Sample records for receptor gamma system

  1. Increase in neutrophil Fc gamma receptor I expression following interferon gamma treatment in rheumatoid arthritis.

    PubMed Central

    Goulding, N J; Knight, S M; Godolphin, J L; Guyre, P M

    1992-01-01

    The therapeutic potential of interferon gamma (IFN gamma) in a number of disease states is still being explored, but progress is hampered by the lack of a suitable measure of in vivo biological activity. To assess the in vivo biological effects of recombinant human IFN gamma (rhIFN gamma), 14 patients were studied in a randomised, prospective, double blind, placebo controlled trial of this cytokine for the treatment of rheumatoid arthritis. The levels of Fc gamma receptors on peripheral blood neutrophils were measured at baseline and after 21 days of once daily, subcutaneous injections of rhIFN gamma or placebo. An induction of neutrophil Fc gamma receptor type I (Fc gamma RI) was seen in the group of patients receiving recombinant human rhIFN gamma but not in those receiving placebo. No change in the expression of Fc gamma RII or Fc gamma RIII was detected. The amount of induction of Fc gamma RI detected on the neutrophils of patients receiving rhIFN gamma did not correlate with clinical measures of response at either 21 days or at the end of the study (24 weeks). No significant clinical responses were observed in the rhIFN gamma group at these times. These data confirm that the reported in vitro effect of IFN gamma on human neutrophil Fc receptor expression can be reproduced in vivo. PMID:1534001

  2. Increase in neutrophil Fc gamma receptor I expression following interferon gamma treatment in rheumatoid arthritis.

    PubMed

    Goulding, N J; Knight, S M; Godolphin, J L; Guyre, P M

    1992-04-01

    The therapeutic potential of interferon gamma (IFN gamma) in a number of disease states is still being explored, but progress is hampered by the lack of a suitable measure of in vivo biological activity. To assess the in vivo biological effects of recombinant human IFN gamma (rhIFN gamma), 14 patients were studied in a randomised, prospective, double blind, placebo controlled trial of this cytokine for the treatment of rheumatoid arthritis. The levels of Fc gamma receptors on peripheral blood neutrophils were measured at baseline and after 21 days of once daily, subcutaneous injections of rhIFN gamma or placebo. An induction of neutrophil Fc gamma receptor type I (Fc gamma RI) was seen in the group of patients receiving recombinant human rhIFN gamma but not in those receiving placebo. No change in the expression of Fc gamma RII or Fc gamma RIII was detected. The amount of induction of Fc gamma RI detected on the neutrophils of patients receiving rhIFN gamma did not correlate with clinical measures of response at either 21 days or at the end of the study (24 weeks). No significant clinical responses were observed in the rhIFN gamma group at these times. These data confirm that the reported in vitro effect of IFN gamma on human neutrophil Fc receptor expression can be reproduced in vivo.

  3. Expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) in canine nasal carcinomas.

    PubMed

    Paciello, O; Borzacchiello, G; Varricchio, E; Papparella, S

    2007-10-01

    Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated transcriptional factor belonging to the steroid receptor superfamily. PPAR-gamma is expressed in multiple normal and neoplastic tissues, such as the breast, colon, lung, ovary and placenta. In addition to adipogenic and anti-inflammatory effects, PPAR-gamma activation has been shown to be anti-proliferative by its differentiation-promoting effect, suggesting that activation of PPAR-gamma may be useful in slowing or arresting the proliferation of de-differentiated tumour cells. In this study, we investigated the expression of PPAR-gamma in normal and neoplastic canine nasal epithelium. Twenty-five samples composed of five normal nasal epithelia and 20 canine nasal carcinomas, were immunohistochemically stained for PPAR-gamma. The specificity of the antibody was verified by Western Blot analysis. Confocal laser scanning microscopical investigation was also performed. In normal epithelium, the staining pattern was cytoplasmic and polarized at the cellular free edge. In carcinomas, the neoplastic cells showed mainly strong cytoplasmatic PPAR-gamma expression; moreover, perinuclear immunoreactivity was also detected and few neoplastic cells exhibited a nuclear positivity. Our results demonstrate different patterns of PPAR-gamma expression in normal canine nasal epithelium when compared with canine nasal carcinoma. The importance of this transcription factor in the pathophysiology of several different tumours has stimulated much research in this field and has opened new opportunities for the treatment of the tumours.

  4. Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lin, Shengchen; Han, Ying; Shi, Yuzhe

    2012-06-28

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR{gamma} agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR{gamma} target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR{gamma} ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination ofmore » RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR{gamma} ligands in the treatment of insulin resistance.« less

  5. The orphan nuclear receptor DAX-1 acts as a novel transcriptional corepressor of PPAR{gamma}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Gwang Sik; Lee, Gha Young; Nedumaran, Balachandar

    2008-05-30

    DAX-1 is an atypical nuclear receptor (NR) which functions primarily as a transcriptional corepressor of other NRs via heterodimerization. Peroxisome proliferator-activated receptor (PPAR) {gamma} is a ligand-dependent NR which performs a key function in adipogenesis. In this study, we evaluated a novel cross-talk mechanism between DAX-1 and PPAR{gamma}. Transient transfection assays demonstrated that DAX-1 inhibits the transactivity of PPAR{gamma} in a dose-dependent manner. DAX-1 directly competed with the PPAR{gamma} coactivator (PGC)-1{alpha} for binding to PPAR{gamma}. Endogenous levels of DAX-1 were significantly lower in differentiated 3T3-L1 adipocytes as compared to preadipocytes. Using a retroviral expression system, we demonstrated that DAX-1 overexpressionmore » downregulates the expression of PPAR{gamma} target genes, resulting in an attenuation of adipogenesis in 3T3-L1 cells. Our results suggest that DAX-1 acts as a corepressor of PPAR{gamma} and performs a potential function in the regulation of PPAR{gamma}-mediated cellular differentiation.« less

  6. Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    O'Sullivan, Saoirse E.; Tarling, Elizabeth J.; Bennett, Andrew J.

    Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251more » (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.« less

  7. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in hepatocellular carcinoma.

    PubMed

    Liu, Rui; Zhang, Haiyang; Zhang, Yan; Li, Shuang; Wang, Xinyi; Wang, Xia; Wang, Cheng; Liu, Bin; Zen, Ke; Zhang, Chen-Yu; Zhang, Chunni; Ba, Yi

    2017-04-01

    Peroxisome proliferator-activated receptor gamma coactivator-1 alpha plays a crucial role in regulating the biosynthesis of mitochondria, which is closely linked to the energy metabolism in various tumors. This study investigated the regulatory role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha in the pathogenesis of hepatocellular carcinoma. In this study, the changes of peroxisome proliferator-activated receptor gamma coactivator-1 alpha messenger RNA levels between normal human liver and hepatocellular carcinoma tissue were examined by quantitative reverse transcription polymerase chain reaction. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by RNA interference in the human liver cell line L02, while overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha complementary DNA in the human hepatocarcinoma cell line HepG2. Cellular morphological changes were observed via optical and electron microscopy. Cellular apoptosis was determined by Hoechst 33258 staining. In addition, the expression levels of 21,400 genes in tissues and cells were detected by microarray. It was shown that peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression was significantly downregulated in hepatocellular carcinoma compared with normal liver tissues. After knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression in L02 cells, cells reverted to immature and dedifferentiated morphology exhibiting cancerous tendency. Apoptosis occurred in the HepG2 cells after transfection by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha. Microarray analysis showed consistent results. The results suggest that peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor

  8. Characterization of cDNAs encoding the chick retinoic acid receptor gamma 2 and preferential distribution of retinoic acid receptor gamma transcripts during chick skin development.

    PubMed

    Michaille, J J; Blanchet, S; Kanzler, B; Garnier, J M; Dhouailly, D

    1994-12-01

    Retinoic acid receptors alpha, beta and gamma (RAR alpha, beta and gamma) are ligand-inductible transcriptional activators which belong to the steroid/thyroid hormone receptor superfamily. At least two major isoforms (1 and 2) of each RAR arise by differential use of two promoters and alternative splicing. In mouse, the three RAR genes are expressed in stage- and tissue-specific patterns during embryonic development. In order to understand the role of the different RARs in chick, RAR gamma 2 cDNAs were isolated from an 8.5-day (stage 35 of Hamburger and Hamilton) chick embryo skin library. The deduced chick RAR gamma 2 amino acid sequence displays uncommon features such as 21 specific amino acid replacements, 12 of them being clustered in the amino-terminal region (domains A2 and B), and a truncated acidic carboxy-terminal region (F domain). However, the pattern of RAR gamma expression in chick embryo resembles that reported in mouse, particularly in skin where RAR gamma expression occurs in both the dermal and epidermal layers at the beginning of feather formation, and is subsequently restricted to the differentiating epidermal cells. Northern blot analysis suggests that different RAR gamma isoforms could be successively required during chick development.

  9. Crosslinking of surface antibodies and Fc sub. gamma. receptors: Theory and application

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wofsy, C.; Goldstein, B.

    1991-03-15

    In an immune response, the crosslinking of surface immunoglobulin (sIg) on B cells by multiply-bound ligand activates a range of cell responses, culminating in the production of antibody-secreting cells. However, when the crosslinking agent is itself an antibody, B cell activation is inhibited. Solution antibody (IgG) can bind simultaneously to sIg and to another cell surface receptor, Fc{sub {gamma}}R, co-crosslinking' the distinct receptors. Experiments point to co-crosslinking as the inhibitory signal. It is not clear how co-crosslinking inhibits B cell stimulation. The authors construct and analyze a mathematical model aimed at clarifying the nature and mechanisms of action of themore » separate cell signals controlling B cell responses to antibodies. Basophils and mast cells respond to the crosslinking of cell surface antibody by releasing histamine. Like B cells, basophils also express FC{sub {gamma}}R. They use their model to analyze new data on the effect of antibody-induced co-crosslinking of the two types of receptor on this family of cells. Predictions of the model indicate that an observed difference between the response patterns induced by antibodies and by antibody fragments that cannot bind to FC{sub {gamma}}R can be explained if co-crosslinking is neither inhibitory nor stimulatory in this system.« less

  10. Identification and characterization of novel peroxisome proliferator-activated receptor-gamma (PPAR-gamma) transcriptional variants in pig and human.

    PubMed

    Omi, T; Brenig, B; Spilar Kramer, S; Iwamoto, S; Stranzinger, G; Neuenschwander, S

    2005-04-01

    The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the steroid/thyroid/retinoid receptor superfamily, and is primarily expressed in fat tissue. To date, two major PPAR-gamma isoforms have been identified in pig, PPAR-gamma1 and PPAR-gamma2. Porcine PPAR-gamma1a consists of two leader exons, designated A1 and A2, followed by six exons containing the open reading frame. Here, we report the isolation and characterization of three novel PPAR-gamma1 transcripts. PPAR-gamma1b is derived from exon A1, with exon A2 spliced out. PPAR-gamma1c and PPAR-gamma1d are derived from the new exon, A', containing exon A2 (gamma1c) or without exon A2 (gamma1d). Based on PCR analysis of PAC clones that included sequences from the 5'-untranslated region of the PPAR-gamma gene, the new A' exon is located between the known exons A1 and A2. We also isolated the human homologue to exon A', as well as the two new PPAR-gamma1c and -gamma1d splice variants, from human adipose tissue. Studies of the expression of porcine PPAR-gamma by real time reverse transcription-polymerase chain reaction analysis show that transcripts derived from exon A1 were not expressed at significantly different levels in visceral fat (lamina subserosa) or subcutaneous fat (back fat, inner and outer layer). In contrast, exon A'-derived transcripts were expressed at progressively higher levels in the inner and outer layers of subcutaneous fat than in visceral fat. The same expression pattern was also observed for PPAR-gamma2. We hypothesize that there are three promoters, which differentially regulate PPAR-gamma1 and PPAR-gamma2 gene expression, depending on the specific localization of the fat tissue.

  11. Acetylcholine modulates gamma frequency oscillations in the hippocampus by activation of muscarinic M1 receptors.

    PubMed

    Betterton, Ruth T; Broad, Lisa M; Tsaneva-Atanasova, Krasimira; Mellor, Jack R

    2017-06-01

    Modulation of gamma oscillations is important for the processing of information and the disruption of gamma oscillations is a prominent feature of schizophrenia and Alzheimer's disease. Gamma oscillations are generated by the interaction of excitatory and inhibitory neurons where their precise frequency and amplitude are controlled by the balance of excitation and inhibition. Acetylcholine enhances the intrinsic excitability of pyramidal neurons and suppresses both excitatory and inhibitory synaptic transmission, but the net modulatory effect on gamma oscillations is not known. Here, we find that the power, but not frequency, of optogenetically induced gamma oscillations in the CA3 region of mouse hippocampal slices is enhanced by low concentrations of the broad-spectrum cholinergic agonist carbachol but reduced at higher concentrations. This bidirectional modulation of gamma oscillations is replicated within a mathematical model by neuronal depolarisation, but not by reducing synaptic conductances, mimicking the effects of muscarinic M1 receptor activation. The predicted role for M1 receptors was supported experimentally; bidirectional modulation of gamma oscillations by acetylcholine was replicated by a selective M1 receptor agonist and prevented by genetic deletion of M1 receptors. These results reveal that acetylcholine release in CA3 of the hippocampus modulates gamma oscillation power but not frequency in a bidirectional and dose-dependent manner by acting primarily through muscarinic M1 receptors. © 2017 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  12. Phospholipase C-gamma 1 binding to intracellular receptors for activated protein kinase C.

    PubMed

    Disatnik, M H; Hernandez-Sotomayor, S M; Jones, G; Carpenter, G; Mochly-Rosen, D

    1994-01-18

    Phospholipase C-gamma 1 (PLC-gamma 1; EC 3.1.4.11) hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate diacylglycerol and inositol 1,4,5-trisphosphate and is activated in response to growth factor stimulation and tyrosine phosphorylation. Concomitantly, the enzyme translocates from the cytosol to the particulate cell fraction. A similar process of activation-induced translocation from the cytosol to the cell particulate fraction has also been described for protein kinase C (PKC). We have previously shown that activated PKC binds to specific receptor proteins, receptors for activated C kinase, or RACKs, of approximately 30 kDa. Here, we show that PLC-gamma 1 bound to these RACKs and inhibited subsequent PKC binding to RACKs. However, unlike PKC, the binding of PLC-gamma 1 to RACKs did not require phospholipids and calcium. After epidermal growth factor treatment of intact A-431 cells, the binding of PLC-gamma 1 to RACKs increased as compared with PLC-gamma 1 from control cells. This increase in PLC-gamma 1 binding to RACKs was due to the phosphorylation of PLC-gamma 1. Additional data indicated that PLC-gamma 1 binds to RACKs in solution; epidermal growth factor receptor-dependent PLC-gamma 1 phosphorylation and activation decreased in the presence of RACKs. It is possible that, in vivo, PLC-gamma 1 associates with RACKs or with other PLC-gamma 1-specific anchoring proteins in the particulate cell fraction. Since a PKC C2 homologous region is present in PLC-gamma 1, the C2 region may mediate the activation-induced translocation of the enzyme to the cell particulate fraction and the anchoring protein-PLC-gamma 1 complex may be the active translocated form of PLC-gamma 1.

  13. First and second generation antipsychotics influence hippocampal gamma oscillations by interactions with 5-HT3 and D3 receptors

    PubMed Central

    Schulz, Steffen B; Heidmann, Karin E; Mike, Arpad; Klaft, Zin-Juan; Heinemann, Uwe; Gerevich, Zoltan

    2012-01-01

    BACKGROUND AND PURPOSE Disturbed cortical gamma band oscillations (30–80 Hz) have been observed in schizophrenia: positive symptoms of the disease correlate with an increase in gamma oscillation power, whereas negative symptoms are associated with a decrease. EXPERIMENTAL APPROACH Here we investigated the effects of first and second generation antipsychotics (FGAs and SGAs, respectively) on gamma oscillations. The FGAs haloperidol, flupenthixol, chlorpromazine, chlorprothixene and the SGAs clozapine, risperidone, ziprasidone, amisulpride were applied on gamma oscillations induced by acetylcholine and physostigmine in the CA3 region of rat hippocampal slices. KEY RESULTS Antipsychotics inhibited the power of gamma oscillations and increased the bandwidth of the gamma band. Haloperidol and clozapine had the highest inhibitory effects. To determine which receptor is responsible for the alterations in gamma oscillations, the effects of the antipsychotics were plotted against their pKi values for 19 receptors and analysed for correlation. Our results indicated that 5-HT3 receptors have an enhancing effect on gamma oscillations whereas dopamine D3 receptors inhibit them. To test this prediction, m-chlorophenylbiguanide, PD 128907 and CP 809101, selective agonists at 5-HT3, D3 and 5-HT2C receptors were applied and revealed that 5-HT3 receptors indeed enhanced the gamma power whereas D3 receptors reduced it. As predicted, 5-HT2C receptors had no effects on gamma oscillations. CONCLUSION AND IMPLICATIONS Our data suggest that antipsychotics alter hippocampal gamma oscillations by interacting with 5-HT3 and dopamine D3 receptors. Moreover, a correlation of receptor affinities with the biological effects can be used to predict targets for the pharmacological effects of multi-target drugs. PMID:22817643

  14. Identification of the low affinity receptor for immunoglobulin E on mouse mast cells and macrophages as Fc gamma RII and Fc gamma RIII.

    PubMed

    Takizawa, F; Adamczewski, M; Kinet, J P

    1992-08-01

    In addition to their well characterized high affinity immunoglobulin E (IgE) receptors (Fc epsilon RI) mast cells have long been suspected to express undefined Fc receptors capable of binding IgE with low affinity. In this paper, we show that Fc gamma RII and Fc gamma RIII, but not Mac-2, on mouse mast cells and macrophages bind IgE-immune complexes. This binding is efficiently competed by 2.4G2, a monoclonal antibody against the extracellular homologous region of both Fc gamma RII and Fc gamma RIII. Furthermore, IgE-immune complexes bind specifically to Fc gamma RII or Fc gamma RIII transfected into COS-7 cells. The association constants of IgE binding estimated from competition experiments are about 3.1 x 10(5) M-1 for Fc gamma RII, and 4.8 x 10(5) M-1 for Fc gamma RIII. Engagement of Fc gamma RII and Fc gamma RIII with IgE-immune complexes (after blocking access to Fc epsilon RI) or with IgG-immune complexes triggers C57.1 mouse mast cells to release serotonin. This release is inhibited by 2.4G2, and at maximum, reaches 30-40% of the intracellular content, about half of the maximal release (60-80%) obtained after Fc epsilon RI engagement. These data demonstrate that mouse Fc gamma RII and Fc gamma RIII are not isotype specific, and that the binding of IgE-immune complexes to these receptors induces cell activation.

  15. Whole-exome sequencing reveals a rare interferon gamma receptor 1 mutation associated with myasthenia gravis.

    PubMed

    Qi, Guoyan; Liu, Peng; Gu, Shanshan; Yang, Hongxia; Dong, Huimin; Xue, Yinping

    2018-04-01

    Our study is aimed to explore the underlying genetic basis of myasthenia gravis. We collected a Chinese pedigree with myasthenia gravis, and whole-exome sequencing was performed on the two affected siblings and their parents. The candidate pathogenic gene was identified by bioinformatics filtering, which was further verified by Sanger sequencing. The homozygous mutation c.G40A (p.V14M) in interferon gamma receptor 1was identified. Moreover, the mutation was also detected in 3 cases of 44 sporadic myasthenia gravis patients. The p.V14M substitution in interferon gamma receptor 1 may affect the signal peptide function and the translocation on cell membrane, which could disrupt the binding of the ligand of interferon gamma and antibody production, contributing to myasthenia gravis susceptibility. We discovered that a rare variant c.G40A in interferon gamma receptor 1 potentially contributes to the myasthenia gravis pathogenesis. Further functional studies are needed to confirm the effect of the interferon gamma receptor 1 on the myasthenia gravis phenotype.

  16. Gamma-hydroxybutyric acid (GHB) and the mesoaccumbens reward circuit: evidence for GABA(B) receptor-mediated effects.

    PubMed

    Pistis, M; Muntoni, A L; Pillolla, G; Perra, S; Cignarella, G; Melis, M; Gessa, G L

    2005-01-01

    Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid naturally occurring in the mammalian brain, which recently emerged as a major recreational drug of abuse. GHB has multiple neuronal mechanisms including activation of both the GABA(B) receptor, and a distinct GHB-specific receptor. This complex GHB-GABA(B) receptor interaction is probably responsible for the multifaceted pharmacological, behavioral and toxicological profile of GHB. Drugs of abuse exert remarkably similar effects upon reward-related circuits, in particular the mesolimbic dopaminergic system and the nucleus accumbens (NAc). We used single unit recordings in vivo from urethane-anesthetized rats to characterize the effects of GHB on evoked firing in NAc "shell" neurons and on spontaneous activity of antidromically identified dopamine (DA) cells located in the ventral tegmental area. GHB was studied in comparison with the GABA(B) receptor agonist baclofen and antagonist (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911). Additionally, we utilized a GHB analog, gamma-(p-methoxybenzil)-gamma-hydroxybutyric acid (NCS-435), devoid of GABA(B) binding properties, but with high affinity for specific GHB binding sites. In common with other drugs of abuse, GHB depressed firing in NAc neurons evoked by the stimulation of the basolateral amygdala. On DA neurons, GHB exerted heterogeneous effects, which were correlated to the baseline firing rate of the cells but led to a moderate stimulation of the DA system. All GHB actions were mediated by GABA(B) receptors, since they were blocked by SCH50911 and were not mimicked by NCS-435. Our study indicates that the electrophysiological profile of GHB is close to typical drugs of abuse: both inhibition of NAc neurons and moderate to strong stimulation of DA transmission are distinctive features of diverse classes of abused drugs. Moreover, it is concluded that addictive and rewarding properties of GHB do not necessarily involve a putative high affinity GHB

  17. Identification of the low affinity receptor for immunoglobulin E on mouse mast cells and macrophages as Fc gamma RII and Fc gamma RIII

    PubMed Central

    1992-01-01

    In addition to their well characterized high affinity immunoglobulin E (IgE) receptors (Fc epsilon RI) mast cells have long been suspected to express undefined Fc receptors capable of binding IgE with low affinity. In this paper, we show that Fc gamma RII and Fc gamma RIII, but not Mac-2, on mouse mast cells and macrophages bind IgE-immune complexes. This binding is efficiently competed by 2.4G2, a monoclonal antibody against the extracellular homologous region of both Fc gamma RII and Fc gamma RIII. Furthermore, IgE-immune complexes bind specifically to Fc gamma RII or Fc gamma RIII transfected into COS-7 cells. The association constants of IgE binding estimated from competition experiments are about 3.1 x 10(5) M-1 for Fc gamma RII, and 4.8 x 10(5) M-1 for Fc gamma RIII. Engagement of Fc gamma RII and Fc gamma RIII with IgE-immune complexes (after blocking access to Fc epsilon RI) or with IgG-immune complexes triggers C57.1 mouse mast cells to release serotonin. This release is inhibited by 2.4G2, and at maximum, reaches 30-40% of the intracellular content, about half of the maximal release (60-80%) obtained after Fc epsilon RI engagement. These data demonstrate that mouse Fc gamma RII and Fc gamma RIII are not isotype specific, and that the binding of IgE-immune complexes to these receptors induces cell activation. PMID:1386873

  18. Modulation of Fc gamma receptors on I cells and monocytes by 15 hydroperoxyeicosatetranoic acid.

    PubMed

    Goodwin, J S; Gualde, N; Aldigier, J; Rigaud, M; Vanderhoek, J Y

    1984-01-01

    We investigated the effects of the 15-lipoxygenase products, 15 hydroperoxyeicosatetranoic acid (15 HPETE) and 15 hydroxyeicosatetranoic acid (15 HETE) on Fc gamma receptor expression on human T cells and monocytes. Incubation of these cells with 15 HPETE but not 15 HETE results in a shift to decreased density of Fc gamma receptors on the cell surface.

  19. Soluble and insoluble immune complexes activate human neutrophil NADPH oxidase by distinct Fc gamma receptor-specific mechanisms.

    PubMed

    Crockett-Torabi, E; Fantone, J C

    1990-11-01

    Signal transduction initiated by interaction of immune complexes (IC) with Fc gamma RII and Fc gamma RIII receptors on human neutrophils was studied by investigating the capacity of well-defined complexes to stimulate O2- generation in neutrophils. IC consisting of polyclonal rabbit antibody to human albumin were prepared at equivalence (insoluble complexes) and at five times Ag excess (soluble complexes). Stimulation of human neutrophils with soluble and insoluble IC caused a dose-dependent activation of the respiratory burst and O2- generation. Incubation of neutrophils with cytochalasin B significantly enhanced O2- generation in neutrophils stimulated with soluble IC. In contrast, cytochalasin B treatment had a minimal effect on O2- generation in neutrophils stimulated with insoluble IC. Treatment of neutrophils with PGE1 or pertussis toxin (PTx) significantly inhibited O2- generation by soluble IC-stimulated neutrophils. However, neither PGE1 nor PTx treatment significantly altered O2- generation in neutrophils stimulated with insoluble complexes. Although O2- generation induced by soluble IC was significantly inhibited by mAb against both Fc gamma RII and Fc gamma RIII receptor, insoluble IC stimulation of neutrophil O2- generation was significantly diminished only by mAb against Fc gamma RIII receptor. Cross-linking of either Fc gamma RII or Fc gamma RIII receptors on neutrophil surfaces induced O2- generation, and this activation was inhibited by both PGE1 and PTx treatment. These findings indicate that soluble and insoluble ICs induce O2- production in human neutrophils through distinct mechanisms. Soluble IC induce activation of neutrophils through a PTx- and PGE1-sensitive pathway that is dependent upon both Fc gamma RII and Fc gamma RIII receptors. Although insoluble IC induce O2- production through a PTx and PGE1 insensitive pathway mediated primarily through Fc gamma RIII receptor.

  20. Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, modulates the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3.

    PubMed

    Ohta, Tetsuo; Elnemr, Ayman; Yamamoto, Miyuki; Ninomiya, Itasu; Fushida, Sachio; Nishimura, Gen-Ichi; Fujimura, Takashi; Kitagawa, Hirohisa; Kayahara, Masato; Shimizu, Koichi; Yi, Shuangqin; Miwa, Koichi

    2002-07-01

    Activation of peroxisome proliferator-activated receptor (PPAR)-gamma induces terminal differentiation and growth inhibition associated with G1 cell cycle arrest in some cancer cells. The multifunctional molecule beta-catenin performs important roles in intercellular adhesion and signal transduction. However, no report has focused on actions of PPAR-gamma in regulating the E-cadherin/beta-catenin system. We examined whether thiazolidinedione (TZD), a potent PPAR-gamma ligand, could modulate the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3, that has been found to express PPAR-gamma. According to Western blotting, TZD markedly increased differentiation markers including E-cadherin and carcinoembryonic antigen, while beta-catenin did not change significantly. In untreated cells, fluorescence immunostaining demonstrated beta-catenin predominantly in the cytoplasm and/or nucleus; in TZD-treated cells, beta-catenin localization had dramatically shifted to the plasma membrane, in association with increased E-cadherin at this site. Thus, a PPAR-gamma ligand appears to participate not only in induction of differentiation in pancreatic cancer cells, but also in the regulation of the E-cadherin/beta-catenin system. Such ligands may prove clinically useful as cytostatic anticancer agents.

  1. Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense.

    PubMed

    Sonoda, Junichiro; Laganière, Josée; Mehl, Isaac R; Barish, Grant D; Chong, Ling-Wa; Li, Xiangli; Scheffler, Immo E; Mock, Dennis C; Bataille, Alain R; Robert, Francois; Lee, Chih-Hao; Giguère, Vincent; Evans, Ronald M

    2007-08-01

    Macrophage activation by the proinflammatory cytokine interferon-gamma (IFN-gamma) is a critical component of the host innate response to bacterial pathogenesis. However, the precise nature of the IFN-gamma-induced activation pathway is not known. Here we show using genome-wide expression and chromatin-binding profiling that IFN-gamma induces the expression of many nuclear genes encoding mitochondrial respiratory chain machinery via activation of the nuclear receptor ERR alpha (estrogen-related receptor alpha, NR3B1). Studies with macrophages lacking ERR alpha demonstrate that it is required for induction of mitochondrial reactive oxygen species (ROS) production and efficient clearance of Listeria monocytogenes (LM) in response to IFN-gamma. As a result, mice lacking ERR alpha are susceptible to LM infection, a phenotype that is localized to bone marrow-derived cells. Furthermore, we found that IFN-gamma-induced activation of ERR alpha depends on coactivator PGC-1 beta (peroxisome proliferator-activated receptor gamma coactivator-1 beta), which appears to be a direct target for the IFN-gamma/STAT-1 signaling cascade. Thus, ERR alpha and PGC-1 beta act together as a key effector of IFN-gamma-induced mitochondrial ROS production and host defense.

  2. Impairment of neutrophil Fc gamma receptor mediated transmembrane signalling in active rheumatoid arthritis.

    PubMed Central

    Goulding, N J; Guyre, P M

    1992-01-01

    Neutrophil Fc gamma receptor (Fc gamma R) signalling responses were compared in healthy subjects, patients with definite rheumatoid arthritis (RA), ankylosing spondylitis, and osteoarthritis. The patients with A were subdivided into those with active synovitis and those with quiescent disease. Basal intracellular calcium ion concentrations in patients with inactive RA were significantly higher than in control subjects, which in turn were greater than in patients with active RA. Transient cytosolic calcium ion fluxes were observed after binding Fc gamma RII or Fc gamma RIII with specific monoclonal antibodies and cross linking with the F(ab')2 fragment of antimouse IgG. Response times were significantly faster for Fc gamma RII than for Fc gamma RIII. Peak concentrations of intracellular calcium ions after neutrophil stimulation were comparable for Fc gamma RII and RIII in healthy subjects. Neutrophils in patients with ankylosing spondylitis and osteoarthritis responded to Fc gamma R triggering, but in the group with active RA fluxes of calcium ions were severely depressed. Neutrophils isolated from patients with RA with quiescent disease showed exaggerated responses when compared with controls. Expression of all three Fc gamma R types on neutrophils from patients with active RA, as measured by monoclonal antibody binding, was comparable with control cells. Impairment of neutrophil Fc gamma R cytosolic signalling in active RA could reflect a receptor signalling defect with potential effects on Fc mediated functions, or a fundamental defect in calcium ion homeostasis within these cells. PMID:1535494

  3. Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-[gamma

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan

    2013-03-07

    Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partialmore » PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.« less

  4. Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPAR gamma) gene.

    PubMed

    Beamer, B A; Negri, C; Yen, C J; Gavrilova, O; Rumberger, J M; Durcan, M J; Yarnall, D P; Hawkins, A L; Griffin, C A; Burns, D K; Roth, J; Reitman, M; Shuldiner, A R

    1997-04-28

    We determined the chromosomal localization and partial genomic structure of the coding region of the human PPAR gamma gene (hPPAR gamma), a nuclear receptor important for adipocyte differentiation and function. Sequence analysis and long PCR of human genomic DNA with primers that span putative introns revealed that intron positions and sizes of hPPAR gamma are similar to those previously determined for the mouse PPAR gamma gene[13]. Fluorescent in situ hybridization localized hPPAR gamma to chromosome 3, band 3p25. Radiation hybrid mapping with two independent primer pairs was consistent with hPPAR gamma being within 1.5 Mb of marker D3S1263 on 3p25-p24.2. These sequences of the intron/exon junctions of the 6 coding exons shared by hPPAR gamma 1 and hPPAR gamma 2 will facilitate screening for possible mutations. Furthermore, D3S1263 is a suitable polymorphic marker for linkage analysis to evaluate PPAR gamma's potential contribution to genetic susceptibility to obesity, lipoatrophy, insulin resistance, and diabetes.

  5. The Gamma-Aminobutyric Acid B Receptor in Depression and Reward.

    PubMed

    Jacobson, Laura H; Vlachou, Styliani; Slattery, David A; Li, Xia; Cryan, John F

    2018-06-01

    The metabotropic gamma-aminobutyric acid B (GABA B ) receptor was the first described obligate G protein-coupled receptor heterodimer and continues to set the stage for discoveries in G protein-coupled receptor signaling complexity. In this review, dedicated to the life and work of Athina Markou, we explore the role of GABA B receptors in depression, reward, and the convergence of these domains in anhedonia, a shared symptom of major depressive disorder and withdrawal from drugs of abuse. GABA B receptor expression and function are enhanced by antidepressants and reduced in animal models of depression. Generally, GABA B receptor antagonists are antidepressant-like and agonists are pro-depressive. Exceptions to this rule likely reflect the differential influence of GABA B1 isoforms in depression-related behavior and neurobiology, including the anhedonic effects of social stress. A wealth of data implicate GABA B receptors in the rewarding effects of drugs of abuse. We focus on nicotine as an example. GABA B receptor activation attenuates, and deactivation enhances, nicotine reward and associated neurobiological changes. In nicotine withdrawal, however, GABA B receptor agonists, antagonists, and positive allosteric modulators enhance anhedonia, perhaps owing to differential effects of GABA B1 isoforms on the dopaminergic system. Nicotine cue-induced reinstatement is more reliably attenuated by GABA B receptor activation. Separation of desirable and undesirable side effects of agonists is achievable with positive allosteric modulators, which are poised to enter clinical studies for drug abuse. GABA B1 isoforms are key to understanding the neurobiology of anhedonia, whereas allosteric modulators may offer a mechanism for targeting specific brain regions and processes associated with reward and depression. Copyright © 2018 Society of Biological Psychiatry. All rights reserved.

  6. Topological dispositions of lysine. alpha. 380 and lysine. gamma. 486 in the acetylcholine receptor from Torpedo californica

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dwyer, B.P.

    1991-04-23

    The locations have been determined, with respect to the plasma membrane, of lysine {alpha}380 and lysine {gamma}486 in the {alpha} subunit and the {gamma} subunit, respectively, of the nicotinic acetylcholine receptor from Torpedo californica. Immunoadsorbents were constructed that recognize the carboxy terminus of the peptide GVKYIAE released by proteolytic digestion from positions 378-384 in the amino acid sequence of the {alpha} subunit of the acetylcholine receptor and the carboxy terminus of the peptide KYVP released by proteolytic digestion from positions 486-489 in the amino acid sequence of the {gamma} subunit. They were used to isolate these peptides from proteolytic digestsmore » of polypeptides from the acetylcholine receptor. Sealed vesicles containing the native acetylcholine receptor were labeled with pyridoxal phosphate and sodium ({sup 3}H)-borohydride. The effect of saponin on the incorporation of pyridoxamine phosphate into lysine {alpha}380 and lysine {gamma}486 from the acetylcholine receptor in these vesicles was assessed with the immunoadsorbents. The conclusions that follow from these results are that lysine {alpha}380 is on the inside surface of a vesicle and lysine {gamma}486 is on the outside surface. Because a majority (85%) of the total binding sites for {alpha}-bungarotoxin bind the toxin in the absence of saponin, the majority of the vesicles are right side out with the inside of the vesicle corresponding to the cytoplasmic surface and the outside of the vesicle corresponding to the extracytoplasmic, synaptic surface. Because lysine {alpha}380 and lysine {gamma}486 lie on opposite sides of the membrane, a membrane-spanning segment must be located between the two positions occupied by these two amino acids in the common sequence of a polypeptide of the acetylcholine receptor.« less

  7. Enhancement of gamma-aminobutyric acid receptor binding by protopine-type alkaloids.

    PubMed

    Kardos, J; Blaskó, G; Simonyi, M

    1986-06-01

    Protopine, cryptopine and allocryptopine were demonstrated to enhance 3H-gamma-aminobutyric acid (3H-GABA) binding to rat brain synaptic membrane receptors. The above finding might be indicative of benzodiazepine-like activity of these alkaloids.

  8. Akt interaction with PLC(gamma) regulates the G(2)/M transition triggered by FGF receptors from MDA-MB-231 breast cancer cells.

    PubMed

    Browaeys-Poly, Edith; Perdereau, Dominique; Lescuyer, Arlette; Burnol, Anne-Françoise; Cailliau, Katia

    2009-12-01

    Estrogen-independent breast cancer cell growth is under the control of fibroblast growth factors receptors (FGFRs), but the role of phospholipase C gamma (PLC(gamma)) and Akt, the downstream effectors activated by FGFRs, in cell proliferation is still unresolved. FGFRs from highly invasive MDA-MB-231 cells were expressed in Xenopus oocyte, a powerful model system to assess the G(2)/M checkpoint regulation. Under FGF1 stimulation, an analysis of the progression in the M-phase of the cell cycle and of the Akt signaling cascades were performed using the phosphatidylinositol-3-kinase inhibitor, LY294002, and a mimetic peptide of the SH3 domain of PLC(gamma). Activated Akt binds and phosphorylates PLC(gamma) before Akt targets the tumor suppressor Chfr. Disruption of the Akt-PLC(gamma) interaction directs Akt binding to Chfr and accelerates the alleviation of the G(2)/M checkpoint. The PLC(gamma)-Akt interaction, triggered by FGF receptors from estrogen-independent breast cancer cells MDA-MB-231, regulates progression in the M-phase of the cell cycle.

  9. Cannabinoid Receptors Mediate Methamphetamine Induction of High Frequency Gamma Oscillations in the Nucleus Accumbens

    PubMed Central

    Morra, Joshua T.; Glick, Stanley D.; Cheer, Joseph F.

    2012-01-01

    Patients suffering from amphetamine---induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (~ 80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders. PMID:22609048

  10. 5-Hydroxytryptamine1A receptor-activation hyperpolarizes pyramidal cells and suppresses hippocampal gamma oscillations via Kir3 channel activation

    PubMed Central

    Johnston, April; McBain, Chris J; Fisahn, André

    2014-01-01

    Rhythmic cortical neuronal oscillations in the gamma frequency band (30–80 Hz, gamma oscillations) have been associated with cognitive processes such as sensory perception and integration, attention, learning, and memory. Gamma oscillations are disrupted in disorders for which cognitive deficits are hallmark symptoms such as schizophrenia and Alzheimer's disease. In vitro, various neurotransmitters have been found to modulate gamma oscillations. Serotonin (5-HT) has long been known to be important for both behavioural and cognitive functions such as learning and memory. Multiple 5-HT receptor subtypes are expressed in the CA3 region of the hippocampus and high doses of 5-HT reduce the power of induced gamma oscillations. Hypothesizing that 5-HT may have cell- and receptor subtype-specific modulatory effects, we investigated the receptor subtypes, cell types and cellular mechanisms engaged by 5-HT in the modulation of gamma oscillations in mice and rats. We found that 5-HT decreases the power of kainate-induced hippocampal gamma oscillations in both species via the 5-HT1A receptor subtype. Whole-cell patch clamp recordings demonstrated that this decrease was caused by a hyperpolarization of CA3 pyramidal cells and a reduction of their firing frequency, but not by alteration of inhibitory neurotransmission. Finally, our results show that the effect on pyramidal cells is mediated via the G protein-coupled receptor inwardly rectifying potassium channel Kir3. Our findings suggest this novel cellular mechanism as a potential target for therapies that are aimed at alleviating cognitive decline by helping the brain to maintain or re-establish normal gamma oscillation levels in neuropsychiatric and neurodegenerative disorders. PMID:25107925

  11. Cannabinoid receptors mediate methamphetamine induction of high frequency gamma oscillations in the nucleus accumbens.

    PubMed

    Morra, Joshua T; Glick, Stanley D; Cheer, Joseph F

    2012-09-01

    Patients suffering from amphetamine-induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely-moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (∼80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Potential effects of curcumin on peroxisome proliferator-activated receptor-gamma in vitro and in vivo

    USDA-ARS?s Scientific Manuscript database

    Natural peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists are found in food and may be important for health through their anti-inflammatory properties. Curcumin (Cur) is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been shown to have many biologi...

  13. IFN-gamma receptor-deficient mice generate antiviral Th1-characteristic cytokine profiles but altered antibody responses.

    PubMed

    Schijns, V E; Haagmans, B L; Rijke, E O; Huang, S; Aguet, M; Horzinek, M C

    1994-09-01

    The lymphokine IFN-gamma is a pleiotropic immunomodulator and possesses intrinsic antiviral activity. We studied its significance in the development of antiviral immune responses by using IFN-gamma receptor-deficient (IFN-gamma R-/-) mice. After inoculation with live attenuated pseudorabies virus (PRV), the mutant mice showed no infectivity titers in various tissues, and transient viral Ag expression only in the spleen, similar as in wild-type mice. However, the absence of the IFN-gamma R resulted in increased proliferative splenocyte responses. The PRV-immune animals showed a normal IFN-gamma and IL-2 production, without detectable IL-4, and with decreased IL-10 secretion in response to viral Ag or Con A. Immunohistochemically, an increased ratio of IFN-gamma:IL-4-producing spleen cells was found. After immunization with either live attenuated or inactivated PRV, IFN-gamma R-/- mice produced significantly less antiviral Ab, and more succumbed to challenge infection than the intact control animals. The reduction in Ab titers in the mutant mice correlated with lower protection by their sera in transfer experiments. Our data demonstrate that ablation of the IFN-gamma receptor surprisingly does not inhibit the generation of antiviral Th1-type and increase Th2-type cytokine responses. However, it profoundly impairs the generation of protective antiviral Ab.

  14. Bidirectional modulation of hippocampal gamma (20-80 Hz) frequency activity in vitro via alpha(α)- and beta(β)-adrenergic receptors (AR).

    PubMed

    Haggerty, D C; Glykos, V; Adams, N E; Lebeau, F E N

    2013-12-03

    Noradrenaline (NA) in the hippocampus plays an important role in memory function and has been shown to modulate different forms of synaptic plasticity. Oscillations in the gamma frequency (20-80 Hz) band in the hippocampus have also been proposed to play an important role in memory functions and, evidence from both in vitro and in vivo studies, has suggested this activity can be modulated by NA. However, the role of different NA receptor subtypes in the modulation of gamma frequency activity has not been fully elucidated. We have found that NA (30 μM) exerts a bidirectional control on the magnitude of kainate-evoked (50-200 nM) gamma frequency oscillations in the cornu Ammonis (CA3) region of the rat hippocampus in vitro via activation of different receptor subtypes. Activation of alpha-adrenergic receptors (α-AR) reduced the power of the gamma frequency oscillation. In contrast, activation of beta-adrenergic receptors (β-AR) caused an increase in the power of the gamma frequency oscillations. Using specific agonists and antagonists of AR receptor subtypes we demonstrated that these effects are mediated specifically via α1A-AR and β1-AR subtypes. NA activated both receptor subtypes, but the α1A-AR-mediated effect predominated, resulting in a reversible suppression of gamma frequency activity. These results suggest that NA is able to differentially modulate on-going gamma frequency oscillatory activity that could result in either increased or decreased information flow through the hippocampus. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-{gamma}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ghosh, Asish K; Wei, Jun; Wu, Minghua

    2008-09-19

    Transforming growth factor-{beta} (TGF-{beta}), a potent inducer of collagen synthesis, is implicated in pathological fibrosis. Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) is a nuclear hormone receptor that regulates adipogenesis and numerous other biological processes. Here, we demonstrate that collagen gene expression was markedly elevated in mouse embryonic fibroblasts (MEFs) lacking PPAR-{gamma} compared to heterozygous control MEFs. Treatment with the PPAR-{gamma} ligand 15d-PGJ{sub 2} failed to down-regulate collagen gene expression in PPAR-{gamma} null MEFs, whereas reconstitution of these cells with ectopic PPAR-{gamma} resulted in their normalization. Compared to control MEFs, PPAR-{gamma} null MEFs displayed elevated levels of the Type I TGF-{beta} receptor (T{beta}RI),more » and secreted more TGF-{beta}1 into the media. Furthermore, PPAR-{gamma} null MEFs showed constitutive phosphorylation of cellular Smad2 and Smad3, even in the absence of exogenous TGF-{beta}, which was abrogated by the ALK5 inhibitor SB431542. Constitutive Smad2/3 phosphorylation in PPAR-{gamma} null MEFs was associated with Smad3 binding to its cognate DNA recognition sequences, and interaction with coactivator p300 previously implicated in TGF-{beta} responses. Taken together, these results indicate that loss of PPAR-{gamma} in MEFs is associated with upregulation of collagen synthesis, and activation of intracellular Smad signal transduction, due, at least in part, to autocrine TGF-{beta} stimulation.« less

  16. Sensorimotor function is modulated by the serotonin receptor 1d, a novel marker for gamma motor neurons

    PubMed Central

    Enjin, Anders; Leão, Katarina E.; Mikulovic, Sanja; Le Merre, Pierre; Tourtellotte, Warren G.; Kullander, Klas

    2012-01-01

    Gamma motor neurons (MNs), the efferent component of the fusimotor system, regulate muscle spindle sensitivity. Muscle spindle sensory feedback is required for proprioception that includes sensing the relative position of neighboring body parts and appropriately adjust the employed strength in a movement. The lack of a single and specific genetic marker has long hampered functional and developmental studies of gamma MNs. Here we show that the serotonin receptor 1d (5-ht1d) is specifically expressed by gamma MNs and proprioceptive sensory neurons. Using mice expressing GFP driven by the 5-ht1d promotor, we performed whole-cell patch-clamp recordings of 5-ht1d∷GFP+ and 5-ht1d∷GFP− motor neurons from young mice. Hierarchal clustering analysis revealed that gamma MNs have distinct electrophysiological properties intermediate to fast-like and slow-like alpha MNs. Moreover, mice lacking 5-ht1d displayed lower monosynaptic reflex amplitudes suggesting a reduced response to sensory stimulation in motor neurons. Interestingly, adult 5-ht1d knockout mice also displayed improved coordination skills on a beam-walking task, implying that reduced activation of MNs by Ia afferents during provoked movement tasks could reduce undesired exaggerated muscle output. In summary, we show that 5-ht1d is a novel marker for gamma MNs and that the 5-ht1d receptor is important for the ability of proprioceptive circuits to receive and relay accurate sensory information in developing and mature spinal cord motor circuits. PMID:22273508

  17. Peroxisome proliferator-activated receptor gamma overexpression suppresses proliferation of human colon cancer cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tsukahara, Tamotsu, E-mail: ttamotsu@shinshu-u.ac.jp; Haniu, Hisao

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer We examined the correlation between PPAR{gamma} expression and cell proliferation. Black-Right-Pointing-Pointer PPAR{gamma} overexpression reduces cell viability. Black-Right-Pointing-Pointer We show the synergistic effect of cell growth inhibition by a PPAR{gamma} agonist. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) plays an important role in the differentiation of intestinal cells and tissues. Our previous reports indicate that PPAR{gamma} is expressed at considerable levels in human colon cancer cells. This suggests that PPAR{gamma} expression may be an important factor for cell growth regulation in colon cancer. In this study, we investigated PPAR{gamma} expression in 4 human colon cancer cell lines, HT-29, LOVO,more » DLD-1, and Caco-2. Real-time polymerase chain reaction (PCR) and Western blot analysis revealed that the relative levels of PPAR{gamma} mRNA and protein in these cells were in the order HT-29 > LOVO > Caco-2 > DLD-1. We also found that PPAR{gamma} overexpression promoted cell growth inhibition in PPAR{gamma} lower-expressing cell lines (Caco-2 and DLD-1), but not in higher-expressing cells (HT-29 and LOVO). We observed a correlation between the level of PPAR{gamma} expression and the cells' sensitivity for proliferation.« less

  18. Characterization of tachykinin receptors mediating bronchomotor and vasodepressor responses to neuropeptide gamma and substance P in the anaesthetized rabbit.

    PubMed

    Yuan, L; Burcher, E; Nail, B S

    1998-02-01

    The effects of i.v. injections of two endogenous tachykinins, substance P (SP) and neuropeptide gamma and the highly selective tachykinin agonists [Sar9,Met(O2)11]-SP, [Lys5,MeLeu9, Nle10]-NKA(4-10) and senktide, on total lung resistance (RL), dynamic lung compliance (Cdyn) and systemic blood pressure, were compared in the anaesthetized rabbit. Senktide, the NK-3 receptor selective agonist, had no effect on RL, Cdyn or blood pressure. The other four agonists caused dose-dependent increases in RL and Cdyn, with [Sar9,Met(O2)11]-SP being the most potent agonist in producing changes in the absence of phosphoramidon. This suggested that NK-1 receptors play an important role in these responses. [Sar9, Met(O2)11]-SP, SP and neuropeptide gamma also decreased blood pressure. Phosphoramidon (1 mg/kg) potentiated the changes in RL and Cdyn evoked by [Sar9,Met(O2)11]-SP and SP, with very marked enhancement of responses to neuropeptide gamma. Responses to [Lys5, MeLeu9,Nle10]-NKA(4-10) were unaffected, suggesting that this NK-2 selective agonist may not be catabolized by neutral endopeptidase (NEP). In the presence of phosphoramidon, the non-peptide tachykinin NK-1 receptor selective antagonist CP 96345 (80 nmol/kg) reduced all responses to [Sar9,Met(O2)11]-SP and SP, whereas the NK-2 selective antagonist SR 48968 (40 nmol/kg) inhibited the bronchomotor but not the vasodepressor responses to neuropeptide gamma and [Lys5,MeLeu9, Nle10]-NKA(4-10). The fall in blood pressure induced by neuropeptide gamma was diminished by CP 96345, whereas bronchoconstriction was unaffected, indicating possible differences in NK-1 receptors in the vasculature and airways. Electrical stimulation of the distal ends of vagus nerves caused increases in RL which were abolished by atropine (1 mg/kg). Copyright 1998 Academic Press Limited

  19. Identification and cloning of a gamma 3 subunit splice variant of the human GABA(A) receptor.

    PubMed

    Poulsen, C F; Christjansen, K N; Hastrup, S; Hartvig, L

    2000-05-31

    cDNA sequences encoding two forms of the GABA(A) gamma 3 receptor subunit were cloned from human hippocampus. The nucleotide sequences differ by the absence (gamma 3S) or presence (gamma 3L) of 18 bp located in the presumed intracellular loop between transmembrane region (TM) III and IV. The extra 18 bp in the gamma 3L subunit generates a consensus site for phosphorylation by protein kinase C (PKC). Analysis of human genomic DNA encoding the gamma 3 subunit reveals that the 18 bp insert is contiguous with the upstream proximal exon.

  20. Activation of peroxisome proliferator-activated receptor-gamma reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells.

    PubMed

    Varley, Claire Lucy; Stahlschmidt, Jens; Smith, Barbara; Stower, Michael; Southgate, Jennifer

    2004-05-01

    We observed that in urothelium, both cornifying and noncornifying forms of squamous metaplasia are accompanied by changes in the localization of the nuclear hormone receptors, peroxisome proliferator activated receptor gamma (PPAR-gamma) and retinoid X receptor (RXR-alpha). To obtain objective evidence for a role for PPAR-gamma-mediated signaling in urothelial differentiation, we examined expression of the cytokeratin isotypes CK13, CK20, and CK14 as indicators of transitional, terminal transitional, and squamous differentiation, respectively, in cultures of normal human urothelial cells. In control culture conditions, normal human urothelial cells showed evidence of squamous differentiation (CK14+, CK13-, CK20-). Treatment with the high-affinity PPAR-gamma agonist, troglitazone (TZ), resulted in gain of CK13 and loss of CK14 protein expression. The effect of TZ was significantly augmented when the autocrine-stimulated epidermal growth factor receptor pathway was inhibited and this resulted in induction of CK20 expression. The RXR-specific inhibitors PA452, HX531, and HX603 inhibited the TZ-induced CK13 expression, supporting a role for RXR in the induction of CK13 expression. Thus, signaling through PPAR-gamma can mediate transitional differentiation of urothelial cells and this is modulated by growth regulatory programs.

  1. gamma. -Preprotachykinin-(72-92)-peptide amide: An endogenous preprotachykinin I gene-derived peptide that preferentially binds to neurokinin-2 receptors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dam, T.V.; Takeda, Y.; Krause, J.E.

    1990-01-01

    The presence of N-terminally extended forms of neurokinin A has recently been reported in the mammalian brain. Among them, gamma-preprotachykinin-(72-92)-peptide amide (gamma-PPT-(72-92)-NH2), a peptide derived by posttranslational processing of gamma-preprotachykinin, is most prominent. We report here that this peptide most likely acts on neurokinin-2 receptor sites since neurokinin A (a putative neurokinin-2 agonist) and gamma-PPT-(72-92)-NH2 are potent competitors of 125I-labeled gamma-PPT-(72-92)-NH2 binding whereas selective neurokinin-1 and -3 agonists are not. Moreover, the distribution of 125I-labeled gamma-PPT-(72-92)-NH2 and 125I-labeled neurokinin A binding sites are very similar in rat brain. On the other hand, 125I-labeled Bolton-Hunter-substance P (a neurokinin-1 ligand) and 125I-labeledmore » Bolton-Hunter-eledoisin (a neurokinin-3 ligand) binding sites are differentially located in this tissue. Thus, it appears that gamma-PPT-(72-92)-NH2 binds to neurokinin-2 receptors and should be considered as a putative endogenous ligand for this receptor class.« less

  2. Peroxisome proliferator-activated receptor gamma signaling in human sperm physiology

    PubMed Central

    Liu, Li-Li; Xian, Hua; Cao, Jing-Chen; Zhang, Chong; Zhang, Yong-Hui; Chen, Miao-Miao; Qian, Yi; Jiang, Ming

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARγ acts as an important molecule for regulating energy homeostasis, modulates the hypothalamic-pituitary-gonadal (HPG) axis, and is reciprocally regulated by HPG. In the human, PPARγ protein is highly expressed in ejaculated spermatozoa, implying a possible role of PPARγ signaling in regulating sperm energy dissipation. PPARγ protein is also expressed in Sertoli cells and germ cells (spermatocytes). Its activation can be induced during capacitation and the acrosome reaction. This mini-review will focus on how PPARγ signaling may affect fertility and sperm quality and the potential reversibility of these adverse effects. PMID:25851655

  3. Peroxisome-proliferator-activated receptor-{gamma} agonists inhibit the release of proinflammatory cytokines from RSV-infected epithelial cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Arnold, Ralf; Koenig, Wolfgang

    2006-03-15

    The epithelial cells of the airways are the target cells for respiratory syncytial virus (RSV) infection and the site of the majority of the inflammation associated with the disease. Recently, peroxisome-proliferator-activated receptor {gamma} (PPAR{gamma}), a member of the nuclear hormone receptor superfamily, has been shown to possess anti-inflammatory properties. Therefore, we investigated the role of PPAR{gamma} agonists (15d-PGJ{sub 2}, ciglitazone and troglitazone) on the synthesis of RSV-induced cytokine release from RSV-infected human lung epithelial cells (A549). We observed that all PPAR{gamma} ligands inhibited dose-dependently the release of TNF-{alpha}, GM-CSF, IL-1{alpha}, IL-6 and the chemokines CXCL8 (IL-8) and CCL5 (RANTES) frommore » RSV-infected A549 cells. Concomitantly, the PPAR{gamma} ligands diminished the cellular amount of mRNA encoding for IL-6, CXCL8 and CCL5 and the RSV-induced binding activity of the transcription factors NF-{kappa}B (p65/p50) and AP-1 (c-fos), respectively. Our data presented herein suggest a potential application of PPAR{gamma} ligands in the anti-inflammatory treatment of RSV infection.« less

  4. Down-regulation of common cytokine receptor gamma chain inhibits inflammatory responses in macrophages stimulated with Riemerella anatipestifer

    USDA-ARS?s Scientific Manuscript database

    Th17-cell-mediated inflammation is affected by the soluble form of common cytokine receptor gamma chain (gamma-c). We previously suggested that inflammatory cytokines including interleukin (IL)-17A are associated with Riemerella anatipestifer infection, which a harmful bacterial pathogen in ducks. H...

  5. Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-{gamma}2

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mitterberger, Maria C.; Kim, Geumsoo; Rostek, Ursula

    2012-05-01

    Carbonic anhydrase III (CAIII) is an isoenzyme of the CA family. Because of its low specific anhydrase activity, physiological functions in addition to hydrating CO{sub 2} have been proposed. CAIII expression is highly induced in adipogenesis and CAIII is the most abundant protein in adipose tissues. The function of CAIII in both preadipocytes and adipocytes is however unknown. In the present study we demonstrate that adipogenesis is greatly increased in mouse embryonic fibroblasts (MEFs) from CAIII knockout (KO) mice, as demonstrated by a greater than 10-fold increase in the induction of fatty acid-binding protein-4 (FABP4) and increased triglyceride formation inmore » CAIII{sup -/-} MEFs compared with CAIII{sup +/+} cells. To address the underlying mechanism, we investigated the expression of the two adipogenic key regulators, peroxisome proliferator-activated receptor-{gamma}2 (PPAR{gamma}2) and CCAAT/enhancer binding protein-{alpha}. We found a considerable (approximately 1000-fold) increase in the PPAR{gamma}2 expression in the CAIII{sup -/-} MEFs. Furthermore, RNAi-mediated knockdown of endogenous CAIII in NIH 3T3-L1 preadipocytes resulted in a significant increase in the induction of PPAR{gamma}2 and FABP4. When both CAIII and PPAR{gamma}2 were knocked down, FABP4 was not induced. We conclude that down-regulation of CAIII in preadipocytes enhances adipogenesis and that CAIII is a regulator of adipogenic differentiation which acts at the level of PPAR{gamma}2 gene expression. -- Highlights: Black-Right-Pointing-Pointer We discover a novel function of Carbonic anhydrase III (CAIII). Black-Right-Pointing-Pointer We show that CAIII is a regulator of adipogenesis. Black-Right-Pointing-Pointer We demonstrate that CAIII acts at the level of PPAR{gamma}2 gene expression. Black-Right-Pointing-Pointer Our data contribute to a better understanding of the role of CAIII in fat tissue.« less

  6. Structural and Biochemical Basis for the Binding Selectivity of Peroxisome Proliferator-activated Receptor [gamma] to PGC-1[alpha

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, Yong; Kovach, Amanda; Suino-Powell, Kelly

    2008-07-23

    The functional interaction between the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and its coactivator PGC-1{alpha} is crucial for the normal physiology of PPAR{gamma} and its pharmacological response to antidiabetic treatment with rosiglitazone. Here we report the crystal structure of the PPAR{gamma} ligand-binding domain bound to rosiglitazone and to a large PGC-1{alpha} fragment that contains two LXXLL-related motifs. The structure reveals critical contacts mediated through the first LXXLL motif of PGC-1{alpha} and the PPAR{gamma} coactivator binding site. Through a combination of biochemical and structural studies, we demonstrate that the first LXXLL motif is the most potent among all nuclear receptor coactivator motifsmore » tested, and only this motif of the two LXXLL-related motifs in PGC-1{alpha} is capable of binding to PPAR{gamma}. Our studies reveal that the strong interaction of PGC-1{alpha} and PPAR{gamma} is mediated through both hydrophobic and specific polar interactions. Mutations within the context of the full-length PGC-1{alpha} indicate that the first PGC-1{alpha} motif is necessary and sufficient for PGC-1{alpha} to coactivate PPAR{gamma} in the presence or absence of rosiglitazone. These results provide a molecular basis for specific recruitment and functional interplay between PPAR{gamma} and PGC-1{alpha} in glucose homeostasis and adipocyte differentiation.« less

  7. Behavioral effects of gamma-hydroxybutyrate, its precursor gamma-butyrolactone, and GABA(B) receptor agonists: time course and differential antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348).

    PubMed

    Koek, Wouter; Mercer, Susan L; Coop, Andrew; France, Charles P

    2009-09-01

    Gamma-hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by which GHB produces its therapeutic and recreational effects is not entirely clear, although GABA(B) receptors seem to play an important role. This role could be complex, because there are indications that different GABA(B) receptor mechanisms mediate the effects of GHB and the prototypical GABA(B) receptor agonist baclofen. To further explore possible differences in underlying GABA(B) receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding and their antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348). Pigeons were trained to peck a key for access to food during response periods that started at different times after the beginning of the session. In these pigeons, GHB, its precursor gamma-butyrolactone (GBL), and the GABA(B) receptor agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) decreased the rate of responding in a dose- and time-dependent manner. CGP35348 shifted the dose-response curve of each agonist to the right, but the magnitude of the shift differed among the agonists. Schild analysis yielded a pA(2) value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7-4.2)] that was different (P = 0.0011) from the pA(2) value to antagonize baclofen and SKF97541 [i.e., 4.5 (4.4-4.7)]. This finding is further evidence that the GABA(B) receptor mechanisms mediating the effects of GHB and prototypical GABA(B) receptor agonists are not identical. A better understanding of the similarities and differences between these mechanisms, and their involvement in the therapeutic effects of GHB and baclofen, could lead to more effective medications with fewer adverse effects.

  8. Phenotypic consequences of deletion of the {gamma}{sub 3}, {alpha}{sub 5}, or {beta}{sub 3} subunit of the type A {gamma}-aminobutyric acid receptor in mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Culia, C.T.; Stubbs, L.J.; Montgomery, C.S.

    1994-03-29

    Three genes (Gabrg3, Gabra5, and Gabrb3) encoding the {gamma}{sub 3}, {alpha}{sub 5}, and {beta}{sub 3} subunits of the type A {gamma}-aminobutyric acid receptor, respectively, are known to map near the pink-eyed dilution (p) locus in mouse chromosome 7. This region shares homology with a segment of human chromosome 15 that is implicated in Angelman syndrome, an inherited neurobehavioral disorder. By mapping Gabrg3-Gabra5-Gabrb3-telomere. Like Gabrb3, neither the Gabra5 nor Gabrg3 gene is functionally imprinted in adult mouse brain. Mice deleted for all three subunits die at birth with a cleft palate, although there are rare survivors ({approximately} 5%) that do notmore » have a cleft palate but do exhibit a neurological abnormality characterized by tremor, jerky gait, and runtiness. The authors have previously suggested that deficiency of the {beta}{sub 3} subunit may be responsible for the clefting defect. Most notably, however, in this report they describe mice carrying two overlapping, complementing p deletions that fail to express the {gamma}{sub 3} transcript, as well as mice from another line that express neither the {gamma}{sub 3} nor {alpha}{sub 5} transcripts. Surprisingly, mice from both of these lines are phenotypically normal and do not exhibit any of the neurological symptoms characteristic of the rare survivors that are deleted for all three ({gamma}{sub 3}, {alpha}{sub 5}, and {beta}{sub 3}) subunits. These mice therefore provide a whole-organism type A {gamma}-aminobutyric-acid receptor background that is devoid of any receptor subtypes that normally contain the {gamma}{sub 3} and/or {alpha}{sub 5} subunits. The absence of an overt neurological phenotype in mice lacking the {gamma}{sub 3} and/or {alpha}{sub 5} subunits also suggests that mutations in these genes are unlikely to provide useful animal models for Angelman syndrome in humans.« less

  9. Dual role of SLP-76 in mediating T cell receptor-induced activation of phospholipase C-gamma1.

    PubMed

    Beach, Dvora; Gonen, Ronnie; Bogin, Yaron; Reischl, Ilona G; Yablonski, Deborah

    2007-02-02

    Phospholipase C-gamma1 (PLC-gamma1) activation depends on a heterotrimeric complex of adaptor proteins composed of LAT, Gads, and SLP-76. Upon T cell receptor stimulation, a portion of PLC-gamma1 is recruited to a detergent-resistant membrane fraction known as the glycosphingolipid-enriched membrane microdomains (GEMs), or lipid rafts, to which LAT is constitutively localized. In addition to LAT, PLC-gamma1 GEM recruitment depended on SLP-76, and, in particular, required the Gads-binding domain of SLP-76. The N-terminal tyrosine phosphorylation sites and P-I region of SLP-76 were not required for PLC-gamma1 GEM recruitment, but were required for PLC-gamma1 phosphorylation at Tyr(783). Thus, GEM recruitment can be insufficient for full activation of PLC-gamma1 in the absence of a second SLP-76-mediated event. Indeed, a GEM-targeted derivative of PLC-gamma1 depended on SLP-76 for T cell receptor-induced phosphorylation at Tyr783 and subsequent NFAT activation. On a biochemical level, SLP-76 inducibly associated with both Vav and catalytically active ITK, which efficiently phosphorylated a PLC-gamma1 fragment at Tyr783 in vitro. Both associations were disrupted upon mutation of the N-terminal tyrosine phosphorylation sites of SLP-76. The P-I region deletion disrupted Vav association and reduced SLP-76-associated kinase activity. A smaller deletion within the P-I region, which does not impair PLC-gamma1 activation, did not impair the association with Vav, but reduced SLP-76-associated kinase activity. These results provide new insight into the multiple roles of SLP-76 and the functional importance of its interactions with other signaling proteins.

  10. Fc gamma receptor 3a genotype predicts overall survival in follicular lymphoma patients treated on SWOG trials with combined monoclonal antibody plus chemotherapy but not chemotherapy alone

    PubMed Central

    Persky, Daniel O.; Dornan, David; Goldman, Bryan H.; Braziel, Rita M.; Fisher, Richard I.; LeBlanc, Michael; Maloney, David G.; Press, Oliver W.; Miller, Thomas P.; Rimsza, Lisa M.

    2012-01-01

    Background Fc gamma receptor polymorphisms were linked to outcome in follicular lymphoma patients treated with single-agent rituximab, an anti-CD20 monoclonal antibody. In particular, 158F/F genotype of Fc gamma receptor 3A and 131R/R genotype of Fc gamma receptor 2A correlated with worse outcome compared to high-affinity 158V/V and 131H/H, respectively. We examined this association in the context of anti-CD20 monoclonal antibody combined with chemotherapy, as compared to chemotherapy alone, in follicular lymphoma patients treated on SWOG clinical trials. Design and Methods Tissue from 142 SWOG patients treated with chemotherapy alone (protocol S8809, n=70) or combined chemotherapy and anti-CD20 monoclonal antibody (rituximab and Iodine I-131 tositumomab on protocols S9800 and S9911, n=30 and 42, respectively) was analyzed. DNA was extracted and assayed for Fc gamma receptor 3A V158F and 2A R131H polymorphisms using a TaqMan SNP assay. Stratified Cox’s regression was used to assess association with overall survival. Results For Fc gamma receptor 3A, there was an association with overall survival in the combination therapy trials but not in the chemotherapy-only trial. Having at least one Fc gamma receptor 3A V allele was associated with improved overall survival versus F/F (HR=0.33, 95% CI, 0.11, 0.96, P=0.042). For overall survival, there was evidence of a statistical interaction between the use of mAb and the number of V alleles (0, 1, or 2) (P=0.006). There was no such association for Fc gamma receptor 2A. Conclusions Fc gamma receptor 3A polymorphism status may be predictive of survival in follicular lymphoma patients receiving treatments containing an anti-CD20 antibody but not treatment with chemotherapy alone. Thus, Fc gamma receptor 3A polymorphisms may be important to consider in designing new follicular lymphoma trials and new anti-CD20 monoclonal antibodies. PMID:22271896

  11. Cell death is induced by ciglitazone, a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonist, independently of PPAR{gamma} in human glioma cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, Myoung Woo; Kim, Dae Seong; Kim, Hye Ryung

    Highlights: Black-Right-Pointing-Pointer Greater than 30 {mu}M ciglitazone induces cell death in glioma cells. Black-Right-Pointing-Pointer Cell death by ciglitazone is independent of PPAR{gamma} in glioma cells. Black-Right-Pointing-Pointer CGZ induces cell death by the loss of MMP via decreased Akt. -- Abstract: Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPAR{gamma} in CGZ-induced cell death was examined. At concentrations of greater than 30 {mu}M, CGZ, a synthetic PPAR{gamma} agonist, activated caspase-3 and induced apoptosis inmore » T98G cells. Treatment of T98G cells with less than 30 {mu}M CGZ effectively induced cell death after pretreatment with 30 {mu}M of the PPAR{gamma} antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPAR{gamma} was down-regulated cells by siRNA, lower concentrations of CGZ (<30 {mu}M) were sufficient to induce cell death, although higher concentrations of CGZ ( Greater-Than-Or-Slanted-Equal-To 30 {mu}M) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPAR{gamma}. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPAR{gamma} in glioma cells, by down-regulating Akt activity and inducing MMP collapse.« less

  12. Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex.

    PubMed

    Özkan, Mazhar; Johnson, Nicholas W; Sehirli, Umit S; Woodhall, Gavin L; Stanford, Ian M

    2017-01-01

    The loss of dopamine (DA) in Parkinson's is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1) and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 μM) and kainic acid (KA, 150 nM) elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84) and 34.97 ± 0.39 Hz (gamma, n = 84). Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1.

  13. Unsaturated free fatty acids increase benzodiazepine receptor agonist binding depending on the subunit composition of the GABAA receptor complex.

    PubMed

    Witt, M R; Westh-Hansen, S E; Rasmussen, P B; Hastrup, S; Nielsen, M

    1996-11-01

    It has been shown previously that unsaturated free fatty acids (FFAs) strongly enhance the binding of agonist benzodiazepine receptor ligands and GABAA receptor ligands in the CNS in vitro. To investigate the selectivity of this effect, recombinant human GABAA/benzodiazepine receptor complexes formed by different subunit compositions (alpha x beta y gamma 2, x = 1, 2, 3, and 5; y = 1, 2, and 3) were expressed using the baculovirus-transfected Sf9 insect cell system. At 10(-4) M, unsaturated FFAs, particularly arachidonic (20:4) and docosahexaenoic (22:6) acids, strongly stimulated (> 200% of control values) the binding of [3H]flunitrazepam ([3H]FNM) to the alpha 3 beta 2 gamma 2 receptor combination in whole cell preparations. No effect or small increases in levels of unsaturated FFAs on [3H]FNM binding to alpha 1 beta x gamma 2 and alpha 2 beta x gamma 2 receptor combinations were observed, and weak effects (130% of control values) were detected using the alpha 5 beta 2 gamma 2 receptor combination. The saturated FFAs, stearic and palmitic acids, were without effect on [3H]FNM binding to any combination of receptor complexes. The hydroxylated unsaturated FFAs, ricinoleic and ricinelaidic acids, were shown to decrease the binding of [3H]FNM only if an alpha 1 beta 2 gamma 2 receptor combination was used. Given the heterogeneity of the GABAA/ benzodiazepine receptor subunit distribution in the CNS, the effects of FFAs on the benzodiazepine receptor can be assumed to vary at both cellular and regional levels.

  14. High-frequency gamma oscillations coexist with low-frequency gamma oscillations in the rat visual cortex in vitro.

    PubMed

    Oke, Olaleke O; Magony, Andor; Anver, Himashi; Ward, Peter D; Jiruska, Premysl; Jefferys, John G R; Vreugdenhil, Martin

    2010-04-01

    Synchronization of neuronal activity in the visual cortex at low (30-70 Hz) and high gamma band frequencies (> 70 Hz) has been associated with distinct visual processes, but mechanisms underlying high-frequency gamma oscillations remain unknown. In rat visual cortex slices, kainate and carbachol induce high-frequency gamma oscillations (fast-gamma; peak frequency approximately 80 Hz at 37 degrees C) that can coexist with low-frequency gamma oscillations (slow-gamma; peak frequency approximately 50 Hz at 37 degrees C) in the same column. Current-source density analysis showed that fast-gamma was associated with rhythmic current sink-source sequences in layer III and slow-gamma with rhythmic current sink-source sequences in layer V. Fast-gamma and slow-gamma were not phase-locked. Slow-gamma power fluctuations were unrelated to fast-gamma power fluctuations, but were modulated by the phase of theta (3-8 Hz) oscillations generated in the deep layers. Fast-gamma was spatially less coherent than slow-gamma. Fast-gamma and slow-gamma were dependent on gamma-aminobutyric acid (GABA)(A) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and gap-junctions, their frequencies were reduced by thiopental and were weakly dependent on cycle amplitude. Fast-gamma and slow-gamma power were differentially modulated by thiopental and adenosine A(1) receptor blockade, and their frequencies were differentially modulated by N-methyl-D-aspartate (NMDA) receptors, GluK1 subunit-containing receptors and persistent sodium currents. Our data indicate that fast-gamma and slow-gamma both depend on and are paced by recurrent inhibition, but have distinct pharmacological modulation profiles. The independent co-existence of fast-gamma and slow-gamma allows parallel processing of distinct aspects of vision and visual perception. The visual cortex slice provides a novel in vitro model to study cortical high-frequency gamma oscillations.

  15. Prefrontal gamma-aminobutyric acid type A receptor insertion controls cue-induced relapse to nicotine seeking.

    PubMed

    Lubbers, Bart R; van Mourik, Yvar; Schetters, Dustin; Smit, August B; De Vries, Taco J; Spijker, Sabine

    2014-11-01

    Current smoking cessation therapies offer limited success, as relapse rates remain high. Nicotine, which is the major component of tobacco smoke, is thought to be primarily responsible for the addictive properties of tobacco. However, little is known about the molecular mechanisms underlying nicotine relapse, hampering development of more effective therapies. The objective of this study was to elucidate the role of medial prefrontal cortex (mPFC) glutamatergic and gamma-aminobutyric acid (GABA)ergic receptors in controlling relapse to nicotine seeking. Using an intravenous self-administration model, we studied glutamate and gamma-aminobutyric acid receptor regulation in the synaptic membrane fraction of the rat mPFC following extinction and cue-induced relapse to nicotine seeking. Subsequently, we locally intervened at the level of GABAergic signaling by using a mimetic peptide of the GABA receptor associated protein-interacting domain of GABA type A (GABAA) receptor subunit γ2 (TAT-GABAγ2) and muscimol, a GABAA receptor agonist. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors were not regulated after the 30-min relapse test. However, GABAA receptor subunits α1 and γ2 were upregulated, and interference with GABAA receptor insertion in the cell membrane using the TAT-GABAγ2 peptide in the dorsal mPFC, but not the ventral mPFC, significantly increased responding during relapse. Increasing GABAA transmission with muscimol in the dorsal and ventral mPFC attenuated relapse. These data indicate that cue-induced relapse entails a GABAergic plasticity mechanism that limits nicotine seeking by restoring inhibitory control in the dorsal mPFC. GABAA receptor-mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  16. Evidence for a gamma-interferon receptor that regulates macrophage tumoricidal activity

    PubMed Central

    1984-01-01

    -beta competed only weakly. Monoclonal antibodies against IFN-gamma either inhibited or enhanced MAF activity by blocking or increasing IFN-gamma binding to macrophages, respectively. These results indicate that IFN-gamma reacts with a receptor on macrophage in a specific and saturable manner and this interaction initiates macrophage activation. PMID:6330272

  17. Disruption of transforming growth factor-beta signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-gamma in rat hepatic stellate cells.

    PubMed

    Zheng, Shizhong; Chen, Anping

    2007-01-01

    Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor-beta (TGF-beta) and a dramatic reduction in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The relationship between them remains obscure. We previously demonstrated that curcumin induced gene expression of PPAR-gamma in activated HSC, leading to reducing cell proliferation, inducing apoptosis and suppressing expression of extracellular matrix genes. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR-gamma activation suppressed gene expression of TGF-beta receptors in activated HSC, leading to the interruption of TGF-beta signaling. This observation supported our assumption of an antagonistic relationship between PPAR-gamma activation and TGF-beta signaling in HSC. In this study, we further hypothesize that TGF-beta signaling might negatively regulate gene expression of PPAR-gamma in activated HSC. The present report demonstrates that exogenous TGF-beta1 inhibits gene expression of PPAR-gamma in activated HSC, which is eliminated by the pretreatment with curcumin likely by interrupting TGF-beta signaling. Transfection assays further indicate that blocking TGF-beta signaling by dominant negative type II TGF-beta receptor increases the promoter activity of PPAR-gamma gene. Promoter deletion assays, site-directed mutageneses, and gel shift assays localize two Smad binding elements (SBEs) in the PPAR-gamma gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Overexpression of Smad4 dose dependently eliminates the inhibitory effects of curcumin on the PPAR-gamma gene promoter and TGF-beta signaling. Taken together, these results demonstrate that the interruption of TGF

  18. Transcriptional corepressor SMILE recruits SIRT1 to inhibit nuclear receptor estrogen receptor-related receptor gamma transactivation.

    PubMed

    Xie, Yuan-Bin; Park, Jeong-Hoh; Kim, Don-Kyu; Hwang, Jung Hwan; Oh, Sangmi; Park, Seung Bum; Shong, Minho; Lee, In-Kyu; Choi, Hueng-Sik

    2009-10-16

    SMILE (small heterodimer partner interacting leucine zipper protein) has been identified as a corepressor of the glucocorticoid receptor, constitutive androstane receptor, and hepatocyte nuclear factor 4alpha. Here we show that SMILE also represses estrogen receptor-related receptor gamma (ERRgamma) transactivation. Knockdown of SMILE gene expression increases ERRgamma activity. SMILE directly interacts with ERRgamma in vitro and in vivo. Domain mapping analysis showed that SMILE binds to the AF2 domain of ERRgamma. SMILE represses ERRgamma transactivation partially through competition with coactivators PGC-1alpha, PGC-1beta, and GRIP1. Interestingly, the repression of SMILE on ERRgamma is released by SIRT1 inhibitors, a catalytically inactive SIRT1 mutant, and SIRT1 small interfering RNA but not by histone protein deacetylase inhibitor. In vivo glutathione S-transferase pulldown and coimmunoprecipitation assays validated that SMILE physically interacts with SIRT1. Furthermore, the ERRgamma inverse agonist GSK5182 enhances the interaction of SMILE with ERRgamma and SMILE-mediated repression. Knockdown of SMILE or SIRT1 blocks the repressive effect of GSK5182. Moreover, chromatin immunoprecipitation assays revealed that GSK5182 augments the association of SMILE and SIRT1 on the promoter of the ERRgamma target PDK4. GSK5182 and adenoviral overexpression of SMILE cooperate to repress ERRgamma-induced PDK4 gene expression, and this repression is released by overexpression of a catalytically defective SIRT1 mutant. Finally, we demonstrated that ERRgamma regulates SMILE gene expression, which in turn inhibits ERRgamma. Overall, these findings implicate SMILE as a novel corepressor of ERRgamma and recruitment of SIRT1 as a novel repressive mechanism for SMILE and ERRgamma inverse agonist.

  19. MHC class I, beta2 microglobulin, and the INF-gamma receptor are upregulated in aged motoneurons.

    PubMed

    Edström, Erik; Kullberg, Susanna; Ming, Yu; Zheng, Huaiyu; Ulfhake, Brun

    2004-12-15

    During aging, spinal cord motoneurons show characteristic changes including the loss of afferent boutons, a selective process that associates with gliosis and behavioral motor impairment. Evidence suggests that the major histocompatibility complex Class I (MHC I) system may be involved in synaptic plasticity of neurons during development and regeneration. In search of a mechanism governing senescent changes in synaptic connectivity, we report evidence for increased expression of MHC I and beta2 microglobulin (beta2M) in motoneurons and glial-like profiles of 30-month-old rats. The regulatory signal(s) for MHC I expression in normal neurons remains unresolved but among tentative molecules are cytokines such as interferon-gamma (INF-gamma) and tumor necrosis factor alpha (TNF-alpha). Interestingly, aged motoneurons, overlapping with those showing increased levels of MHC I, contained increased levels of INF-gamma receptor message. INF-gamma mRNA was detected at low levels in most (8/9) of the aged spinal cords but only infrequently (2/9) in young adult spinal cords; however, the cellular localization of INF-gamma mRNA could not be determined. Our data also indicates that TNF-alpha is upregulated in the senescent spinal cord but that TNF-alpha immunoreactive protein does not associate with motoneurons. We report evidence for an increased expression of MHC I and beta2M in senescent spinal motoneurons and discuss the possibility that this regulation associates with INF-gamma or changes in neurotrophin signaling and neuron activity in senescence. (c) 2004 Wiley-Liss, Inc.

  20. Portable compton gamma-ray detection system

    DOEpatents

    Rowland, Mark S [Alamo, CA; Oldaker, Mark E [Pleasanton, CA

    2008-03-04

    A Compton scattered gamma-ray detector system. The system comprises a gamma-ray spectrometer and an annular array of individual scintillators. The scintillators are positioned so that they are arrayed around the gamma-ray spectrometer. The annular array of individual scintillators includes a first scintillator. A radiation shield is positioned around the first scintillator. A multi-channel analyzer is operatively connected to the gamma-ray spectrometer and the annular array of individual scintillators.

  1. High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R.

    PubMed

    Shields, R L; Namenuk, A K; Hong, K; Meng, Y G; Rae, J; Briggs, J; Xie, D; Lai, J; Stadlen, A; Li, B; Fox, J A; Presta, L G

    2001-03-02

    Immunoglobulin G (IgG) Fc receptors play a critical role in linking IgG antibody-mediated immune responses with cellular effector functions. A high resolution map of the binding site on human IgG1 for human Fc gamma RI, Fc gamma RIIA, Fc gamma RIIB, Fc gamma RIIIA, and FcRn receptors has been determined. A common set of IgG1 residues is involved in binding to all Fc gamma R; Fc gamma RII and Fc gamma RIII also utilize residues outside this common set. In addition to residues which, when altered, abrogated binding to one or more of the receptors, several residues were found that improved binding only to specific receptors or simultaneously improved binding to one type of receptor and reduced binding to another type. Select IgG1 variants with improved binding to Fc gamma RIIIA exhibited up to 100% enhancement in antibody-dependent cell cytotoxicity using human effector cells; these variants included changes at residues not found at the binding interface in the IgG/Fc gamma RIIIA co-crystal structure (Sondermann, P., Huber, R., Oosthuizen, V., and Jacob, U. (2000) Nature 406, 267-273). These engineered antibodies may have important implications for improving antibody therapeutic efficacy.

  2. Digital gamma-gamma coincidence HPGe system for environmental analysis.

    PubMed

    Marković, Nikola; Roos, Per; Nielsen, Sven Poul

    2017-08-01

    The performance of a new gamma-gamma coincidence spectrometer system for environmental samples analysis at the Center for Nuclear Technologies of the Technical University of Denmark (DTU) is reported. Nutech Coincidence Low Energy Germanium Sandwich (NUCLeGeS) system consists of two HPGe detectors in a surface laboratory with a digital acquisition system used to collect the data in time-stamped list mode with 10ns time resolution. The spectrometer is used in both anticoincidence and coincidence modes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Matsui, Takanori; Yamagishi, Sho-ichi, E-mail: shoichi@med.kurume-u.ac.jp; Takeuchi, Masayoshi

    2010-07-23

    Research highlights: {yields} Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma}. {yields} GW9662 treatment alone increased RAGE mRNA levels in tubular cells. {yields} Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-{beta} gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenicmore » reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE

  4. Acetylcholine Release in Prefrontal Cortex Promotes Gamma Oscillations and Theta-Gamma Coupling during Cue Detection.

    PubMed

    Howe, William M; Gritton, Howard J; Lusk, Nicholas A; Roberts, Erik A; Hetrick, Vaughn L; Berke, Joshua D; Sarter, Martin

    2017-03-22

    The capacity for using external cues to guide behavior ("cue detection") constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta-gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection. SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding ("cue detection") is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to

  5. Acetylcholine Release in Prefrontal Cortex Promotes Gamma Oscillations and Theta–Gamma Coupling during Cue Detection

    PubMed Central

    Hetrick, Vaughn L.; Berke, Joshua D.

    2017-01-01

    The capacity for using external cues to guide behavior (“cue detection”) constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta–gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection. SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding (“cue detection”) is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex

  6. Channel opening of gamma-aminobutyric acid receptor from rat brain: molecular mechanisms of the receptor responses.

    PubMed

    Cash, D J; Subbarao, K

    1987-12-01

    The function of gamma-aminobutyric acid (GABA) receptors, which mediate transmembrane chloride flux, can be studied by use of 36Cl- isotope tracer with membrane from mammalian brain by quench-flow technique, with reaction times that allow resolution of the receptor desensitization rates from the ion flux rates. The rates of chloride exchange into the vesicles in the absence and presence of GABA were characterized with membrane from rat cerebral cortex. Unspecific 36Cl- influx was completed in three phases of ca. 3% (t 1/2 = 0.6 s), 56% (t 1/2 = 82 s), and 41% (t 1/2 = 23 min). GABA-mediated, specific chloride exchange occurred with 6.5% of the total vesicular internal volume. The GABA-dependent 36Cl- influx proceeded in two phases, each progressively slowed by desensitization. The measurements supported the presence of two distinguishable active GABA receptors on the same membrane mediating chloride exchange into the vesicles with initial first-order rate constants of 9.5 s-1 and 2.3 s-1 and desensitizing with first-order rate constants of 21 s-1 and 1.4 s-1, respectively, at saturation. The half-response concentrations were similar for both receptors, 150 microM and 114 microM GABA for desensitization and 105 microM and 82 microM for chloride exchange, for the faster and slower desensitizing receptors, respectively. The two receptors were present in the activity ratio of ca. 4/1, similar to the ratio of "low-affinity" to "high-affinity" GABA sites found in ligand binding experiments. The desensitization rates have a different dependence on GABA concentration than the channel-opening equilibria.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Matsui, Takanori; Yamagishi, Sho-ichi, E-mail: shoichi@med.kurume-u.ac.jp; Takeuchi, Masayoshi

    2009-07-24

    The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) productionmore » in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}). Although nifedipine did not affect expression levels of PPAR-{gamma}, it increased the PPAR-{gamma} transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-{gamma} activation.« less

  8. The N-methyl-D-aspartate receptor subunits NR2A and NR2B bind to the SH2 domains of phospholipase C-gamma.

    PubMed

    Gurd, J W; Bissoon, N

    1997-08-01

    The NMDA receptor has recently been found to be phosphorylated on tyrosine. To assess the possible connection between tyrosine phosphorylation of the NMDA receptor and signaling pathways in the postsynaptic cell, we have investigated the relationship between tyrosine phosphorylation and the binding of NMDA receptor subunits to the SH2 domains of phospholipase C-gamma (PLC-gamma). A glutathione S-transferase (GST) fusion protein containing both the N- and the C-proximal SH2 domains of PLC-gamma was bound to glutathione-agarose and reacted with synaptic junctional proteins and glycoproteins. Tyrosine-phosphorylated PSD-GP180, which has been identified as the NR2B subunit of the NMDA receptor, bound to the SH2-agarose beads in a phosphorylation-dependent fashion. Immunoblot analysis with antibodies specific for individual NMDA receptor subunits showed that both NR2A and NR2B subunits bound to the SH2-agarose. No binding occurred to GST-agarose lacking an associated SH2 domain, indicating that binding was specific for the SH2 domains. The binding of receptor subunits increased after the incubation of synaptic junctions with ATP and decreased after treatment of synaptic junctions with exogenous protein tyrosine phosphatase. Immunoprecipitation experiments confirmed that NR2A and NR2B were phosphorylated on tyrosine and further that tyrosine phosphorylation of each of the subunits was increased after incubation with ATP. The results demonstrate that NMDA receptor subunits NR2A and NR2B will bind to the SH2 domains of PLC-gamma and that isolated synaptic junctions contain endogenous protein tyrosine kinase(s) that can phosphorylate both NR2A and NR2B receptor subunits, and suggest that interaction of the tyrosine-phosphorylated NMDA receptor with proteins that contain SH2 domains may serve to link it to signaling pathways in the postsynaptic cell.

  9. Interferon-gamma receptor-deficiency renders mice highly susceptible to toxoplasmosis by decreased macrophage activation.

    PubMed

    Deckert-Schlüter, M; Rang, A; Weiner, D; Huang, S; Wiestler, O D; Hof, H; Schlüter, D

    1996-12-01

    Toxoplasma gondii may cause severe infections in immunocompromised patients including fetuses and those with AIDS. Among the factors mediating protection against T. gondii, IFN-gamma has gained special attention. To analyze the role of IFN-gamma in the early phase of toxoplasmosis, IFN-gamma receptor-deficient (IFN-gamma R0/0) mice were orally infected with low-virulent toxoplasms. IFN-gamma R0/0 mice died of the disease up to day 10 postinfection, whereas immunocompetent wild-type (WT) mice developed a chronic toxoplasmosis. Histopathology revealed that in IFN-gamma R0/0 mice, the parasite multiplied unrestrictedly in the small intestine, the intestinal lymphatic tissue, the liver, and the spleen. Ultimately, animals died of a necrotizing hepatitis. In WT mice, the same organs were effected, but multiplication of the parasite was effectively limited. Compared with WT mice, immunohistochemistry and flow cytometry demonstrated that in IFN-gamma R0/0 mice, macrophages were only marginally activated in response to the infection, as evidenced by a reduced expression of major histocompatability complex class II antigens. In addition, immunohistochemistry and RT-PCR showed a reduced production of the macrophage-derived cytokines tumor necrosis factor-alpha, inducible nitric oxide synthase, and IL-1 beta in the liver of IFN-gamma R0/0 mice. In contrast, activation of T cells, recruitment of immune cells to inflammatory foci, and anti-T. gondii IgM antibody production were unaffected by the mutation of the IFN-gamma R. Moreover, induction of IL-2, IL-4, and IL-10 mRNA transcripts in the liver was normal in IFN-gamma R0/0 mice. Adoptive transfer experiments revealed that the immune T cells of WT animals did not protect IFN-gamma R0/0 mice from lethal infection with highly virulent toxoplasms, whereas WT mice were significantly protected by the adoptive transfer. Based on these studies, we conclude that IFN-gamma is absolutely required for an efficient activation of

  10. The Differential Interactions of Peroxisome Proliferator-Activated Receptor [gamma] Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Einstein, Monica; Akiyama, Taro E.; Castriota, Gino A.

    2008-08-01

    Despite their proven antidiabetic efficacy, widespread use of peroxisome proliferator-activated receptor (PPAR){gamma} agonists has been limited by adverse cardiovascular effects. To overcome this shortcoming, selective PPAR{gamma} modulators (SPPAR{gamma}Ms) have been identified that have antidiabetic efficacy comparable with full agonists with improved tolerability in preclinical species. The results of structural studies support the proposition that SPPAR{gamma}Ms interact with PPAR{gamma} differently from full agonists, thereby providing a physical basis for their novel activities. Herein, we describe a novel PPAR{gamma} ligand, SPPAR{gamma}M2. This compound was a partial agonist in a cell-based transcriptional activity assay, with diminished adipogenic activity and an attenuated gene signaturemore » in cultured human adipocytes. X-ray cocrystallography studies demonstrated that, unlike rosiglitazone, SPPAR{gamma}M2 did not interact with the Tyr473 residue located within helix 12 of the ligand binding domain (LBD). Instead, SPPAR{gamma}M2 was found to bind to and activate human PPAR{gamma} in which the Tyr473 residue had been mutated to alanine (hPPAR{gamma}Y473A), with potencies similar to those observed with the wild-type receptor (hPPAR{gamma}WT). In additional studies, we found that the intrinsic binding and functional potencies of structurally distinct SPPAR{gamma}Ms were not diminished by the Y473A mutation, whereas those of various thiazolidinedione (TZD) and non-TZD PPAR{gamma} full agonists were reduced in a correlative manner. These results directly demonstrate the important role of Tyr473 in mediating the interaction of full agonists but not SPPAR{gamma}Ms with the PPAR{gamma} LBD, thereby providing a precise molecular determinant for their differing pharmacologies.« less

  11. Peroxisome proliferator-activated receptor {gamma} is expressed in hippocampal neurons and its activation prevents {beta}-amyloid neurodegeneration: role of Wnt signaling

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Inestrosa, Nibaldo C.; Godoy, Juan A.; MIFAB, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago

    2005-03-10

    The molecular pathogenesis of Alzheimer's disease (AD) involves the participation of the amyloid-{beta}-peptide (A{beta}), which plays a critical role in the neurodegeneration that triggers the disease. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which are members of the nuclear receptor family. We report here that (1) PPAR{gamma} is present in rat hippocampal neurons in culture. (2) Activation of PPAR{gamma} by troglitazone and rosiglitazone protects rat hippocampal neurons against A{beta}-induced neurodegeneration, as shown by the 3-[4,5 -2yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay, immunofluorescence using an anti-heavy neurofilament antibody, and quantitative electron microscopy. (3) Hippocampal neurons treated with several PPAR{gamma} agonists, includingmore » troglitazone, rosiglitazone, and ciglitazone, prevent the excitotoxic A{beta}-induced rise in bulk-free Ca{sup 2+}. (4) PPAR{gamma} activation results in the modulation of Wnt signaling components, including the inhibition of glycogen synthase kinase-3{beta} (GSK-3{beta}) and an increase of the cytoplasmic and nuclear {beta}-catenin levels. We conclude that the activation of PPAR{gamma} prevents A{beta}-induced neurodegeneration by a mechanism that may involve a cross talk between neuronal PPAR{gamma} and the Wnt signaling pathway. More important, the fact that the activation of PPAR{gamma} attenuated A{beta}-dependent neurodegeneration opens the possibility to fight AD from a new therapeutic perspective.« less

  12. Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-gamma receptor-deficient hosts.

    PubMed

    Delisle, Jean-Sébastien; Gaboury, Louis; Bélanger, Marie-Pier; Tassé, Eliane; Yagita, Hideo; Perreault, Claude

    2008-09-01

    The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I cytokine, interferon-gamma (IFN-gamma), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)-mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-gamma-receptor-deficient (IFN-gammaRKO) MHC-matched C57BL/6 recipients. In IFN-gammaRKO recipients, host cells were unresponsive to IFN-gamma, whereas wt donor cells were exposed to exceptionally high levels of IFN-gamma. From an IFN-gamma perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-of-function on donor cells. We found that lack of IFN-gammaR prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-gammaRKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-gamma: Ccnd1 and Myc. We conclude that IFN-gamma produced by alloreactive T cells may entail a severe graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD.

  13. The insulin receptor substrate-1-related 4PS substrate but not the interleukin-2R gamma chain is involved in interleukin-13-mediated signal transduction.

    PubMed

    Wang, L M; Michieli, P; Lie, W R; Liu, F; Lee, C C; Minty, A; Sun, X J; Levine, A; White, M F; Pierce, J H

    1995-12-01

    Interleukin-13 (IL-13) induced a potent mitogenic response in IL-3-dependent TF-1 cells and DNA synthesis to a lesser extent in MO7E and FDC-P1 cells. IL-13 stimulation of these lines, like IL-4 and insulin-like growth factor-1 (IGF-1), resulted in tyrosine phosphorylation of a 170-kD substrate. The tyrosine-phosphorylated 170-kD substrate strongly associated with the 85-kD subunit of phosphoinositol-3 (PI-3) kinase and with Grb-2. Anti-4PS serum readily detected the 170-kD substrate in lysates from both TF-1 and FDC-P1 cells stimulated with IL-13 or IL-4. These data provide evidence that IL-13 induces tyrosine phosphorylation of the 4PS substrate, providing an essential interface between the IL-13 receptor and signaling molecules containing SH2 domains. IL-13 and IL-4 stimulation of murine L cell fibroblasts, which endogenously express the IL-4 receptor (IL-4R alpha) and lack expression of the IL-2 receptor gamma subunit (IL-2R gamma), resulted in tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1)/4PS. Enhanced tyrosine phosphorylation of IRS-1/4PS was observed in response to IL-4, but not IL-13 treatment of L cells transfected with the IL-2R gamma chain. These results indicate that IL-13 does not use the IL-2R gamma subunit in its receptor complex and that expression of IL-2R gamma enhances, but is not absolutely required for mediating IL-4-induced tyrosine phosphorylation of IRS-1/4PS.

  14. Activation-induced proteolysis of cytoplasmic domain of zeta in T cell receptors and Fc receptors.

    PubMed

    Taupin, J L; Anderson, P

    1994-12-01

    The CD3-T cell receptor (TCR) complex on T cells and the Fc gamma receptor type III (Fc gamma RIII)-zeta-gamma complex on natural killer cells are functionally analogous activation receptors that associate with a family of disulfide-linked dimers composed of the related subunits zeta and gamma. Immunochemical analysis of receptor complexes separated on two-dimensional diagonal gels allowed the identification of a previously uncharacterized zeta-p14 heterodimer. zeta-p14 is a component of both CD3-TCR and Fc gamma RIII-zeta-gamma. Peptide mapping analysis shows that p14 is structurally related to zeta, suggesting that it is either: (i) derived from zeta proteolytically or (ii) the product of an alternatively spliced mRNA. The observation that COS cells transformed with a cDNA encoding zeta express zeta-p14 supports the former possibility. The expression of CD3-TCR complexes including zeta-p14 increases following activation with phorbol 12-myristate 13-acetate or concanavalin A, suggesting that proteolysis of zeta may contribute to receptor modulation or desensitization.

  15. Molecular size of the gamma-aminobutyric acidA receptor purified from mammalian cerebral cortex.

    PubMed

    Mamalaki, C; Barnard, E A; Stephenson, F A

    1989-01-01

    The hydrodynamic behaviour of both the soluble and purified gamma-aminobutyric acidA (GABAA) receptor of bovine or rat cerebral cortex has been investigated in solution in Triton X-100 or in 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulphonate (CHAPS). In all the hydrodynamic separations made, it was found that the binding activities for GABA, benzodiazepine, and (where detectable) t-butylbicyclophosphorothionate comigrated. Conditions were established for gel exclusion chromatography and for sucrose density gradient velocity sedimentation that maintain the GABAA receptor in a nonaggregated form. Using these conditions, the molecular weight of the bovine GABAA receptor in the above-mentioned detergents was calculated using the H2O/2H2O method. A value of Mr 230,000-240,000 was calculated for the bovine pure GABAA receptor purified in sodium deoxycholate/Triton X-100 media. A value of Mr 284,000-290,000 was calculated for the nonaggregated bovine or rat cortex receptor in CHAPS, but the Stokes radius is smaller in the latter than in the former medium and the detergent binding in CHAPS is underestimated. Thus the deduced Mr, 240,000, is the best estimate by this method.

  16. Gamma-Aminobutyric acid and benzodiazepine receptors in the kindling model of epilepsy: a quantitative radiohistochemical study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shin, C.; Pedersen, H.B.; McNamara, J.O.

    1985-10-01

    Quantitative radiohistochemistry was utilized to study alterations of gamma-aminobutyric acid (GABA) and benzodiazepine receptors in the kindling model of epilepsy. The radioligands used for GABA and benzodiazepine receptors were (TH) muscimol and (TH)flunitrazepam, respectively. GABA receptor binding was increased by 22% in fascia dentata of the hippocampal formation but not in neocortex or substantia nigra of kindled rats. Within fascia dentata, GABA receptor binding was increased to an equivalent extent in stratum granulosum and throughout stratum moleculare; no increase was found in dentate hilus or stratum lacunosummoleculare or stratum radiatum of CA1. The increased binding was present at 24 hrmore » but not at 28 days after the last kindled seizure. The direction, anatomic distribution, and time course of the increased GABA receptor binding were paralleled by increased benzodiazepine receptor binding. The anatomic distribution of the increased GABA receptor binding is consistent with a localization to somata and dendritic trees of dentate granule cells. The authors suggest that increased GABA and benzodiazepine receptor binding may contribute to enhanced inhibition of dentate granule cells demonstrated electrophysiologically in kindled animals.« less

  17. Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-{gamma}-dependent activity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro

    2011-07-08

    Highlights: {yields} Telmisartan, an angiotensin receptor blocker, acts as a partial PPAR{gamma} agonist. {yields} The protective effects of telmisartan against diabetic vascular injury were associated with attenuation of vascular NF{kappa}B activation and TNF {alpha}. {yields} PPAR{gamma} activity of telmisartan was involved in the normalization of vascular PPAR{gamma} downregulation in diabetic mice. {yields} We provided the first evidence indicating that PPAR{gamma} activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. -- Abstract: Experimental and clinical data support the notion that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan,more » an angiotensin receptor blocker (ARB), acts as a partial PPAR{gamma} agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPAR{gamma} activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPAR{gamma} antagonist), and losartan with no PPAR{gamma} activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NF{kappa}B) activation and tumor necrosis factor {alpha}. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPAR{gamma} activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation

  18. Gamma-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor pi subunit.

    PubMed

    Takehara, Akio; Hosokawa, Masayo; Eguchi, Hidetoshi; Ohigashi, Hiroaki; Ishikawa, Osamu; Nakamura, Yusuke; Nakagawa, Hidewaki

    2007-10-15

    Gamma-aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter in the mature central nervous system, and GABA/GABA receptors are also present in nonneural tissues, including cancer, but their precise function in nonneuronal or cancerous cells has thus far been poorly defined. Through the genome-wide cDNA microarray analysis of pancreatic ductal adenocarcinoma (PDAC) cells as well as subsequent reverse transcription-PCR and Northern blot analyses, we identified the overexpression of GABA receptor pi subunit (GABRP) in PDAC cells. We also found the expression of this peripheral type GABAA receptor subunit in few adult human organs. Knockdown of endogenous GABRP expression in PDAC cells by small interfering RNA attenuated PDAC cell growth, suggesting its essential role in PDAC cell viability. Notably, the addition of GABA into the cell culture medium promoted the proliferation of GABRP-expressing PDAC cells, but not GABRP-negative cells, and GABAA receptor antagonists inhibited this growth-promoting effect by GABA. The HEK293 cells constitutively expressing exogenous GABRP revealed the growth-promoting effect of GABA treatment. Furthermore, GABA treatment in GABRP-positive cells increased intracellular Ca2+ levels and activated the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) cascade. Clinical PDAC tissues contained a higher level of GABA than normal pancreas tissues due to the up-regulation of glutamate decarboxylase 1 expression, suggesting their autocrine/paracrine growth-promoting effect in PDACs. These findings imply that GABA and GABRP could play important roles in PDAC development and progression, and that this pathway can be a promising molecular target for the development of new therapeutic strategies for PDAC.

  19. A gamma beam profile imager for ELI-NP Gamma Beam System

    NASA Astrophysics Data System (ADS)

    Cardarelli, P.; Paternò, G.; Di Domenico, G.; Consoli, E.; Marziani, M.; Andreotti, M.; Evangelisti, F.; Squerzanti, S.; Gambaccini, M.; Albergo, S.; Cappello, G.; Tricomi, A.; Veltri, M.; Adriani, O.; Borgheresi, R.; Graziani, G.; Passaleva, G.; Serban, A.; Starodubtsev, O.; Variola, A.; Palumbo, L.

    2018-06-01

    The Gamma Beam System of ELI-Nuclear Physics is a high brilliance monochromatic gamma source based on the inverse Compton interaction between an intense high power laser and a bright electron beam with tunable energy. The source, currently being assembled in Magurele (Romania), is designed to provide a beam with tunable average energy ranging from 0.2 to 19.5 MeV, rms energy bandwidth down to 0.5% and flux of about 108 photons/s. The system includes a set of detectors for the diagnostic and complete characterization of the gamma beam. To evaluate the spatial distribution of the beam a gamma beam profile imager is required. For this purpose, a detector based on a scintillator target coupled to a CCD camera was designed and a prototype was tested at INFN-Ferrara laboratories. A set of analytical calculations and Monte Carlo simulations were carried out to optimize the imager design and evaluate the performance expected with ELI-NP gamma beam. In this work the design of the imager is described in detail, as well as the simulation tools used and the results obtained. The simulation parameters were tuned and cross-checked with the experimental measurements carried out on the assembled prototype using the beam from an x-ray tube.

  20. Role of polymorphic Fc receptor Fc gammaRIIa in cytokine release and adverse effects of murine IgG1 anti-CD3/T cell receptor antibody (WT31).

    PubMed

    Tax, W J; Tamboer, W P; Jacobs, C W; Frenken, L A; Koene, R A

    1997-01-15

    Anti-CD3 monoclonal antibody (mAb) OKT3 is immunosuppressive, but causes severe adverse effects during the first administration ("first-dose reaction"). These adverse effects are presumably caused by cytokine release that results from T-cell activation. In vitro, T-cell activation by anti-CD3 mAb requires interaction with monocyte Fc receptors. The Fc receptor for murine IgG1, Fc gammaRIIa, is polymorphic. In some individuals, murine IgG1 anti-CD3 mAb causes T-cell proliferation and cytokine release in vitro (high responders [HR]), whereas in individuals with the low-responder (LR) phenotype it does not. We have now investigated the role of this Fc gammaRIIa polymorphism in the release of cytokines in vivo and the occurrence of adverse effects after the administration of WT31, a murine IgG1 anti-CD3/T cell receptor mAb. WT31 caused an increase of plasma tumor necrosis factor-alpha in all four HR patients and none of the five LR patients. In all HR patients except one, plasma gamma-interferon and interleukin 6 also increased, and a first-dose response was observed, whereas no cytokine release or adverse effects occurred in any of the LR patients. WT31 caused lymphopenia in all HR and none of the LR patients. FACS analysis demonstrated that in HR patients, after the initial disappearance of CD3+ cells from peripheral blood, modulation of CD3 occurred, whereas in LR patients a high degree of coating of the lymphocytes was observed. Surprisingly, WT31 also induced a marked granulocytopenia, as well as a decrease of thrombocytes, in three of the four HR patients (and in none of the LR patients). These data provide direct clinical evidence that Fc receptor interaction determines the release of cytokines and the occurrence of adverse effects after administration of anti-CD3/T cell receptor mAb. Furthermore, these data suggest that tumor necrosis factor-alpha by itself is not sufficient to induce the first-dose reaction.

  1. Membrane receptor location defines receptor interaction with signaling proteins in a polarized epithelium.

    PubMed

    Amsler, K; Kuwada, S K

    1999-01-01

    Signal transduction from receptors is mediated by the interaction of activated receptors with proximate downstream signaling proteins. In polarized epithelial cells, the membrane is divided into subdomains: the apical and basolateral membranes. Membrane receptors may be present in one or both subdomains. Using a combination of immunoprecipitation and Western blot analyses, we tested the hypothesis that a tyrosine kinase growth factor receptor, epidermal growth factor receptor (EGFR), interacts with distinct signaling proteins when present at the apical vs. basolateral membrane of a polarized renal epithelial cell. We report here that tyrosine phosphorylation of phospholipase C-gamma (PLC-gamma) was induced only when basolateral EGFR was activated. In contrast, tyrosine phosphorylation of several other signaling proteins was increased by activation of receptor at either surface. All signaling proteins were distributed diffusely throughout the cytoplasm; however, PLC-gamma protein also displayed a concentration at lateral cell borders. These results demonstrate that in polarized epithelial cells the array of signaling pathways initiated by activation of a membrane receptor is defined, at least in part, by the membrane location of the receptor.

  2. Antagonist of peroxisome proliferator-activated receptor {gamma} induces cerebellar amyloid-{beta} levels and motor dysfunction in APP/PS1 transgenic mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Du, Jing; Sun, Bing; Chen, Kui

    2009-07-03

    Recent evidences show that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is involved in the modulation of the amyloid-{beta} (A{beta}) cascade causing Alzheimer's disease (AD) and treatment with PPAR{gamma} agonists protects against AD pathology. However, the function of PPAR{gamma} steady-state activity in A{beta} cascade and AD pathology remains unclear. In this study, an antagonist of PPAR{gamma}, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPAR{gamma} activity in cerebellum. The results show that inhibition of PPAR{gamma} significantly induced A{beta} levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellarmore » levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degradation of A{beta}. Since cerebellum is spared from significant A{beta} accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPAR{gamma} steady-state activity in protection of cerebellum against AD pathology.« less

  3. Differential expression of largemouth bass (Micropterus salmoides) estrogen receptor isotypes alpha, beta, and gamma by estradiol.

    PubMed

    Sabo-Attwood, Tara; Kroll, Kevin J; Denslow, Nancy D

    2004-04-15

    The expression levels of three estrogen receptor (ER) isotypes alpha, beta, and gamma were quantified in female largemouth bass (Micropterus salmoides) (LMB) liver, ovary, brain, and pituitary tissues. ER alpha and beta expression predominated in the liver, while ERs beta and gamma predominated in the other tissues. Temporally in females, ER alpha was highly up-regulated, ER gamma was slightly up-regulated, and ER beta levels remained unchanged in the liver when plasma 17-beta estradiol (E2) and vitellogenin (Vtg) levels were elevated in the spring. In ovarian tissue from these same fish, all three ERs were maximally expressed in the fall, during early oocyte development and prior to peak plasma E2 levels. When males were injected with E2, ER alpha was highly inducible, ER gamma was moderately up-regulated, and ER beta levels were not affected. None of the ER isotypes were induced by E2 in gonadal tissues. These results combined suggest that the ERs themselves are not regulated in the same manner by E2, and furthermore, do not contribute equally to the transcriptional regulation of genes involved in fish reproduction such as Vtg.

  4. Receptor-selective retinoids implicate retinoic acid receptor alpha and gamma in the regulation of bmp-2 and bmp-4 in F9 embryonal carcinoma cells.

    PubMed

    Rogers, M B

    1996-01-01

    The effect of retinoids on malignant cells and embryos indicates that retinoids influence the expression of growth factors or alter the response of cells to growth factors. The bone morphogenetic proteins, Bmp-2 and Bmp-4, are candidates for such growth factors because retinoic acid (RA) treatment of F9 embryonal carcinoma cells induced Bmp-2 mRNA, while simultaneously repressing Bmp-4 levels. Also, recombinant Bmp-2 affected the growth and differentiation of these cells. Regulation of each gene was concentration dependent and required continuous RA treatment. The short half-lives of the Bmp-2 (75 +/- 11 min) and Bmp-4 (70 +/- 4 min) mRNAs suggest that their abundance is primarily controlled at the transcriptional level. To determine which RA receptor (RAR) controls bmp-2 and bmp-4 expression, F9 cells were exposed to various receptor-selective retinoids. RAR alpha- and gamma-selective retinoids induced Bmp-2 and repressed Bmp-4 equally as well as all-trans RA. In contrast, a RAR beta-selective retinoid had little effect on Bmp-2 induction but repressed Bmp-4. A RAR alpha-selective antagonist inhibited all-trans RA stimulation of Bmp-2, although not as dramatically as a RAR beta gamma-selective antagonist. No differences were observed between Bmp levels in all-trans RA and 9-cis RA-treated cells, indicating that the RXRs play little part in controlling these genes. The results are consistent with RAR alpha and gamma-controlled Bmp-2 and Bmp-4 regulation.

  5. Effects of aberrant gamma frequency oscillations on prepulse inhibition.

    PubMed

    Jones, Nigel C; Anderson, Paul; Rind, Gil; Sullivan, Caley; van den Buuse, Maarten; O'Brien, Terence J

    2014-10-01

    Emerging literature implicates abnormalities in gamma frequency oscillations in the pathophysiology of schizophrenia, with hypofunction of N-methyl-D-aspartate (NMDA) receptors implicated as a key factor. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating, which is disrupted in schizophrenia. We studied relationships between ongoing and sensory-evoked gamma oscillations and PPI using pharmacological interventions designed to increase gamma oscillations (ketamine, MK-801); reduce gamma oscillations (LY379268); or disrupt PPI (amphetamine). We predicted that elevating ongoing gamma power would lead to increased 'neural noise' in cortical circuits, dampened sensory-evoked gamma responses and disrupted behaviour. Wistar rats were implanted with EEG recording electrodes. They received ketamine (5 mg/kg), MK-801 (0.16 mg/kg), amphetamine (0.5 mg/kg), LY379268 (3 mg/kg) or vehicle and underwent PPI sessions with concurrent EEG recording. Ketamine and MK-801 increased the power of ongoing gamma oscillations and caused time-matched disruptions of PPI, while amphetamine marginally affected ongoing gamma power. In contrast, LY379268 reduced ongoing gamma power, but had no effect on PPI. The sensory gamma response evoked by the prepulse was reduced following treatment with all psychotomimetics, associating with disruptions in PPI. This was most noticeable following treatment with NMDA receptor antagonists. We found that ketamine and MK-801 increase ongoing gamma power and reduce evoked gamma power, both of which are related to disruptions in sensorimotor gating. This appears to be due to antagonism of NMDA receptors, since amphetamine and LY379268 differentially impacted these outcomes and possess different neuropharmacological substrates. Aberrant gamma frequency oscillations caused by NMDA receptor hypofunction may mediate the sensory processing deficits observed in schizophrenia.

  6. Epidermal Growth Factor Receptor Signaling Enhances the Proinflammatory Effects of Staphylococcus aureus Gamma-Toxin on the Mucosa.

    PubMed

    Gillman, Aaron N; Breshears, Laura M; Kistler, Charles K; Finnegan, Patrick M; Torres, Victor J; Schlievert, Patrick M; Peterson, Marnie L

    2017-06-28

    Staphylococcus aureus ( S. aureus ) produces many different exotoxins including the gamma-toxins, HlgAB and HlgCB. Gamma-toxins form pores in both leukocyte and erythrocyte membranes, resulting in cell lysis. The genes encoding gamma-toxins are present in most strains of S. aureus, and are commonly expressed in clinical isolates recovered from menstrual Toxic Shock Syndrome (mTSS) patients. This study set out to investigate the cytotoxic and proinflammatory effects of gamma-toxins on vaginal epithelial surfaces. We found that both HlgAB and HlgCB were cytotoxic to cultured human vaginal epithelial cells (HVECs) and induced cytokine production at sub-cytotoxic doses. Cytokine production induced by gamma-toxin treatment of HVECs was found to involve epidermal growth factor receptor (EGFR) signaling and mediated by shedding of EGFR ligands from the cell surface. The gamma-toxin subunits displayed differential binding to HVECs (HlgA 93%, HlgB 97% and HlgC 28%) with both components (HlgAB or HlgCB) required for maximum detectable binding and significant stimulation of cytokine production. In studies using full thickness ex vivo porcine vaginal mucosa, HlgAB or HlgCB stimulated a dose-dependent cytokine response, which was reduced significantly by inhibition of EGFR signaling. The effects of gamma-toxins on porcine vaginal tissue and cultured HVECs were validated using ex vivo human ectocervical tissue. Collectively, these studies have identified the EGFR-signaling pathway as a key component in gamma-toxin-induced proinflammatory changes at epithelial surfaces and highlight a potential therapeutic target to diminish toxigenic effects of S. aureus infections.

  7. Tyrosine phosphorylation and association of Syk with Fc gamma RII in monocytic THP-1 cells.

    PubMed Central

    Ghazizadeh, S; Bolen, J B; Fleit, H B

    1995-01-01

    Although the cytoplasmic portion of the low-affinity receptor for immunoglobulin G, Fc gamma RII, does not contain a kinase domain, rapid tyrosine phosphorylation of intracellular substrates occurs in response to aggregation of the receptor. The use of specific tyrosine kinase inhibitors has suggested that these phosphorylations are required for subsequent cellular responses. We previously demonstrated the coprecipitation of a tyrosine kinase activity with Fc gamma RII, suggesting that non-receptor tyrosine kinases might associate with the cytoplasmic domain of Fc gamma RII. Anti-receptor immune complex kinase assays revealed the coprecipitation of several phosphoproteins, most notably p56/53lyn, an Src-family protein tyrosine kinase (PTK), and a 72 kDa phosphoprotein. Here we identify the 72 kDa Fc gamma RII-associated protein as p72syk (Syk), a member of a newly described family of non-receptor PTKs. A rapid and transient tyrosine phosphorylation of Syk was observed following Fc gamma RII activation. Syk was also tyrosyl-phosphorylated following aggregation of the high-affinity Fc gamma receptor, Fc gamma RI. The Fc gamma RI activation did not result in association of Syk with Fc gamma RII, implying that distinct pools of Syk are activated upon aggregation of each receptor in a localized manner. These results demonstrate a physical association between Syk and Fc gamma RII and suggest that the molecules involved in Fc gamma RII signalling are very similar to the ones utilized by multichain immune recognition receptors such as the B-cell antigen receptor and the high-affinity IgE receptor. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7530449

  8. [Coactivators in energy metabolism: peroxisome proliferator-activated receptor-gamma coactivator 1 family].

    PubMed

    Wang, Rui; Chang, Yong-sheng; Fang, Fu-de

    2009-12-01

    Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) family is highly expressed in tissues with high energy metabolism. They coactivate transcription factors in regulating genes engaged in processes such as gluconeogenesis, adipose beta-oxydation, lipoprotein synthesis and secretion, mitochondrial biogenesis, and oxidative metabolism. Protein conformation studies demonstrated that they lack DNA binding domains and act as coactivators through physical interaction with transcription factors. PGC1 activity is regulated at transcription level or by multiple covalent chemical modifications such as phosphorylation, methylation and acetylation/deacetylation. Abnormal expression of PGC1 coactivators usually is closely correlated with diseases such as diabetes, obesity, hyperglycemia, hyperlipemia, and arterial and brain neuron necrosis diseases.

  9. Over-expression of C/EBP-{alpha} induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-{gamma}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang Xueqing; Huang Guangcun; Mei Shuang

    2009-03-06

    Hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic fibrosis. In our previous studies, CCAAT enhancer binding protein-{alpha} (C/EBP-{alpha}) has been shown to be involved in the activation of HSCs and to have a repression effect on hepatic fibrosis in vivo. However, the mechanisms are largely unknown. In this study, we show that the infection of adenovirus vector expressing C/EBP-{alpha} gene (Ad-C/EBP-{alpha}) could induce HSCs apoptosis in a dose- and time-dependent manner by Annexin V/PI staining, caspase-3 activation assay, and flow cytometry. Also, over-expression of C/EBP-{alpha} resulted in the up-regulation of peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) andmore » P53, while P53 expression was regulated by PPAR-{gamma}. In addition, Fas, FasL, DR4, DR5, and TRAIL were studied. The results indicated that the death receptor pathway was mainly involved and regulated by PPAR-{gamma} and p53 in the process of apoptosis triggered by C/EBP-{alpha} in HSCs.« less

  10. Food deprivation modulates gamma-aminobutyric acid receptors and peripheral benzodiazepine binding sites in rats.

    PubMed

    Weizman, A; Bidder, M; Fares, F; Gavish, M

    1990-12-03

    The effect of 5 days of food deprivation followed by 5 days of refeeding on gamma-aminobutyric acid (GABA) receptors, central benzodiazepine receptors (CBR), and peripheral benzodiazepine binding sites (PBzS) was studied in female Sprague-Dawley rats. Starvation induced a decrease in the density of PBzS in peripheral organs: adrenal (35%; P less than 0.001), kidney (33%; P less than 0.01), and heart (34%; P less than 0.001). Restoration of [3H]PK 11195 binding to normal values was observed in all three organs after 5 days of refeeding. The density of PBzS in the ovary, pituitary, and hypothalamus was not affected by starvation. Food deprivation resulted in a 35% decrease in cerebellar GABA receptors (P less than 0.01), while CBR in the hypothalamus and cerebral cortex remained unaltered. The changes in PBzS observed in the heart and kidney may be related to the long-term metabolic stress associated with starvation and to the functional changes occurring in these organs. The down-regulation of the adrenal PBzS is attributable to the suppressive effect of hypercortisolemia on pituitary ACTH release. The reduction in cerebellar GABA receptors may be an adaptive response to food deprivation stress and may be relevant to the proaggressive effect of hunger.

  11. Peroxisome proliferator-activated receptor-{gamma} agonists inhibit the replication of respiratory syncytial virus (RSV) in human lung epithelial cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Arnold, Ralf; Koenig, Wolfgang

    2006-07-05

    We have previously shown that peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) agonists inhibited the inflammatory response of RSV-infected human lung epithelial cells. In this study, we supply evidence that specific PPAR{gamma} agonists (15d-PGJ{sub 2}, ciglitazone, troglitazone, Fmoc-Leu) efficiently blocked the RSV-induced cytotoxicity and development of syncytia in tissue culture (A549, HEp-2). All PPAR{gamma} agonists under study markedly inhibited the cell surface expression of the viral G and F protein on RSV-infected A549 cells. This was paralleled by a reduced cellular amount of N protein-encoding mRNA determined by real-time RT-PCR. Concomitantly, a reduced release of infectious progeny virus into the cell supernatants ofmore » human lung epithelial cells (A549, normal human bronchial epithelial cells (NHBE)) was observed. Similar results were obtained regardless whether PPAR{gamma} agonists were added prior to RSV infection or thereafter, suggesting that the agonists inhibited viral gene expression and not the primary adhesion or fusion process.« less

  12. Structural analysis and localization of the carbohydrate moieties of a soluble human interferon gamma receptor produced in baculovirus-infected insect cells.

    PubMed Central

    Manneberg, M.; Friedlein, A.; Kurth, H.; Lahm, H. W.; Fountoulakis, M.

    1994-01-01

    A soluble form of the human interferon gamma receptor that is required for the identification of interferon gamma antagonists was expressed in baculovirus-infected insect cells. The protein carried N-linked carbohydrate and showed a heterogeneity on denaturing polyacrylamide gels. We investigated the utilization of the potential sites for N-linked glycosylation and the structure of the carbohydrate moieties of this soluble receptor. Amino acid sequence analysis and ion spray mass spectrometry revealed that of the five potential sites for N-linked glycosylation, Asn17 and Asn69 were always utilized, whereas Asn62 and Asn162 were utilized in approximately one-third of the protein population. Asn223 was never found to be glycosylated. The soluble receptor was treated with N-glycosidase F and the oligosaccharides released were analyzed by matrix-assisted laser desorption mass spectrometry, which showed that the protein carried six types of short carbohydrate chains. The predominant species was a hexasaccharide of molecular mass 1,039, containing a fucose subunit linked to the proximal N-acetylglucosamine residue: [formula: see text] PMID:8142896

  13. Bruton's tyrosine kinase regulates B cell antigen receptor-mediated JNK1 response through Rac1 and phospholipase C-gamma2 activation.

    PubMed

    Inabe, Kazunori; Miyawaki, Toshio; Longnecker, Richard; Matsukura, Hiroyoshi; Tsukada, Satoshi; Kurosaki, Tomohiro

    2002-03-13

    Bruton's tyrosine kinase (Btk) is essential for B cell development and B cell antigen receptor (BCR) function. Recent studies have shown that Btk plays an important role in BCR-mediated c-Jun NH(2)-terminal kinase (JNK) 1 activation; however, the mechanism by which Btk participates in the JNK1 response remains elusive. Here we show that the BCR-mediated Rac1 activation is significantly inhibited by loss of Btk, while this Rac1 activation is not affected by loss of phospholipase C-gamma2 (PLC-gamma2). Since PLC-gamma2 is also required for BCR-mediated JNK1 response, our results suggest that Btk regulates Rac1 pathway as well as PLC-gamma2 pathway, both of which contribute to the BCR-mediated JNK1 response.

  14. GABAB receptor-mediated, layer-specific synaptic plasticity reorganizes gamma-frequency neocortical response to stimulation

    PubMed Central

    Ainsworth, Matthew; Lee, Shane; Kaiser, Marcus; Simonotto, Jennifer; Kopell, Nancy J.

    2016-01-01

    Repeated presentations of sensory stimuli generate transient gamma-frequency (30–80 Hz) responses in neocortex that show plasticity in a task-dependent manner. Complex relationships between individual neuronal outputs and the mean, local field potential (population activity) accompany these changes, but little is known about the underlying mechanisms responsible. Here we show that transient stimulation of input layer 4 sufficient to generate gamma oscillations induced two different, lamina-specific plastic processes that correlated with lamina-specific changes in responses to further, repeated stimulation: Unit rates and recruitment showed overall enhancement in supragranular layers and suppression in infragranular layers associated with excitatory or inhibitory synaptic potentiation onto principal cells, respectively. Both synaptic processes were critically dependent on activation of GABAB receptors and, together, appeared to temporally segregate the cortical representation. These data suggest that adaptation to repetitive sensory input dramatically alters the spatiotemporal properties of the neocortical response in a manner that may both refine and minimize cortical output simultaneously. PMID:27118845

  15. GABAB receptor-mediated, layer-specific synaptic plasticity reorganizes gamma-frequency neocortical response to stimulation.

    PubMed

    Ainsworth, Matthew; Lee, Shane; Kaiser, Marcus; Simonotto, Jennifer; Kopell, Nancy J; Whittington, Miles A

    2016-05-10

    Repeated presentations of sensory stimuli generate transient gamma-frequency (30-80 Hz) responses in neocortex that show plasticity in a task-dependent manner. Complex relationships between individual neuronal outputs and the mean, local field potential (population activity) accompany these changes, but little is known about the underlying mechanisms responsible. Here we show that transient stimulation of input layer 4 sufficient to generate gamma oscillations induced two different, lamina-specific plastic processes that correlated with lamina-specific changes in responses to further, repeated stimulation: Unit rates and recruitment showed overall enhancement in supragranular layers and suppression in infragranular layers associated with excitatory or inhibitory synaptic potentiation onto principal cells, respectively. Both synaptic processes were critically dependent on activation of GABAB receptors and, together, appeared to temporally segregate the cortical representation. These data suggest that adaptation to repetitive sensory input dramatically alters the spatiotemporal properties of the neocortical response in a manner that may both refine and minimize cortical output simultaneously.

  16. 78. Augmenting NMDA Receptor Signaling Enhances Working Memory and Alters Gamma Oscillations in Patients With Schizophrenia

    PubMed Central

    Forsyth, Jennifer; Bachman, Peter; Asarnow, Robert

    2017-01-01

    Abstract Background: Gamma band oscillations (30–80 Hz) are associated with numerous sensory and higher cognitive functions and are abnormal in patients with schizophrenia. Glutamate signaling at the N-methyl-D-aspartate receptor (NMDAR) is theorized to play a key role in the pathophysiology of schizophrenia and NMDAR antagonists disrupt working memory and gamma oscillations in healthy individuals. It has therefore been suggested that NMDAR dysfunction may contribute to abnormalities in gamma oscillations and working memory in schizophrenia. In the current study, we examined the effects of acutely augmenting NMDAR signaling using the NMDAR agonist, d-cycloserine (DCS), on working memory and gamma power in patients with schizophrenia. Methods: In a double-blind design, patients with schizophrenia were randomized to receive a single dose of 100 mg DCS (SZ-DCS; n = 24) or Placebo (SZ-PLC; n = 21). Patients completed a spatial n-back task involving a 0-back control condition and 1-back and 2-back working memory loads while undergoing EEG recording. Gamma power (30–80 Hz) during the 0-back condition assessed gamma power associated with basic perceptual, motor, and attentive processes. Change in gamma power for correct working memory trials relative to the 0-back condition assessed gamma power associated with working memory function. Results: Among patients who performed above chance (SZ-DCS = 17, SZ-PLC = 16), patients who received DCS showed superior working memory performance compared to patients who received Placebo. Gamma power during the 0-back control condition was similar between SZ-DCS and SZ-PLC who performed above chance. However, gamma power associated with working memory function was significantly suppressed in SZ-DCS compared to SZ-PLC, particularly over frontal right channels. In addition, whereas higher working memory gamma power over frontal right channels was associated with better working memory performance in SZ-PLC, this relationship

  17. Molecular And Structural Basis of Cytokine Receptor Pleiotropy in the Interleukin-4/13 System

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    LaPorte, S.L.; Juo, Z.S.; Vaclavikova, J.

    2009-05-20

    Interleukin-4 and Interleukin-13 are cytokines critical to the development of T cell-mediated humoral immune responses, which are associated with allergy and asthma, and exert their actions through three different combinations of shared receptors. Here we present the crystal structures of the complete set of type I (IL-4R{alpha}/{gamma}{sub c}/IL-4) and type II (IL-4R/IL-13R{alpha}1/IL-4, IL-4R{alpha}/IL-13R{alpha}1/IL-13) ternary signaling complexes. The type I complex reveals a structural basis for {gamma}{sub c}'s ability to recognize six different {gamma}{sub c}-cytokines. The two type II complexes utilize an unusual top-mounted Ig-like domain on IL-13R{alpha}1 for a novel mode of cytokine engagement that contributes to a reversal inmore » the IL-4 versus IL-13 ternary complex assembly sequences, which are mediated through substantially different recognition chemistries. We also show that the type II receptor heterodimer signals with different potencies in response to IL-4 versus IL-13 and suggest that the extracellular cytokine-receptor interactions are modulating intracellular membrane-proximal signaling events.« less

  18. Gamma-ray tracking method for pet systems

    DOEpatents

    Mihailescu, Lucian; Vetter, Kai M.

    2010-06-08

    Gamma-ray tracking methods for use with granular, position sensitive detectors identify the sequence of the interactions taking place in the detector and, hence, the position of the first interaction. The improved position resolution in finding the first interaction in the detection system determines a better definition of the direction of the gamma-ray photon, and hence, a superior source image resolution. A PET system using such a method will have increased efficiency and position resolution.

  19. The insecticide fipronil and its metabolite fipronil sulphone inhibit the rat alpha1beta2gamma2L GABA(A) receptor.

    PubMed

    Li, P; Akk, G

    2008-11-01

    Fipronil is the active ingredient in a number of widely used insecticides. Human exposure to fipronil leads to symptoms (headache, nausea and seizures) typically associated with the antagonism of GABA(A) receptors in the brain. In this study, we have examined the modulation of the common brain GABA(A) receptor subtype by fipronil and its major metabolite, fipronil sulphone. Whole-cell and single-channel recordings were made from HEK 293 cells transiently expressing rat alpha1beta2gamma2L GABA(A) receptors. The major effect of fipronil was to increase the rate of current decay in macroscopic recordings. In single-channel recordings, the presence of fipronil resulted in shorter cluster durations without affecting the intracluster open and closed time distributions or the single-channel conductance. The alpha1V256S mutation, previously shown alleviate channel inhibition by inhibitory steroids and several insecticides, had a relatively small effect on channel block by fipronil. The mode of action of fipronil sulphone was similar to that of its parent compound but the metabolite was less potent at inhibiting the alpha1beta2gamma2L receptor. We conclude that exposure to fipronil induces accumulation of receptors in a novel, long-lived blocked state. This process proceeds in parallel with and independently of, channel desensitization. The lower potency of fipronil sulphone indicates that the conversion serves as a detoxifying process in mammalian brain.

  20. Atomic force microscopy of ionotropic receptors bearing subunit-specific tags provides a method for determining receptor architecture

    NASA Astrophysics Data System (ADS)

    Neish, Calum S.; Martin, Ian L.; Davies, Martin; Henderson, Robert M.; Edwardson, J. Michael

    2003-08-01

    We have developed an atomic force microscopy (AFM)-based method for the determination of the subunit architecture of ionotropic receptors, and tested the method using the GABAA receptor as a model system. The most common form of the GABAA receptor probably consists of 2alpha1-, 2beta2- and 1gamma2-subunits. We show here that the arrangement of subunits around the central Cl- ion channel can be deduced by AFM of receptors tagged with subunit-specific antibodies. Transfection of cells with DNA encoding alpha1-, beta2- and gamma2-subunits resulted in the production of receptors containing all three subunits, as judged by both immunoblot analysis and the binding of [3H]-Ro15-1788, a specific radioligand for the GABAA receptor. A His6-tag on the alpha1-subunit was used to purify the receptor from membrane fractions of transfected cells. After incubation with anti-His6 immunoglobulin G, some receptors became tagged with either one or two antibody molecules. AFM analysis of complexes containing two bound antibodies showed that the most common angle between the two tags was 135°, close to the value of 144° expected if the two alpha-subunits are separated by a third subunit. This method is applicable to the complete elucidation of the subunit arrangement around the GABAA receptor rosette, and can also be applied to other ionotropic receptors.

  1. The Advanced Gamma-Ray Imaging System (AGIS)

    NASA Astrophysics Data System (ADS)

    Otte, Nepomuk

    The Advanced Gamma-ray Imaging System (AGIS) is a concept for the next generation of imag-ing atmospheric Cherenkov telescope arrays. It has the goal of providing an order of magnitude increase in sensitivity for Very High Energy Gamma-ray ( 100 GeV to 100 TeV) astronomy compared to currently operating arrays such as CANGAROO, HESS, MAGIC, and VERITAS. After an overview of the science such an array would enable, we discuss the development of the components of the telescope system that are required to achieve the sensitivity goal. AGIS stresses improvements in several areas of IACT technology including component reliability as well as exploring cost reduction possibilities in order to achieve its goal. We discuss alterna-tives for the telescopes and positioners: a novel Schwarzschild-Couder telescope offering a wide field of view with a relatively smaller plate scale, and possibilities for rapid slewing in order to address the search for and/or study of Gamma-ray Bursts in the VHE gamma-ray regime. We also discuss options for a high pixel count camera system providing the necessary finer solid angle per pixel and possibilities for a fast topological trigger that would offer improved realtime background rejection and lower energy thresholds.

  2. Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma.

    PubMed

    Pferschy-Wenzig, Eva-Maria; Atanasov, Atanas G; Malainer, Clemens; Noha, Stefan M; Kunert, Olaf; Schuster, Daniela; Heiss, Elke H; Oberlies, Nicholas H; Wagner, Hildebert; Bauer, Rudolf; Dirsch, Verena M

    2014-04-25

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism. Agonists of this nuclear receptor are used in the treatment of type 2 diabetes and are also studied as a potential treatment of other metabolic diseases, including nonalcoholic fatty liver disease. Silymarin, a concentrated phenolic mixture from milk thistle (Silybum marianum) seeds, is used widely as a supportive agent in the treatment of a variety of liver diseases. In this study, the PPARγ activation potential of silymarin and its main constituents was investigated. Isosilybin A (3) caused transactivation of a PPARγ-dependent luciferase reporter in a concentration-dependent manner. This effect could be reversed upon co-treatment with the PPARγ antagonist T0070907. In silico docking studies suggested a binding mode for 3 distinct from that of the inactive silymarin constituents, with one additional hydrogen bond to Ser342 in the entrance region of the ligand-binding domain of the receptor. Hence, isosilybin A (3) has been identified as the first flavonolignan PPARγ agonist, suggesting its further investigation as a modulator of this nuclear receptor.

  3. Transcriptional activation of peroxisome proliferator-activated receptor-{gamma} requires activation of both protein kinase A and Akt during adipocyte differentiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Sang-pil; Ha, Jung Min; Yun, Sung Ji

    2010-08-13

    Research highlights: {yields} Elevated cAMP activates both PKA and Epac. {yields} PKA activates CREB transcriptional factor and Epac activates PI3K/Akt pathway via Rap1. {yields} Akt modulates PPAR-{gamma} transcriptional activity in concert with CREB. -- Abstract: Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) is required for the conversion of pre-adipocytes. However, the mechanism underlying activation of PPAR-{gamma} is unclear. Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-{gamma}. Hormonal induction of adipogenesis was blocked by a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), by a protein kinase A (PKA) inhibitor (H89), and by amore » Rap1 inhibitor (GGTI-298). Transcriptional activity of PPAR-{gamma} was markedly enhanced by 3-isobutyl-1-methylxanthine (IBMX), but not insulin and dexamethasone. In addition, IBMX-induced PPAR-{gamma} transcriptional activity was blocked by PI3K/Akt, PKA, or Rap1 inhibitors. 8-(4-Chlorophenylthio)-2'-O-methyl-cAMP (8-pCPT-2'-O-Me-cAMP) which is a specific agonist for exchanger protein directly activated by cAMP (Epac) significantly induced the activation of Akt. Furthermore, knock-down of Akt1 markedly attenuated PPAR-{gamma} transcriptional activity. These results indicate that both PKA and Akt signaling pathways are required for transcriptional activation of PPAR-{gamma}, suggesting post-translational activation of PPAR-{gamma} might be critical step for adipogenic gene expression.« less

  4. The structure, logic of operation and distinctive features of the system of triggers and counting signals formation for gamma-telescope GAMMA-400

    NASA Astrophysics Data System (ADS)

    Topchiev, N. P.; Galper, A. M.; Arkhangelskiy, A. I.; Arkhangelskaja, I. V.; Kheymits, M. D.; Suchkov, S. I.; Yurkin, Y. T.

    2017-01-01

    Scientific project GAMMA-400 (Gamma Astronomical Multifunctional Modular Apparatus) relates to the new generation of space observatories intended to perform an indirect search for signatures of dark matter in the cosmic-ray fluxes, measurements of characteristics of diffuse gamma-ray emission and gamma-rays from the Sun during periods of solar activity, gamma-ray bursts, extended and point gamma-ray sources, electron/positron and cosmic-ray nuclei fluxes up to TeV energy region by means of the GAMMA-400 gamma-ray telescope represents the core of the scientific complex. The system of triggers and counting signals formation of the GAMMA-400 gamma-ray telescope constitutes the pipelined processor structure which collects data from the gamma-ray telescope subsystems and produces summary information used in forming the trigger decision for each event. The system design is based on the use of state-of-the-art reconfigurable logic devices and fast data links. The basic structure, logic of operation and distinctive features of the system are presented.

  5. Thy-1+ dendritic epidermal cells express T3 antigen and the T-cell receptor gamma chain.

    PubMed Central

    Stingl, G; Koning, F; Yamada, H; Yokoyama, W M; Tschachler, E; Bluestone, J A; Steiner, G; Samelson, L E; Lew, A M; Coligan, J E

    1987-01-01

    The murine epidermis is a heterogeneous epithelium composed of keratinocytes, melanocytes, Langerhans cells, and a recently described subpopulation (2-3%) of bone-marrow-derived leukocytes with a dendritic morphology and the cell surface phenotype Thy-1+, L3T4-, Lyt-2-. Previous studies have demonstrated that cell lines derived from freshly explanted Thy-1+ dendritic epidermal cells (DEC) have abundant mRNA for rearranged T-cell receptor (TCR) gamma-chain genes. Analysis of Thy-1+ DEC in situ, freshly isolated cell suspensions of Thy-1+ DEC, and long-term Thy-1+ DEC lines demonstrated that 100% of the Thy-1+ DEC reacted with a monoclonal antibody to the epsilon chain of the murine T3 complex and that 40-60% of resident Thy-1+ DEC were also reactive with an antiserum to the TCR gamma chain. Two Thy-1+ DEC lines expressed a disulfide-linked 70-kDa molecule that could be precipitated with an anti-gamma-chain antiserum and could be coprecipitated with an antiserum to the T3 delta chain; the molecule appeared as a single 34-kDa band under reducing conditions. The phenotype of Thy-1+ DEC (T3+, L3T4-, Lyt-2-, TCR gamma chain+) thus resembles that of the recently described subpopulation of murine and human lymphocytes that have been identified in the thymus, peripheral blood, and fetal blood. Images PMID:2885839

  6. Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression.

    PubMed

    Toyota, Yosuke; Nomura, Sayaka; Makishima, Makoto; Hashimoto, Yuichi; Ishikawa, Minoru

    2017-06-15

    Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC 50 : 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. GABA[subscript A] Receptor Downregulation in Brains of Subjects with Autism

    ERIC Educational Resources Information Center

    Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Thuras, Paul D.

    2009-01-01

    Gamma-aminobutyric acid A (GABA[subscript A]) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the…

  8. Absence of Fc epsilonRI alpha chain results in upregulation of Fc gammaRIII-dependent mast cell degranulation and anaphylaxis. Evidence of competition between Fc epsilonRI and Fc gammaRIII for limiting amounts of FcR beta and gamma chains.

    PubMed Central

    Dombrowicz, D; Flamand, V; Miyajima, I; Ravetch, J V; Galli, S J; Kinet, J P

    1997-01-01

    In mouse mast cells, both Fc epsilonRI and Fc gammaRIII are alpha beta gamma2 tetrameric complexes in which different alpha chains confer IgE or IgG ligand recognition while the signaling FcR beta and gamma chains are identical. We used primarily noninvasive techniques (changes in body temperature, dye extravasation) to assess systemic anaphylactic responses in nonanesthetized wild-type, Fc epsilonRI alpha chain -/- and FcR gamma chain -/- mice. We confirm that systemic anaphylaxis in mice can be mediated largely through IgG1 and Fc gammaRIII and we provide direct evidence that these responses reflect activation of Fc gammaRIII rather than Fc gammaRI. Furthermore, we show that Fc gammaRIII-dependent responses are more intense in normal than in congenic mast cell-deficient KitW/KitW-v mice, indicating that Fc gammaRIII responses have mast cell-dependent and -independent components. Finally, we demonstrate that the upregulation of cell surface expression of Fc gammaRIII seen in Fc epsilonRI alpha chain -/- mice corresponds to an increased association of Fc gammaRIII alpha chains with FcR beta and gamma chains and is associated with enhanced Fc gammaRIII-dependent mast cell degranulation and systemic anaphylactic responses. Therefore, the phenotype of the Fc epsilonRI alpha chain -/- mice suggests that expression of Fc epsilonRI and Fc gammaRIII is limited by availability of the FcR beta and gamma chains and that, in normal mice, changes in the expression of one receptor (Fc epsilonRI) may influence the expression of functional responses dependent on the other (Fc gammaRIII). PMID:9062349

  9. Functional genomics analysis of big data identifies novel peroxisome proliferator–activated receptor gamma target single nucleotide polymorphisms showing association with cardiometabolic outcomes

    USDA-ARS?s Scientific Manuscript database

    Background Cardiovascular disease and type 2 diabetes mellitus represent overlapping diseases where a large portion of the variation attributable to genetics remains unexplained. An important player in their pathogenesis is peroxisome proliferator–activated receptor gamma (PPARgamma) that is involve...

  10. The amphiphilic peptide adenoregulin enhances agonist binding to A1-adenosine receptors and [35S]GTP gamma S to brain membranes.

    PubMed

    Moni, R W; Romero, F S; Daly, J W

    1995-08-01

    1. Adenoregulin is an amphilic peptide isolated from skin mucus of the tree frog, Phyllomedusa bicolor. Synthetic adenoregulin enhanced the binding of agonists to several G-protein-coupled receptors in rat brain membranes. 2. The maximal enhancement of agonist binding, and in parentheses, the concentration of adenoregulin affording maximal enhancement were as follows: 60% (20 microM) for A1-adenosine receptors, 30% (100 microM) for A2a-adenosine receptors, 20% (2 microM) for alpha 2-adrenergic receptors, and 30% (10 microM) for 5HT1A receptors. High affinity agonist binding for A1-, alpha 2-, and 5HT1A-receptors was virtually abolished by GTP gamma S in the presence of adenoregulin, but was only partially abolished in its absence. Magnesium ions increased the binding of agonists to receptors and reduced the enhancement elicited by adenoregulin. 3. The effect of adenoregulin on binding of N6-cyclohexyladenosine ([3H]CHA) to A1-receptors was relatively slow and was irreversible. Adenoregulin increased the Bmax value for [3H]CHA binding sites, and the proportion of high affinity states, and slowed the rate of [3H]CHA dissociation. Binding of the A1-selective antagonist, [3H]DPCPX, was maximally enhanced by only 13% at 2 microM adenoregulin. Basal and A1-adenosine receptor-stimulated binding of [35S]GTP gamma S were maximally enhanced 45% and 23%, respectively, by 50 microM adenoregulin. In CHAPS-solubilized membranes from rat cortex, the binding of both [3H]CHA and [3H]DPCPX were enhanced by adenoregulin. Binding of [3H]CHA to membranes from DDT1 MF-2 cells was maximally enhanced 17% at 20 microM adenoregulin. In intact DDT1 MF-2 cells, 20 microM adenoregulin did not potentiate the inhibition of cyclic AMP accumulation mediated via the adenosine A1 receptor. 4. It is proposed that adenoregulin enhances agonist binding through a mechanism involving enhancement of guanyl nucleotide exchange at G-proteins, resulting in a conversion of receptors into a high affinity state

  11. Contributions of Torpedo nicotinic acetylcholine receptor gamma Trp-55 and delta Trp-57 to agonist and competitive antagonist function.

    PubMed

    Xie, Y; Cohen, J B

    2001-01-26

    Results of affinity-labeling studies and mutational analyses provide evidence that the agonist binding sites of the nicotinic acetylcholine receptor (nAChR) are located at the alpha-gamma and alpha-delta subunit interfaces. For Torpedo nAChR, photoaffinity-labeling studies with the competitive antagonist d-[(3)H]tubocurarine (dTC) identified two tryptophans, gammaTrp-55 and deltaTrp-57, as the primary sites of photolabeling in the non-alpha subunits. To characterize the importance of gammaTrp-55 and deltaTrp-57 to the interactions of agonists and antagonists, Torpedo nAChRs were expressed in Xenopus oocytes, and equilibrium binding assays and electrophysiological recordings were used to examine the functional consequences when either or both tryptophans were mutated to leucine. Neither substitution altered the equilibrium binding of dTC. However, the deltaW57L and gammaW55L mutations decreased acetylcholine (ACh) binding affinity by 20- and 7,000-fold respectively. For the wild-type, gammaW55L, and deltaW57L nAChRs, the concentration dependence of channel activation was characterized by Hill coefficients of 1.8, 1.1, and 1.7. For the gammaW55L mutant, dTC binding at the alpha-gamma site acts not as a competitive antagonist but as a coactivator or partial agonist. These results establish that interactions with gamma Trp-55 of the Torpedo nAChR play a crucial role in agonist binding and in the agonist-induced conformational changes that lead to channel opening.

  12. Activation of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) induces cell death through MAPK-dependent mechanism in osteoblastic cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Sung Hun; Yoo, Chong Il; Medical Research Institute, College of Medicine, Pusan National University, Pusan, 602-739

    2006-09-01

    The present study was undertaken to determine the role of the mitogen-activated protein kinase (MAPK) subfamilies in cell death induced by PPAR{gamma} agonists in osteoblastic cells. Ciglitazone and troglitazone, PPAR{gamma} agonists, resulted in a concentration- and time-dependent cell death, which was largely attributed to apoptosis. But a PPAR{alpha} agonist ciprofibrate did not affect the cell death. Ciglitazone caused reactive oxygen species (ROS) generation and ciglitazone-induced cell death was prevented by antioxidants, suggesting an important role of ROS generation in the ciglitazone-induced cell death. ROS generation and cell death induced by ciglitazone were inhibited by the PPAR{gamma} antagonist GW9662. Ciglitazone treatmentmore » caused activation of extracellular signal-regulated kinase (ERK) and p38. Activation of ERK was dependent on epidermal growth factor receptor (EGFR) and that of p38 was independent. Ciglitazone-induced cell death was significantly prevented by PD98059, an inhibitor of ERK upstream kinase MEK1/2, and SB203580, a p38 inhibitor. Ciglitazone treatment increased Bax expression and caused a loss of mitochondrial membrane potential, and its effect was prevented by N-acetylcysteine, PD98059, and SB203580. Ciglitazone induced caspase activation, which was prevented by PD98059 and SB203580. The general caspase inhibitor z-DEVD-FMK and the specific inhibitor of caspases-3 DEVD-CHO exerted the protective effect against the ciglitazone-induced cell death. The EGFR inhibitors AG1478 and suramin protected against the ciglitazone-induced cell death. Taken together, these findings suggest that the MAPK signaling pathways play an active role in mediating the ciglitazone-induced cell death of osteoblasts and function upstream of a mitochondria-dependent mechanism. These data may provide a novel insight into potential therapeutic strategies for treatment of osteoporosis.« less

  13. Analysis of the Fc Gamma Receptor-Dependent Component of Neutralization Measured by Anthrax Toxin Neutralization Assays▿

    PubMed Central

    Verma, Anita; Ngundi, Miriam M.; Meade, Bruce D.; De Pascalis, Roberto; Elkins, Karen L.; Burns, Drusilla L.

    2009-01-01

    Anthrax toxin neutralization assays are used to measure functional antibody levels elicited by anthrax vaccines in both preclinical and clinical studies. In this study, we investigated the magnitude and molecular nature of Fc gamma (Fcγ) receptor-dependent toxin neutralization observed in commonly used forms of the anthrax toxin neutralization assay. Significantly more Fcγ receptor-dependent neutralization was observed in the J774A.1 cell-based assay than in the RAW 264.7 cell-based assay, a finding that could be due to the larger numbers of Fcγ receptors that we found on J774A.1 cells by using flow cytometry. Thus, the extent to which Fcγ receptor-dependent neutralization contributes to the total neutralization measured by the assay depends on the specific cell type utilized in the assay. Using Fcγ receptor blocking monoclonal antibodies, we found that at least three murine Fcγ receptor classes, IIB, III, and IV, can contribute to Fcγ receptor-dependent neutralization. When antibodies elicited by immunization of rabbits with protective-antigen-based anthrax vaccines were analyzed, we found that the magnitude of Fcγ receptor-dependent neutralization observed in the J774A.1 cell-based assay was dependent on the concentration of protective antigen utilized in the assay. Our results suggest that the characteristics of the antibodies analyzed in the assay (e.g., species of origin, isotype, and subclass), as well as the assay design (e.g., cell type and protective antigen concentration), could significantly influence the extent to which Fcγ receptor-dependent neutralization contributes to the total neutralization measured by anthrax toxin neutralization assays. These findings should be considered when interpreting anthrax toxin neutralization assay output. PMID:19656993

  14. Successful combination immunotherapy of anti-gamma aminobutyric acid (GABA)A receptor antibody-positive encephalitis with extensive multifocal brain lesions.

    PubMed

    Fukami, Yuki; Okada, Hiroaki; Yoshida, Mari; Yamaguchi, Keiji

    2017-08-31

    A 78-year old woman who presented with akinetic mutism was admitted to our hospital. Brain MRI showed multifocal increased T 2 /FLAIR signal with extensive cortical-subcortical involvement. We suspected autoimmune encephalitis and the patient received methylprednisolone pulse. Her conscious level gradually recovered, but later relapsed again and presented with refractory status epilepticus. We treated her with intravenous immunoglobulin, plasma exchange and pulsed cyclophosphamide, with satisfactory response. A brain biopsy showed perivascular lymphocytic infiltrates and reactive gliosis. Anti-gamma aminobutyric acid (GABA) A receptor antibodies test came back to be positive after her recovery, and the diagnosis of anti-GABA A receptor antibody-positive encephalitis was made. This is a very rare case where brain biopsies were performed in a patient with anti-GABA A receptor antibody-positive encephalitis.

  15. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hasegawa-Moriyama, Maiko, E-mail: hase-mai@m3.kufm.kagoshima-u.ac.jp; Ohnou, Tetsuya; Godai, Kohei

    Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functionsmore » linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased

  16. Cellular sources and targets of IFN-gamma-mediated protection against viral demyelination and neurological deficits.

    PubMed

    Murray, Paul D; McGavern, Dorian B; Pease, Larry R; Rodriguez, Moses

    2002-03-01

    IFN-gamma is an anti-viral and immunomodulatory cytokine critical for resistance to multiple pathogens. Using mice with targeted disruption of the gene for IFN-gamma, we previously demonstrated that this cytokine is critical for resistance to viral persistence and demyelination in the Theiler's virus model of multiple sclerosis. During viral infections, IFN-gamma is produced by natural killer (NK) cells, CD4(+) and CD8(+) T cells; however, the proportions of lymphocyte subsets responding to virus infection influences the contributions to IFN-gamma-mediated protection. To determine the lymphocyte subsets that produce IFN-gamma to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFN-gamma-production. We demonstrate that IFN-gamma production by both CD4(+) and CD8(+) T cell subsets is critical for resistance to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination and neurological disease, and that CD4(+) T cells make a greater contribution to IFN-gamma-mediated protection. To determine the cellular targets of IFN-gamma-mediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFN-gamma receptor. We demonstrate that IFN-gamma receptor must be present on central nervous system glia, but not bone marrow-derived lymphocytes, in order to maintain resistance to TMEV-induced demyelination.

  17. PYRETHROID INSECTICIDES AND THE GAMMA-AMINOBUTYRIC ACID (ALPHA) RECEPTOR COMPLEX: MOTOR ACTIVITY AND THE ACOUSTIC STARTLE RESPONSE IN THE RAT (JOURNAL VERSION)

    EPA Science Inventory

    Two behavioral tests, locomotor activity and the acoustic startle response (ASR), were utilized to test for dose-addition of cismethrin, a Type I, or deltamethrin, a Type II pyrethroid, with compounds active to the gamma-aminobutryic acid (GABA) receptor complex (picrotoxin, musc...

  18. Activation of human peroxisome-activated receptor-gamma ...

    EPA Pesticide Factsheets

    Obesity in children has become an epidemic and recent research suggests a possible contribution from exposure to environmental chemicals. Several chemicals, such as phthalates, brominated flame retardants, and perfluorinated chemicals, are common in house dust on floors where children play and are suspected obesogens. Obesogens can act via a mechanism that involves activation of peroxisome proliferator-activated receptor-gamma (PPARy). A previous study found that dust collected from children’s homes binds to PPARy. Here, we investigated the ability of house dust to activate PPARy in a transiently transfected cell assay. Dust samples were collected in 2012 from carpeted and hardwood floors in children’s homes using thimbles fitted into a vacuum cleaner hose (“TEO” samples), or from homes in an adult cohort NIEHS study. Dust was extracted with 50:50 hexane:acetone, sonicated, centrifuged, and the organic layer collected. This was repeated 2X. The extracts were filtered to remove particulates, dried with purified nitrogen, and reconstituted in DMS0 at 200 ug/ul. COS-1 cells were transfected for 24 hrs with a human PPARy vector containing a luciferase reporter, and exposed for 24 hrs to negative controls water or DMSO (0.1%), positive controls Troglitazone (3 uM in water) or Rosiglitazone (100 nM in DMSO), or dust extracts serially diluted in DMEM at 50, 100, and 200 ug/ml in 0.1% DMSO. Cells were lysed and luciferase activity was measured. Data were log-tra

  19. Z{gamma}{gamma}{gamma} {yields} 0 Processes in SANC

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bardin, D. Yu., E-mail: bardin@nu.jinr.ru; Kalinovskaya, L. V., E-mail: kalinov@nu.jinr.ru; Uglov, E. D., E-mail: corner@nu.jinr.ru

    2013-11-15

    We describe the analytic and numerical evaluation of the {gamma}{gamma} {yields} {gamma}Z process cross section and the Z {yields} {gamma}{gamma}{gamma} decay rate within the SANC system multi-channel approach at the one-loop accuracy level with all masses taken into account. The corresponding package for numeric calculations is presented. For checking of the results' correctness we make a comparison with the other independent calculations.

  20. Role of a gamma-aminobutryic acid (GABA) receptor mutation in the evolution and spread of Diabrotica virgifera virgifera resistance to cyclodiene insecticides

    USDA-ARS?s Scientific Manuscript database

    An alanine to serine amino acid substitution within the Rdl subunit of the gamma-aminobutyric acid (GABA) receptor confers resistance to cyclodiene insecticides in many species. The corn rootworm, Diabrotica virgifera virgifera, is a damaging pest of cultivated corn that was partially controlled by ...

  1. Nuclear Receptor Regulation of Aquaglyceroporins in Metabolic Organs.

    PubMed

    Tardelli, Matteo; Claudel, Thierry; Bruschi, Francesca Virginia; Trauner, Michael

    2018-06-15

    Nuclear receptors, such as the farnesoid X receptor (FXR) and the peroxisome proliferator-activated receptors gamma and alpha (PPAR-&gamma;, -α), are major metabolic regulators in adipose tissue and the liver, where they govern lipid, glucose, and bile acid homeostasis, as well as inflammatory cascades. Glycerol and free fatty acids are the end products of lipid droplet catabolism driven by PPARs. Aquaporins (AQPs), a family of 13 small transmembrane proteins, facilitate the shuttling of water, urea, and/or glycerol. The peculiar role of AQPs in glycerol transport makes them pivotal targets in lipid metabolism, especially considering their tissue-specific regulation by the nuclear receptors PPAR&gamma; and PPARα. Here, we review the role of nuclear receptors in the regulation of glycerol shuttling in liver and adipose tissue through the function and expression of AQPs.

  2. AGIS -- the Advanced Gamma-ray Imaging System

    NASA Astrophysics Data System (ADS)

    Krennrich, Frank

    2009-05-01

    The Advanced Gamma-ray Imaging System, AGIS, is envisioned to become the follow-up mission of the current generation of very high energy gamma-ray telescopes, namely, H.E.S.S., MAGIC and VERITAS. These instruments have provided a glimpse of the TeV gamma-ray sky, showing more than 70 sources while their detailed studies constrain a wealth of physics and astrophysics. The particle acceleration, emission and absorption processes in these sources permit the study of extreme physical conditions found in galactic and extragalactic TeV sources. AGIS will dramatically improve the sensitivity and angular resolution of TeV gamma-ray observations and therefore provide unique prospects for particle physics, astrophysics and cosmology. This talk will provide an overview of the science drivers, scientific capabilities and the novel technical approaches that are pursued to maximize the performance of the large array concept of AGIS.

  3. INF-gamma rearranges membrane topography of MHC-I and ICAM-1 in colon carcinoma cells.

    PubMed

    Bacsó, Zsolt; Bene, László; Damjanovich, László; Damjanovich, Sándor

    2002-01-18

    Flow-cytometric fluorescence energy transfer (FCET) measurements between fluorescently labeled cell surface MHC-I and ICAM-1 molecules indicated similar receptor patterns in the plasma membrane of interferon-gamma (INF-gamma)-treated colon carcinoma cells as those observed earlier at the surface of lymphoid cells. INF-gamma activation significantly increased the density of MHC-I and ICAM-1 proteins in the membrane. This increase in receptor density was accompanied by decreased proximity level of the homo-associated MHC-I receptors. Hetero-association of MHC-I and ICAM-1 molecules was increased by INF-gamma treatment. INF-gamma changed neither hetero- nor homo-association of transferrin receptors. By staining the sphingomyelin/cholesterol-enriched lipid microdomains with fluorescently labeled cholera toxin B subunit, we found an increase in the amount of lipid-raft associated G(M1)-gangliosides due to INF-gamma treatment. Confocal microscopic results and FCET measurements show that MHC-I and ICAM-1 are components of G(M1)-ganglioside containing lipid-rafts and also support an increase in the size of these lipid-rafts upon INF-gamma treatment.

  4. Decreased agonist sensitivity of human GABA(A) receptors by an amino acid variant, isoleucine to valine, in the alpha1 subunit.

    PubMed

    Westh-Hansen, S E; Rasmussen, P B; Hastrup, S; Nabekura, J; Noguchi, K; Akaike, N; Witt, M R; Nielsen, M

    1997-06-25

    Recombinant human GABA(A) receptors were investigated in vitro by coexpression of cDNAs coding for alpha1, beta2, and gamma2 subunits in the baculovirus/Sf-9 insect cell system. We report that a single amino acid exchange (isoleucine 121 to valine 121) in the N-terminal, extracellular part of the alpha1 subunit induces a marked decrease in agonist GABA(A) receptor ligand sensitivity. The potency of muscimol and GABA to inhibit the binding of the GABA(A) receptor antagonist [3H]SR 95531 (2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide) was higher in receptor complexes of alpha1(ile 121) beta2gamma2 than in those of alpha1(val 121) beta2gamma2 (IC50 values were 32-fold and 26-fold lower for muscimol and GABA, respectively). The apparent affinity of the GABA(A) receptor antagonist bicuculline methiodide to inhibit the binding of [3H]SR 95531 did not differ between the two receptor complex variants. Electrophysiological measurements of GABA induced whole-cell Cl- currents showed a ten-fold decrease in the GABA(A) receptor sensitivity of alpha1 (val 121) beta2gamma2 as compared to alpha1(ile 121) beta2gamma2 receptor complexes. Thus, a relatively small change in the primary structure of the alpha1 subunit leads to a decrease selective for GABA(A) receptor sensitivity to agonist ligands, since no changes were observed in a GABA(A) receptor antagonist affinity and benzodiazepine receptor binding.

  5. Gamma-telescopes Fermi/LAT and GAMMA-400 Trigger Systems Event Recognizing Methods Comparison

    NASA Astrophysics Data System (ADS)

    Arkhangelskaja, I. V.; Murchenko, A. E.; Chasovikov, E. N.; Arkhangelskiy, A. I.; Kheymits, M. D.

    Usually instruments for high-energy γ-quanta registration consists of converter (where γ-quanta produced pairs) and calorimeter for particles energy measurements surrounded by anticoincidence shield used to events identification (whether incident particle was charged or neutral). The influence of pair formation by γ-quanta in shield and the backsplash (moved in the opposite direction particles created due high energy γ-rays interact with calorimeter) should be taken into account. It leads to decrease both effective area and registration efficiency at E>10 GeV. In the presented article the event recognizing methods used in Fermi/LAT trigger system is considered in comparison with the ones applied in counting and triggers signals formation system of gamma-telescope GAMMA-400. The GAMMA-400 (Gamma Astronomical Multifunctional Modular Apparatus) will be the new high-apogee space γ-observatory. The GAMMA-400 consist of converter-tracker based on silicon-strip coordinate detectors interleaved with tungsten foils, imaging calorimeter make of 2 layers of double (x, y) silicon strip coordinate detectors interleaved with planes of CsI(Tl) crystals and the electromagnetic calorimeter CC2 consists only of CsI(Tl) crystals. Several plastics detections systems used as anticoincidence shield, for particles energy and moving direction estimations. The main differences of GAMMA-400 constructions from Fermi/LAT one are using the time-of-flight system with base of 50 cm and double layer structure of plastic detectors provides more effective particles direction definition and backsplash rejection. Also two calorimeters in GAMMA-400 composed the total absorbtion spectrometer with total thickness ∼ 25 X0 or ∼1.2 λ0 for vertical incident particles registration and 54 X0 or 2.5 λ0 for laterally incident ones (where λ0 is nuclear interaction length). It provides energy resolution 1-2% for 10 GeV-3.0×103 GeV events while the Fermi/LAT energy resolution does not reach such a

  6. The gamma-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens

    PubMed Central

    2012-01-01

    Background Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. Methods We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. Results The present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Conclusions Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse. PMID:22559224

  7. A large-area gamma-ray imaging telescope system

    NASA Technical Reports Server (NTRS)

    Koch, D. G.

    1983-01-01

    The concept definition of using the External Tank (ET) of the Space Shuttle as the basis for constructing a large area gamma ray imaging telescope in space is detailed. The telescope will be used to locate and study cosmic sources of gamma rays of energy greater than 100 MeV. Both the telescope properties and the means whereby an ET is used for this purpose are described. A parallel is drawn between those systems that would be common to both a Space Station and this ET application. In addition, those systems necessary for support of the telescope can form the basis for using the ET as part of the Space Station. The major conclusions of this concept definition are that the ET is ideal for making into a gamma ray telescope, and that this telescope will provide a substantial increase in collecting area.

  8. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells.

    PubMed

    Gosset, P; Charbonnier, A S; Delerive, P; Fontaine, J; Staels, B; Pestel, J; Tonnel, A B; Trottein, F

    2001-10-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma ), a member of the nuclear receptor superfamily, has recently been described as a modulator of macrophage functions and as an inhibitor of T cell proliferation. Here, we investigated the role of PPARgamma in dendritic cells (DC), the most potent antigen-presenting cells. We showed that PPARgamma is highly expressed in immature human monocyte-derived DC (MDDC) and that it may affect the immunostimulatory function of MDDC stimulated with lipopolysaccharide (LPS) or via CD40 ligand (CD40L). We found that the synthetic PPARgamma agonist rosiglitazone (as well as pioglitazone and troglitazone) significantly increases on LPS- and CD40L-activated MDDC, the surface expression of CD36 (by 184% and 104%, respectively) and CD86 (by 54% and 48%), whereas it reduces the synthesis of CD80 (by 42% and 42%). Moreover, activation of PPARgamma resulted in a dramatic decreased secretion of the Th1-promoting factor IL-12 in LPS- and CD40L-stimulated cells (by 47% and 62%), while the production of IL-1beta, TNF-alpha, IL-6 and IL-10 was unaffected. Finally, PPARgamma ligands down-modulate the synthesis of IFN-gamma -inducible protein-10 (recently termed as CXCL10) and RANTES (CCL5), both chemokines involved in the recruitment of Th1 lymphocytes (by 49% and 30%), but not the levels of the Th2 cell-attracting chemokines,macrophage-derived chemokine (CCL22) and thymus and activation regulated chemokine (CCL17), in mature MDDC. Taken together, our data suggest that activation of PPARgamma in human DC may have an impact in the orientation of primary and secondary immune responses by favoring type 2 responses.

  9. Hepatitis B virus X protein modulates peroxisome proliferator-activated receptor gamma through protein-protein interaction.

    PubMed

    Choi, Youn-Hee; Kim, Ha-il; Seong, Je Kyung; Yu, Dae-Yeul; Cho, Hyeseong; Lee, Mi-Ock; Lee, Jae Myun; Ahn, Yong-ho; Kim, Se Jong; Park, Jeon Han

    2004-01-16

    Ligand activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been reported to induce growth inhibition and apoptosis in various cancers including hepatocellular carcinoma (HCC). However, the effect of hepatitis B virus X protein (HBx) on PPARgamma activation has not been characterized in hepatitis B virus (HBV)-associated HCC. Herein, we demonstrated that HBx counteracted growth inhibition caused by PPARgamma ligand in HBx-associated HCC cells. We found that HBx bound to DNA binding domain of PPARgamma and HBx/PPARgamma interaction blocked nuclear localization and binding to recognition site of PPARgamma. HBx significantly suppressed a PPARgamma-mediated transactivation. These results suggest that HBx modulates PPARgamma function through protein-protein interaction.

  10. Administration of the peroxisomal proliferator-activated receptor {gamma} agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhao Weiling; Payne, Valerie; Tommasi, Ellen

    2007-01-01

    Purpose: We hypothesized that administration of the anti-inflammatory peroxisomal proliferator-activated receptor {gamma} (PPAR{gamma}) agonist pioglitazone (Pio) to adult male rats would inhibit radiation-induced cognitive impairment. Methods and Materials: Young adult male F344 rats received one of the following: (1) fractionated whole brain irradiation (WBI); 40 or 45 Gy {gamma}-rays in 4 or 4.5 weeks, respectively, two fractions per week and normal diet; (2) sham-irradiation and normal diet; (3) WBI plus Pio (120 ppm) before, during, and for 4 or 54 weeks postirradiation; (4) sham-irradiation plus Pio; or (5) WBI plus Pio starting 24h after completion of WBI. Results: Administration ofmore » Pio before, during, and for 4 or 54 weeks after WBI prevented Radiation-induced cognitive impairment. Administration of Pio for 54 weeks starting after completion of fractionated WBI substantially but not significantly reduced Radiation-induced cognitive impairment. Conclusions: These findings offer the promise of improving the quality of life and increasing the therapeutic window for brain tumor patients.« less

  11. Evaluation of 3D Gamma index calculation implemented in two commercial dosimetry systems

    NASA Astrophysics Data System (ADS)

    Xing, Aitang; Arumugam, Sankar; Deshpande, Shrikant; George, Armia; Vial, Philip; Holloway, Lois; Goozee, Gary

    2015-01-01

    3D Gamma index is one of the metrics which have been widely used for clinical routine patient specific quality assurance for IMRT, Tomotherapy and VMAT. The algorithms for calculating the 3D Gamma index using global and local methods implemented in two software tools: PTW- VeriSoft® as a part of OCTIVIUS 4D dosimeter systems and 3DVHTM from Sun Nuclear were assessed. The Gamma index calculated by the two systems was compared with manual calculated for one data set. The Gamma pass rate calculated by the two systems was compared using 3%/3mm, 2%/2mm, 3%/2mm and 2%/3mm for two additional data sets. The Gamma indexes calculated by the two systems were accurate, but Gamma pass rates calculated by the two software tools for same data set with the same dose threshold were different due to the different interpolation of raw dose data by the two systems and different implementation of Gamma index calculation and other modules in the two software tools. The mean difference was -1.3%±3.38 (1SD) with a maximum difference of 11.7%.

  12. Experimental study of the vidicon system for information recording using the wide-gap spark chamber of gamma - telescope gamma-I

    NASA Technical Reports Server (NTRS)

    Akimov, V. V.; Bazer-Bashv, R.; Voronov, S. A.; Galper, A. M.; Gro, M.; Kalinkin, L. F.; Kerl, P.; Kozlov, V. D.; Koten, F.; Kretol, D.

    1979-01-01

    The development of the gamma ray telescope is investigated. The wide gap spark chambers, used to identify the gamma quanta and to determine the directions of their arrival, are examined. Two systems of information recording with the spark chambers photographic and vidicon system are compared.

  13. Olfactory system gamma oscillations: the physiological dissection of a cognitive neural system

    PubMed Central

    Rojas-Líbano, Daniel

    2008-01-01

    Oscillatory phenomena have been a focus of dynamical systems research since the time of the classical studies on the pendulum by Galileo. Fast cortical oscillations also have a long and storied history in neurophysiology, and olfactory oscillations have led the way with a depth of explanation not present in the literature of most other cortical systems. From the earliest studies of odor-evoked oscillations by Adrian, many reports have focused on mechanisms and functional associations of these oscillations, in particular for the so-called gamma oscillations. As a result, much information is now available regarding the biophysical mechanisms that underlie the oscillations in the mammalian olfactory system. Recent studies have expanded on these and addressed functionality directly in mammals and in the analogous insect system. Sub-bands within the rodent gamma oscillatory band associated with specific behavioral and cognitive states have also been identified. All this makes oscillatory neuronal networks a unique interdisciplinary platform from which to study neurocognitive and dynamical phenomena in intact, freely behaving animals. We present here a summary of what has been learned about the functional role and mechanisms of gamma oscillations in the olfactory system as a guide for similar studies in other cortical systems. PMID:19003484

  14. Improved detector for the measurement of gamma radiation

    NASA Astrophysics Data System (ADS)

    Zelt, F. B.

    1985-07-01

    The present invention lies in the field of gamma ray spectrometry of geologic deposits and other materials, such as building materials (cement, asphalt, etc.) More specifically, the invention is an improved device for the gamma ray spetcrometery of gelogical deposits as a tool for petroleum exploration, geologic research and monitoring of radio-active materials such as in uranium mill tailings and the like. Improvement consists in enlarging the area of the receptor face and without any necessarily substantial increase in the volume of the receptor crystal over the current cylindrical shapes. The invention also provides, as a corollary of the increase in area receptor crystal face, a reduction in the weight of the amount of material necessary to provide effective shielding of the crystal from atmospheric radiation and radiation from deposits not under examination. The area of the receptor crystal face is increased by forming the crystal as a truncated cone with the shielding shaped as a hollow frustrum of a cone. A photomultiplier device is secured to the smaller face of the crystal. The improved detector shape can also be used in scintillometers which measure total gamma radiation.

  15. Peroxisome proliferator-activated receptor (PPAR)-gamma expression in human vascular smooth muscle cells: inhibition of growth, migration, and c-fos expression by the peroxisome proliferator-activated receptor (PPAR)-gamma activator troglitazone.

    PubMed

    Benson, S; Wu, J; Padmanabhan, S; Kurtz, T W; Pershadsingh, H A

    2000-01-01

    This study was conducted to determine whether cultured human coronary artery and aorta vascular smooth muscle (VSM) cells express the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma); whether the thiazolidinedione troglitazone, a ligand for PPARgamma, would inhibit c-fos expression by these cells; and whether troglitazone would inhibit proliferation and migration induced in these cells by mitogenic growth factors. Using immunoblotting and reverse-transcriptase polymerase chain reaction (RT-PCR) techniques, we show that both human aorta and coronary artery VSM cell lines expressed PPARgamma protein and mRNA for both PPARgamma isoforms, PPARgamma1 and PPARgamma2. Immunocytochemical staining localized the PPARgamma protein primarily within the nucleus. Troglitazone inhibited basic fibroblast growth factor and platelet-derived growth factor-BB induced DNA synthesis in a dose-dependent manner and downregulated the growth-factor-induced expression of c-fos. Troglitazone also inhibited the migration of coronary artery VSM cells along a platelet-derived growth factor-BB concentration gradient. These findings demonstrate for the first time the expression and nuclear localization of PPARgamma in human coronary artery and aorta VSM cells. The data also suggest that the downregulation of c-fos expression, growth-factor-induced proliferation, and migration by VSM may, in part, be mediated by activation of the PPARgamma receptor.

  16. PPAR-{gamma} agonist protects against intestinal injury during necrotizing enterocolitis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Baregamian, Naira; Mourot, Joshua M.; Ballard, Amie R.

    2009-02-06

    Necrotizing enterocolitis (NEC) remains a lethal condition for many premature infants. Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}), a member of the nuclear hormone receptor family, has been shown to play a protective role in cellular inflammatory responses; however, its role in NEC is not clearly defined. We sought to examine the expression of PPAR-{gamma} in the intestine using an ischemia-reperfusion (I/R) model of NEC, and to assess whether PPAR-{gamma} agonist treatment would ameliorate I/R-induced gut injury. Swiss-Webster mice were randomized to receive sham (control) or I/R injury to the gut induced by transient occlusion of superior mesenteric artery for 45 min withmore » variable periods of reperfusion. I/R injury resulted in early induction of PPAR-{gamma} expression and activation of NF-{kappa}B in small intestine. Pretreatment with PPAR-{gamma} agonist, 15d-PGJ{sub 2}, attenuated intestinal NF-{kappa}B response and I/R-induced gut injury. Activation of PPAR-{gamma} demonstrated a protective effect on small bowel during I/R-induced gut injury.« less

  17. Structure-activity relationships of seco-prezizaane terpenoids in gamma-aminobutyric acid receptors of houseflies and rats.

    PubMed

    Kuriyama, Tadahiko; Schmidt, Thomas J; Okuyama, Emi; Ozoe, Yoshihisa

    2002-06-01

    Thirteen seco-prezizaane terpenoids isolated from star anise species (Illcium floridanum, Illcium parviflorum, and Illcium verum) were investigated for their ability to inhibit the specific binding of [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist of gamma-aminobutyric acid (GABA) receptors, to housefly-head and rat-brain membranes. Veranisatin A was found to be the most potent inhibitor in both membranes, with an IC(50)(fly) of 78.5 nM and an IC(50)(rat) of 271 nM, followed by anisatin (IC(50)(fly)=123 nM; IC(50)(rat)=282 nM). Six of the other 11 tested compounds were effective only in housefly-head membranes. Pseudoanisatin proved to display a high (>26-fold) selectivity for housefly versus rat GABA receptors (IC(50)(fly)=376 nM; IC(50)(rat) >10,000 nM). Although pseudoanisatin does not structurally resemble EBOB, Scatchard plots indicated that the two compounds bind to the same site in housefly receptors. Anisatin and pseudoanisatin exhibited moderate insecticidal activity against German cockroaches. Comparative molecular field analysis (CoMFA), a method of three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, demonstrated that seco-prezizaane terpenoids can bind to the same site as do picrotoxane terpenoids such as picrotoxinin and picrodendrins, and the CoMFA maps allowed us to identify the parts of the molecules essential to high activity in housefly GABA receptors.

  18. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reverses the adverse effects of diet-induced obesity on oocyte quality.

    PubMed

    Minge, Cadence E; Bennett, Brenton D; Norman, Robert J; Robker, Rebecca L

    2008-05-01

    Obesity and its physiological consequences are increasingly prevalent among women of reproductive age and are associated with infertility. To investigate, female mice were fed a high-fat diet until the onset of insulin resistance, followed by assessments of ovarian gene expression, ovulation, fertilization, and oocyte developmental competence. We report defects to ovarian function associated with diet-induced obesity (DIO) that result in poor oocyte quality, subsequently reduced blastocyst survival rates, and abnormal embryonic cellular differentiation. To identify critical cellular mediators of ovarian responses to obesity induced insulin resistance, DIO females were treated for 4 d before mating with an insulin-sensitizing pharmaceutical: glucose and lipid-lowering AMP kinase activator, 5-aminoimidazole 4-carboxamide-riboside, 30 mg/kg.d; sodium salicylate, IkappaK inhibitor that reverses insulin resistance, 50 mg/kg.d; or peroxisome proliferator activated receptor-gamma agonist rosiglitazone, 10 mg/kg.d. 5-aminoimidazole 4-carboxamide-riboside or sodium salicylate treatment did not have significant effects on the reproductive parameters examined. However, embryonic development to the blastocyst stage was significantly improved when DIO mice were treated with rosiglitazone, effectively repairing development rates. Rosiglitazone also normalized DIO-associated abnormal blastomere allocation to the inner cell mass. Such improvements to oocyte quality were coupled with weight loss, improved glucose metabolism, and changes in ovarian mRNA expression of peroxisome proliferator activated receptor-regulated genes, Cd36, Scarb1, and Fabp4 cholesterol transporters. These studies demonstrate that peri-conception treatment with select insulin-sensitizing pharmaceuticals can directly influence ovarian functions and ultimately exert positive effects on oocyte developmental competence. Improved blastocyst quality in obese females treated with rosiglitazone before mating

  19. A selective peroxisome proliferator-activated receptor-gamma modulator, telmisartan, binds to the receptor in a different fashion from thiazolidinediones.

    PubMed

    Tagami, Tetsuya; Yamamoto, Hiroyuki; Moriyama, Kenji; Sawai, Kuniko; Usui, Takeshi; Shimatsu, Akira; Naruse, Mitsuhide

    2009-02-01

    Angiotensin type 1 receptor blockers are widely used for the treatment of hypertension, and one angiotensin type 1 receptor blocker, telmisartan, specifically activates the peroxisome proliferator-activated receptor (PPAR)-gamma. We studied the impact of PPARgamma mutants on transcriptional control and interaction with cofactors to elucidate differences in the molecular mechanism between telmisartan and other PPARgamma agonists, thiazolidinediones (TZDs). We created several amino acid substitutions in the ligand binding domain of PPARgamma that, based on molecular modeling, may affect the binding of these agents. In transient expression experiments, wild-type PPARgamma-mediated transcription stimulated by telmisartan was more than one third of that stimulated by TZDs. The activation stimulated by TZDs was impaired, whereas activation stimulated by telmisartan was retained, in the H323Y, S342A, and H449A mutants. In the Y473A mutant, the TZD-induced activation was further impaired and lower than that of telmisartan-induced activation. Coexpression of coactivators enhanced the activation by both telmisartan and TZDs, but activation by telmisartan always exceeded that of TZDs in the Y473A mutant. Based on a mammalian two-hybrid assay, the interaction with corepressors was retained in Y473A. Telmisartan and TZDs, but not 9cis retinoic acid, dissociated corepressors from the wild-type PPARgamma. Telmisartan most effectively dissociated corepressors from Y473A. The interaction with coactivators was enhanced by TZD activation of wild-type PPARgamma and both telmisartan and TZD activation of Y473A. Thus, the Y473A mutant is selectively stimulated by telmisartan but not TZDs, suggesting that telmisartan and TZDs have differential effects on the transcriptional control. In conclusion, these PPARgamma mutants could be powerful tools for developing novel therapeutic agents that retain the metabolic efficacy of PPARgamma activation with fewer adverse effects, such as the

  20. Development of gamma-photon/Cerenkov-light hybrid system for simultaneous imaging of I-131 radionuclide

    NASA Astrophysics Data System (ADS)

    Yamamoto, Seiichi; Suzuki, Mayumi; Kato, Katsuhiko; Watabe, Tadashi; Ikeda, Hayato; Kanai, Yasukazu; Ogata, Yoshimune; Hatazawa, Jun

    2016-09-01

    Although iodine 131 (I-131) is used for radionuclide therapy, high resolution images are difficult to obtain with conventional gamma cameras because of the high energy of I-131 gamma photons (364 keV). Cerenkov-light imaging is a possible method for beta emitting radionuclides, and I-131 (606 MeV maximum beta energy) is a candidate to obtain high resolution images. We developed a high energy gamma camera system for I-131 radionuclide and combined it with a Cerenkov-light imaging system to form a gamma-photon/Cerenkov-light hybrid imaging system to compare the simultaneously measured images of these two modalities. The high energy gamma imaging detector used 0.85-mm×0.85-mm×10-mm thick GAGG scintillator pixels arranged in a 44×44 matrix with a 0.1-mm thick reflector and optical coupled to a Hamamatsu 2 in. square position sensitive photomultiplier tube (PSPMT: H12700 MOD). The gamma imaging detector was encased in a 2 cm thick tungsten shield, and a pinhole collimator was mounted on its top to form a gamma camera system. The Cerenkov-light imaging system was made of a high sensitivity cooled CCD camera. The Cerenkov-light imaging system was combined with the gamma camera using optical mirrors to image the same area of the subject. With this configuration, we simultaneously imaged the gamma photons and the Cerenkov-light from I-131 in the subjects. The spatial resolution and sensitivity of the gamma camera system for I-131 were respectively 3 mm FWHM and 10 cps/MBq for the high sensitivity collimator at 10 cm from the collimator surface. The spatial resolution of the Cerenkov-light imaging system was 0.64 mm FWHM at 10 cm from the system surface. Thyroid phantom and rat images were successfully obtained with the developed gamma-photon/Cerenkov-light hybrid imaging system, allowing direct comparison of these two modalities. Our developed gamma-photon/Cerenkov-light hybrid imaging system will be useful to evaluate the advantages and disadvantages of these two

  1. Theoretical study of the NO gamma system

    NASA Technical Reports Server (NTRS)

    Langhoff, Stephen R.; Bauschlicher, Charles W., Jr.; Partridge, Harry

    1988-01-01

    A systematic study of the NO gamma system with level of correlation treatment was carried out using large Gaussian basis sets to determine the potential curves for the X2Pi and A2Sigma(+) states of NO. It is shown that the A2Sigma-X2Pi electronic transition moment (gamma system) increases monotonically with decreasing internuclear distance and that the increase in the moment as r decreases is correlated with the increasing degree of diffuse character in the X2Pi state. The results of a study of the X2Pi and A2Sigma(+) dipole moment functions showed that the X2Pi vibrationally averaged dipole moments and the (1-0) and (2-0) vibration-rotation band intensities agree well with experimental data.

  2. Role of peroxisome proliferator-activated receptors alpha and gamma in gastric ulcer: An overview of experimental evidences.

    PubMed

    Saha, Lekha

    2015-11-06

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Three subtypes, PPARα, PPARβ/δ, and PPARγ, have been identified so far. PPARα is expressed in the liver, kidney, small intestine, heart, and muscle, where it activates the fatty acid catabolism and control lipoprotein assembly in response to long-chain unsaturated fatty acids, eicosanoids, and hypolipidemic drugs (e.g., fenofibrate). PPARβ/δ is more broadly expressed and is implicated in fatty acid oxidation, keratinocyte differentiation, wound healing, and macrophage response to very low density lipoprotein metabolism. This isoform has been implicated in transcriptional-repression functions and has been shown to repress the activity of PPARα or PPARγ target genes. PPARγ1 and γ2 are generated from a single-gene peroxisome proliferator-activated receptors gamma by differential promoter usage and alternative splicing. PPARγ1 is expressed in colon, immune system (e.g., monocytes and macrophages), and other tissues where it participates in the modulation of inflammation, cell proliferation, and differentiation. PPARs regulate gene expression through distinct mechanisms: Ligand-dependent transactivation, ligand-independent repression, and ligand-dependent transrepression. Studies in animals have demonstrated the gastric antisecretory activity of PPARα agonists like ciprofibrate, bezafibrate and clofibrate. Study by Pathak et al also demonstrated the effect of PPARα agonist, bezafibrate, on gastric secretion and gastric cytoprotection in various gastric ulcer models in rats. The majority of the experimental studies is on pioglitazone and rosiglitazone, which are PPARγ activators. In all the studies, both the PPARγ activators showed protection against the gastric ulcer and also accelerate the ulcer healing in gastric ulcer model in rats. Therefore, PPARα and PPARγ may be a target for gastric ulcer therapy

  3. Study of gamma detection capabilities of the REWARD mobile spectroscopic system

    NASA Astrophysics Data System (ADS)

    Balbuena, J. P.; Baptista, M.; Barros, S.; Dambacher, M.; Disch, C.; Fiederle, M.; Kuehn, S.; Parzefall, U.

    2017-07-01

    REWARD is a novel mobile spectroscopic radiation detector system for Homeland Security applications. The system integrates gamma and neutron detection equipped with wireless communication. A comprehensive simulation study on its gamma detection capabilities in different radioactive scenarios is presented in this work. The gamma detection unit consists of a precise energy resolution system based on two stacked (Cd,Zn)Te sensors working in coincidence sum mode. The volume of each of these CZT sensors is 1 cm3. The investigated energy windows used to determine the detection capabilities of the detector correspond to the gamma emissions from 137Cs and 60Co radioactive sources (662 keV and 1173/1333 keV respectively). Monte Carlo and Technology Computer-Aided Design (TCAD) simulations are combined to determine its sensing capabilities for different radiation sources and estimate the limits of detection of the sensing unit as a function of source activity for several shielding materials.

  4. T-cell receptor accessory and co-receptor molecules in channel catfish

    USDA-ARS?s Scientific Manuscript database

    T cell receptor (TCR) associated invariant chains CD3gamma/delta,epsilon, and zeta as well as TCR co-receptors CD8alpha and CD8beta were isolated from the channel catfish, Ictalurus punctatus, at both the gene and cDNA levels. All of catfish CD3 sequences encode for proteins that resemble their resp...

  5. ROBOCAL: An automated NDA (nondestructive analysis) calorimetry and gamma isotopic system

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hurd, J.R.; Powell, W.D.; Ostenak, C.A.

    1989-11-01

    ROBOCAL, which is presently being developed and tested at Los Alamos National Laboratory, is a full-scale, prototype robotic system for remote calorimetric and gamma-ray analysis of special nuclear materials. It integrates a fully automated, multidrawer, vertical stacker-retriever system for staging unmeasured nuclear materials, and a fully automated gantry robot for computer-based selection and transfer of nuclear materials to calorimetric and gamma-ray measurement stations. Since ROBOCAL is designed for minimal operator intervention, a completely programmed user interface is provided to interact with the automated mechanical and assay systems. The assay system is designed to completely integrate calorimetric and gamma-ray data acquisitionmore » and to perform state-of-the-art analyses on both homogeneous and heterogeneous distributions of nuclear materials in a wide variety of matrices.« less

  6. Oxidized LDL binding to LOX-1 upregulates VEGF expression in cultured bovine chondrocytes through activation of PPAR-{gamma}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kanata, Sohya; Akagi, Masao; Nishimura, Shunji

    It has been reported that vascular endothelial growth factor (VEGF) and its receptors play an important role in the destruction of articular cartilage in osteoarthritis through increased production of matrix metalloproteinases. We investigated whether the oxidized low-density lipoprotein (ox-LDL) binding to lectin-like ox-LDL receptor-1 (LOX-1) upregulates VEGF expression in cultured bovine articular chondrocytes (BACs). Ox-LDL markedly increased VEGF mRNA expression and protein release in time- and dose-dependent manners, which was significantly suppressed by anti-LOX-1 antibody pretreatment. Activation of peroxisome proliferator-activated receptor (PPAR)-{gamma} was evident in BACs with ox-LDL addition and was attenuated by anti-LOX-1 antibody. The specific PPAR-{gamma} inhibitor GW9662more » suppressed ox-LDL-induced VEGF expression. These results suggest that the ox-LDL/LOX-1 system upregulates VEGF expression in articular cartilage, at least in part, through activation of PPAR-{gamma} and supports the hypothesis that ox-LDL is involved in cartilage degradation via LOX-1.« less

  7. Peroxisome Proliferator-Activated Receptor Gamma in Obesity and Colorectal Cancer: the Role of Epigenetics.

    PubMed

    Motawi, T K; Shaker, O G; Ismail, M F; Sayed, N H

    2017-09-06

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that is deregulated in obesity. PPARγ exerts diverse antineoplastic effects. Attempting to determine the clinical relevance of the epigenetic mechanisms controlling the expression PPARγ and susceptibility to colorectal cancer (CRC) in obese subjects, this study investigated the role of some microRNAs and DNA methylation on the deregulation of PPARγ. Seventy CRC patients (34 obese and 36 lean), 22 obese and 24 lean healthy controls were included. MicroRNA levels were measured in serum. PPARγ promoter methylation was evaluated in peripheral blood mononuclear cells (PBMC). PPARγ level was evaluated by measuring mRNA level in PBMC and protein level in serum. The tested microRNAs (miR-27b, 130b and 138) were significantly upregulated in obese and CRC patients. Obese and CRC patients had significantly low levels of PPARγ. A significant negative correlation was found between PPARγ levels and the studied microRNAs. There was a significant PPARγ promoter hypermethylation in CRC patients that correlated to low PPARγ levels. Our results suggest that upregulation of microRNAs 27b, 130b and 138 is associated with susceptibility to CRC in obese subjects through PPARγ downregulation. Hypermethylation of PPARγ gene promoter is associated with CRC through suppression of PPARγ regardless of BMI.

  8. The Advanced Gamma-ray Imaging System (AGIS): Simulation Studies

    NASA Astrophysics Data System (ADS)

    Fegan, Stephen; Buckley, J. H.; Bugaev, S.; Funk, S.; Konopelko, A.; Maier, G.; Vassiliev, V. V.; Simulation Studies Working Group; AGIS Collaboration

    2008-03-01

    The Advanced Gamma-ray Imaging System (AGIS) is a concept for the next generation instrument in ground-based very high energy gamma-ray astronomy. It has the goal of achieving significant improvement in sensitivity over current experiments. We present the results of simulation studies of various possible designs for AGIS. The primary characteristics of the array performance, collecting area, angular resolution, background rejection, and sensitivity are discussed.

  9. GABA(C) receptors: a molecular view.

    PubMed

    Enz, R

    2001-08-01

    In the central nervous system inhibitory neurotransmission is primarily achieved through activation of receptors for gamma-aminobutyric acid (GABA). Three types of GABA receptors have been identified on the basis of their pharmacological and electrophysiological properties. The predominant type, termed GABA(A), and a recently identified GABA(C) type, form ligand-gated chloride channels, whereas GABA(B) receptors activate separate cation channels via G proteins. Based on their homology to nicotinic acetylcholine receptors, GABA(C) receptors are believed to be oligomeric protein complexes composed of five subunits in a pentameric arrangement. To date up to five different GABA(C) receptors subunits have been identified in various species. Recent studies have shed new light on the biological characteristics of GABA(C) receptors, including the chromosomal localization of its subunit genes and resulting links to deseases, the cloning of new splice variants, the identification of GABA(C) receptor-associated proteins, the identification of domains involved in subunit assembly, and finally structure/function studies examining functional consequences of introduced mutations. This review summarizes recent data in view of the molecular structure of GABA(C) receptors and presents new insights into the biological function of this protein in the retina.

  10. Regulation of PPAR{gamma} function by TNF-{alpha}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ye Jianping

    2008-09-26

    The nuclear receptor PPAR{gamma} is a lipid sensor that regulates lipid metabolism through gene transcription. Inhibition of PPAR{gamma} activity by TNF-{alpha} is involved in pathogenesis of insulin resistance, atherosclerosis, inflammation, and cancer cachexia. PPAR{gamma} activity is regulated by TNF-{alpha} at pre-translational and post-translational levels. Activation of serine kinases including IKK, ERK, JNK, and p38 may be involved in the TNF-regulation of PPAR{gamma}. Of the four kinases, IKK is a dominant signaling molecule in the TNF-regulation of PPAR{gamma}. IKK acts through at least two mechanisms: inhibition of PPAR{gamma} expression and activation of PPAR{gamma} corepressor. In this review article, literature is reviewedmore » with a focus on the mechanisms of PPAR{gamma} inhibition by TNF-{alpha}.« less

  11. Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha as a Novel Target for Bipolar Disorder and Other Neuropsychiatric Disorders.

    PubMed

    Nierenberg, Andrew A; Ghaznavi, Sharmin A; Sande Mathias, Isadora; Ellard, Kristen K; Janos, Jessica A; Sylvia, Louisa G

    2018-05-01

    Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a protein that regulates metabolism and inflammation by activating nuclear receptors, especially the family of peroxisome proliferator-activated receptors (PPARs). PGC-1 alpha and PPARs also regulate mitochondrial biogenesis, cellular energy production, thermogenesis, and lipid metabolism. Brain energy metabolism may also be regulated in part by the interaction between PGC-1 alpha and PPARs. Because neurodegenerative diseases (Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis) and bipolar disorder have been associated with dysregulated mitochondrial and brain energy metabolism, PGC-1 alpha may represent a potential drug target for these conditions. The purpose of this article is to review the physiology of PGC-1 alpha, PPARs, and the role of PPAR agonists to target PGC-1 alpha to treat neurodegenerative diseases and bipolar disorder. We also review clinical trials of repurposed antidiabetic thiazolidines and anti-triglyceride fibrates (PPAR agonists) for neurodegenerative diseases and bipolar disorder. PGC-1 alpha and PPARs are innovative potential targets for bipolar disorder and warrant future clinical trials. Copyright © 2018. Published by Elsevier Inc.

  12. Time-dependent therapeutic roles of nitazoxanide on high-fat diet/streptozotocin-induced diabetes in rats: effects on hepatic peroxisome proliferator-activated receptor-gamma receptors.

    PubMed

    Elaidy, Samah M; Hussain, Mona A; El-Kherbetawy, Mohamed K

    2018-05-01

    Targeting peroxisome proliferator-activated receptor-gamma (PPAR-γ) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-γ modulators display improvements in the insulin-sensitizing and adverse effects of the traditional thiazolidinediones. Nitazoxanide (NTZ) is proposed as a PPAR-γ receptor ligand with agonistic post-transcriptional effects. Currently, NTZ antidiabetic activities versus pioglitazone (PIO) in a high-fat diet/streptozotocin rat model of type 2 diabetes was explored. Diabetic adult male Wistar rats were treated orally with either PIO (2.7 mg·kg -1 ·day -1 ) or NTZ (200 mg·kg -1 ·day -1 ) for 14, 21, and 28 days. Body masses, fasting blood glucose, IR, lipid profiles, and liver and kidney functions of rats were assayed. Hepatic glucose metabolism and PPAR-γ protein expression levels as well as hepatic, pancreatic, muscular, and renal histopathology were evaluated. Significant time-dependent euglycemic and insulin-sensitizing effects with preservation of liver and kidney functions were offered by NTZ. Higher hepatic levels of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase enzymes and PPAR-γ protein expressions were acquired by NTZ and PIO, respectively. NTZ could be considered an oral therapeutic strategy for DM type 2. Further systematic NTZ/PPAR-γ receptor subtype molecular activations are recommended. Simultaneous use of NTZ with other approved antidiabetics should be explored.

  13. Impact of targeted PPAR gamma disruption on bone remodeling

    USDA-ARS?s Scientific Manuscript database

    Peroxisome proliferator-activated receptor gamma (PPAR gamma), known as the master regulator of adipogenesis, has been regarded as a promising target for new anti-osteoporosis therapy due to its role in regulating bone marrow mesenchymal stem/progenitor cell (BMSC) lineage commitment. However, the p...

  14. Fc gamma receptor IIIb polymorphism and systemic lupus erythematosus: association with disease susceptibility and identification of a novel FCGR3B*01 variant.

    PubMed

    Santos, V C; Grecco, M; Pereira, K M C; Terzian, C C N; Andrade, L E C; Silva, N P

    2016-10-01

    The objective of this study was to evaluate the association between Fc gamma receptor IIIb polymorphism and susceptibility to systemic lupus erythematosus and clinical traits of the disease. Genomic DNA was obtained from 303 consecutive systemic lupus erythematosus patients and 300 healthy blood donors from the southeastern region of Brazil. The polymorphic region of the FCGR3B gene was sequenced and the alleles FCGR3B*01, FCGR3B*02 and FCGR3B*03 were analyzed. The FCGR3B*01 allele was more frequent in systemic lupus erythematosus patients (43.1%) while the FCGR3B*02 allele prevailed among controls (63.7%) (P = 0.001). The FCGR3B*03 allele was found equally in both groups. The FCGR3B*01/*01 (20.7%) and FCGR3B*01/*02 (41.1%) genotypes were more frequent among systemic lupus erythematosus patients (P = 0.028 and P = 0.012, respectively) while the FCGR3B*02/*02 genotype was more frequent in controls (45.5%) (P < 0.001). One variant of the FCGR3B*01 allele previously described in Germany was found in only one control. A new variant of the FCGR3B*01 allele with two substitutions (A227G/G277A) was found in one control. Three variants of the FCGR3B*02 allele previously described in African-Americans, Brazilians, Chinese and Japanese were found in ten 10 patients and two controls. In addition, several single nucleotide polymorphisms at non-polymorphic positions were identified in both patients and controls. Susceptibility to systemic lupus erythematosus was associated with the FCGR3B*01 allele, as well as with the FCGR3B*01/*01 and FCGR3B*01/*02 genotypes. No association was found between FCGR3B genotypes and clinical manifestations, disease severity or the presence of autoantibodies. © The Author(s) 2016.

  15. Affective and cognitive effects of global deletion of alpha3-containing gamma-aminobutyric acid-A receptors.

    PubMed

    Fiorelli, Roberto; Rudolph, Uwe; Straub, Carolin J; Feldon, Joram; Yee, Benjamin K

    2008-09-01

    Gamma-aminobutyric acid (GABA)A receptors characterized by the presence of the alpha3 subunit are the major GABAA receptor subtype expressed in brain stem monoaminergic nuclei. These alpha3-GABAA receptors are therefore in a unique position to regulate monoaminergic functions. To characterize the functional properties of alpha3-GABAA receptors, we present a preliminary assessment of the expression of affective and cognitive behaviour in male mice with a targeted deletion of the Gabra3 gene encoding the alpha3 subunit [alpha3 knockout (KO) mice] on a C57BL/6Jx129X1/SvJ F1 hybrid genetic background. The alpha3 KO mice did not exhibit any gross change of anxiety-like behaviour or spontaneous locomotor behaviour. In the Porsolt forced swim test for potential antidepressant activity, alpha3 KO mice exhibited reduced floating and enhanced swimming behaviour relative to wild-type controls. Performance on a two-choice sucrose preference test, however, revealed no evidence for an increase in sucrose preference in the alpha3 KO mice that would have substantiated a potential phenotype for depression-related behaviour. In contrast, a suggestion of an enhanced negative contrast effect was revealed in a one-bottle sucrose consumption test across different sucrose concentrations. These affective phenotypes were accompanied by alterations in the balance between conditioned responding to the discrete conditioned stimulus and to the context, and a suggestion of faster extinction, in the Pavlovian conditioned freezing paradigm. Spatial learning in the water maze reference memory test, however, was largely unchanged in the alpha3 KO mice, except for a trend of preservation during reversal learning. The novel phenotypes following global deletion of the GABAA receptor alpha3 subunit identified here provided relevant insights, in addition to our earlier study, into the potential behavioural relevance of this specific receptor subtypes in the modulation of both affective and cognitive

  16. Guanine nucleotide-binding protein regulation of melatonin receptors in lizard brain

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rivkees, S.A.; Carlson, L.L.; Reppert, S.M.

    Melatonin receptors were identified and characterized in crude membrane preparations from lizard brain by using {sup 125}I-labeled melatonin ({sup 125}I-Mel), a potent melatonin agonist. {sup 125}I-Mel binding sites were saturable; Scatchard analysis revealed high-affinity and lower affinity binding sites, with apparent K{sub d} of 2.3 {plus minus} 1.0 {times} 10{sup {minus}11} M and 2.06 {plus minus} 0.43 {times} 10{sup {minus}10} M, respectively. Binding was reversible and inhibited by melatonin and closely related analogs but not by serotonin or norepinephrine. Treatment of crude membranes with the nonhydrolyzable GTP analog guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)), significantly reduced the number of high-affinity receptors and increasedmore » the dissociation rate of {sup 125}I-Mel from its receptor. Furthermore, GTP({gamma}S) treatment of ligand-receptor complexes solubilized by Triton X-100 also led to a rapid dissociation of {sup 125}I-Mel from solubilized ligand-receptor complexes. Gel filtration chromatography of solubilized ligand-receptor complexes revealed two major peaks of radioactivity corresponding to M{sub r} > 400,000 and M{sub r} ca. 110,000. This elution profile was markedly altered by pretreatment with GTP({gamma}S) before solubilization; only the M{sub r} 110,000 peak was present in GTP({gamma}S)-pretreated membranes. The results strongly suggest that {sup 125}I-mel binding sites in lizard brain are melatonin receptors, with agonist-promoted guanine nucleotide-binding protein (G protein) coupling and that the apparent molecular size of receptors uncoupled from G proteins is about 110,000.« less

  17. Interferon-gamma promotes the survival and Fc epsilon RI-mediated histamine release in cultured human mast cells.

    PubMed Central

    Yanagida, M; Fukamachi, H; Takei, M; Hagiwara, T; Uzumaki, H; Tokiwa, T; Saito, H; Iikura, Y; Nakahata, T

    1996-01-01

    We examined the effects of interferon-gamma (IFN-gamma) on 100% pure human mast cells generated in suspension cultures of umbilical cord blood mononuclear cells in the presence of stem cell factor (SCF) and interleukin-6 (IL-6). When mast cells were suspended in serum-free medium without any cytokine after the withdrawal of SCF and IL-6, they died over a period of 5 days because of apoptosis. IFN-gamma in the cultures suppressed apoptosis and prolonged their survival in a dose-dependent manner. This survival-promoting effect of IFN-gamma was blocked by neutralizing antibodies to IFN-gamma or to IFN-gamma receptor (IFN-gamma R). When mast cells were incubated with IFN-gamma in serum-free medium for more than 4 hr during sensitization, immunoglobulin E (IgE)/anti-IgE antibody-induced histamine release was effectively enhanced. Polymerase chain reaction (PCR) amplification of the alpha-chain of IFN-gamma R (IFN-gamma R alpha) yielded products of the correct size predicted from the sequence of the receptor. In addition, flow cytometry using anti-IFN-gamma R monoclonal antibodies (mAbs) indicated that these mast cells bear IFN-gamma R on their surface. These findings suggested that IFN-gamma activates human mast cells via specific receptors in certain aspects of inflammatory reactions. Images Figure 2 Figure 4 PMID:9014819

  18. Differential regulation of serotonin-1A receptor-stimulated [35S]GTP gamma S binding in the dorsal raphe nucleus by citalopram and escitalopram.

    PubMed

    Rossi, Dania V; Burke, Teresa F; Hensler, Julie G

    2008-03-31

    The effect of chronic citalopram or escitalopram administration on 5-HT1A receptor function in the dorsal raphe nucleus was determined by measuring [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (R)-(+)-8-OH-DPAT (1nM-10 microM). Although chronic administration of citalopram or escitalopram has been shown to desensitize somatodendritic 5-HT1A autoreceptors, we found that escitalopram treatment decreased the efficacy of 5-HT1A receptors to activate G proteins, whereas citalopram treatment did not. The binding of [3H]8-OH-DPAT to the coupled, high affinity agonist state of the receptor was not altered by either treatment. Interestingly, escitalopram administration resulted in greater occupancy of serotonin transporter sites as measured by the inhibition of [3H]cyanoimipramine binding. As the binding and action of escitalopram is limited by the inactive enantiomer R-citalopram present in racemic citalopram, we propose that the regulation of 5-HT1A receptor function in the dorsal raphe nucleus at the level of receptor-G protein interaction may be a result of greater inhibition of the serotonin transporter by escitalopram.

  19. Genomewide effects of peroxisome proliferator-activated receptor gamma in macrophages and dendritic cells--revealing complexity through systems biology.

    PubMed

    Cuaranta-Monroy, Ixchelt; Kiss, Mate; Simandi, Zoltan; Nagy, Laszlo

    2015-09-01

    Systems biology approaches have become indispensable tools in biomedical and basic research. These data integrating bioinformatic methods gained prominence after high-throughput technologies became available to investigate complex cellular processes, such as transcriptional regulation and protein-protein interactions, on a scale that had not been studied before. Immunology is one of the medical fields that systems biology impacted profoundly due to the plasticity of cell types involved and the accessibility of a wide range of experimental models. In this review, we summarize the most important recent genomewide studies exploring the function of peroxisome proliferator-activated receptor γ in macrophages and dendritic cells. PPARγ ChIP-seq experiments were performed in adipocytes derived from embryonic stem cells to complement the existing data sets and to provide comparators to macrophage data. Finally, lists of regulated genes generated from such experiments were analysed with bioinformatics and system biology approaches. We show that genomewide studies utilizing high-throughput data acquisition methods made it possible to gain deeper insights into the role of PPARγ in these immune cell types. We also demonstrate that analysis and visualization of data using network-based approaches can be used to identify novel genes and functions regulated by the receptor. The example of PPARγ in macrophages and dendritic cells highlights the crucial importance of systems biology approaches in establishing novel cellular functions for long-known signaling pathways. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.

  20. Extrasynaptic GABAA receptors in the crosshairs of hormones and ethanol

    PubMed Central

    Mody, Istvan

    2008-01-01

    Gamma-aminobutyric acid (GABA) is the main chemical inhibitory neurotransmitter in the brain. In the central nervous system (CNS) it acts on two distinct types of receptor: an ion channel, i.e., an “ionotropic” receptor permeable to Cl− and HCO3− (GABAA receptors) and a G-protein coupled “metabotropic” receptor that is linked to various effector mechanisms (GABAB receptors). This review will summarize novel developments in the physiology and pharmacology of GABAA receptors (GABAARs), specifically those found outside synapses. The focus will be on a particular combination of GABAAR subunits sensitive to ovarian and adrenal cortical steroid hormone metabolites that are synthesized in the brain (neurosteroids) and to sobriety impairing concentrations of ethanol. These receptors may be the final common pathway for interactions between ethanol and ovarian and stress-related neurosteroids. PMID:17714830

  1. Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS.

    PubMed

    Moreno, S; Farioli-Vecchioli, S; Cerù, M P

    2004-01-01

    Peroxisome proliferator-activated and retinoid X receptors (PPARs and RXRs) are transcription factors belonging to the steroid hormone receptor superfamily. Upon activation by their ligands, PPARs and RXRs bind to their target genes as heterodimers. Ligands of these receptors include lipophylic molecules, such as retinoids, fatty acids and eicosanoids, the importance of which in the metabolism and functioning of the nervous tissue is well documented. The immunohistochemical distribution of PPARs and RXRs in the CNS of the adult rat was studied by means of a sensitive biotinyl-tyramide method. All PPAR (alpha, beta/delta and gamma) and RXR (alpha, beta and gamma) isotypes were detected and found to exhibit specific patterns of localization in the different areas of the brain and spinal cord. The presence of the nuclear receptors was observed in both neuronal and glial cells. While PPAR beta/delta and RXR beta showed a widespread distribution, alpha and gamma isotypes exhibited a more restricted pattern of expression. The frontal cortex, basal ganglia, reticular formation, some cranial nerve nuclei, deep cerebellar nuclei, and cerebellar Golgi cells appeared rather rich in all studied receptors. Based on our data, we suggest that in the adult CNS, PPARs and RXRs, besides playing roles common to many other tissues, may have specific functions in regulating the expression of genes involved in neurotransmission, and therefore play roles in complex processes, such as aging, neurodegeneration, learning and memory.

  2. Adaptor protein SH2-B linking receptor-tyrosine kinase and Akt promotes adipocyte differentiation by regulating peroxisome proliferator-activated receptor gamma messenger ribonucleic acid levels.

    PubMed

    Yoshiga, Daigo; Sato, Naoichi; Torisu, Takehiro; Mori, Hiroyuki; Yoshida, Ryoko; Nakamura, Seiji; Takaesu, Giichi; Kobayashi, Takashi; Yoshimura, Akihiko

    2007-05-01

    Adipocyte differentiation is regulated by insulin and IGF-I, which transmit signals by activating their receptor tyrosine kinase. SH2-B is an adaptor protein containing pleckstrin homology and Src homology 2 (SH2) domains that have been implicated in insulin and IGF-I receptor signaling. In this study, we found a strong link between SH2-B levels and adipogenesis. The fat mass and expression of adipogenic genes including peroxisome proliferator-activated receptor gamma (PPARgamma) were reduced in white adipose tissue of SH2-B-/- mice. Reduced adipocyte differentiation of SH2-B-deficient mouse embryonic fibroblasts (MEFs) was observed in response to insulin and dexamethasone, whereas retroviral SH2-B overexpression enhanced differentiation of 3T3-L1 preadipocytes to adipocytes. SH2-B overexpression enhanced mRNA level of PPARgamma in 3T3-L1 cells, whereas PPARgamma levels were reduced in SH2-B-deficient MEFs in response to insulin. SH2-B-mediated up-regulation of PPARgamma mRNA was blocked by a phosphatidylinositol 3-kinase inhibitor, but not by a MAPK kinase inhibitor. Insulin-induced Akt activation and the phosphorylation of forkhead transcription factor (FKHR/Foxo1), a negative regulator of PPARgamma transcription, were up-regulated by SH2-B overexpression, but reduced in SH2-B-deficient MEFs. These data indicate that SH2-B is a key regulator of adipogenesis both in vivo and in vitro by regulating the insulin/IGF-I receptor-Akt-Foxo1-PPARgamma pathway.

  3. Gamma Band Activity in the Reticular Activating System

    PubMed Central

    Urbano, Francisco J.; Kezunovic, Nebojsa; Hyde, James; Simon, Christen; Beck, Paige; Garcia-Rill, Edgar

    2012-01-01

    This review considers recent evidence showing that cells in three regions of the reticular activating system (RAS) exhibit gamma band activity, and describes the mechanisms behind such manifestation. Specifically, we discuss how cells in the mesopontine pedunculopontine nucleus (PPN), intralaminar parafascicular nucleus (Pf), and pontine subcoeruleus nucleus dorsalis (SubCD) all fire in the beta/gamma band range when maximally activated, but no higher. The mechanisms behind this ceiling effect have been recently elucidated. We describe recent findings showing that every cell in the PPN have high-threshold, voltage-dependent P/Q-type calcium channels that are essential, while N-type calcium channels are permissive, to gamma band activity. Every cell in the Pf also showed that P/Q-type and N-type calcium channels are responsible for this activity. On the other hand, every SubCD cell exhibited sodium-dependent subthreshold oscillations. A novel mechanism for sleep–wake control based on well-known transmitter interactions, electrical coupling, and gamma band activity is described. The data presented here on inherent gamma band activity demonstrates the global nature of sleep–wake oscillation that is orchestrated by brainstem–thalamic mechanism, and questions the undue importance given to the hypothalamus for regulation of sleep–wakefulness. The discovery of gamma band activity in the RAS follows recent reports of such activity in other subcortical regions like the hippocampus and cerebellum. We hypothesize that, rather than participating in the temporal binding of sensory events as seen in the cortex, gamma band activity manifested in the RAS may help stabilize coherence related to arousal, providing a stable activation state during waking and paradoxical sleep. Most of our thoughts and actions are driven by pre-conscious processes. We speculate that continuous sensory input will induce gamma band activity in the RAS that could participate in the processes of

  4. Development of polarization-controlled multi-pass Thomson scattering system in the GAMMA 10 tandem mirror

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yoshikawa, M.; Morimoto, M.; Shima, Y.

    2012-10-15

    In the GAMMA 10 tandem mirror, the typical electron density is comparable to that of the peripheral plasma of torus-type fusion devices. Therefore, an effective method to increase Thomson scattering (TS) signals is required in order to improve signal quality. In GAMMA 10, the yttrium-aluminum-garnet (YAG)-TS system comprises a laser, incident optics, light collection optics, signal detection electronics, and a data recording system. We have been developing a multi-pass TS method for a polarization-based system based on the GAMMA 10 YAG TS. To evaluate the effectiveness of the polarization-based configuration, the multi-pass system was installed in the GAMMA 10 YAG-TSmore » system, which is capable of double-pass scattering. We carried out a Rayleigh scattering experiment and applied this double-pass scattering system to the GAMMA 10 plasma. The integrated scattering signal was made about twice as large by the double-pass system.« less

  5. 4-Hydroxydocosahexaenoic acid, a potent peroxisome proliferator-activated receptor {gamma} agonist alleviates the symptoms of DSS-induced colitis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yamamoto, Keiko; Ninomiya, Yuichi; Iseki, Mioko

    2008-03-14

    (5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) and antidiabetic agent as has been previously reported. As PPAR{gamma} agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice whenmore » compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.« less

  6. IL-4 function can be transferred to the IL-2 receptor by tyrosine containing sequences found in the IL-4 receptor alpha chain.

    PubMed

    Wang, H Y; Paul, W E; Keegan, A D

    1996-02-01

    IL-4 binds to a cell surface receptor complex that consists of the IL-4 binding protein (IL-4R alpha) and the gamma chain of the IL-2 receptor complex (gamma c). The receptors for IL-4 and IL-2 have several features in common; both use the gamma c as a receptor component, and both activate the Janus kinases JAK-1 and JAK-3. In spite of these similarities, IL-4 evokes specific responses, including the tyrosine phosphorylation of 4PS/IRS-2 and the induction of CD23. To determine whether sequences within the cytoplasmic domain of the IL-4R alpha specify these IL-4-specific responses, we transplanted the insulin IL-4 receptor motif (I4R motif) of the huIL-4R alpha to the cytoplasmic domain of a truncated IL-2R beta. In addition, we transplanted a region that contains peptide sequences shown to block Stat6 binding to DNA. We analyzed the ability of cells expressing these IL-2R-IL-4R chimeric constructs to respond to IL-2. We found that IL-4 function could be transplanted to the IL-2 receptor by these regions and that proliferative and differentiative functions can be induced by different receptor sequences.

  7. Serotonergic hallucinogens differentially modify gamma and high frequency oscillations in the rat nucleus accumbens.

    PubMed

    Goda, Sailaja A; Piasecka, Joanna; Olszewski, Maciej; Kasicki, Stefan; Hunt, Mark J

    2013-07-01

    The nucleus accumbens (NAc) is a site critical for the actions of many drugs of abuse. Psychoactive compounds, such as N-methyl-D-aspartate receptor (NMDAR) antagonists, modify gamma (40-90) and high frequency oscillations (HFO, 130-180 Hz) in local field potentials (LFPs) recorded in the NAc. Lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI) are serotonergic hallucinogens and activation of 5HT2A receptors likely underlies their hallucinogenic effects. Whether these compounds can also modulate LFP oscillations in the NAc is unclear. This study aims to examine the effect of serotonergic hallucinogens on gamma and HFO recorded in the NAc and to test whether 5HT2A receptors mediate the effects observed. LFPs were recorded from the NAc of freely moving rats. Drugs were administered intraperitoneally. LSD (0.03-0.3 mg/kg) and DOI (0.5-2.0 mg/kg) increased the power and reduced the frequency of HFO. In contrast, the hallucinogens produced a robust reduction in the power of low (40-60 Hz), but not high gamma oscillations (70-90 Hz). MDL 11939 (1.0 mg/kg), a 5HT2A receptor antagonist, fully reversed the changes induced by DOI on HFO but only partially for the low gamma band. Equivalent increases in HFO power were observed after TCB-2 (5HT2A receptor agonist, 0.1-1.5 mg/kg), but not CP 809101 (5H2C receptor agonist, 0.1-3 mg/kg). Notably, hallucinogen-induced increases in HFO power were smaller than those produced by ketamine (25 mg/kg). Serotonergic hallucinogen-induced changes in HFO and gamma are mediated, at least in part, by stimulation of 5HT2A receptors. Comparison of the oscillatory changes produced by serotonergic hallucinogens and NMDAR antagonists are also discussed.

  8. Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A possible link between xenobiotic response and nutritional state.

    PubMed

    Shiraki, Takuma; Sakai, Noriko; Kanaya, Eiko; Jingami, Hisato

    2003-03-28

    In contrast to the classical nuclear receptors, the constitutive androstane receptor (CAR) is transcriptionally active in the absence of ligand. In the course of searching for the mediator of CAR activation, we found that ligand-independent activation of CAR was achieved in cooperation with the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). PGC-1 beta, a PGC-1 alpha homologue, also activated CAR to less of an extent than PGC-1 alpha. Coexpression of the ligand-binding domain of a heterodimerization partner, retinoid X receptor alpha, enhanced the PGC-1 alpha-mediated activation of CAR, although it had a weak effect on the basal activity of CAR in the absence of PGC-1 alpha. Both the N-terminal region, with the LXXLL motif, and the C-terminal region, with a serine/arginine-rich domain (RS domain), in PGC-1 alpha were required for full activation of CAR. Pull-down experiments using recombinant proteins revealed that CAR directly interacted with both the LXXLL motif and the RS domain. Furthermore, we demonstrated that the RS domain of PGC-1 alpha was required for CAR localization at nuclear speckles. These results indicate that PGC-1 alpha mediates the ligand-independent activation of CAR by means of subnuclear targeting through the RS domain of PGC-1 alpha.

  9. G-protein-coupled receptors for neurotransmitter amino acids: C-terminal tails, crowded signalosomes.

    PubMed Central

    El Far, Oussama; Betz, Heinrich

    2002-01-01

    G-protein-coupled receptors (GPCRs) represent a superfamily of highly diverse integral membrane proteins that transduce external signals to different subcellular compartments, including nuclei, via trimeric G-proteins. By differential activation of diffusible G(alpha) and membrane-bound G(beta)gamma subunits, GPCRs might act on both cytoplasmic/intracellular and plasma-membrane-bound effector systems. The coupling efficiency and the plasma membrane localization of GPCRs are regulated by a variety of interacting proteins. In this review, we discuss recently disclosed protein interactions found with the cytoplasmic C-terminal tail regions of two types of presynaptic neurotransmitter receptors, the group III metabotropic glutamate receptors and the gamma-aminobutyric acid type-B receptors (GABA(B)Rs). Calmodulin binding to mGluR7 and other group III mGluRs may provide a Ca(2+)-dependent switch for unidirectional (G(alpha)) versus bidirectional (G(alpha) and G(beta)gamma) signalling to downstream effector proteins. In addition, clustering of mGluR7 by PICK1 (protein interacting with C-kinase 1), a polyspecific PDZ (PSD-95/Dlg1/ZO-1) domain containing synaptic organizer protein, sheds light on how higher-order receptor complexes with regulatory enzymes (or 'signalosomes') could be formed. The interaction of GABA(B)Rs with the adaptor protein 14-3-3 and the transcription factor ATF4 (activating transcription factor 4) suggests novel regulatory pathways for G-protein signalling, cytoskeletal reorganization and nuclear gene expression: processes that may all contribute to synaptic plasticity. PMID:12006104

  10. Method and System for Gamma-Ray Localization Induced Spacecraft Navigation Using Celestial Gamma-Ray Sources

    NASA Technical Reports Server (NTRS)

    Hisamoto, Chuck (Inventor); Arzoumanian, Zaven (Inventor); Sheikh, Suneel I. (Inventor)

    2015-01-01

    A method and system for spacecraft navigation using distant celestial gamma-ray bursts which offer detectable, bright, high-energy events that provide well-defined characteristics conducive to accurate time-alignment among spatially separated spacecraft. Utilizing assemblages of photons from distant gamma-ray bursts, relative range between two spacecraft can be accurately computed along the direction to each burst's source based upon the difference in arrival time of the burst emission at each spacecraft's location. Correlation methods used to time-align the high-energy burst profiles are provided. The spacecraft navigation may be carried out autonomously or in a central control mode of operation.

  11. Peroxisome proliferator-activated receptor (PPAR)gamma is highly expressed in normal human pituitary gland.

    PubMed

    Bogazzi, F; Russo, D; Locci, M T; Chifenti, B; Ultimieri, F; Raggi, F; Viacava, P; Cecchetti, D; Cosci, C; Sardella, C; Acerbi, G; Gasperi, M; Martino, E

    2005-11-01

    Expression of peroxisome proliferator-activated receptor (PPAR)gamma in normal pituitary seems to be restricted to ACTH-secreting cells. The aim of the study was to evaluate the expression of PPARgamma in normal human pituitary tissue and to study its localization in the pituitary secreting cells. Normal pituitary tissue samples were obtained form 11 patients with non-secreting adenoma who underwent surgical excision of the tumor. Expression of PPARgamma was evaluated by immunostaining and western blotting; localization of PPARgamma in each pituitary secreting cell lineage was evaluated by double immunofluorescence using confocal microscopy. Pituitary non-functioning adenomas served as Controls. PPARgamma was highly expressed in all pituitary samples with a (mean +/- SD) 81 +/- 6.5% of stained cells; expression of PPARgamma was confirmed by western blotting. Non-functioning pituitary adenomas had 74 +/- 11% PPARgamma positive cells. Expression of PPARy was either in cytoplasm or nuclei. In addition, treatment of GH3 cells, with a PPARgamma ligand was associated with traslocation of the receptor from cytoplasm into the nucleus. Double immunostaining revealed that every pituitary secreting cell (GH, TSH, LH, FSH, PRL and ACTH) had PPARgamma expressed. The present study demonstrated that PPARgamma is highly expressed in every normal pituitary secreting cell lineage. It can translocate into the nucleus by ligand binding; however, its role in pituitary hormone regulation remains to be elucidated.

  12. AT1 receptor signaling pathways in the cardiovascular system.

    PubMed

    Kawai, Tatsuo; Forrester, Steven J; O'Brien, Shannon; Baggett, Ariele; Rizzo, Victor; Eguchi, Satoru

    2017-11-01

    The importance of the renin angiotensin aldosterone system in cardiovascular physiology and pathophysiology has been well described whereas the detailed molecular mechanisms remain elusive. The angiotensin II type 1 receptor (AT1 receptor) is one of the key players in the renin angiotensin aldosterone system. The AT1 receptor promotes various intracellular signaling pathways resulting in hypertension, endothelial dysfunction, vascular remodeling and end organ damage. Accumulating evidence shows the complex picture of AT1 receptor-mediated signaling; AT1 receptor-mediated heterotrimeric G protein-dependent signaling, transactivation of growth factor receptors, NADPH oxidase and ROS signaling, G protein-independent signaling, including the β-arrestin signals and interaction with several AT1 receptor interacting proteins. In addition, there is functional cross-talk between the AT1 receptor signaling pathway and other signaling pathways. In this review, we will summarize an up to date overview of essential AT1 receptor signaling events and their functional significances in the cardiovascular system. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Minimum Detectable Activity for Tomographic Gamma Scanning System

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Venkataraman, Ram; Smith, Susan; Kirkpatrick, J. M.

    2015-01-01

    For any radiation measurement system, it is useful to explore and establish the detection limits and a minimum detectable activity (MDA) for the radionuclides of interest, even if the system is to be used at far higher values. The MDA serves as an important figure of merit, and often a system is optimized and configured so that it can meet the MDA requirements of a measurement campaign. The non-destructive assay (NDA) systems based on gamma ray analysis are no exception and well established conventions, such the Currie method, exist for estimating the detection limits and the MDA. However, the Tomographicmore » Gamma Scanning (TGS) technique poses some challenges for the estimation of detection limits and MDAs. The TGS combines high resolution gamma ray spectrometry (HRGS) with low spatial resolution image reconstruction techniques. In non-imaging gamma ray based NDA techniques measured counts in a full energy peak can be used to estimate the activity of a radionuclide, independently of other counting trials. However, in the case of the TGS each “view” is a full spectral grab (each a counting trial), and each scan consists of 150 spectral grabs in the transmission and emission scans per vertical layer of the item. The set of views in a complete scan are then used to solve for the radionuclide activities on a voxel by voxel basis, over 16 layers of a 10x10 voxel grid. Thus, the raw count data are not independent trials any more, but rather constitute input to a matrix solution for the emission image values at the various locations inside the item volume used in the reconstruction. So, the validity of the methods used to estimate MDA for an imaging technique such as TGS warrant a close scrutiny, because the pair-counting concept of Currie is not directly applicable. One can also raise questions as to whether the TGS, along with other image reconstruction techniques which heavily intertwine data, is a suitable method if one expects to measure samples whose

  14. Up-regulation of peroxidase proliferator-activated receptor gamma in cholesteatoma.

    PubMed

    Hwang, Soon Jae; Kang, Hee Joon; Song, Jae-Jun; Kang, Jae Seong; Woo, Jeong Soo; Chae, Sung Won; Lee, Heung-Man

    2006-01-01

    To evaluate the localization and expression of peroxidase proliferator-activated receptor (PPAR)gamma in cholesteatoma epithelium. Experimental study. Reverse-transcription polymerase chain reaction was performed on cholesteatoma tissues from 10 adult patients undergoing tympanomastoid surgery for middle ear cholesteatoma and on 10 samples of normal external auditory canal skin tissue. The expression levels of PPARgamma to glyceraldehyde-3-phosphate dehydrogenase transcripts were semiquantified by densitometry. We also characterized the cellular localization of the PPARgamma protein immunohistochemically. Ki-67 was also localized to compare the proliferative activity of cells in cholesteatoma epithelium and in normal external auditory canal skin. PPARgamma mRNA and protein were detected in normal external auditory canal skin and in cholesteatoma epithelium. The expression level of PPARgamma mRNA in cholesteatoma was significantly increased compared with that in normal external auditory canal skin. PPARgamma protein was expressed in cells mainly in the granular and prickle cell layers. However, the intensity of its expression was generally decreased in the parabasal layer of the cholesteatoma epithelium. Ki-67 was expressed in the nuclei of cells in the basal and parabasal layers, and a greater number of cells were Ki-67 immunopositive in cholesteatoma epithelium. PPARgamma is up-regulated in the cholesteatoma epithelium compared with normal external auditory canal skin. These results suggest that PPARgamma may play an important role in the pathogenesis of cholesteatoma.

  15. Leukotriene E4 activates peroxisome proliferator-activated receptor gamma and induces prostaglandin D2 generation by human mast cells.

    PubMed

    Paruchuri, Sailaja; Jiang, Yongfeng; Feng, Chunli; Francis, Sanjeev A; Plutzky, Jorge; Boyce, Joshua A

    2008-06-13

    Cysteinyl leukotrienes (cys-LTs) are potent inflammatory lipid mediators, of which leukotriene (LT) E(4) is the most stable and abundant in vivo. Although only a weak agonist of established G protein-coupled receptors (GPCRs) for cys-LTs, LTE(4) potentiates airway hyper-responsiveness (AHR) by a cyclooxygenase (COX)-dependent mechanism and induces bronchial eosinophilia. We now report that LTE(4) activates human mast cells (MCs) by a pathway involving cooperation between an MK571-sensitive GPCR and peroxisome proliferator-activated receptor (PPAR)gamma, a nuclear receptor for dietary lipids. Although LTD(4) is more potent than LTE(4) for inducing calcium flux by the human MC sarcoma line LAD2, LTE(4) is more potent for inducing proliferation and chemokine generation, and is at least as potent for upregulating COX-2 expression and causing prostaglandin D(2) (PGD(2)) generation. LTE(4) caused phosphorylation of extracellular signal-regulated kinase (ERK), p90RSK, and cyclic AMP-regulated-binding protein (CREB). ERK activation in response to LTE(4), but not to LTD(4), was resistant to inhibitors of phosphoinositol 3-kinase. LTE(4)-mediated COX-2 induction, PGD(2) generation, and ERK phosphorylation were all sensitive to interference by the PPARgamma antagonist GW9662 and to targeted knockdown of PPARgamma. Although LTE(4)-mediated PGD(2) production was also sensitive to MK571, an antagonist for the type 1 receptor for cys-LTs (CysLT(1)R), it was resistant to knockdown of this receptor. This LTE(4)-selective receptor-mediated pathway may explain the unique physiologic responses of human airways to LTE(4) in vivo.

  16. Changes in peroxisome proliferator-activated receptor-gamma activity in children with septic shock.

    PubMed

    Kaplan, Jennifer M; Denenberg, Alvin; Monaco, Marie; Nowell, Marchele; Wong, Hector; Zingarelli, Basilia

    2010-01-01

    To assess changes in peroxisome proliferator-activated receptor-gamma (PPARgamma) in peripheral blood mononuclear cells (PBMC) from critically ill children with sepsis. Additionally, to investigate the effects of sepsis on the endogenous activator of PPARgamma, 15-deoxy-(12,14)-PGJ(2) (15d-PGJ(2)), and the downstream targets of PPARgamma activity, adiponectin and resistin. Single-center, prospective case-control study in critically ill children with systemic inflammatory response syndrome, sepsis or septic shock. PPARgamma nuclear protein expression was decreased but PPARgamma activity was increased in PBMC from children with septic shock compared with controls. PPARgamma activity on day 1 was significantly higher in patients with higher pediatric risk of mortality (PRISM) score compared with controls [mean 0.22 optical density (OD) +/- standard error of the mean (SEM) 0.03 versus 0.12 OD +/- 0.02; p < 0.001]. Patients with resolved sepsis had increased levels of the endogenous PPARgamma ligand, 15d-PGJ(2), compared with patients with systemic inflammatory response syndrome (SIRS) and septic shock (77.7 +/- 21.7 versus 58 +/- 16.5 pg/ml; p = 0.03). Plasma high-molecular-weight adiponectin (HMWA) and resistin levels were increased in patients with septic shock on day 1 and were significantly higher in patients with higher PRISM scores. Nonsurvivors from sepsis had higher resistin levels on the first day of hospitalization compared with survivors from septic shock [660 ng/ml, interquartile range (IQR) 585-833 ng/ml versus 143 ng/ml, IQR 66-342 ng/ml; p < 0.05]. Sepsis is associated with altered PPARgamma expression and activity in PBMC. Plasma adipokines correlate with risk of mortality scores in sepsis and may be useful biomarkers. Further studies are needed to understand the mechanisms underlying changes in PPARgamma in sepsis.

  17. The Advanced Gamma-ray Imaging System (AGIS)-Simulation Studies

    NASA Astrophysics Data System (ADS)

    Maier, G.; Buckley, J.; Bugaev, V.; Fegan, S.; Funk, S.; Konopelko, A.; Vassiliev, V. V.

    2008-12-01

    The Advanced Gamma-ray Imaging System (AGIS) is a US-led concept for a next-generation instrument in ground-based very-high-energy gamma-ray astronomy. The most important design requirement for AGIS is a sensitivity of about 10 times greater than current observatories like Veritas, H.E.S.S or MAGIC. We present results of simulation studies of various possible designs for AGIS. The primary characteristics of the array performance, collecting area, angular resolution, background rejection, and sensitivity are discussed.

  18. Performance analysis of OOK-based FSO systems in Gamma-Gamma turbulence with imprecise channel models

    NASA Astrophysics Data System (ADS)

    Feng, Jianfeng; Zhao, Xiaohui

    2017-11-01

    For an FSO communication system with imprecise channel model, we investigate its system performance based on outage probability, average BEP and ergodic capacity. The exact FSO links are modeled as Gamma-Gamma fading channel in consideration of both atmospheric turbulence and pointing errors, and the imprecise channel model is treated as the superposition of exact channel gain and a Gaussian random variable. After we derive the PDF, CDF and nth moment of the imprecise channel gain, and based on these statistics the expressions for the outage probability, the average BEP and the ergodic capacity in terms of the Meijer's G functions are obtained. Both numerical and analytical results are presented. The simulation results show that the communication performance deteriorates in the imprecise channel model, and approaches to the exact performance curves as the channel model becomes accurate.

  19. Recording Gamma Band Oscillations in Pedunculopontine Nucleus Neurons.

    PubMed

    Urbano, Francisco J; Luster, Brennon R; D'Onofrio, Stasia; Mahaffey, Susan; Garcia-Rill, Edgar

    2016-09-14

    Synaptic efferents from the PPN are known to modulate the neuronal activity of several intralaminar thalamic regions (e.g., the centrolateral/parafascicular; Cl/Pf nucleus). The activation of either the PPN or Cl/Pf nuclei in vivo has been described to induce the arousal of the animal and an increment in gamma band activity in the cortical electroencephalogram (EEG). The cellular mechanisms for the generation of gamma band oscillations in Reticular Activating System (RAS) neurons are the same as those found to generate gamma band oscillations in other brains nuclei. During current-clamp recordings of PPN neurons (from parasagittal slices from 9 - 25 day-old rats), the use of depolarizing square steps rapidly activated voltage-dependent potassium channels that prevented PPN neurons from being depolarized beyond -25 mV. Injecting 1 - 2 sec long depolarizing current ramps gradually depolarized PPN membrane potential resting values towards 0 mV. However, injecting depolarizing square pulses generated gamma-band oscillations of membrane potential that showed to be smaller in amplitude compared to the oscillations generated by ramps. All experiments were performed in the presence of voltage-gated sodium channels and fast synaptic receptors blockers. It has been shown that the activation of high-threshold voltage-dependent calcium channels underlie gamma-band oscillatory activity in PPN neurons. Specific methodological and pharmacological interventions are described here, providing the necessary tools to induce and sustain PPN subthreshold gamma band oscillation in vitro.

  20. Missense Gamma-Aminobutyric Acid Receptor Polymorphisms Are Associated with Reaction Time, Motor Time, and Ethanol Effects in Vivo.

    PubMed

    García-Martín, Elena; Ramos, María I; Cornejo-García, José A; Galván, Segismundo; Perkins, James R; Rodríguez-Santos, Laura; Alonso-Navarro, Hortensia; Jiménez-Jiménez, Félix J; Agúndez, José A G

    2018-01-01

    Background: The Gamma-aminobutyric acid type A receptor (GABA-A receptor) is affected by ethanol concentrations equivalent to those reached during social drinking. At these concentrations, ethanol usually causes impairment in reaction and motor times in most, but not all, individuals. Objectives: To study the effect of GABA-A receptor variability in motor and reaction times, and the effect of low ethanol doses. Methods: Two hundred and fifty healthy subjects received one single dose of 0.5 g/Kg ethanol per os . Reaction and motor times were determined before ethanol challenge (basal), and when participants reached peak ethanol concentrations. We analyzed all common missense polymorphisms described in the 19 genes coding for the GABA-A receptor subunits by using TaqMan probes. Results: The GABRA6 rs4454083 T/C polymorphisms were related to motor times, with individuals carrying the C/C genotype having faster motor times, both, at basal and at peak ethanol concentrations. The GABRA4 rs2229940 T/T genotype was associated to faster reaction times and with lower ethanol effects, determined as the difference between basal reaction time and reaction time at peak concentrations. All these associations remained significant after correction for multiple comparisons. No significant associations were observed for the common missense SNPs GABRB3 rs12910925, GABRG2 rs211035, GABRE rs1139916, GABRP rs1063310, GABRQ rs3810651, GABRR1 rs12200969 or rs1186902, GABRR2 rs282129, and GABRR3 rs832032. Conclusions: This study provides novel information supporting a role of missense GABA-A receptor polymorphisms in reaction time, motor time and effects of low ethanol doses in vivo .

  1. Development of Gamma-Emitting Receptor Binding Radiopharmace

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Reba, Richard

    2003-02-20

    The long-term objective is to develop blood-brain barrier (BBB) permeable m2-selective (relative to m1, m3, and m4) receptor-binding radiotracers and utilize these radiotracers for quantifying receptor concentrations obtained from PET or SPECT images of human brain. In initial studies, we concluded that the lipophilicity and high affinity prevented (R,S)-I-QNB from reaching a flow-independent and receptor-dependent state in a reasonable time. Thus, it was clear that (R,S)-I-QNB should be modified. Therefore, during the last portion of this funded research, we proposed that more polar heterocycles should help accomplish that. Since reports of others concluded that radiobromination and radiofluorination of the unactivatedmore » phenyl ring is not feasible (Newkome et al,,1982), we, therefore, explored during this grant period a series of analogues of (R)-QNB in which one or both of the six-membered phenyl rings is replaced by a five-membered thienyl (Boulay et al., 1995), or furyl ring. The chemistry specific aims were to synthesize novel compounds designed to be m2-selective mAChR ligands capable of penetrating into the CNS, and develop methods for efficient radiolabeling of promising m2-selective muscarinic ligands. The pharmacology specific aims were to determine the affinity and subtype-selectivity of the novel compounds using competition binding studies with membranes from cells that express each of the five muscarinic receptor subtypes, to determine the ability of the promising non-radioactive compounds and radiolabeled novel compounds to cross the BBB, to determine the biodistribution, in-vivo pharmacokinetics, and in-vitm kinetics of promising m2-selective radioligands and to determine the distribution of receptors for the novel m2-selective radioligands using quantitative autoradiography of rat brain, and compare this distribution to the distribution of known m2-selective compounds.« less

  2. Ligand and coactivator identity determines the requirement of the charge clamp for coactivation of the peroxisome proliferator-activated receptor gamma.

    PubMed

    Wu, Yifei; Chin, William W; Wang, Yong; Burris, Thomas P

    2003-03-07

    The activation function 2 (AF-2)-dependent recruitment of coactivator is essential for gene activation by nuclear receptors. We show that the peroxisome proliferator-activated receptor gamma (PPARgamma) (NR1C3) coactivator-1 (PGC-1) requires both the intact AF-2 domain of PPARgamma and the LXXLL domain of PGC-1 for ligand-dependent and ligand-independent interaction and coactivation. Although the AF-2 domain of PPARgamma is absolutely required for PGC-1-mediated coactivation, this coactivator displayed a unique lack of requirement for the charge clamp of the ligand-binding domain of the receptor that is thought to be essential for LXXLL motif recognition. The mutation of a single serine residue adjacent to the core LXXLL motif of PGC-1 led to restoration of the typical charge clamp requirement. Thus, the unique structural features of the PGC-1 LXXLL motif appear to mediate an atypical mode of interaction with PPARgamma. Unexpectedly, we discovered that various ligands display variability in terms of their requirement for the charge clamp of PPARgamma for coactivation by PGC-1. This ligand-selective variable requirement for the charge clamp was coactivator-specific. Thus, distinct structural determinants, which may be unique for a particular ligand, are utilized by the receptor to recognize the coactivator. Our data suggest that even subtle differences in ligand structure are perceived by the receptor and translated into a unique display of the coactivator-binding surface of the ligand-binding domain, allowing for differential recognition of coactivators that may underlie distinct pharmacological profiles observed for ligands of a particular nuclear receptor.

  3. Differential control of the tyrosine kinases Lyn and Syk by the two signaling chains of the high affinity immunoglobulin E receptor.

    PubMed

    Jouvin, M H; Adamczewski, M; Numerof, R; Letourneur, O; Vallé, A; Kinet, J P

    1994-02-25

    Nonreceptor tyrosine kinases such as the newly described 70-kDa (ZAP-70/Syk) and Src-related tyrosine kinases are coupled to a variety of receptors, including the antigen receptors on B- and T-cells and the Fc receptors for IgE (Fc epsilon RI) and IgG (Fc gamma RI, Fc gamma RIII/CD16). Various subunits of these receptors contain homologous activation motifs which appear capable of autonomously triggering cell activation. Two forms of this motif are present in the Fc epsilon RI multimeric complex: one in the beta chain and one in the gamma chain. Here we show that each of the two tyrosine kinases known to be involved in Fc epsilon RI signaling is controlled by a distinct motif-containing chain. Lyn associates with the nonactivated beta chain, whereas gamma promotes the activation of Syk. We also show that neither the beta nor the gamma motif alone can account for the full signaling capacity of the entire receptor. We propose that, upon triggering of the tetrameric receptor, Lyn already bound to beta becomes activated and phosphorylates beta and gamma; the phosphorylation of gamma induces the association of Syk with gamma and also the activation of Syk, resulting in the phosphorylation and activation of phospholipase C gamma 1. Cooperative recruitment of specific kinases by the various signaling chains found in this family of antigen receptors could represent a way to achieve the full signaling capacity of the multimeric complexes.

  4. Axons guided by insulin receptor in Drosophila visual system.

    PubMed

    Song, Jianbo; Wu, Lingling; Chen, Zun; Kohanski, Ronald A; Pick, Leslie

    2003-04-18

    Insulin receptors are abundant in the central nervous system, but their roles remain elusive. Here we show that the insulin receptor functions in axon guidance. The Drosophila insulin receptor (DInR) is required for photoreceptor-cell (R-cell) axons to find their way from the retina to the brain during development of the visual system. DInR functions as a guidance receptor for the adapter protein Dock/Nck. This function is independent of Chico, the Drosophila insulin receptor substrate (IRS) homolog.

  5. O-GlcNAc modification of PPAR{gamma} reduces its transcriptional activity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ji, Suena; Park, Sang Yoon; Roth, Juergen

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer We found that PPAR{gamma} is modified by O-GlcNAc in 3T3-L1 adipocytes. Black-Right-Pointing-Pointer The Thr54 of PPAR{gamma}1 is the major O-GlcNAc site. Black-Right-Pointing-Pointer Transcriptional activity of PPAR{gamma}1 was decreased on treatment with the OGA inhibitor. -- Abstract: The peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a member of the nuclear receptor superfamily, is a key regulator of adipogenesis and is important for the homeostasis of the adipose tissue. The {beta}-O-linked N-acetylglucosamine (O-GlcNAc) modification, a posttranslational modification on various nuclear and cytoplasmic proteins, is involved in the regulation of protein function. Here, we report that PPAR{gamma} is modified by O-GlcNAc in 3T3-L1more » adipocytes. Mass spectrometric analysis and mutant studies revealed that the threonine 54 of the N-terminal AF-1 domain of PPAR{gamma} is the major O-GlcNAc site. Transcriptional activity of wild type PPAR{gamma} was decreased 30% by treatment with the specific O-GlcNAcase (OGA) inhibitor, but the T54A mutant of PPAR{gamma} did not respond to inhibitor treatment. In 3T3-L1 cells, an increase in O-GlcNAc modification by OGA inhibitor reduced PPAR{gamma} transcriptional activity and terminal adipocyte differentiation. Our results suggest that the O-GlcNAc state of PPAR{gamma} influences its transcriptional activity and is involved in adipocyte differentiation.« less

  6. Opiate-induced motor stimulation is regulated by gamma-aminobutyric acid type B receptors found in the ventral tegmental area in mice.

    PubMed

    Leite-Morris, Kimberly A; Fukudome, Eugene Y; Kaplan, Gary B

    2002-01-14

    Recent studies suggest that gamma-aminobutyric acid type B (GABA(B)) receptors located on dopaminergic cells in the ventral tegmental area (VTA) regulate mesolimbic dopaminergic (A10) activity. In the current study, we identified GABA(B) receptor subtypes in the area of the VTA and examined their role in modulating acute opiate actions. We studied the effects of intra-VTA infusions of the selective GABA(B) agonist baclofen on morphine-induced locomotor stimulation and A10 neuronal activation. Drug treatments were followed by ambulatory activity monitoring for 180 min. Intra-VTA baclofen treatment produced a 70% inhibition of morphine-stimulated locomotor activity. Furthermore, functional activation of A10 neurons was assessed by immunohistochemical staining of c-Fos in the nucleus accumbens (NAc), where A10 neurons terminate. We found that morphine treatment increased the levels of Fos-positive nuclei in the NAc, while intra-VTA baclofen treatment reversed morphine's effects. Finally, GABA(B) receptor subtypes and isoforms were identified in the ventromedial mesencephalon using immunoblotting. We demonstrated the presence of GABA(B)R1a (130 kDa), GABA(B)R1b (100 kDa), and GABA(B)R2 (120 kDa) receptor subtypes in this region. These results suggest that GABA(B) receptor isoforms are found in the VTA and their activation results in the blockade of behavioral effects of opiates via inhibition of dopaminergic neurotransmission.

  7. The Natural Compound Dansameum Reduces foam Cell Formation by Downregulating CD36 and Peroxisome Proliferator-activated Receptor-gamma; Expression

    PubMed Central

    Park, Kang-Seo; Ahn, Sang Hyun; Lee, Kang Pa; Park, Sun-Young; Cheon, Jin Hong; Choi, Jun-Yong; Kim, Kibong

    2017-01-01

    Background: Atherosclerosis-induced vascular disorders are major causes of death in most western countries. During the development of atherosclerotic lesions, foam cell formation is essential and formed through the expression of CD36 and the peroxisome proliferator-activated receptor gamma (PPAR-γ). Objective: To investigate whether dansameum extract (DSE) could show anti-atherosclerotic effect through down-regulating cellular redox state including CD36 and PARP-γ expression in oxidative low-density lipoprotein (oxLDL)-treated RAW264.7 cells and on differentiated foam cells in ApoE Knockout (ApoE-/-) mice. Materials and Methods: The Korean polyherbal medicine DSE was prepared from three plants in the following proportions: 40 g of Salvia miltiorrhiza root, 4 g of Amomumxanthioides fruit, and 4 g of Santalum album lignum. The immunohistochemistry and reverse transcription-polymerase chain reaction was used for analysis of protein and mRNA involved in foam cell formation. Results: We first showed that effects of DSE on foam cell formation in both oxLDL-induced RAW264.7 cells and in blood vessels from apolipoprotein E deficientApoE-/- mice with high fat diet-fed. DSE treatment significantly reduced the expression of CD36 and PPAR-γ in oxLDL-stimulated RAW264.7 cells and ApoE-/-mice, in the latter case by regulating heme oxygenase-1. Furthermore, DSE treatment also reduced cellular lipid content in vitro and in vivo experiments. Conclusion: Our data suggest that DSE may have anti-atherosclerotic properties through regulating foam cell formation. SUMMARY Dansameum extract (DSE) Regulates the expression of CD36 and peroxisome proliferator-activated receptor gamma in oxidative low-density lipoprotein-stimulated RAW264.7 Cells and ApoE Knockout (ApoE Knockout [ApoE-/-]) miceDSE Regulates Cholesterol Levels in the Serum of ApoE-deficient (ApoE-/-) miceDSE Reduced the Formation of Foam Cells by Regulating heme oxygenase-1 in ApoE-/- mice with high fat diet

  8. The Natural Compound Dansameum Reduces foam Cell Formation by Downregulating CD36 and Peroxisome Proliferator-activated Receptor-gamma; Expression.

    PubMed

    Park, Kang-Seo; Ahn, Sang Hyun; Lee, Kang Pa; Park, Sun-Young; Cheon, Jin Hong; Choi, Jun-Yong; Kim, Kibong

    2018-01-01

    Atherosclerosis-induced vascular disorders are major causes of death in most western countries. During the development of atherosclerotic lesions, foam cell formation is essential and formed through the expression of CD36 and the peroxisome proliferator-activated receptor gamma (PPAR-γ). To investigate whether dansameum extract (DSE) could show anti-atherosclerotic effect through down-regulating cellular redox state including CD36 and PARP-γ expression in oxidative low-density lipoprotein (oxLDL)-treated RAW264.7 cells and on differentiated foam cells in ApoE Knockout (ApoE-/-) mice. The Korean polyherbal medicine DSE was prepared from three plants in the following proportions: 40 g of Salvia miltiorrhiza root, 4 g of Amomumxanthioides fruit, and 4 g of Santalum album lignum. The immunohistochemistry and reverse transcription-polymerase chain reaction was used for analysis of protein and mRNA involved in foam cell formation. We first showed that effects of DSE on foam cell formation in both oxLDL-induced RAW264.7 cells and in blood vessels from apolipoprotein E deficientApoE-/- mice with high fat diet-fed. DSE treatment significantly reduced the expression of CD36 and PPAR-γ in oxLDL-stimulated RAW264.7 cells and ApoE-/-mice, in the latter case by regulating heme oxygenase-1. Furthermore, DSE treatment also reduced cellular lipid content in vitro and in vivo experiments. Our data suggest that DSE may have anti-atherosclerotic properties through regulating foam cell formation. Dansameum extract (DSE) Regulates the expression of CD36 and peroxisome proliferator-activated receptor gamma in oxidative low-density lipoprotein-stimulated RAW264.7 Cells and ApoE Knockout (ApoE Knockout [ApoE-/-]) miceDSE Regulates Cholesterol Levels in the Serum of ApoE-deficient (ApoE-/-) miceDSE Reduced the Formation of Foam Cells by Regulating heme oxygenase-1 in ApoE-/- mice with high fat diet-fed. Abbreviations used: DSE: Dansameum extract, PPAR-γ: Peroxisome proliferator

  9. Activation of peroxisome proliferator-activated receptor beta/delta induces lung cancer growth via peroxisome proliferator-activated receptor coactivator gamma-1alpha.

    PubMed

    Han, Shouwei; Ritzenthaler, Jeffrey D; Sun, Xiaojuan; Zheng, Ying; Roman, Jesse

    2009-03-01

    We previously demonstrated that a selective agonist of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta), GW501516, stimulated human non-small cell lung carcinoma (NSCLC) growth, partly through inhibition of phosphatase and tensin homolog deleted on chromosome 10 expression. Here, we show that GW501516 also decreases the phosphorylation of AMP-activated protein kinase alpha (AMPKalpha), a major regulator of energy metabolism. This was mediated through specific activation of PPARbeta/delta, as a PPARbeta/delta small interfering RNA inhibited the effect. However, AMPKalpha did not mediate the growth-promoting effects of GW501516, as silencing of AMPKalpha did not inhibit GW501516-induced cell proliferation. Instead, we found that GW501516 stimulated peroxisome proliferator-activated receptor coactivator gamma (PGC)-1alpha, which activated the phosphatidylinositol 3 kinase (PI3-K)/Akt mitogenic pathway. An inhibitor of PI3-K, LY294002, had no effect on PGC-1alpha, consistent with PGC-1alpha being upstream of PI3-K/Akt. Of note, an activator of AMPKalpha, 5-amino-4-imidazole carboxamide riboside, inhibited the growth-promoting effects of GW501516, suggesting that although AMPKalpha is not responsible for the mitogenic effects of GW501516, its activation can oppose these events. This study unveils a novel mechanism by which GW501516 and activation of PPARbeta/delta stimulate human lung carcinoma cell proliferation, and suggests that activation of AMPKalpha may oppose this effect.

  10. Nano drug delivery systems and gamma radiation sterilization.

    PubMed

    Sakar, F; Özer, A Y; Erdogan, S; Ekizoglu, M; Kart, D; Özalp, M; Colak, S; Zencir, Y

    2017-09-01

    In recent years, drug delivery systems such as liposomes and microparticles have been used in clinic for the treatment of different diseases and from a regulatory point of view, a parenterally applied drug and drug delivery systems must be sterile and pyrogen free. Radiation sterilization is a method recognized by pharmacopoeias to achieve sterility criteria of parenterals. It has the ability to kill microorganisms in therapeutic products. The ability of, however, irradiation might also affect the performance of drug delivery systems. One of the most critical points is irradiation dose, because certain undesirable chemical and physical changes may accompany with the irradiation, especially with the traditionally applied dose of 25 kGy. Its ionizing property may cause fragmentation of covalent bond. The care must be paid to the applied dose. In this research, the effects of gamma irradiation on different drug delivery systems such as chitosan microparticles, liposomes, niosomes and sphingosomes were investigated. According to the experimental data, it can be concluded that gamma irradiation can be a suitable sterilization technique for liposome, niosome and sphingosome dispersions. When all irradiated drug carrier systems were taken into consideration, chitosan glutamate microparticles were found as the most radioresistant drug delivery system among the others.

  11. Human adaptive immune system Rag2-/-gamma(c)-/- mice.

    PubMed

    Chicha, Laurie; Tussiwand, Roxane; Traggiai, Elisabetta; Mazzucchelli, Luca; Bronz, Lucio; Piffaretti, Jean-Claude; Lanzavecchia, Antonio; Manz, Markus G

    2005-06-01

    Although many biologic principles are conserved in mice and humans, species-specific differences exist, for example, in susceptibility and response to pathogens, that often do not allow direct implementation of findings in experimental mice to humans. Research in humans, however, for ethical and practical reasons, is largely restricted to in vitro assays that lack components and the complexity of a living organism. To nevertheless study the human hematopoietic and immune system in vivo, xenotransplantation assays have been developed that substitute human components to small animals. Here, we summarize our recent findings that transplantation of human cord blood CD34(+) cells to newborn Rag2(-/-)gamma(c)(-/-) mice leads to de novo development of major functional components of the human adaptive immune system. These human adaptive immune system Rag2(-/-)gamma(c)(-/-) (huAIS-RG) mice can now be used as a technically straightforward preclinical model to evaluate in vivo human adaptive immune system development as well as immune responses, for example, to vaccines or live infectious pathogens.

  12. System to quantify gamma-ray radial energy deposition in semiconductor detectors

    DOEpatents

    Kammeraad, Judith E.; Blair, Jerome J.

    2001-01-01

    A system for measuring gamma-ray radial energy deposition is provided for use in conjunction with a semiconductor detector. The detector comprises two electrodes and a detector material, and defines a plurality of zones within the detecting material in parallel with the two electrodes. The detector produces a charge signal E(t) when a gamma-ray interacts with the detector. Digitizing means are provided for converting the charge signal E(t) into a digitized signal. A computational means receives the digitized signal and calculates in which of the plurality of zones the gamma-ray deposited energy when interacting with the detector. The computational means produces an output indicating the amount of energy deposited by the gamma-ray in each of the plurality of zones.

  13. 21 CFR 862.1360 - Gamma-glutamyl transpeptidase and isoenzymes test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1360 Gamma-glutamyl transpeptidase and isoenzymes test system. (a...

  14. 21 CFR 862.1360 - Gamma-glutamyl transpeptidase and isoenzymes test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1360 Gamma-glutamyl transpeptidase and isoenzymes test system. (a...

  15. Identification of novel peroxisome proliferator-activated receptor-gamma (PPARγ) agonists using molecular modeling method

    NASA Astrophysics Data System (ADS)

    Gee, Veronica M. W.; Wong, Fiona S. L.; Ramachandran, Lalitha; Sethi, Gautam; Kumar, Alan Prem; Yap, Chun Wei

    2014-11-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) plays a critical role in lipid and glucose homeostasis. It is the target of many drug discovery studies, because of its role in various disease states including diabetes and cancer. Thiazolidinediones, a synthetic class of agents that work by activation of PPARγ, have been used extensively as insulin-sensitizers for the management of type 2 diabetes. In this study, a combination of QSAR and docking methods were utilised to perform virtual screening of more than 25 million compounds in the ZINC library. The QSAR model was developed using 1,517 compounds and it identified 42,378 potential PPARγ agonists from the ZINC library, and 10,000 of these were selected for docking with PPARγ based on their diversity. Several steps were used to refine the docking results, and finally 30 potentially highly active ligands were identified. Four compounds were subsequently tested for their in vitro activity, and one compound was found to have a K i values of <5 μM.

  16. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma.

    PubMed

    Guillermet-Guibert, Julie; Bjorklof, Katja; Salpekar, Ashreena; Gonella, Cristiano; Ramadani, Faruk; Bilancio, Antonio; Meek, Stephen; Smith, Andrew J H; Okkenhaug, Klaus; Vanhaesebroeck, Bart

    2008-06-17

    The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110alpha, p110beta, and p110delta) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110alpha and p110delta to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110gamma class IB PI3K lack SH2 domains and instead couple p110gamma to G protein-coupled receptors (GPCRs). Here, we show, using small-molecule inhibitors with selectivity for p110beta and cells derived from a p110beta-deficient mouse line, that p110beta is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110beta and p110gamma contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110beta but not p110gamma, p110beta mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1-phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110gamma in these cells reduced the contribution of p110beta to GPCR signaling. Taken together, these data show that p110beta and p110gamma can couple redundantly to the same GPCR agonists. p110beta, which shows a much broader tissue distribution than the leukocyte-restricted p110gamma, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110gamma expression is low or absent.

  17. A system for the measurement of delayed neutrons and gammas from special nuclear materials

    DOE PAGES

    Andrews, M. T.; Corcoran, E. C.; Goorley, J. T.; ...

    2014-11-27

    The delayed neutron counting (DNC) system at the Royal Military College of Canada has been upgraded to accommodate concurrent delayed neutron and gamma measurements. This delayed neutron and gamma counting (DNGC) system uses a SLOWPOKE-2 reactor to irradiate fissile materials before their transfer to a counting arrangement consisting of six ³He and one HPGe detector. The application of this system is demonstrated in an example where delayed neutron and gamma emissions are used in complement to examine ²³³U content and determine fissile mass with an average relative error and accuracy of -2.2 and 1.5 %, respectively.

  18. Peroxisome proliferator-activated receptor gamma agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/- double mutant mice.

    PubMed

    Yang, Kan; Fan, Kun-Hua; Lamprecht, Sergio A; Edelmann, Winfried; Kopelovich, Levy; Kucherlapati, Raju; Lipkin, Martin

    2005-09-10

    The role of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in colon tumorigenesis remains controversial. Notwithstanding evidence that PPAR-gamma ligands impede murine colorectal carcinogenesis, PPAR-gamma agonists have been shown to enhance in vivo tumor formation in mouse models of human colon cancer. Our study was designed to determine whether troglitazone (TGZ) induces colonic tumor formation in normal C57BL/6J mice and enhances colorectal carcinogenesis in double mutant Apc1638N/+ Mlh1+/- mice fed a standard AIN-76A diet. We report herein that not only does TGZ enhance carcinogenesis in the large intestine of mutant mice predisposed to intestinal carcinogenesis but TGZ also induces colonic tumors in normal mice without gene targeting or carcinogen administration. This observation indicates that preexisting mutational events are not necessary for induction of colonic tumors by activated PPAR-gamma in vivo. (c) 2005 Wiley-Liss, Inc.

  19. Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis.

    PubMed Central

    Jouanguy, E; Lamhamedi-Cherradi, S; Altare, F; Fondanèche, M C; Tuerlinckx, D; Blanche, S; Emile, J F; Gaillard, J L; Schreiber, R; Levin, M; Fischer, A; Hivroz, C; Casanova, J L

    1997-01-01

    Complete interferon-gamma receptor 1 (IFNgammaR1) deficiency has been identified previously as a cause of fatal bacillus Calmette-Guérin (BCG) infection with lepromatoid granulomas, and of disseminated nontuberculous mycobacterial (NTM) infection in children who had not been inoculated with BCG. We report here a kindred with partial IFNgammaR1 deficiency: one child afflicted by disseminated BCG infection with tuberculoid granulomas, and a sibling, who had not been inoculated previously with BCG, with clinical tuberculosis. Both responded to antimicrobials and are currently well without prophylactic therapy. Impaired response to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-alpha secretion. Whereas cells from healthy children responded to even low IFN-gamma concentrations (10 IU/ml), and cells from a child with complete IFNgammaR1 deficiency did not respond to even high IFN-gamma concentrations (10,000 IU/ml), cells from the two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations. A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertained by molecular complementation. Thus, whereas complete IFNgammaR1 deficiency in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated NTM infection, partial IFNgammaR1 deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis. PMID:9389728

  20. Alterations in interhemispheric gamma-band connectivity are related to the emergence of auditory verbal hallucinations in healthy subjects during NMDA-receptor blockade.

    PubMed

    Thiebes, Stephanie; Steinmann, Saskia; Curic, Stjepan; Polomac, Nenad; Andreou, Christina; Eichler, Iris-Carola; Eichler, Lars; Zöllner, Christian; Gallinat, Jürgen; Leicht, Gregor; Mulert, Christoph

    2018-06-01

    Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-D-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30-100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

  1. A simultaneous beta and coincidence-gamma imaging system for plant leaves

    NASA Astrophysics Data System (ADS)

    Ranjbar, Homayoon; Wen, Jie; Mathews, Aswin J.; Komarov, Sergey; Wang, Qiang; Li, Ke; O'Sullivan, Joseph A.; Tai, Yuan-Chuan

    2016-05-01

    Positron emitting isotopes, such as 11C, 13N, and 18F, can be used to label molecules. The tracers, such as 11CO2, are delivered to plants to study their biological processes, particularly metabolism and photosynthesis, which may contribute to the development of plants that have a higher yield of crops and biomass. Measurements and resulting images from PET scanners are not quantitative in young plant structures or in plant leaves due to poor positron annihilation in thin objects. To address this problem we have designed, assembled, modeled, and tested a nuclear imaging system (simultaneous beta-gamma imager). The imager can simultaneously detect positrons ({β+} ) and coincidence-gamma rays (γ). The imaging system employs two planar detectors; one is a regular gamma detector which has a LYSO crystal array, and the other is a phoswich detector which has an additional BC-404 plastic scintillator for beta detection. A forward model for positrons is proposed along with a joint image reconstruction formulation to utilize the beta and coincidence-gamma measurements for estimating radioactivity distribution in plant leaves. The joint reconstruction algorithm first reconstructs beta and gamma images independently to estimate the thickness component of the beta forward model and afterward jointly estimates the radioactivity distribution in the object. We have validated the physics model and reconstruction framework through a phantom imaging study and imaging a tomato leaf that has absorbed 11CO2. The results demonstrate that the simultaneously acquired beta and coincidence-gamma data, combined with our proposed joint reconstruction algorithm, improved the quantitative accuracy of estimating radioactivity distribution in thin objects such as leaves. We used the structural similarity (SSIM) index for comparing the leaf images from the simultaneous beta-gamma imager with the ground truth image. The jointly reconstructed images yield SSIM indices of 0.69 and 0.63, whereas the

  2. A simultaneous beta and coincidence-gamma imaging system for plant leaves.

    PubMed

    Ranjbar, Homayoon; Wen, Jie; Mathews, Aswin J; Komarov, Sergey; Wang, Qiang; Li, Ke; O'Sullivan, Joseph A; Tai, Yuan-Chuan

    2016-05-07

    Positron emitting isotopes, such as (11)C, (13)N, and (18)F, can be used to label molecules. The tracers, such as (11)CO2, are delivered to plants to study their biological processes, particularly metabolism and photosynthesis, which may contribute to the development of plants that have a higher yield of crops and biomass. Measurements and resulting images from PET scanners are not quantitative in young plant structures or in plant leaves due to poor positron annihilation in thin objects. To address this problem we have designed, assembled, modeled, and tested a nuclear imaging system (simultaneous beta-gamma imager). The imager can simultaneously detect positrons ([Formula: see text]) and coincidence-gamma rays (γ). The imaging system employs two planar detectors; one is a regular gamma detector which has a LYSO crystal array, and the other is a phoswich detector which has an additional BC-404 plastic scintillator for beta detection. A forward model for positrons is proposed along with a joint image reconstruction formulation to utilize the beta and coincidence-gamma measurements for estimating radioactivity distribution in plant leaves. The joint reconstruction algorithm first reconstructs beta and gamma images independently to estimate the thickness component of the beta forward model and afterward jointly estimates the radioactivity distribution in the object. We have validated the physics model and reconstruction framework through a phantom imaging study and imaging a tomato leaf that has absorbed (11)CO2. The results demonstrate that the simultaneously acquired beta and coincidence-gamma data, combined with our proposed joint reconstruction algorithm, improved the quantitative accuracy of estimating radioactivity distribution in thin objects such as leaves. We used the structural similarity (SSIM) index for comparing the leaf images from the simultaneous beta-gamma imager with the ground truth image. The jointly reconstructed images yield SSIM indices of 0

  3. Telmisartan prevented cognitive decline partly due to PPAR-{gamma} activation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mogi, Masaki; Li Jianmei; Tsukuda, Kana

    Telmisartan is a unique angiotensin receptor blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor (PPAR)-{gamma}. Here, we investigated the preventive effect of telmisartan on cognitive decline in Alzheimer disease. In ddY mice, intracerebroventricular injection of A{beta} 1-40 significantly attenuated their cognitive function evaluated by shuttle avoidance test. Pretreatment with a non-hypotensive dose of telmisartan significantly inhibited such cognitive decline. Interestingly, co-treatment with GW9662, a PPAR-{gamma} antagonist, partially inhibited this improvement of cognitive decline. Another ARB, losartan, which has less PPAR-{gamma} agonistic effect, also inhibited A{beta}-injection-induced cognitive decline; however the effect was smaller than that of telmisartan and was notmore » affected by GW9662. Immunohistochemical staining for A{beta} showed the reduced A{beta} deposition in telmisartan-treated mice. However, this reduction was not observed in mice co-administered GW9662. These findings suggest that ARB has a preventive effect on cognitive impairment in Alzheimer disease, and telmisartan, with PPAR-{gamma} activation, could exert a stronger effect.« less

  4. Growth kinetics of gamma-prime precipitates in a directionally solidified eutectic, gamma/gamma-prime-delta

    NASA Technical Reports Server (NTRS)

    Tewari, S. N.

    1976-01-01

    A directionally solidified eutectic alloy (DSEA), of those viewed as potential candidates for the next generation of aircraft gas turbine blade materials, is studied for the gamma-prime growth kinetics, in the system Ni-Nb-Cr-Al, specifically: Ni-20 w/o Nb-6 w/o Cr-2.5 w/o Al gamma/gamma-prime-delta DSEA. Heat treatment, polishing and etching, and preparation for electron micrography are described, and the size distribution of gamma-prime phase following various anneals is plotted, along with gamma-prime growth kinetics in this specific DSEA, and the cube of gamma-prime particle size vs anneal time. Activation energies and coarsening kinetics are studied.

  5. REBOCOL (Robotic Calorimetry): An automated NDA (Nondestructive assay) calorimetry and gamma isotopic system

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hurd, J.R.; Bonner, C.A.; Ostenak, C.A.

    1989-01-01

    ROBOCAL, which is presently being developed and tested at Los Alamos National Laboratory, is a full-scale, prototypical robotic system, for remote calorimetric and gamma-ray analysis of special nuclear materials. It integrates a fully automated, multi-drawer, vertical stacker-retriever system for staging unmeasured nuclear materials, and a fully automated gantry robot for computer-based selection and transfer of nuclear materials to calorimetric and gamma-ray measurement stations. Since ROBOCAL is designed for minimal operator intervention, a completely programmed user interface and data-base system are provided to interact with the automated mechanical and assay systems. The assay system is designed to completely integrate calorimetric andmore » gamma-ray data acquisition and to perform state-of-the-art analyses on both homogeneous and heterogeneous distributions of nuclear materials in a wide variety of matrices. 10 refs., 10 figs., 4 tabs.« less

  6. Resonance production in. gamma gamma. collisions

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Renard, F.M.

    1983-04-01

    The processes ..gamma gamma.. ..-->.. hadrons can be depicted as follows. One photon creates a q anti q pair which starts to evolve; the other photon can either (A) make its own q anti q pair and the (q anti q q anti q) system continue to evolve or (B) interact with the quarks of the first pair and lead to a modified (q anti q) system in interaction with C = +1 quantum numbers. A review of the recent theoretical activity concerning resonance production and related problems is given under the following headings: hadronic C = +1 spectroscopy (qmore » anti q, qq anti q anti q, q anti q g, gg, ggg bound states and mixing effects); exclusive ..gamma gamma.. processes (generalities, unitarized Born method, VDM and QCD); total cross section (soft and hard contributions); q/sup 2/ dependence of soft processes (soft/hard separation, 1/sup +- +/ resonances); and polarization effects. (WHK)« less

  7. NRF Based Nondestructive Inspection System for SNM by Using Laser-Compton-Backscattering Gamma-Rays

    NASA Astrophysics Data System (ADS)

    Ohgaki, H.; Omer, M.; Negm, H.; Daito, I.; Zen, H.; Kii, T.; Masuda, K.; Hori, T.; Hajima, R.; Hayakawa, T.; Shizuma, T.; Kando, M.

    2015-10-01

    A non-destructive inspection system for special nuclear materials (SNMs) hidden in a sea cargo has been developed. The system consists of a fast screening system using neutron generated by inertial electrostatic confinement (IEC) device and an isotope identification system using nuclear resonance fluorescence (NRF) measurements with laser Compton backscattering (LCS) gamma-rays has been developed. The neutron flux of 108 n/sec has been achieved by the IEC in static mode. We have developed a modified neutron reactor noise analysis method to detect fission neutron in a short time. The LCS gamma-rays has been generated by using a small racetrack microtoron accelerator and an intense sub-nano second laser colliding head-on to the electron beam. The gamma-ray flux has been achieved more than 105 photons/s. The NRF gamma-rays will be measured using LaBr3(Ce) scintillation detector array whose performance has been measured by NRF experiment of U-235 in HIGS facility. The whole inspection system has been designed to satisfy a demand from the sea port.

  8. Fc gamma RII/III and CD2 expression mark distinct subpopulations of immature CD4-CD8- murine thymocytes: in vivo developmental kinetics and T cell receptor beta chain rearrangement status.

    PubMed

    Rodewald, H R; Awad, K; Moingeon, P; D'Adamio, L; Rabinowitz, D; Shinkai, Y; Alt, F W; Reinherz, E L

    1993-04-01

    We have recently identified a dominant wave of CD4-CD8- (double-negative [DN]) thymocytes in early murine fetal development that express low affinity Fc gamma receptors (Fc gamma RII/III) and contain precursors for Ti alpha/beta lineage T cells. Here we show that Fc gamma RII/III is expressed in very immature CD4low single-positive (SP) thymocytes and that Fc gamma RII/III expression is downregulated within the DN subpopulation and before the CD3-CD8low SP stage in T cell receptor (TCR)-alpha/beta lineage-committed thymocytes. DN Fc gamma RII/III+ thymocytes also contain a small fraction of TCR-gamma/delta lineage cells in addition to TCR-alpha/beta progenitors. Fetal day 15.5 DN TCR-alpha/beta lineage progenitors can be subdivided into three major subpopulations as characterized by cell surface expression of Fc gamma RII/III vs. CD2 (Fc gamma RII/III+CD2-, Fc gamma RII/III+CD2+, Fc gamma RII/III-CD2+). Phenotypic analysis during fetal development as well as adoptive transfer of isolated fetal thymocyte subpopulations derived from C57B1/6 (Ly5.1) mice into normal, nonirradiated Ly5.2 congenic recipient mice identifies one early differentiation sequence (Fc gamma RII/III+CD2(-)-->Fc gamma RII/III+CD2(+)-->Fc gamma RII/III-CD2+) that precedes the entry of DN thymocytes into the CD4+CD8+ double-positive (DP) TCRlow/- stage. Unseparated day 15.5 fetal thymocytes develop into DP thymocytes within 2.5 d and remain at the DP stage for > 48 h before being selected into either CD4+ or CD8+ SP thymocytes. In contrast, Fc gamma RII/III+CD2- DN thymocytes follow this same developmental pathway but are delayed by approximately 24 h before entering the DP compartment, while Fc gamma RII/III-CD2+ display accelerated development by approximately 24 h compared with total day 15.5 thymocytes. Fc gamma RII/III-CD2+ are also more developmentally advanced than Fc gamma RII/III+CD2- fetal thymocytes with respect to their TCR beta chain V(D)J rearrangement. At day 15.5 in gestation, beta

  9. delta 9-(16 alpha-/sup 125/I)iodo-19-nortestosterone: a gamma-emitting photoaffinity label for the progesterone receptor

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lamb, D.J.; Bullock, D.W.; Hoyte, R.M.

    1988-05-01

    We have synthesized 16 alpha-iodo-4,9-estradien-17 beta-ol-3-one (delta 9-16 alpha-iodo-19-nortestosterone (delta 9-INT)) labeled with 125I (delta 9-(16 alpha-125I)INT) to provide a new gamma-emitting photoaffinity ligand for the progesterone receptor that has many advantages over the currently available (3H)R5020. We have characterized the interaction of delta 9-(16 alpha-125I)INT with the rabbit uterine progesterone receptor and have demonstrated the usefulness of this compound for studies of receptor structure. The binding of 2 nM (3H)progesterone to receptor in rabbit uterine cytosol was specifically competed for by 19-nortestosterone, 16 alpha-iodo-19-nortestosterone, and delta 9-INT. Scatchard analysis demonstrated that delta 9-(16 alpha-125I)INT and (3H)progesterone estimated the samemore » number of binding sites in rabbit uterine cytosol, with a Kd for delta 9-(16 alpha-125I)INT of about 2.7 nM. The binding of delta 9-(16 alpha-125I)INT was inhibited by both progesterone and R5020, whereas testosterone, estradiol, and 5 alpha-dihydrotestosterone were ineffective. In cytosol, delta 9-(16 alpha-125I)INT covalently labeled the same mol wt receptor forms as (3H)R5020. Although the efficiency of cross-linking was similar for (3H)R5020 (3%) and delta 9-(16 alpha-125I)INT (4%), the radioactivity was 10-fold greater due to the higher specific activity of delta 9-(16 alpha-125I)INT and the lack of sample quench. The use of delta 9-(16 alpha-125I)INT greatly increases the sensitivity and efficiency of the photoaffinity labeling technique; it will provide a valuable tool for further studies of the progesterone receptor, allowing the detection of receptor in dilute cytosol after gel electrophoresis under denaturing conditions.« less

  10. Development of an all-in-one gamma camera/CCD system for safeguard verification

    NASA Astrophysics Data System (ADS)

    Kim, Hyun-Il; An, Su Jung; Chung, Yong Hyun; Kwak, Sung-Woo

    2014-12-01

    For the purpose of monitoring and verifying efforts at safeguarding radioactive materials in various fields, a new all-in-one gamma camera/charged coupled device (CCD) system was developed. This combined system consists of a gamma camera, which gathers energy and position information on gamma-ray sources, and a CCD camera, which identifies the specific location in a monitored area. Therefore, 2-D image information and quantitative information regarding gamma-ray sources can be obtained using fused images. A gamma camera consists of a diverging collimator, a 22 × 22 array CsI(Na) pixelated scintillation crystal with a pixel size of 2 × 2 × 6 mm3 and Hamamatsu H8500 position-sensitive photomultiplier tube (PSPMT). The Basler scA640-70gc CCD camera, which delivers 70 frames per second at video graphics array (VGA) resolution, was employed. Performance testing was performed using a Co-57 point source 30 cm from the detector. The measured spatial resolution and sensitivity were 4.77 mm full width at half maximum (FWHM) and 7.78 cps/MBq, respectively. The energy resolution was 18% at 122 keV. These results demonstrate that the combined system has considerable potential for radiation monitoring.

  11. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: the role of CD4+ T cells and IFN-gamma.

    PubMed

    Day, Yuan-Ji; Huang, Liping; Ye, Hong; Li, Li; Linden, Joel; Okusa, Mark D

    2006-03-01

    A(2A) adenosine receptor (A(2A)R)-expressing bone marrow (BM)-derived cells contribute to the renal protective effect of A(2A) agonists in renal ischemia-reperfusion injury (IRI). We performed IRI in mice lacking T and B cells to determine whether A(2A)R expressed in CD4+ cells mediate protection from IRI. Rag-1 knockout (KO) mice were protected in comparison to wild-type (WT) mice when subjected to IRI. ATL146e, a selective A(2A) agonist, did not confer additional protection. IFN-gamma is an important early signal in IRI and is thought to contribute to reperfusion injury. Because IFN-gamma is produced by kidney cells and T cells we performed IRI in BM chimeras in which the BM of WT mice was reconstituted with BM from IFN-gamma KO mice (IFN-gamma KO-->WT chimera). We observed marked reduction in IRI in comparison to WT-->WT chimeras providing additional indirect support for the role of T cells. To confirm the role of CD4+ A(2A)R in mediating protection from IRI, Rag-1 KO mice were subjected to ischemia-reperfusion. The protection observed in Rag-1 KO mice was reversed in Rag-1 KO mice that were adoptively transferred WT CD4+ cells (WT CD4+-->Rag-1 KO) or A(2A) KO CD4+ cells (A(2A) KO CD4+-->Rag-1 KO). ATL146e reduced injury in WT CD4+-->Rag-1 KO mice but not in A(2A) KO CD4+-->Rag-1 KO mice. Rag-1 KO mice reconstituted with CD4+ cells derived from IFN-gamma KO mice (IFN-gamma CD4+-->Rag-1 KO) were protected from IRI; ATL146e conferred no additional protection. These studies demonstrate that CD4+ IFN-gamma contributes to IRI and that A(2A) agonists mediate protection from IRI through action on CD4+ cells.

  12. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) as a Target for Concurrent Management of Diabetes and Obesity-Related Cancer.

    PubMed

    Wang, Qingqing; Imam, Mustapha Umar; Yida, Zhang; Wang, Fudi

    2017-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor superfamily of ligand-inducible transcription factors that regulate adipogenesis, lipid metabolism, cell proliferation, inflammation and insulin sensitization. Abnormalities in PPARγ signaling have been associated with obesity, diabetes and cancer. The use of agonists to manage these diseases has been limited by their side effects. Accordingly, dual or pan agonists targeting the PPARα or PPARα and PPARδ, respectively, in addition to the PPARγ have been developed to overcome these side effects. This review details the shared PPARγ-dependent mechanisms between obesity-related cancers and diabetes and their potential therapeutic values. We performed a systematic literature search through pubmed, Scopus and google scholar for articles on PPARγ-dependent signaling in diabetes or cancer. There is growing co-occurrence of obesity-related cancers and diabetes, necessitating the use of effective therapies with the least amount of side effects for concurrent management of these diseases, by targeting potentially shared PPARγ-dependent mechanisms including abnormalities of the wnt/β-catenin, lysosomal acid lipase, inflammatory and cell cycle pathways, and the plasminogen activator system. Taking advantage of the multiple docking sites of the PPARγ and the pleiotropic nature of its signaling, structure-activity relationship and molecular docking studies have provided insights into designer PPARγ agonists or dual PPARα/γ agonists that modulate PPARγ signaling and negate side effects of full PPARγ agonists. Effective therapies, possibly devoid of side effects, for concurrent management of obesity-related cancers and diabetes can be developed through diligent structure-activity and molecular docking studies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Plasma interferon-gamma and interleukin-10 concentrations in systemic meningococcal disease compared with severe systemic Gram-positive septic shock.

    PubMed

    Bjerre, Anna; Brusletto, Berit; Høiby, Ernst Arne; Kierulf, Peter; Brandtzaeg, Petter

    2004-02-01

    To analyze plasma interferon-gamma and interleukin-10 concentrations in patients with systemic meningococcal disease and patients with severe Gram-positive septic shock caused by Streptococcus pneumoniae or Staphylococcus aureus. To study the in vitro cytokine (interferon-gamma and interleukin-10) responses in a whole blood model boosted with heat-killed Neisseria meningitidis, S. pneumoniae, and S. aureus before and after treatment with recombinant interleukin-10 or recombinant interferon-gamma. Experimental study. Laboratory. Plasma samples were collected from patients with systemic meningococcal disease (n = 66) and patients with severe Gram-positive septic shock caused by S. pneumoniae (n = 4) or S. aureus (n = 3). Whole blood was boosted with heat-killed N. meningitidis, S. pneumoniae, and S. aureus (1 x 106 colony forming units/mL), and plasmas were analyzed for interleukin-10 or interferon-gamma at 0, 5, 12, and 24 hrs. Furthermore, recombinant interleukin-10 or recombinant interferon-gamma was added before bacteria, and the effect on the secretion of interferon-gamma and interleukin-10, respectively, was analyzed after 24 hrs. The median concentration of interferon-gamma was 15 pg/mL and of interleukin-10 was 10,269 pg/mL in patients with meningococcal septic shock (n = 24) compared with median interferon-gamma concentration of 3400 pg/mL and interleukin-10 concentration of 465 pg/mL in patients with severe Gram-positive shock (p =.001). Increased interferon-gamma concentrations were associated with case fatality (p =.011). In a whole blood model we demonstrated that 1 x 106 colony forming units/mL of N. meningitidis induced more interleukin-10 but less interferon-gamma than S. pneumoniae. S. aureus induced minimal secretion of both cytokines. Recombinant interleukin-10 efficiently down-regulated the secretion of interferon-gamma, and vice versa, as shown in a whole blood model. We speculate whether high concentrations of interleukin-10 contribute to the

  14. Histaminergic regulation of interferon-gamma (IFN-gamma) production by human natural killer (NK) cells.

    PubMed

    Asea, A; Hansson, M; Czerkinsky, C; Houze, T; Hermodsson, S; Strannegård, O; Hellstrand, K

    1996-08-01

    Monocytes, recovered from human peripheral blood by counter-current centrifugal elutriation, effectively inhibit the production of IFN-gamma by CD3-/56+ NK cells in response to IL-2. This study aimed at defining the nature of the inhibitory signal, particularly the importance of monocyte-derived reactive metabolites of oxygen. It was found that monocytes recovered from patients with chronic granulomatous disease (CGD), a condition characterized by deficient NADPH-oxidase activity of phagocytes, did not inhibit IFN-gamma production by NK cells. Further, catalase, a scavenger of hydrogen peroxide, completely reversed the inhibitory signal whereas scavengers of the superoxide anion, hypohalous acids, the hydroxyl radical, or nitric oxide synthesis inhibitors such as L-NMMA were ineffective. Inhibition of IFN-gamma production was operating on a pretranslational level, as indicated by the inability of enriched NK cells to accumulate IFN-gamma mRNA in the presence of elutriated monocytes. Hydrogen peroxide, at micromolar concentrations, reconstituted the inhibition of IFN-gamma production when added to enriched NK cells. Histamine, a biogenic amine which inhibits the generation of reactive oxygen metabolites in monocytes, abrogated the inhibition of IFN-gamma production in NK cells; by this mechanism, histamine strongly synergized with IL-2 to induce IFN-gamma in mixtures of NK cells and monocytes. The synergizing effect of histamine was specifically mediated by H2-type histamine receptors. We conclude that: (i) the induction of IFN-gamma mRNA in NK cells is effectively down-regulated by products of the oxidative metabolism of monocytes; and (ii) histamine effectively enhances IFN-gamma production by preventing monocyte-induced oxidative damage to NK cells.

  15. Altered polymorphonuclear leukocyte Fc gamma R expression contributes to decreased candicidal activity during intraabdominal sepsis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Simms, H.H.; D'Amico, R.; Monfils, P.

    We investigated the effects of untreated intraabdominal sepsis on polymorphonuclear leukocyte (PMN) candicidal activity. Two groups of swine were studied. Group I (n=6) underwent sham laparotomy, group II (n=7) underwent cecal ligation and incision. Untreated intraabdominal sepsis resulted in a progressive decrease in PMN candicidal activity. Concomitant rosetting and phagocytosis assays demonstrated a decrease in both the attachment and phagocytosis of Candida albicans opsonized with both normal and septic swine serum by PMNs in group II. Iodine 125-labeled swine immunoglobulin G (IgG) and fluorescein isothioalanate (FITC)-labeled swine IgG were used to investigate Fc gamma receptor ligand interactions. Scatchard analyses demonstratedmore » a progressive decline in both the binding affinity constant and number of IgG molecules bound per PMN. Stimulation of the oxidative burst markedly reduced 125I-labeled IgG binding in both group I and group II, with a greater decrement being seen in animals with intraabdominal sepsis. Further, in group II, PMN recycling of the Fc gamma receptor to the cell surface after generation of the oxidative burst was reduced by postoperative day 4. Binding of monoclonal antibodies to Fc gamma receptor II, but not Fc gamma receptor I/III markedly reduced intracellular candicidal activity. Immunofluorescence studies revealed a homogeneous pattern of FITC-IgG uptake by nearly all group I PMNs, whereas by postoperative day 8 a substantial number of PMNs from group II failed to internalize the FITC-IgG. These studies suggest that untreated intraabdominal sepsis reduces PMN candicidal activity and that this is due, in part, to altered PMN Fc gamma receptor ligand interactions.« less

  16. Human α1β3γ2L gamma-aminobutyric acid type A receptors: High-level production and purification in a functional state.

    PubMed

    Dostalova, Zuzana; Zhou, Xiaojuan; Liu, Aiping; Zhang, Xi; Zhang, Yinghui; Desai, Rooma; Forman, Stuart A; Miller, Keith W

    2014-02-01

    Gamma-aminobutyric acid type A receptors (GABA(A)Rs) are the most important inhibitory chloride ion channels in the central nervous system and are major targets for a wide variety of drugs. The subunit compositions of GABA(A)Rs determine their function and pharmacological profile. GABAA Rs are heteropentamers of subunits, and (α1)2 (β3)2 (γ2L)1 is a common subtype. Biochemical and biophysical studies of GABA(A)Rs require larger quantities of receptors of defined subunit composition than are currently available. We previously reported high-level production of active human α1β3 GABA(A)R using tetracycline-inducible stable HEK293 cells. Here we extend the strategy to receptors containing three different subunits. We constructed a stable tetracycline-inducible HEK293-TetR cell line expressing human (N)-FLAG-α1β3γ2L-(C)-(GGS)3 GK-1D4 GABA(A)R. These cells achieved expression levels of 70-90 pmol [(3)H]muscimol binding sites/15-cm plate at a specific activity of 15-30 pmol/mg of membrane protein. Incorporation of the γ2 subunit was confirmed by the ratio of [(3)H]flunitrazepam to [(3)H]muscimol binding sites and sensitivity of GABA-induced currents to benzodiazepines and zinc. The α1β3γ2L GABA(A)Rs were solubilized in dodecyl-D-maltoside, purified by anti-FLAG affinity chromatography and reconstituted in CHAPS/asolectin at an overall yield of ∼ 30%. Typical purifications yielded 1.0-1.5 nmoles of [(3)H]muscimol binding sites/60 plates. Receptors with similar properties could be purified by 1D4 affinity chromatography with lower overall yield. The composition of the purified, reconstituted receptors was confirmed by ligand binding, Western blot, and proteomics. Allosteric interactions between etomidate and [(3)H]muscimol binding were maintained in the purified state. © 2013 The Protein Society.

  17. DEPENDENCE OF PPAR LIGAND-INDUCED MAPK SIGNALING ON EPIDERMAL GROWTH FACTOR RECEPTOR TRANSACTIVATION HEPARIN-BINDING EGF CLEAVAGE MEDIATES ZINC-INDUCED EGF RECEPTOR PHOSPHORYLATION

    EPA Science Inventory

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that function as ligand-activated transcription factors regulating lipid metabolism and homeostasis. In addition to their ability to regulate PPAR-mediated gene transcription, PPARalpha and gamma li...

  18. Low-background gamma-ray spectrometry for the international monitoring system

    DOE PAGES

    Greenwood, L. R.; Cantaloub, M. G.; Burnett, J. L.; ...

    2016-12-28

    PNNL has developed two low-background gamma-ray spectrometers in a new shallow underground laboratory, thereby significantly improving its ability to detect low levels of gamma-ray emitting fission or activation products in airborne particulate in samples from the IMS (International Monitoring System). Furthermore, the combination of cosmic veto panels, dry nitrogen gas to reduce radon and low background shielding results in a reduction of the background count rate by about a factor of 100 compared to detectors operating above ground at our laboratory.

  19. Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists

    PubMed Central

    Schröder, W; Lambert, D G; Ko, M C; Koch, T

    2014-01-01

    Despite high sequence similarity between NOP (nociceptin/orphanin FQ opioid peptide) and opioid receptors, marked differences in endogenous ligand selectivity, signal transduction, phosphorylation, desensitization, internalization and trafficking have been identified; underscoring the evolutionary difference between NOP and opioid receptors. Activation of NOP receptors affects nociceptive transmission in a site-specific manner, with antinociceptive effects prevailing after peripheral and spinal activation, and pronociceptive effects after supraspinal activation in rodents. The net effect of systemically administered NOP receptor agonists on nociception is proposed to depend on the relative contribution of peripheral, spinal and supraspinal activation, and this may depend on experimental conditions. Functional expression and regulation of NOP receptors at peripheral and central sites of the nociceptive pathway exhibits a high degree of plasticity under conditions of neuropathic and inflammatory pain. In rodents, systemically administered NOP receptor agonists exerted antihypersensitive effects in models of neuropathic and inflammatory pain. However, they were largely ineffective in acute pain while concomitantly evoking severe motor side effects. In contrast, systemic administration of NOP receptor agonists to non-human primates (NHPs) exerted potent and efficacious antinociception in the absence of motor and sedative side effects. The reason for this species difference with respect to antinociceptive efficacy and tolerability is not clear. Moreover, co-activation of NOP and μ-opioid peptide (MOP) receptors synergistically produced antinociception in NHPs. Hence, both selective NOP receptor as well as NOP/MOP receptor agonists may hold potential for clinical use as analgesics effective in conditions of acute and chronic pain. PMID:24762001

  20. SER Analysis of MPPM-Coded MIMO-FSO System over Uncorrelated and Correlated Gamma-Gamma Atmospheric Turbulence Channels

    NASA Astrophysics Data System (ADS)

    Khallaf, Haitham S.; Garrido-Balsells, José M.; Shalaby, Hossam M. H.; Sampei, Seiichi

    2015-12-01

    The performance of multiple-input multiple-output free space optical (MIMO-FSO) communication systems, that adopt multipulse pulse position modulation (MPPM) techniques, is analyzed. Both exact and approximate symbol-error rates (SERs) are derived for both cases of uncorrelated and correlated channels. The effects of background noise, receiver shot-noise, and atmospheric turbulence are taken into consideration in our analysis. The random fluctuations of the received optical irradiance, produced by the atmospheric turbulence, is modeled by the widely used gamma-gamma statistical distribution. Uncorrelated MIMO channels are modeled by the α-μ distribution. A closed-form expression for the probability density function of the optical received irradiance is derived for the case of correlated MIMO channels. Using our analytical expressions, the degradation of the system performance with the increment of the correlation coefficients between MIMO channels is corroborated.

  1. Mini gamma camera, camera system and method of use

    DOEpatents

    Majewski, Stanislaw; Weisenberger, Andrew G.; Wojcik, Randolph F.

    2001-01-01

    A gamma camera comprising essentially and in order from the front outer or gamma ray impinging surface: 1) a collimator, 2) a scintillator layer, 3) a light guide, 4) an array of position sensitive, high resolution photomultiplier tubes, and 5) printed circuitry for receipt of the output of the photomultipliers. There is also described, a system wherein the output supplied by the high resolution, position sensitive photomultipiler tubes is communicated to: a) a digitizer and b) a computer where it is processed using advanced image processing techniques and a specific algorithm to calculate the center of gravity of any abnormality observed during imaging, and c) optional image display and telecommunications ports.

  2. AMPX: a modular code system for generating coupled multigroup neutron-gamma libraries from ENDF/B

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Greene, N.M.; Lucius, J.L.; Petrie, L.M.

    1976-03-01

    AMPX is a modular system for producing coupled multigroup neutron-gamma cross section sets. Basic neutron and gamma cross-section data for AMPX are obtained from ENDF/B libraries. Most commonly used operations required to generate and collapse multigroup cross-section sets are provided in the system. AMPX is flexibly dimensioned; neutron group structures, and gamma group structures, and expansion orders to represent anisotropic processes are all arbitrary and limited only by available computer core and budget. The basic processes provided will (1) generate multigroup neutron cross sections; (2) generate multigroup gamma cross sections; (3) generate gamma yields for gamma-producing neutron interactions; (4) combinemore » neutron cross sections, gamma cross sections, and gamma yields into final ''coupled sets''; (5) perform one-dimensional discrete ordinates transport or diffusion theory calculations for neutrons and gammas and, on option, collapse the cross sections to a broad-group structure, using the one-dimensional results as weighting functions; (6) plot cross sections, on option, to facilitate the ''evaluation'' of a particular multigroup set of data; (7) update and maintain multigroup cross section libraries in such a manner as to make it not only easy to combine new data with previously processed data but also to do it in a single pass on the computer; and (8) output multigroup cross sections in convenient formats for other codes. (auth)« less

  3. Phenotypic screening of hepatocyte nuclear factor (HNF) 4-{gamma} receptor knockout mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gerdin, Anna Karin; Surve, Vikas V.; Joensson, Marie

    2006-10-20

    Using the mouse as a model organism in pharmaceutical research presents unique advantages as its physiology in many ways resembles the human physiology, it also has a relatively short generation time, low breeding and maintenance costs, and is available in a wide variety of inbred strains. The ability to genetically modify mouse embryonic stem cells to generate mouse models that better mimic human disease is another advantage. In the present study, a comprehensive phenotypic screening protocol is applied to elucidate the phenotype of a novel mouse knockout model of hepatocyte nuclear factor (HNF) 4-{gamma}. HNF4-{gamma} is expressed in the kidneys,more » gut, pancreas, and testis. First level of the screen is aimed at general health, morphologic appearance, normal cage behaviour, and gross neurological functions. The second level of the screen looks at metabolic characteristics and lung function. The third level of the screen investigates behaviour more in-depth and the fourth level consists of a thorough pathological characterisation, blood chemistry, haematology, and bone marrow analysis. When compared with littermate wild-type mice (HNF4-{gamma}{sup +/+}), the HNF4-{gamma} knockout (HNF4-{gamma}{sup -/-}) mice had lowered energy expenditure and locomotor activity during night time that resulted in a higher body weight despite having reduced intake of food and water. HNF4-{gamma}{sup -/-} mice were less inclined to build nest and were found to spend more time in a passive state during the forced swim test.« less

  4. Common gamma chain cytokines: dissidence in the details.

    PubMed

    Alves, Nuno L; Arosa, Fernando A; van Lier, René A W

    2007-02-15

    Cytokines of the common cytokine-receptor gamma-chain (gamma(c)) family are essential for the development and maintenance of lymphocytes. Herein, we will focus on the roles of interleukin-2 (IL-2), IL-7, IL-15 and IL-21, in the orchestration of CD8 T cell responses. Among these cytokines, IL-7 has emerged as a master regulator of survival of immature and mature T lymphocytes, while IL-2, IL-15 and IL-21 appear to have specific functions in T cell homeostasis and differentiation. Hence, the gamma(c) has evolved as an elegant anchor through which related cytokines regulate distinct biological responses in T cells.

  5. A Mobile Automated Tomographic Gamma Scanning System - 13231

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kirkpatrick, J.M.; LeBlanc, P.J.; Nakazawa, D.

    2013-07-01

    Canberra Industries have recently designed and built a new automated Tomographic Gamma Scanning (TGS) system for mobile deployment. The TGS technique combines high-resolution gamma spectroscopy with low spatial resolution 3-dimensional image reconstruction to provide increased accuracy over traditional approaches for the assay of non-uniform source distributions in low-to medium-density, non-heterogeneous matrices. Originally pioneered by R. Estep at Los Alamos National Laboratory (LANL), the TGS method has been further developed and commercialized by Canberra Industries in recent years. The present system advances the state of the art on several fronts: it is designed to be housed in a standard cargo transportmore » container for ease of transport, allowing waste characterization at multiple facilities under the purview of a single operator. Conveyor feed, drum rotator, and detector and collimator positioning mechanisms operated by programmable logic control (PLC) allow automated batch mode operation. The variable geometry settings can accommodate a wide range of waste packaging, including but not limited to standard 220 liter drums, 380 liter overpack drums, and smaller 20 liter cans. A 20 mCi Eu-152 transmission source provides attenuation corrections for drum matrices up to 1 g/cm{sup 3} in TGS mode; the system can be operated in Segmented Gamma Scanning (SGS) mode to measure higher density drums. To support TGS assays at higher densities, the source shield is sufficient to house an alternate Co-60 transmission source of higher activity, up to 250 mCi. An automated shutter and attenuator assembly is provided for operating the system with a dual intensity transmission source. The system's 1500 kg capacity rotator turntable can handle heavy containers such as concrete lined 380 liter overpack drums. Finally, data acquisition utilizes Canberra's Broad Energy Germanium (BEGE) detector and Lynx MCA, with 32 k channels, providing better than 0.1 ke

  6. Neutron monitoring systems including gamma thermometers and methods of calibrating nuclear instruments using gamma thermometers

    DOEpatents

    Moen, Stephan Craig; Meyers, Craig Glenn; Petzen, John Alexander; Foard, Adam Muhling

    2012-08-07

    A method of calibrating a nuclear instrument using a gamma thermometer may include: measuring, in the instrument, local neutron flux; generating, from the instrument, a first signal proportional to the neutron flux; measuring, in the gamma thermometer, local gamma flux; generating, from the gamma thermometer, a second signal proportional to the gamma flux; compensating the second signal; and calibrating a gain of the instrument based on the compensated second signal. Compensating the second signal may include: calculating selected yield fractions for specific groups of delayed gamma sources; calculating time constants for the specific groups; calculating a third signal that corresponds to delayed local gamma flux based on the selected yield fractions and time constants; and calculating the compensated second signal by subtracting the third signal from the second signal. The specific groups may have decay time constants greater than 5.times.10.sup.-1 seconds and less than 5.times.10.sup.5 seconds.

  7. Gamma-aminobutyric acid (GABA)-B receptor 1 in cerebellar cortex of essential tremor.

    PubMed

    Luo, C; Rajput, A H; Robinson, C A; Rajput, A

    2012-06-01

    Some reports suggest cerebellar dysfunction as the basis of essential tremor (ET). Several drugs with the action of gamma-aminobutyric acid (GABA) are known to improve ET. Autopsy studies were performed on brains from nine former patients followed at the Movement Disorders Clinic Saskatchewan, Canada, and compared with five normal control brains. We aimed to measure the concentration of GABA B receptor 1 (GBR1) in the brains of patients who had had ET and to compare them to the GABA concentration in brains of controls. Western blot was used to determine the expression of GBR1 in cerebellar cortex tissue. We found that compared to the controls, the ET brains had three different patterns of GBR1 protein concentration--two with high, four comparable, and three with marginally low levels. There was no association between the age of onset, severity or duration of tremor, the response to alcohol or other drugs and GBR1 level. Thus, we conclude that our study does not support that GBR1 is involved in ET. Further studies are needed to verify these results. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Selective binding of the fluorescent dye 1-anilinonaphthalene-8-sulfonic acid to peroxisome proliferator-activated receptor gamma allows ligand identification and characterization.

    PubMed

    Zorrilla, Silvia; Garzón, Beatriz; Pérez-Sala, Dolores

    2010-04-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily involved in insulin sensitization, atherosclerosis, inflammation, and carcinogenesis. PPARgamma transcriptional activity is modulated by specific ligands that promote conformational changes allowing interaction with coactivators. Here we show that the fluorophore 1-anilinonaphthalene-8-sulfonic acid (ANS) binds to PPARgamma-LBD (ligand binding domain), displaying negligible interaction with other nuclear receptors such as PPARalpha and retinoid X receptor alpha (RXRalpha). ANS binding is competed by PPARgamma agonists such as rosiglitazone, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), and 9,10-dihydro-15-deoxy-Delta(12,14)-prostaglandin J(2) (CAY10410). Moreover, the affinity of PPARgamma for these ligands, determined through ANS competition titrations, is within the range of that reported previously, thereby suggesting that ANS competition could be useful in the screening and characterization of novel PPARgamma agonists. In contrast, gel-based competition assays showed limited performance with noncovalently bound ligands. We applied the ANS binding assay to characterize a biotinylated analog of 15d-PGJ(2) that does not activate PPAR in cells. We found that although this compound bound to PPARgamma with low affinity, it failed to promote PPARgamma interaction with a fluorescent SRC-1 peptide, indicating a lack of receptor activation. Therefore, combined approaches using ANS and fluorescent coactivator peptides to monitor PPARgamma binding and interactions may provide valuable strategies to fully understand the role of PPARgamma ligands. Copyright 2009 Elsevier Inc. All rights reserved.

  9. Proteomic profiling of human plasma exosomes identifies PPAR{gamma} as an exosome-associated protein

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Looze, Christopher; Yui, David; Leung, Lester

    Exosomes are nanovesicles that are released from cells as a mechanism of cell-free intercellular communication. Only a limited number of proteins have been identified from the plasma exosome proteome. Here, we developed a multi-step fractionation scheme incorporating gel exclusion chromatography, rate zonal centrifugation through continuous sucrose gradients, and high-speed centrifugation to purify exosomes from human plasma. Exosome-associated proteins were separated by SDS-PAGE and 66 proteins were identified by LC-MS/MS, which included both cellular and extracellular proteins. Furthermore, we identified and characterized peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), a nuclear receptor that regulates adipocyte differentiation and proliferation, as well as immune and inflammatorymore » cell functions, as a novel component of plasma-derived exosomes. Given the important role of exosomes as intercellular messengers, the discovery of PPAR{gamma} as a component of human plasma exosomes identifies a potential new pathway for the paracrine transfer of nuclear receptors.« less

  10. Region-Specific Changes in Gamma and Beta2 Rhythms in NMDA Receptor Dysfunction Models of Schizophrenia

    PubMed Central

    Roopun, Anita K.; Cunningham, Mark O.; Racca, Claudia; Alter, Kai; Traub, Roger D.; Whittington, Miles A.

    2008-01-01

    Cognitive disruption in schizophrenia is associated with altered patterns of spatiotemporal interaction associated with multiple electroencephalogram (EEG) frequency bands in cortex. In particular, changes in the generation of gamma (30–80 Hz) and beta2 (20–29 Hz) rhythms correlate with observed deficits in communication between different cortical areas. Aspects of these changes can be reproduced in animal models, most notably those involving acute or chronic reduction in glutamatergic synaptic communication mediated by N-methyl D-aspartate (NMDA) receptors. In vitro electrophysiological and immunocytochemical approaches afforded by such animal models continue to reveal a great deal about the mechanisms underlying EEG rhythm generation and are beginning to uncover which basic molecular, cellular, and network phenomena may underlie their disruption in schizophrenia. Here we briefly review the evidence for changes in γ-aminobutyric acidergic (GABAergic) and glutamatergic function and address the problem of region specificity of changes with quantitative comparisons of effects of ketamine on gamma and beta2 rhythms in vitro. We conclude, from available evidence, that many observed changes in markers for GABAergic function in schizophrenia may be secondary to deficits in NMDA receptor–mediated excitatory synaptic activity. Furthermore, the broad range of changes in cortical dynamics seen in schizophrenia—with contrasting effects seen in different brain regions and for different frequency bands—may be more directly attributable to underlying deficits in glutamatergic neuronal communication rather than GABAergic inhibition alone. PMID:18544550

  11. Solubilization and purification of melatonin receptors from lizard brain

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rivkees, S.A.; Conron, R.W. Jr.; Reppert, S.M.

    Melatonin receptors in lizard brain were identified and characterized using {sup 125}I-labeled melatonin (({sup 125}I)MEL) after solubilization with the detergent digitonin. Saturation studies of solubilized material revealed a high affinity binding site, with an apparent equilibrium dissociation constant of 181 +/- 45 pM. Binding was reversible and inhibited by melatonin and closely related analogs, but not by serotonin or norepinephrine. Treatment of solubilized material with the non-hydrolyzable GTP analog, guanosine 5'-(3-O-thiotriphosphate) (GTP-gamma-S), significantly reduced receptor affinity. Gel filtration chromatography of solubilized melatonin receptors revealed a high affinity, large (Mr 400,000) peak of specific binding. Pretreatment with GTP-gamma-S before solubilization resultedmore » in elution of a lower affinity, smaller (Mr 150,000) peak of specific binding. To purify solubilized receptors, a novel affinity chromatography resin was developed by coupling 6-hydroxymelatonin with Epoxy-activated Sepharose 6B. Using this resin, melatonin receptors were purified approximately 10,000-fold. Purified material retained the pharmacologic specificity of melatonin receptors. These results show that melatonin receptors that bind ligand after detergent treatment can be solubilized and substantially purified by affinity chromatography.« less

  12. Solubilization and purification of melatonin receptors from lizard brain.

    PubMed

    Rivkees, S A; Conron, R W; Reppert, S M

    1990-09-01

    Melatonin receptors in lizard brain were identified and characterized using 125I-labeled melatonin ([125I]MEL) after solubilization with the detergent digitonin. Saturation studies of solubilized material revealed a high affinity binding site, with an apparent equilibrium dissociation constant of 181 +/- 45 pM. Binding was reversible and inhibited by melatonin and closely related analogs, but not by serotonin or norepinephrine. Treatment of solubilized material with the non-hydrolyzable GTP analog, guanosine 5'-(3-O-thiotriphosphate) (GTP-gamma-S), significantly reduced receptor affinity. Gel filtration chromatography of solubilized melatonin receptors revealed a high affinity, large (Mr 400,000) peak of specific binding. Pretreatment with GTP-gamma-S before solubilization resulted in elution of a lower affinity, smaller (Mr 150,000) peak of specific binding. To purify solubilized receptors, a novel affinity chromatography resin was developed by coupling 6-hydroxymelatonin with Epoxy-activated Sepharose 6B. Using this resin, melatonin receptors were purified approximately 10,000-fold. Purified material retained the pharmacologic specificity of melatonin receptors. These results show that melatonin receptors that bind ligand after detergent treatment can be solubilized and substantially purified by affinity chromatography.

  13. Immunostaining for peroxisome proliferator gamma distinguishes dedifferentiated liposarcoma from other retroperitoneal sarcomas.

    PubMed

    Horvai, Andrew E; Schaefer, Jochen T; Nakakura, Eric K; O'Donnell, Richard J

    2008-05-01

    Dedifferentiated liposarcoma can be readily diagnosed by the juxtaposition of a well-differentiated liposarcoma to a nonlipogenic sarcoma. However, if the lipogenic component is not abundant due to surgical sampling or small biopsy, dedifferentiated liposarcoma can be difficult to distinguish from other poorly different sarcomas. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a nuclear hormone receptor that plays a critical role in adipocyte differentiation. Prior studies have not only demonstrated PPAR-gamma mRNA in various subtypes of liposarcoma but have also shown that adipocyte differentiation can be induced in some liposarcomas by a PPAR-gamma agonist. In the present study, we investigated whether immunostaining for PPAR-gamma can be used to distinguish dedifferentiated liposarcoma from other retroperitoneal sarcomas. We examined a series of 40 dedifferentiated liposarcoma and compared the staining for PPAR-gamma to a series of 24 retroperitoneal sarcomas that lacked lipogenic differentiation. A monoclonal antibody against PPAR-gamma was used to stain formalin-fixed paraffin-embedded tissue. Specific nuclear immunostaining was present in 37/40 (93%) of the dedifferentiated liposarcoma and 6/24 (25%) of the other sarcomas (two leiomyosarcomas and four undifferentiated sarcomas). Interestingly, immunostaining for CDK4 and/or MDM2 was identified in three of the four PPAR-gamma-positive undifferentiated sarcomas, raising the possibility that these may represent dedifferentiated liposarcoma. This is the first study demonstrating the utility of PPAR-gamma immunohistochemistry in the diagnosis of dedifferentiated liposarcoma in tissue sections. Although not completely specific, the presence of PPAR-gamma staining, in combination with histologic findings and other markers, can aid in the diagnosis of dedifferentiated liposarcoma, particularly on small biopsies that may not sample the well-differentiated component.

  14. Relation of weight maintenance and dietary restraint to peroxisome proliferator-activated receptor gamma2, glucocorticoid receptor, and ciliary neurotrophic factor polymorphisms.

    PubMed

    Vogels, Neeltje; Mariman, Edwin C M; Bouwman, Freek G; Kester, Arnold D M; Diepvens, Kristel; Westerterp-Plantenga, Margriet S

    2005-10-01

    Genetic variation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2), glucocorticoid receptor (GRL), and ciliary neurotrophic factor (CNTF) genes may play a role in the etiology of obesity. We examined biological, psychological, and genetic determinants associated with weight maintenance (WM) after weight loss. Subjects (n = 120) followed a 6-wk diet and then a 1-y period of WM. Body weight (BW), body composition, leptin concentration, attitude toward eating (measured with the Three-Factor Eating Questionnaire), physical activity, and the polymorphisms of the PPARgamma2, GRL, and CNTF genes were measured. BW loss was 7.0 +/- 3.1 kg. After 1 y, 21 subjects showed successful WM (<10% regain); 99 were unsuccessful (> or =10% regain). Compared with unsuccessful subjects, successful subjects had a higher increase in dietary restraint over time (4.8 +/- 5.0 and 1.8 +/- 3.9, respectively; P < 0.01) but significantly less sensation of general hunger (-4.0 +/- 4.9 and -1.2 +/- 2.7, respectively; P < 0.05). Successful subjects had a significantly different frequency distribution for the PPARgamma2 (P = 0.05) and GRL (P < 0.05) genes than did unsuccessful subjects. The more successful genotypes showed a higher baseline body mass index and waist circumference (PPARgamma2), a greater decrease in disinhibition of dietary restraint (GRL), and less sensation of hunger (GRL). The G/G genotype (GRL) was an independent predictor of successful WM. The different genotypes of the PPARgamma2 and GRL genes contribute to WM, either directly (GRL) or indirectly (PPARgamma2 and GRL) via baseline body mass index and waist circumference, and to changes in Three-Factor Eating Questionnaire scores.

  15. Therapeutic actions of an insulin receptor activator and a novel peroxisome proliferator-activated receptor gamma agonist in the spontaneously hypertensive obese rat model of metabolic syndrome X.

    PubMed

    Velliquette, Rodney A; Friedman, Jacob E; Shao, J; Zhang, Bei B; Ernsberger, Paul

    2005-07-01

    Insulin resistance clusters with hyperlipidemia, impaired glucose tolerance, and hypertension as metabolic syndrome X. We tested a low molecular weight insulin receptor activator, demethylasterriquinone B-1 (DMAQ-B1), and a novel indole peroxisome proliferator-activated receptor gamma agonist, 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (PPEIA), in spontaneously hypertensive obese rats (SHROB), a genetic model of syndrome X. Agents were given orally for 19 days. SHROB showed fasting normoglycemia but impaired glucose tolerance after an oral load, as shown by increased glucose area under the curve (AUC) [20,700 mg x min/ml versus 8100 in lean spontaneously hypertensive rats (SHR)]. Insulin resistance was indicated by 20-fold excess fasting insulin and increased insulin AUC (6300 ng x min/ml versus 990 in SHR). DMAQ-B1 did not affect glucose tolerance (glucose AUC = 21,300) but reduced fasting insulin 2-fold and insulin AUC (insulin AUC = 4300). PPEIA normalized glucose tolerance (glucose AUC = 9100) and reduced insulin AUC (to 3180) without affecting fasting insulin. PPEIA also increased food intake, fat mass, and body weight gain (81 +/- 12 versus 45 +/- 8 g in untreated controls), whereas DMAQ-B1 had no effect on body weight but reduced subscapular fat mass. PPEIA but not DMAQ-B1 reduced blood pressure. In skeletal muscle, insulin-stimulated phosphorylation of the insulin receptor and insulin receptor substrate protein 1-associated phosphatidylinositol 3-kinase activity were decreased by 40 to 55% in SHROB relative to lean SHR. PPEIA, but not DMAQ-B1, enhanced both insulin actions. SHROB also showed severe hypertriglyceridemia (355 +/- 42 mg/dl versus 65 +/- 3 in SHR) attenuated by both agents (DMAQ-B1, 228 +/- 18; PPEIA, 79 +/- 3). Both these novel antidiabetic agents attenuate insulin resistance and hypertriglyceridemia associated with metabolic syndrome but via distinct mechanisms.

  16. Research on the system performance evaluation of minimum-shift keying in uplink ground-to-satellite with gamma-gamma distribution

    NASA Astrophysics Data System (ADS)

    Wang, Yi; Zhang, Ao; Ma, Jing

    2017-07-01

    Minimum-shift keying (MSK) has the advantages of constant envelope, continuous phase, and high spectral efficiency, and it is applied in radio communication and optical fiber communication. MSK modulation of coherent detection is proposed in the ground-to-satellite laser communication system; in addition, considering the inherent noise of uplink, such as intensity scintillation and beam wander, the communication performance of the MSK modulation system with coherent detection is studied in the uplink ground-to-satellite laser. Based on the gamma-gamma channel model, the closed form of bit error rate (BER) of MSK modulation with coherent detection is derived. In weak, medium, and strong turbulence, the BER performance of the MSK modulation system is simulated and analyzed. To meet the requirements of the ground-to-satellite coherent MSK system to optimize the parameters and configuration of the transmitter and receiver, the influence of the beam divergence angle, the zenith angle, the transmitter beam radius, and the receiver diameter are studied.

  17. 21 CFR 862.1360 - Gamma-glutamyl transpeptidase and isoenzymes test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1360 Gamma-glutamyl transpeptidase and isoenzymes test system. (a... alcoholic cirrhosis and primary and secondary liver tumors. (b) Classification. Class I (general controls...

  18. Effects of electroacupuncture on the levels of retinal gamma-aminobutyric acid and its receptors in a guinea pig model of lens-induced myopia.

    PubMed

    Sha, F; Ye, X; Zhao, W; Xu, C-L; Wang, L; Ding, M-H; Bi, A-L; Wu, J-F; Jiang, W-J; Guo, D-D; Guo, J-G; Bi, H-S

    2015-02-26

    Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the retina and affects myopic development. Electroacupuncture (EA) is widely utilized to treat myopia in clinical settings. However, there are few reports on whether EA affects the level of retinal GABA during myopic development. To study this issue, in the present study, we explored the changes of retinal GABA content and the expression of its receptor subtypes, and the effects of EA stimulation on them in a guinea pig model with lens-induced myopia (LIM). Our results showed that the content of GABA and the expression of GABAA and GABAC receptors of retina were up-regulated during the development of myopia, and this up-regulation was inhibited by applying EA to Hegu (LI4) and Taiyang (EX-HN5) acupoints. Moreover, these effects of EA show a positional specificity. While applying EA at a sham acupoint, no apparent change of myopic retinal GABA and its receptor subtypes was observed. Taken together, our findings suggest that LIM is effective to up-regulate the level of retinal GABA, GABAA and GABAC receptors in guinea pigs and the effect may be inhibited by EA stimulation at LI4 and EX-HN5 acupoints. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. The effects of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 gene on glucose/insulin metabolism interact with prenatal exposure to famine.

    PubMed

    de Rooij, Susanne R; Painter, Rebecca C; Phillips, David I W; Osmond, Clive; Tanck, Michael W T; Defesche, Joep C; Bossuyt, Patrick M M; Michels, Robert P J; Bleker, Otto P; Roseboom, Tessa J

    2006-05-01

    An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism. We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-gamma2 genotype among 675 term singletons born around the time of the 1944-1945 Dutch famine. A significant interaction effect between exposure to famine during midgestation and the PPAR-gamma2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-gamma2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation. The effects of the PPAR-gamma2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic beta-cell maldevelopment and carrier type of the Ala allele in the PPAR-gamma2 gene.

  20. Test results of a new detector system for gamma ray isotopic measurements

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Malcom, J.E.; Bonner, C.A.; Hurd, J.R.

    1993-08-01

    A new type of gamma-ray detector system for isotopic measurements has been developed. This new system, a ``Duo detector`` array, consists of two intrinsic germanium detectors, a planar followed by a coaxial mounted on the same axis within a single cryostat assembly. This configuration allows the isotopic analysis system to take advantage of spectral data results that are collected simultaneously from different gamma-ray energy regimes. Princeton Gamma Tech (PGT) produced several prototypes of this Duo detector array which were then tested by Rocky Flats personnel until the design was optimized. An application for this detector design is in automated, roboticizedmore » NDA systems such as those being developed at the Los Alamos TA-55 Plutonium Facility. The Duo detector design reduces the space necessary for the isotopic instrument by a factor of two (only one liquid nitrogen dewar is needed), and also reduces the complexity of the mechanical systems and controlling software. Data will be presented on measurements of nuclear material with a Duo detector for a wide variety of matrices. Results indicate that the maximum count rate can be increased up to 100,000 counts per second yet maintaining excellent resolution and energy rate product.« less

  1. [Regulating human interferon-gamma gene expression in marrow stromal cells in mice by Tet-off system].

    PubMed

    Qin, Xin-Tian; Lu, Yue; Tan, Yin-Duo; Chen, Xiao-Qin; Gen, Qi-Rong

    2008-01-01

    We have constructed plasmid "pTre-IFN-gamma" and proved that the Tet-off system could regulate the expression of human interferon-gamma (IFN-gamma) gene in murine marrow stromal cells in vitro. This study was to investigate the regulatory reversibility of Tet-off system and its effect on the expression of human IFN-gamma gene in murine marrow stromal cells in mice. Plasmids pTet-off and pTre-IFN-gamma were co-transfected into murine marrow stromal cells. The expression of IFN-gamma in marrow stromal cells was detected with ELISA. The marrow stromal cells were transfused into BABL/c naked mice after co-transfection. The expression of IFN-gamma mRNA in the spleen was detected by real-time fluorescent quantitative reverse transcription-polymerase chain reaction (RT-PCR). IFN-gamma protein was detected in the culture solution of marrow stromal cells after co-transfection. The secretion peak appeared within the first 72 h. The protein level of IFN-gamma was significantly lower in 300 ng/ml tetracycline hydrochloride-treated marrow stroma cells than in untreated cells [(67.11+/-22.14) pg/1 x 10(7) cells vs. (319.96+/-29.04) pg/1 x 10(7) cells, P<0.001]; its expression was increased when removed tetracycline hydrochloride (P=0.032). The expression of human IFN-gamma mRNA was detected in the spleen. The mRNA level of IFN-gamma was significantly higher in untreated group than in continuous tetracycline hydrochloride-treated group [(1.5+/-0.7)x10(5) copies . (100 mg)(-1) vs. (6.9+/-5.3)x10(2) copies . (100 mg)(-1), P<0.001]; its expression in the mice received tetracycline hydrochloride for one single time lay between the above two groups with significant difference. In mice, Tet-off system could rapidly, efficiently and reversibly regulate the expression of human IFN-gamma gene in marrow stromal cells in vitro and in vivo.

  2. Gamma signatures of the C-BORD Tagged Neutron Inspection System

    NASA Astrophysics Data System (ADS)

    Sardet, A.; Pérot, B.; Carasco, C.; Sannié, G.; Moretto, S.; Nebbia, G.; Fontana, C.; Pino, F.; Iovene, A.; Tintori, C.

    2018-01-01

    In the frame of C-BORD project (H2020 program of the EU), a Rapidly relocatable Tagged Neutron Inspection System (RRTNIS) is being developed to non-intrusively detect explosives, chemical threats, and other illicit goods in cargo containers. Material identification is performed through gamma spectroscopy, using twenty NaI detectors and four LaBr3 detectors, to determine the different elements composing the inspected item from their specific gamma signatures induced by fast neutrons. This is performed using an unfolding algorithm to decompose the energy spectrum of a suspect item, selected by X-ray radiography and on which the RRTNIS inspection is focused, on a database of pure element gamma signatures. This paper reports on simulated signatures for the NaI and LaBr3 detectors, constructed using the MCNP6 code. First experimental spectra of a few elements of interest are also presented.

  3. Pathophysiologic roles of the fibrinogen gamma chain.

    PubMed

    Farrell, David H

    2004-05-01

    Fibrinogen binds through its gamma chains to cell surface receptors, growth factors, and coagulation factors to perform its key roles in fibrin clot formation, platelet aggregation, and wound healing. However, these binding interactions can also contribute to pathophysiologic processes, including inflammation and thrombosis. This review summarizes the latest findings on the role of the fibrinogen gamma chain in these processes, and illustrates the potential for therapeutic intervention. Novel gamma chain epitopes that bind platelet integrin alpha IIbbeta3 and leukocyte integrin alphaMbeta2 have been characterized, leading to the revision of former dogma regarding the processes of platelet aggregation, clot retraction, inflammation, and thrombosis. A series of studies has shown that the gamma chain serves as a depot for fibroblast growth factor-2 (FGF-2), which is likely to play an important role in wound healing. Inhibition of gamma chain function with the monoclonal antibody 7E9 has been shown to interfere with multiple fibrinogen activities, including factor XIIIa crosslinking, platelet adhesion, and platelet-mediated clot retraction. The role of the enigmatic variant fibrinogen gamma chain has also become clearer. Studies have shown that gamma chain binding to thrombin and factor XIII results in clots that are mechanically stiffer and resistant to fibrinolysis, which may explain the association between gammaA/gamma' fibrinogen levels and cardiovascular disease. The identification of new interactions with gamma chains has revealed novel targets for the treatment of inflammation and thrombosis. In addition, several exciting studies have shown new functions for the variant gamma chain that may contribute to cardiovascular disease.

  4. Receptor-Mediated Drug Delivery Systems Targeting to Glioma

    PubMed Central

    Wang, Shanshan; Meng, Ying; Li, Chengyi; Qian, Min; Huang, Rongqin

    2015-01-01

    Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications. PMID:28344260

  5. Toll-like receptor 7 cooperates with IL-4 in activated B cells through antigen receptor or CD38 and induces class switch recombination and IgG1 production.

    PubMed

    Tsukamoto, Yumiko; Nagai, Yoshinori; Kariyone, Ai; Shibata, Takuma; Kaisho, Tsuneyasu; Akira, Shizuo; Miyake, Kensuke; Takatsu, Kiyoshi

    2009-04-01

    IL-4 and 8-mercaptoguanosine (8-SGuo) stimulation of CD38-activated B cells induces mu to gamma1 class switch recombination (CSR) at the DNA level leading to a high level of IgG1 production. Although some of signaling events initiated by IL-4 in activated B cells have been characterized, the involvement of TLR/MyD88 and Btk pathway in IL-4-dependent mu to gamma1 CSR has not been thoroughly evaluated. In this study, we characterized receptors for 8-SGuo and differential roles of 8-SGuo and IL-4 in the induction and mu to gamma1 CSR and IgG1 production. The role of TLR7 and MyD88 in 8-SGuo-induced AID expression and mu to gamma1 CSR was documented, as 8-SGuo did not act on CD38-stimulated splenic B cells from Tlr7(-/-) and Myd88(-/-) mice. CD38-activated B cells from Btk-deficient mice failed to respond to TLR7 ligands for the AID expression and CSR, indicating that Btk is also indispensable for the system. Stimulation of CD38-activated B cells with 8-SGuo induced significant AID expression and DNA double strand breaks, but IL-4 stimulation by itself did not trigger mu to gamma1 CSR. Intriguingly, the mu to gamma1 CSR in the B cells stimulated with CD38 and 8-SGuo totally depends on IL-4 stimulation. Similar results were obtained in the activated B cells through BCR and loxoribine, a well-known TLR7 ligand, in place of 8-SGuo. In vivo administration of TLR7 ligand and anti-CD38 antibody induced the generation of CD138(+) IgG1(+) cells. These results indicate that TLR7 is a receptor for 8-SGuo and plays an essential role in the AID and Blimp-1 expression; however it is not enough to complete mu to gamma1 CSR in CD38-activated B cells. IL-4 may be required for the induction of DNA repair system together with AID for the completion of CSR.

  6. Science with the Advanced Gamma Ray Imaging System (AGIS)

    NASA Astrophysics Data System (ADS)

    Coppi, Paolo

    2009-05-01

    We present the scientific drivers for the Advanced Gamma Ray Imaging System (AGIS), a concept for the next-generation ground- based gamma-ray experiment, comprised of an array of ˜100 imaging atmospheric Cherenkov telescopes. Design requirements for AGIS include achieving a sensitivity an order of magnitude better than the current generation of space or ground-based instruments in the energy range of 40 GeV to ˜100 TeV. We present here an overview of the scientific goals of AGIS, including the prospects for understanding VHE phenomena in the vicinity of accreting black holes, particle acceleration in a variety of astrophysical environments, indirect detection of dark matter, study of cosmological background radiation fields, and particle physics beyond the standard model.

  7. SU-F-T-236: Comparison of Two IMRT/VMAT QA Systems Using Gamma Index Analysis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dogan, N; Denissova, S

    2016-06-15

    Purpose: The goal of this study is to assess differences in the Gamma index pass rates when using two commercial QA systems and provide optimum Gamma index parameters for pre-treatment patient specific QA. Methods: Twenty-two VMAT cases that consisted of prostate, lung, head and neck, spine, brain and pancreas, were included in this study. The verification plans have been calculated using AcurosXB(V11) algorithm for different dose grids (1.5mm, 2.5mm, 3mm). The measurements were performed on TrueBeam(Varian) accelerator using both EPID(S1000) portal imager and ArcCheck(SunNuclearCorp) devices. Gamma index criteria variation of 3%/3mm, 2%/3mm, 2%/2mm and threshold (TH) doses of 5% tomore » 50% were used in analysis. Results: The differences in Gamma pass rates between two devices are not statistically significant for 3%/3mm, yielding pass rate higher than 95%. Increase of lower dose TH showed reduced pass rates for both devices. ArcCheck’s more pronounced effect can be attributed to higher contribution of lower dose region spread. As expected, tightening criteria to 2%/2mm (TH: 10%) decreased Gamma pass rates below 95%. Higher EPID (92%) pass rates compared to ArcCheck (86%) probably due to better spatial resolution. Portal Dosimetry results showed lower Gamma pass rates for composite plans compared to individual field pass rates. This may be due to the expansion in the analyzed region which includes pixels not included in the separate field analysis. Decreasing dose grid size from 2.5mm to 1.5mm did not show statistically significant (p<0.05) differences in Gamma pass rates for both QA devices. Conclusion: Overall, both system measurements agree well with calculated dose when using gamma index criteria of 3%/3mm for a variety of VMAT cases. Variability between two systems increases using different dose GRID, TH and tighter gamma criteria and must be carefully assessed prior to clinical use.« less

  8. A Cell-Permeable Phospholipase C[gamma]1-Binding Peptide Transduces Neurons and Impairs Long-Term Spatial Memory

    ERIC Educational Resources Information Center

    Blum, Sonja; Dash, Pramod K.

    2004-01-01

    Growth factor-mediated signaling has emerged as an essential component of memory formation. In this study, we used a phospholipase C gamma 1 (PLC[gamma]1) binding, cell-penetrating peptide to sequester PLC[gamma]1 away from its target, the phosphotyrosine residues within the activated growth factor receptor. Peptides appear to transduce neurons…

  9. In vitro and in silico analyses of Vicia faba L. on Peroxisome proliferator-activated receptor gamma.

    PubMed

    Prabhu, D Sathya; Rajeswari, V Devi

    2018-06-20

    The agonists of peroxisome proliferator-activated receptor gamma (PPARγ) from natural victual products were used as antidiabetic agents. Faba bean (Vicia faba L.) is a consequential legume that was known to possess potential antidiabetic activity, whose mechanism of action was unknown. The current study was focused to ascertain gene expression of the nuclear receptor PPARγ by Faba bean pod extract in rat cell lines (RINm5F).The real-time polymerase chain reaction analysis demonstrated that Faba bean pod extract in concentrations of 160 µg/mL have shown 4.97-fold stimulation compared with control. The cells treated with 320 µg/mL has shown 5.89-fold upregulation, respectively. Furthermore, in silico docking analysis was carried out against PPARγ, using the bioactive compounds identified from Faba bean pod extracts, which were known reported compounds from the literature. The results suggest that gene expression of PPARγ was inhibited by the constituents in Faba bean. In silico analysis prognosticates, butein has a high binding energy (-8.6 kcal/mol) with an atomic contact energy of -214.10, followed by Apigenin and Quercetin against PPARγ. Similarly, the percentage of interaction was high for butein, followed by Apigenin and Quercetin than other compounds comparatively. Hence, the results conclude inhibition of PPARγ by the bioactive compounds from Faba bean, which may provide insights into developing future therapeutic molecules for diabetes mellitus. © 2018 Wiley Periodicals, Inc.

  10. Increased visual gamma power in schizoaffective bipolar disorder.

    PubMed

    Brealy, J A; Shaw, A; Richardson, H; Singh, K D; Muthukumaraswamy, S D; Keedwell, P A

    2015-03-01

    Electroencephalography and magnetoencephalography (MEG) studies have identified alterations in gamma-band (30-80 Hz) cortical activity in schizophrenia and mood disorders, consistent with neural models of disturbed glutamate (and GABA) neuron influence over cortical pyramidal cells. Genetic evidence suggests specific deficits in GABA-A receptor function in schizoaffective bipolar disorder (SABP), a clinical syndrome with features of both bipolar disorder and schizophrenia. This study investigated gamma oscillations in this under-researched disorder. MEG was used to measure induced gamma and evoked responses to a visual grating stimulus, known to be a potent inducer of primary visual gamma oscillations, in 15 individuals with remitted SABP, defined using Research Diagnostic Criteria, and 22 age- and sex-matched healthy controls. Individuals with SABP demonstrated increased sustained visual cortical power in the gamma band (t 35 = -2.56, p = 0.015) compared to controls. There were no group differences in baseline gamma power, transient or sustained gamma frequency, alpha band responses or pattern onset visual-evoked responses. Gamma power is increased in remitted SABP, which reflects an abnormality in the cortical inhibitory-excitatory balance. Although an interaction between gamma power and medication can not be ruled out, there were no group differences in evoked responses or baseline measures. Further work is needed in other clinical populations and at-risk relatives. Pharmaco-magnetoencephalography studies will help to elucidate the specific GABA and glutamate pathways affected.

  11. The Advanced Gamma-ray Imaging System (AGIS): Telescope Optical System Designs

    NASA Astrophysics Data System (ADS)

    Vassiliev, Vladimir; Buckley, Jim; Falcone, Abe; Fegan, Steven; Finley, John; Gaurino, Victor; Hanna, David; Kaaret, Philip; Konopelko, Alex; Krawczynski, Henric; Romani, Roger; Weekes, Trevor

    2008-04-01

    AGIS is a conceptual design for a future ground-based gamma-ray observatory based on an array of ˜100 imaging atmospheric Cherenkov telescopes (IACTs) with a sensitivity to gamma-rays in the energy range 40 GeV-100 TeV. The anticipated improvement of AGIS sensitivity, angular resolution, and reliability of operation imposes demanding technological and cost requirements on the design of the IACTs. In this submission we focus on the optical system (OS) of the AGIS telescopes and consider options which include traditional Davies-Cotton and the other prime- focus telescope designs, as well as a novel two-mirror aplanatic OS originally proposed by Schwarzschild. Emerging new mirror production technologies based on replication processes such as cold and hot glass slumping, cured CFRP, and electroforming provide new opportunities for cost effective solutions for the design of the OS. We evaluate the capabilities of these mirror fabrication methods for the AGIS project.

  12. Evidence for clonal selection of gamma/delta T cells in response to a human pathogen

    PubMed Central

    1991-01-01

    T cells bearing gamma/delta antigen receptors comprise a resident population of intraepithelial lymphocytes in organs such as skin, gut, and lungs, where they are strategically located to contribute to the initial defense against infection. An important unsolved question about antigen-driven gamma/delta T cell responses regards the breadth of their T cell receptor (TCR) repertoire, since many specific epithelial compartments in mice display limited diversity. We have examined the diversity of TCR delta gene expression among human gamma/delta T cells from skin lesions induced by intradermal challenge with Mycobacterium leprae. We show that the vast majority of gamma/delta cells from M. leprae lesions use either V delta 1-J delta 1 or V delta 2-J delta 1 gene rearrangements and, within a given region of the lesion, display limited junctional diversity. This contrasts markedly with the extensive diversity of gamma/delta T cells from peripheral blood of these same individuals, as well as skin from normal donors. These results indicate that the gamma/delta response to M. leprae involves the selection of a limited number of clones from among a diverse repertoire, probably in response to specific mycobacterial and/or host antigens. PMID:1651977

  13. Regulation by CD45 of the tyrosine phosphorylation of high affinity IgE receptor beta- and gamma-chains.

    PubMed

    Adamczewski, M; Numerof, R P; Koretzky, G A; Kinet, J P

    1995-04-01

    Previous studies using tyrosine phosphatase inhibitors have implicated tyrosine phosphatases in the signal transduction pathway initiated by aggregation of Fc epsilon RI, the high affinity receptor for IgE. To define more precisely a role for the tyrosine phosphatase CD45 in Fc epsilon RI-mediated signaling, we have transfected the three subunits of Fc epsilon RI into wild-type Jurkat and a CD45-deficient Jurkat derivative. Here we demonstrate that CD45 is necessary for the initiation of calcium flux through the transfected Fc epsilon RI. In contrast to the effect of phosphatase inhibitors, the tyrosine phosphorylation levels of beta and gamma after aggregation of Fc epsilon RI are surprisingly reduced, relative to wild-type Jurkat, in the CD45-deficient cells. After reconstitution of the CD45-deficient cells with a chimeric molecule containing the cytoplasmic phosphatase domains of CD45, both the base line and activation-induced tyrosine phosphorylation levels are increased. By examining Lck autophosphorylation, we find that Fc epsilon RI aggregation induces an increase in Lck enzymatic activity only in wild-type Jurkat and the CD45-deficient Jurkat reconstituted with chimeric CD45. This regulation of src-family tyrosine kinase activity may be the means by which CD45 controls aggregation-induced receptor phosphorylation.

  14. GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction.

    PubMed

    Gandal, M J; Sisti, J; Klook, K; Ortinski, P I; Leitman, V; Liang, Y; Thieu, T; Anderson, R; Pierce, R C; Jonak, G; Gur, R E; Carlson, G; Siegel, S J

    2012-07-17

    Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30-80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory-inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1(neo-/-) mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABA(B)-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.

  15. Spontaneous Gamma Activity in Schizophrenia.

    PubMed

    Hirano, Yoji; Oribe, Naoya; Kanba, Shigenobu; Onitsuka, Toshiaki; Nestor, Paul G; Spencer, Kevin M

    2015-08-01

    A major goal of translational neuroscience is to identify neural circuit abnormalities in neuropsychiatric disorders that can be studied in animal models to facilitate the development of new treatments. Oscillations in the gamma band (30-100 Hz) of the electroencephalogram have received considerable interest as the basic mechanisms underlying these oscillations are understood, and gamma abnormalities have been found in schizophrenia (SZ). Animal models of SZ based on hypofunction of the N-methyl-d-aspartate receptor (NMDAR) demonstrate increased spontaneous broadband gamma power, but this phenomenon has not been identified clearly in patients with SZ. To examine spontaneous gamma power and its relationship to evoked gamma oscillations in the auditory cortex of patients with SZ. We performed a cross-sectional study including 24 patients with chronic SZ and 24 matched healthy control participants at the Veterans Affairs Boston Healthcare System from January 1, 2009, through December 31, 2012. Electroencephalograms were obtained during auditory steady-state stimulation at multiple frequencies (20, 30, and 40 Hz) and during a resting state in 18 participants in each group. Electroencephalographic activity in the auditory cortex was estimated using dipole source localization. Auditory steady-state response (ASSR) measures included the phase-locking factor and evoked power. Spontaneous gamma power was measured as induced (non-phase-locked) gamma power in the ASSR data and as total gamma power in the resting-state data. The ASSR phase-locking factor was reduced significantly in patients with SZ compared with controls for the 40-Hz stimulation (mean [SD], 0.075 [0.028] vs 0.113 [0.065]; F1,46 = 6.79 [P = .012]) but not the 20- or the 30-Hz stimulation (0.042 [0.038] vs 0.043 [0.034]; F1,46 = 0.006 [P = .938] and 0.084 [0.040] vs 0.098 [0.050]; F1,46 = 1.605 [P = .212], respectively), repeating previous findings. The mean [SD] broadband-induced (30

  16. Identification of Odorant-Receptor Interactions by Global Mapping of the Human Odorome

    PubMed Central

    Audouze, Karine; Tromelin, Anne; Le Bon, Anne Marie; Belloir, Christine; Petersen, Rasmus Koefoed; Kristiansen, Karsten; Brunak, Søren; Taboureau, Olivier

    2014-01-01

    The human olfactory system recognizes a broad spectrum of odorants using approximately 400 different olfactory receptors (hORs). Although significant improvements of heterologous expression systems used to study interactions between ORs and odorant molecules have been made, screening the olfactory repertoire of hORs remains a tremendous challenge. We therefore developed a chemical systems level approach based on protein-protein association network to investigate novel hOR-odorant relationships. Using this new approach, we proposed and validated new bioactivities for odorant molecules and OR2W1, OR51E1 and OR5P3. As it remains largely unknown how human perception of odorants influence or prevent diseases, we also developed an odorant-protein matrix to explore global relationships between chemicals, biological targets and disease susceptibilities. We successfully experimentally demonstrated interactions between odorants and the cannabinoid receptor 1 (CB1) and the peroxisome proliferator-activated receptor gamma (PPARγ). Overall, these results illustrate the potential of integrative systems chemical biology to explore the impact of odorant molecules on human health, i.e. human odorome. PMID:24695519

  17. An alpha–gamma coincidence spectrometer based on the Photon–Electron Rejecting Alpha Liquid Scintillation (PERALS®) system

    DOE PAGES

    Cadieux, J. R.; Fugate, G. A.; King, III, G. S.

    2015-02-07

    Here, an alpha–gamma coincidence spectrometer has been developed for the measurement of selected actinide isotopes in the presence of high beta/gamma fields. The system is based on a PERALS® liquid scintillation counter for beta/alpha discrimination and was successfully tested with both high purity germanium and bismuth germanate, gamma-ray detectors using conventional analog electronics.

  18. The Gamma-ray Sky with Fermi

    NASA Technical Reports Server (NTRS)

    Thompson, David

    2012-01-01

    Gamma rays reveal extreme, nonthermal conditions in the Universe. The Fermi Gamma-ray Space Telescope has been exploring the gamma-ray sky for more than four years, enabling a search for powerful transients like gamma-ray bursts, novae, solar flares, and flaring active galactic nuclei, as well as long-term studies including pulsars, binary systems, supernova remnants, and searches for predicted sources of gamma rays such as dark matter annihilation. Some results include a stringent limit on Lorentz invariance derived from a gamma-ray burst, unexpected gamma-ray variability from the Crab Nebula, a huge gamma-ray structure associated with the center of our galaxy, surprising behavior from some gamma-ray binary systems, and a possible constraint on some WIMP models for dark matter.

  19. Binding of phycoerythrin and its conjugates to murine low affinity receptors for immunoglobulin G.

    PubMed

    Takizawa, F; Kinet, J P; Adamczewski, M

    1993-06-18

    Conjugates of R-phycoerythrin are widely used for immunohistochemistry, especially for two-color flow cytometry. Their use is however limited by their apparent tendency to bind non-specifically. Using cells transfected with cDNAs for the murine low affinity receptors for immunoglobulin G (Fc gamma RII and -III) and cells naturally expressing these receptors, we demonstrate that R-phycoerythrin and its conjugates bind specifically and inhibitably to Fc gamma RII and -III. Immunofluorescence stainings of cells bearing these receptors, such as macrophages, monocytes, neutrophils, mast cells, subsets of T cells, and natural killer cells, may therefore not reflect the binding of antibody to antigen, but rather the binding of R-phycoerythrin to the receptors.

  20. Angiotensin II stimulates calcineurin activity in proximal tubule epithelia through AT-1 receptor-mediated tyrosine phosphorylation of the PLC-gamma1 isoform.

    PubMed

    Lea, Janice P; Jin, Shao G; Roberts, Brian R; Shuler, Michael S; Marrero, Mario B; Tumlin, James A

    2002-07-01

    Angiotensin II (AngII) contributes to the maintenance of extracellular fluid volume by regulating sodium transport in the nephron. In nonepithelial cells, activation of phospholipase C (PLC) by AT-1 receptors stimulates the generation of 1,4,5-trisphosphate (IP(3)) and the release of intracellular calcium. Calcineurin, a serine-threonine phosphatase, is activated by calcium and calmodulin, and both PLC and calcineurin have been linked to sodium transport in the proximal tubule. An examination of whether AngII activates calcineurin in a model of proximal tubule epithelia (LLC-PK1 cells) was performed; AngII increased calcineurin activity within 30 s. An examination of whether AngII activates PLC in proximal tubule epithelia was also performed after first showing that all three families of PLC isoforms are present in LLC-PK1 cells. Application of AngII increased IP(3) generation by 60% within 15 s, which coincided with AngII-induced tyrosine phosphorylation of the PLC-gamma1 isoform also observed at 15 s. AngII-induced tyrosine phosphorylation was blocked by the AT-1 receptor antagonist, Losartan. Subsequently, an inhibitor of tyrosine phosphorylation blocked the AngII-induced activation of calcineurin, as did coincubation with an inhibitor of PLC activity and with an antagonist of the AT-1 receptor. It is therefore concluded that AngII stimulates calcineurin phosphatase activity in proximal tubule epithelial cells through a mechanism involving AT-1 receptor-mediated tyrosine phosphorylation of the PLC isoform.

  1. Initial results from a multiple monoenergetic gamma radiography system for nuclear security

    NASA Astrophysics Data System (ADS)

    O'Day, Buckley E.; Hartwig, Zachary S.; Lanza, Richard C.; Danagoulian, Areg

    2016-10-01

    The detection of assembled nuclear devices and concealed special nuclear materials (SNM) such as plutonium or uranium in commercial cargo traffic is a major challenge in mitigating the threat of nuclear terrorism. Currently available radiographic and active interrogation systems use ∼1-10 MeV bremsstrahlung photon beams. Although simple to build and operate, bremsstrahlung-based systems deliver high radiation doses to the cargo and to potential stowaways. To eliminate problematic issues of high dose, we are developing a novel technique known as multiple monoenergetic gamma radiography (MMGR). MMGR uses ion-induced nuclear reactions to produce two monoenergetic gammas for dual-energy radiography. This allows us to image the areal density and effective atomic number (Zeff) of scanned cargo. We present initial results from the proof-of-concept experiment, which was conducted at the MIT Bates Research and Engineering Center. The purpose of the experiment was to assess the capabilities of MMGR to measure areal density and Zeff of container cargo mockups. The experiment used a 3.0 MeV radiofrequency quadrupole accelerator to create sources of 4.44 MeV and 15.11 MeV gammas from the 11B(d,nγ)12C reaction in a thick natural boron target; the gammas are detected by an array of NaI(Tl) detectors after transmission through cargo mockups . The measured fluxes of transmitted 4.44 MeV and 15.11 MeV gammas were used to assess the areal density and Zeff. Initial results show that MMGR is capable of discriminating the presence of high-Z materials concealed in up to 30 cm of iron shielding from low- and mid-Z materials present in the cargo mockup.

  2. Gamma ray transients

    NASA Technical Reports Server (NTRS)

    Cline, Thomas L.

    1987-01-01

    The discovery of cosmic gamma ray bursts was made with systems designed at Los Alamos Laboratory for the detection of nuclear explosions beyond the atmosphere. HELIOS-2 was the first gamma ray burst instrument launched; its initial results in 1976, seemed to deepen the mystery around gamma ray transients. Interplanetary spacecraft data were reviewed in terms of explaining the behavior and source of the transients.

  3. Identification of evodiamine as the bioactive compound in evodia (Evodia rutaecarpa Benth.) fruit extract that activates human peroxisome proliferator-activated receptor gamma (PPARγ).

    PubMed

    Rebhun, John F; Roloff, Samantha J; Velliquette, Rodney A; Missler, Stephen R

    2015-03-01

    The dried unripe fruit from Evodia rutaecarpa Benth., known as Wu zhu yu in China, has long been used in traditional Chinese medicine. In this research, we provide evidence that evodia fruit extract activates peroxisome proliferator-activated receptor gamma (PPARγ) and, as identified through HPLC fractionation and mass spectroscopy, the activating phytochemical is evodiamine. Evodiamine was shown to bind to and activate PPARγ. It was also shown to activate PPARγ-regulated gene expression in human hepatoma cells similar to known PPARγ ligands and that the expression was blocked by a PPARγ specific antagonist. Copyright © 2015. Published by Elsevier B.V.

  4. Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

    PubMed

    Charbogne, Pauline; Gardon, Olivier; Martín-García, Elena; Keyworth, Helen L; Matsui, Aya; Mechling, Anna E; Bienert, Thomas; Nasseef, Taufiq; Robé, Anne; Moquin, Luc; Darcq, Emmanuel; Ben Hamida, Sami; Robledo, Patricia; Matifas, Audrey; Befort, Katia; Gavériaux-Ruff, Claire; Harsan, Laura-Adela; von Elverfeldt, Dominik; Hennig, Jurgen; Gratton, Alain; Kitchen, Ian; Bailey, Alexis; Alvarez, Veronica A; Maldonado, Rafael; Kieffer, Brigitte L

    2017-05-01

    Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Real time method and computer system for identifying radioactive materials from HPGe gamma-ray spectroscopy

    DOEpatents

    Rowland, Mark S.; Howard, Douglas E.; Wong, James L.; Jessup, James L.; Bianchini, Greg M.; Miller, Wayne O.

    2007-10-23

    A real-time method and computer system for identifying radioactive materials which collects gamma count rates from a HPGe gamma-radiation detector to produce a high-resolution gamma-ray energy spectrum. A library of nuclear material definitions ("library definitions") is provided, with each uniquely associated with a nuclide or isotope material and each comprising at least one logic condition associated with a spectral parameter of a gamma-ray energy spectrum. The method determines whether the spectral parameters of said high-resolution gamma-ray energy spectrum satisfy all the logic conditions of any one of the library definitions, and subsequently uniquely identifies the material type as that nuclide or isotope material associated with the satisfied library definition. The method is iteratively repeated to update the spectrum and identification in real time.

  6. Evaluation of glucose metabolism and reproductive hormones in polycystic ovary syndrome on the basis of peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala genotype.

    PubMed

    Tok, E C; Aktas, A; Ertunc, D; Erdal, E M; Dilek, S

    2005-06-01

    Peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism has been suggested as a protective factor for polycystic ovary syndrome (PCOS). In this study, we aimed to investigate metabolic features and reproductive hormones in women with PCOS and compare these features with control women on the basis of Pro12Ala genotype. This study involved 60 randomly selected women with PCOS and 60 controls. Main outcome measures were anthropometric measures, variables of glucose metabolism and reproductive hormones. All the patients were genotyped for Pro12Ala variant of PPAR-gamma2 gene. Patients with Pro12Ala polymorphism were more obese in both groups. Furthermore, they had lower fasting insulin levels, were less insulin-resistant and were less glucose-intolerant as demonstrated by 2 h glucose concentrations. However, there was no difference in reproductive hormone levels on the basis of Pro12Ala genotype. Both control women and women with PCOS had significant differences in glucose metabolism on the basis of PPAR-gamma2 Pro12Ala polymorphism. Pro12Ala variant may break the process that leads to PCOS in susceptible women, instead of being a direct causal relationship between Pro12Ala polymorphism and PCOS.

  7. Concordance between isolated cleft palate in mice and alterations within a region including the gene encoding the [beta][sub 3] subunit of the type A [gamma]-aminobutyric acid receptor

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Culiat, C.T.; Stubbs, L.; Nicholls, R.D.

    1993-06-01

    Genetic and molecular analyses of a number of radiation-induced deletion mutations of the pink-eyed dilution (p) locus in mouse chromosome 7 have identified a specific interval on the genetic map associated with a neonatally lethal mutation that results in cleft palate. This interval, closely linked and distal to p, and bracketed by the genes encoding the [alpha][sub 5] and [beta][sub 3] subunits of the type A [gamma]-aminobutyric acid receptor (Gabra5 and Gabrb3, respectively), contains a gene(s) (cp1; cleft palate 1) necessary for normal palate development. The cp1 interval extends from the distal breakpoint of the prenatally lethal p[sup 83FBFo] deletionmore » to the Gabrb3 locus. Among 20 p deletions tested, there was complete concordance between alterations at the Gabrb3 transcription unit and inability to complement the cleft-palate defect. These mapping data, along with previously described in vivo and in vitro teratological effects of [gamma]-aminobutyric acid or its agonists on palate development, suggest the possibility that a particular type A [gamma]-aminobutyric acid receptor that includes the [beta][sub 3] subunit may be necessary for normal palate development. The placement of the cp1 gene within a defined segment of the larger D15S12h (p)-D15S9h-1 interval in the mouse suggests that the highly homologous region of the human genome, 15q11-q13, be evaluated for a role(s) in human fetal facial development. 29 refs., 4 figs., 1 tab.« less

  8. Identification of glabridin as a bioactive compound in licorice (Glycyrrhiza glabra L.) extract that activates human peroxisome proliferator-activated receptor gamma (PPARγ).

    PubMed

    Rebhun, John F; Glynn, Kelly M; Missler, Stephen R

    2015-10-01

    Licorice, the root and stolons of the Glycyrrhiza plant (Fabaceae), has been used for centuries as a food additive (sweetener), in cosmetics, and in traditional medicine. In this research, we provide evidence that licorice extract activates peroxisome proliferator-activated receptor gamma (PPARγ) and, as identified through HPLC fractionation and mass spectroscopy, one of the activating phytochemicals is glabridin. Glabridin was shown to bind to and activate PPARγ. It was also shown to activate PPARγ-regulated gene expression in human hepatoma cells similar to known PPARγ ligands and that the expression was blocked by a PPARγ specific antagonist. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. The Gamma-ray Universe through Fermi

    NASA Technical Reports Server (NTRS)

    Thompson, David J.

    2012-01-01

    Gamma rays, the most powerful form of light, reveal extreme conditions in the Universe. The Fermi Gamma-ray Space Telescope and its smaller cousin AGILE have been exploring the gamma-ray sky for several years, enabling a search for powerful transients like gamma-ray bursts, novae, solar flares, and flaring active galactic nuclei, as well as long-term studies including pulsars, binary systems, supernova remnants, and searches for predicted sources of gamma rays such as dark matter annihilation. Some results include a stringent limit on Lorentz invariance derived from a gamma-ray burst, unexpected gamma-ray variability from the Crab Nebula, a huge ga.nuna-ray structure associated with the center of our galaxy, surprising behavior from some gamma-ray binary systems, and a possible constraint on some WIMP models for dark matter.

  10. Estrogen receptor expert system overview and examples

    EPA Science Inventory

    The estrogen receptor expert system (ERES) is a rule-based system developed to prioritize chemicals based upon their potential for binding to the ER. The ERES was initially developed to predict ER affinity of chemicals from two specific EPA chemical inventories, antimicrobial pe...

  11. Evaluation of the gamma radiation shielding parameters of bismuth modified quaternary glass system

    NASA Astrophysics Data System (ADS)

    Kaur, Parminder; Singh, K. J.; Thakur, Sonika

    2018-05-01

    Glasses modified with heavy metal oxides (HMO) are an interesting area of research in the field of gamma-ray shielding. Bismuth modified lithium-zinc-borate glasses have been studied whereby bismuth oxide is added from 0 to 50 mol%. The gamma ray shielding properties of the glasses were evaluated at photon energy 662 keV with the help of XMuDat computer program by using the Hubbell and Seltzer database. Various gamma ray shielding parameters such as attenuation coefficient, shield thickness in terms of half and tenth value layer, effective atomic number have been studied in this work. A useful comparison of this glass system has been made with standard radiation shielding concretes viz. ordinary, barite and iron concrete. The glass samples containing 20 to 50 mol% bismuth oxide have shown better gamma ray shielding properties and hence have the potential to become good radiation absorbers.

  12. Immunological studies on the structure and function of the nicotinic acetylcholine receptor in mammalian muscle

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gu, Y.

    1989-01-01

    The specificity of the antibodies in the serum of a patient with myasthenia gravis for a the {alpha}-bungarotoxin binding sites of the acetylcholine receptor (AChR) was examined using AChRs in the C2 mouse muscle cell line as a model. The antibodies were shown to be specific for one of the two toxin-binding sites. The effect of the antibodies in this myasthenic serum on the functional response of the receptor to cholinergic agonists was also examined using carbamylcholine-induced {sup 22}Na uptake into C2 myotubes as a measured of the receptor function. Antibodies specific for the {gamma}, {delta}, and {epsilon} subunit, respectively,more » of mammalian muscle AChRs were developed using subunit-specific synthetic peptides as antigens. Using these antibodies and monoclonal antibodies for other subunits as probes, I have identified four ({alpha}, {beta}, {gamma}, and {delta}) subunits of mammalian muscle AChRs on immunoblots. When AChRs from embryonic, neonatal, normal and denervated adult muscles were compared on immunoblots, the {alpha}, {beta}, and {delta} subunits were identical in all four receptor preparations, with or without endoglycosidase digestion. The spatial and temporal distribution of the {gamma}- and {epsilon}- AChRs in developing and in denervated muscles corresponds to the distribution of AChRs with slow and fast channels, respectively, and that the development changes in the channel properties of the receptor arise from a change in the subunit composition of the receptor, in which the {gamma} is replaced by {epsilon}.« less

  13. Yeast as a model system for mammalian seven-transmembrane segment receptors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jeansonne, N.E.

    1994-05-01

    Investigators have used the budding yeast Saccharomyces cerevisiae as a model system in which to study the {beta}-adrenergic receptor, the T-cell receptor pathway, initiation of mammalian DNA replication, initiation of mammalian transcription, secretion, the CDC2 kinase system, cell cycle control, and aging, as well as the function of oncogenes. This list continues to growth with the discovery of an immunoglobulin heavy-chain binding homologue in yeast, an Rb binding protein homologue, and a possible yeast arrestin. Yeast is relatively easy to maintain, to grow, and to genetically manipulate. A single gene can be overexpressed, selectively mutated or deleted from its chromosomalmore » location. In this way, the in vivo function of a gene can be studied. It has become reasonable to consider yeast as a model system for studying the seven transmembrane segments (7-TMS) receptor family. Currently, subtypes of the {beta}-adrenergic receptor are being studied in yeast. The receptor and its G{sub {alpha}}-G-protein, trigger the mating pheromone receptor pathway. This provides a powerful assay for determining receptor function. Studies expressing the muscarinic cholinergic receptor in yeast are underway. The yeast pheromone receptor belongs to this receptor family, sharing sequences and secondary structure homology. An effective strategy has been to identify a yeast pathway or process which is homologous to a mammalian system. The pathway is delineated in yeast, identifying other genetic components. Then yeast genes are used to screen for human homologues of these components. The putative human homologues are then expressed in yeast and in mammalian cells to determine function. When this type of {open_quotes}mixing and matching{close_quotes} works, yeast genetics can be a powerful tool. 115 refs.« less

  14. Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats

    PubMed Central

    Xia, Jingwen; Yang, Li; Dong, Liang; Niu, Mengjie; Zhang, Shengli; Yang, Zhiwei; Wumaier, Gulinuer; Li, Ying; Wei, Xiaomin; Gong, Yi; Zhu, Ning; Li, Shengqing

    2018-01-01

    Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor-gamma (PPARγ) are both potential targets for treatment of pulmonary arterial hypertension (PAH). Expression of IP and PPARγ decreases in PAH, suggesting that screening of dual agonists of IP and PPARγ might be an efficient method for drug discovery. Virtual screening (VS) of potential IP–PPARγ dual-targeting agonists was performed in the ZINC database. Ten of the identified compounds were further screened, and cefminox was found to dramatically inhibit growth of PASMCs with no obvious cytotoxicity. Growth inhibition by cefminox was partially reversed by both the IP antagonist RO113842 and the PPARγ antagonist GW9662. Investigation of the underlying mechanisms of action demonstrated that cefminox inhibits the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway through up-regulation of the expression of phosphatase and tensin homolog (PTEN, which is inhibited by GW9662), and enhances cyclic adenosine monophosphate (cAMP) production in PASMCs (which is inhibited by RO113842). In a rat model of hypoxia-induced pulmonary hypertension, cefminox displayed therapeutic efficacy not inferior to that of the prostacyclin analog iloprost or the PPARγ agonist rosiglitazone. Our results identified cefminox as a dual agonist of IP and PPARγ that significantly inhibits PASMC proliferation by up-regulation of PTEN and cAMP, suggesting that it has potential for treatment of PAH. PMID:29527168

  15. Environmental Chemicals Modulate Polar Bear (Ursus maritimus) Peroxisome Proliferator-Activated Receptor Gamma (PPARG) and Adipogenesis in Vitro.

    PubMed

    Routti, Heli; Lille-Langøy, Roger; Berg, Mari K; Fink, Trine; Harju, Mikael; Kristiansen, Kurt; Rostkowski, Pawel; Rusten, Marte; Sylte, Ingebrigt; Øygarden, Lene; Goksøyr, Anders

    2016-10-04

    We studied interactions between polar bear peroxisome proliferator-activated receptor gamma (pbPPARG) and selected compounds using a luciferase reporter assay and predictions through molecular docking. Furthermore, we studied adipogenesis by liver and adipose tissue extracts from a polar bear and three synthetic mixtures of contaminants in murine 3T3-L1 preadipocytes and polar bear adipose tissue-derived stem cells (pbASCs). PCB153 and p,p'-DDE antagonized pbPPARG, although their predicted receptor-ligand affinity was weak. PBDEs, tetrabromobisphenol A, and PCB170 had a weak agonistic effect on pbPPARG, while hexabromocyclododecane, bisphenol A, oxychlordane, and endosulfan were weak antagonists. pbPPARG-mediated luciferase activity was suppressed by synthetic contaminant mixtures reflecting levels measured in polar bear adipose tissue, as were transcript levels of PPARG and the PPARG target gene fatty acid binding protein 4 (FABP4) in pbASCs. Contaminant extracts from polar bear tissues enhanced triglyceride accumulation in murine 3T3-L1 cells and pbASCs, whereas triglyceride accumulation was not affected by the synthetic mixtures. Chemical characterization of extracts using nontarget methods revealed presence of exogenous compounds that have previously been reported to induce adipogenesis. These compounds included phthalates, tonalide, and nonylphenol. In conclusion, major legacy contaminants in polar bear adipose tissue exert antagonistic effects on PPARG, but adipogenesis by a mixture containing emerging compounds may be enhanced through PPARG or other pathways.

  16. Ultra-wide Range Gamma Detector System for Search and Locate Operations

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Odell, D. Mackenzie Odell; Harpring, Larry J.; Moore, Frank S. Jr.

    2005-10-26

    Collecting debris samples following a nuclear event requires that operations be conducted from a considerable stand-off distance. An ultra-wide range gamma detector system has been constructed to accomplish both long range radiation search and close range hot sample collection functions. Constructed and tested on a REMOTEC Andros platform, the system has demonstrated reliable operation over six orders of magnitude of gamma dose from 100's of uR/hr to over 100 R/hr. Functional elements include a remotely controlled variable collimator assembly, a NaI(Tl)/photomultiplier tube detector, a proprietary digital radiation instrument, a coaxially mounted video camera, a digital compass, and both local andmore » remote control computers with a user interface designed for long range operations. Long range sensitivity and target location, as well as close range sample selection performance are presented.« less

  17. [Interferon. An overview of the state of basic research with special regard to interferon-gamma].

    PubMed

    Günther, G; Otto, B

    1993-02-01

    Interferons / An overview on the state of basic research with special regard to interferon-gamma Interferons are multifunctional glycoproteins with a broad range of antiviral, antiproliferative and immunoregulatory effects on the target cell. This review deals with the basics as well as with more recent developments in interferon research. A historic overview of 35 years of interferon research since the discovery of interferons by Isaacs and Lindenmann in 1957 introduces the most important milestones in this field and appreciates the work of the participating researchers. A brief description of the classification of interferons based on different tissue sources, different antigenic properties and different induction behaviour is made. The main part of this review focuses on human interferon-gamma. We discuss recent work on the structure-function relationship of interferon-gamma. The interferon-gamma receptor and its role in signal transduction is another part of this paper. The structure and length of the C-terminal region of interferon-gamma seems to be important for receptor binding and expression of biological activities. A conservative estimate is that the family of IFN-activated genes numbers 15-20 in most cells.

  18. Dynamic gamma knife radiosurgery

    NASA Astrophysics Data System (ADS)

    Luan, Shuang; Swanson, Nathan; Chen, Zhe; Ma, Lijun

    2009-03-01

    Gamma knife has been the treatment of choice for various brain tumors and functional disorders. Current gamma knife radiosurgery is planned in a 'ball-packing' approach and delivered in a 'step-and-shoot' manner, i.e. it aims to 'pack' the different sized spherical high-dose volumes (called 'shots') into a tumor volume. We have developed a dynamic scheme for gamma knife radiosurgery based on the concept of 'dose-painting' to take advantage of the new robotic patient positioning system on the latest Gamma Knife C™ and Perfexion™ units. In our scheme, the spherical high dose volume created by the gamma knife unit will be viewed as a 3D spherical 'paintbrush', and treatment planning reduces to finding the best route of this 'paintbrush' to 'paint' a 3D tumor volume. Under our dose-painting concept, gamma knife radiosurgery becomes dynamic, where the patient moves continuously under the robotic positioning system. We have implemented a fully automatic dynamic gamma knife radiosurgery treatment planning system, where the inverse planning problem is solved as a traveling salesman problem combined with constrained least-square optimizations. We have also carried out experimental studies of dynamic gamma knife radiosurgery and showed the following. (1) Dynamic gamma knife radiosurgery is ideally suited for fully automatic inverse planning, where high quality radiosurgery plans can be obtained in minutes of computation. (2) Dynamic radiosurgery plans are more conformal than step-and-shoot plans and can maintain a steep dose gradient (around 13% per mm) between the target tumor volume and the surrounding critical structures. (3) It is possible to prescribe multiple isodose lines with dynamic gamma knife radiosurgery, so that the treatment can cover the periphery of the target volume while escalating the dose for high tumor burden regions. (4) With dynamic gamma knife radiosurgery, one can obtain a family of plans representing a tradeoff between the delivery time and the

  19. A feasibility study of an integrated NIR/gamma/visible imaging system for endoscopic sentinel lymph node mapping.

    PubMed

    Kang, Han Gyu; Lee, Ho-Young; Kim, Kyeong Min; Song, Seong-Hyun; Hong, Gun Chul; Hong, Seong Jong

    2017-01-01

    The aim of this study is to integrate NIR, gamma, and visible imaging tools into a single endoscopic system to overcome the limitation of NIR using gamma imaging and to demonstrate the feasibility of endoscopic NIR/gamma/visible fusion imaging for sentinel lymph node (SLN) mapping with a small animal. The endoscopic NIR/gamma/visible imaging system consists of a tungsten pinhole collimator, a plastic focusing lens, a BGO crystal (11 × 11 × 2 mm 3 ), a fiber-optic taper (front = 11 × 11 mm 2 , end = 4 × 4 mm 2 ), a 122-cm long endoscopic fiber bundle, an NIR emission filter, a relay lens, and a CCD camera. A custom-made Derenzo-like phantom filled with a mixture of 99m Tc and indocyanine green (ICG) was used to assess the spatial resolution of the NIR and gamma images. The ICG fluorophore was excited using a light-emitting diode (LED) with an excitation filter (723-758 nm), and the emitted fluorescence photons were detected with an emission filter (780-820 nm) for a duration of 100 ms. Subsequently, the 99m Tc distribution in the phantom was imaged for 3 min. The feasibility of in vivo SLN mapping with a mouse was investigated by injecting a mixture of 99m Tc-antimony sulfur colloid (12 MBq) and ICG (0.1 mL) into the right paw of the mouse (C57/B6) subcutaneously. After one hour, NIR, gamma, and visible images were acquired sequentially. Subsequently, the dissected SLN was imaged in the same way as the in vivo SLN mapping. The NIR, gamma, and visible images of the Derenzo-like phantom can be obtained with the proposed endoscopic imaging system. The NIR/gamma/visible fusion image of the SLN showed a good correlation among the NIR, gamma, and visible images both for the in vivo and ex vivo imaging. We demonstrated the feasibility of the integrated NIR/gamma/visible imaging system using a single endoscopic fiber bundle. In future, we plan to investigate miniaturization of the endoscope head and simultaneous NIR/gamma/visible imaging with

  20. P2 receptor subtypes in the cardiovascular system.

    PubMed Central

    Kunapuli, S P; Daniel, J L

    1998-01-01

    Extracellular nucleotides have been implicated in a number of physiological functions. Nucleotides act on cell-surface receptors known as P2 receptors, of which several subtypes have been cloned. Both ATP and ADP are stored in platelets and are released upon platelet activation. Furthermore, nucleotides are also released from damaged or broken cells. Thus during vascular injury nucleotides play an important role in haemostasis through activation of platelets, modulation of vascular tone, recruitment of neutrophils and monocytes to the site of injury, and facilitation of adhesion of leucocytes to the endothelium. Nucleotides also moderate these functions by generating nitric oxide and prostaglandin I2 through activation of endothelial cells, and by activating different receptor subtypes on vascular smooth muscle cells. In the heart, P2 receptors regulate contractility through modulation of L-type Ca2+ channels, although the molecular mechanisms involved are still under investigation. Classical pharmacological studies have identified several P2 receptor subtypes in the cardiovascular system. Molecular pharmacological studies have clarified the nature of some of these receptors, but have complicated the picture with others. In platelets, the classical P2T receptor has now been resolved into three P2 receptor subtypes: the P2Y1, P2X1 and P2TAC receptors (the last of these, which is coupled to the inhibition of adenylate cyclase, is yet to be cloned). In peripheral blood leucocytes, endothelial cells, vascular smooth muscle cells and cardiomyocytes, the effects of classical P2X, P2Y and P2U receptors have been found to be mediated by more than one P2 receptor subtype. However, the exact functions of these multiple receptor subtypes remain to be understood, as P2-receptor-selective agonists and antagonists are still under development. PMID:9841859

  1. Controlling nuclear JAKs and STATs for specific gene activation by IFN{gamma}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Noon-Song, Ezra N.; Ahmed, Chulbul M.; Dabelic, Rea

    2011-07-08

    Highlights: {yields} Gamma interferon (IFN{gamma}) and its receptor subunit, IFNGR1, interact with the promoter region of IFN{gamma}-associated genes along with transcription factor STAT1{alpha}. {yields} We show that activated Janus kinases pJAK2 and pJAK1 also associate with IFNGR1 in the nucleus. {yields} The activated Janus kinases are responsible for phosphorylation of tyrosine 41 on histone H3, an important epigenetic event for specific gene activation. -- Abstract: We previously showed that gamma interferon (IFN{gamma}) and its receptor subunit, IFNGR1, interacted with the promoter region of IFN{gamma}-activated genes along with transcription factor STAT1{alpha}. Recent studies have suggested that activated Janus kinases pJAK2 andmore » pJAK1 also played a role in gene activation by phosphorylation of histone H3 on tyrosine 41. This study addresses the question of the role of activated JAKs in specific gene activation by IFN{gamma}. We carried out chromatin immunoprecipitation (ChIP) followed by PCR in IFN{gamma} treated WISH cells and showed association of pJAK1, pJAK2, IFNGR1, and STAT1 on the same DNA sequence of the IRF-1 gene promoter. The {beta}-actin gene, which is not activated by IFN{gamma}, did not show this association. The movement of activated JAK to the nucleus and the IRF-1 promoter was confirmed by the combination of nuclear fractionation, confocal microscopy and DNA precipitation analysis using the biotinylated GAS promoter. Activated JAKs in the nucleus was associated with phosphorylated tyrosine 41 on histone H3 in the region of the GAS promoter. Unphosphorylated JAK2 was found to be constitutively present in the nucleus and was capable of undergoing activation in IFN{gamma} treated cells, most likely via nuclear IFNGR1. Association of pJAK2 and IFNGR1 with histone H3 in IFN{gamma} treated cells was demonstrated by histone H3 immunoprecipitation. Unphosphorylated STAT1 protein was associated with histone H3 of untreated cells. IFN{gamma

  2. Modeling and Investigation of Heavy Oxide and Alkali-Halide Scintillators for Potential Use in Neutron and Gamma Detection Systems

    DTIC Science & Technology

    2015-06-01

    INVESTIGATION OF HEAVY OXIDE AND ALKALI-HALIDE SCINTILLATORS FOR POTENTIAL USE IN NEUTRON AND GAMMA DETECTION SYSTEMS by Jeremy S. Cadiente June...AND ALKALI- HALIDE SCINTILLATORS FOR POTENTIAL USE IN NEUTRON AND GAMMA DETECTION SYSTEMS 5. FUNDING NUMBERS 6. AUTHOR(S) Jeremy S. Cadiente 7...fast neutron detection efficiencies well over 40%, were investigated for potential use as highly efficient gamma- neutron radiation detectors. The

  3. Control of peroxisome proliferator-activated receptor gamma2 stability and activity by SUMOylation.

    PubMed

    Floyd, Z Elizabeth; Stephens, Jacqueline M

    2004-06-01

    To determine whether small ubiquitin-related modifier (SUMO)ylation of lysine 107 plays a role in regulating the activity of peroxisome proliferator-activated receptor gamma (PPARgamma). Transient expression of wild-type and K107R-PPARgamma2 in the NIH 3T3 fibroblast cell line was carried out in conjunction with half-life studies, luciferase activity assays, and indirect immunofluorescence localization studies. Additional in vitro analysis was carried out using recombinant SUMOylation pathway proteins along with in vitro transcribed and translated wild-type or K107R-PPARgamma2 to examine the SUMO-1 modification state of wild-type and SUMO-deficient K107R-PPARgamma2. While examining PPARgamma2 for potential ubiquitylation sites, we identified a strong consensus site for SUMO modification that contains lysine 107. In vitro, SUMOylation studies showed that lysine 107 of PPARgamma2 is a major SUMOylation site and that at least one other SUMOylation site is present in PPARgamma. In addition, our results demonstrated that SUMO-1 affects PPARgamma stability and transcriptional activity but not the nuclear localization of PPARgamma. These results indicated that SUMOylation plays a role in regulating PPARgamma, both indirectly and directly by modification of lysine 107. Because PPARgamma is regulated in numerous animal models of obesity, understanding the covalent modifications of PPARgamma may enhance our understanding of the metabolic syndrome.

  4. Lineage-specific co-evolution of the Egf receptor/ligand signaling system.

    PubMed

    Laisney, Juliette A G C; Braasch, Ingo; Walter, Ronald B; Meierjohann, Svenja; Schartl, Manfred

    2010-01-27

    The epidermal growth factor receptor (Egfr) with its numerous ligands has fundamental roles in development, cell differentiation and physiology. Dysfunction of the receptor-ligand system contributes to many human malignancies. Consistent with such various tasks, the Egfr gene family has expanded during vertebrate evolution as a consequence of several rounds of whole genome duplication. Of particular interest is the effect of the fish-specific whole genome duplication (FSGD) on the ligand-receptor system, as it has supplied this largest group of vertebrates with additional opportunities for sub- and/or neofunctionalization in this signaling system. We identified the predicted components of the Egf receptor-ligand signaling system in teleost fishes (medaka, platyfish, stickleback, pufferfishes and zebrafish). We found two duplicated egfr genes, egfra and egfrb, in all available teleost genomes. Surprisingly only one copy for each of the seven Egfr ligands could be identified in most fishes, with zebrafish hbegf being the only exception. Special focus was put on medaka, for which we more closely investigated all Egf receptors and Egfr ligands. The different expression patterns of egfra, egfrb and their ligands in medaka tissues and embryo stages suggest differences in role and function. Preferential co-expression of different subsets of Egfr ligands corroborates the possible subfunctionalization and specialization of the two receptors in adult tissues. Bioinformatic analyses of the ligand-receptor interface between Egfr and its ligands show a very weak evolutionary conservation within this region. Using in vitro analyses of medaka Egfra, we could show that this receptor is only activated by medaka ligands, but not by human EGF. Altogether, our data suggest a lineage-specific Egfr/Egfr ligand co-evolution. Our data indicate that medaka Egfr signaling occurs via its two copies, Egfra and Egfrb, each of them being preferentially coexpressed with different subsets of Egfr

  5. Lineage-specific co-evolution of the Egf receptor/ligand signaling system

    PubMed Central

    2010-01-01

    Background The epidermal growth factor receptor (Egfr) with its numerous ligands has fundamental roles in development, cell differentiation and physiology. Dysfunction of the receptor-ligand system contributes to many human malignancies. Consistent with such various tasks, the Egfr gene family has expanded during vertebrate evolution as a consequence of several rounds of whole genome duplication. Of particular interest is the effect of the fish-specific whole genome duplication (FSGD) on the ligand-receptor system, as it has supplied this largest group of vertebrates with additional opportunities for sub- and/or neofunctionalization in this signaling system. Results We identified the predicted components of the Egf receptor-ligand signaling system in teleost fishes (medaka, platyfish, stickleback, pufferfishes and zebrafish). We found two duplicated egfr genes, egfra and egfrb, in all available teleost genomes. Surprisingly only one copy for each of the seven Egfr ligands could be identified in most fishes, with zebrafish hbegf being the only exception. Special focus was put on medaka, for which we more closely investigated all Egf receptors and Egfr ligands. The different expression patterns of egfra, egfrb and their ligands in medaka tissues and embryo stages suggest differences in role and function. Preferential co-expression of different subsets of Egfr ligands corroborates the possible subfunctionalization and specialization of the two receptors in adult tissues. Bioinformatic analyses of the ligand-receptor interface between Egfr and its ligands show a very weak evolutionary conservation within this region. Using in vitro analyses of medaka Egfra, we could show that this receptor is only activated by medaka ligands, but not by human EGF. Altogether, our data suggest a lineage-specific Egfr/Egfr ligand co-evolution. Conclusions Our data indicate that medaka Egfr signaling occurs via its two copies, Egfra and Egfrb, each of them being preferentially coexpressed

  6. In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR){alpha} and PPAR{gamma} and quantitative analysis of in vivo induction pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Takeuchi, Shinji; Matsuda, Tadashi; Kobayashi, Satoshi

    2006-12-15

    Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors and key regulators of lipid metabolism and cell differentiation. However, there have been few studies reporting on a variety of environmental chemicals, which may interact with these receptors. In the present study, we characterized mouse PPAR{alpha} and PPAR{gamma} agonistic activities of 200 pesticides (29 organochlorines, 11 diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, 11 acid amides, 7 triazines, 8 ureas and 44 others) by in vitro reporter gene assays using CV-1 monkey kidney cells. Three of the 200 pesticides, diclofop-methyl, pyrethrins and imazalil, which have different chemical structures, showed PPAR{alpha}-mediatedmore » transcriptional activities in a dose-dependent manner. On the other hand, none of the 200 pesticides showed PPAR{gamma} agonistic activity at concentrations {<=} 10{sup -5} M. To investigate the in vivo effects of diclofop-methyl, pyrethrins and imazalil, we examined the gene expression of PPAR{alpha}-inducible cytochrome P450 4As (CYP4As) in the liver of female mice intraperitoneally injected with these compounds ({<=} 300 mg/kg). RT-PCR revealed significantly high induction levels of CYP4A10 and CYP4A14 mRNAs in diclofop-methyl- and pyrethrins-treated mice, whereas imazalil induced almost no gene expressions of CYP4As. In particular, diclofop-methyl induced as high levels of CYP4A mRNAs as WY-14643, a potent PPAR{alpha} agonist. Thus, most of the 200 pesticides tested do not activate PPAR{alpha} or PPAR{gamma} in in vitro assays, but only diclofop-methyl and pyrethrins induce PPAR{alpha} agonistic activity in vivo as well as in vitro.« less

  7. Activation of estrogen receptor signaling by the dioxin-like aryl hydrocarbon receptor agonist, 3,3',4,4',5-Pentachlorobiphenyl (PCB126) in salmon in vitro system

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mortensen, Anne Skjetne; Arukwe, Augustine

    2008-03-01

    Available toxicological evidence indicates that environmental contaminants with strong affinity to the aryl hydrocarbon receptor (AhR) have anti-estrogenic properties in both mammalian and non-mammalian in vivo and in vitro studies. The primary objective of the present study was to investigate the interactions between the AhR and estrogen receptor (ER) in salmon in vitro system. Two separate experiments were performed and gene expression patterns were analyzed using real-time PCR, while protein analysis was done by immunoblotting. Firstly, salmon primary hepatocytes were exposed to the dioxin-like PCB126 at 1, 10 and 50 pM and ER agonist nonylphenol (NP) at 5 and 10more » {mu}M, singly or in combination. Our data showed increased levels of ER-mediated gene expression (vitellogenin: Vtg, zona radiata protein: Zr-protein, ER{alpha}, ER{beta} and vigilin) as well as increased cellular ER{alpha} protein levels after treatment with NP and PCB126, singly or in combination. PCB126 treatment alone produced, as expected, increased transcription of AhR nuclear translocator (Arnt), CYP1A1 and AhR repressor (AhRR) mRNA, and these responses were reduced in the presence of NP concentrations. PCB126 exposure alone did not produce significant effect on AhR2{alpha} mRNA but increased (at 1 and 50 pM) and decreased (at 10 pM) AhR2{beta} mRNA below control level. For AhR2{delta} and AhR2{gamma} isotypes, PCB126 (at 1 pM) produced significant decreases (total inhibition for AhR2{gamma}) of mRNA levels but was indifferent at 10 and 50 pM, compared to control. NP exposure alone produced concentration-dependent significant decrease of AhR2{beta} mRNA. In contrast, while 5 {mu}M NP produced an indifferent effect on AhR2{delta} and AhR2{gamma}, 10 {mu}M NP produced significant decrease (total inhibition for AhR2{gamma}) and the presence of NP produced apparent PCB126 concentration-specific modulation of all AhR isotypes. A second experiment was performed to evaluate the involvement of ER

  8. The role of the dynorphin/κ opioid receptor system in anxiety.

    PubMed

    Hang, Ai; Wang, Yu-jun; He, Ling; Liu, Jing-gen

    2015-07-01

    Anxiety disorders are the most common and prevalent forms of psychiatric disease, although the biological basis of anxiety is not well understood. The dynorphin/κ opioid receptor system is widely distributed in the central nervous system and has been shown to play a critical role in modulating mood and emotional behaviors. In the present review, we summarize current literature relating to the role played by the dynorphin/κ opioid receptor system in anxiety and κ opioid receptor antagonists as potential therapeutic agents for the treatment of anxiety disorders.

  9. Molecular and Cellular Designs of Insect Taste Receptor System

    PubMed Central

    Isono, Kunio; Morita, Hiromi

    2010-01-01

    The insect gustatory receptors (GRs) are members of a large G-protein coupled receptor family distantly related to the insect olfactory receptors. They are phylogenetically different from taste receptors of most other animals. GRs are often coexpressed with other GRs in single receptor neurons. Taste receptors other than GRs are also expressed in some neurons. Recent molecular studies in the fruitfly Drosophila revealed that the insect taste receptor system not only covers a wide ligand spectrum of sugars, bitter substances or salts that are common to mammals but also includes reception of pheromone and somatosensory stimulants. However, the central mechanism to perceive and discriminate taste information is not yet elucidated. Analysis of the primary projection of taste neurons to the brain shows that the projection profiles depend basically on the peripheral locations of the neurons as well as the GRs that they express. These results suggest that both peripheral and central design principles of insect taste perception are different from those of olfactory perception. PMID:20617187

  10. Oleamide activates peroxisome proliferator-activated receptor gamma (PPARγ) in vitro.

    PubMed

    Dionisi, Mauro; Alexander, Stephen P H; Bennett, Andrew J

    2012-05-14

    Oleamide (ODA) is a fatty acid primary amide first identified in the cerebrospinal fluid of sleep-deprived cats, which exerts effects on vascular and neuronal tissues, with a variety of molecular targets including cannabinoid receptors and gap junctions. It has recently been reported to exert a hypolipidemic effect in hamsters. Here, we have investigated the nuclear receptor family of peroxisome proliferator-activated receptors (PPARs) as potential targets for ODA action. Activation of PPARα, PPARβ and PPARγ was assessed using recombinant expression in Chinese hamster ovary cells with a luciferase reporter gene assay. Direct binding of ODA to the ligand binding domain of each of the three PPARs was monitored in a cell-free fluorescent ligand competition assay. A well-established assay of PPARγ activity, the differentiation of 3T3-L1 murine fibroblasts into adipocytes, was assessed using an Oil Red O uptake-based assay. ODA, at 10 and 50 μM, was able to transactivate PPARα, PPARβ and PPARγ receptors. ODA bound to the ligand binding domain of all three PPARs, although complete displacement of fluorescent ligand was only evident for PPARγ, at which an IC50 value of 38 μM was estimated. In 3T3-L1 cells, ODA, at 10 and 20 μM, induced adipogenesis. We have, therefore, identified a novel site of action of ODA through PPAR nuclear receptors and shown how ODA should be considered as a weak PPARγ ligand in vitro.

  11. Cyclic phosphatidic acid inhibits the secretion of vascular endothelial growth factor from diabetic human coronary artery endothelial cells through peroxisome proliferator-activated receptor gamma.

    PubMed

    Tsukahara, Tamotsu; Tsukahara, Ryoko; Haniu, Hisao; Matsuda, Yoshikazu; Murakami-Murofushi, Kimiko

    2015-09-05

    Atherosclerosis is a disease characterized by building up plaques formation and leads to a potentially serious condition in which arteries are clogged by fatty substances such as cholesterol. Increasing evidence suggests that atherosclerosis is accelerated in type 2 diabetes. Recent study reported that high level of alkyl glycerophosphate (AGP) was accumulated in atherosclerotic lesions. The presence of this phospholipid in mildly oxidized low-density lipoprotein (LDL) is likely to be involved in atherogenesis. It has been reported that the activation of peroxisome proliferator-activated receptor gamma plays a key role in developing atherosclerosis. Our previous result indicates that cyclic phosphatidic acid (cPA), one of bioactive lipids, potently suppresses neointima formation by inhibiting the activation of peroxisome proliferator-activated receptor gamma (PPARγ). However, the detailed mechanism is still unclear. In this study, to elucidate the mechanism of the cPA-PPARγ axis in the coronary artery endothelium, especially in patients with type 2 diabetes, we investigated the proliferation, migration, and secretion of VEGF in human coronary artery endothelial cells from diabetes patients (D-HCAECs). AGP induced cell growth and migration; however, cPA suppressed the AGP-elicited growth and migration in D-HCAECs. Moreover, AGP increased VEGF secretion from D-HCAECs, and this event was attenuated by cPA. Taken together, these results suggest that cPA suppresses VEGF-stimulated growth and migration in D-HCAECs. These findings could be important for regulatory roles of PPARγ and VEGF in the vascular processes associated with diabetes and atherosclerosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Troglitazone stimulates {beta}-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1{sub A} receptor

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tilley, Douglas G., E-mail: douglas.tilley@jefferson.edu; Center for Translational Medicine, Thomas Jefferson University; Nguyen, Anny D.

    2010-06-11

    Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPAR{gamma}-independent signaling events. Select angiotensin receptor blockers (ARBs) interact with and modulate PPAR{gamma} activity, thus we hypothesized that a PPAR{gamma} agonist may exert physiologic effects via the angiotensin II type 1{sub A} receptor (AT1{sub A}R). In AT1{sub A}R-overexpressing HEK 293 cells, both angiotensin II (Ang II) and the PPAR{gamma} agonist troglitazone (Trog) enhanced AT1{sub A}R internalization and recruitment of endogenous {beta}-arrestin1/2 ({beta}arr1/2) to the AT1{sub A}R. A fluorescence assay to measure diacylglycerolmore » (DAG) accumulation showed that although Ang II induced AT1{sub A}R-G{sub q} protein-mediated DAG accumulation, Trog had no impact on DAG generation. Trog-mediated recruitment of {beta}arr1/2 was selective to AT1{sub A}R as the response was prevented by an ARB- and Trog-mediated {beta}arr1/2 recruitment to {beta}1-adrenergic receptor ({beta}1AR) was not observed. In isolated mouse cardiomyocytes, Trog increased both % and rate of cell shortening to a similar extent as Ang II, effects which were blocked with an ARB. Additionally, these effects were found to be {beta}arr2-dependent, as cardiomyocytes isolated from {beta}arr2-KO mice showed blunted contractile responses to Trog. These findings show for the first time that the PPAR{gamma} agonist Trog acts at the AT1{sub A}R to simultaneously block G{sub q} protein activation and induce the recruitment of {beta}arr1/2, which leads to an increase in cardiomyocyte contractility.« less

  13. [Roles of G protein-coupled estrogen receptor in the male reproductive system].

    PubMed

    Chen, Kai-hong; Zhang, Xian; Jiang, Xue-wu

    2016-02-01

    The G protein-coupled estrogen receptor (GPER), also known as G protein-coupled receptor 30 (GPR30), was identified in the recent years as a functional membrane receptor different from the classical nuclear estrogen receptors. This receptor is widely expressed in the cortex, cerebellum, hippocampus, heart, lung, liver, skeletal muscle, and the urogenital system. It is responsible for the mediation of nongenomic effects associated with estrogen and its derivatives, participating in the physiological activities of the body. The present study reviews the molecular structure, subcellular localization, signaling pathways, distribution, and function of GPER in the male reproductive system.

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

    PubMed

    Tsukahara, Tamotsu; Haniu, Hisao; Matsuda, Yoshikazu

    2013-04-12

    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. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Low gamma counting for measuring NORM/TENORM with a radon reducing system

    NASA Astrophysics Data System (ADS)

    Paschoa, Anselmo S.

    2001-06-01

    A detection system for counting low levels of gamma radiation was built by upgrading an existing rectangular chamber made of 18 metric tonne of steel fabricated before World War II. The internal walls, the ceiling, and the floor of the chamber are covered with copper sheets. The new detection system consists of a stainless steel hollow cylinder with variable circular apertures in the cylindrical wall and in the base, to allow introduction of a NaI (Tl) crystal, or alternatively, a HPGe detector in its interior. This counting system is mounted inside the larger chamber, which in turn is located in a subsurface air-conditioned room. The access to the subsurface room is made from a larger entrance room through a tunnel plus a glass anteroom to decrease the air-exchange rate. Both sample and detector are housed inside the stainless steel cylinder. This cylinder is filled with hyper pure nitrogen gas, before counting a sample, to prevent radon coming into contact with the detector surface. As a consequence, the contribution of the 214Bi photopeaks to the background gamma spectra is minimized. The reduction of the gamma radiation background near the detector facilitates measurement of naturally occurring radioactive materials (NORM), and/or technologically enhanced NORM (TENORM), which are usually at concentration levels only slightly higher than those typically found in the natural radioactive background.

  16. Decreased Phosphorylated Protein Kinase B (Akt) in Individuals with Autism Associated with High Epidermal Growth Factor Receptor (EGFR) and Low Gamma-Aminobutyric Acid (GABA).

    PubMed

    Russo, Anthony J

    2015-01-01

    Dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway could contribute to the pathogenesis of autism spectrum disorders. In this study, phosphorylated Akt concentration was measured in 37 autistic children and 12, gender and age similar neurotypical, controls using an enzyme-linked immunosorbent assay. Akt levels were compared to biomarkers known to be associated with epidermal growth factor receptor (EGFR) and c-Met (hepatocyte growth factor (HGF) receptor) pathways and severity levels of 19 autism-related symptoms. We found phosphorylated Akt levels significantly lower in autistic children and low Akt levels correlated with high EGFR and HGF and low gamma-aminobutyric acid, but not other biomarkers. Low Akt levels also correlated significantly with increased severity of receptive language, conversational language, hypotonia, rocking and pacing, and stimming, These results suggest a relationship between decreased phosphorylated Akt and selected symptom severity in autistic children and support the suggestion that the AKT pathways may be associated with the etiology of autism.

  17. Evolution of neurotransmitter receptor systems.

    PubMed

    Venter, J C; di Porzio, U; Robinson, D A; Shreeve, S M; Lai, J; Kerlavage, A R; Fracek, S P; Lentes, K U; Fraser, C M

    1988-01-01

    The presence of hormones, neurotransmitters, their receptors and biosynthetic and degradative enzymes is clearly not only associated with the present and the recent past but with the past several hundred million years. Evidence is mounting which indicates substantial conservation of protein structure and function of these receptors and enzymes over these tremendous periods of time. These findings indicate that the evolution and development of the nervous system was not dependent upon the formation of new or better transmitter substances, receptor proteins, transducers and effector proteins but involved better utilization of these highly developed elements in creating advanced and refined circuitry. This is not a new concept; it is one that is now substantiated by increasingly sophisticated studies. In a 1953 article discussing chemical aspects of evolution (Danielli, 1953) Danielli quotes Medawar, "... endocrine evolution is not an evolution of hormones but an evolution of the uses to which they are put; an evolution not, to put it crudely, of chemical formulae but of reactivities, reaction patterns and tissue competences." To also quote Danielli, "In terms of comparative biochemistry, one must ask to what extent the evolution of these reactivities, reaction patterns and competences is conditional upon the evolution of methods of synthesis of new proteins, etc., and to what extent the proteins, etc., are always within the synthetic competence of an organism. In the latter case evolution is the history of changing uses of molecules, and not of changing synthetic abilities." (Danielli, 1953). Figure 4 outlines a phylogenetic tree together with an indication of where evidence exists for both the enzymes that determine the biosynthesis and metabolism of the cholinergic and adrenergic transmitters and their specific cholinergic and adrenergic receptors. This figure illustrates a number of important points. For example, the evidence appears to show that the transmitters

  18. Detection system for high-resolution gamma radiation spectroscopy with neutron time-of-flight filtering

    DOEpatents

    Dioszegi, Istvan; Salwen, Cynthia; Vanier, Peter

    2014-12-30

    A .gamma.-radiation detection system that includes at least one semiconductor detector such as HPGe-Detector, a position-sensitive .alpha.-Detector, a TOF Controller, and a Digitizer/Integrator. The Digitizer/Integrator starts to process the energy signals of a .gamma.-radiation sent from the HPGe-Detector instantly when the HPGe-Detector detects the .gamma.-radiation. Subsequently, it is determined whether a coincidence exists between the .alpha.-particles and .gamma.-radiation signal, based on a determination of the time-of-flight of neutrons obtained from the .alpha.-Detector and the HPGe-Detector. If it is determined that the time-of-flight falls within a predetermined coincidence window, the Digitizer/Integrator is allowed to continue and complete the energy signal processing. If, however, there is no coincidence, the Digitizer/Integrator is instructed to be clear and reset its operation instantly.

  19. Neutron interrogation system using high gamma ray signature to detect contraband special nuclear materials in cargo

    DOEpatents

    Slaughter, Dennis R.; Pohl, Bertram A.; Dougan, Arden D.; Bernstein, Adam; Prussin, Stanley G.; Norman, Eric B.

    2008-04-15

    A system for inspecting cargo for the presence of special nuclear material. The cargo is irradiated with neutrons. The neutrons produce fission products in the special nuclear material which generate gamma rays. The gamma rays are detecting indicating the presence of the special nuclear material.

  20. IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure.

    PubMed

    Bémeur, Chantal; Qu, Hong; Desjardins, Paul; Butterworth, Roger F

    2010-01-01

    Previous reports suggested that brain-derived proinflammatory cytokines are involved in the pathogenesis of hepatic encephalopathy (HE) and brain edema in acute liver failure (ALF). To further address this issue, expression of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNAs were measured in the brains of mice with acute liver failure resulting from exposure to azoxymethane. In addition, time to severe encephalopathy (coma) was assessed in mice lacking genes coding for interferon-gamma, the tumor necrosis factor receptor-1 or the interleukin-1 type 1 receptor. Interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma expression were quantified using RT-PCR. Significant increases in interleukin-1beta and tumor necrosis factor-alpha mRNA were observed in the frontal cortex of azoxymethane-treated wild-type mice at coma stages of encephalopathy. Interferon-gamma, however, could not be detected in the brains of these animals. Onset of severe encephalopathy (coma) and brain edema in ALF mice were significantly delayed in interleukin-1 type 1 receptor or tumor necrosis factor receptor-1 knockout mice. Deletion of the interferon-gamma gene, on the other hand, had no significative effect on the neurological status or brain water content of acute liver failure mice. These results demonstrate that toxic liver injury resulting from exposure to azoxymethane is associated with selective induction of proinflammatory cytokines in the brain and that deletion of tumor necrosis factor receptor-1 or interlukin-1 type 1 receptor delays the onset of coma and brain edema in this model of acute liver failure. These findings further support a role for selective brain-derived cytokines in the pathogenesis of the cerebral complications in acute liver failure and suggest that anti-inflammatory strategies could be beneficial in their prevention. Copyright 2009 Elsevier Ltd. All rights reserved.

  1. The 5-HT6 receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture.

    PubMed

    Amat-Foraster, Maria; Leiser, Steven C; Herrik, Kjartan F; Richard, Nelly; Agerskov, Claus; Bundgaard, Christoffer; Bastlund, Jesper F; de Jong, Inge E M

    2017-02-01

    The 5-HT 6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD). The high affinity and selective 5-HT 6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on cortical function using two in vivo electrophysiological methods. Neuronal network oscillations in the frontal cortex were measured during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and by an electroencephalogram (EEG) in the awake, freely moving rat. In conjunction with the EEG study, we investigated the effects of idalopirdine and donepezil on sleep-wake architecture using telemetric polysomnography. Idalopirdine (2 mg/kg i.v.) increased gamma power in the medial prefrontal cortex (mPFC) during nPO stimulation. Donepezil (0.3 and 1 mg/kg i.v.) also increased cortical gamma power and pretreatment with idalopirdine (2 mg/kg i.v.) potentiated and prolonged the effects of donepezil. Similarly, donepezil (1 and 3 mg/kg s.c.) dose-dependently increased frontal cortical gamma power in the freely moving rat and pretreatment with idalopirdine (10 mg/kg p.o.) augmented the effect of donepezil 1 mg/kg. Analysis of the sleep-wake architecture showed that donepezil (1 and 3 mg/kg s.c.) dose-dependently delayed sleep onset and decreased the time spent in both REM and non REM sleep stages. In contrast, idalopirdine (10 mg/kg p.o.) did not affect sleep-wake architecture nor the effects of donepezil. In summary, we show that idalopirdine potentiates the effects of donepezil on frontal cortical gamma oscillations, a pharmacodynamic biomarker associated with cognition, without modifying the effects of donepezil on sleep. The increased cortical excitability may contribute to the procognitive effects of idalopirdine in donepezil

  2. Identification of amino acids in the N-terminal SH2 domain of phospholipase C gamma 1 important in the interaction with epidermal growth factor receptor.

    PubMed

    Gergel, J R; McNamara, D J; Dobrusin, E M; Zhu, G; Saltiel, A R; Miller, W T

    1994-12-13

    Photoaffinity labeling and site-directed mutagenesis have been used to identify amino acid residues of the phospholipase C gamma 1 (PLC gamma 1) N-terminal SH2 domain involved in recognition of the activated epidermal growth factor receptor (EGFR). The photoactive amino acid p-benzoylphenylalanine (Bpa) was incorporated into phosphotyrosine-containing peptides derived from EGFR autophosphorylation sites Tyr992 and Tyr1068. Irradiation of these labels in the presence of SH2 domains showed cross-linking which was time-dependent and specific; labeling was inhibited with non-Bpa-containing peptides from EGFR in molar excess. The phosphotyrosine residue on the peptides was important for SH2 recognition, as dephosphorylated peptides did not cross-link. Radiolabeled peptides were used to identify sites of cross-linking to the N-terminal SH2 of PLC gamma 1. Bpa peptide-SH2 complexes were digested with trypsin, and radioactive fragments were purified by HPLC and analyzed by Edman sequencing. These experiments showed Arg562 and an additional site in the alpha A-beta B region of the SH2 domain, most likely Glu587, to be labeled by the Tyr992-derived peptide. Similar analysis of the reaction with the Tyr1068-derived photoaffinity label identified Leu653 as the cross-linked site. Mutation of the neighboring residues of Glu587 decreased photo-cross-linking, emphasizing the importance of this region of the molecule for recognition. These results are consistent with evidence from the v-Src crystal structure and implicate the loop spanning residues Gln640-Ser654 of PLC gamma 1 in specific recognition of phosphopeptides.

  3. Alpha-7 Nicotinic Receptors in Nervous System Disorders: From Function to Therapeutic Perspectives.

    PubMed

    De Jaco, Antonella; Bernardini, Laura; Rosati, Jessica; Tata, Ada Maria

    2017-01-01

    The α7 nicotinic receptor consists of identical subunits and is one of the most abundant acetylcholine receptors in the mammalian central nervous system. However its expression is also found in the peripheral nervous system as well as in the immune system and various peripheral tissues. Nicotinic Receptors: They are involved in the regulation of several activities ranging from excitatory neurotransmission, the modulation of the release of several neurotransmitters, regulation of neurite outgrowth, and even neuronal survival/death. Its expression is found in brain areas that underlie learning and memory, suggesting their involvement in regulating cognitive functions. The α7-nicotinic receptor has a strategic role during development in regulating molecular pathways activated during neurogenesis. Because of its pleiotropic effects, receptor dysfunction or dysregulated expression is found in pathophysiological conditions of the nervous system including neurodegenerative diseases and neurodevelopmental disorders. Here we review the physiological and pathological roles of alpha-7 nicotinic receptor in different nervous system disorders and the current therapeutic strategies developed to target selectively this receptor for potentiating or reducing its functions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Sneaky Gamma-Rays: Using Gravitational Lensing to Avoid Gamma-Gamma-Absorption

    NASA Astrophysics Data System (ADS)

    Boettcher, Markus; Barnacka, Anna

    2014-08-01

    It has recently been suggested that gravitational lensing studies of gamma-ray blazars might be a promising avenue to probe the location of the gamma-ray emitting region in blazars. Motivated by these prospects, we have investigated potential gamma-gamma absorption signatures of intervening lenses in the very-high-energy gamma-ray emission from lensedblazars. We considered intervening galaxies and individual stars within these galaxies. We find that the collective radiation field of galaxies acting as sources of macrolensing are not expected to lead to significant gamma-gamma absorption. Individual stars within intervening galaxies could, in principle, cause a significant opacity to gamma-gamma absorption for VHE gamma-rays if the impact parameter (the distance of closest approach of the gamma-ray to the center of the star) is small enough. However, we find that the curvature of the photon path due to gravitational lensing will cause gamma-ray photons to maintain a sufficiently large distance from such stars to avoid significant gamma-gamma absorption. This re-inforces the prospect of gravitational-lensing studies of gamma-ray blazars without interference due to gamma-gamma absorption due to the lensing objects.

  5. Calcium/calmodulin-dependent kinase II phosphorylation of the GABAA receptor alpha1 subunit modulates benzodiazepine binding.

    PubMed

    Churn, Severn B; Rana, Aniruddha; Lee, Kangmin; Parsons, J Travis; De Blas, Angel; Delorenzo, Robert J

    2002-09-01

    gamma-Aminobutyric acid (GABA) is the primary neurotransmitter that is responsible for the fast inhibitory synaptic transmission in the central nervous system. A major post-translational mechanism that can rapidly regulate GABAAR function is receptor phosphorylation. This study was designed to test the effect of endogenous calcium and calmodulin-dependent kinase II (CaM kinase II) activation on both allosteric modulator binding and GABAA receptor subunit phosphorylation. Endogenous CaM kinase II activity was stimulated, and GABAA receptors were subsequently analyzed for bothallosteric modulator binding properties and immunoprecipitated and analyzed for subunit phosphorylation levels. A significant increase in allosteric-modulator binding of the GABAAR was observed under conditions maximal for CaM kinase II activation. In addition, CaM kinase II activation resulted in a direct increase in phosphorylation of the GABAA receptor alpha1 subunit. The data suggest that the CaM kinase II-dependent phosphorylation of the GABAA receptor alpha1 subunit modulated allosteric modulator binding to the GABAA receptor.

  6. Characterization of rat leydig cell gonadotropin receptor structure by affinity cross-linking

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Q.Y.; Hwang, J.; Menon, K.M.J.

    1986-05-01

    The gonadotropin receptor from rat leydig cell has been characterized with respect to binding kinetics and physiological regulation. The present study was intended to examine the structure of the receptor. Leydig cell suspension was prepared by either collagenase digestion or by mechanical disruption of the testis. The cells were incubated with /sup 125/I-hCG and the unreacted hCG was removed by centrifugation. The /sup 125/I-hCG was then covalently linked to the cell surface receptor using cleavable (dithiobis (succinimidyl propionate)) and non-cleavable (disuccinimidyl suberate) cross-linking reagents. The extracted cross-linked membrane proteins were resolved on SDS-polyacrylamide gels under reducing and non-reducing conditions andmore » subjected to autoradiographic analysis. Under non-reducing conditions, two labeled species with M/sub r/ = 87,000 and 120,000 were detected. However, only one labeled band was detected under reducing conditions with M/sub r/ = 64,000. The binding of /sup 125/I-hCG to the receptor was inhibited by hCG and LH, but not by a number of peptides and proteins. The data suggest that hCG receptor in leydig cell is an oligomeric complex consisting of four subunits, ..cap alpha cap alpha beta gamma... The ..beta.. and ..gamma.. subunits are each linked to an ..cap alpha.. subunit through disulfide linkage and the hormone binds to each ..cap alpha.. subunit. The two dimers formed (..cap alpha beta cap alpha gamma..) are associated by noncovalent interactions.« less

  7. The synthetic ligand of peroxisome proliferator-activated receptor-gamma ciglitazone affects human glioblastoma cell lines.

    PubMed

    Strakova, Nicol; Ehrmann, Jiri; Dzubak, Petr; Bouchal, Jan; Kolar, Zdenek

    2004-06-01

    Glioblastoma multiforme is the most common malignant brain tumor in adults, and it is among the most lethal of all cancers. Recent studies have shown that ligand activation of peroxisome proliferator-activated receptor (PPAR)-gamma can induce differentiation and inhibit proliferation of several cancer cells. In this study, we have investigated whether one PPARgamma ligand in particular, ciglitazone, inhibits cell viability and, additionally, whether it affects the cell cycle and apoptosis of human glioblastoma cell lines T98G, U-87 MG, A172, and U-118 MG. All glioblastoma cell lines were found to express PPARgamma protein, and following treatment with ciglitazone, localization was unchanged. Ciglitazone inhibited viability in a dose-dependent manner in all four tested glioblastoma cells after 24 h of treatment. Analysis of the cell cycle showed arrest in the G(1) phase and partial block in G(2)/M phase of the cell cycle. Cyclin D1 and cyclin B expression was decreased. Phosphorylation of Rb protein dropped as well. We found that ciglitazone was followed by increased expression of p27(Kip1) and p21(Waf1/Cip1). It also led to apoptosis induction: bax expression in T98G was elevated. Expression of the antiapoptotic protein bcl-2 was reduced in U-118 MG and U-87 MG and showed a slight decrease in A172 cells. Flow cytometry confirmed the induction of apoptosis. Moreover, PPARgamma ligand decreased telomerase activity in U-87 MG and U-118 MG cell lines. Our results demonstrate that ciglitazone inhibits the viability of human glioblastoma cell lines via induction of apoptosis; as a result, this ligand may offer potential new therapy for the treatment of central nervous system neoplasms.

  8. Photodetectors for the Advanced Gamma-ray Imaging System (AGIS)

    NASA Astrophysics Data System (ADS)

    Wagner, Robert G.; Advanced Gamma-ray Imaging System AGIS Collaboration

    2010-03-01

    The Advanced Gamma-Ray Imaging System (AGIS) is a concept for the next generation very high energy gamma-ray observatory. Design goals include an order of magnitude better sensitivity, better angular resolution, and a lower energy threshold than existing Cherenkov telescopes. Each telescope is equipped with a camera that detects and records the Cherenkov-light flashes from air showers. The camera is comprised of a pixelated focal plane of blue sensitive and fast (nanosecond) photon detectors that detect the photon signal and convert it into an electrical one. Given the scale of AGIS, the camera must be reliable and cost effective. The Schwarzschild-Couder optical design yields a smaller plate scale than present-day Cherenkov telescopes, enabling the use of more compact, multi-pixel devices, including multianode photomultipliers or Geiger avalanche photodiodes. We present the conceptual design of the focal plane for the camera and results from testing candidate! focal plane sensors.

  9. Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD

    PubMed Central

    Huang, Lanting; Yang, Xiu-Juan; Huang, Ying; Sun, Eve Y.

    2016-01-01

    NMDA receptors have been widely reported to be involved in the regulation of synaptic plasticity through effects on long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD have been implicated in learning and memory processes. Besides synaptic plasticity, it is known that the phenomenon of gamma oscillations is critical in cognitive functions. Synaptic plasticity has been widely studied, however it is still not clear, to what degree synaptic plasticity regulates the oscillations of neuronal networks. Two NMDA receptor antagonists, ketamine and memantine, have been shown to regulate LTP and LTD, to promote cognitive functions, and have even been reported to bring therapeutic effects in major depression and Alzheimer’s disease respectively. These compounds allow us to investigate the putative interrelationship between network oscillations and synaptic plasticity and to learn more about the mechanisms of their therapeutic effects. In the present study, we have identified that ketamine and memantine could inhibit LTD, without impairing LTP in the CA1 region of mouse hippocampus, which may underlie the mechanism of these drugs’ therapeutic effects. Our results suggest that NMDA-induced LTD caused a marked loss in the gamma power, and pretreatment with 10 μM ketamine prevented the oscillatory loss via its inhibitory effect on LTD. Our study provides a new understanding of the role of NMDA receptors on hippocampal plasticity and oscillations. PMID:27467732

  10. Gamma-ray dose from an overhead plume

    DOE PAGES

    McNaughton, Michael W.; Gillis, Jessica McDonnel; Ruedig, Elizabeth; ...

    2017-05-01

    Standard plume models can underestimate the gamma-ray dose when most of the radioactive material is above the heads of the receptors. Typically, a model is used to calculate the air concentration at the height of the receptor, and the dose is calculated by multiplying the air concentration by a concentration-to-dose conversion factor. Models indicate that if the plume is emitted from a stack during stable atmospheric conditions, the lower edges of the plume may not reach the ground, in which case both the ground-level concentration and the dose are usually reported as zero. However, in such cases, the dose frommore » overhead gamma-emitting radionuclides may be substantial. Such underestimates could impact decision making in emergency situations. The Monte Carlo N-Particle code, MCNP, was used to calculate the overhead shine dose and to compare with standard plume models. At long distances and during unstable atmospheric conditions, the MCNP results agree with the standard models. As a result, at short distances, where many models calculate zero, the true dose (as modeled by MCNP) can be estimated with simple equations.« less

  11. AZ-101 Mixer Pump Demonstration Data Acquisition System and Gamma Cart Data Acquisition Control System Software Configuration Management Plan

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    WHITE, D.A.

    1999-12-29

    This Software Configuration Management Plan (SCMP) provides the instructions for change control of the AZ1101 Mixer Pump Demonstration Data Acquisition System (DAS) and the Sludge Mobilization Cart (Gamma Cart) Data Acquisition and Control System (DACS).

  12. Evidence for two distinct phosphorylation pathways activated by high affinity immunoglobulin E receptors.

    PubMed

    Adamczewski, M; Paolini, R; Kinet, J P

    1992-09-05

    The high affinity receptor for immunoglobulin (Ig) E on mast cells, along with the antigen receptors on T and B cells and Fc receptors for IgG, belongs to a class of receptors which lack intrinsic kinase activity, but activate non-receptor tyrosine and serine/threonine kinases. Receptor engagement triggers a chain of signaling events leading from protein phosphorylation to activation of phosphatidylinositol-specific phospholipase C, an increase in intracellular calcium levels, and ultimately the activation of more specialized functions. IgE receptor disengagement leads to reversal of phosphorylation by undefined phosphatases and to inhibition of activation pathways. Here we show that phenylarsine oxide, a chemical which reacts with thiol groups and has been reported to inhibit tyrosine phosphatases, uncouples the IgE receptor-mediated phosphorylation signal from activation of phosphatidyl inositol metabolism, the increase in intracellular calcium levels, and serotonin release. Phenylarsine oxide inhibits neither the kinases (tyrosine and serine/threonine) phosphorylating the receptor and various cellular substrates nor, unexpectedly, the phosphatases responsible for the dephosphorylation following receptor disengagement. By contrast, it abolishes the receptor-mediated phosphorylation of phospholipase C-gamma 1, but not phospholipase C activity in vitro. Therefore the phosphorylation and activation of phospholipase C likely requires a phenylarsine oxide-sensitive element. Receptor aggregation thus activates at least two distinct phosphorylation pathways: a phenylarsine oxide-insensitive pathway leading to phosphorylation/dephosphorylation of the receptor and of various substrates and a sensitive pathway leading to phospholipase C-gamma 1 phosphorylation.

  13. The control and data acquisition structure for the GAMMA-400 space gamma-telescope

    NASA Astrophysics Data System (ADS)

    Arkhangelskiy, Andrey

    2016-07-01

    The GAMMA-400 space project is intended for precision investigation of the cosmic gamma-emission in the energy band from keV region up to several TeV, electrons and positrons fluxes from ˜~1~GeV up to ˜~10~TeV and high energy cosmic-ray nuclei fluxes. A description of the control and data acquisition structure for gamma-telescope involved in the GAMMA 400 space project is given. The technical capabilities of all specialized equipment providing the functioning of the scientific instrumentation and satellite support systems are unified in a single structure. Control of the scientific instruments is maintained using one-time pulse radio commands and program commands transmitted via onboard control system and scientific data acquisition system. Up to 100~GByte of data per day can be transferred to the ground segment of the project. The correctness of the proposed and implemented structure, engineering solutions and electronic elemental base selection has been verified experimentally with the scientific complex prototype in the laboratory conditions.

  14. T-Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon-Gamma.

    PubMed

    Sun, Xue-Nan; Li, Chao; Liu, Yuan; Du, Lin-Juan; Zeng, Meng-Ru; Zheng, Xiao-Jun; Zhang, Wu-Chang; Liu, Yan; Zhu, Mingjiang; Kong, Deping; Zhou, Li; Lu, Limin; Shen, Zhu-Xia; Yi, Yi; Du, Lili; Qin, Mu; Liu, Xu; Hua, Zichun; Sun, Shuyang; Yin, Huiyong; Zhou, Bin; Yu, Ying; Zhang, Zhiyuan; Duan, Sheng-Zhong

    2017-05-12

    Hypertension remains to be a global public health burden and demands novel intervention strategies such as targeting T cells and T-cell-derived cytokines. Mineralocorticoid receptor (MR) antagonists have been clinically used to treat hypertension. However, the function of T-cell MR in blood pressure (BP) regulation has not been elucidated. We aim to determine the role of T-cell MR in BP regulation and to explore the mechanism. Using T-cell MR knockout mouse in combination with angiotensin II-induced hypertensive mouse model, we demonstrated that MR deficiency in T cells strikingly decreased both systolic and diastolic BP and attenuated renal and vascular damage. Flow cytometric analysis showed that T-cell MR knockout mitigated angiotensin II-induced accumulation of interferon-gamma (IFN-γ)-producing T cells, particularly CD8 + population, in both kidneys and aortas. Similarly, eplerenone attenuated angiotensin II-induced elevation of BP and accumulation of IFN-γ-producing T cells in wild-type mice. In cultured CD8 + T cells, T-cell MR knockout suppressed IFN-γ expression whereas T-cell MR overexpression and aldosterone both enhanced IFN-γ expression. At the molecular level, MR interacted with NFAT1 (nuclear factor of activated T-cells 1) and activator protein-1 in T cells. Finally, T-cell MR overexpressing mice manifested more elevated BP compared with control mice after angiotensin II infusion and such difference was abolished by IFN-γ-neutralizing antibodies. MR may interact with NFAT1 and activator protein-1 to control IFN-γ in T cells and to regulate target organ damage and ultimately BP. Targeting MR in T cells specifically may be an effective novel approach for hypertension treatment. © 2017 American Heart Association, Inc.

  15. Design of Dual-Road Transportable Portal Monitoring System for Visible Light and Gamma-Ray Imaging

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Karnowski, Thomas Paul; Cunningham, Mark F; Goddard Jr, James Samuel

    2010-01-01

    The use of radiation sensors as portal monitors is increasing due to heightened concerns over the smuggling of fissile material. Transportable systems that can detect significant quantities of fissile material that might be present in vehicular traffic are of particular interest, especially if they can be rapidly deployed to different locations. To serve this application, we have constructed a rapid-deployment portal monitor that uses visible-light and gamma-ray imaging to allow simultaneous monitoring of multiple lanes of traffic from the side of a roadway. The system operation uses machine vision methods on the visible-light images to detect vehicles as they entermore » and exit the field of view and to measure their position in each frame. The visible-light and gamma-ray cameras are synchronized which allows the gamma-ray imager to harvest gamma-ray data specific to each vehicle, integrating its radiation signature for the entire time that it is in the field of view. Thus our system creates vehicle-specific radiation signatures and avoids source confusion problems that plague non-imaging approaches to the same problem. Our current prototype instrument was designed for measurement of upto five lanes of freeway traffic with a pair of instruments, one on either side of the roadway. Stereoscopic cameras are used with a third alignment camera for motion compensation and are mounted on a 50 deployable mast. In this paper we discuss the design considerations for the machine-vision system, the algorithms used for vehicle detection and position estimates, and the overall architecture of the system. We also discuss system calibration for rapid deployment. We conclude with notes on preliminary performance and deployment.« less

  16. Design of dual-road transportable portal monitoring system for visible light and gamma-ray imaging

    NASA Astrophysics Data System (ADS)

    Karnowski, Thomas P.; Cunningham, Mark F.; Goddard, James S.; Cheriyadat, Anil M.; Hornback, Donald E.; Fabris, Lorenzo; Kerekes, Ryan A.; Ziock, Klaus-Peter; Bradley, E. Craig; Chesser, J.; Marchant, W.

    2010-04-01

    The use of radiation sensors as portal monitors is increasing due to heightened concerns over the smuggling of fissile material. Transportable systems that can detect significant quantities of fissile material that might be present in vehicular traffic are of particular interest, especially if they can be rapidly deployed to different locations. To serve this application, we have constructed a rapid-deployment portal monitor that uses visible-light and gamma-ray imaging to allow simultaneous monitoring of multiple lanes of traffic from the side of a roadway. The system operation uses machine vision methods on the visible-light images to detect vehicles as they enter and exit the field of view and to measure their position in each frame. The visible-light and gamma-ray cameras are synchronized which allows the gamma-ray imager to harvest gamma-ray data specific to each vehicle, integrating its radiation signature for the entire time that it is in the field of view. Thus our system creates vehicle-specific radiation signatures and avoids source confusion problems that plague non-imaging approaches to the same problem. Our current prototype instrument was designed for measurement of upto five lanes of freeway traffic with a pair of instruments, one on either side of the roadway. Stereoscopic cameras are used with a third "alignment" camera for motion compensation and are mounted on a 50' deployable mast. In this paper we discuss the design considerations for the machine-vision system, the algorithms used for vehicle detection and position estimates, and the overall architecture of the system. We also discuss system calibration for rapid deployment. We conclude with notes on preliminary performance and deployment.

  17. The PPAR{gamma} coding region and its role in visceral obesity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Boon Yin, Khoo; Institute for Research in Molecular Medicine; Najimudin, Nazalan

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is a ligand activated transcription factor, plays many essential roles of biological function in higher organisms. The PPAR{gamma} is mainly expressed in adipose tissue. It regulates the transcriptional activity of genes by binding with other transcription factor. The PPAR{gamma} coding region has been found to be closest to that of monkey in ours and other research groups. Thus, monkey is a more suitable animal model for future PPAR{gamma} studying, although mice and rat are frequently being used. The PPAR{gamma} is involved in regulating alterations of adipose tissue masses result from changes in mature adipocyte sizemore » and/or number through a complex interplay process called adipogenesis. However, the role of PPAR{gamma} in negatively regulating the process of adipogenesis remains unclear. This review may help we investigate the differential expression of key transcription factor in adipose tissue in response to visceral obesity-induced diet in vivo. The study may also provide valuable information to define a more appropriate physiological condition in adipogenesis which may help to prevent diseases cause by negative regulation of the transcription factors in adipose tissue.« less

  18. Therapeutic antibody targeting of individual Notch receptors.

    PubMed

    Wu, Yan; Cain-Hom, Carol; Choy, Lisa; Hagenbeek, Thijs J; de Leon, Gladys P; Chen, Yongmei; Finkle, David; Venook, Rayna; Wu, Xiumin; Ridgway, John; Schahin-Reed, Dorreyah; Dow, Graham J; Shelton, Amy; Stawicki, Scott; Watts, Ryan J; Zhang, Jeff; Choy, Robert; Howard, Peter; Kadyk, Lisa; Yan, Minhong; Zha, Jiping; Callahan, Christopher A; Hymowitz, Sarah G; Siebel, Christian W

    2010-04-15

    The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have progressed into the clinic, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways and cause intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to

  19. Predominant expansion of V gamma 9/V delta 2 T cells in a tularemia patient.

    PubMed Central

    Sumida, T; Maeda, T; Takahashi, H; Yoshida, S; Yonaha, F; Sakamoto, A; Tomioka, H; Koike, T; Yoshida, S

    1992-01-01

    We describe a 58-year-old man with tularemia and expanding gamma delta T cells in his peripheral blood lymphocytes (PBL) (32.7% of total PBL). In the present work, we analyzed the T-cell receptor V gamma/V delta repertoire of these cells by making use of the polymerase chain reaction and flow cytometry and found that they were mostly CD4- CD8- CD3+ V gamma 9/V delta 2+. The sequence analysis of 16 cDNA clones encoding the V gamma 9-J region revealed that the V gamma 9-Jp combination was strikingly overrepresented but that the junctional (N) region was heterogeneous. This suggested that the gamma delta T cells in PBL from a patient with tularemia were polyclonally expanded. Images PMID:1534075

  20. The Advanced Gamma-ray Imaging System (AGIS): Focal Plane Detectors

    NASA Astrophysics Data System (ADS)

    Mukherjee, Reshmi; Byrum, K.; Drake, G.; Falcone, A.; Funk, S.; Horan, D.; Tajima, H.; Wagner, B.; Williams, D.

    2008-04-01

    Report of the Focal Plane Instrumentation Working Group, AGIS collaboration: The Advanced Gamma-ray Imaging System (AGIS) is a concept for the next generation instrument in ground-based very high energy gamma-ray astronomy. It has the goal of achieving significant improvement in sensitivity over current experiments. One of the main requirements for AGIS will be to achieve higher angular resolution than current imaging atmospheric Cherenkov telescopes (IACTs). Simulations show that a substantial improvement in angular resolution may be achieved if the pixel size is reduced to 0.05 deg, below that of current IACTs. Reducing the cost per channel and improving reliability and modularity are other important considerations. Here we present several alternatives being considered for AGIS, including both silicon photomultipliers (SiPMs) and multi-anode photomultipliers (MAPMTs) and summarize results from feasibility testing by various AGIS photodetector group members.

  1. Genetic variation in the peroxisome proliferator-activated receptor (PPAR) and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) gene families and type 2 diabetes

    PubMed Central

    Villegas, Raquel; Williams, Scott M.; Gao, Yu-Tang; Long, Jirong; Shi, Jiajun; Cai, Hui; Li, Honglan; Chen, Ching-Chu; Tai, E. Shyong; Hu, Frank; Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou

    2014-01-01

    Summary We used a two-stage study design to evaluate whether variations in the peroxisome proliferator-activated receptors (PPAR) and the peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) gene families (PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B) are associated with T2D risk. Stage I used data from a genome-wide association study (GWAS) from Shanghai, China (1,019 T2D cases and 1,709 controls) and from a meta-analysis of data from the Asian Genetic Epidemiology Network for T2D (AGEN-T2D). Criteria for selection of SNPs for stage II were: 1) P<0.05 in single marker analysis in Shanghai GWAS and P<0.05 in the meta-analysis or 2) P<10−3 in the meta-analysis alone and 3) minor allele frequency ≥0.10. Nine SNPs from the PGC1 family were assessed in stage II (an independent set of middle-aged men and women from Shanghai with 1,700 T2D cases and 1,647 controls). One SNP in PPARGC1B, rs251464, was replicated in stage II (OR=0.87; 95% CI: 0.77–0.99). Gene-body mass index (BMI) and gene-exercise interactions and T2D risk were evaluated in a combined dataset (Shanghai GWAS and stage II data: 2,719 cases and 3,356 controls). One SNP in PPARGC1A, rs12640088, had a significant interaction with BMI. No interactions between the PPARGC1B gene and BMI or exercise were observed. PMID:24359475

  2. System of Programmed Modules for Measuring Photographs with a Gamma-Telescope

    NASA Technical Reports Server (NTRS)

    Averin, S. A.; Veselova, G. V.; Navasardyan, G. V.

    1978-01-01

    Physical experiments using tracking cameras resulted in hundreds of thousands of stereo photographs of events being received. To process such a large volume of information, automatic and semiautomatic measuring systems are required. At the Institute of Space Research of the Academy of Science of the USSR, a system for processing film information from the spark gamma-telescope was developed. The system is based on a BPS-75 projector in line with the minicomputer Elektronika 1001. The report describes this system. The various computer programs available to the operators are discussed.

  3. Piezoelectric wafer active sensors under gamma radiation exposure toward applications for structural health monitoring of nuclear dry cask storage systems

    NASA Astrophysics Data System (ADS)

    Faisal Haider, Mohammad; Mei, Hanfei; Lin, Bin; Yu, Lingyu; Giurgiutiu, Victor; Lam, Poh-Sang; Verst, Christopher

    2018-03-01

    Structural health monitoring (SHM) is in urgent need and must be integrated into the nuclear-spent fuel storage systems to guarantee the safe operation. The dry cask storage system (DCSS) is such storage facility, which is licensed for temporary storage for nuclear-spent fuel at the independent spent fuel storage installations (ISFSIs) for certain predetermined period of time. Gamma radiation is one of the major radiation sources near DCSS. Therefore, a detailed experimental investigation was completed on the gamma radiation endurance of piezoelectric wafer active sensors (PWAS) transducers for SHM applications to the DCSS system. The irradiation test was done in a Co-60 gamma irradiator. Lead Zirconate Titanate (PZT) and Gallium Orthophosphate (GaPO4) PWAS transducers were exposed to 40.7 kGy gamma radiation. Total radiation dose was achieved in two different radiation dose rates: (a) slower radiation rate at 0.1 kGy/hr for 20 hours (b) accelerated radiation rate at 1.233 kGy/hr for 32 hours. The total cumulative radiation dose of 40.7 kGy is equivalent to 45 years of operation in DCSS system. Electro-mechanical impedance and admittance (EMIA) signatures and electrical capacitance were measured to evaluate the PWAS performance after each gamma radiation exposure. The change in resonance frequency of PZT-PWAS transducer for both in-plane and thickness mode was observed. The GaPO4-PWAS EMIA spectra do not show a significant shift in resonance frequency after gamma irradiation exposure. Radiation endurance of new high-temperature HPZ-HiT PWAS transducer was also evaluated. The HPZ-HiT transducers were exposed to gamma radiation at 1.233 kGy/hr for 160 hours with 80 hours interval. Therefore, the total accumulated gamma radiation dose is 184 kGy. No significant change in impedance spectra was observed due to gamma radiation exposure.

  4. Chemokine receptor binding and signal transduction in native cells of the central nervous system.

    PubMed

    Davis, Christopher N; Chen, Shuzhen; Boehme, Stefen A; Bacon, Kevin B; Harrison, Jeffrey K

    2003-04-01

    Chemokine receptors belong to the superfamily of seven-transmembrane-spanning, G-protein-coupled receptors, and their expression by central nervous system cells is clearly documented. As this gene family has become the target of novel therapeutic development, the analysis of these receptors requires radioligand binding techniques as well as methods that entail assessing receptor stimulation of signal transduction pathways. Herein, we describe specific protocols for measuring radiolabeled chemokine binding to their cognate receptors on cultured glial cells as well as to receptors expressed in heterologous cell systems. Multiple downstream signaling pathways, including intracellular calcium influx and receptor-dependent kinase activation, are associated with chemokine receptor stimulation. Protocols for measuring these signaling events in chemokine-receptor-expressing cells are also presented.

  5. The Z {yields} cc-bar {yields} {gamma}{gamma}*, Z {yields} bb-bar {yields} {gamma}{gamma}* triangle diagrams and the Z {yields} {gamma}{psi}, Z {yields} {gamma}Y decays

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Achasov, N. N., E-mail: achasov@math.nsc.ru

    2011-03-15

    The approach to the Z {yields} {gamma}{psi} and Z {yields} {gamma}Y decay study is presented in detail, based on the sum rules for the Z {yields} cc-bar {yields} {gamma}{gamma}* and Z {yields} bb-bar {yields} {gamma}{gamma}* amplitudes and their derivatives. The branching ratios of the Z {yields} {gamma}{psi} and Z {yields} {gamma}Y decays are calculated for different hypotheses on saturation of the sum rules. The lower bounds of {Sigma}{sub {psi}} BR(Z {yields} {gamma}{psi}) = 1.95 Multiplication-Sign 10{sup -7} and {Sigma}{sub {upsilon}} BR(Z {yields} {gamma}Y) = 7.23 Multiplication-Sign 10{sup -7} are found. Deviations from the lower bounds are discussed, including the possibilitymore » of BR(Z {yields} {gamma}J/{psi}(1S)) {approx} BR(Z {yields} {gamma}Y(1S)) {approx} 10{sup -6}, that could be probably measured in LHC. The angular distributions in the Z {yields} {gamma}{psi} and Z {yields} {gamma}Y decays are also calculated.« less

  6. Focal Plane Detectors for the Advanced Gamma-Ray Imaging System (AGIS)

    NASA Astrophysics Data System (ADS)

    Wagner, R. G.; Byrum, K.; Drake, G.; Funk, S.; Otte, N.; Smith, A.; Tajima, H.; Williams, D.

    2009-05-01

    The Advanced Gamma-Ray Imaging System (AGIS) is a concept for the next generation observatory in ground-based very high energy gamma-ray astronomy. It is being designed to achieve a significant improvement in sensitivity compared to current Imaging Air Cherenkov Telescope (IACT) Arrays. One of the main requirements in order that AGIS fulfills this goal will be to achieve higher angular resolution than current IACTs. Simulations show that a substantial improvement in angular resolution may be achieved if the pixel size is reduced to 0.05 deg, i.e. two to three times smaller than for current IACT cameras. Here we present results from testing of alternatives being considered for AGIS, including both silicon photomultipliers (SiPMs) and multi-anode photomultipliers (MAPMTs).

  7. Opioid, cannabinoid, and transient receptor potential (TRP) systems: effects on body temperature

    PubMed Central

    Rawls, Scott M.; Benamar, Khalid

    2014-01-01

    Cannabinoid and opioid drugs produce marked changes in body temperature. Recent findings have extended our knowledge about the thermoregulatory effects of cannabinoids and opioids, particularly as related to delta opioid receptors, endogenous systems, and transient receptor potential (TRP) channels. Although delta opioid receptors were originally thought to play only a minor role in thermoregulation compared to mu and kappa opioid receptors, their activation has been shown to produce hypothermia in multiple species. Endogenous opioids and cannabinoids also regulate body temperature. Mu and kappa opioid receptors are thought to be in tonic balance, with mu and kappa receptor activation producing hyperthermia and hypothermia, respectively. Endocannabinoids participate in the febrile response, but more studies are needed to determine if a cannabinoid CB1 receptor tone exerts control over basal body temperature. A particularly intense research focus is TRP channels, where TRPV1 channel activation produces hypothermia whereas TRPA1 and TRPM8 channel activation causes hyperthermia. The marked hyperthermia produced by TRPV1 channel antagonists suggests these warm channels tonically control body temperature. A better understanding of the roles of cannabinoid, opioid, and TRP systems in thermoregulation may have broad clinical implications and provide insights into interactions among neurotransmitter systems involved in thermoregulation. PMID:21622235

  8. Cholinergic Blockade Reduces Theta-Gamma Phase Amplitude Coupling and Speed Modulation of Theta Frequency Consistent with Behavioral Effects on Encoding

    PubMed Central

    Gillet, Shea N.; Climer, Jason R.; Hasselmo, Michael E.

    2013-01-01

    Large-scale neural activation dynamics in the hippocampal-entorhinal circuit local field potential, observable as theta and gamma rhythms and coupling between these rhythms, is predictive of encoding success. Behavioral studies show that systemic administration of muscarinic acetylcholine receptor antagonists selectively impairs encoding, suggesting that they may also disrupt the coupling between the theta and gamma bands. Here, we tested the hypothesis that muscarinic antagonists selectively disrupt coupling between theta and gamma. Specifically, we characterized the effects of systemically administered scopolamine on movement-induced theta and gamma rhythms recorded in the superficial layers of the medial entorhinal cortex (MEC) of freely moving rats. We report the novel result that gamma power at the peak of theta was most reduced following muscarinic blockade, significantly shifting the phase of maximal gamma power to occur at later phases of theta. We also characterize the existence of multiple distinct gamma bands in the superficial layers of the MEC. Further, we observed that theta frequency was significantly less modulated by movement speed following muscarinic blockade. Finally, the slope relating speed to theta frequency, a correlate of familiarity with a testing enclosure, increased significantly less between the preinjection and recovery trials when scopolamine was administered during the intervening injection session than when saline was administered, suggesting that scopolamine reduced encoding of the testing enclosure. These data are consistent with computational models suggesting that encoding and retrieval occur during the peak and trough of theta, respectively, and support the theory that acetylcholine regulates the balance between encoding versus retrieval. PMID:24336727

  9. Perilipin, a critical regulator of fat storage and breakdown, is a target gene of estrogen receptor-related receptor {alpha}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Akter, Mst. Hasina; Yamaguchi, Tomohiro; Hirose, Fumiko

    2008-04-11

    Perilipin is a protein localized on lipid droplet surfaces in adipocytes and steroidogenic cells, playing a central role in regulated lipolysis. Expression of the perilipin gene is markedly induced during adipogenesis. We found that transcription from the perilipin gene promoter is activated by an orphan nuclear receptor, estrogen receptor-related receptor (ERR){alpha}. A response element to this receptor was identified in the promoter region by a gene reporter assay, the electrophoretic-gel mobility-shift assay and the chromatin immunoprecipitation assay. Peroxisome proliferator-activated receptor {gamma} coactivator (PGC)-1{alpha} enhanced, whereas small heterodimer partner (SHP) repressed, the transactivating function of ERR{alpha} on the promoter. Thus, themore » perilipin gene expression is regulated by a transcriptional network controlling energy metabolism, substantiating the functional importance of perilipin in the maintenance of body energy balance.« less

  10. Metabotropic GABAB receptors mediate GABA inhibition of acetylcholine release in the rat neuromuscular junction.

    PubMed

    Malomouzh, Artem I; Petrov, Konstantin A; Nurullin, Leniz F; Nikolsky, Evgeny E

    2015-12-01

    Gamma-aminobutyric acid (GABA) is an amino acid which acts as a neurotransmitter in the central nervous system. Here, we studied the effects of GABA on non-quantal, spontaneous, and evoked quantal acetylcholine (ACh) release from motor nerve endings. We found that while the application of 10 μM of GABA had no effect on spontaneous quantal ACh release, as detected by the frequency of miniature endplate potentials, GABA reduced the non-quantal ACh release by 57%, as determined by the H-effect value. Finally, the evoked quantal ACh release, estimated by calculating the quantal content of full-sized endplate potentials (EPPs), was reduced by 34%. GABA's inhibitory effect remained unchanged after pre-incubation with picrotoxin, an ionotropic GABAA receptor blocker, but was attenuated following application of the GABAB receptor blocker CGP 55845, which itself had no effect on ACh release. An inhibitor of phospholipase C, U73122, completely prevented the GABA-induced decrease in ACh release. Immunofluorescence demonstrated the presence of both subunits of the GABAB receptor (GABAB R1 and GABAB R2) in the neuromuscular junction. These findings suggest that metabotropic GABAB receptors are expressed in the mammalian neuromuscular synapse and their activation results in a phospholipase C-mediated reduction in the intensity of non-quantal and evoked quantal ACh release. We investigated the effect of gamma-aminobutyric acid (GABA) on neuromuscular transmission. GABA reduced the non-quantal and evoked quantal release of acetylcholine. These effects are mediated by GABAB receptors and are implemented via phospholipase C (PLC) activation. Our findings suggest that in the mammalian neuromuscular synapse, metabotropic GABAB receptors are expressed and their activation results in a reduction in the intensity of acetylcholine release. © 2015 International Society for Neurochemistry.

  11. A study of interdiffusion in beta + gamma/gamma + gamma prime Ni-Cr-Al. M.S. Thesis. Final Report

    NASA Technical Reports Server (NTRS)

    Carol, L. A.

    1985-01-01

    Ternary diffusion in the NiCrAl system at 1200 C was studied with beta + gamma/gamma + gamma prime infinite diffusion couples. Interdiffusion resulted in the formation of complex, multiphase diffusion zones. Concentration/distance profiles for Cr and Al in the phases present in the diffusion zone were measured after 200 hr. The Ni-rich portion of the NiCrAl phase diagram (1200 C) was also determined. From these data, bulk Cr and Al profiles were calculated and translated to diffusion paths on the ternary isotherm. Growth layer kinetics of the layers present in the diffusion zone were also measured.

  12. Combination neutron-gamma ray detector

    DOEpatents

    Stuart, Travis P.; Tipton, Wilbur J.

    1976-10-26

    A radiation detection system capable of detecting neutron and gamma events and distinguishing therebetween. The system includes a detector for a photomultiplier which utilizes a combination of two phosphor materials, the first of which is in the form of small glass beads which scintillate primarily in response to neutrons and the second of which is a plastic matrix which scintillates in response to gammas. A combination of pulse shape and pulse height discrimination techniques is utilized to provide an essentially complete separation of the neutron and gamma events.

  13. Camera Concepts for the Advanced Gamma-Ray Imaging System (AGIS)

    NASA Astrophysics Data System (ADS)

    Nepomuk Otte, Adam

    2009-05-01

    The Advanced Gamma-Ray Imaging System (AGIS) is a concept for the next generation observatory in ground-based very high energy gamma-ray astronomy. Design goals are ten times better sensitivity, higher angular resolution, and a lower energy threshold than existing Cherenkov telescopes. Each telescope is equipped with a camera that detects and records the Cherenkov-light flashes from air showers. The camera is comprised of a pixelated focal plane of blue sensitive and fast (nanosecond) photon detectors that detect the photon signal and convert it into an electrical one. The incorporation of trigger electronics and signal digitization into the camera are under study. Given the size of AGIS, the camera must be reliable, robust, and cost effective. We are investigating several directions that include innovative technologies such as Geiger-mode avalanche-photodiodes as a possible detector and switched capacitor arrays for the digitization.

  14. The Advanced Gamma-ray Imaging System (AGIS): Galactic Astrophysics

    NASA Astrophysics Data System (ADS)

    Digel, Seth William; Funk, S.; Kaaret, P. E.; Tajima, H.; AGIS Collaboration

    2010-03-01

    The Advanced Gamma-ray Imaging System (AGIS), a concept for a next-generation atmospheric Cherenkov telescope array, would provide unprecedented sensitivity and resolution in the energy range >50 GeV, allowing great advances in the understanding of the populations and physics of sources of high-energy gamma rays in the Milky Way. Extrapolation based on the known source classes and the performance parameters for AGIS indicates that a survey of the Galactic plane with AGIS will reveal hundreds of TeV sources in exquisite detail, for population studies of a variety of source classes, and detailed studies of individual sources. AGIS will be able to study propagation effects on the cosmic rays produced by Galactic sources by detecting the diffuse glow from their interactions in dense interstellar gas. AGIS will complement and extend results now being obtained in the GeV range with the Fermi mission, by providing superior angular resolution and sensitivity to variability on short time scales, and of course by probing energies that Fermi cannot reach.

  15. Tissue-equivalent TL sheet dosimetry system for X- and gamma-ray dose mapping.

    PubMed

    Nariyama, N; Konnai, A; Ohnishi, S; Odano, N; Yamaji, A; Ozasa, N; Ishikawa, Y

    2006-01-01

    To measure dose distribution for X- and gamma rays simply and accurately, a tissue-equivalent thermoluminescent (TL) sheet-type dosemeter and reader system were developed. The TL sheet is composed of LiF:Mg,Cu,P and ETFE polymer, and the thickness is 0.2 mm. For the TL reading, a square heating plate, 20 cm on each side, was developed, and the temperature distribution was measured with an infrared thermal imaging camera. As a result, linearity within 2% and the homogeneity within 3% were confirmed. The TL signal emitted is detected using a CCD camera and displayed as a spatial dose distribution. Irradiation using synchrotron radiation between 10 and 100 keV and (60)Co gamma rays showed that the TL sheet dosimetry system was promising for radiation dose mapping for various purposes.

  16. Antidepressant-like effect of atorvastatin in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway.

    PubMed

    Shahsavarian, Arash; Javadi, Shiva; Jahanabadi, Samane; Khoshnoodi, Mina; Shamsaee, Javad; Shafaroodi, Hamed; Mehr, Shahram Ejtemaei; Dehpour, Ahmadreza

    2014-12-15

    Atorvastatin is a synthetic and lipophilic statin which has been reported to have a positive role in reducing depression. The potential antidepressant-like effects of atorvastatin and the possible involvement of peroxisome proliferator-activated receptor gamma (PPAR_γ) and nitric oxide system were determined using forced swimming test (FST) in mice was studied. Atorvastatin (0.01, 0.1 and 1 mg/kg, p.o.) was administered 1 h before FST. To assess the involvement of PPAR_γ in the possible antidepressant effect of atorvastatin, pioglitazone, a PPAR_γ agonist (5 mg/kg), and GW-9662, a specific PPAR_γ antagonist (2 mg/kg), was co-administered with atorvastatin (0.01 mg/kg, p.o.) and then FST was performed. The possible role of nitric oxide pathway was determined by using co-administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.), and a NO precursor, L-arginine (750 mg/kg, i.p.) with sub-effective doses of atorvastatin and pioglitazone. Immobility time was significantly decreased after atorvastatin administration (0.1 and 1 mg/kg, p.o.). Administration of pioglitazone or L-NAME in combination with the sub-effective dose of atorvastatin (0.01 mg/kg, p.o.) reduced the immobility time in the FST compared to drugs alone, showing the participation of these pathways; while co-administration of non-effective doses of atorvastatin and pioglitazone with GW9662 or L-arginine reversed antidepressant-like effect of atorvastatin in FST. Data from concurrent use of GW9662 and atorvastatin also demonstrated that the antidepressant effect of atorvastatin was significantly reversed by GW9662. The antidepressant-like effect of atorvastatin on mice in the FST is mediated at least in part through PPAR_γ receptors and NO pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis.

    PubMed

    Sarruf, David A; Yu, Fang; Nguyen, Hong T; Williams, Diana L; Printz, Richard L; Niswender, Kevin D; Schwartz, Michael W

    2009-02-01

    In addition to increasing insulin sensitivity and adipogenesis, peroxisome proliferator-activated receptor (PPAR)-gamma agonists cause weight gain and hyperphagia. Given the central role of the brain in the control of energy homeostasis, we sought to determine whether PPARgamma is expressed in key brain areas involved in metabolic regulation. Using immunohistochemistry, PPARgamma distribution and its colocalization with neuron-specific protein markers were investigated in rat and mouse brain sections spanning the hypothalamus, the ventral tegmental area, and the nucleus tractus solitarius. In several brain areas, nuclear PPARgamma immunoreactivity was detected in cells that costained for neuronal nuclei, a neuronal marker. In the hypothalamus, PPARgamma immunoreactivity was observed in a majority of neurons in the arcuate (including both agouti related protein and alpha-MSH containing cells) and ventromedial hypothalamic nuclei and was also present in the hypothalamic paraventricular nucleus, the lateral hypothalamic area, and tyrosine hydroxylase-containing neurons in the ventral tegmental area but was not expressed in the nucleus tractus solitarius. To validate and extend these histochemical findings, we generated mice with neuron-specific PPARgamma deletion using nestin cre-LoxP technology. Compared with littermate controls, neuron-specific PPARgamma knockout mice exhibited dramatic reductions of both hypothalamic PPARgamma mRNA levels and PPARgamma immunoreactivity but showed no differences in food intake or body weight over a 4-wk study period. We conclude that: 1) PPARgamma mRNA and protein are expressed in the hypothalamus, 2) neurons are the predominant source of PPARgamma in the central nervous system, although it is likely expressed by nonneuronal cell types as well, and 3) arcuate nucleus neurons that control energy homeostasis and glucose metabolism are among those in which PPARgamma is expressed.

  18. Effect of Gamma Knife Radiosurgery and Programmed Cell Death 1 Receptor Antagonists on Metastatic Melanoma

    PubMed Central

    Hubbard, Molly; Nordmann, Tyler; Sperduto, Paul W; Clark, H. Brent; Hunt, Matthew A

    2017-01-01

    Learning objectives To evaluate radiation-induced changes in patients with brain metastasis secondary to malignant melanoma who received treatment with Gamma Knife radiosurgery (GKRS) and programmed cell death 1 (PD-1) receptor antagonists. Introduction  Stereotactic radiosurgery and chemotherapeutics are used together for treatment of metastatic melanoma and have been linked to delayed radiation-induced vasculitic leukoencephalopathy (DRIVL). There have been reports of more intense interactions with new immunotherapeutics targeting PD-1 receptors, but their interactions have not been well described and may result in an accelerated response to GKRS. Here we present data on subjects treated with this combination from a single institution. Methods Records from patients who underwent treatment for metastatic melanoma to the brain with GKRS from 2011 to 2016 were reviewed. Demographics, date of brain metastasis diagnosis, cause of death when applicable, immunotherapeutics, and imaging findings were recorded. The timing of radiation therapy and medications were also documented.  Results A total of 79 subjects were treated with GKRS, and 66 underwent treatment with both GKRS and immunotherapy. Regarding the 30 patients treated with anti-PD-1 immunotherapy, 21 patients received pembrolizumab, seven patients received nivolumab, and two patients received pembrolizumab and nivolumab. Serial imaging was available for interpretation in 25 patients, with 13 subjects who received GKRS and anti-PD-1 immunotherapy less than six weeks of each other. While four subjects had indeterminate/mixed findings on subsequent magnetic resonance imaging (MRI), nine subjects were noted to have progression. Two of these patients showed progression but subsequent imaging revealed a decrease in progression or improvement on MRI to previously targeted lesions by GKRS. None of the 13 subjects had surgery following their combined therapies. Conclusions This data suggests that there is need for

  19. Future prospects for gamma-ray

    NASA Technical Reports Server (NTRS)

    Fichtel, C.

    1980-01-01

    Astrophysical phenomena discussed are: the very energetic and nuclear processes associated with compact objects; astrophysical nucleo-synthesis; solar particle acceleration; the chemical composition of the planets and other bodies of the solar system; the structure of our galaxy; the origin and dynamic pressure effects of the cosmic rays; the high energy particles and energetic processes in other galaxies, especially active ones; and the degree of matter antimater symmetry of the universe. The gamma ray results of GAMMA-I, the gamma ray observatory, the gamma ray burst network, solar polar, and very high energy gamma ray telescopes on the ground provide justification for more sophisticated telescopes.

  20. First results of electron temperature measurements by the use of multi-pass Thomson scattering system in GAMMA 10

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yoshikawa, M., E-mail: yosikawa@prc.tsukuba.ac.jp; Nagasu, K.; Shimamura, Y.

    2014-11-15

    A multi-pass Thomson scattering (TS) has the advantage of enhancing scattered signals. We constructed a multi-pass TS system for a polarisation-based system and an image relaying system modelled on the GAMMA 10 TS system. We undertook Raman scattering experiments both for the multi-pass setting and for checking the optical components. Moreover, we applied the system to the electron temperature measurements in the GAMMA 10 plasma for the first time. The integrated scattering signal was magnified by approximately three times by using the multi-pass TS system with four passes. The electron temperature measurement accuracy is improved by using this multi-pass system.

  1. First results of electron temperature measurements by the use of multi-pass Thomson scattering system in GAMMA 10.

    PubMed

    Yoshikawa, M; Yasuhara, R; Nagasu, K; Shimamura, Y; Shima, Y; Kohagura, J; Sakamoto, M; Nakashima, Y; Imai, T; Ichimura, M; Yamada, I; Funaba, H; Kawahata, K; Minami, T

    2014-11-01

    A multi-pass Thomson scattering (TS) has the advantage of enhancing scattered signals. We constructed a multi-pass TS system for a polarisation-based system and an image relaying system modelled on the GAMMA 10 TS system. We undertook Raman scattering experiments both for the multi-pass setting and for checking the optical components. Moreover, we applied the system to the electron temperature measurements in the GAMMA 10 plasma for the first time. The integrated scattering signal was magnified by approximately three times by using the multi-pass TS system with four passes. The electron temperature measurement accuracy is improved by using this multi-pass system.

  2. The Advanced Gamma-ray Imaging System (AGIS): Telescope Mechanical Designs

    NASA Astrophysics Data System (ADS)

    Guarino, V.; Buckley, J.; Byrum, K.; Falcone, A.; Fegan, S.; Finley, J.; Hanna, D.; Horan, D.; Kaaret, P.; Konopelko, A.; Krawczynski, H.; Krennrich, F.; Wagner, R.; Woods, M.; Vassiliev, V.

    2008-04-01

    The concept of a future ground-based gamma-ray observatory, AGIS, in the energy range 40 GeV-100 TeV is based on an array of sim 100 imaging atmospheric Cherenkov telescopes (IACTs). The anticipated improvements of AGIS sensitivity, angular resolution and reliability of operation impose demanding technological and cost requirements on the design of IACTs. The relatively inexpensive Davies-Cotton telescope design has been used in ground-based gamma-ray astronomy for almost fifty years and is an excellent option. We are also exploring alternative designs and in this submission we focus on the recent mechanical design of a two-mirror telescope with a Schwarzschild-Couder (SC) optical system. The mechanical structure provides support points for mirrors and camera. The design was driven by the requirement of minimizing the deflections of the mirror support structures. The structure is also designed to be able to slew in elevation and azimuth at 10 degrees/sec.

  3. Localization of beta and gamma subunits of ENaC in sensory nerve endings in the rat foot pad.

    PubMed

    Drummond, H A; Abboud, F M; Welsh, M J

    2000-11-24

    The molecular mechanisms underlying mechanoelectrical transduction and the receptors that detect light touch remain uncertain. Studies in Caenorhabditis elegans suggest that members of the DEG/ENaC cation channel family may be mechanoreceptors. Therefore, we tested the hypothesis that subunits of the mammalian epithelial Na(+) channel (ENaC) family are expressed in touch receptors in rat hairless skin. We detected betaENaC and gammaENaC, but not alphaENaC transcripts in cervical and lumbar dorsal root ganglia (DRG). Using immunofluorescence, we found betaENaC and gammaENaC expressed in medium to large lumbar DRG neurons. Moreover, we detected these two subunits in Merkel cell-neurite complexes, Meissner-like corpuscles, and small lamellated corpuscles, specialized mechanosensory structures of the skin. Within these structures, betaENaC and gammaENaC were localized in the nerve fibers believed to contain the sensors responsive to mechanical stress. Thus beta and gammaENaC subunits are good candidates as components of the molecular sensor that detects touch.

  4. Is lipid signaling through cannabinoid 2 receptors part of a protective system?

    PubMed Central

    Pacher, P.; Mechoulam, R.

    2011-01-01

    The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB2) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, auto-immune, lung disorders to pain and cancer, and modulating CB2 receptor activity holds tremendous therapeutic potential in these pathologies. While CB2 receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB2 receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB2 receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects. PMID:21295074

  5. Is lipid signaling through cannabinoid 2 receptors part of a protective system?

    PubMed

    Pacher, P; Mechoulam, R

    2011-04-01

    The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB₂) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB₂ receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer, and modulating CB₂ receptor activity holds tremendous therapeutic potential in these pathologies. While CB₂ receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB₂ receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB₂ receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects. Published by Elsevier Ltd.

  6. Gamma-enolase: a well-known tumour marker, with a less-known role in cancer

    PubMed Central

    Vizin, Tjasa; Kos, Janko

    2015-01-01

    Background Gamma-enolase, known also as neuron-specific enolase (NSE), is an enzyme of the glycolytic pathway, which is expressed predominantly in neurons and cells of the neuroendocrine system. As a tumour marker it is used in diagnosis and prognosis of cancer; however, the mechanisms enrolling it in malignant progression remain elusive. As a cytoplasmic enzyme gamma-enolase is involved in increased aerobic glycolysis, the main source of energy in cancer cells, supporting cell proliferation. However, different cellular localisation at pathophysiological conditions, proposes other cellular engagements. Conclusions The C-terminal part of the molecule, which is not related to glycolytic pathway, was shown to promote survival of neuronal cells by regulating neuronal growth factor receptor dependent signalling pathways, resulting also in extensive actin cytoskeleton remodelling. This additional function could be important also in cancer cells either to protect cells from stressful conditions and therapeutic agents or to promote tumour cell migration and invasion. Gamma-enolase might therefore have a multifunctional role in cancer progression: it supports increased tumour cell metabolic demands, protects tumour cells from stressful conditions and promotes their invasion and migration. PMID:26401126

  7. Histamine Enhances Theta-Coupled Spiking and Gamma Oscillations in the Medial Entorhinal Cortex Consistent With Successful Spatial Recognition.

    PubMed

    Chen, Quanhui; Luo, Fenlan; Yue, Faguo; Xia, Jianxia; Xiao, Qin; Liao, Xiang; Jiang, Jun; Zhang, Jun; Hu, Bo; Gao, Dong; He, Chao; Hu, Zhian

    2017-06-07

    Encoding of spatial information in the superficial layers of the medial entorhinal cortex (sMEC) involves theta-modulated spiking and gamma oscillations, as well as spatially tuned grid cells and border cells. Little is known about the role of the arousal-promoting histaminergic system in the modification of information encoded in the sMEC in vivo, and how such histamine-regulated information correlates with behavioral functions. Here, we show that histamine upregulates the neural excitability of a significant proportion of neurons (16.32%, 39.18%, and 52.94% at 30 μM, 300 μM, and 3 mM, respectively) and increases local theta (4-12 Hz) and gamma power (low: 25-48 Hz; high: 60-120 Hz) in the sMEC, through activation of histamine receptor types 1 and 3. During spatial exploration, the strength of theta-modulated firing of putative principal neurons and high gamma oscillations is enhanced about 2-fold by histamine. The histamine-mediated increase of theta phase-locking of spikes and high gamma power is consistent with successful spatial recognition. These results, for the first time, reveal possible mechanisms involving the arousal-promoting histaminergic system in the modulation of spatial cognition. Published by Oxford University Press 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  8. GABAB receptor attenuation of GABAA currents in neurons of the mammalian central nervous system.

    PubMed

    Shen, Wen; Nan, Changlong; Nelson, Peter T; Ripps, Harris; Slaughter, Malcolm M

    2017-03-01

    Ionotropic receptors are tightly regulated by second messenger systems and are often present along with their metabotropic counterparts on a neuron's plasma membrane. This leads to the hypothesis that the two receptor subtypes can interact, and indeed this has been observed in excitatory glutamate and inhibitory GABA receptors. In both systems the metabotropic pathway augments the ionotropic receptor response. However, we have found that the metabotropic GABA B receptor can suppress the ionotropic GABA A receptor current, in both the in vitro mouse retina and in human amygdala membrane fractions. Expression of amygdala membrane microdomains in Xenopus oocytes by microtransplantation produced functional ionotropic and metabotropic GABA receptors. Most GABA A receptors had properties of α -subunit containing receptors, with ~5% having ρ -subunit properties. Only GABA A receptors with α -subunit-like properties were regulated by GABA B receptors. In mouse retinal ganglion cells, where only α -subunit-containing GABA A receptors are expressed, GABA B receptors suppressed GABA A receptor currents. This suppression was blocked by GABA B receptor antagonists, G-protein inhibitors, and GABA B receptor antibodies. Based on the kinetic differences between metabotropic and ionotropic receptors, their interaction would suppress repeated, rapid GABAergic inhibition. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  9. Nondestructive Inspection System for Special Nuclear Material Using Inertial Electrostatic Confinement Fusion Neutrons and Laser Compton Scattering Gamma-Rays

    NASA Astrophysics Data System (ADS)

    Ohgaki, H.; Daito, I.; Zen, H.; Kii, T.; Masuda, K.; Misawa, T.; Hajima, R.; Hayakawa, T.; Shizuma, T.; Kando, M.; Fujimoto, S.

    2017-07-01

    A Neutron/Gamma-ray combined inspection system for hidden special nuclear materials (SNMs) in cargo containers has been developed under a program of Japan Science and Technology Agency in Japan. This inspection system consists of an active neutron-detection system for fast screening and a laser Compton backscattering gamma-ray source in coupling with nuclear resonance fluorescence (NRF) method for precise inspection. The inertial electrostatic confinement fusion device has been adopted as a neutron source and two neutron-detection methods, delayed neutron noise analysis method and high-energy neutron-detection method, have been developed to realize the fast screening system. The prototype system has been constructed and tested in the Reactor Research Institute, Kyoto University. For the generation of the laser Compton backscattering gamma-ray beam, a race track microtron accelerator has been used to reduce the size of the system. For the NRF measurement, an array of LaBr3(Ce) scintillation detectors has been adopted to realize a low-cost detection system. The prototype of the gamma-ray system has been demonstrated in the Kansai Photon Science Institute, National Institutes for Quantum and Radiological Science and Technology. By using numerical simulations based on the data taken from these prototype systems and the inspection-flow, the system designed by this program can detect 1 kg of highly enriched 235U (HEU) hidden in an empty 20-ft container within several minutes.

  10. Peroxisome proliferator-activated receptor gamma (PPARγ) in brown trout: Interference of estrogenic and androgenic inputs in primary hepatocytes.

    PubMed

    Lopes, Célia; Madureira, Tânia Vieira; Ferreira, Nádia; Pinheiro, Ivone; Castro, L Filipe C; Rocha, Eduardo

    2016-09-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a pivotal regulator of lipid and glucose metabolism in vertebrates. Here, we isolated and characterized for the first time the PPARγ gene from brown trout (Salmo trutta f. fario). Hormones have been reported to interfere with the regulatory function of PPARγ in various organisms, albeit with little focus on fish. Thus, primary hepatocytes isolated from juveniles of brown trout were exposed to 1, 10 and 50μM of ethinylestradiol (EE2) or testosterone (T). A significant (3 fold) decrease was obtained in response to 50μM of EE2 and to 10 and 50μM of T (13 and 14 folds), while a 3 fold increase was observed at 1μM of EE2. Therefore, trout PPARγ seems a target for natural/synthetic compounds with estrogenic or androgenic properties and so, we advocate considering PPARγ as another alert sensor gene when assessing the effects of sex-steroid endocrine disruptors. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. The structure of control and data transfer management system for the GAMMA-400 scientific complex

    NASA Astrophysics Data System (ADS)

    Arkhangelskiy, A. I.; Bobkov, S. G.; Serdin, O. V.; Gorbunov, M. S.; Topchiev, N. P.

    2016-02-01

    A description of the control and data transfer management system for scientific instrumentation involved in the GAMMA-400 space project is given. The technical capabilities of all specialized equipment to provide the functioning of the scientific instrumentation and satellite support systems are unified in a single structure. Control of the scientific instruments is maintained using one-time pulse radio commands, as well as program commands in the form of 16-bit code words, which are transmitted via onboard control system and scientific data acquisition system. Up to 100 GByte of data per day can be transferred to the ground segment of the project. The correctness of the proposed and implemented structure, engineering solutions and electronic elemental base selection has been verified by the experimental working-off of the prototype of the GAMMA-400 scientific complex in laboratory conditions.

  12. Use of the peroxisome proliferator-activated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study.

    PubMed

    Burstein, Harold J; Demetri, George D; Mueller, Elisabetta; Sarraf, Pasha; Spiegelman, Bruce M; Winer, Eric P

    2003-06-01

    To evaluate the therapeutic effects of the peroxisome proliferator-activated receptor (PPAR) gamma activating ligand, troglitazone, in patients with refractory metastatic breast cancer. Patients with advanced breast cancer refractory to at least one chemotherapy regimen (ER negative tumors) or two hormonal regimens (ER positive tumors) were treated with troglitazone at 800 mg p.o. QD until disease progression, to determine the percentage of patients free of progression at 6 months. Tumor response, toxicity, and changes in serum tumor markers (CEA, CA27.29) that might reflect alteration in tumor differentiation, were also examined. Twenty-two patients were enrolled before suspension of protocol accrual and treatment when troglitazone was withdrawn from commercial availability following FDA warnings on hepatic toxicity. No objective responses (CR or PR) were observed; only three patients had SD at 8 weeks. Patients came off study for PD (16), DLT (1), FDA withdrawal (2), or other (3) reasons. No patients took troglitazone for more than 20 weeks; all had experienced disease progression or began other systemic therapy within 6 months. All patients with elevated serum tumor markers (CEA and CA27.29) at baseline had rising tumor markers within 8 weeks. While clinical trials among different patient populations might uncover subtle effects on tumor differentiation, PPARgamma activation by troglitazone has little apparent clinical value among patients with treatment-refractory metastatic breast cancer.

  13. The agile alert system for gamma-ray transients

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bulgarelli, A.; Trifoglio, M.; Gianotti, F.

    2014-01-20

    In recent years, a new generation of space missions has offered great opportunities for discovery in high-energy astrophysics. In this article we focus on the scientific operations of the Gamma-Ray Imaging Detector (GRID) on board the AGILE space mission. AGILE-GRID, sensitive in the energy range of 30 MeV-30 GeV, has detected many γ-ray transients of both galactic and extragalactic origin. This work presents the AGILE innovative approach to fast γ-ray transient detection, which is a challenging task and a crucial part of the AGILE scientific program. The goals are to describe (1) the AGILE Gamma-Ray Alert System, (2) a newmore » algorithm for blind search identification of transients within a short processing time, (3) the AGILE procedure for γ-ray transient alert management, and (4) the likelihood of ratio tests that are necessary to evaluate the post-trial statistical significance of the results. Special algorithms and an optimized sequence of tasks are necessary to reach our goal. Data are automatically analyzed at every orbital downlink by an alert pipeline operating on different timescales. As proper flux thresholds are exceeded, alerts are automatically generated and sent as SMS messages to cellular telephones, via e-mail, and via push notifications from an application for smartphones and tablets. These alerts are crosschecked with the results of two pipelines, and a manual analysis is performed. Being a small scientific-class mission, AGILE is characterized by optimization of both scientific analysis and ground-segment resources. The system is capable of generating alerts within two to three hours of a data downlink, an unprecedented reaction time in γ-ray astrophysics.« less

  14. The AGILE Alert System for Gamma-Ray Transients

    NASA Astrophysics Data System (ADS)

    Bulgarelli, A.; Trifoglio, M.; Gianotti, F.; Tavani, M.; Parmiggiani, N.; Fioretti, V.; Chen, A. W.; Vercellone, S.; Pittori, C.; Verrecchia, F.; Lucarelli, F.; Santolamazza, P.; Fanari, G.; Giommi, P.; Beneventano, D.; Argan, A.; Trois, A.; Scalise, E.; Longo, F.; Pellizzoni, A.; Pucella, G.; Colafrancesco, S.; Conforti, V.; Tempesta, P.; Cerone, M.; Sabatini, P.; Annoni, G.; Valentini, G.; Salotti, L.

    2014-01-01

    In recent years, a new generation of space missions has offered great opportunities for discovery in high-energy astrophysics. In this article we focus on the scientific operations of the Gamma-Ray Imaging Detector (GRID) on board the AGILE space mission. AGILE-GRID, sensitive in the energy range of 30 MeV-30 GeV, has detected many γ-ray transients of both galactic and extragalactic origin. This work presents the AGILE innovative approach to fast γ-ray transient detection, which is a challenging task and a crucial part of the AGILE scientific program. The goals are to describe (1) the AGILE Gamma-Ray Alert System, (2) a new algorithm for blind search identification of transients within a short processing time, (3) the AGILE procedure for γ-ray transient alert management, and (4) the likelihood of ratio tests that are necessary to evaluate the post-trial statistical significance of the results. Special algorithms and an optimized sequence of tasks are necessary to reach our goal. Data are automatically analyzed at every orbital downlink by an alert pipeline operating on different timescales. As proper flux thresholds are exceeded, alerts are automatically generated and sent as SMS messages to cellular telephones, via e-mail, and via push notifications from an application for smartphones and tablets. These alerts are crosschecked with the results of two pipelines, and a manual analysis is performed. Being a small scientific-class mission, AGILE is characterized by optimization of both scientific analysis and ground-segment resources. The system is capable of generating alerts within two to three hours of a data downlink, an unprecedented reaction time in γ-ray astrophysics.

  15. Peroxisome proliferator-activated receptor gamma and transforming growth factor-beta pathways inhibit intestinal epithelial cell growth by regulating levels of TSC-22.

    PubMed

    Gupta, Rajnish A; Sarraf, Pasha; Brockman, Jeffrey A; Shappell, Scott B; Raftery, Laurel A; Willson, Timothy M; DuBois, Raymond N

    2003-02-28

    Peroxisome proliferator-activated receptor gamma (PPARgamma) and transforming growth factor-beta (TGF-beta) are key regulators of epithelial cell biology. However, the molecular mechanisms by which either pathway induces growth inhibition and differentiation are incompletely understood. We have identified transforming growth factor-simulated clone-22 (TSC-22) as a target gene of both pathways in intestinal epithelial cells. TSC-22 is member of a family of leucine zipper containing transcription factors with repressor activity. Although little is known regarding its function in mammals, the Drosophila homolog of TSC-22, bunched, plays an essential role in fly development. The ability of PPARgamma to induce TSC-22 was not dependent on an intact TGF-beta1 signaling pathway and was specific for the gamma isoform. Localization studies revealed that TSC-22 mRNA is enriched in the postmitotic epithelial compartment of the normal human colon. Cells transfected with wild-type TSC-22 exhibited reduced growth rates and increased levels of p21 compared with vector-transfected cells. Furthermore, transfection with a dominant negative TSC-22 in which both repressor domains were deleted was able to reverse the p21 induction and growth inhibition caused by activation of either the PPARgamma or TGF-beta pathways. These results place TSC-22 as an important downstream component of PPARgamma and TGF-beta signaling during intestinal epithelial cell differentiation.

  16. A role for gamma-glutamyl transpeptidase and the amino acid transport system xc- in cystine transport by a human pancreatic duct cell line.

    PubMed Central

    Sweiry, J H; Sastre, J; Viña, J; Elsässer, H P; Mann, G E

    1995-01-01

    1. The roles of the gamma-glutamyl cycle and the anionic amino acid transport system xc- in mediating L-cystine uptake were investigated in cultured human pancreatic duct PaTu 8902 cells. This cell line exhibits morphological features of normal pancreatic duct cells and expresses gamma-glutamyl transpeptidase (gamma-GT, EC 2.3.2.2), an enzyme involved in the metabolism and regulation of intracellular glutathione (GSH). 2. Uptake of L-cystine (10 microM) was linear for up to 10 min, temperature dependent, Na+ independent, saturable (Michaelis-Menten constant (Km), 86 +/- 25 microM; maximal velocity (Vmax), 109 +/- 33 nmol (mg protein)-1 h-1) and reduced by 80-90% by a 50-fold excess concentration of L-glutamate and L-homocysteic acid, but not L-aspartate. These transport properties resemble those described for system xc-, which exchanges cystine for intracellular glutamate. 3. Acivicin, a known inhibitor of gamma-GT, decreased gamma-GT activity from 2.58 +/- 0.96 to 0.97 +/- 0.11 mU (mg protein)-1 and decreased the initial rates of L-cystine and L-glutamine uptake by 41-55%. Anthglutin (1-gamma-L-glutamyl-2-(2-carboxyphenylhyl)hydrazine), a structurally different inhibitor of gamma-GT, also caused a concentration-dependent (0.01-1 mM) decrease in gamma-GT activity and L-cystine uptake. 4. Neither acivicin nor anthglutin inhibited the uptake of L-glutamate, a poor substrate for gamma-GT. 5. In the presence of a 500-fold excess concentration of glutamate, which should abolish entry of cystine via system xc-, the remaining fraction of cystine transport was inhibited by 50% by acivicin, suggesting that transport is, in part, dependent on the activity of gamma-GT. 6. Cystine transport was also 60-80% inhibited by a series of gamma-glutamyl amino acids (5 mM) including gamma-glutamyl-glutamate, gamma-glutamyl-glutamine and gamma-glutamyl-glycine. alpha-Dipeptides inhibited cystine transport by only 6-22%. 7. These findings demonstrate that in human pancreatic duct Pa

  17. Effects of guanyl nucleotides on CCKB receptor binding in brain tissue and continuous cell lines: a comparative study.

    PubMed

    Kaufmann, R; Schöneberg, T; Henklein, P; Meyer, R; Martin, H; Ott, T

    1995-07-01

    The effects of non-hydrolyzable guanyl nucleotide analogue GTP-gamma S on CCKB receptor binding in human and guinea-pig cortex, Jurkat T-cells, rat pituitary GH3 cells, rat glioma C6 cells and human small cell lung cancer NCI-H69 cells were investigated by using [3H]CCK-8S saturation and competition binding studies. GTP-gamma S caused inhibition of specific [3H]CCK-8S binding in a concentration dependent manner with a plateau at 10-25 microM. 25 microM GTP-gamma S resulted in a small but significant increase in Kd and IC50 values with amount very similar in all CCKB receptor models tested. However, the maximal number of specific [3H]CCK-8S binding sites (Bmax) was unaffected. Results suggest that CCKB receptors are G-protein coupled in a similar way to human and guinea-pig cortex, Jurkat cells, GH3 cells, C6 cells and NCI-H69 cells.

  18. IgA Fc receptors.

    PubMed

    Monteiro, Renato C; Van De Winkel, Jan G J

    2003-01-01

    The IgA receptor family comprises a number of surface receptors including the polymeric Ig receptor involved in epithelial transport of IgA/IgM, the myeloid specific IgA Fc receptor (FcalphaRI or CD89), the Fcalpha/muR, and at least two alternative IgA receptors. These are the asialoglycoprotein receptor and the transferrin receptor, which have been implicated in IgA catabolism, and tissue IgA deposition. In this review we focus on the biology of FcalphaRI (CD89). FcalphaRI is expressed on neutrophils, eosinophils, monocytes/macrophages, dendritic cells, and Kupffer cells. This receptor represents a heterogeneously glycosylated transmembrane protein that binds both IgA subclasses with low affinity. A single gene encoding FcalphaRI has been isolated, which is located within the leukocyte receptor cluster on chromosome 19. The FcalphaRI alpha chain lacks canonical signal transduction domains but can associate with the FcR gamma-chain that bears an activation motif (ITAM) in the cytoplasmic domain, allowing activatory functions. FcalphaRI expressed alone mediates endocytosis and recyling of IgA. No FcalphaRI homologue has been defined in the mouse, and progress in defining the in vivo role of FcalphaRI has been made using human FcalphaRI transgenic (Tg) mice. FcalphaRI-Tg mice demonstrated FcalphaRI expression on Kupffer cells and so defined a key role for the receptor in mucosal defense. The receptor functions as a second line of antibacterial defense involving serum IgA rather than secretory IgA. Studies in FcalphaRI-Tg mice, furthermore, defined an essential role for soluble FcalphaRI in the development of IgA nephropathy by formation of circulating IgA-FcalphaRI complexes. Finally, recent work points out a role for human IgA in treatment of infectious and neoplastic diseases.

  19. Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nitz, Inke; Ewert, Agnes; Klapper, Maja

    2007-02-09

    Peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1{alpha} gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-{gamma} 2 (PPAR{gamma}2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1{alpha}more » and PPAR{gamma}2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is First study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1{alpha} and Pro12Ala polymorphism in PPAR{gamma}2 do not affect the functional integrity of these proteins.« less

  20. Sizing up the population of gamma-ray binaries

    NASA Astrophysics Data System (ADS)

    Dubus, Guillaume; Guillard, Nicolas; Petrucci, Pierre-Olivier; Martin, Pierrick

    2017-12-01

    Context. Gamma-ray binaries are thought to be composed of a young pulsar in orbit around a massive O or Be star with their gamma-ray emission powered by pulsar spin-down. The number of such systems in our Galaxy is not known. Aims: We aim to estimate the total number of gamma-ray binaries in our Galaxy and to evaluate the prospects for new detections in the GeV and TeV energy range, taking into account that their gamma-ray emission is modulated on the orbital period. Methods: We modelled the population of gamma-ray binaries and evaluated the fraction of detected systems in surveys with the Fermi-LAT (GeV), H.E.S.S., HAWC and CTA (TeV) using observation-based and synthetic template light curves. Results: The detected fraction depends more on the orbit-average flux than on the light-curve shape. Our best estimate for the number of gamma-ray binaries is 101-52+89 systems. A handful of discoveries are expected by pursuing the Fermi-LAT survey. Discoveries in TeV surveys are less likely. However, this depends on the relative amounts of power emitted in GeV and TeV domains. There could be as many as ≈ 200 HESS J0632+057-like systems with a high ratio of TeV to GeV emission compared to other gamma-ray binaries. Statistics allow for as many as three discoveries in five years of HAWC observations and five discoveries in the first two years of the CTA Galactic Plane survey. Conclusions: We favour continued Fermi-LAT observations over ground-based TeV surveys to find new gamma-ray binaries. Gamma-ray observations are most sensitive to short orbital period systems with a high spin-down pulsar power. Radio pulsar surveys (SKA) are likely to be more efficient in detecting long orbital period systems, providing a complementary probe into the gamma-ray binary population.

  1. Gadolinium-doped water cerenkov-based neutron and high energy gamma-ray detector and radiation portal monitoring system

    DOEpatents

    Dazeley, Steven A; Svoboda, Robert C; Bernstein, Adam; Bowden, Nathaniel

    2013-02-12

    A water Cerenkov-based neutron and high energy gamma ray detector and radiation portal monitoring system using water doped with a Gadolinium (Gd)-based compound as the Cerenkov radiator. An optically opaque enclosure is provided surrounding a detection chamber filled with the Cerenkov radiator, and photomultipliers are optically connected to the detect Cerenkov radiation generated by the Cerenkov radiator from incident high energy gamma rays or gamma rays induced by neutron capture on the Gd of incident neutrons from a fission source. The PMT signals are then used to determine time correlations indicative of neutron multiplicity events characteristic of a fission source.

  2. Design and Optimization of a Dual-HPGe Gamma Spectrometer and Its Cosmic Veto System

    NASA Astrophysics Data System (ADS)

    Zhang, Weihua; Ro, Hyunje; Liu, Chuanlei; Hoffman, Ian; Ungar, Kurt

    2017-03-01

    In this paper, a dual high purity germanium (HPGe) gamma spectrometer detection system with an increased solid angle was developed. The detection system consists of a pair of Broad Energy Germanium (BE-5030p) detectors and an XIA LLC digital gamma finder/Pixie-4 data-acquisition system. A data file processor was developed containing five modules that parses Pixie-4 list-mode data output files and classifies detections into anticoincident/coincident events and their specific coincidence types (double/triple/quadruple) for further analysis. A novel cosmic veto system was installed in the detection system. It was designed to be easy to install around an existing system while still providing sufficient cosmic veto shielding comparable to other designs. This paper describes the coverage and efficiency of this cosmic veto and the data processing system. It has been demonstrated that the cosmic veto system can provide a mean background reduction of 66.1%, which results in a mean MDA improvement of 58.3%. The counting time to meet the required MDA for specific radionuclide can be reduced by a factor of 2-3 compared to those using a conventional HPGe system. This paper also provides an initial overview of coincidence timing distributions between an incoming event from a cosmic veto plate and HPGe detector.

  3. Imaging system for cardiac planar imaging using a dedicated dual-head gamma camera

    DOEpatents

    Majewski, Stanislaw [Morgantown, VA; Umeno, Marc M [Woodinville, WA

    2011-09-13

    A cardiac imaging system employing dual gamma imaging heads co-registered with one another to provide two dynamic simultaneous views of the heart sector of a patient torso. A first gamma imaging head is positioned in a first orientation with respect to the heart sector and a second gamma imaging head is positioned in a second orientation with respect to the heart sector. An adjustment arrangement is capable of adjusting the distance between the separate imaging heads and the angle between the heads. With the angle between the imaging heads set to 180 degrees and operating in a range of 140-159 keV and at a rate of up to 500kHz, the imaging heads are co-registered to produce simultaneous dynamic recording of two stereotactic views of the heart. The use of co-registered imaging heads maximizes the uniformity of detection sensitivity of blood flow in and around the heart over the whole heart volume and minimizes radiation absorption effects. A normalization/image fusion technique is implemented pixel-by-corresponding pixel to increase signal for any cardiac region viewed in two images obtained from the two opposed detector heads for the same time bin. The imaging system is capable of producing enhanced first pass studies, bloodpool studies including planar, gated and non-gated EKG studies, planar EKG perfusion studies, and planar hot spot imaging.

  4. Telmisartan, an AT1 receptor blocker and a PPAR gamma activator, alleviates liver fibrosis induced experimentally by Schistosoma mansoni infection.

    PubMed

    Attia, Yasmeen M; Elalkamy, Essam F; Hammam, Olfat A; Mahmoud, Soheir S; El-Khatib, Aiman S

    2013-07-05

    Hepatic schistosomiasis is considered to be one of the most prevalent forms of chronic liver disease in the world due to its complication of liver fibrosis. The demonstration of the pro-fibrogenic role of angiotensin (Ang) II in chronic liver disease brought up the idea that anti-Ang II agents may be effective in improving hepatic fibrosis by either blocking Ang II type 1 (AT1) receptors or inhibiting the angiotensin converting enzyme. Peroxisome proliferator-activated receptors gamma (PPARγ) activation has been also shown to inhibit hepatic stellate cell activation and progression of fibrosis. The present study has aimed at testing the anti-fibrogenic effects of telmisartan; an AT1 receptor blocker and a PPARγ partial agonist, alone or combined with praziquantel (PZQ) on Schistosoma mansoni-induced liver fibrosis in mice. To achieve the aim of the study, two sets of experiments were performed in which telmisartan was initiated at the 5th (set 1) and the 10th (set 2) weeks post infection to assess drug efficacy in both acute and chronic stages of liver fibrosis, respectively. Schistosoma mansoni-infected mice were randomly divided into the following four groups: infected-control (I), telmisartan-treated (II), PZQ-treated (III), and telmisartan+PZQ-treated (IV). In addition, a normal non-infected group was used for comparison. Parasitological (hepatomesenteric worm load and oogram pattern), histopathological, morphometric, immunohistochemical (hepatic expressions of matrix metalloproteinase-2; MMP-2 and tissue inhibitor of metalloproteinase-2; TIMP-2), and biochemical (serum transforming growth factor beta 1; TGF-β1 and liver function tests) studies were performed. Telmisartan failed to improve the parasitological parameters, while it significantly (P<0.05) decreased the mean granuloma diameter, area of fibrosis, and serum TGF-β1. Additionally, telmisartan increased MMP-2 and decreased TIMP-2 hepatic expression. Combined treatment failed to show any additive

  5. The challenges of modulating the 'rest and digest' system: acetylcholine receptors as drug targets.

    PubMed

    VanPatten, Sonya; Al-Abed, Yousef

    2017-01-01

    Acetylcholine, a major neurotransmitter of the parasympathetic and sympathetic nervous systems, was discovered in the early 1900s. Over the years, researchers have revealed much about its regulation, properties of its receptors and features of the downstream signaling that influence its terminal effects. The acetylcholine system, traditionally associated with neuromuscular communication, is now known to play a crucial part in modulation of the immune system and other 'rest and digest' effects. Recent research seeks to elucidate the system's role in brain functions including cognition, sleep, arousal, motivation, reward and pain. We highlight clinically approved and experimental drugs that modulate the acetylcholine receptors. The complexities in targeting the acetylcholine receptors are vast and finding future indications for drug development associated with specific acetylcholine receptors remains a challenge. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Anticonvulsant properties of alpha, gamma, and alpha, gamma-substituted gamma-butyrolactones.

    PubMed

    Klunk, W E; Covey, D F; Ferrendelli, J A

    1982-09-01

    Derivatives of gamma-butyrolactone (GBL) substituted on the alpha- and/or gamma-positions were synthesized and tested for their effects on behavior in mice, on the electroencephalographs and blood pressure of paralyzed-ventilated guinea pigs, and on electrical activity of incubated hippocampal slices. Several compounds, including alpha-ethyl-alpha-methyl GBL (alpha-EMGBL), alpha, alpha-dimethyl GBL, alpha, gamma-diethyl-alpha, gamma-dimethyl GBL, and gamma-ethyl-gamma-methyl GBL, prevented seizures induced by pentylenetetrazol, beta-ethyl-beta-methyl-gamma-butyrolactone (beta-EMGBL), picrotoxin, or all three compounds in mice and guinea pigs but had no effect on seizures induced by maximal electroshock or bicuculline. Neither gamma-hydroxybutyrate (GHB) nor alpha-isopropylidine GBL had any anticonvulsant activity. The anticonvulsant alpha-substituted compounds had a potent hypotensive effect and antagonized the hypertensive effect of beta-EMGBL, alpha-EMGBL was tested in incubated hippocampal slices and was found to depress basal activity and antagonize excitation induced by beta-EMGBL. These results demonstrate that alpha-alkyl-substituted GBL and, to a lesser extent, gamma-substituted derivatives are anticonvulsant agents and that their effects are strikingly different from those of GHB or beta-alkyl-substituted GBLs, which are epileptogenic. Possibly beta- and alpha-substituted GBLs act at the same site as agonists and antagonists, respectively.

  7. The scientific data acquisition system of the GAMMA-400 space project

    NASA Astrophysics Data System (ADS)

    Bobkov, S. G.; Serdin, O. V.; Gorbunov, M. S.; Arkhangelskiy, A. I.; Topchiev, N. P.

    2016-02-01

    The description of scientific data acquisition system (SDAS) designed by SRISA for the GAMMA-400 space project is presented. We consider the problem of different level electronics unification: the set of reliable fault-tolerant integrated circuits fabricated on Silicon-on-Insulator 0.25 mkm CMOS technology and the high-speed interfaces and reliable modules used in the space instruments. The characteristics of reliable fault-tolerant very large scale integration (VLSI) technology designed by SRISA for the developing of computation systems for space applications are considered. The scalable net structure of SDAS based on Serial RapidIO interface including real-time operating system BAGET is described too.

  8. Effect of the feeding system on the fatty acid composition, expression of the Δ9-desaturase, Peroxisome Proliferator-Activated Receptor Alpha, Gamma, and Sterol Regulatory Element Binding Protein 1 genes in the semitendinous muscle of light lambs of the Rasa Aragonesa breed

    PubMed Central

    2010-01-01

    Background Conjugated linoleic acids (CLAs) are receiving increasing attention because of their beneficial effects on human health, with milk and meat products derived from ruminants as important sources of CLA in the human diet. SCD gene is responsible for some of the variation in CLA concentration in adipose tissues, and PPARγ, PPARα and SREBP1 genes are regulator of SCD gene. The aim of this work was to evaluate the effect of the feeding system on fatty acid composition, CLA content and relative gene expression of Δ9-desaturase (SCD), Peroxisome Proliferator-Activated Receptor Gamma (PPARγ), Peroxisome Proliferator-Activated Receptor Alpha, (PPARα) and Sterol Regulatory Element Binding Protein (SREBP1) in Rasa Aragonesa light lambs in semitendinous muscle. Forty-four single-born male lambs were used to evaluate the effect of the feeding system, varying on an intensity gradient according to the use of concentrates: 1. grazing alfalfa, 2. grazing alfalfa with a supplement for lambs, 3. indoor lambs with grazing ewes and 4. drylot. Results Both grazing systems resulted in a higher concentration of vaccenic acid (VA), CLA, CLA/VA acid ratio, and a lower oleic content, oleic acid (C18:1)/stearic acid (C18:0) ratio, PUFA n-6/n-3 ratio and SCD expression compared to other diets. In addition feeding system affected the fatty acid composition and SCD expression, possibly due to CLA concentration or the PUFA n-6/n-3 ratio. Both expression of the SCD gene and the feeding system were important factors affecting CLA concentration in the animal's semitendinous muscle. PPARγ, PPARα and SREBP1 expression seemed to be unaffected by the feeding system. Although no significant results were found, PPARγ, PPARα and SREBP1 showed similar expression pattern as SCD. Moreover, the correlation results between SCD expression and PPARγ (p < 0.01), as well as SREBP1 (p < 0.01) expression, may suggest that these genes were affecting SCD expression in a different way. Conclusions

  9. Irbesartan increased PPAR{gamma} activity in vivo in white adipose tissue of atherosclerotic mice and improved adipose tissue dysfunction

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Iwai, Masaru; Kanno, Harumi; Senba, Izumi

    2011-03-04

    Research highlights: {yields} Atherosclerotic apolipoprotein E-deficient (ApoEKO) mice were treated with irbesartan. {yields} Irbesartan decreased white adipose tissue weight without affecting body weight. {yields} DNA-binding for PPAR{gamma} was increased in white adipose tissue in vivo by irbesartan. {yields} Irbesartan increased adipocyte number in white adipose tissue. {yields} Irbesatan increased the expression of adiponectin and leptin in white adipose tissue. -- Abstract: The effect of the PPAR{gamma} agonistic action of an AT{sub 1} receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with amore » high-cholesterol diet (HCD) with or without irbesartan at a dose of 50 mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPAR{gamma} in white adipose tissue and the DNA-binding activity of PPAR{gamma} in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPAR{gamma} and improved adipose tissue dysfunction including insulin resistance.« less

  10. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody

    DTIC Science & Technology

    2014-05-01

    in May 2013, the difference between nude mice (which lack T- cells , but still have a partially functional adaptive and innate immune system) and NSG...Mangada J, Greiner DL, Handgretinger R. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human...Targeting of Cerebral Breast Cancer Metastases Using a T- Cell Receptor Mimic Antibody PRINCIPAL INVESTIGATOR: Ulrich Bickel

  11. Pattern of cytokine receptors expressed by human dendritic cells migrated from dermal explants.

    PubMed Central

    Larregina, A T; Morelli, A E; Kolkowski, E; Sanjuan, N; Barboza, M E; Fainboim, L

    1997-01-01

    Different reasons account for the lack of information about the expression of cytokine receptors on human dendritic cells (DC): (a) DC are a trace population; (b) the proteolytic treatment used to isolate DC may alter enzyme-sensitive epitopes; and (c) low numbers of receptors per cell. In the present work the expression of cytokine receptors was analysed by flow cytometry on the population of dermal DC (DDC) that spontaneously migrate from short-term culture dermal explants. DDC obtained after dermal culture were CD1alow, CD1b+, CD1c+, human leucocyte antigen (HLA)-DR+, CD11chigh, CD11b+ and CD32+. The DC lineage was confirmed by ultrastructural analysis. DDC expressed interleukin (IL)-1R type 1 (monoclonal antibody (mAb) hIL-1R1-M1; and 6B5); IL-1R type 2 (mAb hIL-1R2-M22); IL-2R alpha chain (mAb anti-Tac; and hIL-2R-M1) and IL-2R gamma chain (mAb 3B5; and AG14C). DDC did not stain for IL-2R beta chain using four mAbs recognizing two different epitopes of IL-2R beta (mAb 2R-B; Mik-beta 1; and CF1; Mik-beta 3, respectively). DDC were also positive for the cytokine binding chains (alpha chains) of IL-3R (mAb 9F5); IL-4R (mAb hIL-4R-M57; and S456C9); and IL-7R (mAb hIL-7R-M20; and R3434). DDC showed low levels of IL-6R alpha chain (mAb B-F19; B-R6; and B-E23) and its signal transducer gp130 (mAb A2; and B1). DDC strongly expressed interferon-gamma receptor (IFN-gamma R) (mAb GIR-208) and were negative for IL-8R (mAb B-G20; and B-F25). All DDC were highly positive for granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) alpha chain (mAb hGM-CSFR-M1; SC06; SC04, and 8G6) and to a lesser extent for the common beta chain of GM-CSFR, IL-3R and IL-5R (mAb 3D7). On the other hand, reactivity was not found for granulocyte colony-stimulating factor receptor (G-CSFR) (mAb hGCSFR-M1) nor macrophage colony-stimulating factor receptor (M-CSFR) (mAb 7-7A3-17) confirming the DC lineage of DDC. As previously reported for lymphoid DC, DDC expressed tumour necrosis

  12. Highlights of GeV Gamma-Ray Astronomy

    NASA Technical Reports Server (NTRS)

    Thompson, David J.

    2010-01-01

    Because high-energy gamma rays are primarily produced by high-energy particle interactions, the gamma-ray survey of the sky by the Fermi Gamma-ray Space Telescope offers a view of sites of cosmic ray production and interactions. Gamma-ray bursts, pulsars, pulsar wind nebulae, binary sources, and Active Galactic Nuclei are all phenomena that reveal particle acceleration through their gamma-ray emission. Diffuse Galactic gamma radiation, Solar System gamma-ray sources, and energetic radiation from supernova remnants are likely tracers of high-energy particle interactions with matter and photon fields. This paper will present a broad overview of the constantly changing sky seen with the Large Area Telescope (LAT) on the Fermi spacecraft.

  13. Hard gamma radiation background from coding collimator of gamma telescope under space experiment conditions

    NASA Astrophysics Data System (ADS)

    Aleksandrov, A. P.; Berezovoy, A. N.; Galper, A. M.; Grachev, V. M.; Dmitrenko, V. V.; Kirillov-Ugryumov, V. G.; Lebedev, V. V.; Lyakhov, V. A.; Moiseyev, A. A.; Ulin, S. Y.

    1985-09-01

    Coding collimators are used to improve the angular resolution of gamma-ray telescopes at energies above 50 MeV. However, the interaction of cosmic rays with the collimation material can lead to the appearance of a gamma-ray background flux which can have a deleterious effect on measurement efficiency. An experiment was performed on the Salyut-6-Soyuz spacecraft system with the Elena-F small-scale gamma-ray telescope in order to measure the magnitude of this background. It is shown that, even at a zenith angle of approximately zero degrees (the angle at which the gamma-ray observations are made), the coding collimator has only an insignificant effect on the background conditions.

  14. Formation of gamma'-Ni3Al via the Peritectoid Reaction: gamma plus beta (+Al2O3) equals gamma'(+Al2O3)

    NASA Technical Reports Server (NTRS)

    Copland, Evan

    2008-01-01

    The activities of Al and Ni were measured using multi-cell Knudsen effusion-cell mass spectrometry (multi-cell KEMS), over the composition range 8 - 32 at.%Al and temperature range T = 1400 - 1750 K in the Ni-Al-O system. These measurements establish that equilibrium solidification of gamma'-Ni3Al-containing alloys occurs by the eutectic reaction, L (+ Al2O3) = gamma + beta (+ Al2O3), at 1640 plus or minus 1 K and a liquid composition of 24.8 plus or minus 0.2 at.%Al (at an unknown oxygen content). The {gamma + beta + Al2O3} phase field is stable over the temperature range 1633 - 1640 K, and gamma'-Ni3Al forms via the peritectiod, gamma + beta (+ Al2O3) = gamma'(+ Al2O3), at 1633 plus or minus 1 K. This behavior is inconsistent with the current Ni-Al phase diagram and a new diagram is proposed. This new Ni-Al phase diagram explains a number of unusual steady state solidification structures reported previously and provides a much simpler reaction scheme in the vicinity of the gamma'-Ni3Al phase field.

  15. Fieldable computer system for determining gamma-ray pulse-height distributions, flux spectra, and dose rates from Little Boy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Moss, C.E.; Lucas, M.C.; Tisinger, E.W.

    1984-01-01

    Our system consists of a LeCroy 3500 data acquisition system with a built-in CAMAC crate and eight bismuth-germanate detectors 7.62 cm in diameter and 7.62 cm long. Gamma-ray pulse-height distributions are acquired simultaneously for up to eight positions. The system was very carefully calibrated and characterized from 0.1 to 8.3 MeV using gamma-ray spectra from a variety of radioactive sources. By fitting the pulse-height distributions from the sources with a function containing 17 parameters, we determined theoretical repsonse functions. We use these response functions to unfold the distributions to obtain flux spectra. A flux-to-dose-rate conversion curve based on the workmore » of Dimbylow and Francis is then used to obtain dose rates. Direct use of measured spectra and flux-to-dose-rate curves to obtain dose rates avoids the errors that can arise from spectrum dependence in simple gamma-ray dosimeter instruments. We present some gamma-ray doses for the Little Boy assembly operated at low power. These results can be used to determine the exposures of the Hiroshima survivors and thus aid in the establishment of radation exposure limits for the nuclear industry.« less

  16. SU-E-T-117: Analysis of the ArcCHECK Dosimetry Gamma Failure Using the 3DVH System

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cho, S; Choi, W; Lee, H

    2015-06-15

    Purpose: To evaluate gamma analysis failure for the VMAT patient specific QA using ArcCHECK cylindrical phantom. The 3DVH system(Sun Nuclear, FL) was used to analyze the dose difference statistic between measured dose and treatment planning system calculated dose. Methods: Four case of gamma analysis failure were selected retrospectively. Our institution gamma analysis indexes were absolute dose, 3%/3mm and 90%pass rate in the ArcCHECK dosimetry. The collapsed cone convolution superposition (CCCS) dose calculation algorithm for VMAT was used. Dose delivery was performed with Elekta Agility. The A1SL(standard imaging, WI) and cavity plug were used for point dose measurement. Delivery QA plansmore » and images were used for 3DVH Reference data instead of patient plan and image. The measured data of ‘.txt’ file was used for comparison at diodes to acquire a global dose level. The,.acml’ file was used for AC-PDP and to calculated point dose. Results: The global dose of 3DVH was calculated as 1.10 Gy, 1.13, 1.01 and 0.2 Gy respectively. The global dose of 0.2 Gy case was induced by distance discrepancy. The TPS calculated point dose of was 2.33 Gy to 2.77 Gy and 3DVH calculated dose was 2.33 Gy to 2.68 Gy. The maximum dose differences were −2.83% and −3.1% for TPS vs. measured dose and TPS vs. 3DVH calculated respectively in the same case. The difference between measured and 3DVH was 0.1% in that case. The 3DVH gamma pass rate was 98% to 99.7%. Conclusion: We found the TPS calculation error by 3DVH calculation using ArcCHECK measured dose. It seemed that our CCCS algorithm RTP system over estimated at the central region and underestimated scattering at the peripheral diode detector point. The relative gamma analysis and point dose measurement would be recommended for VMAT DQA in the gamma failure case of ArcCHECK dosimetry.« less

  17. Expression of group III metabotropic glutamate receptors in the reproductive system of male mice.

    PubMed

    Marciniak, Marcin; Chruścicka, Barbara; Lech, Tomasz; Burnat, Grzegorz; Pilc, Andrzej

    2016-03-01

    Although the presence of metabotropic glutamate (mGlu) receptors in the central nervous system is well documented, they have recently been found in peripheral and non-neuronal tissues. In the present study we investigated the expression of group III mGlu receptors in the reproductive system of male mice. Reverse transcription-polymerase chain reaction analysis revealed the presence of mGlu6, mGlu7 and mGlu8 (but not mGlu4) receptor transcripts in testes and epididymides from adult mice. In addition, expression of mGlu6 (Grm6) and mGlu8 receptor (Grm8) mRNA was detected in spermatozoa isolated from the vas deferens. The vas deferens was found to contain only mGlu7 receptor (Grm7) mRNA, which was particularly intense in 21-day-old male mice. In penile homogenates, only the mGlu7 receptor signal was detected. Genetic ablation of the mGlu7 receptor in males led to fertility disorders manifested by decreased insemination capability as well as deterioration of sperm parameters, particularly sperm motility, vitality, sperm membrane integrity and morphology, with a simultaneous increase in sperm concentration. These results indicate that constitutively expressed mGlu receptors in the male reproductive system may play an important role in ejaculation and/or erection processes, as well as in the formation and maturation of spermatozoa.

  18. The Advanced Gamma-ray Imaging System (AGIS) Telescope Optical System Designs

    NASA Astrophysics Data System (ADS)

    Bugaev, V.; Buckley, J.; Diegel, S.; Falcone, A.; Fegan, S.; Finley, J.; Guarino, V.; Hanna, D.; Kaaret, P.; Konopelko, A.; Krawczynski, H.; Ramsey, B.; Romani, R.; Vassiliev, V.; Weekes, T.

    2008-12-01

    AGIS is a conceptual design for a future ground-based gamma-ray observatory operating in the energy range 25 GeV-100 TeV, which is based on an array of ~20-100 imaging atmospheric Cherenkov telescopes (IACTs). The desired improvement in sensitivity, angular resolution, and reliability of operation of AGIS imposes demanding technological and cost requirements on the design of the IACTs. We are considering several options for the optical system (OS) of the AGIS telescopes, which include the traditional Davies-Cotton design as well as novel two-mirror design. Emerging mirror production technologies based on replication processes such as cold and hot glass slumping, cured carbon fiber reinforced plastic (CFRP), and electroforming provide new opportunities for cost-effective solutions for the design of the OS.

  19. Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates.

    PubMed Central

    Pandey, S C; Davis, J M; Pandey, G N

    1995-01-01

    Serotonergic neurotransmission represents a complex mechanism involving pre- and post-synaptic events and distinct 5-HT receptor subtypes. Serotonin (5-HT) receptors have been classified into several categories, and they are termed as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 type receptors. 5-HT1 receptors have been further subdivided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. 5-HT2 receptors have been divided into 5-HT2A, 5-HT2B and 5-HT2C receptors. All 5-HT2 receptor subtypes are linked to the multifunctional phosphoinositide (PI) signalling system. 5-HT3 receptors are considered ion-gated receptors and are also linked to the PI signalling system by an unknown mechanism. The 5-HT2A receptor subtype is the most widely studied of the 5-HT receptors in psychiatric disorders (for example, suicide, depression and schizophrenia) as well as in relation to the mechanism of action of antidepressant drugs. The roles of 5-HT2C and 5-HT3 receptors in psychiatric disorders are less clear. These 5-HT receptors also play an important role in alcoholism. It has been shown that 5-HT2A, 5-HT2C and 5-HT3 antagonists cause attenuation of alcohol intake in animals and humans. However, the exact mechanisms are unknown. The recent cloning of the cDNAs for 5-HT2A, 5-HT2C and 5-HT3 receptors provides the opportunity to explore the molecular mechanisms responsible for the alterations in these receptors during illness as well as pharmacotherapy. This review article will focus on the current research into the pharmacological properties, molecular biology, and clinical correlates of 5-HT2A, 5-HT2C and 5-HT3 receptors. PMID:7786883

  20. Fermi Gamma-Ray Space Telescope

    NASA Technical Reports Server (NTRS)

    McEnery, Julie E.; Michelson, Peter F.; Paclesas, William S.; Ritz, Steven

    2012-01-01

    The Fermi Gamma-ray Space Telescope, launched in June 2008, is an observatory designed to survey the high-energy gamma-ray sky. The primary instrument, the Large Area Telescope (LAT), provides observations from 20 MeV to greater than 300 GeV. A second instrument, the Gamma-ray Burst Monitor (GBM), provides observations of transients from less than 10 keV to 40 MeV. We describe the design and performance of the instruments and their subsystems, the spacecraft and the ground system.

  1. The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease.

    PubMed

    Guri, Amir J; Mohapatra, Saroj K; Horne, William T; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-06-10

    Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR gamma in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD. PPAR gamma flfl; CD4 Cre+ (CD4cre) or Cre- (WT) mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. The deficiency of PPAR gamma in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+ FoxP3+ regulatory T cells (Treg) and IL10+ CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6) and IL-1beta, and suppressor of cytokine signaling 3 (SOCS-3) on day 7. Gene set enrichment analysis (GSEA) showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR gamma in T cells. The expression of PPAR gamma in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment of Treg to the mucosal inductive

  2. [The interaction between gamma-aminobutyric acid and other related neurotransmitters in depression].

    PubMed

    Li, Zhen; An, Shu-Cheng; Li, Jiang-Na

    2014-06-01

    Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system (CNS) in mammalian, which involved in several mood disorders such as anxiety, depression and schizophrenia. Nowadays, there are growing evidences showed that the depression is concerned with a deficiency in brain GABA. However, there are numerous studies based on the monoamine hypothesis and glutamatergic dysfunction, while the study on GABA is relatively less and scattered. Our aim is to discuss the relationship between depression and GABA by introducing the role of GABA receptors and the interaction between GABA and 5-hydroxytryptamine, dopamine and glutamic acid. It provides new ideas for further study on the pathogenesis and therapy of depression.

  3. Histaminergic and serotonergic receptor blocking substances from the medicinal plant Garcinia mangostana.

    PubMed

    Chairungsrilerd, N; Furukawa, K; Ohta, T; Nozoe, S; Ohizumi, Y

    1996-10-01

    A crude methanolic extract of the fruit hull of Mangosteen, Garcinia mangostana L. inhibited the contractions of isolated thoracic rabbit aorta induced by histamine and serotonin. The extract of the fruit hull has been fractionated by silica gel chromatography, monitoring the pharmacological activity to give alpha- and gamma-mangostin. On the basis of pharmacological data, it is suggested that alpha-mangostin and gamma-mangostin are a histaminergic and a serotonergic receptor blocking agent, respectively.

  4. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes.

    PubMed

    Kotenko, S V; Izotova, L S; Mirochnitchenko, O V; Esterova, E; Dickensheets, H; Donnelly, R P; Pestka, S

    2001-01-26

    Interleukin-10 (IL-10)-related T cell-derived inducible factor (IL-TIF; provisionally designated IL-22) is a cytokine with limited homology to IL-10. We report here the identification of a functional IL-TIF receptor complex that consists of two receptor chains, the orphan CRF2-9 and IL-10R2, the second chain of the IL-10 receptor complex. Expression of the CRF2-9 chain in monkey COS cells renders them sensitive to IL-TIF. However, in hamster cells both chains, CRF2-9 and IL-10R2, must be expressed to assemble the functional IL-TIF receptor complex. The CRF2-9 chain (or the IL-TIF-R1 chain) is responsible for Stat recruitment. Substitution of the CRF2-9 intracellular domain with the IFN-gammaR1 intracellular domain changes the pattern of IL-TIF-induced Stat activation. The CRF2-9 gene is expressed in normal liver and kidney, suggesting a possible role for IL-TIF in regulating gene expression in these tissues. Each chain, CRF2-9 and IL-10R2, is capable of binding IL-TIF independently and can be cross-linked to the radiolabeled IL-TIF. However, binding of IL-TIF to the receptor complex is greater than binding to either receptor chain alone. Sharing of the common IL-10R2 chain between the IL-10 and IL-TIF receptor complexes is the first such case for receptor complexes with chains belonging to the class II cytokine receptor family, establishing a novel paradigm for IL-10-related ligands similar to the shared use of the gamma common chain (gamma(c)) by several cytokines, including IL-2, IL-4, IL-7, IL-9, and IL-15.

  5. Receptor kinase signalling in plants and animals: distinct molecular systems with mechanistic similarities.

    PubMed

    Cock, J Mark; Vanoosthuyse, Vincent; Gaude, Thierry

    2002-04-01

    Plant genomes encode large numbers of receptor kinases that are structurally related to the tyrosine and serine/threonine families of receptor kinase found in animals. Here, we describe recent advances in the characterisation of several of these plant receptor kinases at the molecular level, including the identification of receptor complexes, small polypeptide ligands and cytosolic proteins involved in signal transduction and receptor downregulation. Phylogenetic analysis indicates that plant receptor kinases have evolved independently of the receptor kinase families found in animals. This hypothesis is supported by functional studies that have revealed differences between receptor kinase signalling in plants and animals, particularly concerning their interactions with cytosolic proteins. Despite these dissimilarities, however, plant and animal receptor kinases share many common features, such as their single membrane-pass structure, their inclusion in membrane-associated complexes, the involvement of dimerisation and trans autophosphorylation in receptor activation, and the existence of inhibitors and phosphatases that downregulate receptor activity. These points of convergence may represent features that are essential for a functional receptor-kinase signalling system.

  6. The expression of human natural killer cell receptors in early life.

    PubMed

    Sundström, Y; Nilsson, C; Lilja, G; Kärre, K; Troye-Blomberg, M; Berg, L

    2007-01-01

    Natural killer (NK) cells play an important role in tumour immunosurveillance and the early defence against viral infections. Recognition of altered cells (i.e. infected- or tumour-cells) is achieved through a multiple receptor recognition strategy which gives the NK cells inhibitory or activating signals depending on the ligands present on the target cell. NK cells originate from the bone marrow where they develop and proliferate. However, further maturation processes and homeostasis of NK cells in peripheral blood are not well understood. To determine the proportions of cells and the expression of NK cell receptors, mononuclear cells from children at three time points during early childhood were compared, i.e. cord blood (CB), 2 and 5 years of age. The proportion of NK cells was high in CB, but the interferon-gamma (IFN-gamma) production low compared to later in life. In contrast, the proportion of T cells was low in CB. This may indicate a deviation of the regulatory function of NK cells in CB compared to later in life, implying an importance of innate immunity in early life before the adaptive immune system matures. Additionally, we found that the proportion of LIR-1(+) NK cells increased with increasing age while CD94(+)NKG2C(-) (NKG2A(+)) NK cells and the level of expression of NKG2D, NKp30 and NKp46 decreased with age. These age related changes in NK cell populations defined by the expression of activating and inhibitory receptors may be the result of pathogen exposure and/or a continuation of the maturation process that begins in the bone marrow.

  7. The Advanced Gamma-ray Imaging System (AGIS): Camera Electronics Designs

    NASA Astrophysics Data System (ADS)

    Tajima, Hiroyasu; Buckley, J.; Byrum, K.; Drake, G.; Falcone, A.; Funk, S.; Holder, J.; Horan, D.; Krawczynski, H.; Ong, R.; Swordy, S.; Wagner, R.; Wakely, S.; Williams, D.; Camera Electronics Working Group; AGIS Collaboration

    2008-03-01

    AGIS, a next generation of atmospheric Cherenkov telescope arrays, aims to achieve a sensitivity level of a milliCrab for gamma-ray observations in in the energy band of 40 GeV to 100 TeV. Such improvement requires cost reduction of individual components with high reliability in order to equip the order of 100 telescopes necessary to achieve the sensitivity goal. We are exploring several design concepts to reduce the cost of camera electronics while improving their performance. These design concepts include systems based on multi-channel waveform sampling ASIC optimized for AGIS, a system based on IIT (image intensifier tube) for large channel (order of 1 million channels) readout as well as a multiplexed FADC system based on the current VERITAS readout design. Here we present trade-off studies of these design concepts.

  8. An energetic orphan in an endocrine tissue: a revised perspective of the function of estrogen receptor-related receptor alpha in bone and cartilage.

    PubMed

    Bonnelye, Edith; Aubin, Jane E

    2013-02-01

    Estrogen receptor-related receptor alpha (ERRα) is an orphan nuclear receptor with sequence homology to the estrogen receptors, ERα/β, but it does not bind estrogen. ERRα not only plays a functional role in osteoblasts but also in osteoclasts and chondrocytes. In addition, the ERRs, including ERRα, can be activated by coactivators such as peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1α and β) and are implicated in adipogenesis, fatty acid oxidation, and oxidative stress defense, suggesting that ERRα-through its activity in bone resorption and adipogenesis--may regulate the insulin and leptin pathways and contribute to aging-related changes in bone and cartilage. In this review, we discuss data on ERRα and its cellular and molecular modes of action, which have broad implications for considering the potential role of this orphan receptor in cartilage and bone endocrine function, on whole-organism physiology, and in the bone aging process. Copyright © 2013 American Society for Bone and Mineral Research.

  9. Identification of bioactive compounds from flowers of black elder (Sambucus nigra L.) that activate the human peroxisome proliferator-activated receptor (PPAR) gamma.

    PubMed

    Christensen, Kathrine B; Petersen, Rasmus K; Kristiansen, Karsten; Christensen, Lars P

    2010-06-01

    Obesity is one of the predisposing factors for the development of overt Type 2 diabetes (T2D). T2D is caused by a combination of insulin resistance and beta-cell failure and can be treated with insulin sensitizing drugs that target the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma. Extracts of elderflowers (Sambucus nigra) have been found to activate PPARgamma and to stimulate insulin-dependent glucose uptake suggesting that they have a potential use in the prevention and/or treatment of insulin resistance. Bioassay-guided chromatographic fractionation of a methanol extract of elderflowers resulted in the identification of two well-known PPARgamma agonists; alpha-linolenic acid and linoleic acid as well as the flavanone naringenin. Naringenin was found to activate PPARgamma without stimulating adipocyte differentiation. However, the bioactivities of these three metabolites were not able to fully account for the observed PPARgamma activation of the crude elderflower extracts and further studies are needed to determine whether this is due synergistic effects and/or other ligand-independent mechanisms. Elderflower metabolites such as quercetin-3-O-rutinoside, quercetin-3-O-glucoside, kaempferol-3-O-rutinoside, isorhamnetin-3-O-rutinoside, isorhamnetin-3-O-glucoside, and 5-O-caffeoylquinic acid were unable to activate PPARgamma. These findings suggest that flavonoid glycosides cannot activate PPARgamma, whereas some of their aglycones are potential agonists of PPARgamma.

  10. The effect of alloying on gamma and gamma prime in nickel-base superalloys

    NASA Technical Reports Server (NTRS)

    Dreshfield, R. L.; Wallace, J. F.

    1972-01-01

    An investigation was conducted to determine the compositional limits of gamma and gamma prime phases in nickel-base superalloys. Fifty-one nickel-base alloys were melted under vacuum and heat treated for 4 hours at 1190 C followed by 1008 hours at 850 C. The alloys had the following composition ranges: A1 4.0 to 13 atomic percent, Cr 6.5 to 20.5 percent, Ti 0.25 to 4.75 percent, Mo 0.0 to 6.0 percent, and W 0.0 to 4.0 percent. The residues from the ammonium sulfate electrolytic extraction for the two-phase alloys were analyzed chemically and by X-ray diffraction. The results of the investigation were used to assemble a mathematical model of the gamma-gamma prime region of the Ni-Al-Cr-Ti-Mo-W system. A computer program was written to analyze the model of the phase diagram. Some of these results are also presented graphically. The resulting model is capable of satisfactorily predicting the compositions of conjugate gamma-gamma prime phases in the alloys investigated and twelve of fifteen commercial superalloys studied.

  11. Estimation of neutron energy distributions from prompt gamma emissions

    NASA Astrophysics Data System (ADS)

    Panikkath, Priyada; Udupi, Ashwini; Sarkar, P. K.

    2017-11-01

    A technique of estimating the incident neutron energy distribution from emitted prompt gamma intensities from a system exposed to neutrons is presented. The emitted prompt gamma intensities or the measured photo peaks in a gamma detector are related to the incident neutron energy distribution through a convolution of the response of the system generating the prompt gammas to mono-energetic neutrons. Presently, the system studied is a cylinder of high density polyethylene (HDPE) placed inside another cylinder of borated HDPE (BHDPE) having an outer Pb-cover and exposed to neutrons. The emitted five prompt gamma peaks from hydrogen, boron, carbon and lead can be utilized to unfold the incident neutron energy distribution as an under-determined deconvolution problem. Such an under-determined set of equations are solved using the genetic algorithm based Monte Carlo de-convolution code GAMCD. Feasibility of the proposed technique is demonstrated theoretically using the Monte Carlo calculated response matrix and intensities of emitted prompt gammas from the Pb-covered BHDPE-HDPE system in the case of several incident neutron spectra spanning different energy ranges.

  12. [Association between Fok I vitamin D receptor (VDR) gene polymorphism and plasmatic concentrations of transforming growth factor-beta1 and interferon gamma in type 1 diabetes mellitus].

    PubMed

    López, Tatiana; García, Diego; Angel, Bárbara; Carrasco, Elena; Codner, Ethel; Ugarte, Francisca; Pérez-Bravo, Francisco

    2008-02-02

    In order to assess whether Fok I vitamin D receptor gene (VDR) polymorphism is involved in the genetic susceptibility of type 1 diabetes, a case-control study was conducted and VDR genotypes were related to serum concentrations of 25(OH) vitamin D and cytokines transforming growth factor beta1 (TGF-beta1) and interferon gamma (INF-gamma). 151 incident cases of type 1 diabetes and 182 non related healthy controls from Santiago were studied for VDR polymorphisms in peripheral blood DNA. Exon 2 (Fok I) segments were amplified by polimerase chain reaction and analyzed by means of restriction fragment length polymorphism to determine each corresponding genotype. Differences for allele, genotype and serological markers as 25(OH) vitamin D, TGF-beta1 and INF-gamma levels distribution between patients and controls were analyzed. Fok I polymorphism distribution analysis showed no differences between patients and controls. Among diabetics, higher levels of TGF-beta1 (median, 282.6 pg/ml; range, 131.8-3,031.4) were observed compared with healthy children (median, 232.2 pg/ml; range, 135.7-506.5) (p < 0.0038). Similar results were observed for INF-gamma concentrations (median, 121.1 pg/ml, and range, 5.3-228.8, in cases, and median, 89.6 pg/ml, and range, 10.9-117.2 in controls) (p < 0.0004). The diabetic carriers of the ff genotype showed low levels of 25(OH) vitamin D compared with the carriers of the F allele: mean (standard deviation), 23.1 (5.9) versus 27.9 (10.3) ng/ml (p < 0.03). A similar result was observed for TGF-beta1 concentrations in diabetic carriers of ff genotype and patients carriers of the F allele (298.5 versus 276.6; p < 0.05). Fok I polymorphism of VDR could have a marginal role in the immunologic disturbance in type 1 diabetes.

  13. Gamma-Ray Signatures Improvement of the EURITRACK Tagged Neutron Inspection System Database

    NASA Astrophysics Data System (ADS)

    Kanawati, Wassila El; Carasco, Cedric; Perot, Bertrand; Mariani, Alain; Raoux, Anne-Cecile; Valkovic, Vladivoj; Sudac, Davorin; Obhodas, Jasmina; Baricevic, Martina

    2010-10-01

    The EURopean Illicit TRAfficking Countermeasures Kit (EURITRACK) inspection system uses 14 MeV neutrons produced by the D(T,n α) reaction to detect explosives in cargo containers. Reactions induced by fast neutrons inside the container produce gamma rays, which are detected in coincidence with the associated alpha particle, the detection of which allows the neutron direction to be determined. The neutron path length is obtained from a neutron time-of-flight measurement, thus allowing the origin of the gamma rays inside the container to be determined, while the chemical composition of the target material is correlated with their energy spectrum. Gamma-ray spectra have been collected with the inspection portal equipped with large volume NaI (Tl) detectors, in order to build a database of signatures for various elements (C, O, N, Fe, Pb, Al, Na, Si, Cl, Cu, Zn) with a low energy threshold of 0.6 MeV. The spectra are compared with previous ones, which were acquired with a 1.35 MeV threshold. The new library is currently being tested to unfold the energy spectra of transported goods into elemental contributions. Results are compared with data processed with the old 1.35 MeV threshold database, thus illustrating the improvement for material identification.

  14. Synaptic proteins and receptors defects in autism spectrum disorders

    PubMed Central

    Chen, Jianling; Yu, Shunying; Fu, Yingmei; Li, Xiaohong

    2014-01-01

    Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms contribute to the occurrence of autism spectrum disorders (ASDs). The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95, SH3, and multiple ankyrin repeat domains 3 (SHANK3), synapsin, gephyrin, cadherin, and protocadherin, thousand-and-one-amino acid 2 kinase, and contactin, have been shown to play important roles in the development and function of synapses. In addition, synaptic receptors, such as gamma-aminobutyric acid receptors and glutamate receptors, have also been associated with ASDs. This review will primarily focus on the defects of synaptic proteins and receptors associated with ASDs and their roles in the pathogenesis of ASDs via synaptic pathways. PMID:25309321

  15. A data acquisition and control system for high-speed gamma-ray tomography

    NASA Astrophysics Data System (ADS)

    Hjertaker, B. T.; Maad, R.; Schuster, E.; Almås, O. A.; Johansen, G. A.

    2008-09-01

    A data acquisition and control system (DACS) for high-speed gamma-ray tomography based on the USB (Universal Serial Bus) and Ethernet communication protocols has been designed and implemented. The high-speed gamma-ray tomograph comprises five 500 mCi 241Am gamma-ray sources, each at a principal energy of 59.5 keV, which corresponds to five detector modules, each consisting of 17 CdZnTe detectors. The DACS design is based on Microchip's PIC18F4550 and PIC18F4620 microcontrollers, which facilitates an USB 2.0 interface protocol and an Ethernet (IEEE 802.3) interface protocol, respectively. By implementing the USB- and Ethernet-based DACS, a sufficiently high data acquisition rate is obtained and no dedicated hardware installation is required for the data acquisition computer, assuming that it is already equipped with a standard USB and/or Ethernet port. The API (Application Programming Interface) for the DACS is founded on the National Instrument's LabVIEW® graphical development tool, which provides a simple and robust foundation for further application software developments for the tomograph. The data acquisition interval, i.e. the integration time, of the high-speed gamma-ray tomograph is user selectable and is a function of the statistical measurement accuracy required for the specific application. The bandwidth of the DACS is 85 kBytes s-1 for the USB communication protocol and 28 kBytes s-1 for the Ethernet protocol. When using the iterative least square technique reconstruction algorithm with a 1 ms integration time, the USB-based DACS provides an online image update rate of 38 Hz, i.e. 38 frames per second, whereas 31 Hz for the Ethernet-based DACS. The off-line image update rate (storage to disk) for the USB-based DACS is 278 Hz using a 1 ms integration time. Initial characterization of the high-speed gamma-ray tomograph using the DACS on polypropylene phantoms is presented in the paper.

  16. GABAB receptor modulation of the release of substance P from capsaicin-sensitive neurones in the rat trachea in vitro.

    PubMed Central

    Ray, N. J.; Jones, A. J.; Keen, P.

    1991-01-01

    1. The role of gamma-aminobutyric acid (GABA) as an inhibitory transmitter in the central nervous system is well documented. Recently, GABAA and GABAB receptors have been identified in the peripheral nervous system, notably on primary afferent neurones (PAN). We have utilised a multi-superfusion system to investigate the effect of selective GABA receptor agonists and antagonists on the release of substance P (SP) from the rat trachea in vitro. 2. GABA (1-100 microM) did not affect spontaneous release of SP-like immunoreactivity (LI) but caused dose-related inhibition of calcium-dependent potassium (60 mM)-stimulated SP-LI release. The greatest inhibition of 77.7 +/- 18.8% was observed at 100 microM. 3. The inhibitory effect of GABA was mimicked by the GABAB receptor agonist, (+/-)-baclofen (1-100 microM), but not the GABAA receptor agonist, 3-amino-1-propane-sulphonic acid (3-APS, 1-100 microM). Baclofen (100 microM) had no effect on SP-LI release stimulated by capsaicin (1 microM). 4. The inhibitory effect of baclofen (30 microM) was significantly reduced by prior and concomitant exposure to the GABAB receptor antagonist, phacolofen (100 microM) but not the GABAA receptor antagonist, bicuculline (10 microM). Neither antagonist, alone, affected spontaneous or potassium-stimulated SP-LI release. 5. We conclude that activation of pre-synaptic GABAB receptors on the peripheral termini of PANs in the rat trachea inhibits SP-LI release and suggest that GABAB receptor agonists may be of value in the therapeutic treatment of asthma. PMID:1713105

  17. Technical note: A 3D-printed phantom for routine accuracy check of Gamma Knife Icon HDMM system.

    PubMed

    Wu, Chuan; Radevic, Marlyn B; Glass, Jennifer S; Skubic, Stan E

    2018-05-23

    To report a novel 3D-printed device ("SH phantom") that is designed for routine accuracy check of the Gamma Knife Icon High Definition Motion Management (HDMM) system. SH phantom was designed using tinkerCAD software and printed on a commercial 3D printer. We evaluated the SH phantom on our Gamma Knife Icon unit regarding its usability and accuracy for routine HDMM QA. Single-axis and multiple-axis measurements validated the SH phantom design and implementation. An HDMM QA accuracy of 0.22 mm or better along single axis was found using SH phantom. The SH phantom proved to be a quick and simple tool to use to perform the HDMM system QA. The SH phantom was tested successfully and adopted by us as part of monthly QA for the Gamma Knife Icon. © 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

  18. Association with replication between estrogen-related receptor gamma (ESRRgamma) polymorphisms and bone phenotypes in women of European ancestry.

    PubMed

    Elfassihi, Latifa; Giroux, Sylvie; Bureau, Alexandre; Laflamme, Nathalie; Cole, David Ec; Rousseau, François

    2010-04-01

    Osteoporosis is a bone disease characterized by low bone mineral density (BMD), a highly heritable polygenic trait. Women are more prone than men to develop osteoporosis owing to a lower peak bone mass and accelerated bone loss at menopause. Lack of estrogen thus is a major risk factor for osteoporosis. In addition to having strong similarity to the estrogen receptor 1 (ESR1), the orphan nuclear estrogen-related receptor gamma (ESRRgamma) is widely expressed and shows overlap with ESR1 expression in tissues where estrogen has important physiologic functions. For these reasons, we have undertaken a study of ESRRgamma sequence variants in association with bone measurements [heel quantitative ultrasound (QUS) by measurements of broadband ultrasound attenuation (BUA), speed of sound (SOS), and stiffness index (SI) and dual-energy X-ray absorptiometry (DXA) at the femoral neck (FN) and lumbar spine (LS)]. A silent variant was found to be associated with multiple bone measurements (LS, BUA, SOS, and SI), the p values ranging from .006 to .04 in a sample of 5144 Quebec women. The region of this variant was analyzed using the HapMap database and the Gabriel method to define a block of 20 kb. Using the Tagger method, eight TagSNPs were identified and genotyped in a sample of 1335 women. Four of these SNPs capture the five major block haplotypes. One SNP (rs2818964) and one haplotype were significantly associated with multiple bone measures. All SNPs involved in the associations were analyzed in two other sample sets with significant results in the same direction. These results suggest involvement of ESRRgamma in the determination of bone density in women. Copyright 2010 American Society for Bone and Mineral Research.

  19. Immunoglobulin Fc gamma receptor promotes immunoglobulin uptake, immunoglobulin-mediated calcium increase, and neurotransmitter release in motor neurons

    NASA Technical Reports Server (NTRS)

    Mohamed, Habib A.; Mosier, Dennis R.; Zou, Ling L.; Siklos, Laszlo; Alexianu, Maria E.; Engelhardt, Jozsef I.; Beers, David R.; Le, Wei-dong; Appel, Stanley H.

    2002-01-01

    Receptors for the Fc portion of immunoglobulin G (IgG; FcgammaRs) facilitate IgG uptake by effector cells as well as cellular responses initiated by IgG binding. In earlier studies, we demonstrated that amyotrophic lateral sclerosis (ALS) patient IgG can be taken up by motor neuron terminals and transported retrogradely to the cell body and can alter the function of neuromuscular synapses, such as increasing intracellular calcium and spontaneous transmitter release from motor axon terminals after passive transfer. In the present study, we examined whether FcgammaR-mediated processes can contribute to these effects of ALS patient immunoglobulins. F(ab')(2) fragments (which lack the Fc portion) of ALS patient IgG were not taken up by motor axon terminals and were not retrogradely transported. Furthermore, in a genetically modified mouse lacking the gamma subunit of the FcR, the uptake of whole ALS IgG and its ability to enhance intracellular calcium and acetylcholine release were markedly attenuated. These data suggest that FcgammaRs appear to participate in IgG uptake into motor neurons as well as IgG-mediated increases in intracellular calcium and acetylcholine release from motor axon terminals. Copyright 2002 Wiley-Liss, Inc.

  20. Association of Pro12Ala polymorphism in peroxisome proliferator activated receptor gamma with proliferative diabetic retinopathy

    PubMed Central

    Tariq, Khadija; Malik, Saira Bano; Ali, Syeda Hafiza Benish; Maqsood, Sundas Ejaz; Azam, Aisha; Muslim, Irfan; Khan, Muhammad Shakil; Azam, Maleeha; Waheed, Nadia Khalida

    2013-01-01

    Purpose The association of non-synonymous substitution polymorphism rs1801282 (c.34C>G, p.Pro12Ala) in exon 4 of the peroxisome proliferator activated receptor gamma gene with diabetic retinopathy (DR) has been reported inconsistently. Therefore, the purpose of the present study was to understand the population-specific role of the Pro12Ala polymorphism in DR susceptibility in Pakistani subjects. Methods A total of 180 subjects with DR, 193 subjects with type 2 diabetes mellitus (T2DM) with no diabetic retinopathy, and 200 healthy normoglycemic non-retinopathic Pakistani individuals were genotyped for the rs1801282 (c.34C>G) polymorphism using polymerase chain reaction-restriction fragment length polymorphism. Results We found the individuals with T2DM carrying 12Ala were at a reduced risk of developing DR (odds ratio [OR]=0.53; 95% confidence interval [CI]=0.33–0.87). Upon stratified analysis regarding disease severity, we observed this protective effect was confined to proliferative DR (OR=0.4; 95% CI=0.2–0.8) with non-significant effects on the susceptibility of non-proliferative DR (OR=0.67; 95% CI=0.37–1.19). Conclusions We report a protective role of the 12Ala polymorphism against proliferative DR in individuals with T2DM in Pakistan. PMID:23559865

  1. Role of a Ubiquitously Expressed Receptor in the Vertebrate Olfactory System

    PubMed Central

    DeMaria, Shannon; Berke, Allison P.; Van Name, Eric; Heravian, Anisa; Ferreira, Todd

    2013-01-01

    Odorant cues are recognized by receptors expressed on olfactory sensory neurons, the primary sensory neurons of the olfactory epithelium. Odorant receptors typically obey the “one receptor, one neuron” rule, in which the receptive field of the olfactory neuron is determined by the singular odorant receptor that it expresses. Odor-evoked receptor activity across the population of olfactory neurons is then interpreted by the brain to identify the molecular nature of the odorant stimulus. In the present study, we characterized the properties of a C family G-protein-coupled receptor that, unlike most other odorant receptors, is expressed in a large population of microvillous sensory neurons in the zebrafish olfactory epithelium and the mouse vomeronasal organ. We found that this receptor, OlfCc1 in zebrafish and its murine ortholog Vmn2r1, is a calcium-dependent, low-sensitivity receptor specific for the hydrophobic amino acids isoleucine, leucine, and valine. Loss-of-function experiments in zebrafish embryos demonstrate that OlfCc1 is required for olfactory responses to a diverse mixture of polar, nonpolar, acidic, and basic amino acids. OlfCc1 was also found to promote localization of other OlfC receptor family members to the plasma membrane in heterologous cells. Together, these results suggest that the broadly expressed OlfCc1 is required for amino acid detection by the olfactory system and suggest that it plays a role in the function and/or intracellular trafficking of other olfactory and vomeronasal receptors with which it is coexpressed. PMID:24048853

  2. Classics in Neuroimaging: The Serotonergic 2A Receptor System-from Discovery to Modern Molecular Imaging.

    PubMed

    T L'Estrade, Elina; Hansen, Hanne D; Erlandsson, Maria; Ohlsson, Tomas G; Knudsen, Gitte M; Herth, Matthias M

    2018-06-20

    Already in 1953, Woolley and Shaw speculated that serotonin could be involved in a range of central nervous system (CNS) disorders. Lysergic acid diethylamide (LSD) displayed an important role in this respect. It was used not only to antagonize biological effects of serotonin and to study the system itself, but also to identify serotonergic subtype receptors. The 5-HT 2A receptor was discovered in the 1970s and identified as the responsible receptor mediating psychedelic effects of LSD. The development of positron emission tomography (PET) allowed to study this receptor system in vivo. Parameters such as abundance of 5-HT 2A neuroreceptors or receptor occupancy can be determined using PET. As such, the development of 5-HT 2A receptor tracers started immediately after the introduction of PET in the mid-1970s. In this Viewpoint, we provide a historical overview from the discovery of serotonin to the identification of the 5-HT 2A receptor subtype and the subsequent development of 5-HT 2A receptor subtype specific PET tracers over the last four decades. We emphasize the interplay between pharmacology, medicinal chemistry, radiochemistry, and nuclear medicine that is important while developing a PET tracer. Moreover, we highlight selected examples applying 5-HT 2A receptor PET tracers within neurological diseases and drug occupancy studies.

  3. PPAR{gamma} activates ABCA1 gene transcription but reduces the level of ABCA1 protein in HepG2 cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mogilenko, Denis A., E-mail: denis@iem.sp.ru; Department of Embryology, St. Petersburg State University, 199034 St. Petersburg; Shavva, Vladimir S.

    Research highlights: {yields} PPAR{gamma} activates ABCA1 gene expression but decreases ABCA1 protein content in human hepatoma cell line HepG2. {yields} Treatment of HepG2 cells with PPAR{gamma} agonist GW1929 leads to dissociation of LXR{beta} from ABCA1-LXR{beta} complex. {yields} Inhibition of protein kinases MEK1/2 abolishes PPAR{gamma}-mediated dissociation of LXR{beta} from ABCA1/LXR{beta} complex. {yields} Activation of PPAR{gamma} leads to increasing of the level of LXR{beta} associated with LXRE within ABCA1 gene promoter. -- Abstract: Synthesis of ABCA1 protein in liver is necessary for high-density lipoproteins (HDL) formation in mammals. Nuclear receptor PPAR{gamma} is known as activator of ABCA1 expression, but details of PPAR{gamma}-mediatedmore » regulation of ABCA1 at both transcriptional and post-transcriptional levels in hepatocytes have not still been well elucidated. In this study we have shown, that PPAR{gamma} activates ABCA1 gene transcription in human hepatoma cells HepG2 through increasing of LXR{beta} binding with promoter region of ABCA1 gene. Treatment of HepG2 cells with PPAR{gamma} agonist GW1929 leads to dissociation of LXR{beta} from ABCA1/LXR{beta} complex and to nuclear translocation of this nuclear receptor resulting in reduction of ABCA1 protein level 24 h after treatment. Inhibition of protein kinases MEK1/2 abolishes PPAR{gamma}-mediated dissociation of LXR{beta} from ABCA1/LXR{beta} complex, but does not block PPAR{gamma}-dependent down-regulation of ABCA1 protein in HepG2 cells. These data suggest that PPAR{gamma} may be important for regulation of the level of hepatic ABCA1 protein and indicate the new interplays between PPAR{gamma}, LXR{beta} and MEK1/2 in regulation of ABCA1 mRNA and protein expression.« less

  4. Death receptor Fas (CD95) signaling in the central nervous system: tuning neuroplasticity?

    PubMed

    Reich, Arno; Spering, Christopher; Schulz, Jörg B

    2008-09-01

    For over a decade, neuroscientific research has focused on processes of apoptosis and its contribution to the pathophysiology of neurological diseases. In the central nervous system, the degree of intrinsic mitochondrial-mediated apoptotic signaling expresses a cell's individual metabolic stress, whereas activation of the extrinsic death receptor-induced cascade is regarded as a sign of imbalanced cellular networks. Under physiological conditions, most neurons possess death receptors without being sensitive to receptor-mediated apoptosis. This paradox raises two questions: what is the evolutionary advantage of expressing potentially harmful proteins? How is their signaling controlled? This review summarizes the functional relevance of FasL-Fas signaling--a quintessential death ligand/receptor system--in different neurological disease models ranging from traumatic, inflammatory and ischemic to neurodegenerative processes. Furthermore, it outlines alternative non-apoptotic Fas signaling, shedding new light on its neuroplastic capacity. Finally, receptor-proximal regulatory proteins are introduced and identified as potential protagonists of disease-modifying neurological therapies.

  5. Structure-activity relationships of seco-prezizaane and picrotoxane/picrodendrane terpenoids by Quasar receptor-surface modeling.

    PubMed

    Schmidt, Thomas J; Gurrath, Marion; Ozoe, Yoshihisa

    2004-08-01

    The seco-prezizaane-type sesquiterpenes pseudoanisatin and parviflorolide from Illicium are noncompetitive antagonists at housefly (Musca domestica) gamma-aminobutyric acid (GABA) receptors. They show selectivity toward the insect receptor and thus represent new leads toward selective insecticides. Based on the binding data for 13 seco-prezizaane terpenoids and 17 picrotoxane and picrodendrane-type terpenoids to housefly and rat GABA receptors, a QSAR study was conducted by quasi-atomistic receptor-surface modeling (Quasar). The resulting models provide insight into the structural basis of selectivity and properties of the binding sites at GABA receptor-coupled chloride channels of insects and mammals.

  6. Technical Note: Relationships between gamma criteria and action levels: Results of a multicenter audit of gamma agreement index results.

    PubMed

    Crowe, Scott B; Sutherland, Bess; Wilks, Rachael; Seshadri, Venkatakrishnan; Sylvander, Steven; Trapp, Jamie V; Kairn, Tanya

    2016-03-01

    The aim of this work was to use a multicenter audit of modulated radiotherapy quality assurance (QA) data to provide a practical examination of gamma evaluation criteria and action level selection. The use of the gamma evaluation method for patient-specific pretreatment QA is widespread, with most commercial solutions implementing the method. Gamma agreement indices were calculated using the criteria 1%/1 mm, 2%/2 mm, 2%/3 mm, 3%/2 mm, 3%/3 mm, and 5%/3 mm for 1265 pretreatment QA measurements, planned at seven treatment centers, using four different treatment planning systems, delivered using three different delivery systems (intensity-modulated radiation therapy, volumetric-modulated arc therapy, and helical tomotherapy) and measured using three different dose measurement systems. The sensitivity of each pair of gamma criteria was evaluated relative to the gamma agreement indices calculated using 3%/3 mm. A linear relationship was observed for 2%/2 mm, 2%/3 mm, and 3%/2 mm. This result implies that most beams failing at 3%/3 mm would also fail for those criteria, if the action level was adjusted appropriately. Some borderline plans might be passed or failed depending on the relative priority (tighter tolerance) used for dose difference or distance to agreement evaluation. Dosimeter resolution and treatment modality were found to have a smaller effect on the results of QA measurements than the number of dimensions (2D or 3D) over which the gamma evaluation was calculated. This work provides a method (and a large sample of results) for calculating equivalent action levels for different gamma evaluation criteria. This work constitutes a valuable guide for clinical decision making and a means to compare published gamma evaluation results from studies using different evaluation criteria. More generally, the data provided by this work support the recommendation that gamma criteria that specifically prioritize the property of greatest clinical importance for each

  7. Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations.

    PubMed

    Lewis, David A; Moghaddam, Bita

    2006-10-01

    Impairments in certain cognitive functions mediated by the dorsolateral prefrontal cortex, such as working memory, are core features of schizophrenia. Convergent findings suggest that these disturbances are associated with alterations in markers of inhibitory gamma-aminobutyric acid and excitatory glutamate neurotransmission in the dorsolateral prefrontal cortex. Specifically, reduced gamma-aminobutyric acid synthesis is present in the subpopulation of gamma-aminobutyric acid neurons that express the calcium-binding protein parvalbumin. Despite presynaptic and postsynaptic compensatory responses, the resulting impaired inhibitory regulation of pyramidal neurons contributes to a reduction in the synchronized neuronal activity that is required for working memory function. Several lines of evidence suggest that these changes may be either secondary to or exacerbated by impaired signaling via the N-methyl-d-aspartate class of glutamate receptors. These findings suggest specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.

  8. Gamma-ray background induced by atmospheric neutrons

    NASA Astrophysics Data System (ADS)

    Ma, Y.-Q.

    1984-03-01

    A small piggyback detector system is used to study the reduction of gamma-ray background induced by atmospheric neutrons in the type of actively shielded gamma-ray spectroscopes. The system consists of two 1.5 x 1.5 arcsec NaI crystal units, one of which is surrounded by some neutron shield material. The results of a balloon flight in 1981 are presented. The data show that a shield of 3 cm-thick pure paraffin cannot reduce the gamma-ray background. On the contrary, it may even cause some enhancement.

  9. Peroxisome proliferator-activated receptor gamma (PPARG) rs1801282 C>G polymorphism is associated with cancer susceptibility in asians: an updated meta-analysis

    PubMed Central

    Wang, Yafeng; Chen, Yu; Jiang, Heping; Tang, Weifeng; Kang, Mingqiang; Liu, Tianyun; Guo, Zengqing; Ma, Zhiqiang

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARG) is related to inflammation and plays an important role in the development of cancer. PPARG rs1801282 C>G polymorphism might influence the risk of cancer by regulating production of PPARG gene. Hence, a comprehensive meta-analysis was conducted to explore the association of PPARG rs1801282 C>G polymorphism with cancer susceptibility. An extensive search of PubMed and Embase databases for all relevant publications was carried out. A total of 38 publications with 16,844 cancer cases and 23,736 controls for PPARG rs1801282 C>G polymorphism were recruited in our study. Our results indicated that PPARG rs1801282 C>G variants were associated with an increased cancer risk in Asian populations and gastric cancer. In summary, the findings suggest that PPARG rs1801282 C>G polymorphism may play a crucial role in malignant transformation and the development of cancer. PMID:26550180

  10. Peroxisome proliferator-activated receptor gamma (PPARG) rs1801282 C>G polymorphism is associated with cancer susceptibility in asians: an updated meta-analysis.

    PubMed

    Wang, Yafeng; Chen, Yu; Jiang, Heping; Tang, Weifeng; Kang, Mingqiang; Liu, Tianyun; Guo, Zengqing; Ma, Zhiqiang

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARG) is related to inflammation and plays an important role in the development of cancer. PPARG rs1801282 C>G polymorphism might influence the risk of cancer by regulating production of PPARG gene. Hence, a comprehensive meta-analysis was conducted to explore the association of PPARG rs1801282 C>G polymorphism with cancer susceptibility. An extensive search of PubMed and Embase databases for all relevant publications was carried out. A total of 38 publications with 16,844 cancer cases and 23,736 controls for PPARG rs1801282 C>G polymorphism were recruited in our study. Our results indicated that PPARG rs1801282 C>G variants were associated with an increased cancer risk in Asian populations and gastric cancer. In summary, the findings suggest that PPARG rs1801282 C>G polymorphism may play a crucial role in malignant transformation and the development of cancer.

  11. Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

    DTIC Science & Technology

    2004-09-01

    hippocampus and hypothalamus. J Neurosci Res 63:200-208. Thorpe GH et al. (1989) Chemiluminescent enzyme immunoassay of alpha - fetoprotein based on an...cells. Proc Natl Acad Sci USA 83:6213-6215. Montpied Pet al. (1991) Prolonged ethanol inhalation decreases gamma-aminobutyric acidA receptor alpha ...potentials mediated via alpha -bungarotoxin-sensitive nico- tinic acetylcholine receptors in rat hippocampal interneurons. J Neurosci 18:8228- 8235

  12. Elabela-Apelin Receptor Signaling Pathway is Functional in Mammalian Systems

    PubMed Central

    Wang, Zhi; Yu, Daozhan; Wang, Mengqiao; Wang, Qilong; Kouznetsova, Jennifer; Yang, Rongze; Qian, Kun; Wu, Wenjun; Shuldiner, Alan; Sztalryd, Carole; Zou, Minghui; Zheng, Wei; Gong, Da-Wei

    2015-01-01

    Elabela (ELA) or Toddler is a recently discovered hormone which is required for normal development of heart and vasculature through activation of apelin receptor (APJ), a G protein-coupled receptor (GPCR), in zebrafish. The present study explores whether the ELA-APJ signaling pathway is functional in the mammalian system. Using reverse-transcription PCR, we found that ELA is restrictedly expressed in human pluripotent stem cells and adult kidney whereas APJ is more widely expressed. We next studied ELA-APJ signaling pathway in reconstituted mammalian cell systems. Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor. In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. Finally, we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin. Collectively, we demonstrate that the ELA-AJP signaling pathways are functional in mammalian systems, indicating that ELA likely serves as a hormone regulating the circulation system in adulthood as well as in embryonic development. PMID:25639753

  13. Elabela-apelin receptor signaling pathway is functional in mammalian systems.

    PubMed

    Wang, Zhi; Yu, Daozhan; Wang, Mengqiao; Wang, Qilong; Kouznetsova, Jennifer; Yang, Rongze; Qian, Kun; Wu, Wenjun; Shuldiner, Alan; Sztalryd, Carole; Zou, Minghui; Zheng, Wei; Gong, Da-Wei

    2015-02-02

    Elabela (ELA) or Toddler is a recently discovered hormone which is required for normal development of heart and vasculature through activation of apelin receptor (APJ), a G protein-coupled receptor (GPCR), in zebrafish. The present study explores whether the ELA-APJ signaling pathway is functional in the mammalian system. Using reverse-transcription PCR, we found that ELA is restrictedly expressed in human pluripotent stem cells and adult kidney whereas APJ is more widely expressed. We next studied ELA-APJ signaling pathway in reconstituted mammalian cell systems. Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor. In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. Finally, we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin. Collectively, we demonstrate that the ELA-AJP signaling pathways are functional in mammalian systems, indicating that ELA likely serves as a hormone regulating the circulation system in adulthood as well as in embryonic development.

  14. Multiple melanocortin receptors are expressed in bone cells

    NASA Technical Reports Server (NTRS)

    Zhong, Qing; Sridhar, Supriya; Ruan, Ling; Ding, Ke-Hong; Xie, Ding; Insogna, Karl; Kang, Baolin; Xu, Jianrui; Bollag, Roni J.; Isales, Carlos M.

    2005-01-01

    Melanocortin receptors belong to the seven transmembrane domain, G-protein coupled family of receptors. There are five members of this receptor family labeled MC1R-MC5R. These receptors are activated by fragments derived from a larger molecule, proopiomelanocortin (POMC) and include ACTH, alpha beta and gamma-MSH and beta-endorphin. Because of in vitro and in vivo data suggesting direct effects of these POMC molecules on bone and bone turnover, we examined bone and bone derived cells for the presence of the various members of the melanocortin receptor family. We report that the five known melanocortin receptors are expressed to varying degrees in osteoblast-like and osteoclastic cells. POMC fragments increased proliferation and expression of a variety of genes in osteoblastic cells. Furthermore, POMC mRNA was detected in osteoclastic cells. These data demonstrate that POMC-derived peptide hormones acting through high affinity melanocortin receptors have specific effects on bone cells. Thus, in addition to the indirect effects of POMC-derived hormones on bone turnover through their modulation of steroid hormone secretion, POMC fragments may have direct and specific effects on bone cell subpopulations.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tsukahara, Tamotsu, E-mail: ttamotsu@shinshu-u.ac.jp; Haniu, Hisao; Matsuda, Yoshikazu

    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,more » 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.« less

  16. Nymphaea nouchali Burm. f. hydroalcoholic seed extract increases glucose consumption in 3T3-L1 adipocytes through activation of peroxisome proliferator-activated receptor gamma and insulin sensitization

    PubMed Central

    Parimala, Mabel; Debjani, M.; Vasanthi, Hannah Rachel; Shoba, Francis Gricilda

    2015-01-01

    Nymphaea nouchali Burm. f. (Family – Nymphaeaceae) is a well-known medicinal plant used in the Indian ayurvedic system of medicine for treating diabetes. The seeds especially have been prescribed for diabetes. The hydroalcoholic extract of N. nouchali seeds has been demonstrated to possess anti-hyperglycemic effects in diabetic rats, but the functional mechanism remains unknown. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ) is noted to play an important role in glucose and lipid homeostasis. This study was hence focused in evaluating the effect of the extract on PPARγ activation, adipocyte differentiation, and glucose consumption in 3T3-L1 cells. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), followed by adipogenesis assay using Oil Red O technique. Glucose consumption of preadipocytes and adipocytes in the presence of the extract was also determined. Real-time polymerase chain reaction was performed to identify the expression of genes involved in glucose consumption in the adipocytes. MTT assay confirmed the extract to be nontoxic, and Oil Red O staining confirmed enhanced adipocyte differentiation of 3T3-L1 cells in a dose-dependent manner. The extract also increased the expression of PPARγ target gene, which in turn enhanced the expression of GLUT-4. The data, therefore, suggests that N. nouchali seed extract promotes adipocyte differentiation and glucose consumption by inducing PPARγ activation, which in turn increases mRNA GLUT-4 expression and subsequently enhances insulin-responsiveness in insulin target tissues. PMID:26605160

  17. Formation of gamma(sup prime)-Ni3Al via the Peritectoid Reaction: gamma + beta (+ Al2O3)=gamma(sup prime)(+ Al2O3)

    NASA Technical Reports Server (NTRS)

    Copeland, Evan

    2008-01-01

    The activities of Al and Ni were measured using multi-cell Knudsen effusion-cell mass spectrometry (multi-cell KEMS), over the composition range 8-32 at.%Al and temperature range T=1400-1750 K in the Ni-Al-O system. These measurements establish that equilibrium solidification of gamma(sup prime)-Ni3Al-containing alloys occurs by the eutectic reaction, L (+ Al2O3)=gamma + Beta(+ Al2O3), at 1640 +/- 1 K and a liquid composition of 24.8 +/- 0.2 at.%al (at an unknown oxygen content). The {gamma + Beta (+Al2O3} phase field is stable over the temperature range 1633-1640 K, and gamma(sup prime)-Ni3Al forms via the peritectoid, gamma + Beta (+ Al2O3)=gamma(sup prime) (+ Al2O3), at 1633 +/- 1 K. This behavior is consistent with the current Ni-Al phase diagram and a new diagram is proposed. This new Ni-Al phase diagram explains a number of unusual steady-state solidification structures reported previously and provides a much simpler reaction scheme in the vicinity of the gamma(sup prime)-Ni2Al phase field.

  18. Method and system for determining radiation shielding thickness and gamma-ray energy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Klann, Raymond T.; Vilim, Richard B.; de la Barrera, Sergio

    2015-12-15

    A system and method for determining the shielding thickness of a detected radiation source. The gamma ray spectrum of a radiation detector is utilized to estimate the shielding between the detector and the radiation source. The determination of the shielding may be used to adjust the information from known source-localization techniques to provide improved performance and accuracy of locating the source of radiation.

  19. Terrestrial gamma-ray flashes

    NASA Astrophysics Data System (ADS)

    Marisaldi, Martino; Fuschino, Fabio; Labanti, Claudio; Tavani, Marco; Argan, Andrea; Del Monte, Ettore; Longo, Francesco; Barbiellini, Guido; Giuliani, Andrea; Trois, Alessio; Bulgarelli, Andrea; Gianotti, Fulvio; Trifoglio, Massimo

    2013-08-01

    Lightning and thunderstorm systems in general have been recently recognized as powerful particle accelerators, capable of producing electrons, positrons, gamma-rays and neutrons with energies as high as several tens of MeV. In fact, these natural systems turn out to be the highest energy and most efficient natural particle accelerators on Earth. Terrestrial Gamma-ray Flashes (TGFs) are millisecond long, very intense bursts of gamma-rays and are one of the most intriguing manifestation of these natural accelerators. Only three currently operative missions are capable of detecting TGFs from space: the RHESSI, Fermi and AGILE satellites. In this paper we review the characteristics of TGFs, including energy spectrum, timing structure, beam geometry and correlation with lightning, and the basic principles of the associated production models. Then we focus on the recent AGILE discoveries concerning the high energy extension of the TGF spectrum up to 100 MeV, which is difficult to reconcile with current theoretical models.

  20. The Advanced Gamma-ray Imaging System (AGIS): Camera Electronics Designs

    NASA Astrophysics Data System (ADS)

    Tajima, H.; Buckley, J.; Byrum, K.; Drake, G.; Falcone, A.; Funk, S.; Holder, J.; Horan, D.; Krawczynski, H.; Ong, R.; Swordy, S.; Wagner, R.; Williams, D.

    2008-04-01

    AGIS, a next generation of atmospheric Cherenkov telescope arrays, aims to achieve a sensitivity level of a milliCrab for gamma-ray observations in the energy band of 40 GeV to 100 TeV. Such improvement requires cost reduction of individual components with high reliability in order to equip the order of 100 telescopes necessary to achieve the sensitivity goal. We are exploring several design concepts to reduce the cost of camera electronics while improving their performance. These design concepts include systems based on multi-channel waveform sampling ASIC optimized for AGIS, a system based on IIT (image intensifier tube) for large channel (order of 1 million channels) readout as well as a multiplexed FADC system based on the current VERITAS readout design. Here we present trade-off in the studies of these design concepts.

  1. Interaction of Plant Extracts with Central Nervous System Receptors

    PubMed Central

    Lundstrom, Kenneth; Pham, Huyen Thanh; Dinh, Long Doan

    2017-01-01

    Background: Plant extracts have been used in traditional medicine for the treatment of various maladies including neurological diseases. Several central nervous system receptors have been demonstrated to interact with plant extracts and components affecting the pharmacology and thereby potentially playing a role in human disease and treatment. For instance, extracts from Hypericum perforatum (St. John’s wort) targeted several CNS receptors. Similarly, extracts from Piper nigrum, Stephania cambodica, and Styphnolobium japonicum exerted inhibition of agonist-induced activity of the human neurokinin-1 receptor. Methods: Different methods have been established for receptor binding and functional assays based on radioactive and fluorescence-labeled ligands in cell lines and primary cell cultures. Behavioral studies of the effect of plant extracts have been conducted in rodents. Plant extracts have further been subjected to mood and cognition studies in humans. Results: Mechanisms of action at molecular and cellular levels have been elucidated for medicinal plants in support of standardization of herbal products and identification of active extract compounds. In several studies, plant extracts demonstrated affinity to a number of CNS receptors in parallel indicating the complexity of this interaction. In vivo studies showed modifications of CNS receptor affinity and behavioral responses in animal models after treatment with medicinal herbs. Certain plant extracts demonstrated neuroprotection and enhanced cognitive performance, respectively, when evaluated in humans. Noteworthy, the penetration of plant extracts and their protective effect on the blood-brain-barrier are discussed. Conclusion: The affinity of plant extracts and their isolated compounds for CNS receptors indicates an important role for medicinal plants in the treatment of neurological disorders. Moreover, studies in animal and human models have confirmed a scientific basis for the application of medicinal

  2. Olfactory bulb gamma oscillations are enhanced with task demands.

    PubMed

    Beshel, Jennifer; Kopell, Nancy; Kay, Leslie M

    2007-08-01

    Fast oscillations in neural assemblies have been proposed as a mechanism to facilitate stimulus representation in a variety of sensory systems across animal species. In the olfactory system, intervention studies suggest that oscillations in the gamma frequency range play a role in fine odor discrimination. However, there is still no direct evidence that such oscillations are intrinsically altered in intact systems to aid in stimulus disambiguation. Here we show that gamma oscillatory power in the rat olfactory bulb during a two-alternative choice task is modulated in the intact system according to task demands with dramatic increases in gamma power during discrimination of molecularly similar odorants in contrast to dissimilar odorants. This elevation in power evolves over the course of criterion performance, is specific to the gamma frequency band (65-85 Hz), and is independent of changes in the theta or beta frequency band range. Furthermore, these high amplitude gamma oscillations are restricted to the olfactory bulb, such that concurrent piriform cortex recordings show no evidence of enhanced gamma power during these high-amplitude events. Our results display no modulation in the power of beta oscillations (15-28 Hz) shown previously to increase with odor learning in a Go/No-go task, and we suggest that the oscillatory profile of the olfactory system may be influenced by both odor discrimination demands and task type. The results reported here indicate that enhancement of local gamma power may reflect a switch in the dynamics of the system to a strategy that optimizes stimulus resolution when input signals are ambiguous.

  3. Critical role of FcR gamma-chain, LAT, PLCgamma2 and thrombin in arteriolar thrombus formation upon mild, laser-induced endothelial injury in vivo.

    PubMed

    Kalia, Neena; Auger, Jocelyn M; Atkinson, Ben; Watson, Steve P

    2008-05-01

    The role of collagen receptor complex GPVI-FcR gamma-chain, PLCgamma2 and LAT in laser-induced thrombosis is unclear. Controversy surrounds whether collagen is exposed in this model or whether thrombosis is dependent on thrombin. This study hypothesized that collagen exposure plays a critical role in thrombus formation in this model, which was tested by investigating contributions of FcR gamma-chain, LAT, PLCgamma2 and thrombin. Thrombi were monitored using intravital microscopy in anesthetized wild-type and FcR gamma-chain, LAT and PLCgamma2 knockout mice. Hirudin (thrombin inhibitor) was administered to wild-type and FcR gamma-chain knockout mice. Significantly reduced thrombus formation was observed in FcR gamma-chain and PLCgamma2 knockouts with a greater decrease observed in LAT knockouts. Dramatic reduction was observed in wild-types treated with hirudin, with abolished thrombus formation only observed in FcR gamma-chain knockouts treated with hirudin. GPVI-FcR gamma-chain, LAT and PLCgamma2 are essential for thrombus generation and stability in this laser-induced model of injury. More importantly, a greater role for LAT was identified, which may reflect a role for it downstream of a second matrix protein receptor. However, inhibition of platelet activation by matrix proteins and thrombin generation are both required to maximally prevent thrombus formation.

  4. Role of amino acids in salivation and the localization of their receptors in the rat salivary gland.

    PubMed

    Shida, T; Kondo, E; Ueda, Y; Takai, N; Yoshida, Y; Araki, T; Kiyama, H; Tohyama, M

    1995-11-01

    The distribution of gamma-aminobutyric acid (GABA) receptor subunits such as GABAAR-gamma 1 and GABAAR-gamma 2, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptor subunits such as GluR-1, GluR-2/3 and GluR-4, and N-methyl-D-aspartic acid (NMDA) type subunits such as NR1 were investigated by immunocytochemistry. Furthermore, the roles of these amino acids, GABA and glutamate, on salivation were analyzed in the rat submandibular and sublingual glands. Some similarities were observed in the distribution patterns of GABAA type receptors and AMPA receptors. In the submandibular ganglion cells, collecting ducts and striated ducts, these subunits were expressed strongly; however, there were some differences in their expression patterns between the submandibular and sublingual gland acinar cells. Since these receptor subunits were expressed in the acinar cell bodies of the submandibular gland, they were not expressed in the acinar cells but were expressed in the myoepithelial cells in the sublingual gland. On the other hand, no NR1 expression was observed. To examine the roles of GABA and glutamate in salivation, the submandibular and sublingual glands were perfused partially with Ringer's solution via a facial artery to avoid systemic influence, and substrates were infused into the perfusion solution. No salivary secretion was evoked by GABA or glutamate infusion in the absence of electrical stimulation (2-3 V, 5 ms, 20 Hz). Salivary flow evoked by electrical stimulation of the chorda-lingual nerve caused significant inhibition by GABA (10(-6), 10(-5), 10(-4) and 10(-3) M) and the GABAAR agonist muscimol 10(-3) and 10(-6) M) (n = 6, P < 0.05). Such GABA-induced inhibition was antagonized by the GABAAR antagonists bicuculline (BCC; 10(-6) and 10(-3) M) and picrotoxin (PTX; 10(-6) and 10(-3) M). On the other hand, salivary flow evoked by electrical stimulation (8-10 V, 5 ms, 20 Hz) of the superior cervical ganglion (SCG) was not affected by

  5. Registered particles onboard identification in the various apertures of GAMMA-400 space gamma-telescope

    NASA Astrophysics Data System (ADS)

    Arkhangelskaja, Irene

    2016-07-01

    GAMMA-400 (Gamma Astronomical Multifunctional Modular Apparatus) will be the gamma-telescope onboard international satellite gamma-observatory designed for particle registration in the wide energy band. Its parameters are optimized for detection of gamma-quanta with the energy ˜ 100 GeV in the main aperture. The main scientific goals of GAMMA-400 are to investigate fluxes of γ-rays and the electron-positron cosmic ray component possibly generated by dark matter particles decay or annihilation and to search for and study in detail discrete γ-ray sources, to investigate the energy spectra of Galactic and extragalactic diffuse γ-rays, and to study γ-ray bursts and γ-emission from the active Sun. This article presents analysis of detected events identification procedures and energy resolution in three apertures provide particles registration both from upper and lateral directions based on GAMMA-400 modeling due special designed software. Time and segmentation methods are used to reject backsplash (backscattering particles created when high energy γ-rays interact with the calorimeter's matter and move in the opposite direction) in the main aperture while only energy deposition analysis allows to reject this effect in the additional and lateral ones. The main aperture provides the best angular (all strip layers information analysis) and energy (energy deposition in the all detectors studying) resolution in the energy range 0.1 - 3 × 10^{3} GeV. The energy resolution in this band is 1%. Triggers in the main aperture will be formed using information about particle direction provided by time of flight system and presence of charged particle or backsplash signal formed according to analysis of energy deposition in combination of all two-layers anticoincidence systems individual detectors. In the additional aperture gamma-telescope allows to register events in the energy band 10 × 10^{-3} - 3 × 10^{3} GeV. The additional aperture energy resolution provides due to

  6. Interferon-gamma: biologic functions and HCV therapy (type I/II) (1 of 2 parts).

    PubMed

    Gattoni, A; Parlato, A; Vangieri, B; Bresciani, M; Derna, R

    2006-01-01

    This review is aimed at exhaustively presenting and discussing the interferon-gamma (IFN-gamma), a cytokine that plays an important role in inducing and modulating an array of immune responses. A review of the most significant and recent clinical trials was performed. Although IFN-gamma has some antiviral activity, it is much less active in this regard than type I IFNs. IFN-gamma is involved in the regulation of nearly all phases of the immune and inflammatory responses, including the activation and differentiation of T cells, B cells, NK cells, macrophages, and others. It is therefore best regarded as a distint immunoregulatory cytokine. IFN-gamma secretion is a hallmark of Th1 lymphocytes. It is also secreted by nearly all CD8 T cells, by some Th0 cells, and by NK cells. Each of these cell types secretes IFN-gamma only when activated, usually as part of immune response and especially in response to IL-2 and IL-12. IFN-gamma production is inhibited by IL-4, IL-10, TGFbeta, glucocorticoids, cyclosporin A and FK506. Nearly all cell types express the heterodimeric receptor for IFN-beta and respond to this cytokine by increasing the surface expression of class I MHC proteins. As a result, virtually any cell in the vicinity of an IFN-beta-secreting cell becomes more efficient at presenting endogenous antigens and hence a better target for cytotoxic killing if it harbors an intracellular pathogen. Unlike the type I IFNs, IFN-gamma also increases the expression of class II MHC proteins on professional APCs, and so promotes antigen presentation to helper T cells as well. It also induces de novo expression of class II MHC proteins on venular endothelial cells and on some other epithelial and connective tissue cells that do not otherwise express them, thus enabling these cell types to function as temporary APCs at sites of intense immune reactions. The effector functions of NK cells are to lyse virus-infected cells and to secrete IFN-gamma, which activates macrofages to

  7. Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors.

    PubMed Central

    Hermans, E; Challiss, R A

    2001-01-01

    In 1991 a new type of G-protein-coupled receptor (GPCR) was cloned, the type 1a metabotropic glutamate (mGlu) receptor, which, despite possessing the defining seven-transmembrane topology of the GPCR superfamily, bore little resemblance to the growing number of other cloned GPCRs. Subsequent studies have shown that there are eight mammalian mGlu receptors that, together with the calcium-sensing receptor, the GABA(B) receptor (where GABA is gamma-aminobutyric acid) and a subset of pheromone, olfactory and taste receptors, make up GPCR family C. Currently available data suggest that family C GPCRs share a number of structural, biochemical and regulatory characteristics, which differ markedly from those of the other GPCR families, most notably the rhodopsin/family A GPCRs that have been most widely studied to date. This review will focus on the group I mGlu receptors (mGlu1 and mGlu5). This subgroup of receptors is widely and differentially expressed in neuronal and glial cells within the brain, and receptor activation has been implicated in the control of an array of key signalling events, including roles in the adaptative changes needed for long-term depression or potentiation of neuronal synaptic connectivity. In addition to playing critical physiological roles within the brain, the mGlu receptors are also currently the focus of considerable attention because of their potential as drug targets for the treatment of a variety of neurological and psychiatric disorders. PMID:11672421

  8. [The role of gamma-aminobutyric acid in the mechanism of action of anticonvulsant drugs].

    PubMed

    Chmielewska, B

    2000-01-01

    Decreased activity of gamma-aminobutyric acid, the major inhibitory neurotransmitter in CNS can be epileptogenic. Manipulation of the GABA system has been a target for development of antiepileptic drugs. The different ways for augmenting gabaergic inhibition by conventional and new AEDs are presented in this paper. Among the I generation, barbiturates and benzodiazepines are potent anticonvulsants that act as GABA modulators in postsynaptic GABA-A receptor complex but their usefulness is limited by dependence and tolerance to antiseizure activity. The II generation drugs vigabatrin and tiagabine, and to some extent gabapentin have been developed by a rationale strategy and none of them exert direct action in GABA receptors. Only two former drugs exhibit selective, strictly defined activity: vigabatrine is an irreversible inhibitor of GABA-aminotransferase and tiagabine acts as a GABA-uptake inhibitor from synaptic cleft into neurons and glia. Gabapentin binds to a novel receptors in epileptogenic areas in CNS and enhances GABA turnover. Drugs with multiple mechanisms of action, felbamate and topiramate not only potentiate gabaergic inhibition in several ways but also diminish the activity of excitatory amino acids at their NMDA or AMPA receptors; the later mechanism seems to be essential for their potential neuroprotective activity in epileptogenesis. None of gabamimetic drugs provide optimal seizure control but better tolerability of newer ones and well-established mechanisms of action provide possible harmless therapy.

  9. Effects of Germinated Brown Rice and Its Bioactive Compounds on the Expression of the Peroxisome Proliferator-Activated Receptor Gamma Gene

    PubMed Central

    Imam, Mustapha Umar; Ismail, Maznah; Ithnin, Hairuszah; Tubesha, Zaki; Omar, Abdul Rahman

    2013-01-01

    Dysregulated metabolism is implicated in obesity and other disease conditions like type 2 diabetes mellitus and cardiovascular diseases, which are linked to abnormalities of peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ has been the focus of much research aimed at managing these diseases. Also, germinated brown rice (GBR) is known to possess antidiabetic, antiobesity and hypocholesterolemic effects. We hypothesized that GBR bioactive compounds may mediate some of the improvements in metabolic indices through PPARγ modulation. Cultured HEP-G2 cells were treated with 50 ppm and 100 ppm of extracts from GBR (GABA, ASG and oryzanol) after determination of cell viabilities using MTT assays. Results showed that all extracts upregulated the expression of the PPARγ. However, combination of all three extracts showed downregulation of the gene, suggesting that, in combination, the effects of these bioactives differ from their individual effects likely mediated through competitive inhibition of the gene. Upregulation of the gene may have therapeutic potential in diabetes mellitus and cardiovascular diseases, while its downregulation likely contributes to GBR’s antiobesity effects. These potentials are worth studying further. PMID:23389305

  10. Immunoregulatory actions of epithelial cell PPAR gamma at the colonic mucosa of mice with experimental inflammatory bowel disease.

    PubMed

    Mohapatra, Saroj K; Guri, Amir J; Climent, Montse; Vives, Cristina; Carbo, Adria; Horne, William T; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-04-20

    Peroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC) and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR gamma in IEC on progression of experimental inflammatory bowel disease (IBD). In the first phase, PPAR gamma flfl; Villin Cre- (VC-) and PPAR gamma flfl; Villin Cre+ (VC+) mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS) in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR gamma. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR gamma in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI) or weight loss. In contrast, the IEC-specific PPAR gamma null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR gamma in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN) of IEC-specific PPAR gamma null mice. Our results demonstrate that adequate expression of PPAR gamma in IEC is required for the regulation of mucosal immune responses and prevention of experimental IBD, possibly by modulation of

  11. PACAP/Receptor System in Urinary Bladder Dysfunction and Pelvic Pain Following Urinary Bladder Inflammation or Stress

    PubMed Central

    Girard, Beatrice M.; Tooke, Katharine; Vizzard, Margaret A.

    2017-01-01

    Complex organization of CNS and PNS pathways is necessary for the coordinated and reciprocal functions of the urinary bladder, urethra and urethral sphincters. Injury, inflammation, psychogenic stress or diseases that affect these nerve pathways and target organs can produce lower urinary tract (LUT) dysfunction. Numerous neuropeptide/receptor systems are expressed in the neural pathways of the LUT and non-neural components of the LUT (e.g., urothelium) also express peptides. One such neuropeptide receptor system, pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1) and its cognate receptor, PAC1 (Adcyap1r1), have tissue-specific distributions in the LUT. Mice with a genetic deletion of PACAP exhibit bladder dysfunction and altered somatic sensation. PACAP and associated receptors are expressed in the LUT and exhibit neuroplastic changes with neural injury, inflammation, and diseases of the LUT as well as psychogenic stress. Blockade of the PACAP/PAC1 receptor system reduces voiding frequency in preclinical animal models and transgenic mouse models that mirror some clinical symptoms of bladder dysfunction. A change in the balance of the expression and resulting function of the PACAP/receptor system in CNS and PNS bladder reflex pathways may underlie LUT dysfunction including symptoms of urinary urgency, increased voiding frequency, and visceral pain. The PACAP/receptor system in micturition pathways may represent a potential target for therapeutic intervention to reduce LUT dysfunction. PMID:29255407

  12. Platelet-derived growth factor receptor mediates activation of ras through different signaling pathways in different cell types.

    PubMed Central

    Satoh, T; Fantl, W J; Escobedo, J A; Williams, L T; Kaziro, Y

    1993-01-01

    A series of pieces of evidence have shown that Ras protein acts as a transducer of the platelet-derived growth factor (PDGF) receptor-mediated signaling pathway: (i) formation of Ras.GTP is detected immediately on PDGF stimulation, and (ii) a dominant inhibitory mutant Ras, as well as a neutralizing anti-Ras antibody, can interfere with PDGF-induced responses. On the other hand, several signal transducing molecules including phosphatidylinositol 3-kinase (PI3-K), GTPase-activating protein (GAP), and phospholipase C gamma (PLC gamma) bind directly to the PDGF receptor and become tyrosine phosphorylated. Recently, it was shown that specific phosphorylated tyrosines of the PDGF receptor are responsible for interaction between the receptor and each signaling molecule. However, the roles of these signaling molecules have not been elucidated, and it remains unclear which molecules are implicated in the Ras pathway. In this study, we measured Ras activation in cell lines expressing mutant PDGF receptors that are deficient in coupling with specific molecules. In fibroblast CHO cells, a mutant receptor (Y708F/Y719F [PI3-K-binding sites]) was unable to stimulate Ras, whereas another mutant (Y739F [the GAP-binding site]) could do so, suggesting an indispensable role of PI3-K or a protein that binds to the same sites as PI3-K for PDGF-stimulated Ras activation. By contrast, both of the above mutants were capable of stimulating Ras protein in a pro-B-cell line, BaF3. Furthermore, a mutant receptor (Y977F/Y989F [PLC gamma-binding sites]) could fully activate Ras, and the direct activation of protein kinase C and calcium mobilization had almost no effect on the GDP/GTP state of Ras in this cell line. These results suggest that, in the pro-B-cell transfectants, each of the above pathways (PI3-K, GAP, and PLC gamma) can be eliminated without a loss of Ras activation. It remains unclear whether another unknown essential pathway which regulates Ras protein exists within BaF3 cells

  13. On the G-Protein-Coupled Receptor Heteromers and Their Allosteric Receptor-Receptor Interactions in the Central Nervous System: Focus on Their Role in Pain Modulation

    PubMed Central

    Borroto-Escuela, Dasiel O.; Romero-Fernandez, Wilber; Rivera, Alicia; Van Craenenbroeck, Kathleen; Tarakanov, Alexander O.; Agnati, Luigi F.; Fuxe, Kjell

    2013-01-01

    The modulatory role of allosteric receptor-receptor interactions in the pain pathways of the Central Nervous System and the peripheral nociceptors has become of increasing interest. As integrators of nociceptive and antinociceptive wiring and volume transmission signals, with a major role for the opioid receptor heteromers, they likely have an important role in the pain circuits and may be involved in acupuncture. The delta opioid receptor (DOR) exerts an antagonistic allosteric influence on the mu opioid receptor (MOR) function in a MOR-DOR heteromer. This heteromer contributes to morphine-induced tolerance and dependence, since it becomes abundant and develops a reduced G-protein-coupling with reduced signaling mainly operating via β-arrestin2 upon chronic morphine treatment. A DOR antagonist causes a return of the Gi/o binding and coupling to the heteromer and the biological actions of morphine. The gender- and ovarian steroid-dependent recruitment of spinal cord MOR/kappa opioid receptor (KOR) heterodimers enhances antinociceptive functions and if impaired could contribute to chronic pain states in women. MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, mediating morphine induced itch. Other mechanism for the antinociceptive actions of acupuncture along meridians may be that it enhances the cross-desensitization of the TRPA1 (chemical nociceptor)-TRPV1 (capsaicin receptor) heteromeric channel complexes within the nociceptor terminals located along these meridians. Selective ionotropic cannabinoids may also produce cross-desensitization of the TRPA1-TRPV1 heteromeric nociceptor channels by being negative allosteric modulators of these channels leading to antinociception and antihyperalgesia. PMID:23956775

  14. The effects of AMPA receptor blockade on resting magnetoencephalography recordings.

    PubMed

    Routley, Bethany C; Singh, Krish D; Hamandi, Khalid; Muthukumaraswamy, Suresh D

    2017-12-01

    The ionotropic N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors of the glutamatergic neurotransmitter system are of fundamental importance to healthy brain function. Neuroimaging studies in humans have previously been conducted using various drugs that interact with N-methyl-D-aspartate glutamate receptors, but no such studies have investigated AMPA receptor signalling. The recent approval of perampanel (Fycompa) for use in humans provides a means to specifically study the role of AMPA receptors in the pharmacological basis of neuroimaging signals. Twenty male subjects participated in this placebo-controlled crossover study that consisted of two study days separated by a minimum two-week washout period. On one occasion participants ingested a 6 mg dose of perampanel, and on the other a placebo. Ten minutes of wakeful rest was recorded before and after each dose using magnetoencephalography. Subjective ratings of intoxication were significantly higher following drug than placebo. Cluster-based randomisation testing of sensor-level magnetoencephalography data showed significant drug-induced increases in low frequency power (1-4 Hz, 4-8 Hz, 8-13 Hz, 13-30 Hz), along with a significant decrease in the high gamma range (50-90 Hz). We also observed selective increases in functional connectivity in the alpha and beta bands. The findings are consistent with preclinical work and are similar to the spectral profile of other anti-epileptic drugs.

  15. Studying the High Energy Gamma Ray Sky with Gamma Ray Large Area Space Telescope (GLAST)

    NASA Technical Reports Server (NTRS)

    Kamae, T.; Ohsugi, T.; Thompson, D. J.; Watanabe, K.

    1998-01-01

    Building on the success of the Energetic Gamma Ray Experiment Telescope (EGRET) on the Compton Gamma Ray Observatory, the Gamma Ray Large Area Space Telescope (GLAST) will make a major step in the study of such subjects as blazars, gamma Ray bursts, the search for dark matter, supernova remnants, pulsars, diffuse radiation, and unidentified high energy sources. The instrument will be built on new and mature detector technologies such as silicon strip detectors, low-power low-noise LSI, and a multilevel data acquisition system. GLAST is in the research and development phase, and one full tower (of 25 total) is now being built in collaborating institutes. The prototype tower will be tested thoroughly at Stanford Linear Accelerator Center (SLAC) in the fall of 1999.

  16. Cell surface control of the multiubiquitination and deubiquitination of high-affinity immunoglobulin E receptors.

    PubMed Central

    Paolini, R; Kinet, J P

    1993-01-01

    Multiubiquitination of proteins is a critical step leading to selective degradation for many polypeptides. Therefore, activation-induced multiubiquitination of cell surface receptors, such as the platelet-derived growth factor (PDGF) receptor and the T cell antigen (TCR) receptor, may correspond to a degradation pathway for ligand-receptor complexes. Here we show that the antigen-induced engagement of high-affinity immunoglobulin E receptors (Fc epsilon RI) results in the immediate multiubiquitination of Fc epsilon RI beta and gamma chains. This ubiquitination is independent of receptor phosphorylation and is restricted to activated receptors. Surprisingly, receptor multiubiquitination is immediately reversible when receptors are disengaged. Therefore, multiubiquitination and deubiquitination of Fc epsilon RI receptors is controlled at the cell surface by receptor engagement and disengagement. The rapidity, specificity and, most importantly, the reversibility of the activation-induced receptor multiubiquitination suggest that this process may turn on/off a cell surface receptor signaling function thus far unsuspected. Images PMID:8382611

  17. A novel system of polymorphic and diverse NK cell receptors in primates.

    PubMed

    Averdam, Anne; Petersen, Beatrix; Rosner, Cornelia; Neff, Jennifer; Roos, Christian; Eberle, Manfred; Aujard, Fabienne; Münch, Claudia; Schempp, Werner; Carrington, Mary; Shiina, Takashi; Inoko, Hidetoshi; Knaust, Florian; Coggill, Penny; Sehra, Harminder; Beck, Stephan; Abi-Rached, Laurent; Reinhardt, Richard; Walter, Lutz

    2009-10-01

    There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in "higher" primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire.

  18. A Novel System of Polymorphic and Diverse NK Cell Receptors in Primates

    PubMed Central

    Rosner, Cornelia; Neff, Jennifer; Roos, Christian; Eberle, Manfred; Aujard, Fabienne; Münch, Claudia; Schempp, Werner; Carrington, Mary; Shiina, Takashi; Inoko, Hidetoshi; Knaust, Florian; Coggill, Penny; Sehra, Harminder; Beck, Stephan; Abi-Rached, Laurent; Reinhardt, Richard; Walter, Lutz

    2009-01-01

    There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in “higher” primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire. PMID:19834558

  19. Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

    PubMed Central

    Bruchas, Michael R.; Calo', Girolamo; Cox, Brian M.; Zaveri, Nurulain T.

    2016-01-01

    The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor. PMID:26956246

  20. Focal Plane Detectors for the Advanced Gamma-Ray Imaging System (AGIS)

    NASA Astrophysics Data System (ADS)

    Otte, A. N.; Byrum, K.; Drake, G.; Falcone, A.; Funk, S.; Horan, D.; Mukherjee, R.; Smith, A.; Tajima, H.; Wagner, R. G.; Williams, D. A.

    2008-12-01

    The Advanced Gamma-Ray Imaging System (AGIS) is a concept for the next generation observatory in ground-based very high energy gamma-ray astronomy. Design goals are ten times better sensitivity, higher angular resolution, and a lower energy threshold than existing Cherenkov telescopes. Simulations show that a substantial improvement in angular resolution may be achieved if the pixel diameter is reduced to the order of 0.05 deg, i.e. two to three times smaller than the pixel diameter of current Cherenkov telescope cameras. At these dimensions, photon detectors with smaller physical dimensions can be attractive alternatives to the classical photomultiplier tube (PMT). Furthermore, the operation of an experiment with the size of AGIS requires photon detectors that are among other things more reliable, more durable, and possibly higher efficiency photon detectors. Alternative photon detectors we are considering for AGIS include both silicon photomultipliers (SiPMs) and multi-anode photomultipliers (MAPMTs). Here we present results from laboratory testing of MAPMTs and SiPMs along with results from the first incorporation of these devices into cameras on test bed Cherenkov telescopes.

  1. A gamma-gamma coincidence/anticoincidence spectrometer for low-level cosmogenic (22)Na/(7)Be activity ratio measurement.

    PubMed

    Zhang, Weihua; Ungar, Kurt; Stukel, Matthew; Mekarski, Pawel

    2014-04-01

    In this study, a digital gamma-gamma coincidence/anticoincidence spectrometer was developed and examined for low-level cosmogenic (22)Na and (7)Be in air-filter sample monitoring. The spectrometer consists of two bismuth germanate scintillators (BGO) and an XIA LLC Digital Gamma Finder (DGF)/Pixie-4 software and card package. The spectrometer design allows a more selective measurement of (22)Na with a significant background reduction by gamma-gamma coincidence events processing. Hence, the system provides a more sensitive way to quantify trace amounts of (22)Na than normal high resolution gamma spectrometry providing a critical limit of 3 mBq within a 20 h count. The use of a list-mode data acquisition technique enabled simultaneous determination of (22)Na and (7)Be activity concentrations using a single measurement by coincidence and anticoincidence mode respectively. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Gamma camera dual imaging with a somatostatin receptor and thymidine kinase after gene transfer with a bicistronic adenovirus in mice.

    PubMed

    Zinn, Kurt R; Chaudhuri, Tandra R; Krasnykh, Victor N; Buchsbaum, Donald J; Belousova, Natalya; Grizzle, William E; Curiel, David T; Rogers, Buck E

    2002-05-01

    To compare two systems for assessing gene transfer to cancer cells and xenograft tumors with noninvasive gamma camera imaging. A replication-incompetent adenovirus encoding the human type 2 somatostatin receptor (hSSTr2) and the herpes simplex virus thymidine kinase (TK) enzyme (Ad-hSSTr2-TK) was constructed. A-427 human lung cancer cells were infected in vitro and mixed with uninfected cells at different ratios. A-427 tumors in nude mice (n = 23) were injected with 1 x 10(6) to 5 x 10(8) plaque-forming units (pfu) of Ad-hSSTr2-TK. The expressed hSSTr2 and TK proteins were imaged owing to internally bound, or trapped, technetium 99m ((99m)Tc)-labeled hSSTr2-binding peptide (P2045) and radioiodinated 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodouracil (FIAU), respectively. Iodine 125 ((125)I)-labeled FIAU was used in vitro and iodine 131 ((131)I)-labeled FIAU, in vivo. The (99m)Tc-labeled P2045 and (125)I- or (131)I-labeled FIAU were imaged simultaneously with different window settings with an Anger gamma camera. Treatment effects were tested with analysis of variance. Infected cells in culture trapped (125)I-labeled FIAU and (99m)Tc-labeled P2045; uptake correlated with the percentage of Ad-hSSTr2-TK-positive cells. For 100% of infected cells, 24% +/- 0.4 (mean +/- SD) of the added (99m)Tc-labeled P2045 was trapped, which is significantly lower (P <.05) than the 40% +/- 2 of (125)I-labeled FIAU that was trapped. For the highest Ad-hSSTr2-TK tumor dose (5 x 10(8) pfu), the uptake of (99m)Tc-labeled P2045 was 11.1% +/- 2.9 of injected dose per gram of tumor (thereafter, dose per gram), significantly higher (P <.05) than the uptake of (131)I-labeled FIAU at 1.6% +/- 0.4 dose per gram. (99m)Tc-labeled P2045 imaging consistently depicted hSSTr2 gene transfer in tumors at all adenovirus doses. Tumor uptake of (99m)Tc-labeled P2045 positively correlated with Ad-hSSTr2-TK dose; (131)I-labeled FIAU tumor uptake did not correlate with vector dose. The hSSTr2 and TK

  3. gamma-Hexachlorocyclohexane (gamma-HCH)

    Integrated Risk Information System (IRIS)

    gamma - Hexachlorocyclohexane ( gamma - HCH ) ; CASRN 58 - 89 - 9 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Asse

  4. Mitochondria-dependent and -independent mechanisms in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis are both regulated by interferon-gamma in human breast tumour cells.

    PubMed Central

    Ruiz-Ruiz, Carmen; López-Rivas, Abelardo

    2002-01-01

    Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/APO-2L) induces apoptosis in a variety of tumour cells upon binding to death receptors TRAIL-R1 and TRAIL-R2. Here we describe the sensitization by interferon (IFN)-gamma to TRAIL-induced apoptosis in the breast tumour cell lines MCF-7 and MDA-MB231. IFN-gamma promoted TRAIL-mediated activation of caspase-8, Bcl-2 interacting domain death agonist (Bid) degradation, Bcl-2-associated X protein (Bax) translocation to mitochondria, cytochrome c release to the cytosol and activation of caspase-9 in these cell lines. No changes in the expression of TRAIL receptors were observed upon IFN-gamma treatment. Overexpression of Bcl-2 in MCF-7 cells completely inhibited IFN-gamma-induced sensitization to TRAIL-mediated cell death. Interestingly, TRAIL-induced apoptosis was also clearly enhanced by IFN-gamma in caspase-3-overexpressing MCF-7 cells, in the absence of Bax translocation to mitochondria and cytochrome c release to the cytosol. In summary, our results suggest that IFN-gamma facilitates TRAIL-induced activation of mitochondria-regulated as well as mitochondria-independent apoptotic pathways in breast tumour cells. PMID:11936954

  5. Distinct regulatory functions of SLP-76 and MIST in NK cell cytotoxicity and IFN-gamma production.

    PubMed

    Hidano, Shinya; Sasanuma, Hiroki; Ohshima, Keiko; Seino, Ken-ichiro; Kumar, Lalit; Hayashi, Katsuhiko; Hikida, Masaki; Kurosaki, Tomohiro; Taniguchi, Masaru; Geha, Raif S; Kitamura, Daisuke; Goitsuka, Ryo

    2008-03-01

    Activation of NK cells is triggered by multiple receptors. We demonstrate here that SLP-76 is required for CD16- and NKG2D-mediated NK cell cytotoxicity, while MIST negatively regulates these responses in an SLP-76-dependent manner. Exceptionally, MIST acts as a positive regulator of cytotoxicity against YAC-1 cells, although SLP-76 plays a more key role. SLP-76 acts as a dominant positive regulator for both NKG2D-mediated and YAC-1 cell-triggered IFN-gamma production. Although NKG2D-mediated IFN-gamma production depends on phospholipase C (PLC) gamma 2, YAC-1 cell-triggered IFN-gamma production is PLC gamma 2- and Syk/ZAP-70 independent and nuclear factor-kappa B mediated. SLP-76 is required for this process in the presence of MIST but is dispensable in the absence of MIST. Thus, YAC-1 cell-triggered NKG2D-independent IFN-gamma production appears to be regulated by SLP-76-dependent and -independent pathways, in which the latter is negatively regulated by MIST. Taken together, these results suggest that SLP-76 and MIST distinctly but interactively regulate NK cell cytotoxicity and IFN-gamma production.

  6. Comparison of penumbra regions produced by ancient Gamma knife model C and Gamma ART 6000 using Monte Carlo MCNP6 simulation.

    PubMed

    Banaee, Nooshin; Asgari, Sepideh; Nedaie, Hassan Ali

    2018-07-01

    The accuracy of penumbral measurements in radiotherapy is pivotal because dose planning computers require accurate data to adequately modeling the beams, which in turn are used to calculate patient dose distributions. Gamma knife is a non-invasive intracranial technique based on principles of the Leksell stereotactic system for open deep brain surgeries, invented and developed by Professor Lars Leksell. The aim of this study is to compare the penumbra widths of Leksell Gamma Knife model C and Gamma ART 6000. Initially, the structure of both systems were simulated by using Monte Carlo MCNP6 code and after validating the accuracy of simulation, beam profiles of different collimators were plotted. MCNP6 beam profile calculations showed that the penumbra values of Leksell Gamma knife model C and Gamma ART 6000 for 18, 14, 8 and 4 mm collimators are 9.7, 7.9, 4.3, 2.6 and 8.2, 6.9, 3.6, 2.4, respectively. The results of this study showed that since Gamma ART 6000 has larger solid angle in comparison with Gamma Knife model C, it produces better beam profile penumbras than Gamma Knife model C in the direct plane. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. G-Protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention.

    PubMed

    Conrad, Kirk P

    2016-09-01

    expected to (i) enhance endothelial nitric oxide synthesis and bioactivity, as well as directly reduce vascular smooth muscle cytosolic calcium, thus promoting vasodilation; (ii) improve the local angiogenic balance by augmenting arterial vascular endothelial and placental growth factor (VEGF and PLGF) activities; (iii) ameliorate vascular inflammation; (iv) enhance placental peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PCG1α) expression, and hence, peroxisome proliferator-activated receptor gamma (PPAR-γ) activity and (v) confer cytotrophoblast and endothelial cytoprotection. Insofar as impaired endometrial maturation (decidualization) predisposes to the development of preeclampsia, relaxin administration in the late secretory phase and during early pregnancy would be anticipated to improve decidualization, and hence trophoblast invasion and spiral artery remodeling, thereby reducing the risk of preeclampsia. Relaxin has a favorable safety profile both in the non-pregnant condition and during pregnancy. There is a strong scientific rationale for RXFP1 activation in severe preeclampsia by administration of relaxin, relaxin analogs or small molecule mimetics, in order to mollify the disease pathogenesis for safe prolongation of pregnancy, thus allowing time for more complete fetal maturation, which is a primary therapeutic endpoint in treating the disease. In light of recent data implicating deficient or defective decidualization as a potential etiological factor in preeclampsia and the capacity of relaxin to promote endometrial maturation, the prophylactic application of relaxin to reduce the risk of preeclampsia is a plausible therapeutic approach to consider. Finally, given its pleiotropic and beneficial attributes particularly in the cardiovascular system, relaxin, although traditionally considered as a 'pregnancy' hormone, is likely to prove salutary for several disease indications in the non-pregnant population. © The Author 2016

  8. G-Protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention

    PubMed Central

    Conrad, Kirk P.

    2016-01-01

    attributes in preeclampsia, relaxin supplementation is expected to (i) enhance endothelial nitric oxide synthesis and bioactivity, as well as directly reduce vascular smooth muscle cytosolic calcium, thus promoting vasodilation; (ii) improve the local angiogenic balance by augmenting arterial vascular endothelial and placental growth factor (VEGF and PLGF) activities; (iii) ameliorate vascular inflammation; (iv) enhance placental peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PCG1α) expression, and hence, peroxisome proliferator-activated receptor gamma (PPAR-γ) activity and (v) confer cytotrophoblast and endothelial cytoprotection. Insofar as impaired endometrial maturation (decidualization) predisposes to the development of preeclampsia, relaxin administration in the late secretory phase and during early pregnancy would be anticipated to improve decidualization, and hence trophoblast invasion and spiral artery remodeling, thereby reducing the risk of preeclampsia. Relaxin has a favorable safety profile both in the non-pregnant condition and during pregnancy. WIDER IMPLICATIONS There is a strong scientific rationale for RXFP1 activation in severe preeclampsia by administration of relaxin, relaxin analogs or small molecule mimetics, in order to mollify the disease pathogenesis for safe prolongation of pregnancy, thus allowing time for more complete fetal maturation, which is a primary therapeutic endpoint in treating the disease. In light of recent data implicating deficient or defective decidualization as a potential etiological factor in preeclampsia and the capacity of relaxin to promote endometrial maturation, the prophylactic application of relaxin to reduce the risk of preeclampsia is a plausible therapeutic approach to consider. Finally, given its pleiotropic and beneficial attributes particularly in the cardiovascular system, relaxin, although traditionally considered as a ‘pregnancy’ hormone, is likely to prove salutary for several

  9. Ethanol impairs activation of retinoic acid receptors in cerebellar granule cells in a rodent model of fetal alcohol spectrum disorders.

    PubMed

    Kumar, Ambrish; Singh, Chandra K; DiPette, Donald D; Singh, Ugra S

    2010-05-01

    Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations. In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells. The cerebellum of ethanol unexposed and exposed pups was used to study the expression of retinoic acid receptors (RARs or RXRs) by immunohistochemistry and by Western blot analysis. We also studied the effect of ethanol on expression of RA receptors in the cerebellar granule cells. Activation of RA receptors (DNA-binding activities) in response to high-dose ethanol was determined by electrophoretic mobility shift and supershift assays. Findings from these studies demonstrated that ethanol exposure reduced the expression of RARalpha/gamma while it increased the expression of RXRalpha/gamma in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure. For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells. Taken together, these findings could provide insight into the treatment options for brain defects

  10. Measuring two-dimensional receptor-ligand binding kinetics by micropipette.

    PubMed Central

    Chesla, S E; Selvaraj, P; Zhu, C

    1998-01-01

    We report a novel method for measuring forward and reverse kinetic rate constants, kf0 and kr0, for the binding of individual receptors and ligands anchored to apposing surfaces in cell adhesion. Not only does the method examine adhesion between a single pair of cells; it also probes predominantly a single receptor-ligand bond. The idea is to quantify the dependence of adhesion probability on contact duration and densities of the receptors and ligands. The experiment was an extension of existing micropipette protocols. The analysis was based on analytical solutions to the probabilistic formulation of kinetics for small systems. This method was applied to examine the interaction between Fc gamma receptor IIIA (CD16A) expressed on Chinese hamster ovary cell transfectants and immunoglobulin G (IgG) of either human or rabbit origin coated on human erythrocytes, which were found to follow a monovalent biomolecular binding mechanism. The measured rate constants are Ackf0 = (2.6 +/- 0.32) x 10(-7) micron 4 s-1 and kr0 = (0.37 +/- 0.055) s-1 for the CD16A-hIgG interaction and Ackf0 = (5.7 +/- 0.31) X 10(-7) micron 4 s-1 and kr0 = (0.20 +/- 0.042) s-1 for the CD16A-rIgG interaction, respectively, where Ac is the contact area, estimated to be a few percent of 3 micron 2. PMID:9726957

  11. Theanine, gamma-glutamylethylamide, a unique amino acid in tea leaves, modulates neurotransmitter concentrations in the brain striatum interstitium in conscious rats.

    PubMed

    Yamada, T; Terashima, T; Kawano, S; Furuno, R; Okubo, T; Juneja, L R; Yokogoshi, H

    2009-01-01

    Theanine (gamma-glutamylethylamide) is one of the major amino acid components in green tea and can pass through the blood-brain barrier. Recent studies suggest that theanine affects the mammalian central nervous system; however, the detailed mechanism remains unclear. In this study, we demonstrated the effect of theanine on neurotransmission in the brain striatum by in vivo brain microdialysis. Theanine injection into the rat brain striatum did not increase the concentration of excitatory neurotransmitters in the perfusate. On the other hand, theanine injection increased the concentration of glycine in the perfusate. Because it has been reported that theanine promotes dopamine release in the rat striatum, we investigated the glycine and dopamine concentrations in the perfusate. Co-injection of glycine receptor antagonist, strychnine, reduced theanine-induced changes in dopamine. Moreover, AMPA receptor antagonist, which regulates glycine and GABA release from glia cells, inhibited these effects of theanine and this result was in agreement with the known inhibitory effect of theanine at AMPA receptors.

  12. Biosynthesis and N-glycosylation of human interferon-gamma. Asn25 and Asn97 differ markedly in how efficiently they are glycosylated and in their oligosaccharide composition.

    PubMed

    Sareneva, T; Mørtz, E; Tölö, H; Roepstorff, P; Julkunen, I

    1996-12-01

    Interferon-gamma (IFN-gamma) is a secretory glycoprotein produced by T cells in response to antigenic or mitogenic stimuli. We studied the kinetics of the synthesis, N-glycosylation, and secretion of IFN-gamma in human CD8+ T lymphocytes stimulated via T-cell receptor. Highly elevated IFN-gamma mRNA levels were found as early as 1 h after stimulation. Maximal IFN-gamma protein synthesis was observed 2-4 h after induction and appeared to correlate to steady-state IFN-gamma mRNA levels. As analyzed by pulse/chase experiments, the secretion of IFN-gamma from T cells was very rapid, the secretion half-time being approximately 20-25 min. Inhibition of N-glycosylation by tunicamycin dramatically reduced the expression of IFN-gamma, but did not block its secretion. Natural IFN-gamma is heterogeneously glycosylated and doubly, singly, and unglycosylated forms exist. Experiments performed in a cell-free translation/glycosylation system with mutated IFN-gamma constructs lacking either one of the potential glycosylation sites suggested that Asn25 is more efficiently glycosylated than Asn97. Site-specific oligosaccharide analysis of natural IFN-gamma by glycosidase treatment followed by matrix-assisted-laser-desorption-ionization mass spectrometry revealed considerable variation in the carbohydrate structures, with more than 30 different forms. The glycans at Asn25 consisted of fucosylated, mainly complex-type oligosaccharides, whereas the glycans at Asn97 were more heterogeneous, with hybrid and high-mannose structures. Our results emphasize the essential role of N-linked glycans in the biology of IFN-gamma and show that there is a considerable heterogeneity in the individual sugar chains of this important human cytokine.

  13. Compton Gamma-Ray Observatory

    NASA Technical Reports Server (NTRS)

    1991-01-01

    This photograph shows the Compton Gamma-Ray Observatory (GRO) being deployed by the Remote Manipulator System (RMS) arm aboard the Space Shuttle Atlantis during the STS-37 mission in April 1991. The GRO reentered Earth atmosphere and ended its successful mission in June 2000. For nearly 9 years, the GRO Burst and Transient Source Experiment (BATSE), designed and built by the Marshall Space Flight Center (MSFC), kept an unblinking watch on the universe to alert scientists to the invisible, mysterious gamma-ray bursts that had puzzled them for decades. By studying gamma-rays from objects like black holes, pulsars, quasars, neutron stars, and other exotic objects, scientists could discover clues to the birth, evolution, and death of stars, galaxies, and the universe. The gamma-ray instrument was one of four major science instruments aboard the Compton. It consisted of eight detectors, or modules, located at each corner of the rectangular satellite to simultaneously scan the entire universe for bursts of gamma-rays ranging in duration from fractions of a second to minutes. In January 1999, the instrument, via the Internet, cued a computer-controlled telescope at Las Alamos National Laboratory in Los Alamos, New Mexico, within 20 seconds of registering a burst. With this capability, the gamma-ray experiment came to serve as a gamma-ray burst alert for the Hubble Space Telescope, the Chandra X-Ray Observatory, and major gound-based observatories around the world. Thirty-seven universities, observatories, and NASA centers in 19 states, and 11 more institutions in Europe and Russia, participated in the BATSE science program.

  14. Compton Gamma-Ray Observatory

    NASA Technical Reports Server (NTRS)

    1991-01-01

    This photograph shows the Compton Gamma-Ray Observatory being released from the Remote Manipulator System (RMS) arm aboard the Space Shuttle Atlantis during the STS-35 mission in April 1991. The GRO reentered the Earth's atmosphere and ended its successful mission in June 2000. For nearly 9 years, GRO's Burst and Transient Source Experiment (BATSE), designed and built by the Marshall Space Flight Center, kept an unblinking watch on the universe to alert scientist to the invisible, mysterious gamma-ray bursts that had puzzled them for decades. By studying gamma-rays from objects like black holes, pulsars, quasars, neutron stars, and other exotic objects, scientists could discover clues to the birth, evolution, and death of star, galaxies, and the universe. The gamma-ray instrument was one of four major science instruments aboard the Compton. It consisted of eight detectors, or modules, located at each corner of the rectangular satellite to simultaneously scan the entire universe for bursts of gamma-rays ranging in duration from fractions of a second to minutes. In January 1999, the instrument, via the Internet, cued a computer-controlled telescope at Las Alamos National Laboratory in Los Alamos, New Mexico, within 20 seconds of registering a burst. With this capability, the gamma-ray experiment came to serve as a gamma-ray burst alert for the Hubble Space Telescope, the Chandra X-Ray Observatory, and major gound-based observatories around the world. Thirty-seven universities, observatories, and NASA centers in 19 states, and 11 more institutions in Europe and Russia, participated in BATSE's science program.

  15. Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors.

    PubMed

    Haynes, Nicole M; Trapani, Joseph A; Teng, Michèle W L; Jackson, Jacob T; Cerruti, Loretta; Jane, Stephen M; Kershaw, Michael H; Smyth, Mark J; Darcy, Phillip K

    2002-11-01

    Tumor cells are usually weakly immunogenic as they largely express self-antigens and can down-regulate major histocompatability complex/peptide molecules and critical costimulatory ligands. The challenge for immunotherapies has been to provide vigorous immune effector cells that circumvent these tumor escape mechanisms and eradicate established tumors. One promising approach is to engineer T cells with single-chain antibody receptors, and since T cells require 2 distinct signals for optimal activation, we have compared the therapeutic efficacy of erbB2-reactive chimeric receptors that contain either T-cell receptor zeta (TCR-zeta) or CD28/TCR-zeta signaling domains. We have demonstrated that primary mouse CD8(+) T lymphocytes expressing the single-chain Fv (scFv)-CD28-zeta receptor have a greater capacity to secrete Tc1 cytokines, induce T-cell proliferation, and inhibit established tumor growth and metastases in vivo. The suppression of established tumor burden by cytotoxic T cells expressing the CD28/TCR-zeta chimera was critically dependent upon their interferon gamma (IFN-gamma) secretion. Our study has illustrated the practical advantage of engineering a T-cell signaling complex that codelivers CD28 activation, dependent only upon the tumor's expression of the appropriate tumor associated antigen.

  16. Unidentified Gamma-Ray Sources: Hunting Gamma-Ray Blazars

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Massaro, F.; D'Abrusco, R.; Tosti, G.

    2012-04-02

    One of the main scientific objectives of the ongoing Fermi mission is unveiling the nature of the unidentified {gamma}-ray sources (UGSs). Despite the large improvements of Fermi in the localization of {gamma}-ray sources with respect to the past {gamma}-ray missions, about one third of the Fermi-detected objects are still not associated to low energy counterparts. Recently, using the Wide-field Infrared Survey Explorer (WISE) survey, we discovered that blazars, the rarest class of Active Galactic Nuclei and the largest population of {gamma}-ray sources, can be recognized and separated from other extragalactic sources on the basis of their infrared (IR) colors. Basedmore » on this result, we designed an association method for the {gamma}-ray sources to recognize if there is a blazar candidate within the positional uncertainty region of a generic {gamma}-ray source. With this new IR diagnostic tool, we searched for {gamma}-ray blazar candidates associated to the UGS sample of the second Fermi {gamma}-ray catalog (2FGL). We found that our method associates at least one {gamma}-ray blazar candidate as a counterpart each of 156 out of 313 UGSs analyzed. These new low-energy candidates have the same IR properties as the blazars associated to {gamma}-ray sources in the 2FGL catalog.« less

  17. UNIDENTIFIED {gamma}-RAY SOURCES: HUNTING {gamma}-RAY BLAZARS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Massaro, F.; Ajello, M.; D'Abrusco, R.

    2012-06-10

    One of the main scientific objectives of the ongoing Fermi mission is unveiling the nature of unidentified {gamma}-ray sources (UGSs). Despite the major improvements of Fermi in the localization of {gamma}-ray sources with respect to the past {gamma}-ray missions, about one-third of the Fermi-detected objects are still not associated with low-energy counterparts. Recently, using the Wide-field Infrared Survey Explorer survey, we discovered that blazars, the rarest class of active galactic nuclei and the largest population of {gamma}-ray sources, can be recognized and separated from other extragalactic sources on the basis of their infrared (IR) colors. Based on this result, wemore » designed an association method for the {gamma}-ray sources to recognize if there is a blazar candidate within the positional uncertainty region of a generic {gamma}-ray source. With this new IR diagnostic tool, we searched for {gamma}-ray blazar candidates associated with the UGS sample of the second Fermi {gamma}-ray LAT catalog (2FGL). We found that our method associates at least one {gamma}-ray blazar candidate as a counterpart to each of 156 out of 313 UGSs analyzed. These new low-energy candidates have the same IR properties as the blazars associated with {gamma}-ray sources in the 2FGL catalog.« less

  18. Neuroactive Steroids: Receptor Interactions and Responses

    PubMed Central

    Tuem, Kald Beshir; Atey, Tesfay Mehari

    2017-01-01

    Neuroactive steroids (NASs) are naturally occurring steroids, which are synthesized centrally as de novo from cholesterol and are classified as pregnane, androstane, and sulfated neurosteroids (NSs). NASs modulate many processes via interacting with gamma-aminobutyric acid (GABA), N-methyl-d-aspartate, serotonin, voltage-gated calcium channels, voltage-dependent anion channels, α-adrenoreceptors, X-receptors of the liver, transient receptor potential channels, microtubule-associated protein 2, neurotrophin nerve growth factor, and σ1 receptors. Among these, NSs (especially allopregnanolone) have high potency and extensive GABA-A receptors and hence demonstrate anticonvulsant, anesthetic, central cytoprotectant, and baroreflex inhibitory effects. NSs are also involved in mood and learning via serotonin and anti-nociceptive activity via T-type voltage-gated Ca2+ channels. Moreover, they are modulators of mitochondrial function, synaptic plasticity, or regulators of apoptosis, which have a role in neuroprotective via voltage-dependent anion channels receptors. For proper functioning, NASs need to be in their normal level, whereas excess and deficiency may lead to abnormalities. When they are below the normal, NSs could have a part in development of depression, neuro-inflammation, multiple sclerosis, experimental autoimmune encephalitis, epilepsy, and schizophrenia. On the other hand, stress and attention deficit disorder could occur during excessive level. Overall, NASs are very important molecules with major neuropsychiatric activity. PMID:28894435

  19. Development of Camera Electronics for the Advanced Gamma-ray Imaging System (AGIS)

    NASA Astrophysics Data System (ADS)

    Tajima, Hiroyasu

    2009-05-01

    AGIS, a next generation of atmospheric Cherenkov telescope arrays, aims to achieve a sensitivity level of a milliCrab for gamma-ray observations in in the energy band of 40 GeV to 100 TeV. Such improvement requires cost reduction of individual components with high reliability in order to equip the order of 100 telescopes necessary to achieve the sensitivity goal. We are exploring several design concepts to reduce the cost of camera electronics while improving their performance. We have developed test systems for some of these concepts and are testing their performance. Here we present test results of the test systems.

  20. An improved time of flight gamma-ray telescope to monitor diffuse gamma-ray in the energy range 5 MeV - 50 MeV

    NASA Technical Reports Server (NTRS)

    Dacostafereiraneri, A.; Bui-Van, A.; Lavigne, J. M.; Sabaud, C.; Vedrenne, G.; Agrinier, B.; Gouiffes, C.

    1985-01-01

    A time of flight measuring device is the basic triggering system of most of medium and high energy gamma-ray telescopes. A simple gamma-ray telescope has been built in order to check in flight conditions the functioning of an advanced time of flight system. The technical ratings of the system are described. This telescope has been flown twice with stratospheric balloons, its axis being oriented at various Zenital directions. Flight results are presented for diffuse gamma-rays, atmospheric secondaries, and various causes of noise in the 5 MeV-50 MeV energy range.

  1. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation

    PubMed Central

    Wright, K L; Duncan, M; Sharkey, K A

    2007-01-01

    The emerging potential for the cannabinoid (CB) system in modulating gastrointestinal inflammation has gained momentum over the last few years. Traditional and anecdotal use of marijuana for gastrointestinal disorders, such as diarrhoea and abdominal cramps is recognized, but the therapeutic benefit of cannabinoids in the 21st century is overshadowed by the psychoactive problems associated with CB1 receptor activation. However, the presence and function of the CB2 receptor in the GI tract, whilst not yet well characterized, holds great promise due to its immunomodulatory roles in inflammatory systems and its lack of psychotropic effects. This review of our current knowledge of CB2 receptors in the gastrointestinal tract highlights its role in regulating abnormal motility, modulating intestinal inflammation and limiting visceral sensitivity and pain. CB2 receptors represent a braking system and a pathophysiological mechanism for the resolution of inflammation and many of its symptoms. CB2 receptor activation therefore represents a very promising therapeutic target in gastrointestinal inflammatory states where there is immune activation and motility dysfunction. PMID:17906675

  2. The Advanced Gamma-Ray Imaging System (AGIS)

    NASA Astrophysics Data System (ADS)

    Williams, David A.; AGIS Collaboration

    2009-01-01

    The spectacular astrophysical discoveries made by the present generation of ground-based gamma-ray observatories have opened a new era in the exploration of the highest energy Universe and have conclusively established the field of very-high-energy (VHE) astronomy, covering the energy regime above about 50 GeV. The detection of nearly 100 galactic and extragalactic sources has generated considerable interest in the astronomy, astrophysics and particle physics communities and has stimulated ambitious ideas and plans for future gamma-ray observatories. AGIS is a concept for a next generation VHE observatory with a collecting area on the scale of a square kilometer being developed by an international collaboration. It would have significantly improved angular and energy resolution, increased field of view, and an order of magnitude increase in sensitivity over existing space or ground-based instruments in the energy range 40 GeV to 100 TeV. The scientific motivations and R&D roadmap for AGIS will be discussed.

  3. Cen A Optical Gamma Composite

    NASA Image and Video Library

    2017-12-08

    NASA release April 1, 2010 The gamma-ray output from Cen A's lobes exceeds their radio output by more than ten times. High-energy gamma rays detected by Fermi's Large Area Telescope are depicted as purple in this gamma ray/optical composite of the galaxy. Credit: NASA/DOE/Fermi LAT Collaboration, Capella Observatory To learn more about these images go to: www.nasa.gov/mission_pages/GLAST/news/smokestack-plumes.html NASA Goddard Space Flight Center is home to the nation's largest organization of combined scientists, engineers and technologists that build spacecraft, instruments and new technology to study the Earth, the sun, our solar system, and the universe.

  4. The neutron-gamma Feynman variance to mean approach: Gamma detection and total neutron-gamma detection (theory and practice)

    NASA Astrophysics Data System (ADS)

    Chernikova, Dina; Axell, Kåre; Avdic, Senada; Pázsit, Imre; Nordlund, Anders; Allard, Stefan

    2015-05-01

    Two versions of the neutron-gamma variance to mean (Feynman-alpha method or Feynman-Y function) formula for either gamma detection only or total neutron-gamma detection, respectively, are derived and compared in this paper. The new formulas have particular importance for detectors of either gamma photons or detectors sensitive to both neutron and gamma radiation. If applied to a plastic or liquid scintillation detector, the total neutron-gamma detection Feynman-Y expression corresponds to a situation where no discrimination is made between neutrons and gamma particles. The gamma variance to mean formulas are useful when a detector of only gamma radiation is used or when working with a combined neutron-gamma detector at high count rates. The theoretical derivation is based on the Chapman-Kolmogorov equation with the inclusion of general reactions and corresponding intensities for neutrons and gammas, but with the inclusion of prompt reactions only. A one energy group approximation is considered. The comparison of the two different theories is made by using reaction intensities obtained in MCNPX simulations with a simplified geometry for two scintillation detectors and a 252Cf-source. In addition, the variance to mean ratios, neutron, gamma and total neutron-gamma are evaluated experimentally for a weak 252Cf neutron-gamma source, a 137Cs random gamma source and a 22Na correlated gamma source. Due to the focus being on the possibility of using neutron-gamma variance to mean theories for both reactor and safeguards applications, we limited the present study to the general analytical expressions for Feynman-alpha formulas.

  5. Critical role of IFN-gamma in CFA-mediated protection of NOD mice from diabetes development.

    PubMed

    Mori, Yoshiko; Kodaka, Tetsuro; Kato, Takako; Kanagawa, Edith M; Kanagawa, Osami

    2009-11-01

    IFN-gamma signaling-deficient non-obese diabetic (NOD) mice develop diabetes with similar kinetics to those of wild-type NOD mice. However, the immunization of IFN-gamma signaling-deficient NOD mice with CFA failed to induce long-term protection, whereas wild-type NOD mice receiving CFA remained diabetes-free. CFA also failed to protect IFN-gamma receptor-deficient (IFN-gammaR(-/-)) NOD mice from the autoimmune rejection of transplanted islets, as it does in diabetic NOD mice, and from disease transfer by spleen cells from diabetic NOD mice. These data clearly show that the pro-inflammatory cytokine IFN-gamma is necessary for the CFA-mediated protection of NOD mice from diabetes. There is no difference in the T(h)1/T(h)17 balance between IFN-gammaR(-/-) NOD and wild-type NOD mice. There is also no difference in the total numbers and percentages of regulatory T (Treg) cells in the lymph node CD4(+) T-cell populations between IFN-gammaR(-/-) NOD and wild-type NOD mice. However, pathogenic T cells lacking IFN-gammaR are resistant to the suppressive effect of Treg cells, both in vivo and in vitro. Therefore, it is likely that CFA-mediated protection against diabetes development depends on a change in the balance between Treg cells and pathogenic T cells, and IFN-gamma signaling seems to control the susceptibility of pathogenic T cells to the inhibitory activity of Treg cells.

  6. Ionotropic GABA Receptors and Distal Retinal ON and OFF Responses

    PubMed Central

    Popova, E.

    2014-01-01

    In the vertebrate retina, visual signals are segregated into parallel ON and OFF pathways, which provide information for light increments and decrements. The segregation is first evident at the level of the ON and OFF bipolar cells in distal retina. The activity of large populations of ON and OFF bipolar cells is reflected in the b- and d-waves of the diffuse electroretinogram (ERG). The role of gamma-aminobutyric acid (GABA), acting through ionotropic GABA receptors in shaping the ON and OFF responses in distal retina, is a matter of debate. This review summarized current knowledge about the types of the GABAergic neurons and ionotropic GABA receptors in the retina as well as the effects of GABA and specific GABAA and GABAC receptor antagonists on the activity of the ON and OFF bipolar cells in both nonmammalian and mammalian retina. Special emphasis is put on the effects on b- and d-waves of the ERG as a useful tool for assessment of the overall function of distal retinal ON and OFF channels. The role of GABAergic system in establishing the ON-OFF asymmetry concerning the time course and absolute and relative sensitivity of the ERG responses under different conditions of light adaptation in amphibian retina is also discussed. PMID:25143858

  7. The Advanced Gamma-ray Imaging System (AGIS): Telescope Optical System Designs

    NASA Astrophysics Data System (ADS)

    Hanna, David S.; Buckley, J. H.; Falcone, A.; Fegan, S.; Finley, J.; Guarino, V.; Kaaret, P.; Krawczynski, H.; Krennrich, F.; Konopelko, A.; Romani, R.; Vassilliev, V.; Optical System Working Group; AGIS Collaboration

    2008-03-01

    The concept of a future ground-based gamma-ray observatory, AGIS, in the energy range 20 GeV-200 TeV is based on an array of 50-200 imaging atmospheric Cherenkov telescopes (IACTs). The anticipated improvement of AGIS sensitivity, angular resolution, and reliability of operation imposes demanding technological and cost requirements on the design of IACTs. In this submission we will focus on the optical system (OS) of AGIS telescopes and consider options which include traditional Davies-Cotton and the other prime-focus telescope designs, as well as the novel two-mirror aplanatic OS originally proposed by Schwarzschild. The emerging new mirror production technologies based on replication processes, such as cold and hot glass slumping, cured CFRP, and electroforming, provide new opportunities for cost effective solutions for the design of the OS. We initially evaluate capabilities of these mirror fabrication methods for the AGIS project.

  8. A Compact, Portable, Reduced-Cost, Gamma Ray Spectroscopic System for Nuclear Verification Final Report CRADA No. TSB-1551-98

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lavietes, A.; Kalkhoran, N.

    The overall goal of this project was to demonstrate a compact gamma-ray spectroscopic system with better energy resolution and lower costs than scintillator-based detector systems for uranium enrichment analysis applications.

  9. Quality assurance for gamma knives

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jones, E.D.; Banks, W.W.; Fischer, L.E.

    1995-09-01

    This report describes and summarizes the results of a quality assurance (QA) study of the Gamma Knife, a nuclear medical device used for the gamma irradiation of intracranial lesions. Focus was on the physical aspects of QA and did not address issues that are essentially medical, such as patient selection or prescription of dose. A risk-based QA assessment approach was used. Sample programs for quality control and assurance are included. The use of the Gamma Knife was found to conform to existing standards and guidelines concerning radiation safety and quality control of external beam therapies (shielding, safety reviews, radiation surveys,more » interlock systems, exposure monitoring, good medical physics practices, etc.) and to be compliant with NRC teletherapy regulations. There are, however, current practices for the Gamma Knife not covered by existing, formalized regulations, standards, or guidelines. These practices have been adopted by Gamma Knife users and continue to be developed with further experience. Some of these have appeared in publications or presentations and are slowly finding their way into recommendations of professional organizations.« less

  10. Nuclear fuel microsphere gamma analyzer

    DOEpatents

    Valentine, Kenneth H.; Long, Jr., Ernest L.; Willey, Melvin G.

    1977-01-01

    A gamma analyzer system is provided for the analysis of nuclear fuel microspheres and other radioactive particles. The system consists of an analysis turntable with means for loading, in sequence, a plurality of stations within the turntable; a gamma ray detector for determining the spectrum of a sample in one section; means for analyzing the spectrum; and a receiver turntable to collect the analyzed material in stations according to the spectrum analysis. Accordingly, particles may be sorted according to their quality; e.g., fuel particles with fractured coatings may be separated from those that are not fractured, or according to other properties.

  11. [Cardiotoxicity of lindane, a gamma isomer of hexachlorocyclohexane].

    PubMed

    Sauviat, Martin-Pierre; Pages, Nicole

    2002-01-01

    The goal of the present review is to collect information concerning membrane effects induced by lindane intoxication, a y isomer of hexachiorocyclohexane (gamma-HCH) that has been largely used as an insecticide and disinfectant in agriculture and entered also in the composition of some lotions, creams and shampoos used against parasites (lice and scabies). Absorbed through respiratory, digestive or transcutaneous pathways, lindane accumulates within lipid rich tissues. Lindane accumulation depends on the duration of the exposure and affects tissues in the following order: adipose tissues > brain > kidney > muscle > lungs > heart > liver > blood. Whatever the mode of lindane absorption, it accumulates in blood and is distributed throughout the body. It may affect human health by exerting systemic, immunologic, teratogenic, and/or cancerogenic effects. The symptoms of lindane intoxication are different according to the mode of intoxication, acute or chronic. The absorption of high doses of gamma-HCH is particularly toxic for the central nervous system and for the female and male reproduction apparatus in mammals where lindane is considered as an endocrine disruptor. Lindane is highly lipophilic and incorporates into biological membranes according to the following sequence: mitochondria > sarcoplasmic reticulum > myelin > brain microsomes > erythrocytes. Lindane exerts a stimulating action on synaptic transmission and inhibits the chloride current activated by gamma-amino butyric acid (GABA) of many muscular and nervous preparations by interacting with the receptors GABA-chloride channel complex. It seems to affect calcium homeostasis of many tissues. The similarity between lindane and inositol (1, 4, 5) phosphate (IP3) suggested that lindane releases Ca2+ from IP3-sensitive intracellular stores in macrophages and myometrial cells. Ca2+ release from reticulum endoplasmic, mitochondria and other Ca2+ stores has been reported in cat kidney cells. Lindane altered

  12. HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPAR{gamma}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Kook Hwan; Hong, Sung Pyo; Kim, KyeongJin

    2007-04-20

    Hepatic steatosis is a common feature in patients with chronic hepatitis C virus (HCV) infection. HCV core protein plays an important role in the development of hepatic steatosis in HCV infection. Because SREBP1 (sterol regulatory element binding protein 1) and PPAR{gamma} (peroxisome proliferators-activated receptor {gamma}) are involved in the regulation of lipid metabolism of hepatocyte, we sought to determine whether HCV core protein may impair the expression and activity of SREBP1 and PPAR{gamma}. In this study, it was demonstrated that HCV core protein increases the gene expression of SREBP1 not only in Chang liver, Huh7, and HepG2 cells transiently transfectedmore » with HCV core protein expression plasmid, but also in Chang liver-core stable cells. Furthermore, HCV core protein enhanced the transcriptional activity of SREBP1. In addition, HCV core protein elevated PPAR{gamma} transcriptional activity. However, HCV core protein had no effect on PPAR{gamma} gene expression. Finally, we showed that HCV core protein stimulates the genes expression of lipogenic enzyme and fatty acid uptake associated protein. Therefore, our finding provides a new insight into the mechanism of hepatic steatosis by HCV infection.« less

  13. A luminous gamma-ray binary in the large magellanic cloud

    DOE PAGES

    Corbet, R. H. D.; Chomiuk, L.; Coe, M. J.; ...

    2016-09-27

    Gamma-ray binaries consist of a neutron star or a black hole interacting with a normal star to produce gamma-ray emission that dominates the radiative output of the system. Previously, only a handful of such systems have been discovered, all within our Galaxy. We report the discovery of a luminous gamma-ray binary in the Large Magellanic Cloud, found with the Fermi Large Area Telescope (LAT), from a search for periodic modulation in all sources in the third Fermi LAT catalog. This is the first such system to be found outside the Milky Way. Furthermore, the system has an orbital period ofmore » 10.3 days, and is associated with a massive O5III star located in the supernova remnant DEM L241, previously identified as the candidate high-mass X-ray binary (HMXB) CXOU J053600.0–673507. X-ray and radio emission are also modulated on the 10.3 day period, but are in anti-phase with the gamma-ray modulation. Optical radial velocity measurements suggest that the system contains a neutron star. The source is significantly more luminous than similar sources in the Milky Way, at radio, optical, X-ray, and gamma-ray wavelengths. The detection of this extra-galactic system, but no new Galactic systems, raises the possibility that the predicted number of gamma-ray binaries in our Galaxy has been overestimated, and that HMXBs may be born containing relatively slowly rotating neutron stars.« less

  14. Cost analysis of Gamma Knife stereotactic radiosurgery.

    PubMed

    Griffiths, Alison; Marinovich, Luke; Barton, Michael B; Lord, Sarah J

    2007-01-01

    Stereotactic radiosurgery (SRS) is used to treat intracranial lesions and vascular malformations as an addition or replacement to whole brain radiotherapy and microsurgery. SRS can be delivered by hardware and software appended to standard linear accelerators (Linacs) or by dedicated systems such as Gamma Knife, which has been proposed as a more accurate and user friendly technology. Internationally, dedicated systems have been funded, despite limitations in evidence. However, some countries including Australia have not recommended additional reimbursement for dedicated systems. This study compares the costs of Linac radiosurgery with Gamma Knife radiosurgery. Due to limited evidence on comparative effects, the economic analysis was restricted to a cost evaluation. The base-case analysis assumed a modified Linac was used only to treat SRS patients. However, because a modified Linac could be used to treat other radiotherapy patients, a second analysis assumed spare time was used to meet other radiotherapy needs, and Linac capital costs were apportioned according to SRS use. The incremental cost of Gamma Knife versus a modified Linac was estimated as AU$209 per patient. This result is sensitive to variations in assumptions. A second analysis proportioning capital costs according to SRS use showed that Gamma Knife may cost up to AU$1673 more per patient. Gamma Knife may be cost competitive only if demand for SRS services is high enough to fully use equipment working time. However, given low patient demand and competing radiotherapy needs, Gamma Knife appears more costly and further evidence of survival or quality of life advantages may be required to justify reimbursement.

  15. Focal Plane Detectors for the Advanced Gamma-Ray Imaging System (AGIS)

    NASA Astrophysics Data System (ADS)

    Wagner, Robert G.; AGIS Photodetector Group; Byrum, K.; Drake, G.; Falcone, A.; Funk, S.; Horan, D.; Mukherjee, R.; Tajima, H.; Williams, D.

    2008-03-01

    The Advanced Gamma-Ray Imaging System (AGIS) is a concept for the next generation observatory in ground-based very high energy gamma-ray astronomy. It is being designed to achieve a significant improvement in sensitivity compared to current Imaging Air Cherenkov Telescope (IACT) Arrays. One of the main requirements in order that AGIS fulfill this goal will be to achieve higher angular resolution than current IACTs. Simulations show that a substantial improvement in angular resolution may be achieved if the pixel size is reduced to less than 0.05 deg, i.e. two to three times smaller than the pixel size of current IACT cameras. With finer pixelation and the plan to deploy on the order of 100 telescopes in the AGIS array, the channel count will exceed 1,000,000 imaging pixels. High uniformity and long mean time-to-failure will be important aspects of a successful photodetector technology choice. Here we present alternatives being considered for AGIS, including both silicon photomultipliers (SiPMs) and multi-anode photomultipliers (MAPMTs). Results from laboratory testing of MAPMTs and SiPMs are presented along with results from the first incorporation of these devices in cameras on test bed Cherenkov telescopes.

  16. Derivation of a Multiparameter Gamma Model for Analyzing the Residence-Time Distribution Function for Nonideal Flow Systems as an Alternative to the Advection-Dispersion Equation

    DOE PAGES

    Embry, Irucka; Roland, Victor; Agbaje, Oluropo; ...

    2013-01-01

    A new residence-time distribution (RTD) function has been developed and applied to quantitative dye studies as an alternative to the traditional advection-dispersion equation (AdDE). The new method is based on a jointly combined four-parameter gamma probability density function (PDF). The gamma residence-time distribution (RTD) function and its first and second moments are derived from the individual two-parameter gamma distributions of randomly distributed variables, tracer travel distance, and linear velocity, which are based on their relationship with time. The gamma RTD function was used on a steady-state, nonideal system modeled as a plug-flow reactor (PFR) in the laboratory to validate themore » effectiveness of the model. The normalized forms of the gamma RTD and the advection-dispersion equation RTD were compared with the normalized tracer RTD. The normalized gamma RTD had a lower mean-absolute deviation (MAD) (0.16) than the normalized form of the advection-dispersion equation (0.26) when compared to the normalized tracer RTD. The gamma RTD function is tied back to the actual physical site due to its randomly distributed variables. The results validate using the gamma RTD as a suitable alternative to the advection-dispersion equation for quantitative tracer studies of non-ideal flow systems.« less

  17. The Advanced Gamma-ray Imaging System (AGIS): Extragalactic Science

    NASA Astrophysics Data System (ADS)

    Coppi, Paolo S.; Extragalactic Science Working Group; AGIS Collaboration

    2010-03-01

    The Advanced Gamma-ray Imaging System (AGIS), a proposed next-generation array of Cherenkov telescopes, will provide an unprecedented view of the high energy universe. We discuss how AGIS, with its larger effective area, improved angular resolution, lower threshold, and an order of magnitude increase in sensitivity, impacts the extragalactic science possible in the very high energy domain. Likely source classes detectable by AGIS include AGN, GRBs, clusters, star-forming galaxies, and possibly the cascade radiation surrounding powerful cosmic accelerators. AGIS should see many of the sources discovered by Fermi. With its better sensitivity and angular resolution, AGIS then becomes a key instrument for identifying and characterizing Fermi survey sources, the majority of which will have limited Fermi photon statistics and localizations.

  18. System and plastic scintillator for discrimination of thermal neutron, fast neutron, and gamma radiation

    DOEpatents

    Zaitseva, Natalia P.; Carman, M. Leslie; Faust, Michelle A.; Glenn, Andrew M.; Martinez, H. Paul; Pawelczak, Iwona A.; Payne, Stephen A.

    2017-05-16

    A scintillator material according to one embodiment includes a polymer matrix; a primary dye in the polymer matrix, the primary dye being a fluorescent dye, the primary dye being present in an amount of 3 wt % or more; and at least one component in the polymer matrix, the component being selected from a group consisting of B, Li, Gd, a B-containing compound, a Li-containing compound and a Gd-containing compound, wherein the scintillator material exhibits an optical response signature for thermal neutrons that is different than an optical response signature for fast neutrons and gamma rays. A system according to one embodiment includes a scintillator material as disclosed herein and a photodetector for detecting the response of the material to fast neutron, thermal neutron and gamma ray irradiation.

  19. Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney.

    PubMed

    Yang, T; Michele, D E; Park, J; Smart, A M; Lin, Z; Brosius, F C; Schnermann, J B; Briggs, J P

    1999-12-01

    The discovery that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is a ligand for the gamma-isoform of peroxisome proliferator-activated receptor (PPAR) suggests nuclear signaling by prostaglandins. Studies were undertaken to determine the nephron localization of PPAR isoforms and their heterodimer partners, retinoid X receptors (RXR), and to evaluate the function of this system in the kidney. PPARalpha mRNA, determined by RT-PCR, was found predominately in cortex and further localized to proximal convoluted tubule (PCT); PPARgamma was abundant in renal inner medulla, localized to inner medullary collecting duct (IMCD) and renal medullary interstitial cells (RMIC); PPARbeta, the ubiquitous form of PPAR, was abundant in all nephron segments examined. RXRalpha was localized to PCT and IMCD, whereas RXRbeta was expressed in almost all nephron segments examined. mRNA expression of acyl-CoA synthase (ACS), a known PPAR target gene, was stimulated in renal cortex of rats fed with fenofibrate, but the expression was not significantly altered in either cortex or inner medulla of rats fed with troglitazone. In cultured RMIC cells, both troglitazone and 15d-PGJ2 significantly inhibited cell proliferation and dramatically altered cell shape by induction of cell process formation. We conclude that PPAR and RXR isoforms are expressed in a nephron segment-specific manner, suggesting distinct functions, with PPARalpha being involved in energy metabolism through regulating ACS in PCT and with PPARgamma being involved in modulating RMIC growth and differentiation.

  20. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system

    PubMed Central

    Bateman, Randall J.; Siemers, Eric R.; Mawuenyega, Kwasi G.; Wen, Guolin; Browning, Karen R.; Sigurdson, Wendy C.; Yarasheski, Kevin E.; Friedrich, Stuart W.; DeMattos, Ronald B.; May, Patrick C.; Paul, Steven M.; Holtzman, David M.

    2009-01-01

    Objective Accumulation of amyloid-β (Aβ) by over-production or under-clearance in the central nervous system is hypothesized to be a necessary event in the pathogenesis of Alzheimer Disease. However, previously there has not been a method to determine drug effects on Aβ production or clearance in the human central nervous system. The objective of this study was to determine the effects of a gamma-secretase inhibitor on the production of Aβ in the human CNS. Methods We utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure Aβ production during treatment of a gamma-secretase inhibitor, LY450139. We assessed whether this drug could decrease central nervous system Aβ production in healthy men (age 21–50) at single oral doses of 100mg, 140mg, or 280mg (N=5 per group). Results LY450139 significantly decreased the production of central nervous system Aβ in a dose-dependent fashion, with inhibition of Aβ generation of 47%, 52%, and 84% over a 12 hour period with doses of 100 mg, 140, and 280 mg respectively. There was no difference in Aβ clearance. Interpretation Stable isotope labeling of central nervous system proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease modifying treatments for Alzheimer Disease and other central nervous system disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer Disease, and may accelerate effective drug validation. PMID:19360898

  1. Development of a Competitive Binding Assay System with Recombinant Estrogen Receptors from Multiple Species

    EPA Science Inventory

    ABSTRACT In the current study, we developed a new system using full-length recombinant baculovirus-expressed estrogen receptors which allows for direct comparison of binding across species. Estrogen receptors representing five vertebrate classes were compared: human (hERα), quai...

  2. Agonist-specific coupling of a cloned Drosophila octopamine/tyramine receptor to multiple second messenger systems.

    PubMed Central

    Robb, S; Cheek, T R; Hannan, F L; Hall, L M; Midgley, J M; Evans, P D

    1994-01-01

    A cloned seven transmembrane-spanning Drosophila octopamine/tyramine receptor, permanently expressed in a Chinese hamster ovary cell line, both inhibits adenylate cyclase activity and leads to the elevation of intracellular Ca2+ levels by separate G-protein-coupled pathways. Agonists of this receptor (octopamine and tyramine), differing by only a single hydroxyl group in their side chain, may be capable of differentially coupling it to different second messenger systems. Thus, a single receptor may have a different pharmacological profile depending on which second messenger system is used to assay its efficacy. PMID:8137817

  3. Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease

    PubMed Central

    Rohatgi, Soma; Gohil, Shruti; Kuniholm, Mark H.; Schultz, Hannah; Dufaud, Chad; Armour, Kathryn L.; Badri, Sheila; Mailliard, Robbie B.; Pirofski, Liise-anne

    2013-01-01

    ABSTRACT Cryptococcus neoformans is one of the most common causes of fungal disease in HIV-infected persons, but not all of those who are infected develop cryptococcal disease (CD). Although CD4+ T cell deficiency is a risk factor for HIV-associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, we performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS): 55 who were HIV infected and developed CD and a matched control group of 54 who were HIV infected and 55 who were HIV uninfected. Using additive and allelic statistical models for analysis, the high-affinity FCGR3A 158V allele was significantly associated with CD status after adjusting for race/ethnicity (odds ratio [OR], 2.1; P = 0.005), as was the FCGR3A 158 VV homozygous genotype after adjusting for race/ethnicity, rate of CD4+ T cell decline, and nadir CD4+ T cell count (OR, 21; P = 0.005). No associations between CD and FCGR2A 131 H/R polymorphism were identified. In binding studies, human IgG (hIgG)-C. neoformans complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F, and in cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more C. neoformans-infected monocyte cytotoxicity than those expressing FCGR3A 158F. Together, these results show an association between the FCGR3A 158V allele and risk for HIV-associated CD and suggest that this polymorphism could promote C. neoformans pathogenesis via increased binding of C. neoformans immune complexes, resulting in increased phagocyte cargo and/or immune activation. PMID:23982074

  4. Gamma ray bursts as a signature for entangled gravitational systems

    NASA Astrophysics Data System (ADS)

    Basini, Giuseppe; Capozziello, Salvatore; Longo, Giuseppe

    2004-01-01

    Gamma ray bursts (GRBs), due to their features, can be considered not only extremely energetic, but also as the most relativistic astrophysical objects discovered. Their phenomenology is still matter of debate and, till now, no fully satisfactory model has been formulated to explain the nature of their origin. In the framework of a recently developed new theory, where general conservation laws are always and absolutely conserved in nature, we propose an alternative model where an ``entangled'' gravitational system, dynamically constituted by a black holes connected to a white hole through a worm hole, seems capable of explaining most of the properties inferred for the GRB engine. In particular, it leads to a natural explanation of energetics, beaming, polarization, and, very likely, distribution. On the other hand, GRBs can be considered a signature of such entangled gravitational systems.

  5. Role of GABAA receptors in the physiology and pharmacology of sleep.

    PubMed

    Winsky-Sommerer, Raphaëlle

    2009-05-01

    Most sedative-hypnotics used in insomnia treatment target the gamma-aminobutyric acid (GABA)(A) receptors. A vast repertoire of GABA(A) receptor subtypes has been identified and displays specific electrophysiological and functional properties. GABA(A)-mediated inhibition traditionally refers to 'phasic' inhibition, arising from synaptic GABA(A) receptors which transiently inhibit neurons. However, there is growing evidence that peri- or extra-synaptic GABA(A) receptors are continuously activated by low GABA concentrations and mediate a 'tonic' conductance. This slower type of signaling appears to play a key role in controlling cell excitability. This review aims at summarizing recent knowledge on GABA transmission, including the emergence of tonic conductance, and highlighting the importance of GABA(A) receptor heterogeneity. The mechanism of action of sedative-hypnotic drugs and their effects on sleep and the electroencephalogram will be reported. Furthermore, studies using genetically engineered mice will be emphasized, providing insights into the role of GABA(A) receptors in mechanisms underlying physiological and pharmacological sleep. Finally, we will address the potential of GABA(A) receptor pharmacology for the treatment of insomnia.

  6. Dynamics of mononuclear phagocyte system Fc receptor function in systemic lupus erythematosus. Relation to disease activity and circulating immune complexes.

    PubMed Central

    Kimberly, R P; Parris, T M; Inman, R D; McDougal, J S

    1983-01-01

    Seventeen pairs of longitudinal studies of mononuclear phagocyte system (MPS) Fc receptor function in 15 patients with systemic lupus were performed to explore the dynamic range of Fc receptor dysfunction in lupus and to establish the relationships between MPS function, clinical disease activity and circulating immune complexes (CIC). Fc receptor function was measured by the clearance of IgG sensitized autologous erythrocytes. At the time of first study the degree of MPS dysfunction was correlated with both clinical activity (P less than 0.05) and CIC (P less than 0.05). At follow-up patients with a change in clinical status show significantly larger changes in clearance function compared to clinically stable patients (206 min vs 7 min; P less than 0.001). MPS function changed concordantly with a change in clinical status in all cases (P = 0.002). Longitudinal assessments did not demonstrate concordance of changes in MPS function and CIC, measured by three different assays. The MPS Fc receptor defect in systemic lupus is dynamic and closely associated with disease activity. The lack of concordance of the defect with changes in CIC suggests that either CIC does not adequately reflect receptor site saturation or that other factors may also contribute to the magnitude of MPS dysfunction. PMID:6839542

  7. Documentation of the data analysis system for the gamma ray monitor aboard OSO-H

    NASA Technical Reports Server (NTRS)

    Croteau, S.; Buck, A.; Higbie, P.; Kantauskis, J.; Foss, S.; Chupp, D.; Forrest, D. J.; Suri, A.; Gleske, I.

    1973-01-01

    The programming system is presented which was developed to prepare the data from the gamma ray monitor on OSO-7 for scientific analysis. The detector, data, and objectives are described in detail. Programs presented include; FEEDER, PASS-1, CAL1, CAL2, PASS-3, Van Allen Belt Predict Program, Computation Center Plot Routine, and Response Function Programs.

  8. Associations between Fc gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease.

    PubMed

    Domingo, Pere; Muñiz-Diaz, Eduardo; Baraldès, Maria A; Arilla, Marina; Barquet, Nicolau; Pericas, Roser; Juárez, Cándido; Madoz, Pedro; Vázquez, Guillermo

    2002-01-01

    In vitro studies have shown that the neutrophil Fc gamma receptor IIA (FcgammaRIIA) polymorphism influences the phagocytic capacity of neutrophils and the removal of encapsulated bacteria from the bloodstream. In particular, the R/R131 allotype is associated with less phagocytic activity. We performed a case-control study to determine the influence of the FcgammaRIIA polymorphism (R/R131, R/H131, H/H131) on the risk and outcome of meningococcal disease. The polymorphisms were measured in 130 patients with microbiologically proven meningococcal disease diagnosed from 1987 to 1998 (cases) and 260 asymptomatic sex-matched blood donors (controls). Clinical manifestations and complications of meningococcal disease were recorded, and a prognostic score (based on age, hemorrhagic diathesis, neurologic signs, and the absence of preadmission antibiotic) therapy was calculated. The distributions of FcgammaRIIA allotypes were similar in cases and controls. However, among patients with meningococcal infection, fulminant meningococcal disease (odds ratio [OR] = 3.9; 95% confidence interval [CI]: 1.0 to 16; P = 0.04) and meningococcemia without meningitis (OR = 3.0; 95% CI: 1.4 to 7.8; P = 0.004) were more common in those with the FcgammaRIIA-R/R131 allotype. Complications were also significantly more frequent in these patients. Of the 42 patients with the R/R131 allotype, 31 (74%) had an adverse prognostic score, compared with 7% (4 of 59) of those with the R/H131 allotype and 3% (1 of 29) of those with the H/H131 allotype (P <0.0001). The FcgammaRIIA-R/R131 allotype is associated with more severe forms of meningococcal disease.

  9. Development of a Portable Gamma-ray Survey System for the Measurement of Air Dose Rates

    NASA Astrophysics Data System (ADS)

    Goto, Jun; Shobugawa, Yugo; Kawano, Yoh; Amaya, Yoshihiro; Izumikawa, Takuji; Katsuragi, Yoshinori; Shiiya, Tomohiro; Suzuki, Tsubasa; Takahashi, Takeshi; Takahashi, Toshihiro; Yoshida, Hidenori; Naito, Makoto

    BIo-Safety Hybrid Automatic MOnitor-Niigata (BISHAMON), a portable gamma-ray survey system, was developed to support victims of the Fukushima Daiichi nuclear disaster. BISHAMON is capable of constructing a map of the distribution of ambient dose equivalent rates using vehicle-mounted or on-foot survey methods. In this study, we give an overview of BISHAMON and its measurement results including a comparison with those of other systems such as KURAMA.

  10. Very high-energy gamma rays from gamma-ray bursts.

    PubMed

    Chadwick, Paula M

    2007-05-15

    Very high-energy (VHE) gamma-ray astronomy has undergone a transformation in the last few years, with telescopes of unprecedented sensitivity having greatly expanded the source catalogue. Such progress makes the detection of a gamma-ray burst at the highest energies much more likely than previously. This paper describes the facilities currently operating and their chances for detecting gamma-ray bursts, and reviews predictions for VHE gamma-ray emission from gamma-ray bursts. Results to date are summarized.

  11. Radiation detection system for portable gamma-ray spectroscopy

    DOEpatents

    Rowland, Mark S [Alamo, CA; Howard, Douglas E [Livermore, CA; Wong, James L [Dublin, CA; Jessup, James L [Tracy, CA; Bianchini, Greg M [Livermore, CA; Miller, Wayne O [Livermore, CA

    2006-06-20

    A portable gamma ray detection apparatus having a gamma ray detector encapsulated by a compact isolation structure having at least two volumetrically-nested enclosures where at least one is a thermal shield. The enclosures are suspension-mounted to each other to successively encapsulate the detector without structural penetrations through the thermal shields. A low power cooler is also provided capable of cooling the detector to cryogenic temperatures without consuming cryogens, due to the heat load reduction by the isolation structure and the reduction in the power requirements of the cooler. The apparatus also includes a lightweight portable power source for supplying power to the apparatus, including to the cooler and the processing means, and reducing the weight of the apparatus to enable handheld operation or toting on a user's person.

  12. Estrogen-related receptor {alpha} modulates the expression of adipogenesis-related genes during adipocyte differentiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ijichi, Nobuhiro; Ikeda, Kazuhiro; Horie-Inoue, Kuniko

    2007-07-06

    Estrogen-related receptor {alpha} (ERR{alpha}) is an orphan nuclear receptor that regulates cellular energy metabolism by modulating gene expression involved in fatty acid oxidation and mitochondrial biogenesis in brown adipose tissue. However, the physiological role of ERR{alpha} in adipogenesis and white adipose tissue development has not been well studied. Here, we show that ERR{alpha} and ERR{alpha}-related transcriptional coactivators, peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) coactivator-1{alpha} (PGC-1{alpha}) and PGC-1{beta}, can be up-regulated in 3T3-L1 preadipocytes at mRNA levels under the adipogenic differentiation condition including the inducer of cAMP, glucocorticoid, and insulin. Gene knockdown by ERR{alpha}-specific siRNA results in mRNA down-regulation of fatty acidmore » binding protein 4, PPAR{gamma}, and PGC-1{alpha} in 3T3-L1 cells in the adipogenesis medium. ERR{alpha} and PGC-1{beta} mRNA expression can be also up-regulated in another preadipocyte lineage DFAT-D1 cells and a pluripotent mesenchymal cell line C3H10T1/2 under the differentiation condition. Furthermore, stable expression of ERR{alpha} in 3T3-L1 cells up-regulates adipogenic marker genes and promotes triglyceride accumulation during 3T3-L1 differentiation. These results suggest that ERR{alpha} may play a critical role in adipocyte differentiation by modulating the expression of various adipogenesis-related genes.« less

  13. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function.

    PubMed

    Bubeck Wardenburg, J; Fu, C; Jackman, J K; Flotow, H; Wilkinson, S E; Williams, D H; Johnson, R; Kong, G; Chan, A C; Findell, P R

    1996-08-16

    Two families of tyrosine kinases, the Src and Syk families, are required for T-cell receptor activation. While the Src kinases are responsible for phosphorylation of receptor-encoded signaling motifs and for up-regulation of ZAP-70 activity, the downstream substrates of ZAP-70 are unknown. Evidence is presented herein that the Src homology 2 (SH2) domain-containing leukocyte protein of 76 kDa (SLP-76) is a substrate of ZAP-70. Phosphorylation of SLP-76 is diminished in T cells that express a catalytically inactive ZAP-70. Moreover, SLP-76 is preferentially phosphorylated by ZAP-70 in vitro and in heterologous cellular systems. In T cells, overexpression of wild-type SLP-76 results in a hyperactive receptor, while expression of a SLP-76 molecule that is unable to be tyrosine-phosphorylated attenuates receptor function. In addition, the SH2 domain of SLP-76 is required for T-cell receptor function, although its role is independent of the ability of SLP-76 to undergo tyrosine phosphorylation. As SLP-76 interacts with both Grb2 and phospholipase C-gamma1, these data indicate that phosphorylation of SLP-76 by ZAP-70 provides an important functional link between the T-cell receptor and activation of ras and calcium pathways.

  14. Method and system for the combination of non-thermal plasma and metal/metal oxide doped .gamma.-alumina catalysts for diesel engine exhaust aftertreatment system

    DOEpatents

    Aardahl, Christopher L [Richland, WA; Balmer-Miller, Mari Lou [West Richland, WA; Chanda, Ashok [Peoria, IL; Habeger, Craig F [West Richland, WA; Koshkarian, Kent A [Peoria, IL; Park, Paul W [Peoria, IL

    2006-07-25

    The present disclosure pertains to a system and method for treatment of oxygen rich exhaust and more specifically to a method and system that combines non-thermal plasma with a metal doped .gamma.-alumina catalyst. Current catalyst systems for the treatment of oxygen rich exhaust are capable of achieving only approximately 7 to 12% NO.sub.x reduction as a passive system and only 25 40% reduction when a supplemental hydrocarbon reductant is injected into the exhaust stream. It has been found that treatment of an oxygen rich exhaust initially with a non-thermal plasma and followed by subsequent treatment with a metal doped .gamma.-alumina prepared by the sol gel method is capable of increasing the NO.sub.x reduction to a level of approximately 90% in the absence of SO.sub.2 and 80% in the presence of 20 ppm of SO.sub.2. Especially useful metals have been found to be indium, gallium, and tin.

  15. Terrestrial Gamma Ray Flashes due to Particle Acceleration in Tropical Storm Systems

    NASA Technical Reports Server (NTRS)

    Roberts, O. S.; Fitzpatrick, G.; Priftis, G.; Bedka, K.; Chronis, T.; Mcbreen, S.; Briggs, M.; Cramer, E.; Mailyan, B.; Stanbro, M.

    2017-01-01

    Terrestrial gamma ray flashes (TGFs) are submillisecond flashes of energetic radiation that are believed to emanate from intracloud lightning inside thunderstorms. This emission can be detected hundreds of kilometers from the source by space-based observatories such as the Fermi Gamma-ray Space Telescope (Fermi). The location of the TGF-producing storms can be determined using very low frequency (VLF) radio measurements made simultaneously with the Fermi detection, allowing additional insight into the mechanisms which produce these phenomena. In this paper, we report 37 TGFs originating from tropical storm systems for the first time. Previous studies to gain insight into how tropical cyclones formed and how destructive they can be include the investigation of lightning flash rates and their dependence on storm evolution. We find TGFs to emanate from a broad range of distances from the storm centers. In hurricanes and severe tropical cyclones, the TGFs are observed to occur predominately from the outer rainbands. A majority of our sample also show TGFs occurring during the strengthening phase of the encompassing storm system. These results verify that TGF production closely follows when and where lightning predominately occurs in cyclones. The intrinsic characteristics of these TGFs were not found to differ from other TGFs reported in larger samples. We also find that some TGF-producing storm cells in tropical storm systems far removed from land have a low number of WWLLN sferics. Although not unique to tropical cyclones, this TGF/sferic ratio may imply a high efficiency for the lightning in these storms to generate TGFs.

  16. Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-gamma.

    PubMed

    Revelo, Monica P; Federspiel, Charles; Helderman, Harold; Fogo, Agnes B

    2005-12-01

    Chronic allograft nephropathy (CAN) is a major cause of loss of renal allografts. Mechanisms postulated to be involved include sequelae of rejection, warm ischaemia time, drug toxicity, ongoing hypertension and dyslipidaemia. Plasminogen activator inhibitor-1 (PAI-1) is implicated not only in thrombosis, but also in fibrosis, by inhibiting matrix degradation, and is expressed in renal parenchymal cells as well as in macrophages. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the steroid receptor superfamily, and plays a major beneficial role in lipid regulation, insulin sensitivity and macrophage function, factors that may play a role in CAN. We therefore studied the expression of these molecules in CAN. All renal biopsy/nephrectomy files from Vanderbilt and Nashville VAMC from a 6 year period were reviewed to identify all renal transplant biopsies or nephrectomies more than 6 months after transplant with CAN. CAN was defined as fibrosis in the graft, vascular, interstitial or glomerular. All cases were scored for severity of fibrosis in vasculature (0-3 scale), glomeruli (% affected with either segmental and/or global sclerosis) and interstitial fibrosis (% of sample affected). PAI-1 and PPAR-gamma immunostaining was assessed on a 0-3 scale in glomeruli, vessels and tubules. Eighty-two patients with a total of 106 samples met entry criteria. The population consisted of 59 Caucasians and 23 African-Americans; 49 males, 33 females with average age 37.9+/-1.7 years. Average time after transplant at time of biopsy was 60.5+/-4.9 months (range 7-229). Glomerulosclerosis extent in CAN was on average 26.5+/-2.4% compared with 3.6+/-1.2% in normal control kidneys from native kidney cancer nephrectomies and 0% in transplanted kidney biopsies from patients obtained > or =6 months after transplantation without CAN. Native control kidneys showed mild interstitial fibrosis (8.0+/-1.2%), whereas transplant controls showed very minimal fibrosis (2

  17. A Novel Bioinspired PVDF Micro/Nano Hair Receptor for a Robot Sensing System

    PubMed Central

    Li, Fei; Liu, Weiting; Stefanini, Cesare; Fu, Xin; Dario, Paolo

    2010-01-01

    This paper describes the concept and design of a novel artificial hair receptor for the sensing system of micro intelligent robots such as a cricket-like jumping mini robot. The concept is inspired from the natural hair receptor of animals, also called cilium or filiform hair by different research groups, which is usually used as a vibration receptor or a flow detector by insects, mammals and fishes. The suspended fiber model is firstly built and the influence of scaling down is analyzed theoretically. The design of this artificial hair receptor is based on aligned suspended PVDF (polyvinylidene fluoride) fibers, manufactures with a novel method called thermo-direct drawing technique, and aligned suspended submicron diameter fibers are thus successfully fabricated on a flexible Kapton. In the post process step, some key problems such as separated electrodes deposition along with the fiber drawing direction and poling of micro/nano fibers to impart them with good piezoeffective activity have been presented. The preliminary validation experiments show that the artificial hair receptor has a reliable response with good sensibility to external pressure variation and, medium flow as well as its prospects in the application on sensing system of mini/micro bio-robots. PMID:22315581

  18. GammaScorpion: mobile gamma-ray tomography system for early detection of basal stem rot in oil palm plantations

    NASA Astrophysics Data System (ADS)

    Abdullah, Jaafar; Hassan, Hearie; Shari, Mohamad Rabaie; Mohd, Salzali; Mustapha, Mahadi; Mahmood, Airwan Affendi; Jamaludin, Shahrizan; Ngah, Mohd Rosdi; Hamid, Noor Hisham

    2013-03-01

    Detection of the oil palm stem rot disease Ganoderma is a major issue in estate management and production in Malaysia. Conventional diagnostic techniques are difficult and time consuming when using visual inspection, and destructive and expensive when based on the chemical analysis of root or stem tissue. As an alternative, a transportable gamma-ray computed tomography system for the early detection of basal stem rot (BSR) of oil palms due to Ganoderma was developed locally at the Malaysian Nuclear Agency, Kajang, Malaysia. This system produces high quality tomographic images that clearly differentiate between healthy and Ganoderma infected oil palm stems. It has been successfully tested and used to detect the extent of BSR damage in oil palm plantations in Malaysia without the need to cut down the trees. This method offers promise for in situ inspection of oil palm stem diseases compared to the more conventional methods.

  19. The gamma delta T cell repertoire in Graves' disease and multinodular goitre.

    PubMed Central

    McIntosh, R S; Tandon, N; Pickerill, A P; Davies, R; Barnett, D; Weetman, A P

    1993-01-01

    gamma delta T cells are a subset of T cells with unknown function, and restriction of the gamma delta T cell receptor (TCR) repertoire has been described in rheumatoid arthritis and multiple sclerosis. Elevated numbers of gamma delta T cells have been reported in the peripheral blood and thyroids of patients with Graves' disease. We have carried out flow cytometric analysis on peripheral blood mononuclear cells (PBMC) and intrathyroidal lymphocytes (ITL) from 12 patients with Graves' disease and nine patients with multinodular goitre (MNG), a thyroid disease of unknown etiology. There was no significant difference between the proportion of gamma delta T cells in the PBMC of Graves' and MNG patients, nor between the PBMC and ITL populations in either patient group. We have also carried out polymerase chain reaction amplification on RNA prepared from matched PBMC, ITL and the activated (CD25+) subset of ITL using six TCR V delta-family specific primers. Although there were differences in the amounts of each V delta transcript amplified from PBMC and ITL, there was no difference between the two patient groups. No consistent differences were therefore found between the gamma delta T cell populations in Graves' and MNG patients, arguing against the direct involvement of this T cell subset in the pathogenesis of Graves' disease. Images Fig. 1 PMID:8252809

  20. Implementing displacement damage calculations for electrons and gamma rays in the Particle and Heavy-Ion Transport code System

    NASA Astrophysics Data System (ADS)

    Iwamoto, Yosuke

    2018-03-01

    In this study, the Monte Carlo displacement damage calculation method in the Particle and Heavy-Ion Transport code System (PHITS) was improved to calculate displacements per atom (DPA) values due to irradiation by electrons (or positrons) and gamma rays. For the damage due to electrons and gamma rays, PHITS simulates electromagnetic cascades using the Electron Gamma Shower version 5 (EGS5) algorithm and calculates DPA values using the recoil energies and the McKinley-Feshbach cross section. A comparison of DPA values calculated by PHITS and the Monte Carlo assisted Classical Method (MCCM) reveals that they were in good agreement for gamma-ray irradiations of silicon and iron at energies that were less than 10 MeV. Above 10 MeV, PHITS can calculate DPA values not only for electrons but also for charged particles produced by photonuclear reactions. In DPA depth distributions under electron and gamma-ray irradiations, build-up effects can be observed near the target's surface. For irradiation of 90-cm-thick carbon by protons with energies of more than 30 GeV, the ratio of the secondary electron DPA values to the total DPA values is more than 10% and increases with an increase in incident energy. In summary, PHITS can calculate DPA values for all particles and materials over a wide energy range between 1 keV and 1 TeV for electrons, gamma rays, and charged particles and between 10-5 eV and 1 TeV for neutrons.