel (86.8%) and 31 cases were clopidogrel resistant (13.2%). There was a correlation between gender and genotype distribution but none between age and genotype. In addition, patients with clopidogrel resistance were treated with ticagrelor antiplatelet therapy instead of clopidogrel, and only 1 case in all patients suffered thrombotic events during a 3-12 month follow-up. In conclusion, CYP2C19*2/*3 polymorphisms may be associated with clopidogrel resistance. Wild-type homozygote and single mutant heterozygote of CYP2C19*2/*3 can be given a normal dose of clopidogrel, while carriers with single mutant homozygote or double mutant heterozygote require ticagrelor antiplatelet therapy as an alternative.

  13. Canine parvovirus type 2c infection in a kitten associated with intracranial abscess and convulsions.

    Decaro, Nicola; Desario, Costantina; Amorisco, Francesca; Losurdo, Michele; Colaianni, Maria Loredana; Greco, Maria Fiorella; Buonavoglia, Canio


    A case of canine parvovirus type 2c (CPV-2c) infection in a 3-month-old feral kitten with a cerebral abscess and neurological disease is reported. The cat displayed ataxia and convulsions together with signs of gastroenteritis and profound alteration of the total and differential white blood cell counts. A parvovirus strain was detected by a TaqMan assay in the blood and faeces of the affected kitten, which was characterised as CPV by means of molecular assays but did not react with any of the CPV type-specific probes. By sequence and phylogenetic analyses of the VP2-protein gene, the CPV-2c strain displayed a non-coding mutation in the probe-binding region. Although the role of CPV-2c in this particular case is unclear, it is possible that it predisposed the kitten to the clinical signs seen. Continuous surveillance is needed to monitor future spreading of this CPV-2c mutant, and any associated clinical signs, in the dog and cat population.

  14. Controlled growth of ultrathin Mo2C superconducting crystals on liquid Cu surface

    Geng, Dechao; Zhao, Xiaoxu; Li, Linjun; Song, Peng; Tian, Bingbing; Liu, Wei; Chen, Jianyi; Shi, Dong; Lin, Ming; Zhou, Wu; Loh, Kian Ping


    Exhibiting thickness-dependent change in the critical temperature (T c) for the onset of superconductivity, Mo2C has emerged as an important new member in the family of two-dimensional atomic crystals. Controllable growth in terms of morphology and thickness is necessary to elucidate its intrinsic properties at the 2D limit. Here we demonstrate the chemical vapor deposition of ultrathin Mo2C crystals on liquid Cu surface where the morphology of the crystals can be controlled by tuning the carbon supersaturation. A unique staggered carbon vacancy ordering is discovered in Mo2C crystals having particular geometries. Thickness engineering of the crystal can be achieved by controlling the thickness of the Cu catalyst layer, which affords a facile route to grow ultrathin 2D samples. Ultrathin Mo2C crystals so obtained, have been characterized using aberration corrected scanning transmission electron microscopy annular dark field imaging, where the co-existence of both AA and AB stacking modes is observed. The high crystallinity of the Mo2C crystals synthesized in this work is attested by its characteristic sharp superconducting transition.

  15. Liver-specific deletion of Ppp2cα enhances glucose metabolism and insulin sensitivity.

    Xian, Li; Hou, Siyuan; Huang, Zan; Tang, An; Shi, Peiliang; Wang, Qinghua; Song, Anying; Jiang, Shujun; Lin, Zhaoyu; Guo, Shiying; Gao, Xiang


    Protein phosphatase 2A (PP2A) is a key negative regulator of phosphatidylinositol 3-kinase/Akt pathway. Previous study showed that, in the liver, the catalytic subunit of PP2A (PP2Ac) is closely associated with insulin resistance syndrome, which is characterized by glucose intolerance and dyslipidemia. Here we studied the role of liver PP2Ac in glucose metabolism and evaluated whether PP2Ac is a suitable therapeutic target for treating insulin resistance syndrome. Liver-specific Ppp2cα knockout mice (Ppp2cα(loxp/loxp): Alb) exhibited improved glucose homeostasis compared with littermate controls in both normal and high-fat diet conditions, despite no significant changes in body weight and liver weight under chow diet. Ppp2cα(loxp/loxp): Alb mice showed enhanced glycogen deposition, serum triglyceride, cholesterol, low density lipoprotein and high density lipoprotein, activated insulin signaling, decreased expressions of gluconeogenic genes G6P and PEPCK, and lower liver triglyceride. Liver-specific Ppp2cα knockout mice showed enhanced glucose homeostasis and increased insulin sensitivity by activation of insulin signaling through Akt. These findings suggest that inhibition of hepatic Ppp2cα may be a useful strategy for the treatment of insulin resistance syndrome.

  16. Quantifying the reliability of image replication studies: the image intraclass correlation coefficient (I2C2).

    Shou, H; Eloyan, A; Lee, S; Zipunnikov, V; Crainiceanu, A N; Nebel, N B; Caffo, B; Lindquist, M A; Crainiceanu, C M


    This article proposes the image intraclass correlation (I2C2) coefficient as a global measure of reliability for imaging studies. The I2C2 generalizes the classic intraclass correlation (ICC) coefficient to the case when the data of interest are images, thereby providing a measure that is both intuitive and convenient. Drawing a connection with classical measurement error models for replication experiments, the I2C2 can be computed quickly, even in high-dimensional imaging studies. A nonparametric bootstrap procedure is introduced to quantify the variability of the I2C2 estimator. Furthermore, a Monte Carlo permutation is utilized to test reproducibility versus a zero I2C2, representing complete lack of reproducibility. Methodologies are applied to three replication studies arising from different brain imaging modalities and settings: regional analysis of volumes in normalized space imaging for characterizing brain morphology, seed-voxel brain activation maps based on resting-state functional magnetic resonance imaging (fMRI), and fractional anisotropy in an area surrounding the corpus callosum via diffusion tensor imaging. Notably, resting-state fMRI brain activation maps are found to have low reliability, ranging from .2 to .4. Software and data are available to provide easy access to the proposed methods.

  17. Ultrasmall and phase-pure W2C nanoparticles for efficient electrocatalytic and photoelectrochemical hydrogen evolution

    Gong, Qiufang; Wang, Yu; Hu, Qi; Zhou, Jigang; Feng, Renfei; Duchesne, Paul N.; Zhang, Peng; Chen, Fengjiao; Han, Na; Li, Yafei; Jin, Chuanhong; Li, Yanguang; Lee, Shuit-Tong


    Earlier research has been primarily focused on WC as one of the most promising earth-abundant electrocatalysts for hydrogen evolution reaction (HER), whereas the other compound in this carbide family—W2C—has received far less attention. Our theoretical calculations suggest that such a focus is misplaced and W2C is potentially more HER-active than WC. Nevertheless, the preparation of phase pure and sintering-free W2C nanostructures represents a formidable challenge. Here we develop an improved carburization method and successfully prepare ultrasmall and phase-pure W2C nanoparticles. When evaluated for HER electrocatalysis, W2C nanoparticles exhibit a small onset overpotential of 50 mV, a Tafel slope of 45 mV dec−1 and outstanding long-term cycling stability, which are dramatically improved over all existing WC-based materials. In addition, the integration of W2C nanoparticles with p-type Si nanowires enables highly active and sustainable solar-driven hydrogen production. Our results highlight the great potential of this traditionally non-popular material in HER electrocatalysis. PMID:27752046

  18. Lrrc75b is a novel negative regulator of C2C12 myogenic differentiation

    Zhong, Yuechun; Zou, Liyi; Wang, Zonggui; Pan, Yaqiong; Dai, Zhong; Liu, Xinguang; Cui, Liao; Zuo, Changqing


    Many transcription factors and signaling molecules involved in the guidance of myogenic differentiation have been investigated in previous studies. However, the precise molecular mechanisms of myogenic differentiation remain largely unknown. In the present study, by performing a meta-analysis of C2C12 myogenic differentiation microarray data, we found that leucine-rich repeat-containing 75B (Lrrc75b), also known as AI646023, a molecule of unknown biological function, was downregulated during C2C12 myogenic differentiation. The knockdown of Lrrc75b using specific siRNA in C2C12 myoblasts markedly enhanced the expression of muscle-specific myogenin and increased myoblast fusion and the myotube diameter. By contrast, the adenovirus-mediated overexpression of Lrrc75b in C2C12 cells markedly inhibited myoblast differentiation accompanied by a decrease in myogenin expression. In addition, the phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) was suppressed in the cells in which Lrrc75b was silenced. Taken together, our results demonstrate that Lrrc75b is a novel suppressor of C2C12 myogenic differentiation by modulating myogenin and Erk1/2 signaling. PMID:27633041

  19. Re-engineering of CYP2C9 to probe acid-base substrate selectivity.

    Tai, Guoying; Dickmann, Leslie J; Matovic, Nicholas; DeVoss, James J; Gillam, Elizabeth M J; Rettie, Allan E


    A common feature of many CYP2C9 ligands is their weak acidity. As revealed by crystallography, the structural basis for this behavior involves a charge-pairing interaction between an anionic moiety on the substrate and an active site R108 residue. In the present study we attempted to re-engineer CYP2C9 to better accept basic ligands by charge reversal at this key residue. We expressed and purified the R108E and R108E/D293N mutants and compared their ability with that of native CYP2C9 to interact with (S)-warfarin, diclofenac, pyrene, propranolol, and ibuprofen amine. As expected, the R108E mutant maintained all the native enzyme's pyrene 1-hydroxylation activity, but catalytic activity toward diclofenac and (S)-warfarin was abrogated. In contrast, the double mutant displayed much less selectivity in its behavior toward these control ligands. Neither of the mutants displayed significant enhancement of propranolol metabolism, and all three preparations exhibited a type II (inhibitor) rather than type I (substrate) spectrum with ibuprofen amine, although binding became progressively weaker with the single and double mutants. Collectively, these data underscore the importance of the amino acid at position 108 in the acid substrate selectivity of CYP2C9, highlight the accommodating nature of the CYP2C9 active site, and provide a cautionary note regarding facile re-engineering of these complex cytochrome P450 active sites.

  20. HDAC5 controls MEF2C-driven sclerostin expression in osteocytes.

    Wein, Marc N; Spatz, Jordan; Nishimori, Shigeki; Doench, John; Root, David; Babij, Philip; Nagano, Kenichi; Baron, Roland; Brooks, Daniel; Bouxsein, Mary; Pajevic, Paola Divieti; Kronenberg, Henry M


    Osteocytes secrete paracrine factors that regulate the balance between bone formation and destruction. Among these molecules, sclerostin (encoded by the gene SOST) inhibits osteoblastic bone formation and is an osteoporosis drug target. The molecular mechanisms underlying SOST expression remain largely unexplored. Here, we report that histone deacetylase 5 (HDAC5) negatively regulates sclerostin levels in osteocytes in vitro and in vivo. HDAC5 shRNA increases, whereas HDAC5 overexpression decreases SOST expression in the novel murine Ocy454 osteocytic cell line. HDAC5 knockout mice show increased levels of SOST mRNA, more sclerostin-positive osteocytes, decreased Wnt activity, low trabecular bone density, and reduced bone formation by osteoblasts. In osteocytes, HDAC5 binds and inhibits the function of MEF2C, a crucial transcription factor for SOST expression. Using chromatin immunoprecipitation, we have mapped endogenous MEF2C binding in the SOST gene to a distal intergenic enhancer 45 kB downstream from the transcription start site. HDAC5 deficiency increases SOST enhancer MEF2C chromatin association and H3K27 acetylation and decreases recruitment of corepressors NCoR and HDAC3. HDAC5 associates with and regulates the transcriptional activity of this enhancer, suggesting direct regulation of SOST gene expression by HDAC5 in osteocytes. Finally, increased sclerostin production achieved by HDAC5 shRNA is abrogated by simultaneous knockdown of MEF2C, indicating that MEF2C is a major target of HDAC5 in osteocytes.

  1. Notch pathway activation contributes to inhibition of C2C12 myoblast differentiation by ethanol.

    Michelle A Arya

    Full Text Available The loss of muscle mass in alcoholic myopathy may reflect alcohol inhibition of myogenic cell differentiation into myotubes. Here, using a high content imaging system we show that ethanol inhibits C2C12 myoblast differentiation by reducing myogenic fusion, creating smaller and less complex myotubes compared with controls. Ethanol administration during C2C12 differentiation reduced MyoD and myogenin expression, and microarray analysis identified ethanol activation of the Notch signaling pathway target genes Hes1 and Hey1. A reporter plasmid regulated by the Hes1 proximal promoter was activated by alcohol treatment in C2C12 cells. Treatment of differentiating C2C12 cells with a gamma secretase inhibitor (GSI abrogated induction of Hes1. On a morphological level GSI treatment completely rescued myogenic fusion defects and partially restored other myotube parameters in response to alcohol. We conclude that alcohol inhibits C2C12 myoblast differentiation and the inhibition of myogenic fusion is mediated by Notch pathway activation.

  2. Preparation of the flexible ZrO{sub 2}/C composite nanofibrous film via electrospinning

    Yin, Xin; Song, Lixin; Xie, Xueyao; Zhou, Yangyang; Guan, Yingli; Xiong, Jie [Zhejiang Sci-Tech University, College of Materials and Textiles, Hangzhou (China); Zhejiang Sci-Tech University, Key Laboratory of Advanced Textile Materials and Manufacturing Technology of Ministry of Education, Hangzhou (China)


    The flexible ZrO{sub 2}/C composite nanofibrous film was fabricated by electrospinning and thermal treatment. Field-emission scanning electron microscopy, transmission electron microscopy, X-ray diffractometer, and Fourier transform infrared spectra were used to characterize the morphology and microstructure of the ZrO{sub 2}/C composite nanofibrous film. The ZrO{sub 2}/C nanofibers exhibited rough surface and had the average diameter of about 230 ± 35 nm. And the ZrO{sub 2} nanoparticles were incorporated in carbon matrix and in tetragonal and monoclinic. The flexural property of the ZrO{sub 2}/C composite nanofibrous film was investigated in detail. The results showed that the flexural property of the nanofibrous film was greatly improved with addition of the ZrO{sub 2} nanoparticles. Besides, with the increase of the contents of ZrO{sub 2} nanoparticles, the flexural modulus of the nanofibrous film decreased, reached a lowest value, and then increased. The lowest flexural modulus of the ZrO{sub 2}/C composite nanofibrous film in precursor concentration of 7.0 wt% was 8.55 ± 0.06 MPa. (orig.)

  3. Structural analysis of CYP2C9 and CYP2C5 and an evaluation of commonly used molecular modeling techniques

    Afzelius, Lovisa; Raubacher, Florian; Karlén, Anders;


    This work had two separate aims: to evaluate different modeling techniques and to make a detailed structural characterization of CYP2C9. To achieve these goals, the consensus principal component analysis (CPCA) technique and distance measurements were used to explore available crystal structures...... by the CPCA. Advantages and drawbacks are presented for the different modeling techniques. Despite the varying modeling success, the models give insight and understanding by the mutual forming and discarding of hypotheses. This is a dynamic process since the crystal structures are improving with time and...

  4. Molecular pharmacology of human NMDA receptors

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


    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...

  5. Catalytic performance of Fe modified K/Mo2C catalyst for CO hydrogenation

    Minglin Xiang; Dudu Wu; Juan Zou; Debao Li; Yuhan Sun; Xichun She


    Fe modified and un-modified K/Mo2C were prepared and investigated as catalysts for CO hydrogenation reaction.Compared with K/Mo2C catalyst,the addition of Fe increased the production of alcohols,especially the C2+OH.Meanwhile,considerable amounts of C5+ hydrocarbons and C=2-C=4 were formed,whereas methane selectivity greatly decreased.Also,the activity and selectivity of the catalyst were readily affected by the reaction pressure and temperature employed.According to the XPS results,Mo4+ might be responsible for the production of alcohols,whereas the low valence state of Mo species such as Moo and/or Mo2+ might be account for the high activity and selectivity toward hydrocarbons.

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

    Xiong, Ke; Yu, Weiting; Chen, Jingguang G.


    The selective deoxygenation of aldehydes and alcohols without cleaving the Csbnd 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 Cdbnd O and Csbnd OH bonds.

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

    Minglin Xiang


    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.

  8. Magnetic properties of Y1- xGdxCo2B2C series of borocarbides

    Bud'ko, S. L.; Giordanengo, B.; Sulpice, A.; Fontes, M. B.; Baggio-Saitovitch, E. M.


    Magnetic properties of Y1- xGdxCo2B2C series of compounds were studied. Two magnetically ordered phases were observed for 0.7 ≤ x ≤ 1. Change of the magnetic ordering temperatures T 1 and T 2 with the Gd concentration is argued to be related to the dilution of magnetic Gd by nonmagnetic Y and to the reduction of the distance between ( Y1- xGdx) C planes. However, significant contribution to the changes in T 1 between pure GdNi2B2C and GdCo2B2C samples is suggested to be due to the different 3 d band filling in these compounds.

  9. Transport properties of carbide superconductor La{sub 2}C{sub 3}

    Kim, J. S. [Dept. of Physics, Pohang University of Science and Technology, Pohang (Korea, Republic of); Kremer, R. K. [Max-Planck-Institut fuer Festkoerperforschung, Stuttgart (Korea, Republic of)


    We investigate the electrical and thermal transport properties of a sesquicarbide superconductor La{sub 2}C{sub 3}, including electrical resistivity, thermoelectric power, and thermal conductivity. The electrical resistivity exhibits a typical metallic character with a saturation behavior at high temperatures. The thermoelectric power shows a metallic behavior with pronounced phonon-drag effect, comparable with pure metals. The broad peak of the thermal conductivity is observed in the superconducting state, which is rapidly suppressed by magnetic fields. These observations suggest that the electron-phonon scattering is significant in La{sub 2}C{sub 3}, which is relevant with the relatively high-T{sub c} in La{sub 2}C{sub 3} through strong electron-phonon coupling with low frequency phonon modes.

  10. First principle investigation of the electronic and thermoelectric properties of Mg2C

    Kulwinder, Kaur; Ranjan, Kumar


    In this paper, electronic and thermoelectric properties of Mg2C are investigated by using first principle pseudo potential method based on density functional theory and Boltzmann transport equations. We calculate the lattice parameters, bulk modulus, band gap and thermoelectric properties (Seebeck coefficient, electrical conductivity, and thermal conductivity) of this material at different temperatures and compare them with available experimental and other theoretical data. The calculations show that Mg2C is indirect band semiconductor with a band gap of 0.75 eV. The negative value of Seebeck coefficient shows that the conduction is due to electrons. The electrical conductivity decreases with temperature and Power factor (PF) increases with temperature. The thermoelectric properties of Mg2C have been calculated in a temperature range of 100 K-1200 K. Kulwinder Kaur thanks Council of Scientific & Industrial Research (CSIR), India for providing fellowship.

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

    Nuala Ann Helsby


    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.

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

    HE Dehua; LU Yaobin; ZHOU Deyi


    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.

  13. Differential expression of cytochrome P450 enzymes from the CYP2C subfamily in the human brain.

    Booth Depaz, Iris M; Toselli, Francesca; Wilce, Peter A; Gillam, Elizabeth M J


    Cytochrome P450 enzymes from the CYP2C subfamily play a prominent role in the metabolic clearance of many drugs. CYP2C enzymes have also been implicated in the metabolism of arachidonic acid to vasoactive epoxyeicosatrienoic acids. CYP2C8, CYP2C9, and CYP2C19 are expressed in the adult liver at significant levels; however, the expression of CYP2C enzymes in extrahepatic tissues such as the brain is less well characterized. Form-specific antibodies to CYP2C9 and CYP2C19 were prepared by affinity purification of antibodies raised to unique peptides. CYP2C9 and CYP2C19 were located in microsomal fractions of all five human brain regions examined, namely the frontal cortex, hippocampus, basal ganglia, amygdala, and cerebellum. Both CYP2C9 and CYP2C19 were detected predominantly within the neuronal soma but with expression extending down axons and dendrites in certain regions. Finally, a comparison of cortex samples from alcoholics and age-matched controls suggested that CYP2C9 expression was increased in alcoholics.

  14. CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP.

    Huezo-Diaz, Patricia; Perroud, Nader; Spencer, Edgar P; Smith, Rebecca; Sim, Sarah; Virding, Susanne; Uher, Rudolf; Gunasinghe, Cerisse; Gray, Jo; Campbell, Desmond; Hauser, Joanna; Maier, Wolfgang; Marusic, Andrej; Rietschel, Marcella; Perez, Jorge; Giovannini, Caterina; Mors, Ole; Mendlewicz, Julien; McGuffin, Peter; Farmer, Anne E; Ingelman-Sundberg, Magnus; Craig, Ian W; Aitchison, Katherine J


    In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) (p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio (p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration (p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.

  15. CYP2C subfamily, primarily CYP2C9, catalyses the enantioselective demethylation of the endocrine disruptor pesticide methoxychlor in human liver microsomes: use of inhibitory monoclonal antibodies in P450 identification.

    Hu, Y; Krausz, K; Gelboin, H V; Kupfer, D


    1. The endocrine disruptor pesticide methoxychlor undergoes O-demethylation by mammalian liver microsomes forming chiral mono-phenolic (1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane, i.e. mono-OH-M) and achiral bis-phenolic oestrogenic metabolites. Human liver microsomes (HLM) generated primarily the S-mono-OH-M. 2. Inhibitory monoclonal antibodies (MAb) identified those P450s catalysing the enantioselective O-demethylation of methoxychlor. In HLM, O-demethylation was inhibited by MAb anti-2C9 (30-40%), diminishing the per cent of S-mono-OH-M from about 80 to 55-60%. MAb anti-CYP1A2, 2A6, 2B6, 2C8, 2C19, 2D6 and 3A4 did not affect the demethylation rate in HLM. Nevertheless, MAb anti-CYP1A2 decreased the formation of R-mono-OH-M from 21-23 to 10-17%, indicating that CYP1A2 exhibits a role in generating the R-enantiomer. 3. Among cDNA-expressed human P450s (supersomes), CYP2C19 was the most active in demethylation, but in HLM, CYP2C19 appeared inactive (no inhibition by MAb anti-CYP2C19). There was a substantial difference in the per cent inhibition of demethylation by MAb anti-CYP2C9 and anti-rat CYP2C (MAb inhibiting all human CYP2C forms) and in altering the enantioselectivity, suggesting that demethylation by combined CYP2C8, 2C18 and 2C19 was significant (20-30%). 4. Polymorphism of methoxychlor demethylation was examined with supersomes and HLM-expressing CYP2C9 allelic variants. CYP2C9*1 and 2C9*2 were highly active; however, CYP2C9*3 appeared inactive.

  16. China's B2C e-commerce development and its future prospects


    China’s E-commerce environment is improving all the time. Consumers are getting more and more habituated to this form of consumption mode. The recent trend shows that China’s e- commerce market is booming mainly because of major enterprises’ fierce competition within Business To Customer E-commerce market. People are optimistic about B2C E-commerce which strengthens the China’s B2C E-commerce market. Even though E-commerce business in China is soaring, there still persists a problem, too. ...

  17. Anisotropic Multiband Many-Body Interactions in LuNi2B2C

    Bergk, B.; Petzold, V.; Rosner, H.; Drechsler, S.-L.; Bartkowiak, M.; Ignatchik, O.; Bianchi, A. D.; Sheikin, I.; Canfield, P. C.; Wosnitza, J.


    We present a comprehensive de Haas-van Alphen study on the nonmagnetic borocarbide superconductor LuNi{sub 2}B{sub 2}C. The analysis of the angular-dependent effective masses for different bands in combination with full-potential density functional calculations allowed us to determine the mass-enhancement factors, {lambda}, for the different electronic bands and their wave-vector dependences. Our data clearly show the anisotropic multiband character of the superconductivity in LuNi{sub 2}B{sub 2}C.

  18. Sc3N and Sc2C2 encapsulated B40: Smarter than its carbon analogue

    Shah, Esha V.; Roy, Debesh R.


    A detailed comparative investigation on the recently synthesised B40 and C40 along with their metal nitride (Sc3N)and carbide (Sc2C2) encapsulated endohedral fullerenes, is performed under density functional theory for the first time. The structures, electronic, thermodynamic and magnetic properties of all the considered compounds are explored in detail. The present study identifies borospherene (B40) and its encapsulated nitride (Sc3N@B40) and carbide (Sc2C2@B40) endohedral borofullerenes as the better candidates for future novel nano-applications compared to their carbon bucky ball analogues.

  19. Modelling the B2C Marketplace: Evaluation of a Reputation Metric for e-Commerce

    Gutowska, Anna; Sloane, Andrew

    This paper evaluates recently developed novel and comprehensive reputation metric designed for the distributed multi-agent reputation system for the Business-to-Consumer (B2C) E-commerce applications. To do that an agent-based simulation framework was implemented which models different types of behaviours in the marketplace. The trustworthiness of different types of providers is investigated to establish whether the simulation models behaviour of B2C e-Commerce systems as they are expected to behave in real life.

  20. Preparation of SnO2/C biomorphic materials by biotemplating from ramie fibres

    Xin-Hai He; Le-Hua Qi; Jun-Bo Wang; Ming-Qian Shen; Wei Chang; Chong Fu; Min-Ge Yang; Xiao-Lei Su


    A new SnO2/C biomorphic material has been prepared by molding into a composite billet and carbothermal-reduction under vacuum from ramie fibres/Sn(OH)4 precursors. The phase composition and microstructure of the prepared materials were characterized. The effects of the carbonization temperature, holding time and other factors on the crystal structure, morphology and ingredients of the prepared samples were discussed. The results showed that the sintering temperature and holding time have significant effects on the final products. When the sintering temperature reached 480°C, the SnO2/C biomorphic materials were synthesized successfully.

  1. E2C(R2) Periodic Benefit-Risk Evaluation Report and E2C(R2) Periodic Benefit-Risk Evaluation Report--Questions and Answers; International Council for Harmonisation; Guidances for Industry; Availability. Notice.


    The Food and Drug Administration (FDA or Agency) is announcing the availability of guidances for industry entitled ``E2C(R2) Periodic Benefit-Risk Evaluation'' (E2C(R2) guidance) and ``E2C(R2) Periodic Benefit-Risk Evaluation Report--Questions and Answers'' (E2C(R2) Q&A guidance). These guidances were prepared under the auspices of the International Council for Harmonisation (ICH), formerly the International Conference on Harmonisation. The E2C(R2) draft guidance, issued April 11, 2012, updated and combined two ICH guidances, ``E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs'' (E2C guidance) and ``Addendum to E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs'' (addendum to the E2C guidance). The E2C(R2) guidance is intended to describe the format, content, and timing of a Periodic Benefit-Risk Evaluation Report (PBRER) for an approved drug or biologic, and it finalizes the draft guidance. The E2C(R2) Q&A guidance is a supplementary guidance that is intended to clarify key issues in the E2C(R2) guidance.

  2. MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease.

    Yelamanchili, S V; Chaudhuri, A Datta; Chen, L-N; Xiong, Huangui; Fox, H S


    MicroRNAs (miRNAs) play important roles in regulating a plethora of physiological and pathophysiogical processes including neurodegeneration. In both HIV associated dementia in humans and its monkey model SIV encephalitis we find miR-21, a miRNA largely known for its link to oncogenesis, to be significantly upregulated in the brain. In situ hybridization of the diseased brain sections revealed induction of miR-21 in neurons. MiR-21 can be induced in neurons by prolonged N-methyl-D-aspartic acid receptor stimulation, an excitotoxic process active in HIV and other neurodegenerative diseases. Introduction of miR-21 into human neurons leads to pathological functional defects. Furthermore, we show that miR-21 specifically targets the mRNA of myocyte enhancer factor 2C (MEF2C), a transcription factor crucial for neuronal function, and reduces its expression. MEF2C is dramatically downregulated in neurons of HIV-associated dementia patients as well as monkeys with SIVE. Together, this study elucidates a novel role for miR-21 in the brain, not only as a potential signature of neurological disease but also as a crucial effector of HIV induced neuronal dysfunction and neurodegeneration.

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

    Rafael Linden


    Full Text Available 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 drawn before and three hours after an oral administration of 20 mg omeprazole. The plasma concentrations of omeprazole and hydroxy-omeprazole were determined by high performance liquid chromatography. The genotyping assay was carried out using a Real-Time-PCR-based assay, identifying the alleles *1 (completely functional, *2, *3 and *4 (null. The phenotyping procedure estimated the presence of 4 poor, 34 extensive and 1 ultra-extensive metabolizer. The genotyping identified 4 poor, 23 extensive and 11 intensive metabolizers. The groups of volunteers classified according to the number of active alleles of CYP2C19 had significant differences in the metabolic ratios of omeprazole hydroxylation. However, volunteers exhibiting the same number of active alleles presented different phenotypes. Therefore, the phenotyping of CYP2C19 is a more promising alternative to dose individualization of CYP2C19 substrate drugs.O gene CYP2C19 apresenta polimorfismo genético, com impacto importante na farmacocinética de diversos fármacos de importância clínica. O objetivo deste estudo foi avaliar a correlação entre genótipo e fenótipo de CYP2C19 em um grupo de 38 voluntários brasileiros, avaliando a capacidade de predição do fenótipo a partir de testes de genotipagem. Para a fenotipagem, utilizou-se omeprazol (OME como fármaco-sonda para CYP2C19, empregando sua razão metabólica de hidroxilação como indicador fenotípico. Amostras de sangue foram coletadas antes e tr

  4. Comprehensive Evaluation for Substrate Selectivity of Cynomolgus Monkey Cytochrome P450 2C9, a New Efavirenz Oxidase.

    Hosaka, Shinya; Murayama, Norie; Satsukawa, Masahiro; Uehara, Shotaro; Shimizu, Makiko; Iwasaki, Kazuhide; Iwano, Shunsuke; Uno, Yasuhiro; Yamazaki, Hiroshi


    Cynomolgus monkeys are widely used as primate models in preclinical studies, because of their evolutionary closeness to humans. In humans, the cytochrome P450 (P450) 2C enzymes are important drug-metabolizing enzymes and highly expressed in livers. The CYP2C enzymes, including CYP2C9, are also expressed abundantly in cynomolgus monkey liver and metabolize some endogenous and exogenous substances like testosterone, S-mephenytoin, and diclofenac. However, comprehensive evaluation regarding substrate specificity of monkey CYP2C9 has not been conducted. In the present study, 89 commercially available drugs were examined to find potential monkey CYP2C9 substrates. Among the compounds screened, 20 drugs were metabolized by monkey CYP2C9 at a relatively high rates. Seventeen of these compounds were substrates or inhibitors of human CYP2C9 or CYP2C19, whereas three drugs were not, indicating that substrate specificity of monkey CYP2C9 resembled those of human CYP2C9 or CYP2C19, with some differences in substrate specificities. Although efavirenz is known as a marker substrate for human CYP2B6, efavirenz was not oxidized by CYP2B6 but by CYP2C9 in monkeys. Liquid chromatography-mass spectrometry analysis revealed that monkey CYP2C9 and human CYP2B6 formed the same mono- and di-oxidized metabolites of efavirenz at 8 and 14 positions. These results suggest that the efavirenz 8-oxidation could be one of the selective markers for cynomolgus monkey CYP2C9 among the major three CYP2C enzymes tested. Therefore, monkey CYP2C9 has the possibility of contributing to limited specific differences in drug oxidative metabolism between cynomolgus monkeys and humans.

  5. Ndrg2 is a PGC-1α/ERRα target gene that controls protein synthesis and expression of contractile-type genes in C2C12 myotubes.

    Foletta, Victoria C; Brown, Erin L; Cho, Yoshitake; Snow, Rod J; Kralli, Anastasia; Russell, Aaron P


    The stress-responsive, tumor suppressor N-myc downstream-regulated gene 2 (Ndrg2) is highly expressed in striated muscle. In response to anabolic and catabolic signals, Ndrg2 is suppressed and induced, respectively, in mouse C2C12 myotubes. However, little is known about the mechanisms regulating Ndrg2 expression in muscle, as well as the biological role for Ndrg2 in differentiated myotubes. Here, we show that Ndrg2 is a target of a peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and estrogen-related receptor alpha (ERRα) transcriptional program and is induced in response to endurance exercise, a physiological stress known also to increase PGC-1α/ERRα activity. Analyses of global gene and protein expression profiles in C2C12 myotubes with reduced levels of NDRG2, suggest that NDRG2 affects muscle growth, contractile properties, MAPK signaling, ion and vesicle transport and oxidative phosphorylation. Indeed, suppression of NDRG2 in myotubes increased protein synthesis and the expression of fast glycolytic myosin heavy chain isoforms, while reducing the expression of embryonic myosin Myh3, other contractile-associated genes and the MAPK p90 RSK1. Conversely, enhanced expression of NDRG2 reduced protein synthesis, and furthermore, partially blocked the increased protein synthesis rates elicited by a constitutively active form of ERRα. In contrast, suppressing or increasing levels of NDRG2 did not affect mRNA expression of genes involved in mitochondrial biogenesis that are regulated by PGC-1α or ERRα. This study shows that in C2C12 myotubes Ndrg2 is a novel PGC-1α/ERRα transcriptional target, which influences protein turnover and the regulation of genes involved in muscle contraction and function.

  6. Identification and mechanism of ABA receptor antagonism

    Melcher, Karsten


    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.

  7. User-Interface Design Characteristics of Fortune 500 B2C E-Commerce Sites and Industry Differences

    Zhao, Jensen J.; Truell, Allen D.; Alexander, Melody W.


    This study examined the user-interface design characteristics of 107 Fortune 500 B2C e-commerce Web sites and industry differences. Data were collected from corporate homepages, B2C product/service pages, B2C interactive shopping pages, as well as customer satisfaction of 321 online shoppers. The findings indicate that (a) to attract online…

  8. Impact of CYP2C8*3 on paclitaxel clearance in ovarian cancer patients

    Bergmann, Troels Korshøj; Vach, Werner; Gréen, Henrik;

    be partly responsible for this variation. Paclitaxel is mainly metabolized by CYP2C8; SNPs have been investigated in this context before but conclusions are still lacking. We present a prospective study of paclitaxel clearance (CL) in 93 Caucasian females with epithelial ovarian cancer with regard...

  9. "Expectations to Change" ((E2C): A Participatory Method for Facilitating Stakeholder Engagement with Evaluation Findings

    Adams, Adrienne E.; Nnawulezi, Nkiru A.; Vandenberg, Lela


    From a utilization-focused evaluation perspective, the success of an evaluation is rooted in the extent to which the evaluation was used by stakeholders. This paper details the "Expectations to Change" (E2C) process, an interactive, workshop-based method designed to engage primary users with their evaluation findings as a means of…

  10. Dynamical Trust and Reputation Computation Model for B2C E-Commerce

    Bo Tian


    Full Text Available Trust is one of the most important factors that influence the successful application of network service environments, such as e-commerce, wireless sensor networks, and online social networks. Computation models associated with trust and reputation have been paid special attention in both computer societies and service science in recent years. In this paper, a dynamical computation model of reputation for B2C e-commerce is proposed. Firstly, conceptions associated with trust and reputation are introduced, and the mathematical formula of trust for B2C e-commerce is given. Then a dynamical computation model of reputation is further proposed based on the conception of trust and the relationship between trust and reputation. In the proposed model, classical varying processes of reputation of B2C e-commerce are discussed. Furthermore, the iterative trust and reputation computation models are formulated via a set of difference equations based on the closed-loop feedback mechanism. Finally, a group of numerical simulation experiments are performed to illustrate the proposed model of trust and reputation. Experimental results show that the proposed model is effective in simulating the dynamical processes of trust and reputation for B2C e-commerce.

  11. Effect of Carbon Sources on the Catalytic Performance of Ni/β-Mo2C.

    Zeng, Li-Zhen; Zhao, Shao-Fei; Li, Wei-Shan


    In this paper, Ni/β-Mo2C(S) and Ni/β-Mo2C(G) were prepared from solution-derived precursor with two different carbon sources (starch and glucose) and tested as anodic noble-metal-free catalysts in air-cathode microbial fuel cells (MFCs). The carburized catalyst samples were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), and Brunauer-Emmett-Teller (BET). The activity of the electrocatalyst towards the oxidation of several common microbial fermentation products (formate, lactate, and ethanol) was studied for MFC based on Klebsiella pneumoniae conditions. The composite MFC anodes were fabricated, and their catalytic behavior was investigated. With different carbon sources, the crystalline structure does not change and the crystallinity and surface area increase. The electrocatalytic experiments show that the Ni/β-Mo2C(G) gives the better bio- and electrocatalytic performance than Ni/β-Mo2C(S) due to its higher crystallinity and BET surface area.

  12. Deoxygenation of glycolaldehyde and furfural on Mo2C/Mo(100)

    McManus, Jesse R.; Vohs, John M.


    The desire to produce fuels and chemicals in an energy conscious, environmentally sympathetic approach has motivated considerable research on the use of cellulosic biomass feedstocks. One of the major challenges facing the utilization of biomass is finding effective catalysts for the efficient and selective removal of oxygen from the highly-oxygenated, biomass-derived platform molecules. Herein, a study of the reaction pathways for the biomass-derived platform molecule furfural and biomass-derived sugar model compound glycolaldehyde provides insight into the mechanisms of hydrodeoxygenation (HDO) on a model molybdenum carbide catalyst, Mo2C/Mo(100). Using temperature programmed desorption (TPD) and high resolution electron energy loss spectroscopy (HREELS), it was found that the Mo2C/Mo(100) catalyst was active for selective deoxygenation of the aldehyde carbonyl by facilitating adsorption of the aldehyde in an η2(C,O) bonding configuration. Furthermore, the catalyst showed no appreciable activity for furanic ring hydrogenation, highlighting the promise of relatively inexpensive Mo2C catalysts for selective HDO chemistry.

  13. Magnetotransport Properties in High-Quality Ultrathin Two-Dimensional Superconducting Mo2C Crystals.

    Wang, Libin; Xu, Chuan; Liu, Zhibo; Chen, Long; Ma, Xiuliang; Cheng, Hui-Ming; Ren, Wencai; Kang, Ning


    Ultrathin transition metal carbides are a class of developing two-dimensional (2D) materials with superconductivity and show great potentials for electrical energy storage and other applications. Here, we report low-temperature magnetotransport measurements on high-quality ultrathin 2D superconducting α-Mo2C crystals synthesized by a chemical vapor deposition method. The magnetoresistance curves exhibit reproducible oscillations at low magnetic fields for temperature far below the superconducting transition temperature of the crystals. We interpret the oscillatory magnetoresistance as a consequence of screening currents circling around the boundary of triangle-shaped terraces found on the surface of ultrathin Mo2C crystals. As the sample thickness decreases, the Mo2C crystals exhibit negative magnetoresistance deep in the superconducting transition regime, which reveals strong phase fluctuations of the superconducting order parameters associated with the superconductor-insulator transition. Our results demonstrate that the ultrathin superconducting Mo2C crystals provide an interesting system for studying rich transport phenomena in a 2D crystalline superconductor with enhanced quantum fluctuations.

  14. Surface morphology of orthorhombic Mo2C catalyst and high coverage hydrogen adsorption

    Wang, Tao; Tian, Xinxin; Yang, Yong; Li, Yong-Wang; Wang, Jianguo; Beller, Matthias; Jiao, Haijun


    High coverage hydrogen adsorption on twenty two terminations of orthorhombic Mo2C has been systematically studied by using density functional theory and ab initio thermodynamics. Hydrogen stable coverage on the surfaces highly depends on temperatures and H2 partial pressure. The estimated hydrogen desorption temperatures under ultra-high vacuum condition on Mo2C are in reasonable agreement with the available temperature-programmed desorption data. Obviously, hydrogen adsorption can affect the surface stability and therefore modify the surface morphology of Mo2C. Upon increasing the chemical potential of hydrogen which can be achieved by increasing the H2 partial pressure and/or decreasing the temperature, the proportions of the (001), (010), (011) and (100) surfaces increase, while those of the (101), (110) and (111) surfaces decrease. Among these surfaces, the (100) surface is most sensitive upon hydrogen adsorption and the (111) surface is most exposed under a wide range of conditions. Our study clearly reveals the role of hydrogen on the morphology of orthorhombic Mo2C catalyst in conjugation with hydro-treating activity.

  15. High reflectance and low stress Mo2C/Be multilayers

    Bajt, Sasa; Barbee, Jr., Troy W.


    A material for extreme ultraviolet (EUV) multilayers that will reflect at about 11.3 nm, have a high reflectance, low stress, and high thermal and radiation stability. The material consists of alternating layers of Mo.sub.2 C and Be deposited by DC magnetron sputtering on a substrate, such as silicon. In one example a Mo.sub.2 C/Be multilayer gave 65.2% reflectance at 11.25 nm measured at 5 degrees off normal incidence angle, and consisted of 70 bilayers with a deposition period of 5.78 nm, and was deposited at 0.83 mTorr argon (Ar) sputtering pressure, with the first and last layers being Be. The stress of the multilayer is tensile and only +88 MPa, compared to +330 MPa of a Mo/Be multilayers of the same thickness. The Mo.sub.2 C/Be multilayer was capped with carbon which produced an increase in reflectivity of about 7% over a similar multilayer with no carbon capping material, thus raising the reflectivity from 58.3% to over 65%. The multilayers were formed using either Mo.sub.2 C or Be as the first and last layers, and initial testing has shown the formation of beryllium carbide at the interfaces between the layers which both stabilizes and has a smoothing effect, and appear to be smoother than the interfaces in Mo/Be multilayers.

  16. L-carnitine protects C2C12 cells against mitochondrial superoxide overproduction and cell death

    Le Borgne, Françoise; Ravaut, Gaétan; Bernard, Arnaud; Demarquoy, Jean


    AIM To identify and characterize the protective effect that L-carnitine exerted against an oxidative stress in C2C12 cells. METHODS Myoblastic C2C12 cells were treated with menadione, a vitamin K analog that engenders oxidative stress, and the protective effect of L-carnitine (a nutrient involved in fatty acid metabolism and the control of the oxidative process), was assessed by monitoring various parameters related to the oxidative stress, autophagy and cell death. RESULTS Associated with its physiological function, a muscle cell metabolism is highly dependent on oxygen and may produce reactive oxygen species (ROS), especially under pathological conditions. High levels of ROS are known to induce injuries in cell structure as they interact at many levels in cell function. In C2C12 cells, a treatment with menadione induced a loss of transmembrane mitochondrial potential, an increase in mitochondrial production of ROS; it also induces autophagy and was able to provoke cell death. Pre-treatment of the cells with L-carnitine reduced ROS production, diminished autophagy and protected C2C12 cells against menadione-induced deleterious effects. CONCLUSION In conclusion, L-carnitine limits the oxidative stress in these cells and prevents cell death.

  17. Midway Atoll Site P2C 9/21/2002 18-19M

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P2C (28.260 N, 177.345 W), between 18 and 19 meters along a permanent transect.

  18. Midway Atoll Site P2C 9/21/2002 24-25M

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P2C (28.260 N, 177.345 W), between 24 and 25 meters along a permanent transect.

  19. BAMBI Promotes C2C12 Myogenic Differentiation by Enhancing Wnt/β-Catenin Signaling

    Qiangling Zhang


    Full Text Available Bone morphogenic protein and activin membrane-bound inhibitor (BAMBI is regarded as an essential regulator of cell proliferation and differentiation that represses transforming growth factor-β and enhances Wnt/β-catenin signaling in various cell types. However, its role in skeletal muscle remains largely unknown. In the current study, we found that the expression level of BAMBI peaked in the early differentiation phase of the C2C12 rodent myoblast cell line. Knockdown of BAMBI via siRNA inhibited C2C12 differentiation, indicated by repressed MyoD, MyoG, and MyHC expression as well as reductions in the differentiation and fusion indices. BAMBI knockdown reduced the activity of Wnt/β-catenin signaling, as characterized by the decreased nuclear translocation of β-catenin and the lowered transcription of Axin2, which is a well-documented target gene of the Wnt/β-catenin signaling pathway. Furthermore, treatment with LiCl, an activator of Wnt/β-catenin signaling, rescued the reduction in C2C12 differentiation caused by BAMBI siRNA. Taken together, our data suggest that BAMBI is required for normal C2C12 differentiation, and that its role in myogenesis is mediated by the Wnt/β-catenin pathway.

  20. The High-Pressure Phase of MgB2C2

    Woerle, Michael; Fischbach, Urs; Widmer, Daniel; Krumeich, Frank; Nesper, Reinhard; Evers, Juergen; Stalder, Roland; Ulmer, Peter


    A high-pressure modification of MgB2C2 was synthesized and structurally characterized. The compound crystallizes in the orthorhombic space group Pnnm, with the lattice parameters a = 7.19633(3) angstrom, b = 4.61791(13) angstrom and c = 2.77714(8) angstrom. The compound contains heterographene B-C n

  1. Midway Atoll Site P2C 9/21/2002 21-22M

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P2C (28.260 N, 177.345 W), between 21 and 22 meters along a permanent transect.

  2. Midway Atoll Site P2C 9/21/2002 13-14M

    US Fish and Wildlife Service, Department of the Interior — One-meter-square (1 meter x 1 meter) benthic substrate at Midway Atoll, site P2C (28.260 N, 177.345 W), between 13 and 14 meters along a permanent transect.

  3. Hysteresis in the field-induced magnetic structure in TmNi2B2C

    Eskildsen, M.R.; Harada, K.; Gammel, P.L:


    Using small-angle neutron scattering we have studied the flux line lattice and the magnetic structure in TmNi2B2C. With an applied field parallel to the crystalline c-axis several magnetic and flux line lattice symmetry transitions have been reported. The subject of this paper is the held-induced...

  4. Thermal ramp tritium release in COBRA-1A2 C03 beryllium pebbles

    Baldwin, D.L. [Pacific Northwest National Lab., Richland, WA (United States)


    Tritium release kinetics, using the method of thermal ramp heating at three linear ramp rates, were measured on the COBRA-1A2 C03 1-mm beryllium pebbles. This report includes a brief discussion of the test, and the test data in graph format.


    Chunru Wang; Lihua Gan; Chunli Bai; Hisanori Shinohara


    The isolation of multiple-isomers of Sc2@C80 (Ⅰ, Ⅱ, Ⅲ) endohedral metallofullerenes is reported for the first time. The new C80-based Sc-metallofullerenes are characterized by UV-Vis-NIR absorption spectroscopy and detailed chromatographic retention time data. A close relationship between the isomer structure and the corresponding HPLC retention time of the metallofullerenes is presented.

  6. B2C social media value gap-model: a study of the Dutch online retailing

    Constantinides, Efthymios; Schepers, Lonieke; Vries, de Sjoerd


    Social media are extensively used by customers and businesses in the B2C domain but the objectives and the way the two parties use them are different. Based on the uses and gratifications theory, the article identifies similarities and differences in motives and use of social media in retailing. The

  7. The Development of B2C E-Commerce in Greece: Current Situation and Future Potential.

    Kardaras, Dimitris; Papathanassiou, Eleutherios


    Reports on the results of a survey of 120 companies in Greece that evaluated the potential of business to customer (B2C) Internet applications and investigated how the Internet and e-commerce can offer new opportunities for businesses to improve their customers' satisfaction. Discusses electronic commerce problems and future technology. (Contains…

  8. 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.


    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 tolerant to high salt and mannitol stresses during seed germination, root growth and overall seedling growth. At adult stage, OsPP108 overexpression leads to high tolerance to salt, mannitol and drought stresses with far better physiological parameters such as water loss, fresh weight, chlorophyll content and photosynthetic potential (Fv/Fm) in transgenic Arabidopsis plants. Expression profile of various stress marker genes in OsPP108 overexpressing plants revealed interplay of ABA dependent and independent pathway for abiotic stress tolerance. Overall, this study has identified a potential rice group A PP2C, which regulates ABA signaling negatively and abiotic stress signaling positively. Transgenic rice plants overexpressing this gene might provide an answer to the problem of low crop yield and productivity during adverse environmental conditions. PMID:25886365

  9. 76 FR 77833 - Scientific Information Request on CYP2C19 Variants and Platelet Reactivity Tests


    ... Variants and Platelet Reactivity Tests AGENCY: Agency for Healthcare Research and Quality (AHRQ), HHS... platelet reactivity tests. Scientific information is being solicited to inform our Comparative... for studies that report on CYP2C19 variants and platelet reactivity tests, including those...

  10. Apoptosis in differentiating C2C12 muscle cells selectively targets Bcl-2-deficient myotubes.

    Schöneich, Christian; Dremina, Elena; Galeva, Nadezhda; Sharov, Victor


    Muscle cell apoptosis accompanies normal muscle development and regeneration, as well as degenerative diseases and aging. C2C12 murine myoblast cells represent a common model to study muscle differentiation. Though it was already shown that myogenic differentiation of C2C12 cells is accompanied by enhanced apoptosis in a fraction of cells, either the cell population sensitive to apoptosis or regulatory mechanisms for the apoptotic response are unclear so far. In the current study we characterize apoptotic phenotypes of different types of C2C12 cells at all stages of differentiation, and report here that myotubes of differentiated C2C12 cells with low levels of anti-apoptotic Bcl-2 expression are particularly vulnerable to apoptosis even though they are displaying low levels of pro-apoptotic proteins Bax, Bak and Bad. In contrast, reserve cells exhibit higher levels of Bcl-2 and high resistance to apoptosis. The transfection of proliferating myoblasts with Bcl-2 prior to differentiation did not protect against spontaneous apoptosis accompanying differentiation of C2C12 cells but led to Bcl-2 overexpression in myotubes and to significant protection from apoptotic cell loss caused by exposure to hydrogen peroxide. Overall, our data advocate for a Bcl-2-dependent mechanism of apoptosis in differentiated muscle cells. However, downstream processes for spontaneous and hydrogen peroxide induced apoptosis are not completely similar. Apoptosis in differentiating myoblasts and myotubes is regulated not through interaction of Bcl-2 with pro-apoptotic Bcl-2 family proteins such as Bax, Bak, and Bad.

  11. Pharmacokinetics of lansoprazole in Chinese healthy subjects in relation to CYP2C19 genotypes

    Yu-rong HU; Hai-ling QIAO; Quan-cheng KAN


    AIM: To study the kinetic characteristics of lansoprazole in healthy Chinese subjects in relation to CYP2C19 genotype status for the individualized dose regimen of lansoprazole. METHODS: Nine homozygous extensive metabolizers (homo EMs) and 9 poor metabolizers (PMs) were recruited for the study from a total of 70 healthy Chinese volunteers, whose CYP2C19 genotype status was determined by the PCR-RFLP techniques. After a single oral dose of 30 mg lansoprazole capsule, plasma concentrations of lansoprazole were determined with HPLC method. RESULTS: In Chinese subjects, the allele frequencies of the CYP2C19ml and CYP2C19m2 mutation were 0.35 and 0.07, respectively. The concentration-time curves in the two groups were best fitted to a one-compartment model. In the homo EMs and the PMs groups, the main kinetic parameters were as follows: Tmax(2.44±0.85)and (2.33±0.94) h, Cmax (1.10±0.34) and (1.73±0.56) mg/L, Cl/F (16.55±6.38) and (3.58± 1) L/h, T1/2ke (1.96±0.51)Cmax values existed between the two groups (P<0.01). CONCLUSION: CYP2C19 genotype is the major factor to influence the interindividual kinetic variability of lansoprazole. Individualized dose regimen of lansoprazole, based on identification of genotype, can be of great benefit for the reasonable use of this drug.

  12. First-principles study of He trapping in η-Fe2C

    He, Bing-Ling; Wang, Jin-Long; Tian, Zhi-Xue; Jiang, Li-Juan; Song, Wei; Wang, Bin


    The distribution of He in η-Fe2C has been studied by first-principles calculations. The formation energies of interstitial He and substitutional He (replacing Fe) are 3.76 eV and 3.49 eV, respectively, which are remarkably smaller than those in bcc Fe, indicating that He is more soluble in η-Fe2C than in bcc Fe. The binding potencies of both a substitutional-interstitial He pair (1.28 eV) and a substitutional-substitutional He pair (0.76 eV) are significantly weaker than those in bcc Fe. The binding energy between the two He atoms in an interstitial-interstitial He pair (0.31 eV) is the same as that in bcc Fe, but the diffusion barrier of interstitial He (0.35 eV) is much larger than that in bcc Fe, suggesting that it is more difficult for the interstitial He atom to agglomerate in η-Fe2C than in bcc Fe. Thus, self-trapping of He in η-Fe2C is less powerful than that in bcc Fe. As a consequence, small and dense η-Fe2C particles in ferritic steels might serve as scattered trapping centers for He, slow down He bubble growth at the initial stage, and make the steel more swelling resistant. Project supported by the Research Key Project of Science and Technology of Education Bureau of Henan Province, China (Grant Nos. 14A140030, 15A140032, 15B150010, and 15A430037) and the Innovation Talents Program of Science and Technology of Institution of Higher Education of Henan Province, China (Grant No. 14HASTIT044).

  13. Characterization of potential ABA receptors in Vitis vinifera.

    Boneh, Uri; Biton, Iris; Zheng, Chuanlin; Schwartz, Amnon; Ben-Ari, Giora


    Molecular control mechanisms for abiotic stress tolerance are based on the activation and regulation of specific stress-related genes. The phytohormone abscisic acid (ABA) is a key endogenous messenger in a plant's response to such stresses. A novel ABA binding mechanism which plays a key role in plant cell signaling cascades has recently been uncovered. In the absence of ABA, a type 2C protein phosphatase (PP2C) interacts and inhibits the kinase SnRK2. Binding of ABA to the PYR/PYLs receptors enables interaction between the ABA receptor and the PP2C protein, and abrogates the SnRK2 inactivation. The active SnRK2 is then free to activate the ABA-responsive element Binding Factors which target ABA-dependent gene expression. We used the grape as a model to study the ABA perception mechanism in fruit trees. The grape ABA signaling cascade consists of at least seven ABA receptors and six PP2Cs. We used a yeast two-hybrid system to examine physical interaction in vitro between the grape ABA receptors and their interacting partners, and found that twenty-two receptor-PP2C interactions can occur. Moreover, quantifying these affinities by the use of the LacZ reporter enables us to show that VvPP2C4 and VvPP2C9 are the major binding partners of the ABA receptor. We also tested in vivo the root and leaf gene expression of the various ABA receptors and PP2Cs in the presence of exogenic ABA and under different abiotic stresses such as high salt concentration, cold and drought, and found that many of these genes are regulated by such abiotic environmental factors. Our results indicate organ specificity in the ABA receptor genes and stress specificity in the VvPP2Cs. We suggest that VvPP2C4 is the major PP2C involved in ABA perception in leaves and roots, and VvRCAR6 and VvRCAR5 respectively, are the major receptors involved in ABA perception in these organs. Identification, characterization and manipulation of the central players in the ABA signaling cascades in fruit trees is

  14. Toward reduction in animal sacrifice for drugs: molecular modeling of Macaca fascicularis P450 2C20 for virtual screening of Homo sapiens P450 2C8 substrates.

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


    Macaca fascicularis P450 2C20 shares 92% identity with human cytochrome P450 2C8, which is involved in the metabolism of more than 8% of all prescribed drugs. To date, only paclitaxel and amodiaquine, two substrate markers of the human P450 2C8, have been experimentally confirmed as M. fascicularis P450 2C20 drugs. To bridge the lack of information on the ligands recognized by M. fascicularis P450 2C20, in this study, a three-dimensional homology model of this enzyme was generated on the basis of the available crystal structure of the human homologue P450 2C8 using YASARA. The results indicated that 90.0%, 9.0%, 0.5%, and 0.5% of the residues of the P450 2C20 model were located in the most favorable, allowed, generously allowed, and disallowed regions, respectively. The root-mean-square deviation of the C-alpha superposition of the M. fascicularis P450 2C20 model with the Homo sapiens P450 2C8 was 0.074 Å, indicating a very high similarity of the two structures. Subsequently, the 2C20 model was used for in silico screening of 58 known P450 2C8 substrates and 62 inhibitors. These were also docked in the active site of the crystal structure of the human P450 2C8. The affinity of each compound for the active site of both cytochromes proved to be very similar, meaning that the few key residues that are mutated in the active site of the M. fascicularis P450 do not prevent the P450 2C20 from recognizing the same substrates as the human P450 2C8.

  15. Effect of Mo{sub 2}C/(Mo{sub 2}C + WC) weight ratio on the microstructure and mechanical properties of Ti(C,N)-based cermet tool materials

    Xu, Qingzhong; Zhao, Jun, E-mail:; Ai, Xing; Qin, Wenzhen; Wang, Dawei; Huang, Weimin


    To optimize the Mo{sub 2}C content in Ti(C,N)-based cermet tool materials used for cutting the high-strength steel of 42CrMo (AISI 4140/4142 steel), the cermets with different Mo{sub 2}C/(Mo{sub 2}C + WC) weight ratios were prepared. And the microstructure and mechanical properties of cermets were investigated by scanning electron microscope (SEM), X-ray diffraction (XRD) and measurements of transverse rupture strength (TRS), Vickers hardness (HV) and fracture toughness (K{sub IC}). The results indicate that the Mo{sub 2}C/(Mo{sub 2}C + WC) ratios have great influences on the microstructure features and mechanical properties of Ti(C,N)-based cermets. When the Mo{sub 2}C/(Mo{sub 2}C + WC) ratio increases, the Ti(C,N) grains become finer with smaller black cores surrounded by thinner rims, and the structure of cermets tends to be more compact with smaller binder mean free path. Owing to the medium grains and moderate rims, the cermets with a Mo{sub 2}C/(Mo{sub 2}C + WC) ratio of 0.4 exhibit better mechanical properties, and can be chosen as the tool material for machining 42CrMo steel due to the lower Mo content. - Highlights: • Mo{sub 2}C/(Mo{sub 2}C + WC) ratios affect microstructure and mechanical properties of cermets. • Grains become fine and structure of cermets tends to be compact with raised Mo{sub 2}C. • The cermets with a Mo{sub 2}C/(Mo{sub 2}C + WC) ratio of 0.4 can be used to machine 42CrMo steel.

  16. Effects of 5-hydroxytryptamine and 5-hydroxytryptamine 2A/2C agonist on the genioglossus activity and sleep apnea in rats

    ZHONG Yi-jue; ZHANG Cheng; WANG Guang-fa


    Background 5-hydroxytryptamine (5-HT) is a common neurotransmitter in the brain which plays an important role in the pathogenesis of sleep apnea.Dysfunction of 5-HT and 5-HT2 receptors may lead to the collapse of the upper airway and the instability of respiratory control, which in turn produce apnea.Genioglossus (GG) is one of the most important oropharyngeal muscles maintaining the upper airway open.The present study aimed to investigate the effects of 5-HT and 5-HT2 receptor on GG activity and the sleep apnea in Sprague-Dawley (SD) rats.Methods Microinjection probes were placed within the fourth ventricle of sixteen SD rats.After recovery for a week, the electromyogram (EMG) of GG was recorded in the anesthetized and vagotomized rats.The changes of GG activity before and after the microinjection of 5-HT or 5-HT2A/2c agonist -2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)were observed.Probes were also laid in another eight SD rats.Electroencephalogram (EEG), EMG of neck muscle and respiration were recorded at the same time a week later.The effects of DOI on the occurrence of sleep apnea were explored.Results Both 5-HT and DOI significantly enhanced the activity of GG just 3 minutes after the completion of injection.The effect of 5-HT disappeared quickly and the effect of DOI lasted for more than 27 minutes.DOI also significantly decreased the post-sigh apnea index in non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep and decreased the spontaneous apnea index only in NREM sleep (P <0.05, respectively).Conclusion 5-HT and 5-HT2A/2c system correlated closely with the pathogenesis of the sleep apnea syndrome and 5-HT receptors may become the target of the drug treatment.

  17. 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


    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...... of follow-up; the Copenhagen General Population Study, a cross-sectional study including 21 629 participants; and the Copenhagen Ischemic Heart Disease Study, a case-control study including 5082 cases and 14 904 controls. CYP2C9 carriers versus noncarriers did not associate with subclinical atherosclerosis......% power. In conclusion, in three independent studies totaling more than 52 000 individuals, we found no association between CYP2C9(*)2 and CYP2C9(*)3 polymorphisms and risk of subclinical atherosclerosis, ischemic vascular disease or death after ischemic heart disease....

  18. Dissolution and electrochemical properties of molybdenum carbide (Mo{sub 2}C) in basic solutions

    Maslennikov, A.; Boudanova, N. [Academy of Sciences, Moscow (Russian Federation). A.N. Frumkin Inst. of Physical Chemistry and Electrochemistry; Cannes, C.; Fourest, B. [Institut de Physique Nucleaire (INP), 91 - Orsay (France); Vivier, V. [Lab. Interfaces et Systemes Electrochimiques, 75 - Paris (France); Moisy, P. [CEA VALRHO DEN/DRCP/SCPS, 30 - Bagnols sur Ceze (France)


    The dissolution and electrochemical properties of molybdenum carbide were investigated using a number of electrochemical techniques, including general corrosion tests (GCT), linear voltammetry (LV), potential controlled electrolysis (PCE) and Scanning Electrochemical Microscopy (SECM), in basic media (0.5-4 M NaOH and 1 M NaHCO{sub 3}/Na{sub 2}CO{sub 3}, pH 9.1-11.3). It was shown that the Mo2C corrosion potential (E{sub corr}) shifted towards negative values from -0.39 to -0.96 V/SCE with an increase of the OH{sup -} concentration and did not depend on the CO{sub 3}{sup 2-} concentration in the electrolyte. LV measurements in carbonate buffer (pH 9.2), evidenced three potential regions: passivation from E{sub corr} to -0.2 V/SCE, pseudopassivation from -0.25 to 0 V/SCE and anodic dissolution (transpassivation) at E > 0.1 V/SCE. The potentials delimiting the mentioned regions decreased with the increase of the OH{sup -} concentration, becoming undistinguished in 2 M NaOH. The Mo{sub 2}C dissolution rate (k{sub diss}) in the transpassive state was estimated using LV data. In 4 M NaOH at -0.1 V/SCE, k{sub diss} reached 430 mg cm{sup -2}h{sup -1} and decreased with the decrease of the OH{sup -} concentration and the electrolysis potential. The Mo{sub 2}C dissolution current efficiency varied between 12 and 13Fmol{sup -1} Mo{sub 2}C, proving the formation of the intermediate products of a carbon oxidative degradation during PCE. The presence of C{sub 2}O{sub 4}{sup 2-} and non-identified aromatic compounds in the electrolytes after Mo{sub 2}C dissolution was ascertained, using capillary zone electrophoresis. Scanning electrochemical microscopy (SECM) confirmed the formation of a pseudopassive film and demonstrated the increase of its thickness with the increase of the applied potential. The effect of the presence of Mo{sub 2}C on the irradiated UC fuel dissolution rate and the mechanisms involved are discussed. (orig.)

  19. Impact of CYP2C8*3 polymorphism on in vitro metabolism of imatinib to N-desmethyl imatinib.

    Khan, Muhammad Suleman; Barratt, Daniel T; Somogyi, Andrew A


    1. Imatinib is metabolized to N-desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-desmethyl imatinib formation was unknown. 2. We examined imatinib N-demethylation in human liver microsomes (HLMs) genotyped for CYP2C8*3, in CYP2C8*3/*3 pooled HLMs and in recombinant CYP2C8 and CYP3A4 enzymes. Effects of CYP-selective inhibitors on N-demethylation were also determined. 3. A single-enzyme Michaelis-Menten model with autoinhibition best fitted CYP2C8*1/*1 HLM (n = 5) and recombinant CYP2C8 kinetic data (median ± SD Ki = 139 ± 61 µM and 149 µM, respectively). Recombinant CYP3A4 showed two-site enzyme kinetics with no autoinhibition. Three of four CYP2C8*1/*3 HLMs showed single-enzyme kinetics with no autoinhibition. Binding affinity was higher in CYP2C8*1/*3 than CYP2C8*1/*1 HLM (median ± SD Km = 6 ± 2 versus 11 ± 2 µM, P=0.04). CYP2C8*3/*3 (pooled HLM) also showed high binding affinity (Km = 4 µM) and single-enzyme weak autoinhibition (Ki = 449 µM) kinetics. CYP2C8 inhibitors reduced HLM N-demethylation by 47-75%, compared to 0-30% for CYP3A4 inhibitors. 4. In conclusion, CYP2C8*3 is a gain-of-function polymorphism for imatinib N-demethylation, which appears to be mainly mediated by CYP2C8 and not CYP3A4 in vitro in HLM.

  20. Be{sub 2}C formation in beryllium-carbon binary system by vacuum heating

    Ashida, Kan; Watanabe, Kuniaki [Toyama Univ. (Japan). Hydrogen Isotope Research Center


    The surface chemical states of beryllium and carbon binary systems at elevated temperature were investigated by means of x-ray photoelectron spectroscopy (XPS) and secondary ion mass spectroscopy (SIMS). The XPS measurements revealed that the mixed subsurface layers containing Be and C readily yield Be{sub 2}C layers by vacuum heating and ion bombardment. The SIMS measurements showed that hydrogen isotope atoms are trapped by three distinct sites; namely Be, C, and O-sites on the sample surface. The SIMS measurements also showed that carbon atoms lose its ability to bind with hydrogen isotope atoms on forming Be{sub 2}C. It would be a key to control hydrogen inventory when Be and C are used together as PFM. (author)

  1. Carbon-nitrogen place exchange on NO exposed beta-Mo2C.

    Siaj, Mohamed; Maltais, Carl; Zahidi, El Mamoune; Oudghiri-Hassani, Hicham; Wang, Jiqing; Rosei, Federico; McBreen, Peter H


    Atomic nitrogen and oxygen were deposited on beta-Mo(2)C through dissociative adsorption of NO. Reflectance absorbance infrared spectroscopy (RAIRS), thermal desorption, and synchrotron X-ray photoelectron spectroscopy (XPS) measurements were used to investigate the interplay between atomic nitrogen, carbon, and oxygen in the 400-1250 K region. The combination of the high resolution and high surface sensitivity offered by the synchrotron XPS technique was used to show that atomic nitrogen displaces interstitial carbon onto the carbide surface. Thermal desorption measurements show that the burnoff of the displaced carbon occurs at approximately 890 K. The incorporation of nitrogen into interstitial sites inhibits oxygen dissolution into the bulk. RAIRS spectroscopy was used to identify surface oxo, terminal oxygen, species formed from O(2) and NO on beta-Mo(2)C.

  2. Degradation of triclocarban by a triclosan-degrading Sphingomonas sp. strain YL-JM2C.

    Mulla, Sikandar I; Hu, Anyi; Wang, Yuwen; Sun, Qian; Huang, Shir-Ly; Wang, Han; Yu, Chang-Ping


    Bacterial degradation plays a vital role in determining the environmental fate of micropollutants like triclocarban. The mechanism of triclocarban degradation by pure bacterium is not yet explored. The purpose of this study was to identify metabolic pathway that might be involved in bacterial degradation of triclocarban. Triclosan-degrading Sphingomonas sp. strain YL-JM2C was first found to degrade up to 35% of triclocarban (4 mg L(-1)) within 5 d. Gas chromatography-mass spectrometry detected 3,4-dichloroaniline, 4-chloroaniline and 4-chlorocatechol as the major metabolites of the triclocarban degradation. Furthermore, total organic carbon results confirmed that the intermediates, 3,4-dichloroaniline (4 mg L(-1)) and 4-chloroaniline (4 mg L(-1)) could be degraded up to 77% and 80% by strain YL-JM2C within 5 d.

  3. Type II collagen C2C epitope in human synovial fluid and serum after knee injury

    Kumahashi, N; Swärd, P; Larsson, S;


    PURPOSE: Investigate in a cross-sectional study time-dependent changes of synovial fluid type II collagen epitope C2C concentrations after knee injury and correlate to other joint injury biomarkers. METHODS: Synovial fluid samples were aspirated between 0 days and 7 years after injury (n = 235......). Serum was collected from 71 of the knee injured patients. Synovial fluid from 8 knee-healthy subjects was used as reference. C2C was quantified by immunoassay and structural injury was determined from magnetic resonance images (MRI) of the injured knee acquired 1-38 days after injury (n = 98...... = 0.403, P type II collagen (r = 0.444, P = 0.003), ARGS-aggrecan (r = 0.337, P

  4. Neutron Scattering Study of Na_2C_60 in (P,T)-Plane

    Trevino, S. F.; Yildirim, T.; Neumann, D. A.; Fischer, J. E.


    Na_2C_60 forms the simplest system to investigate various intermolecular interactions. Therefore, we have studied Na_2C_60 for 0 250 K and P > 1 kbar, the structure is distorted, qualitatively similar to suggested pressure induced polymer phase of Na_2RbC_60[1]. Here the peaks at low Q are significantly broaden while the higher Q peaks are almost completely smeared out. Inelastic neutron scattering measurements performed at T=150 K and with P=0 and 4 kbar did not show any new lattice modes in the range 100-200 cm-1, inconsistent with C_60 polymerization. Instead, we observed an excess of low energy states in the distorted phase, reminiscent of what is observed in glassy solids. fˇill [1] Q.Zhu, Phys. Rev. B 52, R723 (1995).

  5. Silencing myotubularin related protein 7 enhances proliferation and early differentiation of C2C12 myoblast.

    Yuan, Zhuning; Chen, Yaosheng; Zhang, Xumeng; Zhou, Xingyu; Li, Mingsen; Chen, Hu; Wu, Ming; Zhang, Ying; Mo, Delin


    Myotubularin related protein 7 (MTMR7) is a key member of the highly conserved myotubularin related proteins (MTMRs) family, which has phosphatase activity. MTMR7 was increased during myoblast differentiation and exhibited high expression level at primary fibers formation stages in pigs. This suggests that MTMR7 may be involved in myogenesis. In our study, we investigated the roles of MTMR7 on proliferation and differentiation of C2C12 myoblasts. Knocking down MTMR7 not only enhanced myoblast early differentiation via altering the expression of Myf5, but also promoted myoblast proliferation through increasing cyclinA2 expression. The improved proliferation capacity was related to the increased phosphorylation of AKT. Taken together, our research demonstrates that MTMR7 plays an important role in proliferation and early differentiation of C2C12 myoblast.




    Full Text Available In this paper, the generating functions for ultraspherical polynomials Cα n (x (Gegenbaur polynomials are obtained by using the representa- tion theory of the Lie group SL(2, C (the complex special linear group giving a suitable interpretation to the index 0 n0 . Further, linearly inde- pendent differential J-operators derived, which generate a Lie algebra isomorphic to sl(2, C. The principle interest in our results lies in the fact that, how thecomplex special linear group can be applied suitably to the Gegenbaur polynomials in order to derive six bilinear/bilateral generating functions. The generating functions, in turn yield, Legendre polynomials as special cases. Many results obtained are well known but some of them are believed to be new in the theory of specialfunctions.

  7. A phylogenetic study of canine parvovirus type 2c in midwestern Brazil

    Danúbia S. Fontana


    Full Text Available Since the late 1970s, canine parvovirus type 2 (CPV-2 has emerged as a causative agent of fatal severe acute hemorrhagic enteritis in dogs. To date, three antigenic types of CPV-2 were described worldwide (CPV-2a/b/c. This study was conducted to determine the variants of CPV-2 circulating in dogs from the Cuiabá Municipality in Midwestern Brazil. Out of 50 fecal samples, collected between 2009 and 2011, 27 tested positive for CPV-2. A 583 bp fragment of the VP2 gene was amplified by PCR, 13 representative samples were analyzed further by DNA sequencing. All strains were characterized as CPV-2c, displayed a low genetic variability although observed several amino acid substitution. These findings indicated that CPV-2c has been circulating in dogs from the Cuiabá Municipality in Midwestern Brazil.

  8. Occurrence of canine parvovirus type 2c in the dogs with haemorrhagic enteritis in India.

    Nandi, S; Chidri, S; Kumar, Manoj; Chauhan, R S


    Canine parvovirus 2 (CPV-2) causes a highly contagious and often fatal disease in dogs. Since its sudden emergence in the early 1970s, CPV-2 has been evolving through the generation of novel genetic and antigenic variants (CPV-2a/b/c) that are unevenly distributed throughout the world. In the present study we have examined 36 clinical cases of dogs suspected of CPV collected during year 2006. A fragment of the VP2 gene of the virus was analyzed using polymerase chain reaction (PCR), restriction endonuclease (RE) and DNA sequence analysis. Out of the 36 samples analyzed, 16 were found positive for CPV-2a/2b by conventional PCR. DNA sequencing was done for 6 PCR positive samples, out of which three were characterized as CPV-2c, indicating that this CPV type 2c is currently circulating in India.

  9. Establishing Efficient C2C E-alliance Based on Mobile Agent

    YU Xiao-bing; GUO Shun-sheng; GUO Jun


    In order to alleviate difficulties of conducting consumer-to-consumer(C2C)e-commerce transaction,establishing efficient e-alliance was proposed.E-alliance is the union of e-commerce sites.It is constructed by mobile agents.The mobile agent architecture was discussed.The process of selecting suitable e-commerce site to e-alliance was presented based on support vector machine(SVM)and fuzzy method.A prototype of the proposed system is implemented on a web platform.To enable data exchange between e-alliance and e-commerce,the system employs XML as data format.The prototype has demonstrated that the efficient C2C e-alliance is reasonable.

  10. Rab8A regulates insulin-stimulated GLUT4 translocation in C2C12 myoblasts.

    Li, Hanbing; Ou, Liting; Fan, Jiannan; Xiao, Mei; Kuang, Cuifang; Liu, Xu; Sun, Yonghong; Xu, Yingke


    Rab proteins are important regulators of GLUT4 trafficking in muscle and adipose cells. It is still unclear which Rabs are involved in insulin-stimulated GLUT4 translocation in C2C12 myoblasts. In this study, we detect the colocalization of Rab8A with GLUT4 and the presence of Rab8A at vesicle exocytic sites by TIRFM imaging. Overexpression of dominant-negative Rab8A (T22N) diminishes insulin-stimulated GLUT4 translocation, while constitutively active Rab8A (Q67L) augments it. In addition, knockdown of Rab8A inhibits insulin-stimulated GLUT4 translocation, which is rescued by replenishment of RNAi-resistant Rab8A. Together, these results indicate an indispensable role for Rab8A in insulin-regulated GLUT4 trafficking in C2C12 cells.

  11. Lysine suppresses protein degradation through autophagic-lysosomal system in C2C12 myotubes.

    Sato, Tomonori; Ito, Yoshiaki; Nedachi, Taku; Nagasawa, Takashi


    Muscle mass is determined between protein synthesis and protein degradation. Reduction of muscle mass leads to bedridden condition and attenuation of resistance to diseases. Moreover, bedridden condition leads to additional muscle loss due to disuse muscle atrophy. In our previous study (Sato et al. 2013), we showed that administered lysine (Lys), one of essential amino acid, suppressed protein degradation in skeletal muscle. In this study, we investigated that the mechanism of the suppressive effects of Lys on skeletal muscle proteolysis in C2C12 cell line. C2C12 myotubes were incubated in the serum-free medium containing 10 mM Lys or 20 mM Lys, and myofibrillar protein degradation was determined by the rates of 3-methylhistidine (MeHis) release from the cells. The mammalian target of rapamycin (mTOR) activity from the phosphorylation levels of p70-ribosormal protein S6 kinase 1 and eIF4E-binding protein 1 and the autophagic-lysosomal system activity from the ratio of LC3-II/I in C2C12 myotubes stimulated by 10 mM Lys for 0-3 h were measured. The rates of MeHis release were markedly reduced by addition of Lys. The autophagic-lysosomal system activity was inhibited upon 30 min of Lys supplementation. The activity of mTOR was significantly increased upon 30 min of Lys supplementation. The suppressive effect of Lys on the proteolysis by the autophagic-lysosomal system was maintained partially when mTOR activity was inhibited by 100 nM rapamycin, suggesting that some regulator other than mTOR signaling, for example, Akt, might also suppress the autophagic-lysosomal system. From these results, we suggested that Lys suppressed the activity of the autophagic-lysosomal system in part through activation of mTOR and reduced myofibrillar protein degradation in C2C12 myotubes.

  12. 3,4-O-Isopropylidene-2-C-methyl-d-galactonolactone

    N. Dai


    Full Text Available X-ray crystallography unequivocally confirmed the stereochemistry of the 2-C-methyl group in the title molecule, C10H16O6, in which the 1,5-lactone ring exists in a boat conformation. The use of d-galactose in the synthesis determined the absolute stereochemistry. The crystal exists as O—H...O hydrogen-bonded layers in the ab plane, with each molecule acting as a donor and acceptor for two hydrogen bonds.

  13. Harvesting and preparation of cadaveric osseoligamentous lower cervical spine (C2-C7) for biomechanical testing

    Yeh, J; Jackowski, A


    Cadaveric osseoligamentous lower cervical spines (C2-C7) are often used in the investigation of spinal biomechanics in vitro. Surprisingly, however, the techniques of harvesting at postmortem and preparation of cadaveric osseoligamentous lower cervical spine for biomechanical testing have not been described in detail. We describe a simple and effective method that can be readily integrated into the routine autopsy procedure. Points on the avoidance of disfiguring the cadaver and damaging the ...

  14. Intercomparison of an improved 20th Century reanalysis version 2c dataset spanning 1850 to 2012

    Compo, G. P.; Whitaker, J. S.; Sardeshmukh, P. D.; Giese, B. S.; Brohan, P.


    The historical reanalysis dataset generated by NOAA ESRL and the University of Colorado CIRES, the Twentieth Century Reanalysis version 2 (20CRv2), is a comprehensive global atmospheric circulation dataset spanning 1871-2012, assimilating only surface pressure and using monthly Hadley Centre SST and sea ice distributions (HadISST1.1) as boundary conditions. It has been made possible through collaboration with GCOS, WCRP, and the ACRE initiative. It is chiefly motivated by a need to provide an observational validation dataset, with quantified uncertainties, for assessments of climate model simulations of the 20th century, with emphasis on the statistics of daily weather. It uses, together with an NCEP global numerical weather prediction (NWP) land/atmosphere model to provide background "first guess" fields, an Ensemble Kalman Filter (EnKF) data assimilation method. This yields a global analysis every 6 hours as the most likely state of the atmosphere, and also yields the uncertainty of that analysis. Improvements in the new version ("2c") include an extension back to 1850 and the specification of new boundary conditions. These come from new fields of monthly COBE-SST2 sea ice concentrations and an ensemble of daily Simple Ocean Data Assimilation with Sparse Input (SODAsi.2c) sea surface temperatures. SODAsi.2c itself was forced with 20CR, allowing these boundary conditions to be more consistent with the atmospheric reanalysis. Millions of additional pressure observations contained in the new International Surface Pressure Databank version 3 are also included. These improvements result in 20CR version "2c" having comparable or better analyses, as suggested by improved 24 hour forecast skill, more realistic uncertainty in near-surface air temperature, and a reduction in spurious centennial trends in the tropical and polar regions. An intercomparison with ERA-Interim, MERRA, and JRA-55 reanalyses that assimilate all available upper-air and satellite observations will

  15. Diameter-Specific Growth of Semiconducting SWNT Arrays Using Uniform Mo2C Solid Catalyst.

    Zhang, Shuchen; Tong, Lianming; Hu, Yue; Kang, Lixing; Zhang, Jin


    Semiconducting single-walled nanotube (s-SWNT) arrays with specific diameters are urgently demanded in the applications in nanoelectronic devices. Herein, we reported that by using uniform Mo2C solid catalyst, aligned s-SWNT (∼90%) arrays with narrow-diameter distribution (∼85% between 1.0 and 1.3 nm) on quartz substrate can be obtained. Mo2C nanoparticles with monodisperse sizes were prepared by using molybdenum oxide-based giant clusters, (NH4)42[Mo132O372(H3CCOO)30(H2O)72]·10H3CCOONH4·300H2O(Mo132), as the precursor that was carburized by a gas mixture of C2H5OH/H2 during a temperature-programmed reduction. In this approach, the formation of volatile MoO3 was inhibited due to the annealing and reduction at a low temperature. As a result, uniform Mo2C nanoparticles are formed, and their narrow size-dispersion strictly determines the diameter distribution of SWNTs. During the growth process, Mo2C selectively catalyzes the scission of C-O bonds of ethanol molecules, and the resultant absorbed oxygen (Oads) preferentially etches metallic SWNTs (m-SWNTs), leading to the high-yield of s-SWNTs. Raman spectroscopic analysis showed that most of the s-SWNTs can be identified as (14, 4), (13, 6), or (10, 9) tubes. Our findings open up the possibility of the chirality-controlled growth of aligned-SWNTs using uniform carbide nanoparticles as solid catalysts for practical nanoelectronics applications.

  16. Interdependence of magnetism and superconductivity in the borocarbide TmNi2B2C

    Nørgaard, K.; Eskildsen, M.R.; Andersen, N.H.


    We have discovered anew antiferromagnetic phase in TmNi2B2C by neutron diffraction. The ordering vector is Q(A) = (0.48,0,0) and the phase appears shove a critical in-plans magnetic field of 0.9 T. The field was applied in order to test the assumption that the zero-field magnetic structure at Q...

  17. Effect of the Ni site substitution on superconducting properties of YNi 2B 2C

    Bud'ko, S. L.; Elmassalami, M.; Fontes, M. B.; Mondragon, J.; Vanoni, W.; Giordanengo, B.; Baggio-Saitovitch, E. M.


    Structural and superconducting properties of Y(Ni 1- xM x) 2B 2C compounds with MCo, Fe and Ru have been studied. A fast decrease of Tc with the concentration of the dopants was found. This effect can be attributed to the shift of the Fermi level induced by the dopant concentration with the additional contributions from the chemical-pressure effects and from the decrease of the electronic mean free path.

  18. Floating zone growth and magnetic properties of Y2C two-dimensional electride

    Otani, Shigeki; Hirata, Kazuto; Adachi, Yutaka; Ohashi, Naoki


    The floating zone method was used to obtain single crystals several mm in size of the low-temperature rhombohedral form of Y2C rather than its typical rocksalt-type cubic form. This was achieved through optimization of the chemical compositions of the starting materials with the aim of producing a two-dimensional electride material. The crystals obtained exhibited a paramagnetic temperature-dependence at 1.8-300 K, with no trace of any obvious magnetic ordering.

  19. I2C: a system for the indexing, storage, and retrieval of medical images by content.

    Orphanoudakis, S C; Chronaki, C; Kostomanolakis, S


    Image indexing, storage, and retrieval based on pictorial content is a feature of image database systems which is becoming of increasing importance in many application domains. Medical image database systems, which support the retrieval of images generated by different modalities based on their pictorial content, will provide added value to future generation picture archiving and communication systems (PACS), and can be used as a diagnostic decision support tools and as a tool for medical research and training. We present the architecture and features of I2C, a system for the indexing, storage, and retrieval of medical images by content. A unique design feature of this architecture is that it also serves as a platform for the implementation and performance evaluation of image description methods and retrieval strategies. I2C is a modular and extensible system, which has been developed based on object-oriented principles. It consists of a set of cooperating modules which facilitate the addition of new graphical tools, image description and matching algorithms. These can be incorporated into the system at the application level. The core concept of I2C is an image class hierarchy. Image classes encapsulate different segmentation and image content description algorithms. Medical images are assigned to image classes based on a set of user-defined attributes such as imaging modality, type of study, anatomical characteristics, etc. This class-based treatment of images in the I2C system achieves increased accuracy and efficiency of content-based retrievals, by limiting the search space and allowing specific algorithms to be fine-tuned for images acquired by different modalities or representing different parts of the anatomy.

  20. Oxygen adsorption and dissociation during the oxidation of monolayer Ti2C

    Gan, Liyong


    Exfoliated two-dimensional early transition metal carbides and carbonitrides are usually not terminated by metal atoms but saturated by O, OH, and/or F, thus making it difficult to understand the surface structure evolution and the induced electronic modifications. To fill this gap, density functional theory and molecular dynamics simulations are performed to capture the initial stage of the oxidation process of Ti2C, a prototypical example from the recently fabricated class of two-dimensional carbides and carbonitrides. It is shown that the unsaturated Ti 3d orbitals of the pristine Ti2C surface interact strongly with the approaching O2 molecules, resulting in barrierless O2 dissociation. The diffusion of the dissociated O atoms is also found to be very facile. Molecular dynamics simulations suggest that both dissociation and diffusion are enhanced as the O2 coverage increases to 0.25 monolayer. For a coverage of less than 0.11 monolayer, the adsorbates lead to a minor modification of the electronic properties of Ti2C, while the modification is remarkable at 0.25 monolayer. The formed Ti2CO2 after O saturation is an indirect narrow gap semiconductor (0.33 eV) with high intrinsic carrier concentration at room temperature and high thermodynamic stability at intermediate temperature (e.g., 550 °C).

  1. Cyclotron Production of (99m)Tc using (100)Mo2C targets.

    Richards, Vernal N; Mebrahtu, Efrem; Lapi, Suzanne E


    An investigative study of the (100)Mo (p,2n)(99m)Tc reaction on a medical cyclotron using (100)Mo2C is reported. This is the first report of this compound being used as a target for this reaction. (100)Mo2C, a refractory carbide with high thermal conductivity, properties which underscore its use on a cyclotron, was synthesized using (100)MoO3. Its ease of oxidation back to (100)MoO3 under air at elevated temperatures facilitates the use of thermo-chromatography, a high temperature gas phase separation technique for the separation and isolation of (99m)Tc. Activity yields for (99m)Tc averaged 84% of the calculated theoretical yields. Additionally, the percent recovery of MoO3, the precursor for Mo2C, was consistently high at 85% ensuring a good life cycle for this target material. The produced (99m)Tc was radio-chemically pure and easily labeled MDP for imaging purposes.

  2. Interface observation of heat-treated Co/Mo2C multilayers

    Yuan, Yanyan; Le Guen, Karine; André, Jean-Michel; Mény, Christian; Ulhaq, Corinne; Galtayries, Anouk; Zhu, Jingtao; Wang, Zhanshan; Jonnard, Philippe


    We study the interface evolution of a series of periodic Co/Mo2C multilayers as a function of the annealing temperature up to 600 °C. Different complementary techniques are implemented to get information on the phenomenon taking place at the interfaces of the stack. The periodical structure of Co/Mo2C multilayer is proven by time-of-flight secondary ion mass spectrometry (ToF-SIMS) depth profiles which demonstrate the formation of an oxide layer at both air/stack and stack/substrate interfaces. From Nuclear magnetic resonance (NMR) spectra, we observed the intermixing phenomenon of Co and C atoms for the as-deposited sample, and then at annealing temperature above 300 °C Co and C atoms separate from their mixed regions. Comparison of NMR results between Co/Mo2C and Co/C references confirms this phenomenon. This is in agreement with X-ray emission spectroscopy (XES) measurements. Furthermore the calculation of the Co-C, Co-Mo and Mo-C mixing enthalpy using Miedema's model gives a proof of the demixing of Co and C atoms present within the stacks above 300 °C. From the transmission electron microscopy (TEM) analysis, we found the presence of some crystallites within the as-deposited sample as well as the mainly amorphous nature of all layers. This is confirmed using X-ray diffraction (XRD) patterns which also demonstrate the growth of crystallites induced upon annealing.

  3. First intron of nestin gene regulates its expression during C2C12 myoblast ifferentiation

    Hua Zhong; Zhigang Jin; Yongfeng Chen; Ting Zhang; Wei Bian; Xing Cui; Naihe Jing


    Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China Nestin is an intermediate filament protein expressed in neural progenitor cells and in developing skeletal muscle. Nestin has been widely used as a neural progenitor cell marker. It is well established that the specific expression of the nestin gene in neural progenitor cells is conferred by the neural-specific enhancer located in the second intron of the nestin gene. However, the transcriptional mechanism of nestin expression in developing muscle is still unclear. In this study, we identified a muscle cell-specific enhancer in the first intron of mouse nestin gene in mouse myoblast C2C12 cells.We localized the core enhancer activity to the 291-661 region of the first intron, and showed that the two E-boxes in the core enhancer region were important for enhancer activity in differentiating C2C12 cells. We also showed that MyoD protein was involved in the regulation of nestin expression in the myogenic differentiation of C2C12 cells.

  4. Effect of Additives on Properties of MgO-ZrO2-C Material

    TIAN Shouxin; LIU Shanlin; XIE Mengqin


    The paper describes the effect of additives Al, Si,SiC and B4 C on the expansion of MgO-ZrO2-C material after being coked . The results indicate that Al and Si can not increase its hot and cold strength. Al and Si were oxidized to form Al2 O3 and SiO2 respectively, and then reacted with CaZrO3 or stabilizer in c-ZrO2 to form calcium aluminate , spinel ( MA ), dicalcium silicate ( C2 S ) and forsterite (M2S). Meanwhile, α-C2S was transformed to γ-C2S and c-ZrO2 to m-ZrO2 when temperature changed.All the above reactions resulted in the decrease of the amount of Al4 C3 and SiC and the increase in bulk volume ,which caused the structure of MgO-ZrO2-C material destroyed. Hence, contrary to the MgO-C material, when adding Al. and Si, the MgO-ZrO2-C material would be structurally deteriorated after heat-treatment and its strength and corrosion resistance decreased.

  5. Elementary Steps of Syngas Reactions on Mo2C(001): Adsorption Thermochemistry and Bond Dissociation

    Medford, Andrew


    Density functional theory (DFT) and ab initio thermodynamics are applied in order to investigate the most stable surface and subsurface terminations of Mo{sub 2}C(001) as a function of chemical potential and in the presence of syngas. The Mo-terminated (001) surface is then used as a model surface to evaluate the thermochemistry and energetic barriers for key elementary steps in syngas reactions. Adsorption energy scaling relations and Broensted-Evans-Polanyi relationships are established and used to place Mo{sub 2}C into the context of transition metal surfaces. The results indicate that the surface termination is a complex function of reaction conditions and kinetics. It is predicted that the surface will be covered by either C{sub 2}H{sub 2} or O depending on conditions. Comparisons to transition metals indicate that the Mo-terminated Mo{sub 2}C(001) surface exhibits carbon reactivity similar to transition metals such as Ru and Ir, but is significantly more reactive towards oxygen.

  6. Magnetic structure and spin reorientation of quaternary Dy2Fe2Si2C

    Susilo, R. A.; Cadogan, J. M.; Hutchison, W. D.; Stewart, G. A.; Avdeev, M.; Campbell, S. J.


    We have investigated the low temperature magnetic properties of Dy2Fe2Si2C by using magnetisation, specific heat, x-ray diffraction, neutron powder diffraction and 57Fe Mössbauer spectroscopy measurements over the temperature range 1.5 K–300 K. Dy2Fe2Si2C exhibits two magnetic transitions at low temperatures: an antiferromagnetic transition at {{T}\\text{N}}∼ 26 K and a spin-reorientation transition at {{T}t}∼ 6 K. The magnetic structure above T t can be described with a propagation vector \\mathbf{k}~=~≤ft(0~0~\\frac{1}{2}\\right) with the ordering of the Dy magnetic moments along the monoclinic b-axis whereas on cooling below T t the Dy moment tips away from the b-axis towards the ac-plane. We find that the spin-reorientation in Dy2Fe2Si2C is mainly driven by the competition between the second-order crystal field term B 20 and the higher-order terms, in particular B 40 and B 64.

  7. Role of Nodal-PITX2C signaling pathway in glucose-induced cardiomyocyte hypertrophy.

    Su, Dongmei; Jing, Sun; Guan, Lina; Li, Qian; Zhang, Huiling; Gao, Xiaobo; Ma, Xu


    Pathological cardiac hypertrophy is a major cause of morbidity and mortality in cardiovascular disease. Recent studies have shown that cardiomyocytes, in response to high glucose (HG) stimuli, undergo hypertrophic growth. While much work still needs to be done to elucidate this important mechanism of hypertrophy, previous works have showed that some pathways or genes play important roles in hypertrophy. In this study, we showed that sublethal concentrations of glucose (25 mmol/L) could induce cardiomyocyte hypertrophy with an increase in the cellular surface area and the upregulation of the atrial natriuretic peptide (ANP) gene, a hypertrophic marker. High glucose (HG) treatments resulted in the upregulation of the Nodal gene, which is under-expressed in cardiomyocytes. We also determined that the knockdown of the Nodal gene resisted HG-induced cardiomyocyte hypertrophy. The overexpression of Nodal was able to induce hypertrophy in cardiomyocytes, which was associated with the upregulation of the PITX2C gene. We also showed that increases in the PITX2C expression, in response to Nodal, were mediated by the Smad4 signaling pathway. This study is highly relevant to the understanding of the effects of the Nodal-PITX2C pathway on HG-induced cardiomyocyte hypertrophy, as well as the related molecular mechanisms.

  8. High efficiency photocatalysis for pollutant degradation with MoS2/C3N4 heterostructures.

    Li, Qian; Zhang, Ning; Yang, Yong; Wang, Guozhong; Ng, Dickon H L


    Porous graphitic carbon nitride was synthesized by controllable thermal polymerization of urea in air. Their textural, electrical, and optical properties were tuned by varying the heating rate. The presence of proper residual oxygen in carbon nitride matrix had enhanced light absorption and inhibited the recombination of charge carriers. Furthermore, the MoS2 nanosheets were coupled into the carbon nitride to form MoS2/C3N4 heterostructures via a facile ultrasonic chemical method. The optimized MoS2/C3N4 heterostructure with 0.05 wt % MoS2 showed a reaction rate constant as high as 0.301 min(-1), which was 3.6 times that of bare carbon nitride. As analyzed by SEM, TEM, UV-vis absorption, PL and photoelectrochemical measurements, intimate contact interface, extended light response range, enhanced separation speed of charge carriers, and high photocurrent density upon MoS2 coupling led to the photocatalytic promotion of the MoS2/C3N4 heterostructures. In this architecture, MoS2 served as electron trapper to extend the lifetime of separated electron-hole pairs. Meanwhile, the accumulated holes on the surface of carbon nitride oxidized the organic dye directly, which was a predominant process in the photodegradation of organic pollutants in water treatment. The promotional mechanisms and principles reported here would have great significance in heterogeneous photocatalysis.

  9. Li2C2, a High-Capacity Cathode Material for Lithium Ion Batteries.

    Tian, Na; Gao, Yurui; Li, Yurong; Wang, Zhaoxiang; Song, Xiaoyan; Chen, Liquan


    As a typical alkaline earth metal carbide, lithium carbide (Li2C2) has the highest theoretical specific capacity (1400 mA h g(-1)) among all the reported lithium-containing cathode materials for lithium ion batteries. Herein, the feasibility of using Li2C2 as a cathode material was studied. The results show that at least half of the lithium can be extracted from Li2C2 and the reversible specific capacity reaches 700 mA h g(-1). The C≡C bond tends to rotate to form C4 (C≡C⋅⋅⋅C≡C) chains during lithium extraction, as indicated with the first-principles molecular dynamics (FPMD) simulation. The low electronic and ionic conductivity are believed to be responsible for the potential gap between charge and discharge, as is supported with density functional theory (DFT) calculations and Arrhenius fitting results. These findings illustrate the feasibility to use the alkali and alkaline earth metal carbides as high-capacity electrode materials for secondary batteries.

  10. Cited3 activates Mef2c to control muscle cell differentiation and survival.

    Devakanmalai, Gnanapackiam Sheela; Zumrut, Hasan E; Ozbudak, Ertuğrul M


    Vertebrate muscle development occurs through sequential differentiation of cells residing in somitic mesoderm - a process that is largely governed by transcriptional regulators. Our recent spatiotemporal microarray study in zebrafish has identified functionally uncharacterized transcriptional regulators that are expressed at the initial stages of myogenesis. cited3 is one such novel gene encoding a transcriptional coactivator, which is expressed in the precursors of oxidative slow-twitch myofibers. Our experiments placed cited3 into a gene regulatory network, where it acts downstream of Hedgehog signaling and myoD/myf5 but upstream of mef2c. Knockdown of expression of cited3 by antisense morpholino oligonucleotides impaired muscle cell differentiation and growth, caused muscle cell death and eventually led to total immotility. Transplantation experiments demonstrated that Cited3 cell-autonomously activates the expression of mef2c in slow myofibers, while it non-cell-autonomously regulates expression of structural genes in fast myofibers. Restoring expression of cited3 or mef2c rescued all the cited3 loss-of-function phenotypes. Protein truncation experiments revealed the functional necessity of C-terminally conserved domain of Cited3, which is known to mediate interactions of Cited-family proteins with histone acetylases. Our findings demonstrate that Cited3 is a critical transcriptional coactivator functioning during muscle differentiation and its absence leads to defects in terminal differentiation and survival of muscle cells.

  11. TiO2@C Core-Shell Nanoparticles Formed by Polymeric Nano-Encapsulation

    Mitra eVasei


    Full Text Available TiO2 semiconducting nanoparticles are known to be photocatalysts of moderate activity due to their high band-gap and high rate of electron-hole recombination. The formation of a shell of carbon around the core of TiO2, i.e. the formation of TiO2@C nanoparticles, is believed to partly alleviate these problems. It is usually achieved by a hydrothermal treatment in a presence of a sugar derivative. We present here a novel method for the formation of highly uniform C shell around TiO2 nanoparticles. For this purpose, TiO2 nanoparticles were dispersed in water using an oligomeric dispersant prepared by Reversible Addition-Fragmentation chain Transfer (RAFT polymerization. Then the nanoparticles were engaged into an emulsion polymerization of acrylonitrile, resulting in the formation of a shell of polyacrylonitrile (PAN around each TiO2 nanoparticles. Upon pyrolisis, the PAN was transformed into carbon, resulting in the formation of TiO2@C nanoparticles. The structure of the resulting particles was elucidated by X-Ray diffraction, FTIR, UV-VIS and Raman spectroscopy as well as TEM microscopy. Preliminary results about the use of the TiO2@C particles as photocatalysts for the splitting of water are presented. They indicate that the presence of the C shell is responsible for a significant enhancement of the photocurrent.

  12. TiO2@C core-shell nanoparticles formed by polymeric nano-encapsulation.

    Vasei, Mitra; Das, Paramita; Cherfouth, Hayet; Marsan, Benoît; Claverie, Jerome P


    TiO2 semiconducting nanoparticles are known to be photocatalysts of moderate activity due to their high band-gap and high rate of electron-hole recombination. The formation of a shell of carbon around the core of TiO2, i.e., the formation of TiO2@C nanoparticles, is believed to partly alleviate these problems. It is usually achieved by a hydrothermal treatment in a presence of a sugar derivative. We present here a novel method for the formation of highly uniform C shell around TiO2 nanoparticles. For this purpose, TiO2 nanoparticles were dispersed in water using an oligomeric dispersant prepared by Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization. Then the nanoparticles were engaged into an emulsion polymerization of acrylonitrile, resulting in the formation of a shell of polyacrylonitrile (PAN) around each TiO2 nanoparticles. Upon pyrolysis, the PAN was transformed into carbon, resulting in the formation of TiO2@C nanoparticles. The structure of the resulting particles was elucidated by X-Ray diffraction, FTIR, UV-VIS and Raman spectroscopy as well as TEM microscopy. Preliminary results about the use of the TiO2@C particles as photocatalysts for the splitting of water are presented. They indicate that the presence of the C shell is responsible for a significant enhancement of the photocurrent.

  13. Leucine Modulates Mitochondrial Biogenesis and SIRT1-AMPK Signaling in C2C12 Myotubes

    Chunzi Liang


    Full Text Available Previous studies from this laboratory demonstrate that dietary leucine protects against high fat diet-induced mitochondrial impairments and stimulates mitochondrial biogenesis and energy partitioning from adipocytes to muscle cells through SIRT1-mediated mechanisms. Moreover, β-hydroxy-β-methyl butyrate (HMB, a metabolite of leucine, has been reported to activate AMPK synergistically with resveratrol in C2C12 myotubes. Therefore, we hypothesize that leucine-induced activation of SIRT1 and AMPK is the central event that links the upregulated mitochondrial biogenesis and fatty acid oxidation in skeletal muscle. Thus, C2C12 myotubes were treated with leucine (0.5 mM, alanine (0.5 mM, valine (0.5 mM, EX527 (SIRT1 inhibitor, 25 μM, and Compound C (AMPK inhibitor, 25 μM alone or in combination to determine the roles of AMPK and SIRT1 in leucine-modulation of energy metabolism. Leucine significantly increased mitochondrial content, mitochondrial biogenesis-related genes expression, fatty acid oxidation, SIRT1 activity and gene expression, and AMPK phosphorylation in C2C12 myotubes compared to the controls, while EX527 and Compound C markedly attenuated these effects. Furthermore, leucine treatment for 24 hours resulted in time-dependent increases in cellular NAD+, SIRT1 activity, and p-AMPK level, with SIRT1 activation preceding that of AMPK, indicating that leucine activation of SIRT1, rather than AMPK, is the primary event.

  14. Opioid Receptors.

    Stein, Christoph


    Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute (e.g., postoperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny. This article reviews mechanisms underlying opioid analgesia and other opioid actions. It discusses the structure, function, and plasticity of opioid receptors; the central and peripheral sites of analgesic actions and side effects; endogenous and exogenous opioid receptor ligands; and conventional and novel opioid compounds. Challenging clinical situations, such as the tension between chronic pain and addiction, are also illustrated.

  15. Identification of the Most Stable Sc2C80 Isomers: Structure, Electronic Property, and Molecular Spectra Investigations

    吴静怡; 王太山; 舒春英; 吕鑫; 王春儒


    A systematic density functional theory investigation has been carried out to explore the possible structures of Sc2C80 at the BMK/6-31 G(d) level. The results clearly show that Sc2@C80-Ih, Sc2@Cso-Dsh, and Sc2C2@C78-C2v can be identified as three isomers of Sc2C80 metallofullerene with the lowest energy. Frontier molecular orbital analysis indicates that the two Sc2@C80 isomers have a charge state as (Sc〉)2@ C60 and the Sc2C2@C78 has a charge state of (Sc3+)2 C22- @ C784-. Moreover, the metal-cage covalent interactions have been studied to reveal the dynamics of endohedral moiety. The vertical electron affinity, vertical ionization potential, infrared spectra and 13C nuclear mag- netic resonance spectra have been also computed to further disclose the molecular structures and properties.

  16. IMPACT2C: Quantifying projected impacts under 2°C warming

    Jacob, D.; Kotova, L.; Impact2C Team


    Political discussions on the European goal to limit global warming to 2°C demand, that information is provided to society by the best available science on projected impacts and possible benefits. The new project IMPACT2C is supported by the European Commission's 7th Framework Programme as a 4 year large-scale integrating project. IMPACT2C is coordinated by the Climate Service Center, Helmholtz-Zentrum Geesthacht. IMPACT2C enhances knowledge, quantifies climate change impacts, and adopts a clear and logical structure, with climate and impacts modelling, vulnerabilities, risks and economic costs, as well as potential responses, within a pan-European sector based analysis. The project utilises a range of models within a multi-disciplinary international expert team and assesses effects on water, energy, infrastructure, coasts, tourism, forestry, agriculture, ecosystems services, and health and air quality-climate interactions. IMPACT2C introduces key innovations. First, harmonised socio-economic assumptions/scenarios will be used, to ensure that both individual and cross-sector assessments are aligned to the 2°C (1.5°C) scenario for both impacts and adaptation, e.g. in relation to land-use pressures between agriculture and forestry. Second, it has a core theme of uncertainty, and will develop a methodological framework integrating the uncertainties within and across the different sectors, in a consistent way. In so doing, analysis of adaptation responses under uncertainty will be enhanced. Finally, a cross-sectoral perspective is adopted to complement the sector analysis. A number of case studies will be developed for particularly vulnerable areas, subject to multiple impacts (e.g. the Mediterranean), with the focus being on cross-sectoral interactions (e.g. land use competition) and cross-cutting themes (e.g. cities). The project also assesses climate change impacts in some of the world's most vulnerable regions: Bangladesh, Africa (Nile and Niger basins), and the

  17. g4c2c: A Model for Citizen Engagement at Arms’ Length from Government

    Axel Bruns


    Full Text Available Normal 0 false false false EN-AU X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} The recognition that Web 2.0 applications and social media sites will strengthen and improve interaction between governments and citizens has resulted in a global push into new e-democracy or Government 2.0 spaces. These typically follow government-to-citizen (g2c or citizen-to-citizen (c2c models, but both these approaches are problematic: g2c is often concerned more with service delivery to citizens as clients, or exists to make a show of ‘listening to the public’ rather than to genuinely source citizen ideas for government policy, while c2c often takes place without direct government participation and therefore cannot ensure that the outcomes of citizen deliberations are accepted into the government policy-making process. Building on recent examples of Australian Government 2.0 initiatives, we suggest a new approach based on government support for citizen-to-citizen engagement, or g4c2c, as a workable compromise, and suggest that public service broadcasters should play a key role in facilitating this model of citizen engagement.

  18. Breach of information duties in the B2C e-commerce: adequacy of available remedies

    Zofia Bednarz


    Full Text Available

    B2C e-commerce is characterised by the information asymmetry between the contracting parties. Various information duties are imposed on traders, both at the European and national level to correct this asymmetry and to ensure proper market functioning. The mandated disclosure is based on the assumption of consumers' rationality. However, developments of behavioural economics challenge this assumption. The utility of mandated disclosure in consumer contracts depends also on the remedies available to consumers in a case of breach of information duties. Those remedies are often heavily influenced by the national general private law applicable to the contractual relationship between the parties. Nevertheless, since the economics of general contract law differ importantly from principles of consumer e-commerce, various problems can be associated with the application of general law remedies to the breach of information duties in B2C contracts. The limited value of the majority of the online B2C transactions is incompatible with costly and lengthy court proceedings. Moreover, breach of information duties will often not produce enough material damage on the side of the consumer to make the remedies available. Different solutions are explored, from ADR, to the duty to advise, to non-legal mechanisms making the information easier to use for consumers throughlimiting disclosure. Finally, the right of withdrawal is analysed as an example of a specific remedy, adapted to the economics of the B2C electronic transactions, where the aims parties pursue through contracts are different than in commercial contracts, and their relationship is marked with the inequality of economic power and information asymmetry. However, the legally established cooling-off period is not free from limitations, and only a combination of various measures, including effective

  19. CYP2C19基因型和CYP2C9对人肝微粒体中氟西汀N-去甲基代谢的影响%Effects of CYP2C19 genotype and CYP2C9 on fluoxetine N-demethylation in human liver microsomes

    刘昭前; 舒焱; 黄松林; 王连生; 何楠; 周宏灏


    目的:本实验旨在研究CYP2C19基因型人肝微粒体中氟西汀N-去甲基代谢的酶促动力学特点并鉴定参与此代谢途径的细胞色素P-450酶.方法:测定基因型CYP2C19肝微粒体中去甲氟西汀形成的酶促动力学.鉴定氟西汀N-去甲基酶活性与细胞色素P-450 2C9,2C19,1A2和2D6酶活性的相关性,同时应用各种细胞色素P-450酶的选择性抑制剂和化学探针进行抑制实验,从而确定参与氟西汀N-去甲基代谢的细胞色素P-450酶.结果:去甲氟西汀生成的酶促动力学数据符合单酶模型,并具有Michaelis-Menten动力学特征.当底物浓度为氟西汀25μmol/L和100 μmol/L时,去甲氟西汀(N-FLU)的生成率分别与甲磺丁脲3-羟化酶活性显著相关(r1=0.821,P1=0.001;r2=0.668,P2=0.013),当底物浓度为氟西汀100 μmol/L时,N-FLU的生成率与S-美芬妥因4'-羟化酶活性显著相关(r=0.717,P=0.006).PM肝微粒中磺胺苯吡唑和醋竹桃霉素对氟西汀N-去甲基代谢的抑制作用显著大于EM(73%vs 45%,P<0.01).结论:在生理底物浓度下,CYP2C9是催化人肝微粒体中氟西汀N-去甲基代谢的主要CYP-450酶;而高底物浓度时,以CYP2C19的作用为主.%AIM: The present study was designed to define the kinetic behavior of fluoxetine N-demethylation in human liver microsomes and to identify the isoforms of cytochrome P-450 (CYP) involved in this metabolic pathway. METHODS: The kinetics of the formation of norfluoxetine was determined in human liver microsomes from six genotyped CYP2C19 extensive metabolizers (EM). The correlation studies between the fluoxetine N-demethylase activity and various CYP enzyme activities were performed. Selective inhibitors or chemical probes of various cytochrome P-450 isoforms were also employed. RESULTS: The kinetics of norfluoxetine formation in all liver microsomes were fitted by a singleenzyme Michaelis-Menten equation (mean Km=32 μmol/L±7

  20. Genetic variability of CYP2C19 in a Mexican population: contribution to the knowledge of the inheritance pattern of CYP2C19*17 to develop the ultrarapid metabolizer phenotype

    Alma Faviola Favela-Mendoza; Gabriela Martinez-Cortes; Marcelo Hernandez-Zaragoza; Joel Salazar-Flores; Jose Francisco Muñoz-Valle; Victor Manuel Martinez-Sevilla; Noemi Yolanda Velazquez-Suarez; Hector Rangel-Villalobos


    CYP2C19 is a polymorphic enzyme that metabolizes a wide variety of therapeutic drugs that has been associated with altered enzymatic activity and adverse drug reactions. Differences in allele frequencies of the CYP2C19 gene have been detected in populations worldwide. Thus, we analysed the alleles CYP2C19*2, CYP2C19*3, CYP2C19*4 and CYP2C19*5 related to the poor metabolizer (PM) phenotype in a Mexican population sample ( = 238), as well as CYP2C19*17, unique allele related to ultrarapid metabolizer phenotype (UMs). Genotypes were determined using SNaPshot and TaqManqPCR assays. In addition to the wild-type CYP2C19*1 allele (77.1%), we only found CYP2C19*17 (14.3%) and CYP2C19*2 (8.6%). Comparison with previous population reports demonstrated that these two SNPs are homogeneously distributed in Latin America ( > 0.05). Based on comparison with a previous pharmacokinetic study that determined the frequency of CYP2C19 phenotypes in the same population (western Mexican), we obtained the following findings: (i) based on the difference between the frequency of genotypes CYP2C19*2/*2 (presumably PM) versus the observed prevalence of PM phenotypes (0.4 versus 6.3%; 2 = 9.58, = 0.00196), we inferred the plausible presence of novel CYP2C19 alleles related to the PM phenotype; (ii) the prevalence of UMs was in disagreement with the dominant inheritance pattern suggested for CYP2C19*17 (23.1 versus 4%; < 0.00001); (iii) the apparent recessive inheritance pattern of CYP2C19*17, based on the agreement between homozygous CYP2C19*17/*17 (presumably UMs) and the observed prevalence of UMs (2.1 versus 4%; (2 = 1.048; = 0.306).

  1. Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.

    Daniel Holl

    Full Text Available BACKGROUND: The transcription factor Tcfap2c has been demonstrated to be essential for various processes during mammalian development. It has been found to be upregulated in various undifferentiated tumors and is implicated with poor prognosis. Tcfap2c is reported to impinge on cellular proliferation, differentiation and apoptosis. However, the physiological consequences of Tcfap2c-expression remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Therefore we established a gain of function model to analyze the role of Tcfap2c in development and disease. Induction of the transgene led to robust expression in all tissues (except brain and testis and lead to rapid mortality within 3-7 days. In the liver cellular proliferation and apoptosis was detected. Accumulation of microvesicular lipid droplets and breakdown of major hepatic metabolism pathways resulted in steatosis. Serum analysis showed a dramatic increase of enzymes indicative for hepatic failure. After induction of Tcfap2c we identified a set of 447 common genes, which are deregulated in both liver and primary hepatocyte culture. Further analysis showed a prominent repression of the cytochrome p450 system, PPARA, Lipin1 and Lipin2. These data indicate that in the liver Tcfap2c represses pathways, which are responsible for fatty acid metabolism. In the intestine, Tcfap2c expression resulted in expansion of Sox9 positive and proliferative active epithelial progenitor cells resulting in dysplastic growth of mucosal crypt cells and loss of differentiated mucosa. CONCLUSIONS: The transgenic mice show that ectopic expression of Tcfap2c is not tolerated. Due to the phenotype observed, iTcfap2c-mice represent a model system to study liver failure. In intestine, Tcfap2c induced cellular hyperplasia and suppressed terminal differentiation indicating that Tcfap2c serves as a repressor of differentiation and inducer of proliferation. This might be achieved by the Tcfap2c mediated activation of Sox9

  2. Direct conversion of cellulose using carbon monoxide and water on a Pt-Mo2C/C catalyst

    Li, Jing


    CO and H2O were employed as the hydrogen source for cellulose conversion to polyols. Pt-Mo2C/C tandem catalyst with the Pt-Mo 2C domain responsible for H2 and/or H production and the Pt-C domain for cellulose conversion was fabricated. Considerable polyols were obtained over this tandem Pt-Mo2C/C catalyst. This journal is © 2014 The Royal Society of Chemistry.

  3. Allele and genotype frequencies of the polymorphic cytochrome P450 genes (CYP1A1, CYP3A4, CYP3A5, CYP2C9 and CYP2C19) in the Jordanian population.

    Yousef, Al-Motassem; Bulatova, Nailya R; Newman, William; Hakooz, Nancy; Ismail, Said; Qusa, Hisham; Zahran, Farah; Anwar Ababneh, Nidaa; Hasan, Farah; Zaloom, Imad; Khayat, Ghada; Al-Zmili, Rawan; Naffa, Randa; Al-Diab, Ola


    Drug metabolizing enzymes participate in the neutralizing of xenobiotics and biotransformation of drugs. Human cytochrome P450, particularly CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5, play an important role in drug metabolism. The genes encoding the CYP enzymes are polymorphic, and extensive data have shown that certain alleles confer reduced enzymatic function. The goal of this study was to determine the frequencies of important allelic variants of CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 in the Jordanian population and compare them with the frequency in other ethnic groups. Genotyping of CYP1A1(m1 and m2), CYP2C9 (2 and 3), CYP2C19 (2 and 3), CYP3A4 5, CYP3A5 (3 and 6), was carried out on Jordanian subjects. Different variants allele were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). CYP1A1 allele frequencies in 290 subjects were 0.764 for CYP1A1 1, 0.165 for CYP1A1 2A and 0.071 for CYP1A1 2C. CYP2C9 allele frequencies in 263 subjects were 0.797 for CYP2C9 1, 0.135 for CYP2C9 2 and 0.068 for CYP2C9 3. For CYP2C19, the frequencies of the wild type (CYP2C19 1) and the nonfunctional (2 and 3) alleles were 0.877, 0.123 and 0, respectively. Five subjects (3.16 %) were homozygous for 2/2. Regarding CYP3A4 1B, only 12 subjects out of 173 subjects (6.9 %) were heterozygote with none were mutant for this polymorphism. With respect to CYP3A5, 229 were analyzed, frequencies of CYP3A5 1, 3 and 6 were 0.071, 0.925 and 0.0022, respectively. Comparing our data with that obtained in several Caucasian, African-American and Asian populations, Jordanians are most similar to Caucasians with regard to allelic frequencies of the tested variants of CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5.

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

    Kaur-Knudsen, D.; Bojesen, S.E.; Nordestgaard, Børge


    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-reactive...... protein), ischemic vascular diseases (ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease and ischemic stroke) and death after an ischemic heart disease diagnosis. We genotyped the Copenhagen City Heart Study, a prospective study including 10 398 participants with 30-32 years...

  5. Effects of CYP2C9*1/*3 genotype on the pharmacokinetics of flurbiprofen in Korean subjects.

    Lee, Yun-Jeong; Byeon, Ji-Yeong; Kim, Young-Hoon; Kim, Se-Hyung; Choi, Chang-Ik; Bae, Jung-Woo; Sohn, Uy-Dong; Jang, Choon-Gon; Lee, Jeongmi; Lee, Seok-Yong


    The aim of this study was to investigate the impact of CYP2C9*1/*3 genotype on the pharmacokinetics of flurbiprofen and its metabolite. The CYP2C9 genotypes were determined with the use of polymerase chain reaction and restriction fragment and DNA sequencing analysis in 358 healthy Koreans. Among them, twenty individuals with CYP2C9*1/*1 (n = 12) or CYP2C9*1/*3 (n = 8) genotypes received a single 40 mg oral dose of flurbiprofen. The plasma concentrations of flurbiprofen and its metabolite, 4'-hydroxyflurbiprofen were measured by HPLC. AUCinf of flurbiprofen was significantly higher and its clearance was significantly lower in the CYP2C9*1/*3 individuals than in those with CYP2C9*1/*1. The AUC ratio of 4'-hydroxyflurbiprofen to flurbiprofen was significantly lower in the CYP2C9*1/*3 individuals than in those with CYP2C9*1/*1. These results indicate that the individuals carrying of CYP2C9*3 have significant reduction in flurbiprofen metabolism. The clinical use of this information may allow for more efficient personalized pharmacotherapy.

  6. LT^2C^2: A language of thought with Turing-computable Kolmogorov complexity

    Santiago Figueira


    Full Text Available In this paper, we present a theoretical effort to connect the theory of program size to psychology by implementing a concrete language of thought with Turing-computable Kolmogorov complexity (LT^2C^2 satisfying the following requirements: 1 to be simple enough so that the complexity of any given finite binary sequence can be computed, 2 to be based on tangible operations of human reasoning (printing, repeating,. . . , 3 to be sufficiently powerful to generate all possible sequences but not too powerful as to identify regularities which would be invisible to humans. We first formalize LT^2C^2, giving its syntax and semantics, and defining an adequate notion of program size. Our setting leads to a Kolmogorov complexity function relative to LT^2C^2 which is computable in polynomial time, and it also induces a prediction algorithm in the spirit of Solomonoff’s inductive inference theory. We then prove the efficacy of this language by investigating regularities in strings produced by participants attempting to generate random strings. Participants had a profound understanding of randomness and hence avoided typical misconceptions such as exaggerating the number of alternations. We reasoned that remaining regularities would express the algorithmic nature of human thoughts, revealed in the form of specific patterns. Kolmogorov complexity relative to LT^2C^2 passed three expected tests examined here: 1 human sequences were less complex than control PRNG sequences, 2 human sequences were not stationary showing decreasing values of complexity resulting from fatigue 3 each individual showed traces of algorithmic stability since fitting of partial data was more effective to predict subsequent data than average fits. This work extends on previous efforts to combine notions of Kolmogorov complexity theory and algorithmic information theory to psychology, by explicitly proposing a language which may describe the patterns of human thoughts.Received: 12

  7. SL(2,C) Gauge Theory of Gravitation and the Quantization of the Gravitational Field

    Carmeli, M; Carmeli, Moshe; Malin, Shimon


    A new approach to quantize the gravitational field is presented. It is based on the observation that the quantum character of matter becomes more significant as one gets closer to the big bang. As the metric loses its meaning, it makes sense to consider Schrodinger's three generic types of manifolds - unconnected differentiable, affinely connected, and metrically connected - as a temporal sequence following the big bang. Hence one should quantize the gravitational field on general differentiable manifolds or on affinely connected manifolds. The SL(2,C) gauge theory of gravitation is employed to explore this possibility. Within this framework, the quantization itself may well be canonical.

  8. A B2C Digital Marketing Plan for the Sushi Restaurant Makuja

    Maisuradze, Veronika


    This thesis was made for the sushi restaurant Makuja, which operates in Helsinki. The objective of the project was to create and partly implement a B2C digital marketing plan for the company: to make the first steps in building online presence, which would allow people to find Makuja on the Internet, get to know the restaurant better and interact with it. One of the main goals of online presence was to spread awareness and to gain followers, fans and customers. Five project tasks were set...

  9. Longitudinal Structure Function FL from Charm Structure Function F2c

    B.Rezaei; G.R.Boroun


    We predict the effect of the charm structure function on the longitudinal structure function at small x.In NLO analysis we find that the hard Pomeron behavior gives a good description of FL and Fkc (k =2,L) at small x values.We conclude that a direct relation between FL∝ F2c would provide useful information on how to measure longitudinal structure function at high Q2 values.Having checked that this model gives a good description of the data,when compared with other models.

  10. Electronic spectra of linear HC$_5$H and cumulene carbene H$_2$C$_5$

    Steglich, M; Maity, S; Nagy, A; Maier, J P


    The $1 ^3\\Sigma_u^- \\leftarrow X^3\\Sigma_g^-$ transition of linear HC$_5$H (A) has been observed in a neon matrix and gas phase. The assignment is based on mass-selective experiments, extrapolation of previous results of the longer HC$_{2n+1}$H homologues, and density functional and multi-state CASPT2 theoretical methods. Another band system starting at 303 nm in neon is assigned as the $1 ^1 A_1 \\leftarrow X ^1 A_1$ transition of the cumulene carbene pentatetraenylidene H$_2$C$_5$ (B).

  11. Design guidelines for B2C e-commerce in virtual worlds

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


    Virtual worlds are three-dimensional (3D) persistent multi-user online environments in which users interact through avatars. Virtual worlds support many kinds of activities, including education, socialising, gaming and e-commerce. Our research focuses on how virtual worlds can be used to facilitate business-to-consumer (B2C) e-commerce involving real items. Examples of affordances of virtual worlds for e-commerce include 3D simulations, multi-user environments and avatar-based interactions. W...

  12. Search for an interstellar Si2C molecule: A theoretical prediction

    Suresh Chandra


    We suggest that Si2C molecule may be identified in astronomical objects through its transitions 414 → 505, 515 → 606, 212 → 303, 313 → 404, and 111 → 202 at 15.9, 5.1, 33.6, 24.9, and 42.3 GHz in absorption even against the cosmic 2.7 K background, in a region having low temperature. The absorption phenomenon is found rather large in the first two transitions. Dependence of results on the set of molecular parameters is discussed.

  13. Using the I2C Interface and Localization Inforamtion to Achieve Personalization of a Device Operation

    Jacek Dlugopolski


    Full Text Available The article refers to the part of the hardware and software research which concerns the problem of personalization of a common used device operation. The proposed solution is bascd on the ABS system (Active Badge System developed by ORL (Olivetti research Laboratories in the United Kingdom, which delivers localization and identification information, and the universal communication interface I2C (Inter Integrated Circuit developed by PHILIPS. The two above mentioned elements were used to create both the system of the automatic video signal flow control and the system to identify a TV program being currently viewed.

  14. Supply-side hurdles in internet B2C e-commerce: An empirical investigation

    Cheung, MT; Liao, Z


    Given Hong Kong's special circumstances of small physical size, advanced infrastructure, and low shopping cost, a survey is designed under which supply-side problems in Internet business-to-consumer (B2C) e-commerce are indirectly revealed by responses on the demand side. Difficulties arising from the reluctance to answer questionnaires on the part of e-firms wary about trade and innovation secrets and their small number at the outset are thereby overcome. Survey data on demand-side obstacle ...

  15. Test-retest reliability of {sup 11}C-ORM-13070 in PET imaging of α{sub 2C}-adrenoceptors in vivo in the human brain

    Lehto, Jussi; Peltonen, Juha M.; Volanen, Iina; Scheinin, Mika [University of Turku, Clinical Research Services Turku CRST, Turku (Finland); TYKSLAB, Unit of Clinical Pharmacology, Turku (Finland); Virta, Jere R. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); Oikonen, Vesa; Roivainen, Anne; Luoto, Pauliina; Arponen, Eveliina; Helin, Semi; Virtanen, Kirsi [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Hietamaeki, Johanna; Holopainen, Aila; Rouru, Juha; Sallinen, Jukka [Orion Pharma, Turku (Finland); Kailajaervi, Marita [Turku Imanet, GE Healthcare, Turku (Finland); Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); University of Turku, Clinical Research Services Turku CRST, Turku (Finland)


    α{sub 2C}-Adrenoceptors share inhibitory presynaptic functions with the more abundant α{sub 2A}-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α{sub 2}-adrenoceptor subtypes. PET imaging with the specific α{sub 2C}-adrenoceptor antagonist tracer [{sup 11}C]ORM-13070 was performed twice in six healthy male subjects to investigate the test-retest reliability of tracer binding. The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 - 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test-retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also <10 % in the caudate nucleus and thalamus. Intraclass correlation coefficients (ICC) ranged from 0.50 in the hippocampus to 0.89 in the thalamus (ICC >0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [{sup 11}C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method. The results of this study support the use of [{sup 11}C]ORM-13070 PET in the quantitative assessment of α{sub 2C}-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios. (orig.)

  16. Atractylenolide III Enhances Energy Metabolism by Increasing the SIRT-1 and PGC1α Expression with AMPK Phosphorylation in C2C12 Mouse Skeletal Muscle Cells.

    Song, Mi Young; Jung, Hyo Won; Kang, Seok Yong; Park, Yong-Ki


    Targeting energy expenditure provides a potential alternative strategy for achieving energy balance to combat obesity and the development of type 2 diabetes mellitus (T2DM). In the present study, we investigated whether atractylenolide III (AIII) regulates energy metabolism in skeletal muscle cells. Differentiated C2C12 myotubes were treated with AIII (10, 20, or 50 µM) or metformin (2.5 mM) for indicated times. The levels of glucose uptake, the expressions of key mitochondrial biogenesis-related factors and their target genes were measured in C2C12 myotubes. AIII significantly increased the glucose uptake levels, and significantly increased the expressions of peroxisome proliferator-activated receptor coactivator-1α (PGC1α) and mitochondrial biogenesis-related markers, such as, nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM) and mitochondrial mass and total ATP contents. In addition, AIII significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of sirtuin1 (SIRT1). These results suggest that AIII may have beneficial effects on obesity and T2DM by improving energy metabolism in skeletal muscle.

  17. Association and treatment response to capecitabine-based chemoradiotherapy with CYP2C9 polymorphism in head and neck cancer

    S Paul


    Full Text Available Aims : The aim of the present study is to investigate the association of polymorphism in cytochrome P450 2C9 (CYP2C9 with head and neck squamous cell carcinoma (HNSCC and response in patients receiving chemoradiotherapy. Materials and Methods : One hundred ten males suffering from locally advanced head and neck squamous cell carcinoma and an equal number of healthy controls were genotyped for CYP2C9FNx012 and CYP2C9FNx013, leading to poor metabolizers (PMs by PCR-based RFLP. Each case was assessed thoroughly for treatment response following WHO criteria. Results : The frequency of heterozygous genotypes of both CYP2C9FNx012 (27.3% and CYP2C9FNx013 (20.1% were found to be significantly higher in the HNSCC cases as compared to the healthy controls. Tobacco intake in the form of chewing or smoking and alcohol intake resulted in several fold increase in the risk to HNSCC in the cases carrying variant genotypes of CYP2C9FNx012 or CYP2C9FNx013. Further, majority of the cases assessed for response (134 carrying variant alleles of both CYP2C9FNx012 (65.3% or CYP2C9FNx013 (70.58% were found to respond poorly to the radio-chemotherapy. Conclusions : The data suggests a significant association of the CYP2C9 polymorphism with HNSCC and treatment outcome underlining the importance of pretherapeutic genotyping in determining the treatment schedule.

  18. BAP31 is involved in the retention of cytochrome P450 2C2 in the endoplasmic reticulum.

    Szczesna-Skorupa, Elzbieta; Kemper, Byron


    Microsomal cytochrome P450 2C2 is an integral endoplasmic reticulum (ER) membrane protein that is directly retained in the ER and excluded from transport vesicles. We have used bimolecular fluorescence complementation and co-immunoprecipitation to show that a ubiquitous ER membrane protein (BAP31) interacts with P450 2C2 in transfected COS-1 cells. A chimera containing only the N-terminal signal anchor of P450 2C1 (P450 2C1-(1-29)) also interacted with BAP31, which is consistent with interaction of the two proteins via their transmembrane domains. Down-regulation of BAP31 expression with small interfering RNA resulted in redistribution of green fluorescent protein-tagged P450 2C2 or P450 2C1-(1-29) from the ER into the nuclear membrane and compact perinuclear compartment structures as well as the cell surface in a small fraction of the cells. In Bap31-null embryonic stem cells, a significant fraction of P450 2C2 or P450 2C1-(1-29) was detected at the cell surface and nuclear envelope, but was redistributed to the ER by expression of BAP31. The expression level of P450 2C2 was significantly increased in COS-1 cells with repressed levels of BAP31. Formation of the pro-apoptotic p20 fragment of BAP31 was detected in transfected COS-1 cells expressing P450 2C2, and annexin V staining was consistent with the activation of an apoptotic pathway in these cells. Down-regulation of BAP31 with small interfering RNA partially reversed the apoptosis. These results suggest that interaction of P450 2C2 with BAP31 is important for its ER retention and expression level and that BAP31 may be involved in the regulation of apoptosis induced by the ER overload response to increased expression of P450.

  19. Automatic Tracking and Characterization of Cumulonimbus Clouds from FY-2C Geostationary Meteorological Satellite Images

    Yu Liu


    Full Text Available This paper presents an automated method to track cumulonimbus (Cb clouds based on cloud classification and characterizes Cb behavior from FengYun-2C (FY-2C. First, a seeded region growing (SRG algorithm is used with artificial neural network (ANN cloud classification as preprocessing to identify consistent homogeneous Cb patches from infrared images. Second, a cross-correlation-based approach is used to track Cb patches within an image sequence. Third, 7 pixel parameters and 19 cloud patch parameters of Cb are derived. To assess the performance of the proposed method, 8 cases exhibiting different life stages and the temporal evolution of a single case are analyzed. The results show that (1 the proposed method is capable of locating and tracking Cb until dissipation and can account for the eventual splitting or merging of clouds; (2 compared to traditional brightness temperature (TB thresholds-based cloud tracking methods, the proposed method reduces the uncertainty stemming from TB thresholds by classifying clouds with multichannel data in an advanced manner; and (3 the configuration and developmental stages of Cb that the method identifies are close to reality, suggesting that the characterization of Cb can provide detailed insight into the study of the motion and development of thunderstorms.

  20. SL(2,C) Chern-Simons Theory and Quantum Gravity with a Cosmological Constant

    Haggard, Hal; Han, Muxin; Kaminski, Wojciech; Riello, Aldo


    We show a relation between 4-dimensional quantum gravity with a cosmological constant and SL(2,C) Chern-Simons theory in 3-dimensions with knotted graph defects. In particular, we study the expectation value of a non-planar Wilson graph operator in SL(2,C) Chern-Simons theory on S3. We analyze its asymptotic behavior in the double-scaling limit in which both the representation labels and the Chern-Simons coupling are taken to be large, but with fixed ratio. We find that a class of flat connections in the graph complement manifold are in correspondence with the geometries of constant curvature 4-simplices. We show that the asymptotic behavior of the amplitude contains an oscillatory part proportional to the Regge action for the single 4-simplex in the presence of a cosmological constant. In particular, the cosmological term contains the full-fledged curved volume of the 4-simplex. Interestingly, the volume term stems from the asymptotics of the Chern-Simons action. Another peculiarity of our approach is that the sign of the curvature of the reconstructed geometry, and hence of the cosmological constant in the Regge action, is not fixed a priori, but rather emerges semiclassically and dynamically from the solution of the equations of motion. This work was supported by the U.S. National Science Foundation, the European Marie Curie actions, and the Perimeter Institute.

  1. The Effect of Non-technical Factors in B2C E-Commerce

    Sanayei, Ali; Shafe'Ei, Reza

    As e-commerce grows across industries worldwide , business are building web sites for presence as well as for online business. It is more than transferring current business operations to a new medium. This situation requires explaining main models, changing infrastructures, and notice to customer needs as their vital rights. Whilst increasing numbers of firms have launched themselves on the Internet, they are trying to consideration of the strategic implications of developing, implementing or running a Web site. Global competition, laws, and customer preferences are among the issues being affected by e-commerce. In this study many factors that effect on e-commerce are considered these factors have no technical issue in nature. Companies related factors, customers' knowledge, customers' trust and customers' behavior are the main effective factors in development of B2C e-commerce. In this research we surveyed the mentioned aspects by offering questionnaire to experts of e-commerce for companies. The results show there is a meaningful relationship between perception, knowledge, trust and attitude of customers and the company's capabilities in the other side with B2C e-commerce development.

  2. Dynamic Entangled Porous Framework for Hydrocarbon (C2-C3) Storage, CO2 Capture, and Separation.

    Sikdar, Nivedita; Bonakala, Satyanarayana; Haldar, Ritesh; Balasubramanian, Sundaram; Maji, Tapas Kumar


    Storage and separation of small (C1-C3) hydrocarbons are of great significance as these are alternative energy resources and also can be used as raw materials for many industrially important materials. Selective capture of greenhouse gas, CO2 from CH4 is important to improve the quality of natural gas. Among the available porous materials, MOFs with permanent porosity are the most suitable to serve these purposes. Herein, a two-fold entangled dynamic framework {[Zn2 (bdc)2 (bpNDI)]⋅4DMF}n with pore surface carved with polar functional groups and aromatic π clouds is exploited for selective capture of CO2 , C2, and C3 hydrocarbons at ambient condition. The framework shows stepwise CO2 and C2 H2 uptake at 195 K but type I profiles are observed at 298 K. The IAST selectivity of CO2 over CH4 is the highest (598 at 298 K) among the MOFs without open metal sites reported till date. It also shows high selectivity for C2 H2 , C2 H4 , C2 H6 , and C3 H8 over CH4 at 298 K. DFT calculations reveal that aromatic π surface and the polar imide (RNC=O) functional groups are the primary adsorption sites for adsorption. Furthermore, breakthrough column experiments showed CO2 /CH4 C2 H6 /CH4 and CO2 /N2 separation capability at ambient condition.

  3. Magnetic ordering in Ho{sub 2}Fe{sub 2}Si{sub 2}C

    Susilo, R. A., E-mail:; Cadogan, J. M.; Cobas, R.; Hutchison, W. D.; Campbell, S. J. [School of Physical, Environmental and Mathematical Sciences, UNSW Canberra at the Australian Defence Force Academy, Canberra BC 2610 (Australia); Avdeev, M. [Bragg Institute, ANSTO, PMB 1, Menai, New South Wales 2234 (Australia)


    We have used neutron diffraction and {sup 57}Fe Mössbauer spectroscopy, complemented by magnetisation and specific heat measurements, to examine the magnetic ordering of Ho{sub 2}Fe{sub 2}Si{sub 2}C. We have established that Ho{sub 2}Fe{sub 2}Si{sub 2}C orders antiferromagnetically below T{sub N} = 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 ]. {sup 57}Fe Mössbauer spectra collected below T{sub N} 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 {sup 57}Fe spectra below T{sub N}, which is due to a transferred hyperfine field—estimated to be around 0.3 T at 10 K—from the Ho sublattice.

  4. Research on CPFR pattern of the Internet of things based on B2C

    Zhou, Ling; Yang, Jie


    The CPFR pattern proposed by this article is based on the internet of things platform, using frontier technology of internet of things to realize real-time monitoring and the feedback in logistics, information stream in B2C mode, and simultaneously construct an e-business mode which takes the customer guidance as the center to be possible to meet the customers' need and realize the service made by customer. This new pattern uses the coordination, plan, prediction and replenishment of CPFR to realize custom-made stock based on B2C for terminal customer and specialized service for commodity stock. Moreover, it can bring suppliers real-time monitoring of terminal logistics, storage and users' notes for use, and feed back users' bugs, adjustment of orders and plan of replenishment. Furthermore, based on new pattern, we can data min users' interests and undertake a study in increment modeling, process reengineering in enterprise, optimizing enterprise's interior resources and conformity industry of supply chain. Above all it provides a new mentality and the operation pattern for the electronic commerce marketing.

  5. Evolutionary genetic analyses of MEF2C gene: implications for learning and memory in Homo sapiens.

    Kalmady, Sunil V; Venkatasubramanian, Ganesan; Arasappa, Rashmi; Rao, Naren P


    MEF2C facilitates context-dependent fear conditioning (CFC) which is a salient aspect of hippocampus-dependent learning and memory. CFC might have played a crucial role in human evolution because of its advantageous influence on survival of species. In this study, we analyzed 23 orthologous mammalian gene sequences of MEF2C gene to examine the evidence for positive selection on this gene in Homo sapiens using Phylogenetic Analysis by Maximum Likelihood (PAML) and HyPhy software. Both PAML Bayes Empirical Bayes (BEB) and HyPhy Fixed Effects Likelihood (FEL) analyses supported significant positive selection on 4 codon sites in H. sapiens. Also, haplotter analysis revealed significant ongoing positive selection on this gene in Central European population. The study findings suggest that adaptive selective pressure on this gene might have influenced human evolution. Further research on this gene might unravel the potential role of this gene in learning and memory as well as its pathogenetic effect in certain hippocampal disorders with evolutionary basis like schizophrenia.

  6. Canine parvovirus--a review of epidemiological and diagnostic aspects, with emphasis on type 2c.

    Decaro, Nicola; Buonavoglia, Canio


    Canine parvovirus type 2 (CPV-2) emerged in late 1970s causing severe epizootics in kennels and dog shelters worldwide. Soon after its emergence, CPV-2 underwent genetic evolution giving rise consecutively to two antigenic variants, CPV-2a and CPV-2b that replaced progressively the original type. In 2000, a new antigenic variant, CPV-2c, was detected in Italy and rapidly spread to several countries. In comparison to the original type CPV-2, the antigenic variants display increased pathogenicity in dogs and extended host range, being able to infect and cause disease in cats. Epidemiological survey indicate that the newest type CPV-2c is becoming prevalent in different geographic regions and is often associated to severe disease in adult dogs and also in dogs that have completed the vaccination protocols. However, the primary cause of failure of CPV vaccination is interference by maternally derived immunity. Diagnosis of CPV infection by traditional methods has been shown to be poorly sensitive, especially in the late stages of infections. New diagnostic approaches based on molecular methods have been developed for sensitive detection of CPV in clinical samples and rapid characterisation of the viral type. Continuous surveillance will help assess whether there is a real need to update currently available vaccines and diagnostic tests.

  7. Implementation of I2C-DMA & SPI-DMA Interface: A Comparative Study



    Full Text Available This paper describes the designing and implementation of I2C (master-DMA and SPI (master-DMA interface. Direct Memory Access (DMA, being the feature of modern computers and microprocessors permits certain hardware subsystem in a computer machine to access system memory for reading/writing independently of CPU. Sometimes CPU is fully occupied for entire duration of read/write operation and unavailable to perform other work. With DMA, CPU would initiate data transfers and performs other operations while transfer is in progress. For intra-chip serial data transfers, SPI and I2C are used. Both serial protocols are widely used but both have some merits and demerits. In this research work both protocols are interfaced with DMA for SoC (System on Chip applications and their performance analysis is carried out by implementing on FPGA. VERILOG-HDL is used for designing RTL Code and test-bench verification. Simulations are observed in Modelsim-Altera 6.3 (Quartus II 8.1 simulator.

  8. Climate change impacts in the Mediterranean resulting from a 2C global temperature rise

    Giannakopoulos, C.; Tin, T. [National Observatory of Athens, Athens (Greece); Bindi, M.; Moriondo, M. [Department of Agronomy and Land Management, Florence (Italy)


    The goal of the present study is to provide the first piece of the puzzle in understanding the impacts of a 2C global temperature rise on the Mediterranean region, using high temporal resolution climate model output that has been made newly available. The analysis has been based on the temperature, precipitation and wind daily outputs of the HadCM3 model using the IPCC SRES A2 and B2 emission scenarios. The study is focussed on the thirty-year period (2031-2060) centred on the time that global temperature is expected to reach 2C above pre-industrial levels, as defined by an earlier companion study. Changes in both the mean (temperature, precipitation) and the extremes (heatwaves, drought) under the different scenarios were assessed. The impacts of these climatic changes on energy demand, forest fire, tourism and agriculture were subsequently investigated either using existing numerical models or an expertbased approach. Based on recent studies, the impacts on biodiversity, water resources and sea level rise in the region were also discussed.

  9. Electronic Commerce in Tourism in China: B2B or B2C?

    Li, Hongxiu; Suomi, Reima

    E-commerce has significantly changed the distribution channels of travel products in the world including China. Online channels are growing important in travel service distribution. In China tourism industry has been developed rapidly with the economic development, more and more international travel service providers are trying to expand their Chinese market through the Internet. This paper sheds lights on the e-commerce development models in China for international travel service providers. It explores the current e-tourism in China from the three different participants in the value chain in tourism industry - consumer, travel agent and travel service provider. The paper also identifies the barriers in B2C arena in international outbound travel market, and discusses the possible approaches for international travel service providers to develop their e-commerce in the huge Chinese market. The results in this study reveal that international travel service providers should focus on B2B model to expand their electronic market in China. B2C development in tourism largely depends on the change of Chinese customers' behavior and the change of international tourism regulations. The findings of the study are expected to assist international travel service providers to understand current e-tourism in China and to support their planning for future e-commerce development in China.

  10. A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites

    Kongsbak, Kristine Grønning; Bergmann, Rikke; Sørensen, Pernille Louise


    We present a full-length a1b2c2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate...

  11. Influence of the genetic polymorphisms in the 5' flanking and exonic regions of CYP2C19 on proguanil oxidation.

    Satyanarayana, Chakradhara Rao Uppugunduri; Devendran, Anichavezhi; Jayaraman, Muthukumaran; Mannu, Jayakanthan; Mathur, Premendu P; Gopal, Shewade Deepak; Rajagopal, Krishnamoorthy; Chandrasekaran, Adithan


    CYP2C19 is a polymorphic enzyme which metabolizes several clinically important drugs including proguanil. Variation in the 5' regulatory region may influence CYP2C19 activity. This study evaluates the relationship between proguanil metabolic ratio and genetic variations of CYP2C19 in a South Indian population. Fifty unrelated healthy subjects were genotyped for CYP2C19 (*)2 and (*)3 alleles and the 5' flanking region of CYP2C19 was sequenced. Plasma concentrations of proguanil and cycloguanil were estimated by reverse phase HPLC after single oral doses (200 mg) of proguanil. In silico docking analysis of transcription factors binding to its sites in CYP2C19 5' regulatory region was performed. The mean metabolic ratios (proguanil/cycloguanil) were highest in (*)1/(*)2 or (*)1/(*)3 subjects and in (*)2/(*)2 or (*)2/(*)3 as compared to (*)1/(*)1 subjects. Subjects with promoter region variation -98T>C showed decrease in the metabolic ratios irrespective of other variation, which may explain the deviation from the genotype-phenotype association of CYP2C19. In silico analysis predicted alteration in the interaction of transcription factors to their binding sites in the presence of variant alleles. The results of this study would be useful in predicting interindividual differences in the metabolism of substrates of CYP2C19.

  12. An optimized methodology for combined phenotyping and genotyping on CYP2D6 and CYP2C19

    Tamminga, C.A; Wemer, J; Oosterhuis, B; Brakenhoff, J.P G; Gerrits, M.G F; de Zeeuw, R.A; de Leij, Lou; Jonkman, J.H.G.


    A method for simultaneous phenotyping and genotyping for CYP2D6 and CYP2C19 was tested. Six healthy volunteers were selected (three extensive and three poor metabolisers for CYP2D6). CYP2D6 was probed with dextromethorphan and metoprolol and CYP2C19 was probed with omeprazole. Blood samples were col

  13. The prevalence of CYP2D6 and CYP2C19 genotypes in a population of healthy Dutch volunteers

    Tamminga, W.J; Wemer, J; Oosterhuis, B; de Zeeuw, R.A; de Leij, Lou; Jonkman, J.H.G.


    Aim: This study was performed in a sample of the Dutch population to estimate the prevalence of noncoding mutations of CYP2D6 and CYP2C19 as obtained by genotyping. In addition, the predictability of the genotyping strategy was assessed. Methods: The CYP2D6 and CYP2C19 status of 765 unrelated health

  14. Vergelijking van de zuurremmende effecten van esomeprazol en pantoprazol in relatie tot farmacokinetiek en CYP2C19-polymorfisme

    Hunfeld, Nicole G. M.; Touw, Daan J.; Mathôt, Ron A. A.; Mulder, Paul G. H.; Van Schaik, Ron H. N.; Kuipers, Ernst J.; Kooiman, Johan C.; Geus, Willem P.


    OBJECTIVE: To compare the acid-inhibitory effects of esomeprazole 40 mg and pantoprazole 40 mg at 4, 24 and 120 h after oral administration in relation to CYP2C19 genotype and pharmacokinetics. Esomeprazole and pantoprazole are metabolized in the liver and the polymorphic CYP2C19 enzyme is involved

  15. Photobiomodulation Protects and Promotes Differentiation of C2C12 Myoblast Cells Exposed to Snake Venom

    da Silva, Aline; Vieira, Rodolfo Paula; Mesquita-Ferrari, Raquel Agnelli; Cogo, José Carlos; Zamuner, Stella Regina


    Background Snakebites is a neglected disease and in Brazil is considered a serious health problem, with the majority of the snakebites caused by the genus Bothrops. Antivenom therapy and other first-aid treatments do not reverse local myonecrose which is the main sequel caused by the envenomation. Several studies have shown the effectiveness of low level laser (LLL) therapy in reducing local myonecrosis induced by Bothropic venoms, however the mechanism involved in this effect is unknown. In this in vitro study, we aimed to analyze the effect of LLL irradiation against cytotoxicity induced by Bothrops jararacussu venom on myoblast C2C12 cells. Methodology C2C12 were utilized as a model target and were incubated with B. jararacussu venom (12.5 μg/mL) and immediately irradiated with LLL at wavelength of red 685 nm or infrared 830 nm with energy density of 2.0, 4.6 and 7.0 J/cm2. Effects of LLL on cellular responses of venom-induced cytotoxicity were examined, including cell viability, measurement of cell damage and intra and extracellular ATP levels, expression of myogenic regulatory factors, as well as cellular differentiation. Results In non-irradiated cells, the venom caused a decrease in cell viability and a massive release of LDH and CK levels indicating myonecrosis. Infrared and red laser at all energy densities were able to considerably decrease venom-induced cytotoxicity. Laser irradiation induced myoblasts to differentiate into myotubes and this effect was accompanied by up regulation of MyoD and specially myogenin. Moreover, LLL was able to reduce the extracellular while increased the intracellular ATP content after venom exposure. In addition, no difference in the intensity of cytotoxicity was shown by non-irradiated and irradiated venom. Conclusion LLL irradiation caused a protective effect on C2C12 cells against the cytotoxicity caused by B. jararacussu venom and promotes differentiation of these cells by up regulation of myogenic factors. A modulatory

  16. Combined Effects of Androgen and Growth Hormone on Osteoblast Marker Expression in Mouse C2C12 and MC3T3-E1 Cells Induced by Bone Morphogenetic Protein

    Kimura, Kosuke; Terasaka, Tomohiro; Iwata, Nahoko; Katsuyama, Takayuki; Komatsubara, Motoshi; Nagao, Ryota; Inagaki, Kenichi; Otsuka, Fumio


    Osteoblasts undergo differentiation in response to various factors, including growth factors and steroids. Bone mass is diminished in androgen- and/or growth hormone (GH)-deficient patients. However the functional relationship between androgen and GH, and their combined effects on bone metabolism, remains unclear. Here we investigated the mutual effects of androgen and GH on osteoblastic marker expression using mouse myoblastic C2C12 and osteoblast-like MC3T3-E1 cells. Combined treatment with dihydrotestosterone (DHT) and GH enhanced BMP-2-induced expression of Runx2, ALP, and osteocalcin mRNA, compared with the individual treatments in C2C12 cells. Co-treatment with DHT and GH activated Smad1/5/8 phosphorylation, Id-1 transcription, and ALP activity induced by BMP-2 in C2C12 cells but not in MC3T3-E1 cells. The insulin-like growth factor (IGF-I) mRNA level was amplified by GH and BMP-2 treatment and was restored by co-treatment with DHT in C2C12 cells. The mRNA level of the IGF-I receptor was not significantly altered by GH or DHT, while it was increased by IGF-I. In addition, IGF-I treatment increased collagen-1 mRNA expression, whereas blockage of endogenous IGF-I activity using an anti-IGF-I antibody failed to suppress the effect of GH and DHT on BMP-2-induced Runx2 expression in C2C12 cells, suggesting that endogenous IGF-I was not substantially involved in the underlying GH actions. On the other hand, androgen receptor and GH receptor mRNA expression was suppressed by BMP-2 in both cell lines, implying the existence of a feedback action. Collectively the results showed that the combined effects of androgen and GH facilitated BMP-2-induced osteoblast differentiation at an early stage by upregulating BMP receptor signaling. PMID:28067796

  17. Pharmacogenetic evaluation of ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase polymorphisms in teratogenicity of anti-epileptic drugs in women with epilepsy

    Manna Jose


    Full Text Available Aim: Pregnancy in women with epilepsy (WWE who are on anti-epileptic drugs (AEDs has two- to three-fold increased risk of fetal malformations. AEDs are mostly metabolized by Cyp2C9, Cyp2C19 and Cyp3A4 and transported by ABCB1. Patients on AED therapy can have folate deficiency. We hypothesize that the polymorphisms in ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase (MTHFR might result in differential expression resulting in differential drug transport, drug metabolism and folate metabolism, which in turn may contribute to the teratogenic impact of AEDs. Materials and Methods: The ABCB1, Cyp2C9, Cyp2C19 and MTHFR polymorphisms were genotyped for their role in teratogenic potential and the nature of teratogenecity in response to AED treatment in WWE. The allelic, genotypic associations were tested in 266 WWE comprising of 143 WWE who had given birth to babies with WWE-malformation (WWE-M and 123 WWE who had normal offsprings (WWE-N. Results: In WWE-M, CC genotype of Ex07 + 139C/T was overrepresented (P = 0.0032 whereas the poor metabolizer allele FNx012 and FNx012 FNx012 genotype of CYP2C219 was significantly higher in comparison to WWE-N group (P = 0.007 and P = 0.005, respectively. All these observations were independent of the nature of malformation (cardiac vs. non cardiac malformations. Conclusion: Our study indicates the possibility that ABCB1 and Cyp2C19 may play a pivotal role in the AED induced teratogenesis, which is independent of nature of malformation. This is one of the first reports indicating the pharmacogenetic role of Cyp2C19 and ABCB1 in teratogenesis of AED in pregnant WWE.

  18. Analysis of adhesive binding forces between laminin-1 and C2C12 muscle cell membranes measured via high resolution force spectroscopy

    Gluck, George; Gilbert, Richard; Ortiz, Christine


    Laminins are a family of glycoproteins that regulate cell differentiation, shape, and motility through interactions with various cell surface receptors. Here, we have directly measured the biomolecular adhesive binding forces between a cantilever / probe tip that was covalently attached with laminin-1 and membrane receptors on C2C12 muscle cells using the technique of high-resolution force spectroscopy (HRFS). On retraction of the probe tip away from the membrane surface, discrete, long-range adhesive unbinding events were always observed. Statistical analysis of the data revealed an initial broad distribution of heterogeneous unbinding events (occurring at separation distances, D=0-2µm from the point of maximum compression) of magnitude 92.23±37.87pN followed by a narrow distribution of homogeneous unbinding events (occurring at D > 2µm) of magnitude 38.16±9.10pN, which is suggestive of an individual biomolecular adhesive interaction. On-going studies include loading rate dependence and effect of dystroglycan mutation.

  19. Impact of CYP2C8*3 on paclitaxel clearance

    Bergmann, T K; Brasch-Andersen, C; Gréen, H;


    , the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h(-1) (range 176-726 l h(-1)). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0.03. This has not been shown before in similar studies......; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible...

  20. Scanning Hall Probe Imaging of ErNi2B2C

    Bluhm, Hendrik; Sebastian, Suchitra; Guikema, Janice W.; Fisher, I.R.; Moler, Kathryn A.; /Stanford U., Appl. Phys. Dept.


    We report scanning Hall probe imaging of ErNi{sub 2}B{sub 2}C in the superconducting, antiferromagnetic, and weakly ferromagnetic regimes in magnetic fields up to 20 Oe, well below H{sub c1}, with two results. First, imaging isolated vortices shows that they spontaneously rearrange on cooling through the antiferromagnetic transition temperature T{sub N} = 6 K to pin on twin boundaries, forming a striped pattern. Second, a weak, random magnetic signal appears in the ferromagnetic phase below T{sub WFM} = 2.3 K, and no spontaneous vortex lattice is present down to 1.9 K. We conclude that ferromagnetism coexists with superconductivity either by forming small ferromagnetic domains or with oscillatory variation of the magnetization on sub-penetration depth length scales.

  1. Mo2C nanowires and nanoribbons on Si by two-step vapor-phase growth

    Tsakalakos, L.; Rahmane, M.; Larsen, M.; Gao, Y.; Denault, L.; Wilson, P.; Balch, J.


    Transition-metal carbides in bulk form have historically been of technological interest primarily due to their excellent mechanical and refractory properties. As electronic materials these ceramic compounds are also particularly intriguing in that their electrical resistivity is relatively low compared to other ceramics and shows metallic temperature-dependent behavior. Some compositions also have superconducting transitions temperatures above 10°K. However, the synthesis of such materials in the form of one-dimensional nanostructures, which may be of interest for various nanoelectronic applications, is relatively difficult due to their refractory nature (Tmelt⩾2000°C). Here we report the synthesis of well-defined Mo2C nanowires and ribbons using a two-step approach in which we catalytically grow metal oxide nanostructures followed by in situ carburization. The growth mechanisms, microstructure, and initial electrical property measurements are discussed.

  2. On Desideratum for B2C E-Commerce Reputation Systems

    Anna Gutowska; Andrew Sloane; Kevan A.Buckley


    This paper reviews existing approaches to reputation systems,their constraints as well as available presents and evaluates a novel and comprehensive reputation model devoted to the distributed reputation system for Business-to-Consumer(B2C)E-commerce applications that overcomes the discussed drawbacks.The algorithm offers a comprehensive approach as it considers a number of issues that have a bearing on trust and reputation such as age of ratings,transaction value,credibility of referees,number of malicious incidents,collusion and unfair ratings.Moreover,it also extends the existing frameworks based on information about past behaviour,with other aspects affecting online trading decisions which relate to the characteristic of the providers,such as existence of trustmark seals,payment intermediaries,privacy statements,security/privacy strategies,purchase protection/insurance,alternative dispute resolutions as well as the existence of first party information.

  3. New Synthetic Method of Azuleno[1,2-c]thiophenes

    WANG,Bing; WANG,Dao-Lin; IMAFUKU,Kimiakic


    @@ On the viewpoints of physical and chemical properties and biological activities, syntheses of a variety of heterocycle-fused azulenes have been repoted.[1] Of them, thiophene-fused azulenes were prepared by using different types of stating materials as follows. Azuleno[2,1-b] thiophenes are readily obtained from the reactions of 2-chloroazulene derivatives with ethyl mercaptoacetate in a few steps in good yield by Matsui[2] and Yamane.[3] On the other hand, the first synthesis of azuleno[1,2-c]thiophenes was accomplished by the reaction of 3-methoxycarbonyl-2H-cyclohepta[b]furan2-one with morpholino enamine of 3-oxotetrahydro-thiophene followed by dehydrogenation in poor yield by Fujimori.

  4. Possibility of spontaneous vortex phase in ErNi_2^11B_2C

    Kawano-Furukawa, Hazuki; Habuta, Emi; Nagata, Takashi; Yoshizawa, Hideki; Takeya, Hiroyuki; Kadowaki, Kazuo


    Recently, a possible coexistence of ferromagnetism and superconductivity was proposed in ErNi_2^11B_2C [P. C. Canfield et. al., Physica C 262, 249 (1996)]. Following this finding, we have performed unpolarized and polarized neutron diffraction experiments on a ^11B substituted large single crystal, and confirmed microscopically that such an exotic phase is realized below T_WFM=2.75K [H. Kawano et al., The Journal of Physics and Chemistry of Solids 60 (1999) 1053]. In the present study, we aim to search a possibility of the spontaneous vortex phase in this material by means of magnetization and neutron diffraction measurements. After the zero field cooled procedure the magnetization curve shows diamagnetic behavior even below T_WFM, indicating that there is no spontaneous vortex phase in this condition. The data in the field cooled condition, on the other hand, indicates H_c1 becomes zero below T_WFM.

  5. Existence of aromatic sp~2 C-H…O = C intramolecular interaction similar to hydrogen bond

    Zeper Abliz; Hiroshi Moriyama; Junji Aoki; Toyotoshi Ueda


    A ’H NMR signal shifted drastically to down field (δ - 10.0) at the bay area and in dose proximity to C = O group for H-1 was observed through complete assignments of 1H NMR spectra for pyridino- and benzobenzanthrones. It is concluded that this phenomenon is due not only to the anisotropy effect of C=O plus aromatic ring current effect, but also to the electrostatic attraction of C-H (δ+)…O(δ-)=C interaction. The evidence for the sp2C-H…O = C intramolecular interaction similar to hydrogen bond has also been given by EI-MS and MS/MS (CID) spectroscopy and IR spectroscopy, as well as MNDO-PM3 calculations. This new kind of interaction might be called ’quasi-hydrogen bond’.

  6. Algebraic theory of endohedrally confined diatomic molecules: application to H$_2$@C$_{60}$

    Fortunato, Lorenzo


    A simple and yet powerful approach for modeling the structure of endohedrally confined diatomic molecules is introduced. The theory, based on a $u(4)\\oplus u(3)$ dynamical algebra, combines the vibron model with an isotropic three dimensional oscillator. The first describes the internal roto-vibrations degrees of freedom of the molecule, while the second takes into account the confined molecule center-of-mass degrees of freedom. A resulting subalgebra chain is connected to the underlying physics and the model is applied to the prototypical case of H$_2$ caged in a fullerene molecule. The spectrum of the supramolecular complex H$_2$@C$_{60}$ is described with a few parameters and predictions for not yet detected levels are made. Our fits suggest that the quantum numbers of a few lines should be reassigned to obtain better agreement with data.

  7. Magnetism and superconductivity in ErNi2B2C

    N J Bancroft; D McK Paul; G McIntyre; C D Dewhurst; R Cubitt


    We have performed a series of neutron diffraction experiments from the magnetic order and the vortex lattice in single crystal ErNi2B2C. The incommensurate magnetic structure develops additional even harmonics below the `ferromagnetic' ordering temperature, F of 2.3 K. This feature and the existence of rods of diffuse scattering suggest the development of ferromagnetic microdomain walls. The magnetic structure is very sensitive to the application of a magnetic field with changes in modulation vector and harmonic content. Studies of the vortex lattice show the presence of a 45° reorientation transition and a distorted hexagonal to square transition as a function of applied field. Further distortions of the vortex lattice occur at N, but no changes are seen at F.

  8. Many-body effects in LuNi{sub 2}B{sub 2}C

    Bergk, B; Bartkowiak, M; Ignatchik, O; Wosnitza, J [Hochfeld-Magnetlabor Dresden (HLD), Forschungszentrum Dresden-Rossendorf, D-01314 Dresden (Germany); Petzold, V; Rosner, H [Max-Planck-Institut fuer Chemische Physik fester Stoffe, D-01187 Dresden (Germany); Drechsler, S-L; Sheikin, I [Leibniz-Institute for Solid State and Materials Research (IFW-Dresden), D-01171 Dresden (Germany); Canfield, P C, E-mail: b.bergk@fzd.d [Grenoble High Magnetic Field Laboratory, CNRS, BP 166, F-38042 Grenoble Cedex 09 (France)


    We present de Haas-van Alphen measurements of the nonmagnetic borocarbide superconductor LuNi{sub 2}B{sub 2}C. The electronic band structure is extracted from the magnetic quantum oscillations in the normal state. In accordance with previous investigations we find a complex band structure with different open and closed Fermi-surface sheets. From the temperature dependence of the oscillations amplitude the effective mass of the single bands can be determined. Due to many-body interactions we observe enhancements of the effective masses compared to the results by full-potential-density-functional calculations. Therefore, we are able to determine the angular dependence of the interaction strength for the different bands separately.

  9. Magnetic phase diagram of ErNi2B2C

    Jensen, A.; Toft, K.N.; Abrahamsen, A.B.;


    an analysis of bulk magnetization and zero-field neutron diffraction data. The model accounts for most of the observed features but fails to explain the occurrence of a small component Qdelta approximate to -0.005b* observed close to H-c2 when the field is applied along [110]. (C) 2004 Elsevier B.V. All......The magnetic phase diagram of the superconductor ErNi2B2C (T-c = 11 K and T-N = 6 K) has been studied by neutron diffraction as a function of temperature and magnetic field applied along the symmetry directions [010], [110] and [001] of the tetragonal crystal structure. A series of commensurate...... magnetic structures, consistent with a transversely polarized spin-density wave with modulation vectors Q = n/ma* (0.55 less than or equal to n/m

  10. Biped 4R2C six-bar mechanism with inner and outer feet

    Liu, Chao; Wang, Hao; Yao, Yan-an


    Most current biped robots are equipped with two feet arranged in the right and left which inspired by the human body system. Different from the existing configurations, a novel biped robot with inner and outer feet based on a spatial six-bar 4R2C(R and C denote revolute and cylindric joints, respectively) mechanism is proposed. It can move along a line or a curve by three walking modes that are dwell adjustment mode, limit position adjustment mode and any position adjustment mode. Kinematic, gait planning and stability analyses are performed respectively, and a prototype is developed. Lastly, a potential application is considered and two manipulating modes(sphere and cylinder manipulating modes) are carried out. This interesting mechanism feathering its single closed-chain structure and unique work performance is expected to motivate the configuration creation of biped robots.

  11. Ni-CeO2/C Catalysts with Enhanced OSC for the WGS Reaction

    Laura Pastor-Pérez


    Full Text Available In this work, the WGS performance of a conventional Ni/CeO2 bulk catalyst is compared to that of a carbon-supported Ni-CeO2 catalyst. The carbon-supported sample resulted to be much more active than the bulk one. The higher activity of the Ni-CeO2/C catalyst is associated to its oxygen storage capacity, a parameter that strongly influences the WGS behavior. The stability of the carbon-supported catalyst under realistic operation conditions is also a subject of this paper. In summary, our study represents an approach towards a new generation of Ni-ceria based catalyst for the pure hydrogen production via WGS. The dispersion of ceria nanoparticles on an activated carbon support drives to improved catalytic skills with a considerable reduction of the amount of ceria in the catalyst formulation.

  12. Flux line lattice symmetries in the borocarbide superconductor LuNi2B2C

    M R Eskildsen; A B Abrahamsen; P L Gammel; D J Bishop; N H Andersen; K Mortensen; P C Canfield


    We compare the results of small angle neutron scattering on the flux line lattice (FLL) obtained in the borocarbide superconductor LuNi2B2C with the applied field along the - and -axes. For $\\mathbf{H}||\\mathbf{c}$ the temperature dependence of the FLL structural phase transition from square to hexagonal symmetry was investigated. Above 10 K the transition onset field, 2(), rises sharply, bending away from c2() in contradiction to theoretical predictions of the two merging. For $\\mathbf{H}||\\mathbf{a}$ a first order FLL reorientation transition is observed at tr =3-3.5 kOe. Below tr the FLL nearest neighbor direction is parallel to the -axis, and above tr to the -axis. This transition cannot be explained using nonlocal corrections to the London model.

  13. A Study of Online Review Promptness in a B2C System

    Junqiang Zhang


    Full Text Available Web 2.0 technologies have attracted an increasing number of active online writers and viewers. A deeper understanding of when customers will review and what motivates them to write online reviews is of both theoretical and practical significance. In this paper, we present a novel methodological framework, which consists of theoretical modeling and text-mining technologies, to study the relationships among customers’ review promptness, their review opinions, and their review motivations. We first study customers’ online “purchase-review” behavior dynamics; then, we introduce the LDA method to mine customers’ opinion from their review text; finally, we propose a theoretical model to explore some motivations for those people publishing review online. The analytical and experimental results with real data from a Chinese B2C website demonstrate that the behavior dynamics of customers’ online review are influenced by the multidimensional motivations, and some of them can be observed from their review behaviors, such as review promptness.

  14. Perceived Compatibility and the Adoption of B2C E-Commerce by Non-buyers

    Hernández-García, Ángel; Iglesias-Pradas, Santiago; Chaparro-Peláez, Julián; Pascual-Miguel, Félix

    The purpose of this article is to study the factors which affect the intention to buy online for users who have never made any prior purchase using the electronic channel, with special focus to the role of perceived compatibility. To do so, an adoption model for e-commerce was proposed on the basis of the Technology Adoption Model (TAM) and the Innovations Diffusion Theory (IDT). In order to validate the model, data gathered amongst Spanish consumers who had no experience using e-commerce, were analyzed using the partial least squares (PLS) method. The results have demonstrated the importance of perceived compatibility as a significant factor to foster non-buyers' adoption of electronic business-to-consumer e-commerce (eB2C).

  15. On-line Shopping on B2C Markets in the Czech Republic

    Pilík Michal


    Full Text Available The paper deals with the e-commerce theory and is aimed primarily at its usage in business-toconsumer markets. On-line purchasing management is increasing not only in the Czech Republic but also in Europe and all over the world. The customers who think rationally use on-line shopping because of money saving, speed delivery and the possibility of product comparison. This paper presents the results of a project financed by the Czech Science Foundation P403/11/ P175: The factors influencing customers’ on-line behaviour in e-commerce environment on B2C and B2B markets in the Czech Republic. 89 % of respondents use e-shops for buying products in the Czech Republic. 32 % of them use the Internet for regular purchases and 57 % of them irregularly. 11 % of respondents have not used e-shops yet.

  16. A new tetragonal structure type for Li2B2C.

    Pavlyuk, Volodymyr; Milashys, Viktoriya; Dmytriv, Grygoriy; Ehrenberg, Helmut


    The ternary dilithium diboron carbide, Li2B2C (tetragonal, space group P-4m2, tP10), crystallizes as a new structure type and consists of structural fragments which are typical for structures of elemental lithium and boron or binary borocarbide B13C2. The symmetries of the occupied sites are .m. and 2mm. for the B and C atoms, and -4m2 and 2mm. for the Li atoms. The coordination polyhedra around the Li atoms are cuboctahedra and 15-vertex distorted pseudo-Frank-Kasper polyhedra. The environment of the B atom is a ten-vertex polyhedron. The nearest neighbours of the C atom are two B atoms, and this group is surrounded by a deformed cuboctahedron with one centred lateral facet. Electronic structure calculations using the TB-LMTO-ASA method reveal strong B...C and B...B interactions.

  17. Cytoprotective Role of Nrf2 in Electrical Pulse Stimulated C2C12 Myotube.

    Masaki Horie

    Full Text Available Regular physical exercise is central to a healthy lifestyle. However, exercise-related muscle contraction can induce reactive oxygen species and reactive nitrogen species (ROS/RNS production in skeletal muscle. The nuclear factor-E2-related factor-2 (Nrf2 transcription factor is a cellular sensor for oxidative stress. Regulation of nuclear Nrf2 signaling regulates antioxidant responses and protects organ structure and function. However, the role of Nrf2 in exercise- or contraction-induced ROS/RNS production in skeletal muscle is not clear. In this study, using differentiated C2C12 cells and electrical pulse stimulation (EPS of muscle contraction, we explored whether Nrf2 plays a role in the skeletal muscle response to muscle contraction-induced ROS/RNS. We found that EPS (40 V, 1 Hz, 2 ms stimulated ROS/RNS accumulation and Nrf2 activation. We also showed that expression of NQO1, HO-1 and GCLM increased after EPS-induced muscle contraction and was remarkably suppressed in cells with Nrf2 knockdown. We also found that the antioxidant N-acetylcysteine (NAC significantly attenuated Nrf2 activation after EPS, whereas the nitric oxide synthetase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME did not. Furthermore, Nrf2 knockdown after EPS markedly decreased ROS/RNS redox potential and cell viability and increased expression of the apoptosis marker Annexin V in C2C12 myotubes. These results indicate that Nrf2 activation and expression of Nrf2 regulated-genes protected muscle against the increased ROS caused by EPS-induced muscle contraction. Thus, our findings suggest that Nrf2 may be a key factor for preservation of muscle function during muscle contraction.

  18. The Effect of Mo2C Synthesis and Pretreatment on Catalytic Stability in Oxidative Reforming Environments

    Lamont, David C.(8392); Gilligan, Andrew J.(Washington University); Darujati, Anna R S.(Washington State University); Chellappa, Anand S.(WASHINGTON STATE UNIV); Thomson, Wiliam J.(8392)


    The role of catalyst pretreatment on the stability of Mo2C catalysts in oxidative reforming environments has been studied. Catalysts were produced by both the temperature programmed reaction (TPR) and a solution-derived (SD) synthesis method, and compared to a low surface area commercial catalyst. Using a variety of techniques, including in situ dynamic X-ray diffraction (DXRD), the effects of various hydrogen pretreatment protocols were evaluated, including catalyst thermal stability, oxidation resistance and susceptibility to coking. The high surface areas produced by the SD synthesis is attributed to the presence of excess synthesis carbon and, whereas the presence of excess synthesis carbon enhances thermal stability, it also appears to accelerate coking. It is pointed out that the lowered oxidation resistance of the high surface area catalysts is due to a combination of smaller crystallite sizes and competitive oxidation of the excess synthesis carbon, which alters the oxidation mechanism. In addition, it was also found that incomplete carburization during TPR synthesis, forms an oxycarbide and its acidity also promotes coking. Hydrogen pretreatment at 700 .C not only removes all excess synthesis carbon, but it also reduces the oxycarbide to Mo, which is easily carburized under reforming conditions. Pretreatment at 600 .C, was largely ineffective and it is concluded that high temperature pretreatment is necessary to form the stoichiometric carbide, which is required for stability during reforming. Both the TPR and SD catalysts pretreated at 700 .C, were found to be stable over a 72 h period, whereas the commercial carbide had almost identical activity but slowly deactivated over the same period, probably because of its low surface area. Finally, labeled isotope experiments revealed that carbon exchange occurs readily with bulk Mo2C at temperatures above 550 .C, lending credence to a reforming redox mechanism.

  19. Evaluation of flurbiprofen urinary ratios as in vivo indices for CYP2C9 activity

    Zgheib, N K; Frye, R F; Tracy, T S; Romkes, M; Branch, R A


    Aims We investigated flurbiprofen pharmacokinetics in 12 volunteers to develop a phenotypic trait measure that correlates with the fractional clearance to 4′-hydroxyflurbiprofen. The effect of the CYP2C9 inhibitor fluconazole on flurbiprofen metabolism was also evaluated. Methods Flurbiprofen pharmacokinetics were evaluated before and after the first and seventh doses of fluconazole. The urinary recovery ratio was calculated as FLRR = 4′-OHF/ [4′-OHF + Ftot] and the urinary metabolic ratio was calculated as FLMR = 4′-OHF/Ftot, where 4′-OHF and Ftot represent total (conjugated and unconjugated) amounts recovered in urine. Results There was a statistically significant relationship between the 4′-OHF formation clearance (4OHCLf) and both the 8-h FLRR and the 8-h FLMR with and without administration of fluconazole. The flurbiprofen apparent oral clearance (CL/F) was decreased by 53% [90% confidence interval (CI) −58, −48] and 64% (90% CI −69, −59), respectively, after administration of one and seven doses of fluconazole when compared with administration of flurbiprofen alone; similarly, the 4OHCLf decreased by 69% (90% CI −74, −64) and 78% (90% CI −83, −73), the 8-h FLRR decreased by 35% (90% CI −41, −29) and 40% (90% CI −46, −35) and the 8-h FLMR decreased by 61% (90% CI −65, −58) and 67% (90% CI −70, −63). The magnitude of decrease in CL/F and 4OHCLf was greater after seven doses compared with after one dose of fluconazole (P < 0.005). Conclusions This study provides strong evidence that both the 8-h FLRR and the 8-h FLMR are suitable phenotypic indices for CYP2C9 activity. PMID:17054666

  20. Impact Studies of a 2 C Global Warming on the Arctic Sea Ice Cover

    Comiso, Josefino C.


    The possible impact of an increase in global temperatures of about 2 C, as may be caused by a doubling of atmospheric CO2, is studied using historical satellite records of surface temperatures and sea ice from late 1970s to 2003. Updated satellite data indicate that the perennial ice continued to decline at an even faster rate of 9.2 % per decade than previously reported while concurrently, the surface temperatures have steadily been going up in most places except for some parts of northern Russia. Surface temperature is shown to be highly correlated with sea ice concentration in the seasonal sea ice regions. Results of regression analysis indicates that for every 1 C increase in temperature, the perennial ice area decreases by about 1.48 x 10(exp 6) square kilometers with the correlation coefficient being significant but only -0.57. Arctic warming is estimated to be about 0.46 C per decade on average in the Arctic but is shown to be off center with respect to the North Pole, and is prominent mainly in the Western Arctic and North America. The length of melt has been increasing by 13 days per decade over sea ice covered areas suggesting a thinning in the ice cover. The length of melt also increased by 5 days per decade over Greenland, 7 days per decade over the permafrost areas of North America but practically no change in Eurasia. Statistically derived projections indicate that the perennial sea ice cover would decline considerably in 2025, 2035, and 2060 when temperatures are predicted by models to reach the 2 C global increase.

  1. Climate and Health Impacts of US Emissions Reductions Consistent with 2 C

    Shindell, Drew T.; Lee, Yunha; Faluvegi, Greg


    An emissions trajectory for the US consistent with 2 C warming would require marked societal changes, making it crucial to understand the associated benefits. Previous studies have examined technological potentials and implementation costs and public health benefits have been quantified for less-aggressive potential emissions-reduction policies, but researchers have not yet fully explored the multiple benefits of reductions consistent with 2 C. We examine the impacts of such highly ambitious scenarios for clean energy and vehicles. US transportation emissions reductions avoid approx.0.03 C global warming in 2030 (0.15 C in 2100), whereas energy emissions reductions avoid approx.0.05-0.07 C 2030 warming (approx.0.25 C in 2100). Nationally, however, clean energy policies produce climate disbenefits including warmer summers (although these would be eliminated by the remote effects of similar policies if they were undertaken elsewhere). The policies also greatly reduce damaging ambient particulate matter and ozone. By 2030, clean energy policies could prevent approx.175,000 premature deaths, with approx.22,000 (11,000-96,000; 95% confidence) fewer annually thereafter, whereas clean transportation could prevent approx.120,000 premature deaths and approx.14,000 (9,000-52,000) annually thereafter. Near-term national benefits are valued at approx.US$250 billion (140 billion to 1,050billion) per year, which is likely to exceed implementation costs. Including longer-term, worldwide climate impacts, benefits roughly quintuple, becoming approx.5-10 times larger than estimated implementation costs. Achieving the benefits, however, would require both larger and broader emissions reductions than those in current legislation or regulations.

  2. 5-Hydroxytryptamine Receptor Subtypes and their Modulators with Therapeutic Potentials

    Pithadia, Anand B.; Jain, Sunita M.


    5-hydroxytryptamine (5-HT) has become one of the most investigated and complex biogenic amines. The main receptors and their subtypes, e.g., 5-HTI (5-HT1A, 5-HT1B, 5-HTID, 5-HTIE and 5-HT1F), 5-HT2 (5-HT2A, 5-HT2B and 5-HT2C), 5-HT3, 5-HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6 and 5-HT7 have been identified. Specific drugs which are capable of either selectively stimulating or inhibiting these receptor subtypes are being designed. This has generated therapeutic potentials of 5-HT receptor modulators...

  3. CYP2C9基因多态性对美洛昔康代谢动力学的影响%Effect of CYP2C9 Genetic Polymorphism on the Pharmacokinetics of Meloxicam Metabolism in Chiness Subjects

    张梅; 许景峰; 杨永革; 徐林; 邸晓辉; 姜楠; 徐娟; 许雪廷


    目的 研究CYP2C9基因多态性对美洛昔康代谢动力学的影响.方法 用焦磷酸测序法对24名健康受试者进行CYP2C9基因多态性检测;用LC-MS-MS法测定美洛昔康的血药浓度;用DAS2.0软件进行房室拟合及药代动力学参数计算,分析美洛昔康人体药代动力学特征,并比较CYP2C9*3突变型和野生型个体对美洛昔康代谢动力学特性的差异.结果 24名受试者中CYP2C9*3等位基因有2种表型(A/A,A/C),其中2名受试者为CYP2C9 * 3杂合突变型(A/C),其余为野生型(A/A);CYP2C9*3代谢美洛昔康的酶活性A/A>A/C.结论 CYP2C9基因多态性对美洛昔康的代谢具有显著影响,CYP2C9*3代谢美洛昔康的酶活性是A/A>A/C.检测突变型个体对指导美洛昔康临床个体化用药具有重要意义.%Objective To investigate the effect of CYP2C9 polymorphism on the pharmacokinetics of meloxi-cam in Chinese healthy subjects. Methods The CYP2C9 genotypes of twenty-four Chinese healthy male subjects were selected by the pyrosequencing method. The subjects were genotyped with CYP2C9 * 3 wild-type and mutation. HPLC-MS-MS method was used for the determination of meloxicam in plasma. The important pharmacokinetic parameters were caculated by DAS 2.0 software. The pharmacokinetics of meloxicam based on identification of genotypes (CYP2C9 * 3 wild-type and mutation) was compared. Results Two kinds of CYP2C9 * 3 phenotype existed in the subjects . CYP2C9 * 3 (A/A) was found in twenty-two subjects while CYP2C9 *3(A/C) in two subjects. For meloxicam,the A/A of CYP2C9 * 3 alleles was more active than the A/C. Conclusion CYP2C9 genetic polymorphism has significant influence on the pharmacokinetics of meloxicam. A/A is more active than A/C. Pharma-cogenomic studies will help rational and individualized medication.

  4. CYP2C9 genotype does not affect risk of tobacco-related cancer in the general population

    Kaur-Knudsen, Diljit; Nordestgaard, B.G.; Bojesen, S.E.


    tolbutamide and warfarin, while this has not been investigated for PAHs. We hypothesised that these two variants in the CYP2C9 gene influence risk of tobacco-related cancer. Methods: In a prospective study of the general population (n = 10 392) with 60 years of follow-up, the Copenhagen City Heart Study, we...... associated two variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) with risk of tobacco-related cancer and all cancer. All results were re-tested in a cross-sectional study of the general population (n = 36 856), the Copenhagen General Population Study. Results: We found no association between any of the CYP2C9...... genotypes and risk of tobacco-related cancer, individual tobacco-related cancers, or all cancer. For the combined carriers (any CYP2C9*2 or CYP2C9*3 heterozygotes or homozygotes) vs. non-carriers we had 90% statistical power to exclude measures of relative risks below/above 0.8/1.2 and 0...

  5. UBE2C is overexpressed in ESCC tissues and its abrogation attenuates the malignant phenotype of ESCC cell lines

    Palumbo, Antonio; Costa, Nathalia Meireles Da; De Martino, Marco; Sepe, Romina; Pellecchia, Simona; Leite de Sousa, Vanessa Paiva; Neto, Pedro Nicolau; Kruel, Cleber Dario; Bergman, Anke; Nasciutti, Luiz Eurico; Fusco, Alfredo; Pinto, Luis Felipe Ribeiro


    The esophageal squamous cell carcinoma (ESCC) is widely known as a highly lethal and poor understood cancer, then requiring the search for novel molecular markers to improve its management and patients survival. Recently, ubiquitin-conjugating enzyme E2C (UBE2C) has been figuring as a prominent tumor biomarker candidate, once it has been recognized as a key player in cell cycle progression. In this way, the aim of this study was to evaluate the expression profile of UBE2C gene and protein in ESCC samples, as well as its diagnostic and prognostic marker potential, and its contribution to ESSC genesis and/or progression by performing in vitro functional assays. The analysis of UBE2C gene expression in 52 paired ESCC samples (tumor and respective histologically normal surrounding tissue), by qRT-PCR, revealed that this gene is overexpressed in 73% of ESCC samples. Subsequently, immunohistochemical analysis confirmed that UBE2C protein expression was upregulated in all ESCC cases, but absent in the histologically normal tumor surrounding tissues. Moreover, we showed that UBE2C mRNA expression was able to accurately discriminate ESCC tissue from both healthy esophageal and histologically normal tumor surrounding tissues, pointing out its role as a diagnostic marker for this cancer. Finally, we report that UBE2C affects proliferation rates and cell cycle profile of ESCC cell lines, by directly interfering with cyclin B1 protein levels, suggesting its involvement in crucial steps of ESCC carcinogenesis. PMID:27588470

  6. Actin-associated protein palladin is required for migration behavior and differentiation potential of C2C12 myoblast cells

    Nguyen, Ngoc Uyen Nhi; Liang, Vincent Roderick; Wang, Hao-Ven, E-mail:


    Highlights: • Palladin is involved in myogenesis in vitro. • Palladin knockdown by siRNA increases myoblast proliferation, viability and differentiation. • Palladin knockdown decreases C2C12 myoblast migration ability. - Abstract: The actin-associated protein palladin has been shown to be involved in differentiation processes in non-muscle tissues. However, but its function in skeletal muscle has rarely been studied. Palladin plays important roles in the regulation of diverse actin-related signaling in a number of cell types. Since intact actin-cytoskeletal remodeling is necessary for myogenesis, in the present study, we pursue to investigate the role of actin-associated palladin in skeletal muscle differentiation. Palladin in C2C12 myoblasts is knocked-down using specific small interfering RNA (siRNA). The results show that down-regulation of palladin decreased migratory activity of mouse skeletal muscle C2C12 myoblasts. Furthermore, the depletion of palladin enhances C2C12 vitality and proliferation. Of note, the loss of palladin promotes C2C12 to express the myosin heavy chain, suggesting that palladin has a role in the modulation of C2C12 differentiation. It is thus proposed that palladin is required for normal C2C12 myogenesis in vitro.

  7. Cu-Mo2C/MCM-41: An Efficient Catalyst for the Selective Synthesis of Methanol from CO2

    Xiaoran Liu


    Full Text Available Supported molybdenum carbide (yMo2C/M41 and Cu-promoted molybdenum carbide, using a mechanical mixing and co-impregnation method (xCuyMo2C/M41-M and xCuyMo2C/M41-I on a mesoporous molecular sieve MCM-41, were prepared by temperature-programmed carburization method in a CO/H2 atmosphere at 1073 K, and their catalytic performances were tested for CO2 hydrogenation to form methanol. Both catalysts, which were promoted by Cu, exhibited higher catalytic activity. In comparison to 20Cu20Mo2C/M41-M, the 20Cu20Mo2C/M41-I catalyst exhibited a stronger synergistic effect between Cu and Mo2C on the catalyst surface, which resulted in a higher selectivity for methanol in the CO2 hydrogenation reaction. Under the optimal reaction conditions, the highest selectivity (63% for methanol was obtained at a CO2 conversion of 8.8% over the 20Cu20Mo2C/M41-I catalyst.

  8. Deletion of the α2A/α2C-adrenoceptors accelerates cutaneous wound healing in mice.

    Romana-Souza, Bruna; Nascimento, Adriana P; Brum, Patricia C; Monte-Alto-Costa, Andréa


    The α2-adrenoceptors regulate the sympathetic nervous system, controlling presynaptic catecholamine release. However, the role of the α2-adrenoceptors in cutaneous wound healing is poorly understood. Mice lacking both the α2A/α2C-adrenoceptors were used to evaluate the participation of the α2-adrenoceptor during cutaneous wound healing. A full-thickness excisional lesion was performed on the dorsal skin of the α2A/α2C-adrenoceptor knockout and wild-type mice. Seven or fourteen days later, the animals were euthanized and the lesions were formalin-fixed and paraffin-embedded or frozen. Murine skin fibroblasts were also isolated from α2A/α2C-adrenoceptor knockout and wild-type mice, and fibroblast activity was evaluated. The in vivo study demonstrated that α2A/α2C-adrenoceptor depletion accelerated wound contraction and re-epithelialization. A reduction in the number of neutrophils and macrophages was observed in the α2A/α2C-adrenoceptor knockout mice compared with wild-type mice. In addition, α2A/α2C-adrenoceptor depletion enhanced the levels of nitrite and hydroxyproline, and the protein expression of transforming growth factor-β and vascular endothelial growth factor. Furthermore, α2A/α2C-adrenoceptor depletion accelerated blood vessel formation and myofibroblast differentiation. The in vitro study demonstrated that skin fibroblasts isolated from α2A/α2C-adrenoceptor knockout mice exhibited enhanced cell migration, α-smooth muscle actin _protein expression and collagen deposition compared with wild-type skin fibroblasts. In conclusion, α2A/α2C-adrenoceptor deletion accelerates cutaneous wound healing in mice.

  9. Electronic spectrum and photodissociation chemistry of the linear methyl propargyl cation H2C4H3+

    Catani, Katherine J.; Muller, Giel; da Silva, Gabriel; Bieske, Evan J.


    The electronic spectrum of the methyl propargyl cation (2-butyn-1-yl cation, H2C4H3+) is measured over the 230-270 nm range by photodissociating the bare cation and its Ar and N2 tagged complexes in a tandem mass spectrometer. The observed '1A←'1A band system has an origin at 37 753 cm-1 for H2C4H3+ , 37738 cm-1 for H2C4H3+ - Ar, and 37 658 cm-1 for H2C4H3+ - N2. The methyl propargyl cation photodissociates to produce either C2H3++C2H2 (protonated acetylene + acetylene) or H2C4H+ +H2 (protonated diacetylene + dihydrogen). Photodissociation spectra of H2C4H3+ , H2C4H3+ - Ar, and H2C4H3+ - N2 exhibit similar vibronic structure, with a strong progression of spacing 630 cm-1 corresponding to excitation of the C—C stretch mode. Interpretation of the spectra is aided by ground and excited state calculations using time dependent density functional theory at the ωB97X-D/aug-cc-pVDZ level of theory. Ab initio calculations and master equation simulations were used to interpret the dissociation of H2C4H3+ on the ground state manifold. These calculations support the experimentally observed product branching ratios in which acetylene elimination dominates and also suggests that channel switching occurs at higher energies to favor H2 elimination.

  10. LAMP-2C Inhibits MHC Class II Presentation of Cytoplasmic Antigens by Disrupting Chaperone-Mediated Autophagy.

    Pérez, Liliana; McLetchie, Shawna; Gardiner, Gail J; Deffit, Sarah N; Zhou, Delu; Blum, Janice S


    Cells use multiple autophagy pathways to sequester macromolecules, senescent organelles, and pathogens. Several conserved isoforms of the lysosome-associated membrane protein-2 (LAMP-2) regulate these pathways influencing immune recognition and responses. LAMP-2A is required for chaperone-mediated autophagy (CMA), which promotes Ag capture and MHC class II (MHCII) presentation in B cells and signaling in T cells. LAMP-2B regulates lysosome maturation to impact macroautophagy and phagocytosis. Yet, far less is known about LAMP-2C function. Whereas LAMP2A and LAMP2B mRNA were broadly detected in human tissues, LAMP2C expression was more limited. Transcripts for the three LAMP2 isoforms increased with B cell activation, although specific gene induction varied depending on TLR versus BCR engagement. To examine LAMP-2C function in human B cells and specifically its role in Ag presentation, we used ectopic gene expression. Increased LAMP-2C expression in B cells did not alter MHCII expression or invariant chain processing, but did perturb cytoplasmic Ag presentation via CMA. MHCII presentation of epitopes from exogenous and membrane Ags was not affected by LAMP-2C expression in B cells. Similarly, changes in B cell LAMP-2C expression did not impact macroautophagy. The gene expression of other LAMP2 isoforms and proteasome and lysosomal proteases activities were unperturbed by LAMP-2C ectopic expression. LAMP-2C levels modulated the steady-state expression of several cytoplasmic proteins that are targeted for degradation by CMA and diminished peptide translocation via this pathway. Thus, LAMP-2C serves as a natural inhibitor of CMA that can selectively skew MHCII presentation of cytoplasmic Ags.

  11. 加味逍遥丸对CYP2C19酶活性的影响%Effect of Modified Xiaoyao pill on the activity of CYP2C19

    赵钢涛; 杨凡; 许茜; 丁媛媛; 郑绯; 许景峰


    AIM: To investigate the effect of Modified Xiaoyao pill on CYP2C19, and provide foundation for clinical drug using. METHODS: Twenty volunteers were divided into two groups according to CYP2C19* 2 gene type, ten for WW gene type and ten for MM gene type. Omeprazole used as probe drug of CYP2C19, the effect of Modified Xiaoyao pill on the activity of CYP2C19 were investigated. Genetic classification was fulfilled by pyrosequencing method, and the blood concentration of probe drug and its metabolic product were determined by HPLCMS/MS. RESULTS: The volunteers took Modified Xiaoyao pill for two weeks, AUC0-12 was used as the standard of the activity of CYP2C19. The activity value was 5.7±1.6 before drug and 6.0±1.7 after drug using. So the activity of CYP2C19 was increased after drug using, t-test was used for comparison, there was no remarkable difference between the data. CONCLUSION: Modified Xiaoyao pill has no obvious affection on the activity of CYP2C19.%目的:探讨加味逍遥丸对CYP2C19活性的影响,为临床指导联合用药提供依据.方法:将20名受试者按照CYP2C19 2基因型进行分类,野生型纯合子(WW)及突变型纯合子(MM)各10名.以奥美拉唑作为CYP2C19的探针药,研究服用加味道遥丸对人体内代谢酶CYP2C19活性的影响.采用pyrosequencing测序法对CYP2C19进行基因分型,采用HPLC-MS/MS法测定探针药及其代谢产物的血药浓度.结果:连续服用14 d加味逍遥丸.以AUCo-12为指标,评价CYP2C19代谢酶的活性.受试者用药前CYP2C19代谢酶活性为5.7±1.6,服用加味逍遥丸后CYP2C19代谢酶活性为6.0±1.7.用药后代谢酶的活性升高,用药前后比较采用配对t检验,差异没有统计学意义.结论:服用加味逍遥丸对CYP2C19代谢酶活性没有明显影响.

  12. Synthesis and Photooxygenation of Furo[3,2-c]coumarin Derivatives as Antibacterial and DNA Intercalating Agent

    Al-Sehemi, Abdullah G.; EI-Gogary, Sameh R.


    Syntheses of 2,3-dimethyl-4H-furo[3,2-c]coumarin and 3-phenyl-4H-furo[3,2-c]coumarin as angular furocou- marins were carried out through Williamson reaction of 4-hydroxycoumarin with a-haloketones followed by cycli- zation. Photooxygenation of the synthesized furocoumarin derivatives was performed and the photoproducts were isolated and characterized. The affinity of 2,3-dimethyl-4H-furo[3,2-c]coumarin towards DNA and the antibacterial activity were evaluated and compared with 8-methoxypsoralen (8-MOP).

  13. A pharmacological analysis of serotonergic receptors: effects of their activation of blockade in learning.

    Meneses, A; Hong, E


    1. The authors have tested several 5-HT selective agonists and antagonists (5-HT1A/1B, 5-HT2A/2B/2C, 5-HT3 or 5-HT4), an uptake inhibitor and 5-HT depletors in the autoshaping learning task. 2. The present work deals with the receptors whose stimulation increases or decreases learning. 3. Impaired consolidation of learning was observed after the presynaptic activation of 5-HT1B, 5-HT3 or 5-HT4 or the blockade of postsynaptic 5-HT2C/2B receptors. 4. In contrast, an improvement occurred after the presynaptic activation of 5-HT1A, 5-HT2C, and the blockade of presynaptic 5-HT2A, 5-HT2C and 5-HT3 receptors. 5. The blockade of postsynaptic 5-HT1A, 5-HT1B, 5-HT3 or 5-HT4 receptors and 5-HT inhibition of synthesis and its depletion did no alter learning by themselves. 6. The present data suggest that multiple pre- and postsynaptic serotonergic receptors are involved in the consolidation of learning. 7. Stimulation of most 5-HT receptors increases learning, however, some of 5-HT subtypes seem to limit the data storage. 8. Furthermore, the role of 5-HT receptors in learning seem to require an interaction with glutamatergic, GABAergic and cholinergic neurotransmission systems.

  14. Effects of green tea catechins on cytochrome P450 2B6, 2C8, 2C19, 2D6 and 3A activities in human liver and intestinal microsomes.

    Misaka, Shingen; Kawabe, Keisuke; Onoue, Satomi; Werba, José Pablo; Giroli, Monica; Tamaki, Sekihiro; Kan, Toshiyuki; Kimura, Junko; Watanabe, Hiroshi; Yamada, Shizuo


    The effects of green tea catechins on the main drug-metabolizing enzymatic system, cytochrome P450 (CYP), have not been fully elucidated. The objective of the present study was to evaluate the effects of green tea extract (GTE, total catechins 86.5%, w/w) and (-)-epigallocatechin-3-gallate (EGCG) on the activities of CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A in vitro, using pooled human liver and intestinal microsomes. Bupropion hydroxylation, amodiaquine N-deethylation, (S)-mephenytoin 4'-hydroxylation, dextromethorphan O-demethylation and midazolam 1'-hydroxylation were assessed in the presence or absence of various concentrations of GTE and EGCG to test their effects on CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A activities, respectively. Each metabolite was quantified using UPLC/ESI-MS, and the inhibition kinetics of GTE and EGCG on CYP enzymes was analyzed. In human liver microsomes, IC50 values of GTE were 5.9, 4.5, 48.7, 25.1 and 13.8 µg/mL, for CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A, respectively. ECGC also inhibited these CYP isoforms with properties similar to those of GTE, and produced competitive inhibitions against CYP2B6 and CYP2C8, and noncompetitive inhibition against CYP3A. In human intestinal microsomes, IC50 values of GTE and EGCG for CYP3A were 18.4 µg/mL and 31.1 µM, respectively. EGCG moderately inhibited CYP3A activity in a noncompetitive manner. These results suggest that green tea catechins cause clinically relevant interactions with substrates for CYP2B6 and CYP2C8 in addition to CYP3A.

  15. Mo2 C as Non-Noble Metal Co-Catalyst in Mo2 C/CdS Composite for Enhanced Photocatalytic H2 Evolution under Visible Light Irradiation.

    Ma, Baojun; Xu, Haojie; Lin, Keying; Li, Jie; Zhan, Haijuan; Liu, Wanyi; Li, Can


    Co-catalysts are a major factor to enhance photocatalytic H2 activity; they are mainly composed of expensive noble metals. Here, we reported a new non-noble-metal co-catalyst Mo2 C that efficiently improves the photocatalytic H2 evolution of CdS under visible light irradiation. Mo2 C is prepared by temperature-programmed reaction with molybdenum oxide as precursor, and the Mo2 C/CdS composite is prepared by deposition of CdS on Mo2 C. The optimum composite 2.0 % Mo2 C/CdS shows a high H2 evolution rate of 161 μmol h(-1) , which is ten times higher than that of CdS alone and 2.3 times higher than the optimum for 1.0 % Pt/CdS. Moreover, the Mo2 C/CdS is stable for 50 h. This study presents a new low-cost non-noble-metal co-catalyst as a photocatalyst to achieve highly efficient H2 evolution.

  16. A mouse model for Betacoronavirus subgroup 2c using a bat coronavirus strain HKU5 variant.

    Agnihothram, Sudhakar; Yount, Boyd L; Donaldson, Eric F; Huynh, Jeremy; Menachery, Vineet D; Gralinski, Lisa E; Graham, Rachel L; Becker, Michelle M; Tomar, Sakshi; Scobey, Trevor D; Osswald, Heather L; Whitmore, Alan; Gopal, Robin; Ghosh, Arun K; Mesecar, Andrew; Zambon, Maria; Heise, Mark; Denison, Mark R; Baric, Ralph S


    Cross-species transmission of zoonotic coronaviruses (CoVs) can result in pandemic disease outbreaks. Middle East respiratory syndrome CoV (MERS-CoV), identified in 2012, has caused 182 cases to date, with ~43% mortality, and no small animal model has been reported. MERS-CoV and Pipistrellus bat coronavirus (BtCoV) strain HKU5 of Betacoronavirus (β-CoV) subgroup 2c share >65% identity at the amino acid level in several regions, including nonstructural protein 5 (nsp5) and the nucleocapsid (N) protein, which are significant drug and vaccine targets. BtCoV HKU5 has been described in silico but has not been shown to replicate in culture, thus hampering drug and vaccine studies against subgroup 2c β-CoVs. We report the synthetic reconstruction and testing of BtCoV HKU5 containing the severe acute respiratory syndrome (SARS)-CoV spike (S) glycoprotein ectodomain (BtCoV HKU5-SE). This virus replicates efficiently in cell culture and in young and aged mice, where the virus targets airway and alveolar epithelial cells. Unlike some subgroup 2b SARS-CoV vaccines that elicit a strong eosinophilia following challenge, we demonstrate that BtCoV HKU5 and MERS-CoV N-expressing Venezuelan equine encephalitis virus replicon particle (VRP) vaccines do not cause extensive eosinophilia following BtCoV HKU5-SE challenge. Passage of BtCoV HKU5-SE in young mice resulted in enhanced virulence, causing 20% weight loss, diffuse alveolar damage, and hyaline membrane formation in aged mice. Passaged virus was characterized by mutations in the nsp13, nsp14, open reading frame 5 (ORF5) and M genes. Finally, we identified an inhibitor active against the nsp5 proteases of subgroup 2c β-CoVs. Synthetic-genome platforms capable of reconstituting emerging zoonotic viral pathogens or their phylogenetic relatives provide new strategies for identifying broad-based therapeutics, evaluating vaccine outcomes, and studying viral pathogenesis. IMPORTANCE The 2012 outbreak of MERS-CoV raises the specter

  17. Effects of New Fossil Fuel Developments on the Possibilities of Meeting 2C Scenarios

    Meindertsma, W.; Blok, K.


    Recent years have seen an increasing activity in developing new fossil fuel production capacity. This includes unconventional fossil fuels, such as tar sands and shale gas, fossil fuels from remote locations, and fossil fuels with a very large increase in production in the near future. In this report, the impact of such developments on our ability to mitigate climate change is investigated. Our inventory shows that the new fossil fuel developments currently underway consist of 29,400 billion cubic meters of natural gas, 260,000 million barrels of oil and 49,600 million tonnes of coal. The development of these new fossil fuels would result in emissions of 300 billion tonnes of CO2 -equivalent (CO2e) from 2012 until 2050. Until 2050, a 'carbon budget' of 1550 billion tonnes CO2e is still available if we want to of keep global warming below 2C with a 50% probability. For a 75% probability to stay below 2C this budget is only 1050 billion tonnes CO2e. So, the new fossil fuel developments identified in this report consume 20-33% of the remaining carbon budget until 2050. In a scenario where the new fossil fuels are developed, we need to embark on a rapid emission reductions pathway at the latest in 2019 in order to meet the 50% probability carbon budget. Avoiding the development of new fossil fuels will give us until 2025 to start further rapid emission reductions. These calculations are based on the assumption that the maximum emission reduction rate is 4% per year and that the maximum change in emission trend is 0.5 percentage point per year. The starting year for rapid emission reductions depends on the choice of these parameters. A sensitivity analysis shows that, in all cases, refraining from new fossil fuel development allows for a delay of 5 to 8 years before we should embark on a rapid emission reduction pathway. The high investments required for developing new fossil fuels lead to a lock in effect; once developed, these fossil fuels need to be

  18. Surface Turbulent Fluxes, 1x1 deg Monthly Grid, Set1 and Interpolated Data 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...

  19. Pseudosubluxación C2-C3: un hallazgo radiológico frecuente en la infancia

    Pellicer García, V.; Baeza Oliete, J.; Miranda, L.; Bas Hermida, T.; Bas Hermida, P.


    Objetivo: Mostrar un hallazgo radiológico fisiológico de la columna cervical infantil que tiende a ser malinterpretado como patológico: la pseudosubluxación C2-C3. Se presenta un caso de una niña de 14 meses de edad remitida a nuestro centro bajo sospecha de subluxación C2-C3. Se aporta una metodología para el diagnóstico diferencial entre pseudosubluxación C2-C3 y subluxación C2-C3 verdadera. Una anamnesis detallada así como una exploración clínica y radiográfica minuciosas, perm...

  20. Identification of cytochrome P450 2D6 and 2C9 substrates and inhibitors by QSAR analysis

    Jónsdóttir, Svava Ósk; Ringsted, Tine; Nikolov, Nikolai G.;


    these compounds. A large fraction of these chemicals were found to be CYP active, and thus potentially capable of affecting human physiology. 20% of the compounds within applicability domain of the models were predicted to be CYP2C9 substrates, and 17% to be inhibitors. The corresponding numbers for CYP2D6 were 9...... of specific CYP activity. An overrepresentation was seen for poly-aromatic hydrocarbons (group of procarcinogens) among CYP2C9 active and mutagenic compounds compared to CYP2C9 inactive and mutagenic compounds. The mutagenicity was predicted with a QSAR model based on Ames in vitro test data.......% and 21%. Where the majority of CYP2C9 active compounds were predicted to be both a substrate and an inhibitor at the same time, the CYP2D6 active compounds were primarily predicted to be only inhibitors. It was demonstrated that the models could identify compound classes with a high occurrence...

  1. Electronic structure and electrical transport characteristics of C60, 2C60 and 4C60 fullerene molecules

    SHEN Haijun; MU Xiancai


    The extended Hückel method and the Green's function method were used to calculate the electronic struc-ture and electrical transport of Au electrode-C60,2C60 or 4C60 fullerene-Au electrode systems.Furthermore,their electronic structure and electrical transport characteristics were com-pared and analyzed.The results show that (I) owing to the contact with the Au electrodes,the C60,2C60 and 4C60 mole-cules change in their electronic structures ignificantly,and their energy gaps between LUMO and HOMO are narrow;(ii) the bonding between C60,2C60 or 4C60 fullerene and Au electrodes is partially covalent and partially electrovalent;and (iii) the conductance of the three fullerenes conforms to the order of C60>2C60>4C60.

  2. Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker

    Noehr-Jensen, L; Zwisler, S; Larsen, F


    PURPOSE: To investigate the impact of cytochrome P450 2C19 (CYP2C19) phenotypes on escitalopram metabolism and to evaluate pupillometry as a serotonergic biomarker. METHODS: This was a double-blind, crossover design study with single and multiple doses of 10 mg escitalopram and placebo in panels...... of CYP2C19 extensive (EM) and poor metabolisers (PM). Pupillometry was measured by a NeurOptics Pupillometer-PLR. RESULTS: Five PM and eight EM completed the study. The CYP2C19 phenotype significantly affected the metabolism of escitalopram. The area under the time-plasma concentration curve (AUC(0......-24)) was 1.8-fold higher in PM than in EM after both single and multiple doses. Escitalopram treatment did not affect the maximum pupil size, but it did statistically significantly decrease the relative amplitude of the pupil light reflex compared to the placebo; this effect was equal in both phenotype...

  3. Cloning of cytochrome P-450 2C9 cDNA from human liver and its expression in CHL cells

    Ge-Jian Zhu; Ying-Nian Yu; Xin Li; Yu-Li Qian


    AIM: Using bacterial, yeast, or mammalian cell expressing a human drug metabolism enzyme would seem good way to study drug metabolism-related problems. Human cytochrome P-450 2C9 ( CYP2 C9) is a polymorphic enzyme responsible for the metabolism of a large number of clinically important drugs. It ranks among the most important drug metabolizing enzymes in humans. In order to provide a sufficient amount of the enzyme for drug metabolic research, the CYP2 C9 eDNA was cloned and expressed stably in CHL cellsMETHODS: After extraction of total RNA from human livertissue, the human CYP2C9 eDNA was amplified withreverse transcription-polymerase chain reaction (RT-PCR),and cloned into cloning vector pGEM-T. The cDNA fragmentwas identified by DNA sequencing and subcloned into amammalian expression vector pREP9. A transgenic cell linewas established by transfecting the recombinant vector ofpREP9-CYP2C9 into CHL cells. The enzyme activity ofCYP2C9 catalyzing oxidation of tolbutamide to hydroxytolbutamide in S9 fraction of the cell was determined by highperformance liquid chromatography(HPLC).RESULTS: The amino acid sequence predicted from theeDNA segment was identical to that of CYP2 C9 * 1, the wildtype CYP2 C9. However, there were two base differences, i.e. 21T > C, 1146C > T, but the encoding amino acidsequence was the same, L7, P382. The S9 fraction of theestablished cell line metabolizes tolbutamide to hydroxytolbutamide; tolbutamide hydroxylass activity was found to be0.465 ± 0.109 μmol@ min-1 . g1 S9 protein or 8.62 ± 2.02 mol@ min 1 ~mol-1 CYP, but was undetectable in parental CHL cell.CONCLUSION: The cDNA of human CYP2C9 was successfullycloned and a cell line of CHL- CYP2C9, efficiently expressingthe protein of CYP2C9, was established.

  4. Determination of the inhibitory potential of 6 fluoroquinolones on CYPIA2 and CYP2C9 in human liver microsomes

    Li ZHANG; Min-ji WEI; Cai-yun ZHAO; Hui-min QI


    Aim: To determine the inhibitory potential of 2 new fluoroquinolones, caderofloxacin and antofloxacin, together with 4 marketed fluoroquinolones, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin, on the activity of cytochrome P450 isoforms 1A2 (CYP1A2) and 2C9 (CYP2C9). Methods: Probe substrates, phenacetin (CYP1A2), and tolbutamide (CYP2C9) were incubated with human liver microsomes and the metabolites were analyzed by liquid chromatography/mass spectrometry using electrospray ionization in positive or negative mode. Glipizide was used as the internal standard in both modes. The inhibitory potential of fluoroquinolones on CYP1A2 and CYP2C9 was investigated. Results: The IC50 values (μmol/L) determined with the cocktail were in agreement with individual probe substrates (α-naphthoflavone: 0.27 vs 0.26; sulfaphenazole: 0.49 vs 0.37). Ciprofloxacin showed weak inhibition on both the activity of CYPIA2 (IC50 135 μmol/L) and CYP2C9 (IC50 180 μmol/L), whereas levofloxacin inhibited only CYP2C9 (IC50 210 μmol/L). Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin showed little or no inhibition on the activity of CYPIA2 or CYP2C9 when tested at comparable concentrations (0-200 mg/L). Conclusion: Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin are negligible inhibitors to CYP1A2 and CYP2C9. The in vitro system can be used as a high-throughput model to screen similar compounds for the early identification of drug-drug interaction potential.

  5. Drug-drug Interaction between Losartan and Paclitaxel in Human Liver Microsomes with Different CYP2C8 Genotypes.

    Mukai, Yuji; Senda, Asuna; Toda, Takaki; Hayakawa, Toru; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo


    The cytochrome P450 (CYP) 2C8*3 allele is associated with reduced metabolic activity of paclitaxel. This study was aimed to investigate the inhibitory effect of losartan on paclitaxel metabolism in human liver microsomes (HLMs) and to determine the impact of the CYP2C8*3 polymorphism. HLMs that contained the CYP2C8*1 homozygote (HL60) or CYP2C8*3 heterozygote (HL54) genotype were used for the inhibition study. Losartan, at a concentration of 50 μmol/L, significantly inhibited paclitaxel metabolism by 29% and 57% in the HL60 (p losartan and the CYP3A4-selective inhibitors, erythromycin and ketoconazole, caused a greater inhibition of the paclitaxel metabolism than quercetin, a CYP2C8-selective inhibitor. This demonstrated that the paclitaxel metabolism was mainly catalysed by CYP3A4 in HL60. There were no significant differences found for the inhibitory effects caused by the four inhibitors of the paclitaxel metabolism in HL54, indicating that both CYP2C8 and CYP3A4 play important roles in paclitaxel metabolism in HL54. These findings suggest that 50 μmol/L of losartan inhibits both CYP2C8 and CYP3A4 in HLMs. In summary, losartan inhibited paclitaxel metabolism, with concentrations over 50 μmol/L in HLMs. The CYP2C8*3 allele carriers are likely susceptible to the interactions of losartan and CYP3A4 inhibitors to paclitaxel metabolism.

  6. Effect of Cytochrome P450 2C19 681G>A Polymorphism on Premature Coronary Heart Disease

    Zhong-hai Chi


    Full Text Available Objective: The aim of our study was to evaluate the association between cytochrome P450 2C19 (CYP2C19 681G>A polymorphisms and the age of development of coronary heart disease. Additionally, the study might find some biological indicators at the gene level that could help to predict and evaluate the risk of coronary heart disease in time. Methods: This study included 352 individuals with coronary heart disease. Polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP was used to identify CYP2C19 681G>A. The objects were divided into wild type (GG or homozygous CYP2C19*1 wild-type and mutant type (GA/AA or the mutant CYP2C19*2 allele on the basis of genotype. The association between CYP2C19 gene polymorphism and the age of onset of coronary heart disease was assessed by multivariate linear regression analysis. Results: There was a significant association in the age of onset between the two groups (t=3.398, P=0.001, which was 58.51+12.72 years in the wild type and 53.95+11.63 years in the mutant group. The frequency of CYP2C19 681A (CYP2C19*2 allele was 3.32, 0.268, 0.227 in different age groups, which was significantly different (χ2=10.745, P=0.005 in different groups, as well as in the genotype. The result, assessed by multiple linear regression, showed that genotype, smoking, obesity, and hyperlipidemia affect the age of onset of coronary heart disease (β was -0.167, 0.156, 0.155, and 0.112, PA gene polymorphism may be one of the risk factors in susceptibility to early onset of coronary heart disease, but not an independent factor because other factors may play a synergistic role.

  7. Canine parvovirus types 2c and 2b circulating in North American dogs in 2006 and 2007.

    Kapil, Sanjay; Cooper, Emily; Lamm, Cathy; Murray, Brandy; Rezabek, Grant; Johnston, Larry; Campbell, Gregory; Johnson, Bill


    Parvovirus is the most common viral cause of diarrhea in young puppies. Based on the analysis of a partial VP2 sequence of 54 samples, canine parvovirus type 2c (CPV-2c) (n = 26), CPV-2b (n = 25), and CPV-2 (n = 3) were detected in the United States. The American CPV-2b isolates have unique codons (494 and 572) in VP2.

  8. Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation.

    Hosoi, Yoshio; Uno, Yasuhiro; Murayama, Norie; Fujino, Hideki; Shukuya, Mitsunori; Iwasaki, Kazuhide; Shimizu, Makiko; Utoh, Masahiro; Yamazaki, Hiroshi


    Cynomolgus monkeys are widely used as primate models in preclinical studies. However, some differences are occasionally seen between monkeys and humans in the activities of cytochrome P450 enzymes. R- and S-warfarin are model substrates for stereoselective oxidation in humans. In this current research, the activities of monkey liver microsomes and 14 recombinantly expressed monkey cytochrome P450 enzymes were analyzed with respect to R- and S-warfarin 6- and 7-hydroxylation. Monkey liver microsomes efficiently mediated both R- and S-warfarin 7-hydroxylation, in contrast to human liver microsomes, which preferentially catalyzed S-warfarin 7-hydroxylation. R-Warfarin 7-hydroxylation activities in monkey liver microsomes were not inhibited by α-naphthoflavone or ketoconazole, and were roughly correlated with P450 2C19 levels and flurbiprofen 4-hydroxylation activities in microsomes from 20 monkey livers. In contrast, S-warfarin 7-hydroxylation activities were not correlated with the four marker drug oxidation activities used. Among the 14 recombinantly expressed monkey P450 enzymes tested, P450 2C19 had the highest activities for R- and S-warfarin 7-hydroxylations. Monkey P450 3A4 and 3A5 slowly mediated R- and S-warfarin 6-hydroxylations. Kinetic analysis revealed that monkey P450 2C19 had high V(max) and low K(m) values for R-warfarin 7-hydroxylation, comparable to those for monkey liver microsomes. Monkey P450 2C19 also mediated S-warfarin 7-hydroxylation with V(max) and V(max)/K(m) values comparable to those for recombinant human P450 2C9. R-warfarin could dock favorably into monkey P450 2C19 modeled. These results collectively suggest high activities for monkey liver P450 2C19 toward R- and S-warfarin 6- and 7-hydroxylation in contrast to the saturation kinetics of human P450 2C9-mediated S-warfarin 7-hydroxylation.

  9. Převodník mezi sběrnicemi I2C a RS232

    Bednařík, Martin


    Cílem tohoto projektu je obeznámit se s funkcí sběrnice I2C a mikrokontroléry AVR a s principem propojení mikrokontroléru s ostatními obvody pomocí této sběrnice. Dále navrhnout takové zařízení, které bude schopno zprostředkovat komunikaci mezi osobním počítačem a ovládanými obvody. Součástí projektu je tvorba potřebného programového vybavení pro mikrokontrolér a návrh vlastního komunikačního protokolu. Dalším cílem projektu je získat přehled o použitích technologiích, možnostech jejich využi...

  10. The Third Party Logistics Partner Selection of B2C E-Commerce Enterprise

    Xu Wei


    Full Text Available In recent years, with the rapid development of Internet, e-commerce enterprises in China is at an alarming rate of sustainable development, the B2C e-commerce in the online shopping market accounted for a large proportion, with the rapid change of the market and customer needs to establish a flexible distribution service is one of the many e-commerce companies need to solve. Using self logistics capital occupancy bigger; the logistics alliance, with the risk of internal information disclosure; and on the third party logistics, not only capital and manpower can be effectively used, helps enterprises to strengthen the core business. Therefore, it is very important to choose the appropriate third party logistics providers to reduce operating costs and improve the market influence. This paper analyses the existing problems in the third party logistics, the establishment of a more complete index system, according to the actual situation of the suppliers, using the improved AHP method and the entropy coefficient method to get the comprehensive weight, finally get the approximation method to meet the business requirements of the logistics service providers use the ideal, for commercial enterprises to third party logistics service provider selection and puts forward some available models.