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Sample records for receptor gamma system

  1. Localization of Fc gamma receptors in the human central nervous system.

    PubMed

    Nyland, H; Nilsen, R

    1982-08-01

    Immune complexes of horseradish peroxidase (HRP) and rabbit IgG antibodies to HRP were used to study the Fc gamma receptors in the human central nervous system (CNS). The peroxidase activity was demonstrated with 3,3'-diaminobenzidine tetrahydrochloride and H2O2. The majority of the pia and arachnoid cells of the leptomeninges, the stroma cells of the arachnoid granulations and the adventitial cells in the perivascular spaces of the nervous tissue were stained. The villi of the choroid plexus were also stained. By electron microscopy the reaction products were localized to the plasma membranes of the stroma cells and at the basal aspects of the epithelial cells in the choroid villi. In addition, reaction product was demonstrated on pericytes of some of the brain capillaries. The immune complexes did not bind to the brain parenchyma.

  2. Fc gamma receptor IIIb enhances Fc gamma receptor IIa function in an oxidant-dependent and allele-sensitive manner.

    PubMed Central

    Salmon, J E; Millard, S S; Brogle, N L; Kimberly, R P

    1995-01-01

    Two classes of receptors for IgG, Fc gamma RIIa and Fc gamma RIIIb, both of which exist in two allelic forms, are expressed on human neutrophils. Neutrophils from normal donors, homozygous for the different allelic phenotypes of Fc gamma RIIIb, have significantly different levels of Fc gamma receptor-mediated phagocytosis of IgG-opsonized erythrocytes (EA). However, the observation that Fc gamma RIIIb mediates phagocytosis of specific mAb-targeted erythrocytes poorly suggests that this receptor may influence EA internalization by Fc gamma RIIa in an allele-sensitive fashion. Donors homozygous for the NA1 allele of Fc gamma RIIIb showed greater activation of Fc gamma RIIa after Fc gamma RIIIb cross-linking than donors homozygous for the NA2 allele of Fc gamma RIIIb. This increase in receptor-specific internalization reflects both an increase in ligand binding by Fc gamma RIIa and an increase in internalization efficiency of targets bound. Activation of Fc gamma RIIa by Fc gamma RIIIb is transferable by supernatants from activated cells and is blocked by inhibitors of reactive oxygen species and the H2O2-myeloperoxidase-chloride system and by serine protease inhibitors. Thus, cross-linking of Fc gamma RIIIb, which leads to neutrophil degranulation and the generation of reactive oxygen intermediates, in turn alters Fc gamma RIIa avidity and efficiency. These oxidant-mediated changes in Fc gamma RIIa function provide a novel mechanism for receptors to collaborate in both an autocrine and paracrine fashion. The allele sensitivity of these effects suggests that Fc gamma receptor polymorphisms may be inherited disease susceptibility factors in host defense against infection and in the development of autoimmunity. Images PMID:7769129

  3. The central nervous system convulsant pentylenetetrazole stimulates gamma-aminobutyric acid (GABA)-activated current in picrotoxin-resistant GABA(A) receptors in HEK293 cells.

    PubMed

    Dibas, M I; Dillon, G H

    2000-05-19

    We tested the ability of the central nervous system convulsant pentylenetetrazole (PTZ) to inhibit gamma-aminobutyric acid (GABA)-gated current in receptors expressing a mutation that rendered them resistant to picrotoxin. Consistent with previous reports, receptors expressing beta2(T246F), along with alpha3 and gamma2 subunits, resulted in a greatly diminished sensitivity to picrotoxin. Sensitivity to PTZ was completely abolished in the mutant receptor, confirming the hypothesis that PTZ acts at the picrotoxin site. Quite unexpected, however, was our finding that PTZ elicited marked stimulation (up to 400% of control) in the mutated receptors. This stimulatory effect was not mediated via an interaction with the benzodiazepine site, as preincubation with the benzodiazepine antagonist flumazenil did not block the PTZ-induced stimulation. Our results reveal the existence of a novel stimulatory domain of PTZ in GABA(A) receptors.

  4. Analysis of T cells bearing different isotypic forms of the gamma/delta T cell receptor in patients with systemic autoimmune diseases.

    PubMed

    Gerli, R; Agea, E; Bertotto, A; Tognellini, R; Flenghi, L; Spinozzi, F; Velardi, A; Grignani, F

    1991-10-01

    The expression of gamma/delta T cell receptor (TCR) on peripheral blood CD3+ cells circulating in 74 patients with different systemic autoimmune diseases was evaluated. There was a significant increase in the gamma/delta T cell number only in patients with primary Sjögren's syndrome (SS) and in untreated patients with systemic lupus erythematosus (SLE). Unlike healthy subjects, a subgroup of patients with SLE and SS displayed a marked increase in gamma/delta T cells. Immunosuppressive treatment of patients with active SLE led to a normalization of the gamma/delta T cell number. Analysis of surface phenotype showed that when patient gamma/delta T cells were expanded in the peripheral blood, they were not activated but bore "memory" markers. In addition, they preferentially expressed the disulfide linked form of the TCR, except in progressive systemic sclerosis where the nondisulfide form was displayed. Serial determinations in single patients demonstrated that the gamma/delta T cell increase is a persistent immunological feature in these patient subgroups. PMID:1837314

  5. Peroxisome proliferator-activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus

    PubMed Central

    Aprahamian, Tamar R; Bonegio, Ramon G; Weitzner, Zachary; Gharakhanian, Raffi; Rifkin, Ian R

    2014-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are known to have many immunomodulatory effects. We have previously shown that the PPARγ agonist rosiglitazone is beneficial when used early in prevention of disease in murine models of systemic lupus erythematosus (SLE) and SLE-related atherosclerosis. In this report, we demonstrate that another PPARγ agonist, pioglitazone is also beneficial as a treatment for early murine lupus, indicating that this is a class effect and not agent-specific. We further attempt to define the ability of PPARγ agonists to ameliorate established or severe autoimmune disease using two mouse models: the MRL.lpr SLE model and the gld.apoE−/− model of accelerated atherosclerosis and SLE. We demonstrate that, in contrast to the marked amelioration of disease seen when PPARγ agonist treatment was started before disease onset, treatment with rosiglitazone after disease onset in MRL.lpr or gld.apoE−/− mice had minimal beneficial effect on the development of the autoimmune phenotype; however, rosiglitazone treatment remained highly effective at reducing lupus-associated atherosclerosis in gld.apoE−/− mice after disease onset or when mice were maintained on a high cholesterol Western diet. These results suggest that beneficial effects of PPARγ agonists on the development of autoimmunity might be limited to the early stages of disease, but that atherosclerosis, a major cause of death in SLE patients, may be ameliorated even in established or severe disease. PMID:24456224

  6. Differential expression of gamma-aminobutyric acid type B receptor subunit mRNAs in the developing nervous system and receptor coupling to adenylyl cyclase in embryonic neurons.

    PubMed

    Martin, Stella C; Steiger, Janine L; Gravielle, María Clara; Lyons, Helen R; Russek, Shelley J; Farb, David H

    2004-05-17

    gamma-Aminobutyric acid type B receptors (GABA(B)Rs) mediate both slow inhibitory synaptic activity in the adult nervous system and motility signals for migrating embryonic cortical cells. Previous papers have described the expression of GABA(B)Rs in the adult brain, but the expression and functional significance of these gene products in the embryo are largely unknown. Here we examine GABA(B)R expression from rat embryonic day 10 (E10) to E18 compared with adult and ask whether embryonic cortical neurons contain functional GABA(B)R. GABA(B)R1 transcript levels greatly exceed GABA(B)R2 levels in the developing neural tube at E11, and olfactory bulb and striatum at E17 but equalize in most regions of adult nervous tissue, except for the glomerular and granule cell layers of the main olfactory bulb and the striatum. Consistent with expression differences, the binding affinity of GABA for GABA(B)Rs is significantly lower in adult striatum compared with cerebellum. Multiple lines of evidence from in situ hybridization, RNase protection, and real-time PCR demonstrate that GABA(B)R1a, GABA(B)R1b, GABA(B)R1h (a subunit subtype, lacking a sushi domain, that we have identified in embryonic rat brain), GABA(B)R2, and GABA(B)L transcript levels are not coordinately regulated. Despite the functional requirement for a heterodimer of GABA(B)R subunits, the expression of each subunit mRNA is under independent control during embryonic development, and, by E18, GABA(B)Rs are negatively coupled to adenylyl cyclase in neocortical neurons. The presence of embryonic GABA(B)R transcripts and protein and functional receptor coupling indicates potentially important roles for GABA(B)Rs in modulation of synaptic transmission in the developing embryonic nervous system.

  7. Gamma interferon (IFN-γ) receptor restricts systemic dengue virus replication and prevents paralysis in IFN-α/β receptor-deficient mice.

    PubMed

    Prestwood, Tyler R; Morar, Malika M; Zellweger, Raphaël M; Miller, Robyn; May, Monica M; Yauch, Lauren E; Lada, Steven M; Shresta, Sujan

    2012-12-01

    We previously reported that mice lacking alpha/beta and gamma interferon receptors (IFN-α/βR and -γR) uniformly exhibit paralysis following infection with the dengue virus (DENV) clinical isolate PL046, while only a subset of mice lacking the IFN-γR alone and virtually no mice lacking the IFN-α/βR alone develop paralysis. Here, using a mouse-passaged variant of PL046, strain S221, we show that in the absence of the IFN-α/βR, signaling through the IFN-γR confers approximately 140-fold greater resistance against systemic vascular leakage-associated dengue disease and virtually complete protection from dengue-induced paralysis. Viral replication in the spleen was assessed by immunohistochemistry and flow cytometry, which revealed a reduction in the number of infected cells due to IFN-γR signaling by 2 days after infection, coincident with elevated levels of IFN-γ in the spleen and serum. By 4 days after infection, IFN-γR signaling was found to restrict DENV replication systemically. Clearance of DENV, on the other hand, occurred in the absence of IFN-γR, except in the central nervous system (CNS) (brain and spinal cord), where clearance relied on IFN-γ from CD8(+) T cells. These results demonstrate the roles of IFN-γR signaling in protection from initial systemic and subsequent CNS disease following DENV infection and demonstrate the importance of CD8(+) T cells in preventing DENV-induced CNS disease. PMID:22973027

  8. Analysis of subcomponents of the gamma-aminobutyric acid/benzodiazepine receptor macromolecular complex in mammalian central nervous system

    SciTech Connect

    McCabe, R.T.

    1987-01-01

    Since the presence of endogenous gamma-aminobutyric acid (GABA) may affect benzodiazepine binding to tissue sections in autoradiographic studies, a protocol designed to check for this influence has been investigated. (/sup 3/H)Flunitrazepam (1 nM) was used to label benzodiazepine receptors for autoradiographic localization. Bicuculline was added to the incubation medium of an additional set of tissue sections to antagonize any potential effect of endogenous GABA. Binding in these sections was compared to that occurring in another set in which excess GABA was added to create further GABA enhancement. Binding was also compared to adjacent sections which were treated similarly but also preincubated in distilled-deionized water to burst the cells by osmotic shock and eliminate endogenous GABA, thereby preventing any effect on benzodiazepine binding. The results indicated that endogenous GABA is indeed present in the slide-mounted tissue sections and is affecting benzodiazepine receptor binding differentially in various regions of the brain depending on the density of GABAergic innervation. Scatchard analysis of saturation data demonstrated that the alteration in BZ binding due to GABA was a result of a change in the affinity rather than number of receptors present.

  9. Interferon enhances the expression of Fc gamma receptors.

    PubMed

    Fridman, W H; Gresser, I; Bandu, M T; Aguet, M; Neauport-Sautes, C

    1980-05-01

    Murine T2D4 cells derived from a T cell hybrid line were incubated with partially purified or electrophoretically pure mouse interferon and tested for the expression of Fc gamma R as assessed by a) counting the number of cells forming rosettes with IgG-sensitized sheep erythrocytes, and b) incubating the cells with heat-aggregated rabbit IgG and then determining either the number of cells stained with fluorescein conjugated goat anti-rabbit IgG or the extent of labeling by using radioactive iodinated staphylococcus protein A. Although interferon induced a rapid increase in Fc gamma R expression on the Fc gamma R-positive T2D4 cells, it did not induce either Fc gamma R on the Fc gamma R negative BW5147 cells or Fc gamma R on either cell line. Human leukocyte interferon enhanced the expression of Fc gamma R on human Burkitt cells (Daudi) but did not affect the expression of Fc gamma R on mouse cells. We suggest that interferon may influence several effector functions of the immune system by modulating Fc receptor expression. PMID:6154103

  10. Benzodiazepine receptor agonists affect both binding and gating of recombinant alpha1beta2gamma2 gamma-aminobutyric acid-A receptors.

    PubMed

    Mercik, Katarzyna; Piast, Michał; Mozrzymas, Jerzy W

    2007-05-28

    Benzodiazepines are known to act by enhancing the effect of gamma-aminobutyric acid-A receptor agonists. Positive modulation by benzodiazepines is typically ascribed to upregulation of agonist binding affinity but their effect on gamma-aminobutyric acid-A receptor gating remain unclear. In this work, we have used the ultrafast application system to examine the impact of flurazepam and zolpidem on recombinant alpha1beta2gamma2 gamma-aminobutyric acid-A receptors. As expected, both drugs strongly enhanced currents evoked by low [gamma-aminobutyric acid]. These compounds, however, also affected currents elicited by saturating agonist concentration. In particular, flurazepam and zolpidem reduced current amplitudes and slowed down the recovery process in paired-pulse experiments. Moreover, flurazepam accelerated the current rise time and zolpidem enhanced the rate and extent of desensitization. We propose that flurazepam and zolpidem modulate gamma-aminobutyric acid-A receptors by strong enhancement of agonist binding with a superimposed limited effect on the receptor gating.

  11. A third human retinoic acid receptor, hRAR-. gamma

    SciTech Connect

    Krust, A.; Kastner, Ph.; Petkovich, M.; Zelent, A.; Chambon, P. )

    1989-07-01

    Retinoic acid receptors (RARs) are retinoic acid (RA)-inducible enhancer factors belonging to the superfamily of steroid/thyroid nuclear receptors. The authors have previously characterized two human RAR (hRAR-{alpha} and hRAR-{beta}) cDNAs and have recently cloned their murine cognates (mRAR-{alpha} and mRAR-{beta}) together with a third RAR (mRAR-{gamma}) whose RNA was detected predominantly in skin, a well-known target for RA. mRAR-{gamma} cDNA was used here to clone its human counterpart (hRAR-{gamma}) from a T47D breast cancer cell cDNA library. Using a transient transfection assay in HeLa cells and a reporter gene harboring a synthetic RA responsive element, they demonstrate that hRAR-{gamma} cDNA indeed encodes a RA-inducible transcriptional trans-activator. Interestingly, comparisons of the amino acid sequences of all six human and mouse RARs indicate that the interspecies conservation of a given member of the RAR subfamily (either {alpha}, {beta}, or {gamma}) is much higher than the conservation of all three receptors within a given species. These observations indicate that RAR-{alpha}, -{beta}, and -{gamma} may perform specific functions. They show also that hRAR-{gamma} RNA is the predominant RAR RNA species in human skin, which suggests that hRAR-{gamma} mediates some of the retinoid effects in this tissue.

  12. Orexin Receptor Activation Generates Gamma Band Input to Cholinergic and Serotonergic Arousal System Neurons and Drives an Intrinsic Ca2+-Dependent Resonance in LDT and PPT Cholinergic Neurons

    PubMed Central

    Ishibashi, Masaru; Gumenchuk, Iryna; Kang, Bryan; Steger, Catherine; Lynn, Elizabeth; Molina, Nancy E.; Eisenberg, Leonard M.; Leonard, Christopher S.

    2015-01-01

    A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30–60 Hz) – a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT) and pedunculopontine (PPT) tegmental neurons and serotonergic dorsal raphe (DR) neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca2+-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal targets. Since key arousal input arises from hypothalamic orexin (hypocretin) neurons, we investigated whether the unusually noisy, depolarizing orexin current could provide significant gamma input to cholinergic and serotonergic neurons, and whether such input could drive Ca2+-dependent oscillations. Whole-cell recordings in brain slices were obtained from mice expressing Cre-induced fluorescence in cholinergic LDT and PPT, and serotonergic DR neurons. After first quantifying reporter expression accuracy in cholinergic and serotonergic neurons, we found that the orexin current produced significant high frequency, including gamma, input to both cholinergic and serotonergic neurons. Then, by using a dynamic clamp, we found that adding a noisy orexin conductance to cholinergic neurons induced a Ca2+-dependent resonance that peaked in the theta and alpha frequency range (4–14 Hz) and extended up to 100 Hz. We propose that this orexin current noise and the Ca2+ dependent resonance work synergistically to boost the encoding of high-frequency synaptic inputs into action potentials and to help ensure cholinergic neurons fire during EEG activation. This activity could reinforce thalamocortical states supporting arousal, REM sleep, and intracortical gamma. PMID

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

    SciTech Connect

    Kim, Gwang Sik; Lee, Gha Young; Nedumaran, Balachandar; Park, Yun-Yong; Kim, Kyung Tae; Park, Sang Chul; Lee, Young Chul; Kim, Jae Bum Choi, Hueng-Sik

    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 overexpression 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.

  14. Novel regulation of p38gamma by dopamine D2 receptors during hypoxia.

    PubMed

    Conrad, P W; Millhorn, D E; Beitner-Johnson, D

    2000-07-01

    The p38 signalling pathway is part of the MAPK superfamily and is activated by various stressors. Our previous results have shown that two p38 isoforms, p38alpha and p38gamma, are activated by hypoxia in the neural-like PC12 cell line. PC12 cells also synthesize and secrete catecholamines, including dopamine, in response to hypoxia. We have now used this system to study the interaction between D2-dopamine receptor signalling and the p38 stress-activated protein kinases. Our results show that two D2 receptor antagonists, butaclamol and sulpiride, enhance hypoxia-induced phosphorylation of p38gamma, but not p38. This effect persists in protein kinase A (PKA)-deficient PC12 cells, demonstrating that p38gamma modulation by the D2 receptor is independent of the cAMP/PKA signalling system. We further show that removal of extracellular calcium blocks the hypoxia-induced increase in p38gamma activity. These results are the first to demonstrate that p38gamma can be regulated by the D2 receptor and calcium following hypoxic exposure. PMID:10989281

  15. Novel Fc gamma receptor I family gene products in human mononuclear cells.

    PubMed Central

    Porges, A J; Redecha, P B; Doebele, R; Pan, L C; Salmon, J E; Kimberly, R P

    1992-01-01

    Unlike the human Fc gamma RII and Fc gamma RIII families, which exhibit considerable diversity at both the nucleic acid and protein levels, the human Fc gamma RI family has only a single recognized product expressed as a 70-kD cell surface receptor with high affinity for monomeric IgG (hFc gamma RIa1). Using both polymerase chain reaction-based amplification and Northern hybridization, we document multiple interferon-gamma-inducible hFc gamma RI RNA transcripts in human mononuclear cells and neutrophils. The sequences of two of these Fc gamma RI related transcripts indicate that they are alternatively spliced products of a second Fc gamma RI family gene, termed Fc gamma RIB. The cDNA derived from the larger of these transcripts, termed hFc gamma RIb1, encodes a surface molecule that is not recognized by Fc gamma RI specific monoclonal antibodies when transfected into COS-7 cells. Unlike the interferon-gamma-inducible hFc gamma RIA gene product, hFc gamma RIb1 does not bind monomeric IgG with high affinity. However, both hFc gamma RIa1 and hFc gamma RIb1 do bind aggregated human IgG. Previously unrecognized diversity within the hFc gamma RI family includes an interferon-gamma-inducible, putative low affinity Fc gamma receptor that may play an important role in the mechanism by which Fc gamma receptors participate in the humoral immune response. Images PMID:1430234

  16. Expression and characterization of a truncated murine Fc gamma receptor

    PubMed Central

    1988-01-01

    We have isolated a recombinant secreted Fc gamma R beta molecule by deletion of the transmembrane and cytoplasmic domains encoding sequence from a Fc gamma R beta 1 cDNA clone, and insertion of the truncated cDNA into a eukaryotic expression vector, pcEXV-3. To express and amplify the production of the truncated Fc gamma R beta molecule, we transfected the truncated cDNA plasmid into a dihydrofolate reductase- minus CHO cell line along with a dhfr minigene, and amplified the gene products with methotrexate. The resulting cell line secretes 2-3 micrograms/ml/24 h of truncated Fc gamma R beta, which can be readily purified by affinity chromatography on IgG-Sepharose. The truncated Fc gamma R beta has a Mr of 31-33,000 on SDS-PAGE and is glycosylated. N- glycosidase F cleavage reduces the Mr to 19,000, consistent with the size of the truncated product, 176 amino acid residues. There are two disulfide bonds in the protein. Binding of immune complexes formed between DNP20BSA and anti-DNP mAbs reveals better binding of IgG1 aggregates than that of IgG2b and IgG2a aggregates. The binding of the immune complexes was somewhat better at more acidic pH, in contrast to previous experiments with binding of purified Fc gamma R to immune complex-coated beads. We were surprised to observe that the truncated Fc gamma R beta did not react with the anti-Fc gamma R mAb 6B7C. Previous work had shown that 6B7C reacts with Fc gamma R on immunoblots, fails to bind to the surface of resting B cells and peritoneal macrophages, but does bind to macrophage cell lines and LPS- stimulated B cells. We show, by binding of mAb 6B7C to a peptide conjugate, that the 6B7C epitope lies within residues 169-183 of the intact Fc gamma R beta, which is just outside the plasma membrane. The availability of the truncated Fc gamma R beta in microgram quantities should facilitate further analysis of structure and function of these receptors. PMID:2450951

  17. Portable compton gamma-ray detection system

    DOEpatents

    Rowland, Mark S.; Oldaker, Mark E.

    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.

  18. Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors.

    PubMed Central

    Günther, U; Benson, J; Benke, D; Fritschy, J M; Reyes, G; Knoflach, F; Crestani, F; Aguzzi, A; Arigoni, M; Lang, Y

    1995-01-01

    Vigilance, anxiety, epileptic activity, and muscle tone can be modulated by drugs acting at the benzodiazepine (BZ) site of gamma-aminobutyric acid type A (GABAA) receptors. In vivo, BZ sites are potential targets for endogenous ligands regulating the corresponding central nervous system states. To assess the physiological relevance of BZ sites, mice were generated containing GABAA receptors devoid of BZ sites. Following targeted disruption of the gamma 2 subunit gene, 94% of the BZ sites were absent in brain of neonatal mice, while the number of GABA sites was only slightly reduced. Except for the gamma 2 subunit, the level of expression and the regional and cellular distribution of the major GABAA receptor subunits were unaltered. The single channel main conductance level and the Hill coefficient were reduced to values consistent with recombinant GABAA receptors composed of alpha and beta subunits. The GABA response was potentiated by pentobarbital but not by flunitrazepam. Diazepam was inactive behaviorally. Thus, the gamma 2 subunit is dispensable for the assembly of functional GABAA receptors but is required for normal channel conductance and the formation of BZ sites in vivo. BZ sites are not essential for embryonic development, as suggested by the normal body weight and histology of newborn mice. Postnatally, however, the reduced GABAA receptor function is associated with retarded growth, sensorimotor dysfunction, and drastically reduced life-span. The lack of postnatal GABAA receptor regulation by endogenous ligands of BZ sites might contribute to this phenotype. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7644489

  19. Response kinetics and pharmacological properties of heteromeric receptors formed by coassembly of GABA rho- and gamma 2-subunits.

    PubMed

    Qian, H; Ripps, H

    1999-12-01

    Two of the gamma-aminobutyric acid (GABA) receptors, GABAA and GABAC, are ligand-gated chloride channels expressed by neurons in the retina and throughout the central nervous system. The different subunit composition of these two classes of GABA receptor result in very different physiological and pharmacological properties. Although little is known at the molecular level as to the subunit composition of any native GABA receptor, it is thought that GABAC receptors are homomeric assemblies of rho-subunits. However, we found that the kinetic and pharmacological properties of homomeric receptors formed by each of the rho-subunits cloned from perch retina did not resemble those of the GABAC receptors on perch bipolar cells. Because both GABAA and GABAC receptors are present on retinal bipolar cells, we attempted to determine whether subunits of these two receptor classes are capable of interacting with each other. We report here that, when coexpressed in Xenopus oocytes, heteromeric (rho 1B gamma 2) receptors formed by coassembly of the rho 1B-subunit with the gamma 2-subunit of the GABAA receptor displayed response properties very similar to those obtained with current recordings from bipolar cells. In addition to being unresponsive to bicuculline and diazepam, the time-constant of deactivation, and the sensitivities to GABA, picrotoxin and zinc closely approximated the values obtained from the native GABAC receptors on bipolar cells. These results provide the first direct evidence of interaction between GABA rho and GABAA receptor subunits. It seems highly likely that coassembly of GABAA and rho-subunits contributes to the molecular organization of GABAC receptors in the retina and perhaps throughout the nervous system. PMID:10643085

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

    SciTech Connect

    Wofsy, C.; Goldstein, B. Los Alamos National Lab., NM )

    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 the 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.

  1. Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors.

    PubMed

    Liu, F; Wan, Q; Pristupa, Z B; Yu, X M; Wang, Y T; Niznik, H B

    2000-01-20

    GABA(A) (gamma-aminobutyric-acid A) and dopamine D1 and D5 receptors represent two structurally and functionally divergent families of neurotransmitter receptors. The former comprises a class of multi-subunit ligand-gated channels mediating fast interneuronal synaptic transmission, whereas the latter belongs to the seven-transmembrane-domain single-polypeptide receptor superfamily that exerts its biological effects, including the modulation of GABA(A) receptor function, through the activation of second-messenger signalling cascades by G proteins. Here we show that GABA(A)-ligand-gated channels complex selectively with D5 receptors through the direct binding of the D5 carboxy-terminal domain with the second intracellular loop of the GABA(A) gamma2(short) receptor subunit. This physical association enables mutually inhibitory functional interactions between these receptor systems. The data highlight a previously unknown signal transduction mechanism whereby subtype-selective G-protein-coupled receptors dynamically regulate synaptic strength independently of classically defined second-messenger systems, and provide a heuristic framework in which to view these receptor systems in the maintenance of psychomotor disease states.

  2. Expression of the human interleukin-2 receptor gamma chain in insect cells using a baculovirus expression vector.

    PubMed

    Raivio, E; Oetken, C; Oker-Blom, C; Engberg, C; Akerman, K; Lindqvist, C

    1995-04-01

    The gene encoding the gamma-chain of the human Interleukin-2 receptor was expressed in lepidopteran insect cells using the baculovirus expression vector system. The corresponding gene was inserted under the polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus and expressed in the Spodoptera frugiperda insect cell line Sf9 during viral infection. The recombinant receptor protein was identified by immunoblotting in cell lysates, prepared from insect cells infected with the recombinant virus. At 40 h post infection the corresponding protein was detected as two major bands with apparent molecular weights of 50-60 kDa using a rabbit anti-human IL-2R gamma-receptor specific antiserum. Metabolic labelling with [35S]-methionine and SDS-PAGE analysis of the recombinant baculovirus infected insect cells verified the immunoblotting data. The expressed IL-2R gamma- protein could also be determined on the surface of infected insect cells by flow cytometer analysis. PMID:7899821

  3. Purification and characterization of the human interferon-. gamma. receptor from placenta

    SciTech Connect

    Calderon, J.; Sheehan, K.C.F.; Chance, C.; Thomas, M.L.; Schreiber, R.D. )

    1988-07-01

    Purification of the human interferon-{gamma} (IFN-{gamma}) receptor was facilitated by identification of human placenta as a large-scale receptor source. When analyzed in radioligand binding experiments, intact placental membranes and detergent-solubilized membrane proteins expressed 1.3 and 5.9 {times} 10{sup 12} receptors per mg of protein, respectively, values that were 13-163 times greater than that observed for U937 membranes. Two protocols were followed to purify the IFN-{gamma} receptor from octyl glucoside-solubilized membranes: (i) sequential affinity chromatography over wheat germ agglutinin- and INF-{gamma}-Sepharose and (ii) affinity chromatography over columns containing receptor-specific monoclonal antibody and wheat germ agglutinin. Both procedures resulted in fully active preparations that were 70-90% pure. Purified receptor migrated as a single molecular species of 90 kDa either when analyzed on silver-stained NaDodSO{sub 4}/polyacrylamide gels or when subjected to electrophoretic transfer blot analysis using a labeled IFN-{gamma} receptor-specific monoclonal antibody. The identity of the 90-kDa component as the receptor was confirmed by demonstrating its ability to specifically bind {sup 125}I-labeled IFN-{gamma} following NaDodSO{sub 4}/PAGE and transfer to nitrocellulose. The ligand binding site, the epitope for the receptor-specific monoclonal antibody, and all of the N-linked carbohydrate could be localized to the 55-kDa domain of the molecule.

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

    SciTech Connect

    Lin, Shengchen; Han, Ying; Shi, Yuzhe; Rong, Hui; Zheng, Songyang; Jin, Shikan; Lin, Shu-Yong; Lin, Sheng-Cai; Li, Yong

    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 of 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.

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

    SciTech Connect

    O'Sullivan, Saoirse E. . E-mail: Saoirse.o'sullivan@nottingham.ac.uk; Tarling, Elizabeth J.; Bennett, Andrew J.; Kendall, David A.; Randall, Michael D.

    2005-11-25

    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 AM251 (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.

  6. Kaempferol is an estrogen-related receptor alpha and gamma inverse agonist.

    PubMed

    Wang, Junjian; Fang, Fang; Huang, Zhiyan; Wang, Yanfei; Wong, Chiwai

    2009-02-18

    Kaempferol is a dietary flavonoid that is thought to function as a selective estrogen receptor modulator. In this study, we established that kaempferol also functions as an inverse agonist for estrogen-related receptors alpha and gamma (ERRalpha and ERRgamma). We demonstrated that kaempferol binds to ERRalpha and ERRgamma and blocks their interaction with coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). Kaempferol also suppressed the expressions of ERR-target genes pyruvate dehydrogenase kinase 2 and 4 (PDK2 and PDK4). This evidence suggests that kaempferol may exert some of its biological effect through both estrogen receptors and estrogen-related receptors. PMID:19171140

  7. Dopamine D3 Receptors Inhibit Hippocampal Gamma Oscillations by Disturbing CA3 Pyramidal Cell Firing Synchrony

    PubMed Central

    Lemercier, Clément E.; Schulz, Steffen B.; Heidmann, Karin E.; Kovács, Richard; Gerevich, Zoltan

    2016-01-01

    Cortical gamma oscillations are associated with cognitive processes and are altered in several neuropsychiatric conditions such as schizophrenia and Alzheimer’s disease. Since dopamine D3 receptors are possible targets in treatment of these conditions, it is of great importance to understand their role in modulation of gamma oscillations. The effect of D3 receptors on gamma oscillations and the underlying cellular mechanisms were investigated by extracellular local field potential and simultaneous intracellular sharp micro-electrode recordings in the CA3 region of the hippocampus in vitro. D3 receptors decreased the power and broadened the bandwidth of gamma oscillations induced by acetylcholine or kainate. Blockade of the D3 receptors resulted in faster synchronization of the oscillations, suggesting that endogenous dopamine in the hippocampus slows down the dynamics of gamma oscillations by activation of D3 receptors. Investigating the underlying cellular mechanisms for these effects showed that D3 receptor activation decreased the rate of action potentials (APs) during gamma oscillations and reduced the precision of the AP phase coupling to the gamma cycle in CA3 pyramidal cells. The results may offer an explanation how selective activation of D3 receptors may impair cognition and how, in converse, D3 antagonists may exert pro-cognitive and antipsychotic effects. PMID:26779018

  8. Cellular localization of retinoic acid receptor-gamma expression in normal and neoplastic skin.

    PubMed Central

    Finzi, E.; Blake, M. J.; Celano, P.; Skouge, J.; Diwan, R.

    1992-01-01

    Retinoids profoundly affect the normal growth and differentiation of epithelial tissues. Retinoic acid receptor-gamma (RAR-gamma) is a member of a family of retinoid receptors, and has been shown to be expressed almost exclusively in skin. However, little is known about the cellular localization of this receptor in human skin. The authors studied the expression of RAR-gamma in normal skin and human skin tumors by Northern blot analysis and in situ hybridization. RAR-gamma mRNA was detected in normal skin as well as in cultures of neonatal keratinocytes. Using an oligonucleotide specific for the RAR-gamma cDNA isoform 1 (RAR-gamma 1), RAR-gamma 1 mRNA was localized to all layers of the epidermis, the outer root sheath of hair follicles, follicular hair bulbs, eccrine and sebaceous glands. Basal cell carcinoma constitutively expressed gamma-1 mRNA and one of seven squamous cell carcinomas showed loss of gamma-1 mRNA expression, relative to adjacent epithelium. By contrast, normal melanocytic nevi and tumor-associated lymphocytes expressed little or no RAR-gamma mRNA. These results suggest that RAR-gamma 1 may play an important role in the maintenance and differentiation of normal epidermis and skin appendages. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:1318641

  9. IP receptor-dependent activation of PPAR{gamma} by stable prostacyclin analogues

    SciTech Connect

    Falcetti, Emilia; Flavell, David M.; Staels, Bart; Tinker, Andrew; Haworth, Sheila G.; Clapp, Lucie H. . E-mail: l.clapp@ucl.ac.uk

    2007-09-07

    Stable prostacyclin analogues can signal through cell surface IP receptors or by ligand binding to nuclear peroxisome proliferator-activated receptors (PPARs). So far these agents have been reported to activate PPAR{alpha} and PPAR{delta} but not PPAR{gamma}. Given PPAR{gamma} agonists and prostacyclin analogues both inhibit cell proliferation, we postulated that the IP receptor might elicit PPAR{gamma} activation. Using a dual luciferase reporter gene assay in HEK-293 cells stably expressing the IP receptor or empty vector, we found that prostacyclin analogues only activated PPAR{gamma} in the presence of the IP receptor. Moreover, the novel IP receptor antagonist, RO1138452, but not inhibitors of the cyclic AMP pathway, prevented activation. Likewise, the anti-proliferative effects of treprostinil observed in IP receptor expressing cells, were partially inhibited by the PPAR{gamma} antagonist, GW9662. We conclude that PPAR{gamma} is activated through the IP receptor via a cyclic AMP-independent mechanism and contributes to the anti-growth effects of prostacyclin analogues.

  10. Gamma-hydroxybutyrate (GHB) induces cognitive deficits and affects GABAB receptors and IGF-1 receptors in male rats.

    PubMed

    Johansson, Jenny; Grönbladh, Alfhild; Hallberg, Mathias

    2014-08-01

    In recent years, the abuse of the club drug gamma-hydroxybutyrate (GHB) has become increasingly popular among adolescents. The drug induces euphoria but can also result in sedation, anaesthesia as well as short-term amnesia. In addition, the abuse of GHB causes cognitive impairments and the mechanism by which GHB induces these impairments is not clarified. The present study investigates the impact of GHB treatment on spatial learning and memory using a water maze (WM) test in rats. Furthermore, the behavioural data is combined with an autoradiographic analysis of the GABAB and the IGF-1 receptor systems. The results demonstrate that the animals administered with GHB display an impaired performance in the WM test as compared to controls. In addition, significant alterations in GABAB and IGF-1 receptor density as well as GABAB receptor functionality, were observed in several brain regions associated with cognitive functions e.g. hippocampus. To conclude, our findings suggest that GHB treatment can affect spatial learning and memory, and that this outcome at least to some extent is likely to involve both GABAB and IGF-1 receptors.

  11. Gamma beam system at ELI-NP

    SciTech Connect

    Ur, Calin Alexandru

    2015-02-24

    The Gamma Beam System of ELI-NP will produce brilliant, quasi-monochromatic gamma-ray beams via Inverse Compton Scattering of short laser pulses on relativistic electron beam pulses. The scattered radiation is Doppler upshifted by more than 1,000,000 times and is forward focused in a narrow, polarized, tunable, laser-like beam. The gamma-ray beam at ELI-NP will be characterized by large spectral density of about 10{sup 4} photons/s/eV, narrow bandwidth (< 0.5%) and tunable energy from 200 keV up to about 20 MeV. The Gamma Beam System is a state-of-the-art equipment employing techniques and technologies at the limits of the present-day's knowledge.

  12. Demonstration and partial characterization of the interferon-gamma receptor on human mononuclear phagocytes.

    PubMed Central

    Celada, A; Allen, R; Esparza, I; Gray, P W; Schreiber, R D

    1985-01-01

    Radioiodinated recombinant human interferon-gamma (IFN gamma) bound to human monocytes, U937, and HL60 cells in a specific, saturable, and reversible manner. At 4 degrees C, the different cell types bound 3,000-7,000 molecules of IFN gamma, and binding was of comparable affinity (Ka = 4-12 X 10(8) M-1). No change in the receptor was observed after monocytes differentiated to macrophages or when the cell lines were pharmacologically induced to differentiate. The functional relevance of the receptor was validated by the demonstration that receptor occupancy correlated with induction of Fc receptors on U937. Binding studies using U937 permeabilized with digitonin showed that only 46% of the total receptor pool was expressed at the cell surface. The receptor appears to be a protein, since treatment of U937 with trypsin or pronase reduced 125I-IFN gamma binding by 87 and 95%, respectively. At 37 degrees C, ligand was internalized, since 32% of the cell-associated IFN gamma became resistant to trypsin stripping. Monocytes degraded 125I-IFN gamma into trichloroacetic acid-soluble counts at 37 degrees C but not at 4 degrees C, at an approximate rate of 5,000 molecules/cell per h. The receptor was partially characterized by SDS-polyacrylamide gel electrophoresis analysis of purified U937 membranes that had been incubated with 125I-IFN gamma. After cross-linking, the receptor-ligand complex migrated as a broad band that displayed an Mr of 104,000 +/- 18,000 at the top and 84,000 +/- 6,000 at the bottom. These results thereby define and partially characterize the IFN gamma receptor of human mononuclear phagocytes. Images PMID:2934408

  13. Rearrangement of variable region T cell receptor gamma genes in acute lymphoblastic leukemia. V gamma gene usage differs in mature and immature T cells.

    PubMed Central

    Hara, J; Benedict, S H; Yumura, K; Ha-Kawa, K; Gelfand, E W

    1989-01-01

    Using probes recognizing variable regions (V gamma) and joining regions (J gamma) of the T cell receptor (TCR) gamma gene, we have analyzed the usage of V gamma genes in 24 patients with T cell acute lymphoblastic leukemia (ALL) and 36 patients with B-precursor ALL. In CD3- T-ALL derived from immature T cells, V gamma genes more proximal to J gamma were frequently rearranged; V gamma 8, V gamma 9, V gamma 10, and V gamma 11 were used in 19 of 24 rearrangements. In contrast, CD3+ T-ALL derived from a more mature stage of T cell ontogeny, showed a high frequency of rearrangements involving V gamma genes distal to J gamma; V gamma 2, V gamma 3, V gamma 4, and V gamma 5 were used in 17 of 25 rearrangements. In B-precursor ALL, no notable bias of V gamma gene usage was observed. This probably reflects the possibility that TCR genes may not rearrange according to a T cell hierarchy when under control of a B cell gene program. Furthermore, deletions of those V gamma genes located 3' to rearranged V gamma genes were observed in all patients analyzed. This supports the theory that loop deletion is a major mechanism for TCR-gamma gene rearrangement. Images PMID:2522937

  14. 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.

  15. Expression cloning of the murine interferon gamma receptor cDNA.

    PubMed Central

    Munro, S; Maniatis, T

    1989-01-01

    A cDNA encoding a receptor for murine interferon gamma (IFN-gamma) was isolated from an expression library made from murine thymocytes. The clone was identified by transfecting the library into monkey COS cells and probing the transfected monolayer with radiolabeled murine IFN-gamma. Cells expressing the receptor were identified by autoradiography and plasmids encoding the receptor were directly rescued from those cells producing a positive signal. A partial cDNA so obtained was used to isolate a full-length cDNA from mouse L929 cells by conventional means. When this cDNA was expressed in COS cells it produced a specific binding site for murine IFN-gamma with an affinity constant similar to that of the receptor found on L929 cells. The predicted amino acid sequence of the murine IFN-gamma receptor shows homology to that previously reported for the human IFN-gamma receptor. However, although the two proteins are clearly related, they show less than 60% identity in both the putative extracellular domain and the intracellular domain. Images PMID:2531896

  16. Gamma ray observations of the solar system

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Two general categories are discussed concerning the evolution of the solar system: the dualistic view, the planetesimal approach; and the monistic view, the nebular hypothesis. The major points of each view are given and the models that are developed from these views are described. Possible applications of gamma ray astronomical observations to the question of the dynamic evolution of the solar system are discussed.

  17. Gamma ray observations of the solar system

    SciTech Connect

    Not Available

    1981-01-01

    Two general categories are discussed concerning the evolution of the solar system: the dualistic view, the planetesimal approach and the monistic view, the nebular hypothesis. The major points of each view are given and the models that are developed from these views are described. Possible applications of gamma ray astronomical observations to the question of the dynamic evolution of the solar system are discussed.

  18. Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors.

    PubMed Central

    van den Broek, M F; Müller, U; Huang, S; Aguet, M; Zinkernagel, R M

    1995-01-01

    Alpha/beta interferon (IFN) and gamma IFN exert widely overlapping biological effects. Still, mice with individually inactivated alpha/beta or gamma receptors exhibit variably severely reduced resistance to infection and altered immune responses. To investigate to what extent the two IFN systems are functionally redundant, we generated mice with a combined receptor defect (AG129 mice). Like mice with individual mutations, AG129 mice had no apparent anomalies, confirming that in the mouse the IFN system is not essential for normal development. These mice showed an additive phenotype with respect to antiviral defense and exhibited an increased susceptibility to lymphocytic choriomeningitis virus (LCMV) and notably vaccinia virus infection. Because of unlimited replication and subsequent rapid exhaustion of cytotoxic T lymphocyte (CTL) precursors, these mice were unable to mount a CTL response to LCMV. CD8(+)-mediated immunopathology was absent in LCMV-infected mice, and virus persisted. Vaccinia virus replicated much faster in AG129 mice, and a 10(4)-fold lower dose of vaccinia virus was sufficient to prime these mice. With the normal priming dose of 10(6) PFU, cytopathic effects and overwhelming infection possibly causing partial exhaustion of CTL interfered with the anti-vaccinia virus response. Even though global antiviral immunoglobulin G (IgG) titers were within normal ranges, the IgG subclass distribution was heavily biased toward IgG1. PMID:7609046

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

    SciTech Connect

    Tsukahara, Tamotsu; 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, 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.

  20. Expression of the mouse interleukin-2 receptor gamma chain in insect cells using a baculovirus expression vector--comparison with the human common gamma chain.

    PubMed

    Stenroos, K; West, A; Raivio, E; Lindqvist, C

    1997-02-01

    The gene encoding the gamma-chain of the mouse Interleukin-2 receptor was expressed in lepidopteran insect cells using the baculovirus expression vector system. The corresponding gene was inserted under the polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus and expressed in the Spodoptera frugiperda insect cell line Sf9 during viral infection. The recombinant receptor protein was identified by immunoblotting in cell lysates prepared from insect cells infected with the produced recombinant virus VL1392-mIL-2R gamma. Kinetic analysis demonstrated that the corresponding protein could be detected as an approximately 50 kDa protein already at 24 h post-infection. Intrinsic labelling with [35S]-methionine/cysteine and SDS-PAGE analysis of the recombinant baculovirus infected insect cells verified the immunoblotting data. The expressed IL-2R gamma protein could also be determined on the surface of infected insect cells by flow cytometric analysis. Comparison of the molecular weights between baculovirus expressed human and mouse IL-2R gamma chains indicated differences in the glycosylation pattern despite similar numbers of N-linked glycosylation sites. PMID:9042425

  1. Effects of beer and hop on ionotropic gamma-aminobutyric acid receptors.

    PubMed

    Aoshima, Hitoshi; Takeda, Katsuichi; Okita, Yoichi; Hossain, Sheikh Julfikar; Koda, Hirofumi; Kiso, Yoshinobu

    2006-04-01

    Beer induced the response of the ionotropic gamma-aminobutyric acid receptors (GABA(A) receptors) expressed in Xenopus oocytes, indicating the presence of gamma-aminobutyric acid (GABA)-like activity. Furthermore, the pentane extract of the beer, hop (Humulus lupulus L.) oil, and myrcenol potentiated the GABA(A) receptor response elicited by GABA. The GABA(A) receptor responses were also potentiated by the addition of aliphatic esters, most of which are reported to be present in beer flavor. Aliphatic esters showed the tendency to decrease in the potentiation of the GABA(A) receptor response with an increase in their carbon chain length. When myrcenol was injected to mice prior to intraperitoneal administration of pentobarbital, the pentobarbital-induced sleeping time of mice increased additionally. Therefore, the beer contained not only GABA-like activity but also the modulator(s) of the GABA(A) receptor response.

  2. Localization of Fc gamma receptors and complement receptors CR1 on human peripheral nerve fibres by immunoelectron microscopy.

    PubMed

    Vedeler, C A; Nilsen, R; Matre, R

    1989-06-01

    The localization of receptors for the Fc part of IgG (Fc gamma R) and for the complement C3b/C4b components (CR1) on human peripheral nerve fibres was investigated by indirect immunoperoxidase staining of frozen nerve sections with monoclonal antibodies. Transmission electron microscopy revealed that Fc gamma R and CR1 are localized to the entire surface membrane and inner membrane (axolemma) of the Schwann cell. Myelin and axons were not stained. The presence of Fc gamma R and CR1 in human Schwann cells adds further evidence for the immunocompetence of these cells.

  3. T cell receptor gamma and delta rearrangements in hematologic malignancies. Relationship to lymphoid differentiation.

    PubMed Central

    Griesinger, F; Greenberg, J M; Kersey, J H

    1989-01-01

    We have studied recombinatorial events of the T cell receptor delta and gamma chain genes in hematopoietic malignancies and related these to normal stages of lymphoid differentiation. T cell receptor delta gene recombinatorial events were found in 91% of acute T cell lymphoblastic leukemia, 68% of non-T, non-B lymphoid precursor acute lymphoblastic leukemia (ALL) and 80% of mixed lineage acute leukemias. Mature B-lineage leukemias and acute nonlymphocytic leukemias retained the T-cell receptor delta gene in the germline configuration. The incidence of T cell receptor gamma and delta was particularly high in CD10+CD19+ non-T, non-B lymphoid precursor ALL. In lymphoid precursor ALL, T cell receptor delta was frequently rearranged while T cell receptor gamma was in the germline configuration. This suggests that TCR delta rearrangements may precede TCR gamma rearrangements in lymphoid ontogeny. In T-ALL, only concordant T cell receptor delta and gamma rearrangements were observed. Several distinct rearrangements were defined using a panel of restriction enzymes. Most of the rearrangements observed in T-ALL represented joining events of J delta 1 to upstream regions. In contrast, the majority of rearrangements in lymphoid precursor ALL most likely represented D-D or V-D rearrangements, which have been found to be early recombinatorial events of the TCR delta locus. We next analyzed TCR delta rearrangements in five CD3+TCR gamma/delta+ ALL and cell lines. One T-ALL, which demonstrated a different staining pattern with monoclonal antibodies against the products of the TCR gamma/delta genes than the PEER cell line, rearranges J delta 1 to a currently unidentified variable region. Images PMID:2547833

  4. Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction.

    PubMed

    Davidson, Gary; Wu, Wei; Shen, Jinlong; Bilic, Josipa; Fenger, Ursula; Stannek, Peter; Glinka, Andrei; Niehrs, Christof

    2005-12-01

    Signalling by Wnt proteins (Wingless in Drosophila) has diverse roles during embryonic development and in adults, and is implicated in human diseases, including cancer. LDL-receptor-related proteins 5 and 6 (LRP5 and LRP6; Arrow in Drosophila) are key receptors required for transmission of Wnt/beta-catenin signalling in metazoa. Although the role of these receptors in Wnt signalling is well established, their coupling with the cytoplasmic signalling apparatus remains poorly defined. Using a protein modification screen for regulators of LRP6, we describe the identification of Xenopus Casein kinase 1 gamma (CK1gamma), a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells. In Xenopus embryos, CK1gamma is required during anterio-posterior patterning to promote posteriorizing Wnt/beta-catenin signalling. CK1gamma is associated with LRP6, which has multiple, modular CK1 phosphorylation sites. Wnt treatment induces the rapid CK1gamma-mediated phosphorylation of these sites within LRP6, which, in turn, promotes the recruitment of the scaffold protein Axin. Our results reveal an evolutionarily conserved mechanism that couples Wnt receptor activation to the cytoplasmic signal transduction apparatus. PMID:16341016

  5. A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity.

    PubMed

    Schupp, Michael; Curtin, Joshua C; Kim, Roy J; Billin, Andrew N; Lazar, Mitchell A

    2007-05-01

    Nuclear receptors (NRs) are transcription factors whose activity is regulated by the binding of small lipophilic ligands, including hormones, vitamins, and metabolites. Pharmacological NR ligands serve as important therapeutic agents; for example, all-trans retinoic acid, an activating ligand for retinoic acid receptor alpha (RARalpha), is used to treat leukemia. Another RARalpha ligand, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid (Ro 41-5253), is a potent antagonist that has been a useful and purportedly specific probe of RARalpha function. Here, we report that Ro 41-5253 also activates the peroxisome proliferator-activated receptor gamma (PPARgamma), a master regulator of adipocyte differentiation and target of widely prescribed antidiabetic thiazolidinediones (TZDs). Ro 41-5253 enhanced differentiation of mouse and human preadipocytes and activated PPARgamma target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARgamma protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARgamma-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARalpha agonist or by depleting cells of RARalpha, indicating that PPARgamma activation was not related to RARalpha antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARgamma, suggesting that Ro 41-5253 directly affects PPAR activity. These results vividly demonstrate that pharmacological NR ligands may have "off-target" effects on other NRs. Ro 41-5253 is a PPARgamma agonist as well as an RARalpha antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.

  6. Molecular characterization of the murine interferon gamma receptor cDNA.

    PubMed

    Kumar, C S; Muthukumaran, G; Frost, L J; Noe, M; Ahn, Y H; Mariano, T M; Pestka, S

    1989-10-25

    Interferon gamma receptors (IFN-gamma R) exhibit remarkable species specificity. In order to understand the basis for this phenomenon, we have isolated a recombinant cDNA clone corresponding to the mouse (Mu) IFN-gamma R. Microinjection of the mRNA synthesized in vitro corresponding to the cloned cDNA into Xenopus laevis oocytes resulted in the synthesis of a protein that specifically binds Mu-IFN-gamma. Analysis of murine genomic and RNA blots with the cDNA probe indicates the presence of a single gene and a single mRNA species of about 2300 bases. Sequence analysis of the cDNA encoding the Mu-IFN-gamma R and comparison with the corresponding human IFN-gamma R sequence shows about 68% conservation of the extracellular domains and 51% conservation of the cytoplasmic domains at the nucleotide level. The results indicate that, as expected, the sequence of the receptor confers species specificity for the binding of IFN-gamma to the cell surface receptor. Moreover, it was previously shown that a human factor is required in addition to the receptor for the human IFN-gamma to function in hamster or mouse cells (Jung, V., Rashidbaigi, A., Jones, C., Tischfield, J.A., Shows, T.B., and Pestka, S. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 4151-4155). These results suggest an explanation for the second species-specific event required for function of the human receptor in mouse or hamster cells in that the intracellular domains are significantly different and thus cannot interact with the corresponding heterologous factor. PMID:2530216

  7. Molecular characterization of the murine interferon gamma receptor cDNA.

    PubMed

    Kumar, C S; Muthukumaran, G; Frost, L J; Noe, M; Ahn, Y H; Mariano, T M; Pestka, S

    1989-10-25

    Interferon gamma receptors (IFN-gamma R) exhibit remarkable species specificity. In order to understand the basis for this phenomenon, we have isolated a recombinant cDNA clone corresponding to the mouse (Mu) IFN-gamma R. Microinjection of the mRNA synthesized in vitro corresponding to the cloned cDNA into Xenopus laevis oocytes resulted in the synthesis of a protein that specifically binds Mu-IFN-gamma. Analysis of murine genomic and RNA blots with the cDNA probe indicates the presence of a single gene and a single mRNA species of about 2300 bases. Sequence analysis of the cDNA encoding the Mu-IFN-gamma R and comparison with the corresponding human IFN-gamma R sequence shows about 68% conservation of the extracellular domains and 51% conservation of the cytoplasmic domains at the nucleotide level. The results indicate that, as expected, the sequence of the receptor confers species specificity for the binding of IFN-gamma to the cell surface receptor. Moreover, it was previously shown that a human factor is required in addition to the receptor for the human IFN-gamma to function in hamster or mouse cells (Jung, V., Rashidbaigi, A., Jones, C., Tischfield, J.A., Shows, T.B., and Pestka, S. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 4151-4155). These results suggest an explanation for the second species-specific event required for function of the human receptor in mouse or hamster cells in that the intracellular domains are significantly different and thus cannot interact with the corresponding heterologous factor.

  8. Amiloride inhibition of gamma-aminobutyric acid(A) receptors depends upon the alpha subunit subtype.

    PubMed

    Fisher, Janet L

    2002-06-01

    gamma-Aminobutyric acid(A) (GABA(A)) receptors (GABARs) are responsible for most fast inhibitory neurotransmission in the mammalian brain. The GABARs contain several allosteric modulatory sites, many of which are useful clinically. The activity of most of these modulators depends upon the subunit composition of the receptor. The diuretic amiloride was previously reported to inhibit GABARs in frog sensory neurons. We measured its effects on recombinant GABARs to determine its mechanism of action at mammalian receptors and to examine the effect of subunit composition. Amiloride acted primarily as a competitive antagonist, reducing the sensitivity of the receptor to GABA without affecting the maximal current amplitude. Receptors containing an alpha6 subunit were about 10-fold more sensitive to amiloride than those containing other alpha subunits. In contrast, the identity of the beta or gamma subtype had little effect on amiloride sensitivity. Although several other modulators have specific effects at alpha6-containing receptors, amiloride is the first inhibitor to be reported with no additional dependence on the identity of the beta or gamma subunit. Therefore, it probably represents a unique modulatory site on the GABAR, which could be useful for developing drugs targeting these receptors. The selective activity of amiloride could also be helpful for isolating the contribution of receptors composed of alpha6 subtypes in heterogeneous native GABAR populations.

  9. Picrotoxin inhibition mechanism of a gamma-aminobutyric acid A receptor investigated by a laser-pulse photolysis technique.

    PubMed

    Ramakrishnan, Latha; Hess, George P

    2005-06-14

    The gamma-aminobutyric acid(A) (GABA(A)) receptor, a major inhibitory neurotransmitter receptor, belongs to a family of membrane-bound proteins that regulate signal transmission between approximately 10(12) cells of the nervous system. It plays a major role in many neurological disorders, including epilepsy. It is the target of many pharmacological agents, including the convulsant picrotoxin. Here, we present the mechanism of inhibition by picrotoxin of the rat alpha1beta2gamma2L GABA(A) receptor investigated using rapid kinetic techniques in combination with whole-cell current recordings. The following new results were obtained by using transient kinetic techniques, the cell-flow method and the laser-pulse photolysis (LaPP) technique with a microsecond to millisecond time resolution. (i) The apparent dissociation constant of picrotoxin for the open-channel form of the receptor was approximately 5 times higher than that of the closed-channel form. (ii) Picrotoxin increased the channel-closing rate constant (k(cl)) approximately 4-fold, while the rate constant for channel opening (k(op)) remained essentially unaffected. (iii) The mechanism indicates that picrotoxin binds to an allosteric site of the receptor with higher affinity for the closed-channel form than for the open-channel form and thereby inhibits the receptor by decreasing 4-fold its channel-opening equilibrium constant [Phi(I)(-)(1) = k(op(I))/k(cl(I))]. (iv) The mechanism further indicates that compounds that bind with equal affinity to the picrotoxin-binding site on the open-channel form of the receptor and the closed-channel form will not affect the channel-opening equilibrium and can, therefore, displace picrotoxin and prevent inhibition of the GABA(A) receptor by picrotoxin. Such compounds may be therapeutically useful in counteracting the effects of compounds and diseases that unfavorably affect the channel-opening equilibrium of the receptor channel.

  10. An alternative Fc gamma-receptor ligand: potential role in T-cell development.

    PubMed Central

    Sandor, M; Galon, J; Takacs, L; Tatsumi, Y; Mueller, A L; Sautes, C; Lynch, R G

    1994-01-01

    Fetal pre-T cells express low-affinity receptors for IgG (Fc gamma R) at a developmental stage prior to the rearrangement and expression of immunoglobulin genes. The present studies investigated the possible functional significance of Fc gamma R on fetal pre-T cells. Between 13 and 17 days of fetal development a subpopulation of T-cell receptor-, Thy-1+ thymocytes express for gamma R. The same cells contain mRNA for several forms of Fc gamma R (Fc gamma RII beta 1, beta 2, and Fc gamma RIII). Concurrently, a Pgp-1-, Thy-1-, surface-immunoglobulin- fetal thymic cell binds recombinant soluble Fc gamma R. In principle this cell can interact with the pre-T cells through this counter-receptor. To test this possibility anti-Fc gamma RII/III antibody (2.4G2) was injected into pregnant mice and then into their offspring for 6 wk postpartum. The injected antibody induced a slight increase in the proportion of CD4 or CD8 single-positive, alpha/beta T cells in the thymus. However, in fetal thymic cultures in the presence of 2.4G2 or the recombinant soluble Fc gamma R there was an accelerated differentiation of thymocytes to single-positive, CD3-bright, heat-stable antigen-dull, alpha/beta T cells. These experiments show that Fc gamma Rs are present on pre-T cells during early fetal thymic development, and that a non-IgG ligand of the Fc gamma R is expressed concurrently on Thy- fetal thymocytes. Furthermore, the presumed interaction of Fc gamma R and the alternative ligand(s) influences T-cell development. IgG binding could be an adapted function of Fc gamma Rs, and, as shown for many members of the Ig super family, these receptors may have originally served as cell-cell recognition/interaction molecules required for hematopoietic development. Images Fig. 2 PMID:7809135

  11. Another mechanism for creating diversity in gamma-aminobutyrate type A receptors: RNA splicing directs expression of two forms of gamma 2 phosphorylation site.

    PubMed Central

    Whiting, P; McKernan, R M; Iversen, L L

    1990-01-01

    Diversity of gamma-aminobutyrate type A (GABAA) receptors has recently been proposed to be achieved by assembly of receptor subtypes from a multitude of subunits (alpha 1-6, beta 1-3, gamma 1-2, and delta) encoded by different genes. Here we report a further mechanism for creating GABAA receptor diversity: alternative RNA splicing. Two forms of bovine gamma 2 subunit cDNA were isolated (gamma 2S and gamma 2L) that differed by the presence or absence of a 24-base-pair (8-amino acid) insertion in the cytoplasmic domain between the third and fourth putative membrane-spanning regions. Polymerase chain reaction from RNA demonstrated that the two forms of gamma 2 subunit are expressed in bovine, human, and rat brain. Sequencing of genomic DNA clones encoding the gamma 2 subunit demonstrated that the 24-base-pair insert is organized as a separate exon. Analysis of the sequence of the 8-amino acid insert revealed that it contains a protein kinase C consensus phosphorylation site. Expression of the large cytoplasmic loop domains of gamma 2S and gamma 2L in Escherichia coli, followed by phosphorylation of the recombinant proteins by protein kinase C, demonstrated that gamma 2L, but not gamma 2S, could be phosphorylated. Thus the two forms of gamma 2 subunit differ by the presence or absence of a protein kinase C phosphorylation site. This mechanism for creating GABAA receptor diversity may allow differential regulation of the function of receptor subtypes. Images PMID:1702226

  12. T cell receptor gamma/delta+ lymphocyte subsets during HIV infection.

    PubMed Central

    Autran, B; Triebel, F; Katlama, C; Rozenbaum, W; Hercend, T; Debre, P

    1989-01-01

    The gamma/delta T cell receptor is expressed on 1-15% of normal human peripheral blood lymphocytes (PBL). This subpopulation is recognized by anti-TcR-delta 1 MoAb which is functionally defined as a pan-delta MoAb. Two other antibodies, anti-Ti-gamma A and anti-delta-TcS1 are directed at variable determinants of either the gamma or the delta chain, respectively. In normal individuals anti-Ti-gamma A characterizes two thirds of the TcR-delta 1+ subpopulation whereas anti-delta TcS1 reacts with most of the delta-TcR1+, Ti-gamma A- cells. In the present study, we have used these three MoAbs to characterize the TcR gamma/delta+ peripheral lymphocytes during HIV infection. Fifty patients at three distinct clinical stages (SPC/PGL, ARC, AIDS) of the infection have been studied. The Ti-gamma A+ subset in the whole group accounted for 3.45% of PBL and did not differ from controls; it was also unchanged when the three groups were analysed separately. The Ti-gamma A+ circulating cells were in a resting state as assessed by the absence of surface-expressed activation markers. In contrast, in some patients the proportion of circulating TcR-delta 1+, Ti-gamma A-, delta TcS1+ cells was increased (4.75%) leading to an inversion of the Ti-gamma A/delta-TcS1 ratio. Altogether, those data suggest a conservation of the Ti-gamma A+ subset during HIV infection, contrasting with an increase of the delta-TcS1+, Ti-gamma A- fraction in some cases. PMID:2522839

  13. Color gamma camera system for radiation monitoring

    NASA Astrophysics Data System (ADS)

    Mu, Zhiping; Deng, Jingkang; Wang, Yanfeng

    2000-11-01

    Radiation monitoring systems are desired in many places where radioactive materials are utilized. In this paper, a color gamma camera system developed in Tsinghua University (P.C. China) is reported. The system consist of a compact X - (gamma) ray detector system, a single hole collimator, the scanning mechanism and computer system. The MLEM method is implemented for image reconstruction, which enables one to generate images of high resolution with relatively big aperture. With the associated software, several scanning modes, which work with different speeds and resolutions, are provided and can be selected in the operations. In addition, the system can detect radioactive sources emitting rays of different energies and display them with color images. Experiments were made using Am-241 (59.5 KeV) and Na-22 (511 KeV) to test the performance of the system. The results are presented which show that the resolution of this system can be as high as 1.5 degrees. Furthermore, simulations using Matlab were made to examine the capability of imaging point sources with a small number of counts and imaging distributed sources. Promising results were obtained and are reported. Discussions about camera design and further improvements are given at the end.

  14. Binding interactions of convulsant and anticonvulsant gamma-butyrolactones and gamma-thiobutyrolactones with the picrotoxin receptor

    SciTech Connect

    Holland, K.D.; McKeon, A.C.; Covey, D.F.; Ferrendelli, J.A. )

    1990-08-01

    Alkyl-substituted gamma-butyrolactones (GBLs) and gamma-thiobutyrolactones (TBLs) are neuroactive chemicals. beta-Substituted compounds are convulsant, whereas alpha-alkyl substituted GBLs and TBLs are anticonvulsant. The structural similarities between beta-alkyl GBLs and the convulsant picrotoxinin suggested that alkyl substituted GBLs and TBLs act at the picrotoxin receptor. To test this hypothesis we examined the interactions of convulsant and anticonvulsant GBLs and TBLs with the picrotoxin, benzodiazepine and gamma-aminobutyric acid (GABA) binding sites of the GABA receptor complex. All of these convulsants and anticonvulsants studied competitively displaced 35S-t-butylbicyclophosphorothionate (35S-TBPS), a ligand that binds to the picrotoxin receptor. This inhibition of 35S-TBPS binding was not blocked by the GABA antagonist bicuculline methobromide. The convulsant GBLs and TBLs also partially inhibited (3H)muscimol binding to the GABA site and (3H)flunitrazepam binding to the benzodiazepine site, but they did so at concentrations substantially greater than those that inhibited 35S-TBPS binding. The anticonvulsant GBLs and TBLs had no effect on either (3H)muscimol or (3H)flunitrazepam binding. In contrast to the GBLs and TBLs, pentobarbital inhibited TBPS binding in a manner that was blocked by bicuculline methobromide, and it enhanced both (3H)flunitrazepam and (3H)muscimol binding. Both ethosuximide and tetramethylsuccinimide, neuroactive compounds structurally similar to GBLs, competitively displaced 35S-TBPS from the picrotoxin receptor and both compounds were weak inhibitors of (3H) muscimol binding. In addition, ethosuximide also partially diminished (3H)flunitrazepam binding. These data demonstrate that the site of action of alkyl-substituted GBLs and TBLs is different from that of GABA, barbiturates and benzodiazepines.

  15. Age-dependent alterations of Fc gamma receptor-mediated effector functions of human polymorphonuclear leucocytes.

    PubMed Central

    Fülöp, T; Fóris, G; Wórum, I; Leövey, A

    1985-01-01

    Changes in the effector functions in polymorphonuclear leucocytes (PMNL), harvested from blood of young and aged healthy subjects of both sexes, were studied. FC gamma-receptor (Fc gamma R)-mediated incorporation of IgG coated 51Cr-HRBC significantly increased in the aged male group, while the phagocytosis of pre-opsonized fungi (Saccharomyces cerevisiae and Candida albicans) was independent of both the age and sex. However, the intracellular killing capacity of neutrophils obtained from aged male subjects significantly decreased toward 51Cr-labelled c. albicans. The antibody-dependent cellular cytotoxicity (ADCC) was also impaired with ageing in both sexes. The age-dependent decrease in the effector functions of PMNL may be explained, among others, by the fact that during yeast cell incorporation the increased cAMP level does not return to the basic level in the old group. On the other hand, the cGMP level which increased in PMNL of aged subjects does not show any progressive increase as in the young subjects, but remains unchanged. The oxidative metabolism producing free radicals being necessary for the effective intracellular killing and ADCC diminished in PMNL of aged subjects of both sexes. The above findings indicate that the adaptation of cyclic nucleotide system and the oxidative burst to the cell activation becomes impaired with ageing. PMID:2994926

  16. T-cell receptor gamma--delta lymphocytes and Eimeria vermiformis infection.

    PubMed Central

    Rose, M E; Hesketh, P; Rothwell, L; Gramzinski, R A

    1996-01-01

    The role of T-cell receptor gamma--delta T lymphocytes in coccidiosis was examined by determining the course of infection with Eimeria vermiformis in BALB/c mice depleted of gamma--delta lymphocytes by treatment with GL3 monoclonal antibody. The replication of the parasite in primary infections was not greatly, or consistently, affected by this treatment, and there was no correlation between the extent of depletion of small intestinal intraepithelial lymphocytes and the number of oocysts produced. The resistance of immunized mice to challenge was not compromised by depletion of intraintestinal epithelial lymphocytes when their depletion was effected at the time of primary infection and/or administration of the challenge inoculum. Thus, T-cell receptor gamma--delta T lymphocytes do not appear to be crucial to the establishment, or the control, of primary infection with E. vermiformis and are not principal mediators of the solid immunity to challenge that this infection induces. PMID:8890252

  17. The Fc receptor gamma-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen.

    PubMed Central

    Poole, A; Gibbins, J M; Turner, M; van Vugt, M J; van de Winkel, J G; Saito, T; Tybulewicz, V L; Watson, S P

    1997-01-01

    Activation of mouse platelets by collagen is associated with tyrosine phosphorylation of multiple proteins including the Fc receptor gamma-chain, the tyrosine kinase Syk and phospholipase Cgamma2, suggesting that collagen signals in a manner similar to that of immune receptors. This hypothesis has been tested using platelets from mice lacking the Fc receptor gamma-chain or Syk. Tyrosine phosphorylation of Syk and phospholipase Cgamma2 by collagen stimulation is absent in mice lacking the Fc receptor gamma-chain. Tyrosine phosphorylation of phospholipase Cgamma2 by collagen stimulation is also absent in mice platelets which lack Syk, although phosphorylation of the Fc receptor gamma-chain is maintained. In contrast, tyrosine phosphorylation of platelet proteins by the G protein-coupled receptor agonist thrombin is maintained in mouse platelets deficient in Fc receptor gamma-chain or Syk. The absence of Fc receptor gamma-chain or Syk is accompanied by a loss of secretion and aggregation responses in collagen- but not thrombin-stimulated platelets. These observations provide the first direct evidence of an essential role for the immunoreceptor tyrosine-based activation motif (ITAM) in signalling by a non-immune receptor stimulus. PMID:9171347

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

    SciTech Connect

    Lee, Myoung Woo; Kim, Dae Seong; Kim, Hye Ryung; Kim, Hye Jin; Yang, Jin Mo; Ryu, Somi; Noh, Yoo Hun; Lee, Soo Hyun; Son, Meong Hi; Jung, Hye Lim; Yoo, Keon Hee; Koo, Hong Hoe; Sung, Ki Woong

    2012-01-06

    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 in 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.

  19. Development of Gamma-Emitting Receptor Binding Radiopharmace

    SciTech Connect

    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 unactivated 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.

  20. Triggering of Toll-like receptors modulates IFN-gamma signaling: involvement of serine 727 STAT1 phosphorylation and suppressors of cytokine signaling.

    PubMed

    Dalpke, Alexander H; Eckerle, Susan; Frey, Markus; Heeg, Klaus

    2003-07-01

    Microbial stimuli activate cells of the innate immune system by triggering Toll-like receptors (TLR). Activation of macrophages and dendritic cells is further enhanced by secondary signals like IFN-gamma. Here we analyzed the interplay of IFN-gamma and TLR signaling in cells of the innate immune system. Using a STAT1-dependent reporter construct we show that IFN-gamma signaling can be enhanced as well as inhibited by simultaneous stimulation with either defined TLR agonists or whole-bacterial lysates. Short costimulation resulted in the amplification of IFN-gamma signaling and was attributable to the p38 mitogen-activated protein kinase (MAPK)-dependent phosphorylation of signal transducer and activator of transcription (STAT)1 on serine 727. In contrast, prolonged co-incubation as well as pre-incubation with TLR agonists led to an inhibition of IFN-gamma signaling. TLR triggering induced expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3 and cytokine-inducible SH2 domain-containing protein (CIS). Overexpression of SOCS-1 and, to a lesser extend, of SOCS-3 and CIS inhibited IFN-gamma signaling as measured by activation of STAT1. Moreover, pre-incubation with TLR-dependent stimuli impaired IFN-gamma-induced MHC class II regulation but enhanced CD40 and CD86 expression. Taken together, the results indicate a tight interplay between TLR and IFN-gamma signaling pathways which involve induction of SOCS proteins and serine phosphorylation of STAT1.

  1. Compounds exhibiting selective efficacy for different beta subunits of human recombinant gamma-aminobutyric acid A receptors.

    PubMed

    Smith, Alison J; Oxley, Beth; Malpas, Sallie; Pillai, Gopalan V; Simpson, Peter B

    2004-11-01

    Inhibitory GABA(A) receptor modulators are widely used therapeutic agents for a variety of central nervous system disorders. Ltk(-) cells stably expressing human recombinant GABA(A) subunits (alpha1beta1-3gamma2s) were seeded into 96-well plates, loaded with chlorocoumarin-2-dimyristoyl phosphatidylethanolamine and bis(1,3-diethyl-2-thiobarbiturate)trimethineoxonol, and rapid fluorescence resonance energy transfer technique (FRET) measurements were made of GABA-evoked depolarizations in low-Cl(-) buffer using a voltage/ion probe reader. The influence of different betasubunits on the ability of agents to modulate and directly activate the ion channel was examined. GABA evoked concentration-dependent decreases in FRET, increasing fluorescence emission ratio (460/580 nm) at alpha1beta1gamma2, alpha1beta2gamma2, and alpha1beta3gamma2 receptors with similar maximal amplitude (P > 0.05, n = 17) and EC(50) values of 2.4 +/- 0.2, 2.5 +/- 0.2, and 1.3 +/- 0.1 microM, respectively. Piperidine-4-sulfonic acid and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol were less potent, with EC(50) values of 8.7 +/- 0.9, 9.2 +/- 0.5, and 11.7 +/- 1.2, and 43.7 +/- 6.4, 24.8 +/- 1.6, and 26.1 +/- 2.4 microM, respectively. Potency and maximal efficacy of propofol, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, pentobarbital, and steroids, 5alpha-pregnan-3alpha-ol-20-one and 5beta-pregnan-3alpha-ol-20-one, were unaffected by the beta isoform present in the receptor complex. However, several compounds displayed beta2/3 subunit selectivity, notably loreclezole, R(-)-etomidate, and a group of anti-inflammatory agents including mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, niflumic acid, and diflunisal. The anti-inflammatories exhibited varying levels of efficacy at beta2/3 subunits, with micromolar potency, while having antagonist or weak inverse agonist profiles at alpha1beta1gamma2. Diflunisal was the most efficacious compound, eliciting greater

  2. Effect of paraoxon on muscarinic, dopamine and. gamma. -aminobutyric acid receptors of brain and sensitivity to muscarinic antagonists

    SciTech Connect

    Fernando, J.C.R.; Hoskins, B.; Ho, I.K.

    1986-03-05

    Several acetylcholinesterase (AChE) inhibitors decrease muscarinic cholinergic (mACh) receptors in the brain, alteration of dopamine (DA) and ..gamma..-aminobutyric acid (GABA) receptors after AChE inhibition was also reported. In view of the important interactions among DA, GABA and ACh systems, whether this is a common effect of AChE inhibitors should be established. They report the effect of the AChE inhibitor, paraoxon, on DA, GABA and mACh receptors in the rat. The binding of /sup 3/H-QNB (for mACh), /sup 3/H-spiperone (for DA) and /sup 3/H-muscimol (for GABA) to striatal and hippocampal membranes was analyzed. Also, behavioral sensitivity to atropine was studied. Twenty-four hr after a single dose (0.75 mg/kg, s.c.) of paraoxon, the density of mACh receptors in the striatum was decreased but, at 3 days, no change was seen. In the hippocampus, the mACh receptors were not affected. Repeated treatment with paraoxon (0.3 mg/kg, 48 hourly) for 2 weeks reduced the mACh receptor density in both regions. Neither single nor repeated paraoxon treatment had an effect on DA or GABA receptors. After single or repeated dosing with paraoxon, myoclonus induced by atropine (10 mg/kg, i.p.) was enhanced. The results show rapid downregulation of mACh receptors by paraoxon. DA or GABA, however, appear not to be affected under these treatment regimens.

  3. Production of interferon-gamma and tumour necrosis factor-alpha by human T-cell clones expressing different forms of the gamma delta receptor.

    PubMed

    Christmas, S E; Meager, A

    1990-12-01

    Panels of human T-cell clones bearing the gamma delta T-cell receptor (TcR) were obtained from peripheral blood and decidual tissue and maintained in the presence of interleukin-2 (IL-2). TcR V gamma and V delta gene expression was determined in 40 TcR delta 1+ clones using the gamma delta T-cell subset markers Ti gamma A and delta TCS1, in conjunction with Southern blot analysis using TcR J gamma and J delta probes. gamma delta T-cell clones, together with control alpha beta T-cell clones derived from the same lymphocyte populations, were stimulated with phytohaemagglutinin (PHA) and their ability to produce interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) tested using specific ELISA. Many clones representative of the major peripheral V gamma 9/V delta 2J1 subset produced high amounts of both cytokines and mean levels were not significantly different from those produced by alpha beta T-cell clones. Panels of clones expressing V gamma 9 and V delta 2J1 produced significantly higher levels of TNF-alpha than clones not expressing V delta 2J1 and those expressing V delta 1J1. There was no relationship between levels of IFN-gamma and TNF-alpha produced by individual gamma delta T-cell clones and also no relationship between their non-major histocompatibility complex (MHC)-restricted cytotoxic activity and levels of either cytokine. There was a significant tendency for gamma delta T-cell clones to produce more TNF-alpha than IFN-gamma in comparison to alpha beta T-cell clones. The significance of these findings is discussed in the light of the reported differences in distribution in vivo of V delta 1J1+ and V delta 2J1+ cells.

  4. GABAB receptor blockade enhances theta and gamma rhythms in the hippocampus of behaving rats.

    PubMed

    Leung, L Stan; Shen, Bixia

    2007-01-01

    The participation of GABA(B) receptors in hippocampal EEG generation was studied by intracerebroventricular (icv) and intracerebral infusions of GABA(B) receptor antagonist p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid (CGP35348) in freely behaving rats. During awake-immobility, icv CGP35348 induced a theta rhythm and increased gamma waves (30-100 Hz) in the hippocampus. The immobility theta peaked at 6-7 Hz and had a theta phase in CA1 stratum radiatum of approximately 160 degrees with reference to the theta at the alveus, when compared with approximately 130 degrees during walking. Immobility theta power peaks at 6-7 Hz was also found in normal rats, and it was detected in 27% of the EEG segments during immobility. Incidence of immobility theta increased to 87.5% after 480 nmol of CGP35348 icv. Muscarinic antagonist scopolamine (5 mg/kg, ip) suppressed the induction of immobility theta and the gamma power increase after icv CGP35348. CGP35348 icv did not significantly change the hippocampal theta power at 7-8 Hz during walking (theta fundamental), but it increased power at 12-15 Hz, at the second harmonic of theta. CGP35348 icv also increased 30-50 Hz gamma power during walking. Medial septal infusion of CGP35348 (12 nmol in 0.4 microl) increased the power and the frequency of the hippocampal theta second harmonic during walking, but did not increase gamma activity. Infusion of CGP35348 (8 nmol in 0.4 microl) in the hippocampus increased the local gamma activity at 30-100 Hz, but did not induce immobility theta or affect the walking theta rhythm. In conclusion, icv GABA(B) receptor blockade increased an atropine-sensitive input that generated an immobility theta rhythm, while GABA(B) receptor blockade of the medial septum increased atropine-resistant theta harmonics possibly generated by apical dendritic spikes. GABA(B) receptor blockade may enhance cognitive task performance by activating hippocampal theta and gamma rhythms in behaving rats.

  5. A peroxisome proliferator-activated receptor-gamma agonist and other constituents from Chromolaena odorata.

    PubMed

    Dat, Nguyen Tien; Lee, Kyeong; Hong, Young-Soo; Kim, Young Ho; Minh, Chau Van; Lee, Jung Joon

    2009-06-01

    Peroxisome proliferator-activated receptors (PPARs) are key regulators of lipid and glucose metabolism and have become important therapeutic targets for various diseases. The phytochemical investigation of the chloroform-soluble extract of Chromolaena odorata led to the isolation of a PPAR-gamma agonist, (9 S,13 R)-12-oxo-phytodienoic acid (1), together with 12 other compounds. The structures of chromomoric acid G (2), a new dehydrogenated derivative of 1, and chromolanone (3) were elucidated based on spectroscopic methods. Compound 1 showed a significant effect on PPAR-gamma activation in comparison with rosiglitazone. However, compound 2 was inactive, suggesting that the dehydrogenation of the prostaglandin-like structure in 1 abrogates its PPAR-gamma agonistic activity.

  6. mu-Opioid receptor-stimulated guanosine-5'-O-(gamma-thio)-triphosphate binding in rat thalamus and cultured cell lines: signal transduction mechanisms underlying agonist efficacy.

    PubMed

    Selley, D E; Sim, L J; Xiao, R; Liu, Q; Childers, S R

    1997-01-01

    G protein activation by different mu-selective opioid agonists was examined in rat thalamus, SK-N-SH cells, and mu-opioid receptor-transfected mMOR-CHO cells using agonist-stimulated guanosine-5'-O-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding to membranes in the presence of excess GDP. [D-Ala2, N-MePhe4, Gly5-ol]Enkephalin (DAMGO) was the most efficacious agonist in rat thalamus and SK-N-SH cells, followed by (in rank order) fentanyl = morphine > > buprenorphine. In mMOR-CHO cells expressing a high density of mu receptors, no differences were observed among DAMGO, morphine or fentanyl, but these agonists were more efficacious than buprenorphine, which was more efficacious than levallorphan. In all three systems, efficacy differences were magnified by increasing GDP concentrations, indicating that the activity state of G proteins can affect agonist efficacy. Scatchard analysis of net agon stimulated [35S]GTP gamma S binding revealed two major components responsible for agonist efficacy differences. First, differences in the KD values of agonist-stimulated [35S]GTP gamma S binding between high efficacy agonists (DAMGO, fentanyl, and morphine) and classic partial agonists (buprenorphine and levallorphan) were observed in all three systems. Second, differences in the Bmax value of agonist-stimulated [35S]GTP gamma S binding were observed between DAMGO and morphine or fentanyl in rat thalamus and SK-N-SH cells and between the high efficacy agonists and buprenorphine or levallorphan in all three systems. These results suggest that mu-opioid agonist efficacy is determined by the magnitude of the receptor-mediated affinity shift in the binding of GTP (or[35S]GTP gamma S) versus GDP to the G protein and by the number of G proteins activated per occupied receptor.

  7. Rearrangement and expression of T cell antigen receptor and gamma genes during thymic development

    PubMed Central

    1986-01-01

    Rearrangement and expression of the T cell antigen receptor and the gamma genes during T cell ontogeny is a regulated process; the gamma genes are rearranged and expressed first, followed by the beta and then the alpha genes. Expression of both functional alpha and beta gene RNA first occurs at day 17 of gestation, along with the expression of T3 delta chain RNA. T cell antigen receptor gene rearrangements occur primarily or exclusively in the thymus, although some gamma gene rearrangements occur outside the thymus in fetal liver cells that may be committed T cell progenitors. There is no gross difference in the extent of beta and gamma gene rearrangements in the adult thymocyte subpopulations that were analyzed, despite the fact that some of these populations cannot respond to antigen and never emigrate from the thymus. Quantitative analysis of rearrangements in total adult thymocyte DNA shows that beta gene rearrangements generally occur on both chromosomal homologs, and that rearrangements occur preferentially to the J beta 2 gene segment cluster. PMID:3487610

  8. Detection of three nonsense mutations and one missense mutation in the interleukin-2 receptor [gamma] chain gene in SCIDX1 that differently affect the mRNA processing

    SciTech Connect

    Markiewicz, S.; Fischer, A.; Saint Basile, G. de ); Subtil, A.; Dautry-Varsat, A. )

    1994-05-01

    The interleukin-2 receptor [gamma] (IL-2R[gamma]) chain gene encodes a 64-kDa protein that not only composes the high-affinity form of the IL-2 binding receptor in association with the 2R [alpha] and [beta] chains, but also participates in at least the IL-4 and IL-7 receptor complexes. Mutations in this gene have recently been shown to cause X-linked severe combined immunodeficiency (SCIDX1). This disease of the immune system results from an early block of T lymphocyte and natural killer (NK) cell differentiation, which leads to a severe cellular and humoral immune defect that is lethal unless treated by bone marrow transplantation. Analysis of the IL-2R[gamma] gene in SCIDX1 patients has revealed the presence of heterogeneous mutations principally located in the extracellular domain of the molecule. We report here three intraexonic mutations and one deletion in the IL-2R[gamma] gene in four SCIDX1 patients. These mutations appear to differentially affect RNA processing, either by decreasing IL-2R[gamma] mRNA level or by the skipping of a constitutive exon. 16 refs., 1 fig.

  9. Ubiquitination of the common cytokine receptor {gamma}{sub c} and regulation of expression by an ubiquitination/deubiquitination machinery

    SciTech Connect

    Gesbert, Franck; Malarde, Valerie; Dautry-Varsat, Alice . E-mail: adautry@pasteur.fr

    2005-08-26

    The common cytokine receptor {gamma}{sub c} is shared by the interleukin-2, -4, -7, -9, -15, and -21 receptors, and is essential for lymphocyte proliferation and survival. The regulation of {gamma}{sub c} receptor expression level is therefore critical for the ability of cells to respond to these cytokines. We previously reported that {gamma}{sub c} is efficiently constitutively internalized and addressed towards a degradation endocytic compartment. We show that {gamma}{sub c} is ubiquitinated and also associated to ubiquitinated proteins. We report that the ubiquitin-ligase c-Cbl induces {gamma}{sub c} down-regulation. In addition, the ubiquitin-hydrolase, DUB-2, counteracts the effect of c-Cbl on {gamma}{sub c} expression. We show that an increase in DUB-2 expression correlates with an increased {gamma}{sub c} half-life, resulting in the up-regulation of the receptor. Altogether, we show that {gamma}{sub c} is the target of an ubiquitination mechanism and its expression level can be regulated through the activities of a couple of ubiquitin-ligase/ubiquitin-hydrolase enzymes, namely c-Cbl/DUB-2.

  10. Interferon-gamma-responsive neuronal sites in the normal rat brain: receptor protein distribution and cell activation revealed by Fos induction.

    PubMed

    Robertson, B; Kong, G; Peng, Z; Bentivoglio, M; Kristensson, K

    2000-05-01

    Constitutive expression of the interferon-gamma receptor protein (IFN-gammaR), and the distribution of cells in which Fos, a marker of cell activation, is induced by intracerebroventricular administration of IFN-gamma, were studied in the rat brain by immunohistochemistry. IFN-gammaR immunopositivity was found in neuronal elements, which exhibited a selective distribution being concentrated in the piriform and entorhinal cortex, midline thalamus and medial hypothalamic structures, brainstem nociceptive relays (including the periaqueductal gray, the parabrachial nuclei and the caudal part of the spinal trigeminal nuclei), and circumventricular organs such as the median eminence and area postrema. IFN-gamma-induced Fos expression mostly corresponded to neuronal sites of receptor distribution. Because of its topographical distribution, it is suggested that activation of the IFN-gammaR in neurons may play a role to limit spread of infections in the brain and, in concert with other proinflammatory cytokines, to modulate adaptive responses to an antigen challenge mediated by the central nervous system. PMID:10779704

  11. Mouse muscle nicotinic acetylcholine receptor gamma subunit: cDNA sequence and gene expression.

    PubMed Central

    Yu, L; LaPolla, R J; Davidson, N

    1986-01-01

    Clones coding for the mouse nicotinic acetylcholine receptor (AChR) gamma subunit precursor have been selected from a cDNA library derived from a mouse myogenic cell line and sequenced. The deduced protein sequence consists of a signal peptide of 22 amino acid residues and a mature gamma subunit of 497 amino acid residues. There is a high degree of sequence conservation between this mouse sequence and published human and calf AChR gamma subunits and, after allowing for functional amino acid substitutions, also to the more distantly related chicken and Torpedo AChR gamma subunits. The degree of sequence conservation is especially high in the four putative hydrophobic membrane spanning regions, supporting the assignment of these domains. RNA blot hybridization showed that the mRNA level of the gamma subunit increases by 30 fold or more upon differentiation of the two mouse myogenic cell lines, BC3H-1 and C2C12, suggesting that the primary controls for changes in gene expression during differentiation are at the level of transcription. One cDNA clone was found to correspond to a partially processed nuclear transcript containing two as yet unspliced intervening sequences. Images PMID:3010242

  12. Gamma interferon expression during acute and latent nervous system infection by herpes simplex virus type 1.

    PubMed Central

    Cantin, E M; Hinton, D R; Chen, J; Openshaw, H

    1995-01-01

    This study was initiated to evaluate a role for gamma interferon (IFN-gamma) in herpes simplex virus type 1 (HSV-1) infection. At the acute stage of infection in mice, HSV-1 replication in trigeminal ganglia and brain stem tissue was modestly but consistently enhanced in mice from which IFN-gamma was by ablated monoclonal antibody treatment and in mice genetically lacking the IFN-gamma receptor (Rgko mice). As determined by reverse transcriptase PCR, IFN-gamma and tumor necrosis factor alpha transcripts were present in trigeminal ganglia during both acute and latent HSV-1 infection. CD4+ and CD8+ T cells were detected initially in trigeminal ganglia at day 5 after HSV-1 inoculation, and these cells persisted for 6 months into latency. The T cells were focused around morphologically normal neurons that showed no signs of active infection, but many of which expressed HSV-1 latency-associated transcripts. Secreted IFN-gamma was present up to 6 months into latency in areas of the T-cell infiltration. By 9 months into latency, both the T-cell infiltrate and IFN-gamma expression had cleared, although there remained a slight increase in macrophage levels in trigeminal ganglia. In HSV-1-infected brain stem tissue, T cells and IFN-gamma expression were present at 1 month but were gone by 6 months after infection. Our hypothesis is that the persistence of T cells and the sustained IFN-gamma expression occur in response to an HSV-1 antigen(s) in the nervous system. This hypothesis is consistent with a new model of HSV-1 latency which suggests that limited HSV-1 antigen expression occurs during latency (M. Kosz-Vnenchak, J. Jacobson, D.M. Coen, and D.M. Knipe, J. Virol. 67:5383-5393, 1993). We speculate that prolonged secretion of IFN-gamma during latency may modulate a reactivated HSV-1 infection. PMID:7609058

  13. RELAXIN ACTIVATES PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA

    PubMed Central

    Singh, Sudhir; Bennett, Robert G

    2009-01-01

    SUMMARY Relaxin is a polypeptide hormone that triggers multiple signaling pathways through its receptor RXFP1. Many of relaxin’s functions, including vascular and antifibrotic effects, are similar to those induced by activation of PPARγ. In this study, we tested the hypothesis that relaxin signaling through RXFP1 would activate PPARγ activity. In cells overexpressing RXFP1 (HEK-RXFP1), relaxin increased transcriptional activity through a PPAR response element (PPRE) in a concentration-dependent manner. In cells lacking RXFP1, relaxin had no effect. Relaxin increased both the baseline activity and the response to the PPARγ agonists rosiglitazone and 15d-PGJ2, but not to agonists of PPARα or PPARδ. In HEK-RXFP1 cells infected with adenovirus expressing PPARγ, relaxin increased transcriptional activity through PPRE, and this effect was blocked with an adenovirus expressing a dominant-negative PPARγ. Knockdown of PPARγ using siRNA resulted in a decrease in the response to both relaxin and rosiglitazone. Both relaxin and rosiglitazone increased expression of the PPARγ target genes CD36 and LXRα in HEK-RXFP1 and in THP-1 cells naturally expressing RXFP1. Relaxin did not increase PPARγ mRNA or protein levels. Treatment of cells with GW9662, an inhibitor of PPARγ ligand binding, effectively blocked rosiglitazone-induced PPARγ activation, but had no effect on relaxin activation of PPARγ. These results suggest that relaxin activates PPARγ activity, and increases the overall response in the presence PPARγ agonists. This activation is dependent on the presence of RXFP1. Furthermore, relaxin activates PPARγ via a ligand-independent mechanism. These studies represent the first report that relaxin can activate the transcriptional activity of PPARγ. PMID:19712722

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

    SciTech Connect

    Mitterberger, Maria C.; Kim, Geumsoo; Rostek, Ursula; Levine, Rodney L.; Zwerschke, Werner

    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 in 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.

  15. VERITAS Observations of Gamma-ray Binary Systems

    NASA Astrophysics Data System (ADS)

    Holder, Jamie; VERITAS Collaboration

    2016-01-01

    Gamma-ray emitting binary systems constitute a small fraction of the high-energy catalogue, with only five objects confirmed to emit photons above 100 GeV. They comprise a compact object (black hole or neutron star) and a high-mass stellar companion, with gamma-ray emission arising as the result of particle acceleration within the system. The details of how and where this acceleration takes place, and the mechanisms which modulate the subsequent emission, remain unclear. We report here on recent observations of gamma-ray binary systems with the VERITAS observatory.

  16. Human macrophage activation. Modulation of mannosyl, fucosyl receptor activity in vitro by lymphokines, gamma and alpha interferons, and dexamethasone.

    PubMed Central

    Mokoena, T; Gordon, S

    1985-01-01

    We describe a sensitive assay to measure immune activation of human macrophages in cell culture. Freshly isolated blood monocytes from normal subjects lack the ability to endocytose and degrade mannosyl-terminated glycoconjugates via specific receptors, but acquired this activity after cultivation in autologous serum for approximately 3 d. Addition of specific antigen, purified protein derivative, or T cell mitogens to mononuclear cells prevented the appearance of macrophage mannosyl receptor activity and lymphokine, gamma-, and alpha-interferons selectively down-regulated receptor activity in monocyte-macrophage targets. The effects of antigen challenge and gamma-interferon on mannosyl receptors can be prevented by 10(-8) M dexamethasone. Dexamethasone also inhibited release of another macrophage activation marker, plasminogen activator, which was increased by both gamma- and alpha-interferons. These studies show that activation of human macrophages is regulated by opposing actions of lymphokines and glucocorticoids. PMID:2579101

  17. Insights into the Relationship between Toll Like Receptors and Gamma Delta T Cell Responses

    PubMed Central

    Dar, Asif Amin; Patil, Rushikesh Sudam; Chiplunkar, Shubhada Vivek

    2014-01-01

    The tumor microenvironment is an important aspect of cancer biology that contributes to tumor initiation, tumor progression and responses to therapy. The composition and characteristics of the tumor microenvironment vary widely and are important in determining the anti-tumor immune response. Successful immunization requires activation of both innate and adaptive immunity. Generally, immune system is compromised in patients with cancer due to immune suppression, loss of tumor antigen expression and dysfunction of antigen presenting cells (APC). Thus, therapeutic immunization leading to cancer regression remains a significant challenge. Certain cells of the immune system, including dendritic cells (DCs) and gamma delta (γδ) T cells are capable of driving potent anti-tumor responses. The property of MHC-unrestricted cytotoxicity, high potential of cytokine release, tissue tropism and early activation in infections and malignant disease makes γδ T cells as an emerging candidate for immunotherapy. Various strategies are being developed to enhance anti-tumor immune responses of γδ T cells and DCs one of them is the use of novel adjuvants like toll like receptors (TLR) agonists, which enhance γδ T cell function directly or through DC activation, which has ability to prime γδ T cells. TLR agonists are being used clinically either alone or in combination with tumor antigens and has shown initial success in both enhancing immune responses and eliciting anti-tumor activity. TLR activated γδ T cells and DCs nurture each other’s activation. This provides a potent base for first line of defense and manipulation of the adaptive response against pathogens and cancer. The available data provides a strong rationale for initiating combinatorial therapy for the treatment of diseases and this review will summarize the application of adjuvants (TLRs) for boosting immune response of γδ T cells to treat cancer and infectious diseases and their use in combinatorial therapy

  18. Pattern of retinoid-induced teratogenic effects: possible relationship with relative selectivity for nuclear retinoid receptors RAR alpha, RAR beta, and RAR gamma.

    PubMed

    Elmazar, M M; Reichert, U; Shroot, B; Nau, H

    1996-03-01

    Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development. Excess as well as deficiency of retinoids were found to be teratogenic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RAR's and RXR's, which exhibit a specific temporal and spatial expression during development. The significance of the retinoid receptors was investigated here by studying the teratogenic effects of retinoid ligands with relative selectivity for binding and transactivation of the retinoic acid receptors RAR alpha, RAR beta and RAR gamma. Pregnant NMRI mice were administered 5 or 15 mg/kg of CD 336 (Am 580) (alpha-ligand), CD 2019 (beta-ligand), CD 437 (gamma-ligand) or 37.5 mg/kg all-trans-retinoic acid in 25% Cremophor EL on day 8.25 or day 11 of gestation by gastric intubation. External, visceral and skeletal malformations were observed on day 18 of gestation. The order of teratogenic potency was: alpha-ligand > beta-ligand > gamma-ligand. In addition, these retinoids also produced a different spectrum of defects. The alpha-ligand induced the most varied defects including severe ear, mandible, and limb malformations. The beta-ligand induced defects of the urinary system and liver in greater frequency than expected from its relative potency. The gamma-ligand preferentially induced ossification deficiencies and defects of the sternebrae and vertebral body. Our results show that these three retinoids, which were previously demonstrated to exhibit retinoid-like activities in several systems, exert differing teratogenic activities, in regard to both potency and regioselectivity: we hypothesize that the relative selectivity for binding and transactivation of the three retinoic acid receptors could possibly be related to the differences of teratogenic effects observed in this study. The low potency of the gamma-ligand may lead the way to

  19. Opsonin-independent ligation of Fc gamma receptors. The 3G8-bearing receptors on neutrophils mediate the phagocytosis of concanavalin A- treated erythrocytes and nonopsonized Escherichia coli

    PubMed Central

    1987-01-01

    We report that phagocytosis by human neutrophils of Con A-treated erythrocytes (E-Con A) and nonopsonized Escherichia coli with mannose- binding adhesions is mediated by the Fc gamma receptor bearing the 3G8 epitope. Modulation of Fc receptors by pretreating with aggregated-IgG or with 3G8 anti-Fc gamma receptor mAb markedly inhibited internalization of E-Con A and E. coli without altering their cell surface attachment. Phagocytosis of these probes was specifically blocked by alpha-methylmannoside and D-mannose and not by other monosaccharides. Thus, recognition of E-Con A and E. coli by the Fc receptor is dependent upon the mannose-specific interaction with lectin or lectin-like adhesions. These data demonstrate that ligands other than the classical IgG opsonins can bind to classical immune receptors for IgG through lectin-carbohydrate interactions. PMID:2445895

  20. Coactivation of the human vitamin D receptor by the peroxisome proliferator-activated receptor gamma coactivator-1 alpha.

    PubMed

    Savkur, Rajesh S; Bramlett, Kelli S; Stayrook, Keith R; Nagpal, Sunil; Burris, Thomas P

    2005-08-01

    The vitamin D receptor (VDR) belongs to the superfamily of steroid/thyroid hormone receptors that is activated by 1alpha,25-dihydroxyvitamin D(3). Traditional targets for 1alpha,25-dihydroxyvitamin D(3) action include tissues involved in the maintenance of calcium homeostasis and bone development and remodeling. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a transcriptional coactivator that plays a role in mitochondrial biogenesis and energy metabolism, is predominantly expressed in kidney, heart, liver, and skeletal muscle. Because VDR and PGC-1alpha display an overlapping pattern of expression, we investigated the possibility that PGC-1alpha could serve as a coactivator for VDR. Transient cotransfection assays demonstrate that PGC-1alpha augments ligand-dependent VDR transcription when either full-length VDR or Gal4 DNA binding domain-VDR-ligand binding domain chimeras were analyzed. Furthermore, mammalian two-hybrid assays, coimmunoprecipitation analyses, and biochemical coactivator recruitment assays demonstrate a ligand-dependent interaction between the two proteins both in cells and in vitro. The coactivation potential of PGC-1alpha requires an intact AF-2 domain of VDR and the LXXLL motif in PGC-1alpha. Taken together, these results indicate that PGC-1alpha serves as a coactivator for VDR.

  1. 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

  2. Gamma Ray Imaging System (GRIS) GammaCam{trademark}. Final report, January 3, 1994--May 31, 1996

    SciTech Connect

    1996-12-31

    This report describes the activities undertaken during the development of the Gamma Ray Imaging System (GRIS) program now referred to as the GammaCam{trademark}. The purpose of this program is to develop a 2-dimensional imaging system for gamma-ray energy scenes that may be present in nuclear power plants. The report summarizes the overall accomplishments of the program and the most recent GammaCam measurements made at LANL and Estonia. The GammaCam is currently available for sale from AIL Systems as an off-the-shelf instrument.

  3. 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.

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

    PubMed

    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.

  5. Wakayama Symposium: Peroxisome Proliferator-Activated Receptor-gamma (PPARγ) and Meibomian Gland Dysfunction

    PubMed Central

    Jester, James V.; Brown, Donald J.

    2012-01-01

    Recently we have shown that mouse and human meibomian glands undergo specific age-related changes, including decreased acinar cell proliferation, acinar atrophy, and altered peroxisome proliferator-activated receptor gamma (PPARγ) localization from cytoplasmic-vesicular/nuclear in young mice and humans to nuclear in old mice and humans. Since PPARγ is a lipid-sensitive, nuclear receptor implicated in regulating adipocyte and sebocyte differentiation and lipogenesis, our findings suggest that PPARγ may be involved in modulating meibomian gland differentiation during aging. Based on these findings, we propose that aging of the meibomian gland results in downregulation of PPARγ, leading to decreased meibocyte differentiation and lipid synthesis, gland atrophy, and a hyposecretory meibomian gland dysfunction. PMID:23084144

  6. Wakayama Symposium: Peroxisome proliferator-activated receptor-gamma (PPARγ) and meibomian gland dysfunction.

    PubMed

    Jester, James V; Brown, Donald J

    2012-10-01

    Recently we have shown that mouse and human meibomian glands undergo specific age-related changes, including decreased acinar cell proliferation, acinar atrophy, and altered peroxisome proliferator-activated receptor gamma (PPARγ) localization from cytoplasmic-vesicular/nuclear in young mice and humans to nuclear in old mice and humans. Since PPARγ is a lipid-sensitive, nuclear receptor implicated in regulating adipocyte and sebocyte differentiation and lipogenesis, our findings suggest that PPARγ may be involved in modulating meibomian gland differentiation during aging. Based on these findings, we propose that aging of the meibomian gland results in downregulation of PPARγ, leading to decreased meibocyte differentiation and lipid synthesis, gland atrophy, and a hyposecretory meibomian gland dysfunction.

  7. Steroid receptor coactivator 1 links the steroid and interferon gamma response pathways.

    PubMed

    Tzortzakaki, Eleni; Spilianakis, Charalambos; Zika, Eleni; Kretsovali, Androniki; Papamatheakis, Joseph

    2003-12-01

    We show here that steroid receptor coactivator 1 (SRC-1) is a coactivator of MHC class II genes that stimulates their interferon gamma (IFNgamma) and class II transactivator (CIITA)-mediated expression. SRC-1 interacts physically with the N-terminal activation domain of CIITA through two regions: one central [extending from amino acids (aa) 360-839] that contains the nuclear receptors binding region and one C-terminal (aa 1138-1441) that contains the activation domain 2. Using chromatin immunoprecipitation assays we show that SRC-1 recruitment on the class II promoter is enhanced upon IFNgamma stimulation. Most importantly, SRC-1 relieves the inhibitory action of estrogens on the IFNgamma-mediated induction of class II genes in transient transfection assays. We provide evidence that inhibition by estradiol is due to multiple events such as slightly reduced recruitment of CIITA and SRC-1 and severely inhibited assembly of the preinitiation complex.

  8. Steroid receptor coactivator 1 links the steroid and interferon gamma response pathways.

    PubMed

    Tzortzakaki, Eleni; Spilianakis, Charalambos; Zika, Eleni; Kretsovali, Androniki; Papamatheakis, Joseph

    2003-12-01

    We show here that steroid receptor coactivator 1 (SRC-1) is a coactivator of MHC class II genes that stimulates their interferon gamma (IFNgamma) and class II transactivator (CIITA)-mediated expression. SRC-1 interacts physically with the N-terminal activation domain of CIITA through two regions: one central [extending from amino acids (aa) 360-839] that contains the nuclear receptors binding region and one C-terminal (aa 1138-1441) that contains the activation domain 2. Using chromatin immunoprecipitation assays we show that SRC-1 recruitment on the class II promoter is enhanced upon IFNgamma stimulation. Most importantly, SRC-1 relieves the inhibitory action of estrogens on the IFNgamma-mediated induction of class II genes in transient transfection assays. We provide evidence that inhibition by estradiol is due to multiple events such as slightly reduced recruitment of CIITA and SRC-1 and severely inhibited assembly of the preinitiation complex. PMID:12933903

  9. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2

    PubMed Central

    1996-01-01

    Defects in the gene encoding Bruton's tyrosine kinase (Btk) result in a disease called X-linked agammaglobulinemia, in which there is a profound decrease of mature B cells due to a block in B cell development. Recent studies have shown that Btk is tyrosine phosphorylated and activated upon B cell antigen receptor (BCR) stimulation. To elucidate the functions of this kinase, we examined BCR signaling of DT40 B cells deficient in Btk. Tyrosine phosphorylation of phospholipase C (PLC)-gamma 2 upon receptor stimulation was significantly reduced in the mutant cells, leading to the loss of both BCR-coupled phosphatidylinositol hydrolysis and calcium mobilization. Pleckstrin homology and Src-homology 2 domains of Btk were required for PLC-gamma 2 activation. Since Syk is also required for the BCR-induced PLC-gamma 2 activation, our findings indicate that PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions. PMID:8691147

  10. Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands

    PubMed Central

    Lewis, Stephanie N.; Garcia, Zulma; Hontecillas, Raquel; Bassaganya-Riera, Josep; Bevan, David R.

    2015-01-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear hormone receptor involved in regulating various metabolic and immune processes. The PPAR family of receptors possesses a large binding cavity that imparts promiscuity of ligand binding not common to other nuclear receptors. This feature increases the challenge of using computational methods to identify PPAR ligands that will dock favorably into a structural model. Utilizing both ligand- and structure-based pharmacophore methods, we sought to improve agonist prediction by grouping ligands according to pharmacophore features, and pairing models derived from these features with receptor structures for docking. For 22 of the 33 receptor structures evaluated we observed an increase in true positive rate (TPR) when screening was restricted to compounds sharing molecular features found in rosiglitazone. A combination of structure models used for docking resulted in a higher TPR (40%) when compared to docking with a single structure model (less than 20%). Prediction was also improved when specific protein-ligand interactions between the docked ligands and structure models were given greater weight than the calculated free energy of binding. A large-scale screen of compounds using a marketed drug database verified the predictive ability of the selected structure models. This study highlights the steps necessary to improve screening for PPARγ ligands using multiple structure models, ligand-based pharmacophore data, evaluation of protein-ligand interactions, and comparison of docking datasets. The unique combination of methods presented here holds potential for more efficient screening of compounds with unknown affinity for PPARγ that could serve as candidates for therapeutic development. PMID:25616366

  11. The Advanced Gamma-ray Imaging System (AGIS): Simulation studies

    SciTech Connect

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

    2011-06-14

    The Advanced Gamma-ray Imaging System (AGIS) is a next-generation ground-based gamma-ray observatory being planned in the U.S. The anticipated sensitivity of AGIS is about one order of magnitude better than the sensitivity of current observatories, allowing it to measure gamma-ray emission from a large number of Galactic and extra-galactic sources. We present here 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.

  12. Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator.

    PubMed

    Ghosh, Asish K; Bhattacharyya, Swati; Wei, Jun; Kim, Suyeon; Barak, Yaacov; Mori, Yasuji; Varga, John

    2009-09-01

    Ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-beta). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-gamma in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-beta activity by PPAR-gamma ligands involves cellular PPAR-gamma, since 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) failed to block TGF-beta-induced responses in either primary cultures of PPAR-gamma-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-gamma. Next, we examined the molecular basis underlying the abrogation of TGF-beta signaling by PPAR-gamma in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-gamma without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-beta, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-gamma. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-beta-induced stimulation of COL1A2 in the presence of PPAR-gamma ligands. Collectively, these results indicate that PPAR-gamma blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-beta-induced collagen gene expression. Pharmacological activation of PPAR-gamma thus may represent a novel therapeutic approach to target p300-dependent TGF-beta profibrotic responses such as stimulation of collagen gene expression.

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

    SciTech Connect

    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 digests 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.

  14. Modeling of gamma/gamma-prime phase equilibrium in the nickel-aluminum system

    NASA Technical Reports Server (NTRS)

    Sanchez, J. M.; Barefoot, J. R.; Jarrett, R. N.; Tien, J. K.

    1984-01-01

    A theoretical model is proposed for the determination of phase equilibrium in alloys, taking into consideration dissimilar lattice parameters. Volume-dependent pair interactions are introduced by means of phenomenological Lennard-Jones potentials and the configurational entropy of the system is treated in the tetrahedron approximation of the cluster variation method. The model is applied to the superalloy-relevant, nickel-rich, gamma/gamma-prime phase region of the Ni-Al phase diagram. The model predicts reasonable values for the lattice parameters and the enthalpy of formation as a function of composition, and the calculated phase diagram closely approximates the experimental diagram.

  15. Gamma detectors in explosives and narcotics detection systems

    NASA Astrophysics Data System (ADS)

    Bystritsky, V. M.; Zubarev, E. V.; Krasnoperov, A. V.; Porohovoi, S. Yu.; Rapatskii, V. L.; Rogov, Yu. N.; Sadovskii, A. B.; Salamatin, A. V.; Salmin, R. A.; Slepnev, V. M.; Andreev, E. I.

    2013-11-01

    Gamma detectors based on BGO crystals were designed and developed at the Joint Institute for Nuclear Research. These detectors are used in explosives and narcotics detection systems. Key specifications and design features of the detectors are presented. A software temperature-compensation method that makes it possible to stabilize the gamma detector response and operate the detector in a temperature range from -20 to 50°C is described.

  16. Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor gamma and retinoid X receptor alpha in human keratinocytes.

    PubMed

    Boudjelal, M; Wang, Z; Voorhees, J J; Fisher, G J

    2000-04-15

    Repeated exposure of human skin to solar UV radiation leads to premature aging (photoaging) and skin cancer. UV-induced skin damage can be ameliorated by all-trans retinoic acid treatment. The actions of retinoic acid in skin keratinocytes are mediated primarily by nuclear retinoic acid receptor gamma (RARgamma) and retinoid X receptor alpha (RXRalpha). We found that exposure of cultured primary human keratinocytes to UV irradiation (30 mJ/cm2) substantially reduced (50-90%) RARgamma and RXRalpha mRNA and protein within 8 h. The rates of disappearance of RARgamma and RXRalpha proteins after UV exposure or treatment with the protein synthesis inhibitor cycloheximide were similar. UV irradiation did not increase the rate of breakdown of RARgamma or RXRalpha but rather reduced their rate of synthesis. The addition of proteasome inhibitors MG132 and LLvL, but not the lysosomal inhibitor E64, prevented loss of RARgamma and RXRalpha proteins after exposure of keratinocytes to either UV radiation or cycloheximide. Soluble extracts from nonirradiated or UV-irradiated keratinocytes possessed similar levels of proteasome activity that degraded RARgamma and RXRalpha proteins in vitro. Furthermore, RARgamma and RXRalpha were polyubiquitinated in intact cells. RXRalpha was found to contain two proline, glutamate/aspartate, serine, and threonine (PEST) motifs, which confer rapid turnover of many short-lived regulatory proteins that are degraded by the ubiquitin/proteasome pathway. However, the PEST motifs in RXRalpha did not function to regulate its stability, because deletion of the PEST motifs individually or together did not alter ubiquitination or proteasome-mediated degradation of RXRalpha. These results demonstrate that loss of RARgamma and RXRalpha proteins after UV irradiation results from degradation via the ubiquitin/proteasome pathway. Taken together, the data here indicate that ubiquitin/proteasome-mediated breakdown is an important mechanism regulating the levels of

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

    SciTech Connect

    Hasegawa-Moriyama, Maiko; Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi

    2012-09-14

    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 functions 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, whereas

  18. SDP1 is a peroxisome-proliferator-activated receptor gamma 2 co-activator that binds through its SCAN domain.

    PubMed Central

    Babb, Robert; Bowen, Benjamin R

    2003-01-01

    Peroxisome-proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily, play an important role in the regulation of lipid metabolism and energy homoeostasis. In a yeast two-hybrid experiment using the zinc-finger transcription factor ZNF202 as bait, we previously identified the SCAN-domain-containing protein SDP1. SDP1 shares a high degree of amino acid sequence identity with PGC-2, a previously identified PPAR gamma 2 co-activator from the mouse. Here we show that SDP1 and PGC-2 interact with PPAR gamma 2 through their SCAN domains, even though PPAR gamma 2 does not contain a SCAN domain. Similar to PGC-2, SDP1 enhanced PPAR gamma 2-dependent gene transcription in transiently transfected cells but did not alter the affinity of PPAR gamma 2 for agonists. Although the SCAN domain was necessary for binding to PPAR gamma 2, it was not sufficient for co-activation in cells, suggesting that other features of SDP1 are responsible for transcriptional co-activation. The ability of SDP1 to interact with two different transcription factors that regulate genes involved in lipid metabolism, ZNF202 and PPAR gamma 2, suggests that SDP1 may be an important co-regulator of such genes. PMID:12444922

  19. SWEPP Gamma-Ray Spectrometer System software design description

    SciTech Connect

    Femec, D.A.; Killian, E.W.

    1994-08-01

    To assist in the characterization of the radiological contents of contract-handled waste containers at the Stored Waste Examination Pilot Plant (SWEPP), the SWEPP Gamma-Ray Spectrometer (SGRS) System has been developed by the Radiation Measurements and Development Unit of the Idaho National Engineering Laboratory. The SGRS system software controls turntable and detector system activities. In addition to determining the concentrations of gamma-ray-emitting radionuclides, this software also calculates attenuation-corrected isotopic mass ratios of-specific interest. This document describes the software design for the data acquisition and analysis software associated with the SGRS system.

  20. On the capacity of MISO FSO systems over gamma-gamma and misalignment fading channels.

    PubMed

    Boluda-Ruiz, Rubén; García-Zambrana, Antonio; Castillo-Vázquez, Beatriz; Castillo-Vázquez, Carmen

    2015-08-24

    In this work, the ergodic capacity performance for multiple-input/single-output (MISO) free-space optical (FSO) communications system with equal gain combining (EGC) reception is analyzed over gamma-gamma and misalignment fading channels, which are modeled as statistically independent, but not necessarily identically distributed (i.n.i.d.). Novel and analytical closed-form ergodic capacity expression is obtained in terms of H-Fox function by using the well-known inequality between arithmetic and geometric mean of positive random variables (RV) in order to obtain an approximate closed-form expression of the distribution of the sum of M gamma-gamma with pointing errors variates. In addition, we present an asymptotic ergodic capacity expression at high signal-to-noise ratio (SNR) for the ergodic capacity of MISO FSO systems. It can be concluded that the use of MISO technique can significantly reduce the effect of the atmospheric turbulence as well as pointing errors and, hence, provide significant capacity gain over the direct path link (DL). The impact of pointing errors on the MISO FSO system is also analyzed, which only depends on the number of laser sources and pointing error parameters. Moreover, it can be also concluded that the ergodic capacity performance is dramatically reduced as a consequence of the severity of pointing error effects. Simulation results are further demonstrated to confirm the analytical results.

  1. Immunochemical demonstration that amino acids 360-377 of the acetylcholine receptor gamma-subunit are cytoplasmic

    PubMed Central

    1985-01-01

    Two monoclonal antibodies (mabs) previously prepared against Torpedo acetylcholine receptor are shown to recognize a synthetic nonadecapeptide corresponding to lys360-glu377 of the gamma subunit. The reaction was demonstrated by solid-phase enzyme-linked immunoabsorbent assays, by inhibition of binding of the mabs to receptor, and by immunoprecipitation of the peptide conjugated to bovine serum albumin. Immunogold electron microscopy on isolated postsynaptic membranes from Torpedo showed that both mabs bind to intracellular epitopes on the receptor. These results establish that amino acid residues 360-377 of the receptor gamma-subunit, and probably the analogous region of the delta-subunit, reside on the cytoplasmic side of the membrane. Since the primary structures of all four subunits suggest a common transmembrane arrangement, the corresponding domains of the alpha- and beta-subunits are probably also cytoplasmic. PMID:3972889

  2. Gamma spectrometry of the minor bodies of the solar system

    SciTech Connect

    Surkov, Yu.A.; Moskaleva, L.P.; Manvelyan, O.S.

    1987-01-01

    The authors investigate the possibility of determining the elemental composition of the surfaces of minor bodies of the solar system (asteroids, the Martian satellites Phobos and Deimos, etc.) using spacecraft-based ..gamma..-spectrometry. The dependence of ..gamma..-photon flux on altitude above the body was calculated for body radii from 13 to 500 km. Estimates were made of the sensitivity of the determination of basic rock-forming elements with respect to changes in geometry of a factor of two, using ..gamma..-spectrometry with a 100 mm by 100 mm crystal of NaI(Tl). Finally, the time required to determine the stipulated characteristic ..gamma..-radiation of surface rocks with the given precision was derived as a function of altitude.

  3. Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?

    PubMed Central

    Förstera, Benjamin; Castro, Patricio A.; Moraga-Cid, Gustavo; Aguayo, Luis G.

    2016-01-01

    In recent years there has been an increase in the understanding of ethanol actions on the type A γ-aminobutyric acid chloride channel (GABAAR), a member of the pentameric ligand gated ion channels (pLGICs). However, the mechanism by which ethanol potentiates the complex is still not fully understood and a number of publications have shown contradictory results. Thus many questions still remain unresolved requiring further studies for a better comprehension of this effect. The present review concentrates on the involvement of GABAAR in the acute actions of ethanol and specifically focuses on the immediate, direct or indirect, synaptic and extra-synaptic modulatory effects. To elaborate on the immediate, direct modulation of GABAAR by acute ethanol exposure, electrophysiological studies investigating the importance of different subunits, and data from receptor mutants will be examined. We will also discuss the nature of the putative binding sites for ethanol based on structural data obtained from other members of the pLGICs family. Finally, we will briefly highlight the glycine gated chloride channel (GlyR), another member of the pLGIC family, as a suitable target for the development of new pharmacological tools. PMID:27199667

  4. Rearrangement and junctional-site sequence analyses of T-cell receptor gamma genes in intestinal intraepithelial lymphocytes from murine athymic chimeras.

    PubMed

    Whetsell, M; Mosley, R L; Whetsell, L; Schaefer, F V; Miller, K S; Klein, J R

    1991-12-01

    The molecular organization of rearranged T-cell receptor (TCR) gamma genes intraepithelial lymphocytes (IEL) was studied in athymic radiation chimeras and was compared with the organization of gamma gene rearrangements in IEL from thymus-bearing animals by polymerase chain reaction and by sequence analyses of DNA spanning the junction of the variable (V) and joining (J) genes. In both thymus-bearing mice and athymic chimeras, IEL V-J gamma-gene rearrangements occurred for V gamma 1.2, V gamma 2, and V gamma 5 but not for V gamma 3 or V gamma 4. Sequence analyses of cloned V-J polymerase chain reaction-amplified products indicated that in both thymus-bearing mice and athymic chimeras, rearrangement of V gamma 1.2 and V gamma 5 resulted in in-frame as well as out-of-frame genes, whereas nearly all V gamma 2 rearrangements were out of frame from either type of animal. V-segment nucleotide removal occurred in most V gamma 1.2, V gamma 2, and V gamma 5 rearrangements; J-segment nucleotide removal was common in V gamma 1.2 but not in V gamma 2 or V gamma 5 rearrangements. N-segment nucleotide insertions were present in V gamma 1.2, V gamma 2, and V gamma 5 IEL rearrangements in both thymus-bearing mice and athymic chimeras, resulting in a predominant in-frame sequence for V gamma 5 and a predominant out-of-frame sequence for V gamma 2 genes. These findings demonstrate that (i) TCR gamma-gene rearrangement occurs extrathymically in IEL, (ii) rearrangements of TCR gamma genes involve the same V gene regardless of thymus influence; and (iii) the thymus does not determine the degree to which functional or nonfunctional rearrangements occur in IEL.

  5. The UCR gamma ray telescope data acquisition system

    NASA Technical Reports Server (NTRS)

    O'Neill, T. J.; Sweeney, W. E.; Tumer, O. T.; Zych, A. D.; White, R. S.

    1988-01-01

    A description is given of an electronics system based on the DEC Falcon SBC-11/23+, which has been designed and built to support a balloon-borne double Compton gamma-ray telescope. The system provides support for commands, data acquisition, data routing and compression, and photomultiplier tube gain control. The software consists of a number of interrupt-driven routines of differing priorities to handle each system task. This includes two circular buffers for onboard processing and bit encoding before transmission of the information to the ground computer. Acquisition of gamma-ray events at rates above the 200-Hz telemetry constraint is easily achieved.

  6. Gamma-ray Albedo of Small Solar System Bodies

    SciTech Connect

    Moskalenko, I.V.

    2008-03-25

    We calculate the {gamma}-ray albedo flux from cosmic-ray (CR) interactions with the solid rock and ice in Main Belt asteroids and Kuiper Belt objects (KBOs) using the Moon as a template. We show that the {gamma}-ray albedo for the Main Belt and KBOs strongly depends on the small-body mass spectrum of each system and may be detectable by the forthcoming Gamma Ray Large Area Space Telescope (GLAST). If detected, it can be used to derive the mass spectrum of small bodies in the Main Belt and Kuiper Belt and to probe the spectrum of CR nuclei at close-to-interstellar conditions. The orbits of the Main Belt asteroids and KBOs are distributed near the ecliptic, which passes through the Galactic center and high Galactic latitudes. Therefore, the {gamma}-ray emission by the Main Belt and Kuiper Belt has to be taken into account when analyzing weak {gamma}-ray sources close to the ecliptic. The asteroid albedo spectrum also exhibits a 511 keV line due to secondary positrons annihilating in the rock. This may be an important and previously unrecognized celestial foreground for the INTErnational Gamma-Ray Astrophysics Laboratory (INTEGRAL) observations of the Galactic 511 keV line emission including the direction of the Galactic center. For details of our calculations and references see [1].

  7. In Situ Underwater Gamma Spectroscopy System. Innovative Technology Summary Report

    SciTech Connect

    2001-06-01

    The baseline approach to characterize underwater objects is to use radiation sensors on an extendable pole or the Remote Underwater Characterization System to detect gamma radiation and to collect samples for laboratory analysis to determine concentrations of specific radionuclides. The In-Situ Underwater Gamma Spectroscopy (ISUGS) System is essentially a submersible In-Situ Object Counting System from Canberra that can determine both the total gamma radiation and quantify the specific radionuclides contributing to the radiation. ISUGS was demonstrated to characterize objects in the canal of the Materials Test Reactor in INEEL's Test Reactor Area. Cost analysis based on demonstration data revealed that ISUGS reduced costs by 80% for characterization of ten objects compared to the baseline approach. Frammatome provides ISUGS as part of its characterization services. Based on these promising results, INEEL and other DOE sites plan to use ISUGS to characterize their reactor fuel pools.

  8. A Gamma Memory Neural Network for System Identification

    NASA Technical Reports Server (NTRS)

    Motter, Mark A.; Principe, Jose C.

    1992-01-01

    A gamma neural network topology is investigated for a system identification application. A discrete gamma memory structure is used in the input layer, providing delayed values of both the control inputs and the network output to the input layer. The discrete gamma memory structure implements a tapped dispersive delay line, with the amount of dispersion regulated by a single, adaptable parameter. The network is trained using static back propagation, but captures significant features of the system dynamics. The system dynamics identified with the network are the Mach number dynamics of the 16 Foot Transonic Tunnel at NASA Langley Research Center, Hampton, Virginia. The training data spans an operating range of Mach numbers from 0.4 to 1.3.

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

    SciTech Connect

    Arnold, Ralf . E-mail: ralf.arnold@medizin.uni-magdeburg.de; 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) from 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.

  10. 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

  11. GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid

    PubMed Central

    Gould, Timothy; Chen, Lixin; Emri, Zsuzsa; Pirttimaki, Tiina; Errington, Adam C.; Crunelli, Vincenzo; Parri, H. Rheinallt

    2014-01-01

    The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABAB receptors (GABABRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABAA and GABABRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABABR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca2+ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABABRs and mediated by Ca2+ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB. PMID:25225100

  12. Expression and function of a variant T cell receptor complex lacking CD3-gamma

    PubMed Central

    1991-01-01

    A T cell line termed DIL2 has been derived from an infant with a polyclonal T cell receptor (TCR)/CD3 cell surface expression defect. Indirect immunofluorescence showed that the expression of certain TCR/CD3 epitopes (like those detected by WT31 and BMA031 monoclonals) was strongly reduced (around five-fold) on DIL2, whereas other epitopes (like those detected by SP34 and Leu4) were only around two-fold lower than in normal T cell lines. Specific immunoprecipitates of surface- radioiodinated DIL2 cells contained TCR-alpha, TCR-beta, CD3-delta, CD3- epsilon and TCR-zeta chains, but lacked CD3-gamma. This structural TCR/CD3 variant was, however, capable of transducing certain activation signals, since normal proliferation and a low but significant calcium flux was observed in DIL2 cells after engagement with specific antibodies. Our data suggest that a functional TCR/CD3 complex can be expressed on the surface of T cells in the absence of CD3-gamma. PMID:1713248

  13. T-cell receptor heterogeneity of gamma delta T-cell clones from human female reproductive tissues.

    PubMed

    Christmas, S E; Brew, R; Deniz, G; Taylor, J J

    1993-03-01

    gamma delta T cells were isolated from human decidua parietalis, decidua basalis and cervix and cloned in the presence of interleukin-2 (IL-2). T-cell receptor (TcR) expression was then analysed and compared with that of a panel of gamma delta T-cell clones from peripheral blood. Only 17/40 (42.5%) clones from decidua parietalis were V gamma 9+/V delta 2+ as compared to 68/94 (72%) of peripheral blood clones (P < 0.005). Conversely, 50% of clones from decidua parietalis but only 15% of clones from peripheral blood were V delta 1+ (P < 0.001). At least seven distinct TcR types were identified among the panel of clones from decidua parietalis and at least six different types were expressed by the panel of 17 clones from cervix. This receptor heterogeneity was not a result of interdonor variation as in all instances where more than one clone was obtained from a single sample, individual clones having between two and five receptor types were identified. However, 23/24 (95.8%) of clones from decidua basalis were V gamma 9+/V delta 2+. Most clones from decidua parietalis and cervix, whether V gamma 9+/V delta 2+ or V delta 1+, were positive for the mucosal lymphocyte marker, HML-1, but expression was often heterogeneous within a single clone. In contrast, almost all gamma delta T-cell clones from peripheral blood were HML-1-. Thus, unlike the mouse, gamma delta T cells within these human female reproductive tissues have a diverse TcR repertoire which, in decidua parietalis, is distinct from that of peripheral blood.

  14. [Expression of retinoic acid receptor gamma gene in ES cells and its effect on their differentiation and apoptosis].

    PubMed

    Du, Z W; Tsung, H C; Yao, Z

    1998-06-01

    We have constructed pSG5-RAR gamma-neo plasmid containing mouse retinoic acid receptor gamma (RAR gamma) gene and neo gene, and introduced it into embryonic stem ES-5 cells, by calcium phosphate mediated transfection. Some G418-resistant clones were isolated and from RNA dot blot analysis of these clones, a clone overexpressing RAR gamma gene was established, designated as ES-gamma cell line. Northern blot hydridization and Southern blot hydridization analysis of ES-gamma cells (Fig 3, 4) demonstrated that ES-gamma cells overexpressed exogenous RAR gamma mRNA and the exogenous RAR gamma cDNA integrated into the genome of ES cells. ES-gamma cells retained undifferentiated morphology and positive alkaline phosphatase activity (Plate I, Fig. 1, 2), so it resembled ES-5 cells in terms of stem cell characteristics. When ES-gamma cells were subcutaneously inoculated into nude mouse and differentiated in vivo, tumorous nodules containing various tissue structures were obtained, demonstrating their pluripotent properties just like parent ES-5 cells. Contrasting with ES-5 cells, the histological features of tumors showed no cartilage tissues, but abundant muscle tissues and keratinized cyst like structures constituted by stratified squamous epithelia (Plate I, Fig. 3). Differentiating in vitro by hanging drop culture methods, ES-gamma cells differentiated mostly into fibroblast-like cells, (Plate II, Fig. 1-5). The above results indicated that overexpression of RAR gamma gene changed the cell type of ES cells differentiating in vivo and in vitro. During the differentiation of ES-5 cells induced by RA, a large number of cells rounded up, detached from the dish and tended to die. We suspected that this phenomenon may be apoptosis. The ultrastructure appearance of the dying cells displayed typical apoptotic changes including chromatin condensation and nuclear fragmentation (Plate I, Fig. 4, 5). Detection of DNA fragments using agarose gel electrophoresis showed characteristic

  15. 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.

  16. Peroxisome proliferator-activated receptor gamma agonists as insulin sensitizers: from the discovery to recent progress.

    PubMed

    Cho, Nobuo; Momose, Yu

    2008-01-01

    An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. The peroxisome proliferator-activated receptor gamma (PPARgamma) is one of the ligand-activated transcription factors in the nuclear hormone receptor superfamily and a pivotal regulator of glucose and lipid homeostasis. The discovery of PPARgamma as a target of multimodal insulin sensitizers, represented by thiazolidinediones (TZDs), has attracted remarkable scientific interest and had a great impact on the pharmaceutical industry. With the clinical success of the PPARgamma agonists, pioglitazone (Actos) and rosiglitazone (Avandia), development of novel and potent insulin-sensitizing agents with diverse clinical profiles has been accelerated. Currently, a number of PPARgamma agonists from different chemical classes and with varying pharmacological profiles are being developed. Despite quite a few obstacles to the development of PPAR-related drugs, PPARgamma-targeted agents still hold promise. There are new concepts and encouraging evidence emerging that suggest this class can yield improved anti-diabetic agents. This review covers the discovery of TZDs, provides an overview of PPARgamma including the significance of PPARgamma as a drug target, describes the current status of a wide variety of novel PPARgamma ligands including PPAR dual and pan agonists and selective PPARgamma modulators (SPPARgammaMs), and highlights new approaches for identifying agents targeting PPARgamma in the treatment of type 2 diabetes. PMID:19075761

  17. Ligation of Fc gamma receptor IIB inhibits antibody-dependent enhancement of dengue virus infection.

    PubMed

    Chan, Kuan Rong; Zhang, Summer Li-Xin; Tan, Hwee Cheng; Chan, Ying Kai; Chow, Angelia; Lim, Angeline Pei Chiew; Vasudevan, Subhash G; Hanson, Brendon J; Ooi, Eng Eong

    2011-07-26

    The interaction of antibodies, dengue virus (DENV), and monocytes can result in either immunity or enhanced virus infection. These opposing outcomes of dengue antibodies have hampered dengue vaccine development. Recent studies have shown that antibodies neutralize DENV by either preventing virus attachment to cellular receptors or inhibiting viral fusion intracellularly. However, whether the antibody blocks attachment or fusion, the resulting immune complexes are expected to be phagocytosed by Fc gamma receptor (FcγR)-bearing cells and cleared from circulation. This suggests that only antibodies that are able to block fusion intracellularly would be able to neutralize DENV upon FcγR-mediated uptake by monocytes whereas other antibodies would have resulted in enhancement of DENV replication. Using convalescent sera from dengue patients, we observed that neutralization of the homologous serotypes occurred despite FcγR-mediated uptake. However, FcγR-mediated uptake appeared to be inhibited when neutralized heterologous DENV serotypes were used instead. We demonstrate that this inhibition occurred through the formation of viral aggregates by antibodies in a concentration-dependent manner. Aggregation of viruses enabled antibodies to cross-link the inhibitory FcγRIIB, which is expressed at low levels but which inhibits FcγR-mediated phagocytosis and hence prevents antibody-dependent enhancement of DENV infection in monocytes. PMID:21746897

  18. [Thiazolidinediones in type 2 diabetes. Role of peroxisome proliferator-activated receptor gamma (PPARgamma)].

    PubMed

    Dubois, M; Vantyghem, M-C; Schoonjans, K; Pattou, F

    2002-12-01

    Thiazolidinediones (TZDs) form a new class of oral antidiabetic agents. They improve insulin sensitivity and reduce glycemia, lipidemia and insulinemia in patients with type 2 diabetes. Their mechanism is original, since they activate the nuclear receptor Peroxisome Proliferator-Activated Receptor gamma (PPARgamma), altering the expression of genes involved in glucose and lipid homeostasis. Stimulating PPARgamma improves insulin sensitivity via several mechanisms: 1) it raises the expression of GLUT4 glucose transporter; 2) it regulates release of adipocyte-derived signaling factors that affect insulin sensitivity in muscle, and 3) it contributes to a turn-over in adipose tissue, inducing the production of smaller, more insulin sensitive adipocytes. TZDs also affect free fatty acids (FFA) lipotoxicity on islets, improving pancreatic B-cell function. In addition, triglycerides and FFA levels are lowered by TZDs. Two TZDs, rosiglitazone and pioglitazone, have recently obtained the European commercial licence, but their use is restricted to the association with metformin or sulfonylureas. At the moment, they are indicated in type 2 diabetes but could be of interest in a broader array of diseases related to insulin resistance. As for side effects, rosiglitazone and pioglitazone may cause increased plasma volume, edema and dose-related weight gain. TZDs offer an attractive option in the treatment of type 2 diabetes, though it may be too soon to determine if they prevent vascular complications, as do other oral antidiabetic agents. An important issue for the future will be to assess the influence of weight gain in the long time. PMID:12527853

  19. KR-62980: a novel peroxisome proliferator-activated receptor gamma agonist with weak adipogenic effects.

    PubMed

    Kim, Kwang Rok; Lee, Jeong Hyung; Kim, Seung Jun; Rhee, Sang Dal; Jung, Won Hoon; Yang, Sung-Don; Kim, Sung Soo; Ahn, Jin Hee; Cheon, Hyae Gyeong

    2006-08-14

    The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is the target for the anti-diabetic drugs including thiazolidinediones. We report here the identification and characterization of a novel PPARgamma agonist KR-62980. KR-62980 acted as a selective PPARgamma agonist in transactivation assay with an EC50 of 15 nM. In fully differentiated 3T3-L1 adipocytes, KR-62980 induced [3H]-deoxyglucose uptake in a concentration-dependent manner in the presence of insulin. KR-62980 was weakly adipogenic with little induction of aP2 mRNA, and was able to antagonize the adipogenic effects of rosiglitazone in C3H10T1/2 cells. In vivo pharmacokinetic profile of KR-62980 revealed that the compound exhibited good oral bioavailability of 65% with a terminal elimination half-life of 2.5 h in the rat. Treatment of high fat diet-induced C57BL/6J mice with KR-62980 for 14 days reduced plasma glucose levels with little side effects with regard to weight gain, cardiac hypertrophy and hepatotoxicity. These results suggest that KR-62980 acts as a selective PPARgamma modulator with anti-hyperglycemic activity, and that the mechanism of actions of KR-62980 appears to be different from that of rosiglitazone with improved side effect profiles.

  20. 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

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

    PubMed

    Saha, Lekha

    2015-11-01

    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

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

    PubMed Central

    Saha, Lekha

    2015-01-01

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

    SciTech Connect

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

    2008-12-24

    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.

  4. 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.

  5. Identification of clathrin heavy chain as a direct interaction partner for the gamma-aminobutyric acid type A receptor associated protein.

    PubMed

    Mohrlüder, Jeannine; Hoffmann, Yvonne; Stangler, Thomas; Hänel, Karen; Willbold, Dieter

    2007-12-18

    Gamma-aminobutyric acid type A receptors (GABAA receptors) are the major sites of GABA-mediated fast synaptic inhibition in the central nervous system. Variation of the cell surface receptor count is postulated to be of importance in modulating inhibitory synaptic transmission. The GABAA receptor associated protein (GABARAP) is a ubiquitin-like modifier, implicated in GABAA receptor clustering, trafficking, and turnover. GABARAP pull-down experiments with brain lysate identified clathrin heavy chain to be GABARAP-associated. Phage display screening of a randomized peptide library for GABARAP ligands yielded a sequence motif which characterizes the peptide binding specificity of GABARAP. Sequence database searches with this motif revealed clathrin heavy chain as a protein containing the identified sequence motif within its residues 510-522, supporting the result of the pull-down experiments. Calreticulin, which was identified recently as a GABARAP ligand, contains a very similar sequence motif. We demonstrate that calreticulin indeed competes with clathrin heavy chain for GABARAP binding. Finally, employing nuclear magnetic resonance spectroscopy, we mapped the GABARAP residues responsible for binding to clathrin. The hereby mapped GABARAP regions overlap very well with the homologue residues in yeast Atg8 that were recently shown to be important for autophagy. Together with the knowledge that GABARAP and clathrin are known to be involved in GABAA receptor trafficking within the cell, this strongly suggests a clear physiological relevance of the direct interaction of GABARAP with clathrin heavy chain. PMID:18027972

  6. Genital tract infection with Chlamydia trachomatis fails to induce protective immunity in gamma interferon receptor-deficient mice despite a strong local immunoglobulin A response.

    PubMed Central

    Johansson, M; Schön, K; Ward, M; Lycke, N

    1997-01-01

    CD4+ T cells have been found to play a critical role in immune protection against Chlamydia trachomatis infection. Since both humoral and cell-mediated antichlamydial immunity have been implicated in host protection, the crucial effector functions provided by the CD4+ T cells may rely on Th1 or Th2 functions or both. In the present study, we evaluated the development of natural immunity following vaginal infection with C. trachomatis serovar D in female gamma interferon receptor-deficient (IFN-gammaR-/-) mice with a disrupted Th1 effector system. We found that in comparison with wild-type mice, the IFN-gammaR-/- mice exhibited a severe ascending primary infection of prolonged duration which stimulated almost 10-fold-stronger specific local immunoglobulin A (IgA) and IgG responses in the genital tract. Following resolution of the primary infection and despite the augmented antibody responses to chlamydiae, the IFN-gammaR-/- mice were completely unprotected against reinfection, suggesting that local antibodies play a subordinate role in host protection against chlamydial infection. Immunohistochemical analysis of frozen sections of the genital tract revealed many CD4+ T cells in the IFN-gammaR-/- mice, with a dominance of interleukin 4-containing cells in mice following resolution of the secondary infection. However, in contrast to the findings with wild-type mice, the typical clusters of CD4+ T cells were not found in the IFN-gammaR-/- mice. Few and similarly distributed CD8+ T cells were observed in IFN-gammaR-/- and wild-type mice. Whereas chlamydia-infected macrophages from wild-type mice had no inclusion bodies (IB) and produced significant amounts of nitric oxide (NO) in the presence of IFN-gamma, macrophages from IFN-gammaR-/- mice contained many IB but no NO. These results indicate that CD4+ Th1 cells and IFN-gamma, rather than local antibodies, are critical elements in host immune protection stimulated by a natural ascending C. trachomatis infection in the

  7. Crosstalk between the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and the vitamin D receptor (VDR) in human breast cancer cells: PPAR{gamma} binds to VDR and inhibits 1{alpha},25-dihydroxyvitamin D{sub 3} mediated transactivation

    SciTech Connect

    Alimirah, Fatouma; Peng, Xinjian; Yuan, Liang; Mehta, Rajeshwari R.; Knethen, Andreas von; Choubey, Divaker; Mehta, Rajendra G.

    2012-11-15

    Heterodimerization and cross-talk between nuclear hormone receptors often occurs. For example, estrogen receptor alpha (ER{alpha}) physically binds to peroxisome proliferator-activated receptor gamma (PPAR{gamma}) and inhibits its transcriptional activity. The interaction between PPAR{gamma} and the vitamin D receptor (VDR) however, is unknown. Here, we elucidate the molecular mechanisms linking PPAR{gamma} and VDR signaling, and for the first time we show that PPAR{gamma} physically associates with VDR in human breast cancer cells. We found that overexpression of PPAR{gamma} decreased 1{alpha},25-dihydroxyvitamin D{sub 3} (1,25D{sub 3}) mediated transcriptional activity of the vitamin D target gene, CYP24A1, by 49% and the activity of VDRE-luc, a vitamin D responsive reporter, by 75% in T47D human breast cancer cells. Deletion mutation experiments illustrated that helices 1 and 4 of PPAR{gamma}'s hinge and ligand binding domains, respectively, governed this suppressive function. Additionally, abrogation of PPAR{gamma}'s AF2 domain attenuated its repressive action on 1,25D{sub 3} transactivation, indicating that this domain is integral in inhibiting VDR signaling. PPAR{gamma} was also found to compete with VDR for their binding partner retinoid X receptor alpha (RXR{alpha}). Overexpression of RXR{alpha} blocked PPAR{gamma}'s suppressive effect on 1,25D{sub 3} action, enhancing VDR signaling. In conclusion, these observations uncover molecular mechanisms connecting the PPAR{gamma} and VDR pathways. -- Highlights: PPAR{gamma}'s role on 1{alpha},25-dihydroxyvitamin D{sub 3} transcriptional activity is examined. Black-Right-Pointing-Pointer PPAR{gamma} physically binds to VDR and inhibits 1{alpha},25-dihydroxyvitamin D{sub 3} action. Black-Right-Pointing-Pointer PPAR{gamma}'s hinge and ligand binding domains are important for this inhibitory effect. Black-Right-Pointing-Pointer PPAR{gamma} competes with VDR for the availability of their binding partner, RXR{alpha}.

  8. Safety and efficacy of recombinant gamma interferon in the treatment of systemic sclerosis.

    PubMed Central

    Vlachoyiannopoulos, P G; Tsifetaki, N; Dimitriou, I; Galaris, D; Papiris, S A; Moutsopoulos, H M

    1996-01-01

    OBJECTIVE: To evaluate the safety and efficacy of recombinant gamma interferon (rIFN gamma) in the treatment of patients with systemic sclerosis. METHODS: Sixteen patients with systemic sclerosis were treated with r-IFN gamma, 60 micrograms m-2 (low dose, n = 10) and 150 micrograms m-2 (high dose, n = 6), three times weekly in an open phase I/II trial of eight months duration. The patients were stratified in low and high dose according to the severity and the extent of scleroderma; the two groups were comparable. RESULTS: The treatment was well tolerated. The most common side effects, almost certainly related to r-IFN gamma, were fever, chills, dizziness, headache, and severe flu-like syndrome with decreasing intensity with the time of treatment. Severe aphthous stomatitis (n = 1), ventricular tachycardia (n = 1), severe oesophageal ulcers due to gastro-oesophageal reflux (n = 1), disease exacerbation alone with frank arthritis and slight pericardial effusion (n = 1), and inability to conform to the requirements of the study (n = 1) were the reasons for discontinuing treatment. Side effects and degree of response were evident during the first five months of treatment. A significant decrease in mean skin thickness score was observed and was higher in the high dose group. Reactive oxygen species of peripheral neutrophils and soluble interleukin-2 receptor serum concentrations were higher than those of normal individuals at study entry and decreased in parallel with clinical improvement. CONCLUSIONS: Treatment of systemic sclerosis patients with r-IFN gamma was relatively safe and well tolerated for doses as high as 150 micrograms m-2 three times weekly. Side effects and the degree of response can be seen during the first months of therapy and can be used as predictors of ultimate toxicity or response. The drug seems to be effective in treating cutaneous scleroderma. PMID:8984943

  9. A gamma-ray verification system for special nuclear material

    SciTech Connect

    Lanier, R.G.; Prindle, A.L.; Friensehner, A.V.; Buckley, W.M.

    1994-07-01

    The Safeguards Technology Program at the Lawrence Livermore National Laboratory (LLNL) has developed a gamma-ray screening system for use by the Materials Management Section of the Engineering Sciences Division at LLNL for verifying the presence or absence of special nuclear material (SNM) in a sample. This system facilitates the measurements required under the ``5610`` series of US Department of Energy orders. MMGAM is an intelligent, menu driven software application that runs on a personal computer and requires a precalibrated multi-channel analyzer and HPGe detector. It provides a very quick and easy-to-use means of determining the presence of SNM in a sample. After guiding the operator through a menu driven set-up procedure, the system provides an on-screen GO/NO-GO indication after determining the system calibration status. This system represents advances over earlier used systems in the areas of ease-of use, operator training requirements, and quality assurance. The system records the gamma radiation from a sample using a sequence of measurements involving a background measurement followed immediately by a measurement of the unknown sample. Both spectra are stored and available for analysis or output. In the current application, the presence of {sup 235}U, {sup 238}U, {sup 239}Pu, and {sup 208}Tl isotopes are indicated by extracting, from the stored spectra, four energy ``windows`` preset around gamma-ray lines characteristic of the radioactive decay of these nuclides. The system is easily extendible to more complicated problems.

  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. Two isoforms of Xenopus retinoic acid receptor gamma 2 (B) exhibit differential expression and sensitivity to retinoic acid during embryogenesis.

    PubMed

    Crawford, M J; Liversage, R A; Varmuza, S L

    1995-01-01

    We report the isolation of two retinoic acid receptor isoforms (RAR gamma), which differ only in the 5'untranslated and putative N-terminus A regions. The two isoforms appear to serve as early markers for the presumptive neural axis; however, their expression patterns differ. RAR-gamma 2.1 is first expressed at gastrulation at the dorsal lip and subsequently along the presumptive neural axis. RAR- gamma 2.2 represents the full-length sequence of a receptor cDNA already partially characterized and present as a maternal transcript [Ellinger-Ziegelbauer and Dreyer (1991); Genes Dev 5:94-104, (1993): Mech Dev 41:31-46; Pfeffer and DeRobertis, (1994) Mech Dev: 45:147-153]. Unlike RAR-gamma 2.2, the 2.1 variant is not expressed either in pre-somitic mesoderm or notochord. RAR-gamma 2.1 is strongly expressed in branchial arches and to a lesser extent in the neural floor plate. The two isoforms also exhibit differential sensitivity to retinoic acid. Constitutive expression of RAR gamma 2.2 following neurulation appears to be depressed by treatment with retinoic acid, but domains of highest expression, namely, the head and tail, remain relatively unaffected, as do patterns of expression prior to late neurulation. By contrast, RAR-gamma 2.1 is not transcribed in retinoid-inhibited structures. Using microinjection techniques, we show that changes of RAR-gamma 2.1 expression in presumptive head structures occur as an early and local consequence of retinoic acid administration. Since RAR-gamma 2.1 expression is inhibited by retinoic acid, we tested to see if other treatments that perturb axis formation had any effect. Surprisingly, UV irradiation did not suppress that its inhibition by retinoic acid is not due solely to inhibition of anterior neural development. These experiments demonstrate a new subdivision of isoforms that undergo differential expression during development and that exhibit differential sensitivity to retinoic acid and to UV. This sensitivity and the presence

  12. Dopamine, cognitive function, and gamma oscillations: role of D4 receptors

    PubMed Central

    Furth, Katrina E.; Mastwal, Surjeet; Wang, Kuan H.; Buonanno, Andres; Vullhorst, Detlef

    2013-01-01

    Cognitive deficits in individuals with schizophrenia (SCZ) are considered core symptoms of this disorder, and can manifest at the prodromal stage. Antipsychotics ameliorate positive symptoms but only modestly improve cognitive symptoms. The lack of treatments that improve cognitive abilities currently represents a major obstacle in developing more effective therapeutic strategies for this debilitating disorder. While D4 receptor (D4R)-specific antagonists are ineffective in the treatment of positive symptoms, animal studies suggest that D4R drugs can improve cognitive deficits. Moreover, recent work from our group suggests that D4Rs synergize with the neuregulin/ErbB4 signaling pathway, genetically identified as risk factors for SCZ, in parvalbumin (PV)-expressing interneurons to modulate gamma oscillations. These high-frequency network oscillations correlate with attention and increase during cognitive tasks in healthy subjects, and this correlation is attenuated in affected individuals. This finding, along with other observations indicating impaired GABAergic function, has led to the idea that abnormal neural activity in the prefrontal cortex (PFC) in individuals with SCZ reflects a perturbation in the balance of excitation and inhibition. Here we review the current state of knowledge of D4R functions in the PFC and hippocampus, two major brain areas implicated in SCZ. Special emphasis is given to studies focusing on the potential role of D4Rs in modulating GABAergic transmission and to an emerging concept of a close synergistic relationship between dopamine/D4R and neuregulin/ErbB4 signaling pathways that tunes the activity of PV interneurons to regulate gamma frequency network oscillations and potentially cognitive processes. PMID:23847468

  13. Acceptance test report for the 241-SY-101 Flexible Receiver Gamma Detector System

    SciTech Connect

    Dowell, J.L.

    1995-02-17

    This Acceptance Test Report is for the 241-SY-101 Flexible Receiver Gamma Detector System. This test verified that the data logger and data converter for the gamma detector system functions as intended.

  14. Fetal liver T cell receptor gamma/delta+ T cells as cytotoxic T lymphocytes specific for maternal alloantigens

    PubMed Central

    1992-01-01

    We have established fetal liver-derived T cell receptor (TCR) gamma/delta+, CD3+ T cell lines that are cytotoxic for maternal T cells. Fetal liver-derived lymphoid progenitors yielded predominantly TCR-gamma/delta+ cell clusters when cultured on fetal bone marrow- derived stromal cells in the presence of a cytokine cocktail under magnetic force. These tightly adherent clusters were cloned by limiting dilution and the resulting cell lines analyzed for phenotype and function. Six of eight TCR-gamma/delta lines from 8-9.5-wk gestation fetuses were V delta 2+ as compared with zero of eight lines from later stages of gestation (10 and 15 wk), where all the lines were V delta 1+. In cytotoxicity assays, these TCR-gamma/delta+, CD3+, CD4-, and CD8+ or CD8- long-term cultured lymphoid cells (LLC) were killer cells active against the class I antigens on maternal T cells. Of the cell lines, the CD8+ TCR-gamma/delta+ LLC had the highest levels of killer activity. Thus fetal liver TCR-gamma/delta+ T cells may play a crucial role in protection against invading maternal T cells generated in the feto-maternal interaction. PMID:1535364

  15. 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

    2013-12-01

    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.

  16. 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

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

    SciTech Connect

    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 hr 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.

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

    SciTech Connect

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

    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), 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.

  19. Deficiency of interferon-gamma or its receptor promotes colorectal cancer development.

    PubMed

    Wang, Lu; Wang, Yan; Song, Zhiyu; Chu, Jiahui; Qu, Xianjun

    2015-04-01

    Genetic variations in interferon-gamma (IFN-γ) and its receptor (IFNγR) subunits are closely associated with the risk of colorectal cancer (CRC) and survival after diagnosis. However, the role of loss of IFN-γ or IFNγR function in the pathogenesis of CRC remains unclear. Here, we investigated the role of endogenous IFN-γ deficiency in adenomatous polyposis coli (Apc)-mediated intestinal tumor by developing a variant of Apc(Min/+) mice. The Apc(Min/+)IFN-γ(+/-) mice presented with increased number and size of adenomas, and 41.7% of these mice developed adenocarcinoma. Molecular analyses of the adenomas suggested that heterozygous deletion of IFN-γ promoted EGFR/Erk1/2 and Wnt/β-catenin signaling. In vitro, IFN-γ administration inhibited Apc-mutated HT-29 colon cancer cell proliferation and had no effect on the proliferation of HCT-116 colon cancer cells that express wild-type Apc. Besides, we challenged HT-29 cells with small interfering RNA targeting one of its receptor subunits IFNγR1. We found that knockdown of IFNγR1 in HT-29 cells stimulated cell proliferation and colony formation, which was also related to the regulation of EGFR/Erk1/2 and Wnt/β-catenin signaling. Thus, our results strongly support the notion that IFN-γ and IFNγR1 act as a rate-limiting factor in the development of CRC, uncovering a novel role for them in cancer biology.

  20. Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-{gamma} activation

    SciTech Connect

    Moriuchi, Akie ||. E-mail: f1195@cc.nagasaki-u-ac.jp; Shimamura, Mika; Kita, Atsushi; Kuwahara, Hironaga; Satoh, Tsuyoshi; Satoh, Tsuyoshi; Fujishima, Keiichiro; Fukushima, Keiko |; Hayakawa, Takao; Mizuguchi, Hiroyuki; Nagayama, Yuji; Kawasaki, Eiji

    2007-05-18

    Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-{gamma}, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR-{gamma}.

  1. Gamma scintillator system using boron carbide for neutron detection

    NASA Astrophysics Data System (ADS)

    Ben-Galim, Y.; Wengrowicz, U.; Raveh, A.; Orion, I.

    2014-08-01

    A new approach for neutron detection enhancement to scintillator gamma-ray detectors is suggested. By using a scintillator coupled with a boron carbide (B4C) disc, the 478 keV gamma-photon emitted from the excited Li in 94% of the 10B(n,α)7Li interactions was detected. This suggests that the performance of existing gamma detection systems in Homeland security applications can be improved. In this study, a B4C disc (2 in. diameter, 0.125 in. thick) with ~19.8% 10B was used and coupled with a scintillator gamma-ray detector. In addition, the neutron thermalization moderator was studied in order to be able to increase the neutron sensitivity. An improvement in the detector which is easy to assemble, affordable and efficient was demonstrated. Furthermore, a tailored Monte-Carlo code written in MATLAB was developed for validation of the proposed application through efficiency estimation for thermal neutrons. Validation of the code was accomplished by showing that the MATLAB code results were well correlated to a Monte-Carlo MCNP code results. The measured efficiency of the assembled experimental model was observed to be in agreement with both models calculations.

  2. Letter: Iatrogenic lipomatosis: a rare manifestation of treatment with a peroxisome proliferator-activated receptor gamma agonist.

    PubMed

    Femia, Alisa; Klein, Peter A

    2010-04-15

    Lipomas are common benign neoplasms of adipose tissue. Lipomatosis, the progressive appearance of multiple lipomas, is most often associated with specific congenital, familial, or idiopathic syndromes. In one reported case, the development of multiple lipomas occurred as a result of treatment with rosiglitazone, a peroxisome proliferator-activated receptor (PPAR) gamma agonist. We report a second case of lipomatosis occurring as a result of treatment with a PPAR gamma agonist. This case occurred in a 77-year-old woman who developed multiple lipomas two years after beginning treatment with pioglitazone, a PPAR gamma agonist. Histopathologic examination confirmed these lesions to be lipomas. Within four weeks of discontinuation of pioglitazone, regression of the lipomas began. We describe a case of PPAR agonist-induced lipoma formation, review relevant literature, and provide a molecular mechanism for this side effect.

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

    SciTech Connect

    Einstein, Monica; Akiyama, Taro E.; Castriota, Gino A.; Wang, Chuanlin F.; McKeever, Brian; Mosley, Ralph T.; Becker, Joseph W.; Moller, David E.; Meinke, Peter T.; Wood, Harold B.; Berger, Joel P.

    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 signature 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  5. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma.

    PubMed Central

    De Vos, P; Lefebvre, A M; Miller, S G; Guerre-Millo, M; Wong, K; Saladin, R; Hamann, L G; Staels, B; Briggs, M R; Auwerx, J

    1996-01-01

    The ob gene product, leptin, is a signaling factor regulating body weight and energy balance. ob gene expression in rodents is increased in obesity and is regulated by feeding patterns and hormones, such as insulin and glucocorticoids. In humans with gross obesity, ob mRNA levels are higher, but other modulators of human ob expression are unknown. In view of the importance of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipocyte differentiation, we analyzed whether ob gene expression is subject to regulation by factors activating PPARs. Treatment of rats with the PPARalpha activator fenofibrate did not change adipose tissue and body weight and had no significant effect on ob mRNA levels. However, administration of the thiazolidinedione BRL49653, a PPARgamma ligand, increased food intake and adipose tissue weight while reducing ob mRNA levels in rats in a dose-dependent manner. The inhibitory action of the thiazolidinedione BRL49653 on ob mRNA levels was also observed in vitro. Thiazolidinediones reduced the expression of the human ob promoter in primary adipocytes, however, in undifferentiated 3T3-L1 preadipocytes lacking endogenous PPARgamma, cotransfection of PPARgamma was required to observe the decrease. In conclusion, these data suggest that PPARgamma activators reduce ob mRNA levels through an effect of PPARgamma on the ob promoter. PMID:8770873

  6. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma.

    PubMed

    De Vos, P; Lefebvre, A M; Miller, S G; Guerre-Millo, M; Wong, K; Saladin, R; Hamann, L G; Staels, B; Briggs, M R; Auwerx, J

    1996-08-15

    The ob gene product, leptin, is a signaling factor regulating body weight and energy balance. ob gene expression in rodents is increased in obesity and is regulated by feeding patterns and hormones, such as insulin and glucocorticoids. In humans with gross obesity, ob mRNA levels are higher, but other modulators of human ob expression are unknown. In view of the importance of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipocyte differentiation, we analyzed whether ob gene expression is subject to regulation by factors activating PPARs. Treatment of rats with the PPARalpha activator fenofibrate did not change adipose tissue and body weight and had no significant effect on ob mRNA levels. However, administration of the thiazolidinedione BRL49653, a PPARgamma ligand, increased food intake and adipose tissue weight while reducing ob mRNA levels in rats in a dose-dependent manner. The inhibitory action of the thiazolidinedione BRL49653 on ob mRNA levels was also observed in vitro. Thiazolidinediones reduced the expression of the human ob promoter in primary adipocytes, however, in undifferentiated 3T3-L1 preadipocytes lacking endogenous PPARgamma, cotransfection of PPARgamma was required to observe the decrease. In conclusion, these data suggest that PPARgamma activators reduce ob mRNA levels through an effect of PPARgamma on the ob promoter.

  7. Interferon-gamma receptor 1 promoter polymorphisms: population distribution and functional implications.

    PubMed

    Rosenzweig, Sergio D; Schäffer, Alejandro A; Ding, Li; Sullivan, Rachel; Enyedi, Balasz; Yim, Jae-Joon; Cook, James L; Musser, James M; Holland, Steven M

    2004-07-01

    Different polymorphisms have been described in the minimal promoter region (MPR) of the interferon-gamma receptor 1 (IFNGR1), a molecule that plays a critical role in mycobacterial control. We sequenced the IFNGR1 MPR from African American, Caucasian and Korean controls, and from mycobacteria-infected patients. Six different single nucleotide polymorphisms (SNPs) were detected in the IFNGR1 MPR. The three ethnic groups showed different SNP distribution patterns, but no significant differences were detected between mycobacterial cases and controls. Two polymorphisms were found in all populations (G-611A, T-56C). We cloned the four allelic variants (var) of haplotype G-611A/T-56C into a luciferase reporter vector and determined their promoter activity. Polymorphisms at position -611 had a stronger effect on the promoter activity than those at position -56, and constructs carrying G-611 produced a stronger promoter activity than -611A constructs. The IFNGR1 MPR is a polymorphic region with at least two SNPs influencing its activity, but these are not associated with increased mycobacterial susceptibility.

  8. Estrogen-related receptor gamma and hearing function: evidence of a role in humans and mice

    PubMed Central

    Nolan, Lisa S.; Maier, Hannes; Hermans-Borgmeyer, Irm; Girotto, Giorgia; Ecob, Russell; Pirastu, Nicola; Cadge, Barbara A.; Hübner, Christian; Gasparini, Paolo; Strachan, David P.; Davis, Adrian; Dawson, Sally J.

    2013-01-01

    Since estrogen is thought to protect pre-menopausal women from age-related hearing loss, we investigated whether variation in estrogen-signalling genes is linked to hearing status in the 1958 British Birth Cohort. This analysis implicated the estrogen-related receptor gamma (ESRRG) gene in determining adult hearing function and was investigated further in a total of 6134 individuals in 3 independent cohorts: (i) the 1958 British Birth Cohort; (ii) a London ARHL case-control cohort; and (iii) a cohort from isolated populations of Italy and Silk Road countries. Evidence of an association between the minor allele of single nucleotide polymorphism (SNP) rs2818964 and hearing status was found in females, but not in males in 2 of these cohorts: p = 0.0058 (London ARHL) and p = 0.0065 (Carlantino, Italy). Furthermore, assessment of hearing in Esrrg knock-out mice revealed a mild 25-dB hearing loss at 5 weeks of age. At 12 weeks, average hearing thresholds in female mice(-/-) were 15 dB worse than in males(-/-). Together these data indicate ESRRG plays a role in maintenance of hearing in both humans and mice. PMID:23540940

  9. Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor {gamma}, controls hepatitis B virus replication

    SciTech Connect

    Yoon, Sarah; Jung, Jaesung; Kim, Taeyeung; Park, Sun; Chwae, Yong-Joon; Shin, Ho-Joon; Kim, Kyongmin

    2011-01-20

    In this study, HepG2-hepatitis B virus (HBV)-stable cells that did not overexpress HBx and HBx-deficient mutant-transfected cells were analyzed for their expression of HBV-induced, upregulated adipogenic and lipogenic genes. The mRNAs of CCAAT enhancer binding protein {alpha} (C/EBP{alpha}), peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), adiponectin, liver X receptor {alpha} (LXR{alpha}), sterol regulatory element binding protein 1c (SREBP1c), and fatty acid synthase (FAS) were expressed at higher levels in HepG2-HBV and lamivudine-treated stable cells and HBx-deficient mutant-transfected cells than in the HepG2 cells. Lamivudine treatment reduced the mRNA levels of PPAR{gamma} and C/EBP{alpha}. Conversely, HBV replication was upregulated by adiponectin and PPAR{gamma} agonist rosiglitazone treatments and was downregulated by adiponectin siRNAs. Collectively, our results demonstrate that HBV replication and/or protein expression, even in the absence of HBx, upregulated adipogenic or lipogenic genes, and that the control of adiponectin might prove useful as a therapeutic modality for the treatment of chronic hepatitis B.

  10. Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells.

    PubMed

    Desch, Michael; Schreiber, Andrea; Schweda, Frank; Madsen, Kirsten; Friis, Ulla G; Weatherford, Eric T; Sigmund, Curt D; Sequeira Lopez, Maria Luisa; Gomez, R Ariel; Todorov, Vladimir T

    2010-03-01

    We recently found that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome proliferator-activated receptor (PPAR)gamma stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARgamma. The mouse renin gene is regulated by PPARgamma through a distal enhancer direct repeat closely related to consensus PPAR response element (PPRE). In vitro studies demonstrated that PPARgamma knockdown stimulated PPRE-driven transcription. These data predicted that deficiency of PPARgamma would upregulate mouse renin expression. Consistent with these observations knockdown of PPARgamma increased the transcription of a reporter gene driven by the mouse renin PPRE-like motif in vitro. To study the impact of PPARgamma on renin production in vivo, we used a cre/lox system to generate double-transgenic mice with disrupted PPARgamma locus in renin-producing juxtaglomerular (JG) cells of the kidney (RC-PPARgamma(fl/fl) mice). We provide evidence that PPARgamma expression was effectively reduced in JG cells of RC-PPARgamma(fl/fl) mice. Fluorescent immunohistochemistry showed stronger renin signal in RC-PPARgamma(fl/fl) than in littermate control RC-PPARgamma(wt/wt) mice. Renin mRNA levels and plasma renin concentration in RC-PPARgamma(fl/fl) mice were almost 2-fold higher than in littermate controls. Arterial blood pressure and pressure control of renal vascular resistance, which play decisive roles in the regulation of renin production were indistinguishable between RC-PPARgamma(wt/wt) and RC-PPARgamma(fl/fl) mice. These data demonstrate that the JG-specific PPARgamma deficiency results in increased mouse renin expression in vivo thus corroborating earlier in vitro results. PPARgamma appears to be a relevant transcription factor for the control of renin gene in JG cells.

  11. Molecular characterization, transcriptional activity and nutritional regulation of peroxisome proliferator activated receptor gamma in Nile tilapia (Oreochromis niloticus).

    PubMed

    He, An-Yuan; Liu, Cai-Zhi; Chen, Li-Qiao; Ning, Li-Jun; Qin, Jian-Guang; Li, Jia-Ming; Zhang, Mei-Ling; Du, Zhen-Yu

    2015-11-01

    Peroxisome proliferator activated receptor gamma (PPARγ) is a master regulator in lipid metabolism and widely exists in vertebrates. However, the molecular structure and transcriptional activity of PPARγ in fish are still unclear. This study cloned PPARγ from Nile tilapia (Oreochromis niloticus) referred as NtPPARγ and transfected the NtPPARγ plasmids into HEK-293 cells to explore its mechanism of transcriptional regulation in fish. The expression of NtPPARγ was compared in fed and fasted fish. Two transcripts of NtPPARγ varied at the 5'-untranslated region and the DNA binding domain was highly conserved. Thirty-nine amino acid residues in the ligand binding domain in Nile tilapia were different from those in human. Two transcripts showed different expression profiles in 11 tissues, but both were highly expressed in liver, intestine and kidney. The transcriptional activity assay showed that NtPPARγ collaborates with retinoid X-receptor α (NtRXRα) to regulate the expression of Nile tilapia fatty acid binding protein 4 (FABP4), the compartment of which have been identified as the target gene of PPARγ in human. In the fish fasting trial, the mRNA expression of NtPPARγ1 and NtPPARγ2 in intestine and liver at 3h post-feeding (HPF) was lower than those at 8 HPF, 24 HPF and in fish fasted for 36h, but was relatively stable in kidney among different feeding treatments. In conclusion, the DNA binding domain in PPARγ was highly conserved, while the ligand binding domain was moderately conserved. In Nile tilapia, the PPARγ collaborates with RXRα to perform transcriptional regulation of FABP4 at least in vitro. The plasmid system established in this study along with a cell line from Nile tilapia will be useful tools for the further functional study of PPARγ in fish.

  12. Molecular characterization, transcriptional activity and nutritional regulation of peroxisome proliferator activated receptor gamma in Nile tilapia (Oreochromis niloticus).

    PubMed

    He, An-Yuan; Liu, Cai-Zhi; Chen, Li-Qiao; Ning, Li-Jun; Qin, Jian-Guang; Li, Jia-Ming; Zhang, Mei-Ling; Du, Zhen-Yu

    2015-11-01

    Peroxisome proliferator activated receptor gamma (PPARγ) is a master regulator in lipid metabolism and widely exists in vertebrates. However, the molecular structure and transcriptional activity of PPARγ in fish are still unclear. This study cloned PPARγ from Nile tilapia (Oreochromis niloticus) referred as NtPPARγ and transfected the NtPPARγ plasmids into HEK-293 cells to explore its mechanism of transcriptional regulation in fish. The expression of NtPPARγ was compared in fed and fasted fish. Two transcripts of NtPPARγ varied at the 5'-untranslated region and the DNA binding domain was highly conserved. Thirty-nine amino acid residues in the ligand binding domain in Nile tilapia were different from those in human. Two transcripts showed different expression profiles in 11 tissues, but both were highly expressed in liver, intestine and kidney. The transcriptional activity assay showed that NtPPARγ collaborates with retinoid X-receptor α (NtRXRα) to regulate the expression of Nile tilapia fatty acid binding protein 4 (FABP4), the compartment of which have been identified as the target gene of PPARγ in human. In the fish fasting trial, the mRNA expression of NtPPARγ1 and NtPPARγ2 in intestine and liver at 3h post-feeding (HPF) was lower than those at 8 HPF, 24 HPF and in fish fasted for 36h, but was relatively stable in kidney among different feeding treatments. In conclusion, the DNA binding domain in PPARγ was highly conserved, while the ligand binding domain was moderately conserved. In Nile tilapia, the PPARγ collaborates with RXRα to perform transcriptional regulation of FABP4 at least in vitro. The plasmid system established in this study along with a cell line from Nile tilapia will be useful tools for the further functional study of PPARγ in fish. PMID:26002036

  13. A novel, rapid, inhibitory effect of insulin on alpha1beta2gamma2s gamma-aminobutyric acid type A receptors.

    PubMed

    Williams, Daniel B

    2008-09-26

    In the CNS, GABA and insulin seem to contribute to similar processes, including neuronal survival; learning and reward; and energy balance and food intake. It is likely then that insulin and GABA may interact, perhaps at the GABA(A) receptor. One such interaction has already been described [Q. Wan, Z.G. Xiong, H.Y. Man, C.A. Ackerley, J. Braunton, W.Y. Lu, L.E. Becker, J.F. MacDonald, Y.T. Wang, Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin, Nature 388 (1997) 686-690]; in it a micromolar concentration of insulin causes the insertion of GABA(A) receptors into the cell membrane, increasing GABA current. I have discovered another effect of insulin on GABA(A) currents. Using a receptor isoform, alpha(1)beta(2)gamma(2s) that is the likely main neuronal GABA(A) isoform expressed recombinantly in Xenopus oocytes, insulin inhibits GABA-induced current when applied simultaneously with low concentrations of GABA. Insulin will significantly inhibit currents induced by EC(30-50) concentrations of GABA by about 38%. Insulin is potent in this effect; IC(50) of insulin was found to be about 4.3 x 10(-10) M. The insulin effect on the GABA dose responses looked like that of an antagonist similar to bicuculline or beta-carbolines. However, an effect of phosphorylation on the GABA(A) receptor from the insulin receptor signal transduction pathway cannot yet be dismissed.

  14. Structure of the T-cell receptor in a Ti alpha beta, Ti gamma delta double positive T-cell line.

    PubMed

    Kuhlmann, J; Geisler, C

    1993-02-01

    The multichain T-cell receptor is composed of at least six different polypeptide chains. The clonotypic Ti heterodimer (Ti alpha beta or Ti gamma delta) is non-covalently associated with the CD3 chains (CD3 gamma delta epsilon zeta). The exact number of subunits constituting the T-cell receptor is still not known. It has been suggested that each T-cell receptor contains two Ti dimers. To gain insight into the structure of the T-cell receptor we constructed a Ti alpha beta, Ti gamma delta double positive T-cell line which contained four functional Ti chains (Ti alpha, beta, gamma, and delta). The data demonstrated an absence of Ti dimers containing mixtures of chains other than the typical Ti alpha beta and Ti gamma delta combinations. Furthermore, by co-modulation experiments we demonstrated that the Ti alpha beta and the Ti gamma delta dimers were not expressed in the same T-cell receptor. Our data indicate that the T-cell receptor does not contain two Ti dimers.

  15. T-cell receptor gamma/delta expressing acute leukemia emerging from sideroblastic anemia: morphological, immunological, and cytogenetic features.

    PubMed

    Meckenstock, G; Fonatsch, C; Heyll, A; Schneider, E M; Kögler, G; Söhngen, D; Aul, C; Schneider, W

    1992-01-01

    Striking numerical and structural chromosome abnormalities (-Y, +8, i(7q), del (10)(q24), and del (11)(q21)) were detected by cytogenetic analysis in a patient's bone marrow with morphological features of both acute lymphoblastic leukemia and myelodysplastic disorder. Surface marker analysis characterized blast cells to be CD2+ CD7+ CD3+ CD4- CD8- expressing gamma/delta-T-cell receptor antigen and coexpressing CD11b and CD16. Exhibiting an identical phenotype as the leukemic cells, a prominent gamma/delta-TCR+ lymphocyte population was found in the bone marrow as well as in the peripheral blood. Cells of the latter compartment coexpressed CD56 and HLA-DR antigens and exhibited nonspecific cytotoxic activity. In the bone marrow cells NSCA could be induced after stimulation with interleukin 2 in vitro. Morphological, immunological, and cytogenetic findings suggest that gamma/delta-T-ALL emerged from a myelodysplastic disorder after sequential steps of malignant transformation. Leukemic cells with "mixed lineage" character may provide evidence for a common progenitor cell in the bone marrow. Assuming that the leukemic cells represent the malignant counterpart of normal CD3+ gamma/delta-TCR+ cells the results may contribute to our understanding of the origin and differentiation as well as the possible steps of malignant transformation of a gamma/delta-TCR+ lymphocyte population.

  16. Functional co-localization of monocytic aminopeptidase N/CD13 with the Fc{gamma} receptors CD32 and CD64

    SciTech Connect

    Riemann, Dagmar; Wulfaenger, Jens

    2005-06-17

    Information about the function of aminopeptidase N/CD13 on monocytes is limited. In order to gain more insight into its interaction with other proteins, we have identified molecules that co-localize with the membrane ectoenzyme at the cell surface of monocytes. Using laser scanning and electron microscopy as well as fluorescence resonance energy transfer (FRET) measured by flow cytometry we show that monocytic CD13 co-localized with the Fc{gamma} receptor II/CD32 after Fc receptor ligation by a CD32-specific antibody. FRET was also observed between CD13 and the Fc{gamma} receptor I/CD64, but not with the myeloid marker CD33 representing a member of the sialoadhesin family. Our results imply a novel functional role of CD13 and Fc{gamma} receptors as members of a multimeric receptor complex. Further studies have to be done to elucidate common signaling pathways of these molecules.

  17. Dual action of isoflurane on the gamma-aminobutyric acid (GABA)-mediated currents through recombinant alpha(1)beta(2)gamma(2L)-GABA(A)-receptor channels.

    PubMed

    Neumahr, S; Hapfelmeier, G; Scheller, M; Schneck, H; Franke, C; Kochs, E

    2000-05-01

    Isoflurane (ISO) increased the agonist-induced chloride flux through the gamma-aminobutyric acid A receptor (GABA(A)R). This may reflect an anesthetic-induced increase in the apparent agonist affinity. A dual effect of anesthetics was postulated for both the nicotinic acetylcholine receptor (nAChR) and the GABA(A)R. We tested the hypothesis that, in addition to a blocking effect, ISO increases gamma-aminobutyric acid (GABA)-gated currents through recombinant GABA(A)R channels. HEK293 cells were transfected with rat cDNA for alpha(1),beta(2),gamma(2L) subunits. Currents elicited by 1 mM or 0. 01 mM GABA, respectively, alone, or with increasing concentrations of ISO, were recorded by using standard patch clamp techniques. ISO reduced the peak current elicited by 1 mM GABA. Currents induced by 0.01 mM GABA were potentiated by small ISO (twofold at 0.5 mM ISO) and inhibited by larger concentrations. Withdrawal of ISO and GABA induced rebound currents, suggesting an open-channel block by ISO. These currents increased with increasing concentrations of ISO. At large concentrations of ISO, the inhibitory effect predominated and was caused by, at least partly, an open-channel block. At small concentrations of ISO, potentiation of the GABA-gated currents was more prominent. This dual action of ISO indicates different binding sites at the GABA(A)R. The balance between potentiation and block depends on the concentrations of both ISO and GABA.

  18. 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.

  19. 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.

  20. Effect of extracellular pH on recombinant alpha1beta2gamma2 and alpha1beta2 GABAA receptors.

    PubMed

    Mercik, Katarzyna; Pytel, Maria; Cherubini, Enrico; Mozrzymas, Jerzy W

    2006-08-01

    Recently, we have reported that extracellular protons allosterically modulated neuronal GABA(A) receptors [Mozrzymas, J.W., Zarnowska, E.D., Pytel, M., Mercik, K., 2003a. Modulation of GABA(A) receptors by hydrogen ions reveals synaptic GABA transient and a crucial role of desensitiztion process. Journal of Neuroscience 23, 7981-7992]. However, GABAARs in neurons are heterogeneous and the effect of hydrogen ions depends on the receptor subtype. In particular, gamma2 subunit sets the receptor sensibility to several modulators including protons. However, the mechanisms whereby protons modulate gamma2-containing and gamma2-free GABAARs have not been fully elucidated. To this end, current responses to ultrafast GABA applications were recorded for alpha1beta2gamma2 and alpha1beta2 receptors at different pH values. For both receptor types, increase in pH induced a decrease in amplitudes of currents elicited by saturating [GABA] but this effect was stronger for alpha1beta2 receptors. In the case of alpha1beta2gamma2 receptors, protons strongly affected the current time course due to a down regulation of binding and desensitization rates. This effect was qualitatively similar to that described in neurons. Protons strongly influenced the amplitude of alpha1beta2 receptor-mediated currents but the effect on their kinetics was weak suggesting a predominant direct non-competitive inhibition with a minor allosteric modulation. In conclusion, we provide evidence that extracellular protons strongly affect GABAA receptors and that, depending on the presence of the gamma2 subunit, the modulatory mechanisms show profound quantitative and qualitative differences.

  1. Peroxisome proliferator-activated receptor gamma (PPARG) polymorphisms and breast cancer susceptibility: a meta-analysis

    PubMed Central

    Tang, Weifeng; Chen, Yuanmei; Wang, Yafeng; Gu, Haiyong; Chen, Shuchen; Kang, Mingqiang

    2015-01-01

    Background: Peroxisome proliferator-activated receptor gamma (PPARG), a nuclear hormone receptor, plays a critical role in the lipid and glucose homeostasis, adipocyte differentiation, as well as intracellular insulin-signaling events. Several studies have been conducted to explore the associations of PPARG polymorphisms with breast cancer (BC), yet the findings are inconsistent. Methods: Databases of Pubmed and Embase were searched until October 5, 2014. The association between PPARG polymorphisms and BC risk was determined by crude odds ratios (ORs) with their 95% confidence intervals (CIs). Results: Finally, there are nine publications involving 3,931 BC cases and 5,382 controls included in this meta-analysis. No significant association was observed between PPARG rs1801282 C>G variants and overall BC risk in all genetic comparison models. However, in a subgroup analysis by ethnicity, significant association was observed between PPARG rs1801282 C>G variants and decreased BC risk in three genetic models: GG+CG vs. CC (OR, 0.83; 95% CI, 0.71-0.96; P = 0.011), CG vs. CC (OR, 0.82; 95% CI, 0.71-0.96; P = 0.011) and G vs. C (OR, 0.85; 95% CI, 0.75-0.97; P = 0.016) in Caucasians and in a subgroup analysis by menopausal status, significantly decreased BC risk was also found in two genetic models: GG+CG vs. CC (OR, 0.79; 95% CI, 0.67-0.95; P = 0.011) and CG vs. CC (OR, 0.77; 95% CI, 0.64-0.92; P = 0.005) in post-menopause subgroup. For PPARG rs3856806 C>T, we found no significant association between PPARG rs3856806 C>T polymorphism and breast cancer. Conclusions: In summary, despite some limitations, the results suggest that PPARG rs1801282 C>G polymorphism may be a protective factor for BC in Caucasians and in post-menopause women. PMID:26550133

  2. Fc gamma receptor type III (CD16) is included in the zeta NK receptor complex expressed by human natural killer cells.

    PubMed Central

    Anderson, P; Caligiuri, M; O'Brien, C; Manley, T; Ritz, J; Schlossman, S F

    1990-01-01

    We recently reported that CD3- natural killer (NK) cells express the zeta chain of the T-cell receptor complex (zeta NK) in association with higher molecular weight structures whose expression differs between individual NK cell clones. Because NK cell cytolytic activity is known to be triggered by perturbation of the type III Fc gamma receptor (CD16), we sought to determine whether this activating molecule is included in the zeta NK molecular complex. Biochemical evidence for a physical association between CD16 and zeta NK was obtained by comparing immunoprecipitates formed using monoclonal antibodies reactive with each of these molecules by SDS/polyacrylamide gel electrophoresis, immunoblotting, and peptide mapping. In both clonal and polyclonal populations of CD3- NK cells, CD16 and zeta NK specifically associated with one another. Functional evidence for a specific association between CD16 and zeta NK in intact cells was obtained by demonstrating a coordinate down-modulation of both of these molecules induced by either phorbol 12-myristate 13-acetate or monoclonal antibodies reactive with CD16. Our results suggest that Fc gamma receptor type III (CD16) is included in the zeta NK complex and that this complex is likely to play an important role in NK cell activation. Images PMID:2138330

  3. Role of Fc Gamma Receptors in Triggering Host Cell Activation and Cytokine Release by Borrelia burgdorferi

    PubMed Central

    Talkington, Jeffrey; Nickell, Steven P.

    2001-01-01

    Borrelia burgdorferi, the spirochetal bacterium that causes human Lyme disease, encodes numerous lipoproteins which have the capacity to trigger the release of proinflammatory cytokines from a variety of host cell types, and it is generally believed that these cytokines contribute to the disease process in vivo. We previously reported that low-passage-number infectious B. burgdorferi spirochetes express a novel lipidation-independent activity which induces secretion of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) by the mouse MC/9 mast cell line. Using RNase protection assays, we determined that mast cells exposed in vitro to low-passage-number, but not high-passage-number, B. burgdorferi spirochetes show increased expression of additional mRNAs representing several chemokines, including macrophage-inflammatory protein 1α (MIP-1α), MIP-1β, and TCA3, as well as the proinflammatory cytokine interleukin-6. Furthermore, mast cell TNF-α secretion can be inhibited by the phosphatidylinositol 3-kinase inhibitor wortmannin and also by preincubation with purified mouse immunoglobulin G1 (IgG1) and IgG2a, but not mouse IgG3, and by a mouse Fc gamma receptor II and III (FcγRII/III)-specific rat monoclonal antibody, suggesting the likely involvement of host FcγRIII in B. burgdorferi-mediated signaling. A role for passively adsorbed rabbit or bovine IgG or serum components in B. burgdorferi-mediated FcγR signaling was excluded in control experiments. These studies confirm that low-passage-number B. burgdorferi spirochetes express a novel activity which upregulates the expression of a variety of host cell chemokine and cytokine genes, and they also establish a novel antibody-independent role for FcγRs in transduction of activation signals by bacterial products. PMID:11119532

  4. T cell receptor junctional regions of V gamma 9+/V delta 2+ T cell clones in relation to non-MHC restricted cytotoxic activity.

    PubMed

    Flanagan, B F; Wheatcroft, N J; Thornton, S M; Christmas, S E

    1993-05-01

    Human gamma delta T cell clones having V gamma 9JP and V delta 2DJ1 T cell receptor (TCR) gene rearrangements were isolated form an individual donor and tested for non-MHC restricted cytotoxicity against the B lymphoblastoid cell line, BSM. Most clones were highly cytotoxic but 3/9 clones had very low activity, comparable to that of CD4+ alpha beta T cell clones. Although there was a tendency for clones with low cytotoxic function to produce high levels of interferon-gamma and tumor necrosis factor-alpha, this correlation was not complete. TCR gamma and delta junctional sequences were obtained and were found to be different for all clones. There were no consistent structural differences between gamma delta TCRs of cytotoxic and non-cytotoxic clones, but gamma or delta junctional regions of all three non-cytotoxic clones had unusual features. One clone had a particularly short gamma chain junctional sequence, one had a short delta chain junctional sequence and the third clone was the only one of the panel which failed to utilise the D delta 3 segment. If the gamma delta TCR is involved in target cell recognition in this model of non-MHC restricted killing, such variations in receptor structure may be sufficient to inhibit recognition and thereby reduce the cytotoxic capacity of a minority of V gamma 9+/V delta 2+ clones. Also, a panel of gamma delta T cell clones expressing V gamma 8/V delta 3 isolated from a different donor, were all highly cytotoxic against BSM, indicating that these target cells can be recognised by effector cells expressing a TCR other than the V gamma 9/V delta 2 receptor. The possible influence of other cell surface molecules on non-MHC restricted cytotoxic function is discussed.

  5. Estrogen-related receptor gamma regulates dopaminergic neuronal phenotype by activating GSK3β/NFAT signaling in SH-SY5Y cells.

    PubMed

    Lim, Juhee; Choi, Hueng-Sik; Choi, Hyun Jin

    2015-05-01

    The orphan nuclear receptor estrogen-related receptor gamma (ERRγ) is highly expressed in the nervous system during embryogenesis and in adult brains, but its physiological role in neuronal development remains unknown. In this study, we evaluated the relevance of ERRγ in regulating dopaminergic (DAergic) phenotype and the corresponding signaling pathway. We used retinoic acid (RA) to differentiate human neuroblastoma SH-SY5Y cells. RA induced neurite outgrowth of SH-SY5Y cells with an increase in DAergic neuron-like properties, including up-regulation of tyrosine hydroxylase, dopamine transporter, and vesicular monoamine transporter 2. ERRγ, but not ERRα, was up-regulated by RA, and participated in RA effect on SH-SY5Y cells. ERRγ over-expression enhanced mature DAergic neuronal phenotype with neurite outgrowth as with RA treatment; and RA-induced increase in DAergic phenotype was attenuated by silencing ERRγ expression. ERRγ appears to have a crucial role in morphological and functional regulation of cells that is selective for DAergic neurons. Polo-like kinase 2 was up-regulated in ERRγ-over-expressing SH-SY5Y cells, which was involved in phosphorylation of glycogen synthase kinase 3β and resulting downstream activation of nuclear factor of activated T cells. The likely involvement of ERRγ in regulating the DAergic neuronal phenotype makes this orphan nuclear receptor a novel target for understanding DAergic neuronal differentiation. We propose the relevance of estrogen-related receptor gamma (ERRγ) in regulating dopaminergic neuronal phenotype: ERRγ is up-regulated by retinoic acid in SH-SY5Y cells, and enhances dopaminergic phenotypes and induces neurite outgrowth; Polo-like kinase 2 (PLK2) and glycogen synthase kinase 3 beta/nuclear factor of activated T cells (GSK3β/NFAT) signaling are responsible for the ERRγ effect. Our findings provide the first insights into the role of ERRγ in the brain, as a novel approach toward understanding

  6. 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....

  7. 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....

  8. Cloning of the. gamma. -aminobutyric acid (GABA). rho. sub 1 cDNA: A GABA receptor subunit highly expressed in the retina

    SciTech Connect

    Cutting, G.R.; Lu, Luo; Kasch, L.M.; Montrose-Rafizadeh, C.; Antonarakis, S.E.; Guggino, W.B.; Kazazian, H.H. Jr. ); O'Hara, B.F.; Donovan, D.M.; Shimada, Shoichi ); Uhl, G.R. Johns Hopkins Univ. School of Medicine, Baltimore, MD )

    1991-04-01

    Type A {gamma}-aminobutyric acid (GABA{sub A}) receptors are a family of ligand-gated chloride channels that are the major inhibitory neurotransmitter receptors in the nervous system. Molecular cloning has revealed diversity in the subunits that compose this heterooligomeric receptor, but each previously elucidated subunit displays amino acid similarity in conserved structural elements. The authors have used these highly conserved regions to identify additional members of this family by using the polymerase chain reaction (PCR). One PCR product was used to isolate a full-length cDNA from a human retina cDNA library. The mature protein predicted from this cDNA sequence is 458 amino acids long and displays between 30 and 38% amino acid similarity to the previously identified GABA{sub A} subunits. This gene is expressed primarily in the retina but transcripts are also detected in the brain, lung, and thymus. Injection of Xenopus oocytes with RNA transcribed in vitro produces a GABA-responsive chloride conductance and expression of the cDNA in COS cells yields GABA-displaceable muscimol binding. These features are consistent with our identification of a GABA subunit, GABA {rho}{sub 1}, with prominent retinal expression that increases the diversity and tissue specificity of this ligand-gated ion-channel receptor family.

  9. Laser System for Livermore's Mono Energetic Gamma-Ray Source

    SciTech Connect

    Gibson, D; Albert, F; Bayramian, A; Marsh, R; Messerly, M; Ebbers, C; Hartemann, F

    2011-03-14

    A Mono-energetic Gamma-ray (MEGa-ray) source, based on Compton scattering of a high-intensity laser beam off a highly relativistic electron beam, requires highly specialized laser systems. To minimize the bandwidth of the {gamma}-ray beam, the scattering laser must have minimal bandwidth, but also match the electron beam depth of focus in length. This requires a {approx}1 J, 10 ps, fourier-transform-limited laser system. Also required is a high-brightness electron beam, best provided by a photoinjector. This electron source requires a second laser system with stringent requirements on the beam including flat transverse and longitudinal profiles and fast rise times. Furthermore, these systems must be synchronized to each other with ps-scale accuracy. Using a novel hyper-dispersion compressor configuration and advanced fiber amplifiers and diode-pumped Nd:YAG amplifiers, we have designed laser systems that meet these challenges for the X-band photoinjector and Compton-scattering source being built at Lawrence Livermore National Laboratory.

  10. Gamma-quanta onboard identification in the GAMMA-400 experiment using the counting and triggers signals formation system.

    NASA Astrophysics Data System (ADS)

    Arkhangelskaja, I. V.; Arkhangelskiy, A. I.; Chasovikov, E. N.; Galper, A. M.; Kheymits, M. D.; Murchenko, A. E.; Yurkin, Y. T.

    2016-02-01

    GAMMA-400 (Gamma Astronomical Multifunctional Modular Apparatus) will be the new generation satellite gamma-observatory. Gamma-telescope GAMMA-400 consists of anticoincidence system (top and lateral sections - ACtop and AClat), the converter-tracker (C), time-of-flight system (2 sections S1 and S2), position-sensitive calorimeter CC1 makes of 2 strips layers and 2 layers of CsI(Tl) detectors, electromagnetic calorimeter CC2 composed of CsI(Tl) crystals, neutron detector ND, scintillation detectors of the calorimeter (S3 and S4) and lateral detectors of the calorimeter (LD). All detector systems ACtop, AClat, S1-S4, LD consist of two BC-408 based sensitive layers of 1 cm thickness each. Three apertures provide events registration both from upper and lateral directions. The main aperture provides the best angular (all strip layers information analysis) and energy (energy deposition in the all detectors studying) resolution. Gamma-telescope GAMMA-400 is optimized for the gamma-quanta and charged particles with energy 100 GeV detection with the best parameters in the main aperture. 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 both layers anticoincidence systems ACtop and AClat individual detectors. For double-layer ACtop taking into account both amplitude and temporal trigger marker onboard analysis only 2.8% photons will be wrongly recognized as electrons or protons for 100 GeV particles. The part of charged particles mistakenly identified as gammas is ∼10-5 using described algorithms. For E∼3 GeV less than 3% photons will be wrongly recognized as charged particles and fraction of wrongly identified charged particles will be also ∼10-5. In the additional aperture the particles identification is provided by analysis of signals corresponding to energy deposition in the

  11. Minimum Detectable Activity for Tomographic Gamma Scanning System

    SciTech Connect

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

    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 Tomographic 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 activities

  12. Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma.

    PubMed Central

    Byrd, T F; Horwitz, M A

    1993-01-01

    We have investigated the regulation of key human iron binding proteins in mononuclear phagocytes by IFN gamma and iron transferrin. In a previous study, we demonstrated that IFN gamma downregulates the expression on human monocytes of transferrin receptors, the major source of iron for the cell. In the present study, we show that IFN gamma also downregulates the intracellular concentration of ferritin, the major iron storage protein in the cell. By radioimmunoassay, the mean ferritin content of nonactivated monocytes was 361 +/- 107 fg/monocyte (mean +/- SEM) whereas the mean ferritin content of IFN gamma-activated monocytes was 64 +/- 13 fg/monocyte, an 82% reduction with activation (P < 0.01, t test). Consistent with its downregulating effect on these iron proteins, IFN gamma treatment also results in decreased iron incorporation. IFN gamma-activated monocytes incorporated 33% less iron from 59Fe-transferrin than nonactivated monocytes (P < 0.05, t test). Gel filtration chromatography revealed that incorporated iron is located primarily in ferritin in both nonactivated and IFN gamma-activated monocytes. Ferritin in IFN gamma-activated monocytes is saturated with approximately three times as much 59Fe as ferritin in nonactivated monocytes. We have also explored the effect of iron transferrin on transferrin receptor expression and intracellular ferritin content in human monocytes. We have found that iron transferrin markedly upregulates both transferrin receptor expression and intracellular ferritin content in both nonactivated (2.3- and 1.3-fold, respectively) and IFN gamma-activated (3.4- and 2.9-fold, respectively) monocytes. This study demonstrates that transferrin receptor expression and intracellular ferritin content in human monocytes is unidirectionally and coordinately upregulated by iron transferrin and unidirectionally and coordinately downregulated by IFN gamma. PMID:8450071

  13. T helper cell recognition of muscle acetylcholine receptor in myasthenia gravis. Epitopes on the gamma and delta subunits.

    PubMed Central

    Manfredi, A A; Protti, M P; Dalton, M W; Howard, J F; Conti-Tronconi, B M

    1993-01-01

    We tested the response of CD4+ cells and/or total lymphocytes from the blood of 22 myasthenic patients and 10 healthy controls to overlapping synthetic peptides, 20 residues long, to screen the sequence of the gamma and delta subunits of human muscle acetylcholine receptor (AChR). The gamma subunit is part of the AChR expressed in embryonic muscle and is substituted in the AChRs of most adult muscles by an epsilon subunit. The delta subunit is present in both embryonic and adult AChRs. Adult extrinsic ocular muscles, which are preferentially and sometimes uniquely affected by myasthenic symptoms, and thymus, which has a still obscure but important role in the pathogenesis of myasthenia gravis, express the embryonic gamma subunit. Anti-AChR CD4+ responses were more easily detected after CD8+ depletion. All responders recognized epitopes on both the gamma and delta subunits and had severe symptoms. In four patients the CD4+ cell response was tested twice, when the symptoms were severe and during a period of remission. Consistently, the response was only detectable, or larger, when the patients were severely affected. Images PMID:7688757

  14. Guidance Receptors in the Nervous and Cardiovascular Systems.

    PubMed

    Rubina, K A; Tkachuk, V A

    2015-10-01

    Blood vessels and nervous fibers grow in parallel, for they express similar receptors for chemokine substances. Recently, much attention is being given to studying guidance receptors and their ligands besides the growth factors, cytokines, and chemokines necessary to form structures in the nervous and vascular systems. Such guidance molecules determine trajectory for growing axons and vessels. Guidance molecules include Ephrins and their receptors, Neuropilins and Plexins as receptors for Semaphorins, Robos as receptors for Slit-proteins, and UNC5B receptors binding Netrins. Apart from these receptors and their ligands, urokinase and its receptor (uPAR) and T-cadherin are also classified as guidance molecules. The urokinase system mediates local proteolysis at the leading edge of cells, thereby providing directed migration. T-cadherin is a repellent molecule that regulates the direction of growing axons and blood vessels. Guidance receptors also play an important role in the diseases of the nervous and cardiovascular systems.

  15. Adenosine 5'-(gamma-thio) triphosphate (ATPgammaS) stimulates both P2Y receptors linked to inositol phosphates production and cAMP accumulation in bovine adrenocortical fasciculata cells.

    PubMed

    Nishi, Haruhisa; Hori, Seiji; Niitsu, Akiyoshi; Kawamura, Masahiro

    2004-01-16

    The study was aimed to investigate the existence of at least two kinds of P2Y receptors linked to steroidogenesis in bovine adrenocortical fasciculata cells (BAFCs). Extracellular nucleotides facilitated steroidogenesis in BAFCs. The potency order was UTP > adenosine 5'-(gamma-thio) triphosphate (ATPgammaS) > ATP > 2-methylthio ATP (2MeSATP) > adenosine 5'-(beta-thio) diphosphate (ADPbetaS) > alpha,beta-methylene ATP (alpha,beta-me-ATP), beta,gamma-methylene ATP (beta,gamma -me-ATP). ATPgammaS (10-100 microM) remarkably stimulated both total inositol phosphates (IPs) production and cyclic AMP (cAMP) accumulation. Competitive displacement experiments by using [35S]ATPgammaS as a radioactive ligand in BAFCs showed that the potency under these unlabelled ligands was ATPgammaS > ATP > ADPbetaS > 2MeSATP > UTP > alpha,beta-me-ATP, beta,gamma-me-ATP. These suggest that two different binding sites of [35S]ATPgammaS, namely P2Y receptors, exist in BAFCs, and that these receptors are linked to steroidogenesis via distinct second messenger systems in the cells.

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

    SciTech Connect

    Kim, Sung Hun; Yoo, Chong Il; Kim, Hui Taek; Park, Ji Yeon; Kwon, Chae Hwa; Keun Kim, Yong . E-mail: kim430@pusan.ac.kr

    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 treatment 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.

  17. Analysis of beta, gamma, and delta T-cell receptor genes in mycosis fungoides and Sezary syndrome.

    PubMed

    Whittaker, S J; Smith, N P; Jones, R R; Luzzatto, L

    1991-10-01

    The authors have analyzed the configuration of immunoglobulin (Ig) and beta, gamma and delta T-cell receptor (TCR) genes in DNA extracted from skin, lymph nodes, and peripheral blood mononuclear cells obtained from 41 patients with mycosis fungoides (MF), 14 patients with Sezary syndrome, and 13 patients with benign inflammatory dermatoses. No discrete rearranged bands (DRB) were detected in patients with inflammatory dermatoses. In tissue DNA from 19 patients with MF DRB were detected with beta and gamma, but not delta TCR probes. Only one patient with MF had a rearrangement of gamma and delta with germ line beta TCR genes. In 13 patients multiple biopsies were analyzed and DRB, when present, were identical in different lesions from individual patients. In three patients analysis of DNA from dermatopathic lymph nodes did not reveal DRB. Analysis of peripheral blood DNA from 24 patients revealed a discrete rearrangement of the gamma TCR gene in four patients and both beta and gamma genes in four additional patients. In MF DRB were detected more frequently with advancing stage of disease in tissues (P less than 0.01) but not in peripheral blood (P equals 0.36). Of 14 patients with Sezary syndrome, eight had DRB in peripheral blood DNA with both beta and gamma probes and in three of these patients identical DRB were also detected in DNA from skin biopsy samples. In contrast, DRB were not detected in the peripheral blood of the other six patients. In both MF and Sezary syndrome there was no restricted usage of particular V gamma genes. These results indicate that in MF (1) T-cell clones can be detected in skin biopsy specimens from the majority of patients with early stage disease, (2) gamma delta T-cell clones are only rarely found, and (3) TCR gene analysis can detect T-cell clones in the peripheral blood with a greater degree of specificity than conventional light microscopic study. In Sezary syndrome these studies also suggest that a subset of patients have a

  18. Ligand-dependent coactivation of the human bile acid receptor FXR by the peroxisome proliferator-activated receptor gamma coactivator-1alpha.

    PubMed

    Savkur, Rajesh S; Thomas, Jeffrey S; Bramlett, Kelli S; Gao, Yunling; Michael, Laura F; Burris, Thomas P

    2005-01-01

    Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) has been shown to play an important role in energy metabolism by coordinating transcriptional programs involved in mitochondrial biogenesis, adaptive thermogenesis, gluconeogenesis, and fatty acid oxidation. PGC-1alpha also plays a crucial role in cholesterol metabolism by serving as a coactivator of the liver X receptor-alpha and inducing the expression of cholesterol 7-alpha-hydroxylase. Here, we demonstrate that PGC-1alpha also functions as an effective coactivator of farnesoid X receptor (FXR), the bile acid receptor. Transient cotransfection assays demonstrate that PGC-1alpha enhances ligand-mediated FXR transcription when either full-length FXR or Gal4 DNA binding domain-FXR-ligand binding domain chimeras were analyzed. Mammalian two-hybrid analyses, glutathione S-transferase affinity chromatography and biochemical coactivator recruitment assays demonstrate ligand-dependent interaction between the two proteins both in vivo and in vitro. PGC-1alpha-mediated coactivation of FXR was highly ligand-dependent and absolutely required an intact activation function-2 (AF-2) domain of FXR and the LXXLL motif in PGC-1alpha. The integrity of the charge clamp was required, further illustrating the role of the ligand binding domain of FXR in PGC-1alpha recognition. Together, these results indicate that PGC-1alpha functions as a potent coactivator for FXR and further implicates its role in the regulation of genes that are involved in bile acid and lipid metabolism.

  19. Syk interacts with tyrosine-phosphorylated proteins in human platelets activated by collagen and cross-linking of the Fc gamma-IIA receptor.

    PubMed Central

    Yanaga, F; Poole, A; Asselin, J; Blake, R; Schieven, G L; Clark, E A; Law, C L; Watson, S P

    1995-01-01

    Activation of human platelets by cross-linking of the platelet low-affinity IgG receptor, the Fc gamma receptor IIA (Fc gamma-RIIA), or by collagen is associated with rapid phosphorylation on tyrosine of the non-receptor tyrosine kinase syk. Phosphorylation is still observed, albeit sometimes reduced, in the presence of a combination of a protein kinase C inhibitor, Ro 31-8220, and the intracellular calcium chelator, BAPTA-AM, demonstrating independence from phosphoinositide-specific phospholipase C (PLC) activity. In contrast, the combination of Ro 31-8220 and BAPTA-AM completely inhibits phosphorylation of syk in thrombin-stimulated platelets. Phosphorylation of syk increases its autophosphorylation activity measured in a kinase assay performed on syk immunoprecipitates. Fc gamma-RIIA also undergoes phosphorylation in syk immunoprecipitates from platelets activated by cross-linking of Fc gamma-RIIA but not by collagen, suggesting that it associates with the kinase. Consistent with this, tyrosine-phosphorylated Fc gamma-RIIA is precipitated by a glutathione S-transferase (GST) fusion protein containing the tandem src homology (SH2) domains of syk from Fc gamma-RIIA- but not collagen-activated cells. Two uncharacterized tyrosine-phosphorylated proteins of 40 and 65 kDa are uniquely precipitated by a GST fusion protein containing the tandem syk-SH2 domains in collagen-stimulated platelets. A peptide based on the antigen recognition activation motif (ARAM) of Fc gamma-RIIA, and phosphorylated on the two tyrosine residues found within this region, selectively binds syk from lysates of resting platelets; this interaction is not seen with a non-phosphorylated peptide. Kinase assays on Fc gamma-RIIA immunoprecipitates reveal the constitutive association of an unidentified kinase activity in resting cells which phosphorylates a 67 kDa protein. Syk is not detected in Fc gamma-RIIA immunoprecipitates from resting cells but associates with the receptor following activation

  20. Molecular Recognition of Paired Receptors in the Immune System

    PubMed Central

    Kuroki, Kimiko; Furukawa, Atsushi; Maenaka, Katsumi

    2012-01-01

    Cell surface receptors are responsible for regulating cellular function on the front line, the cell membrane. Interestingly, accumulating evidence clearly reveals that the members of cell surface receptor families have very similar extracellular ligand-binding regions but opposite signaling systems, either inhibitory or stimulatory. These receptors are designated as paired receptors. Paired receptors often recognize not only physiological ligands but also non-self ligands, such as viral and bacterial products, to fight infections. In this review, we introduce several representative examples of paired receptors, focusing on two major structural superfamilies, the immunoglobulin-like and the C-type lectin-like receptors, and explain how these receptors distinguish self and non-self ligands to maintain homeostasis in the immune system. We further discuss the evolutionary aspects of these receptors as well as the potential drug targets for regulating diseases. PMID:23293633

  1. Development of gamma-emitting, receptor binding radiotracers for imaging the brain and pancreas

    SciTech Connect

    Reba, R.C.

    1990-01-01

    This progress report covers period from Nov. 1, 1989 to Aug. 31, 1990. The long term objective was to develop receptor-binding radiotracers for SPECT or PET imaging of CNS or peripheral nervous system. The specific chemistry aims, as understood on the basis of past findings, were: to synthesize and develop a more polar analogs of 4IQNB, possessing similar binding characteristics but eliminated more rapidly from the surrounding tissues and the target organ, to design a method of introducing a technetium chelating group onto a molecule or cholinergic agent without drastic lowering of its apparent affinity, to synthesize and develop radiotracers based on m-AChR antagonists selective for one of the subtypes of the receptor. The chemistry service aims were to prepare and characterize (R,R)- and (R,S)-4IQNB and derivatives, to provide the triazene intermediate to other investigators, and to provide ({sup 123}I)4IQNB for in vivo imaging. The biochemistry aims were to characterize the vitro and in vivo properties of novel compounds and to perform the pharmacokinetic studies. 3 refs., 5 tabs.

  2. Histamine H3 receptor activation decreases kainate-induced hippocampal gamma oscillations in vitro by action potential desynchronization in pyramidal neurons

    PubMed Central

    Andersson, Richard; Lindskog, Maria; Fisahn, André

    2010-01-01

    The study of rhythmic electrical activity in slice preparations has generated important insights into neural network function. While the synaptic mechanisms involved in the generation of in vitro network oscillations have been studied widely, little is known about the modulatory influence exerted on rhythmic activity in neuronal networks by neuropeptides and biogenic amines. Gamma oscillations play an important role in cognitive processes and are altered or disrupted in disorders such as Alzheimer's disease (AD) and schizophrenia. Given the importance of gamma oscillations for learning, memory and cognition processes as well as the recent interest in histamine H3 receptors in the development of pro-cognitive drugs to treat disorders such as AD and schizophrenia, it is relevant to study the impact of histaminergic mechanisms on network gamma oscillations. Here we show for the first time a modulation of gamma oscillation by histaminergic mechanisms. Selective activation of the H3 receptor by R-α-methylhistamine significantly reduces the power of kainate-induced gamma oscillations, but not carbachol-induced gamma oscillations, in the rat hippocampal slice preparation without affecting oscillation frequency. This effect is neither caused by a decrease in excitatory or inhibitory postsynaptic currents, nor a decrease in cellular excitability. Instead, we find that the decrease in oscillation power following H3 receptor activation results from a desynchronization of pyramidal neuron action potential firing with regard to the local field potential oscillation cycle. Our data provide a possible mechanism of action for histamine in regulating gamma oscillations in the hippocampal network. PMID:20156850

  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. [Effect of gamma-hydroxybutyric acid receptor on focal cerebral ischemia-reperfusion injury in rats].

    PubMed

    Jin, Rong; Jiang, Xin-Ying; Ma, Xing; Gu, Shu-Ling; Dai, Ti-Jun

    2007-08-01

    This study is to investigate the effect of gamma-hydroxybutyric acid receptor (GHBR) on focal cerebral ischemia-reperfusion injury in rats and its mechanism. NCS-356 (the agonist of GHBR) and NCS-382 (the antagonist of GHBR) were adopted as the tool medicine. The ripe male Sprague-Dawley rats weighing 240 - 280 g were randomly divided into seven groups: sham operation group (sham), ischemia-reperfusion group (Isc/R), NCS-356 160 microg x kg(-1) group (N1), NCS-356 320 microg x kg(-1) group (N2), NCS-356 640 microg x kg(-1) group (N3), NCS-382 640 microg x kg(-1) + NCS-356 640 microg x kg(-1) group (NCS-382 + N3), and nimodipine (Nim) 600 microg x kg(-1) group. The middle cerebral artery occlusion (MCAO) model referring to Longa's method with modifications was adopted. The effect of GHBR on behavioral consequence of MCAO rats was studied after 2 h of ischemia-reperfusion. After 24 h of ischemia-reperfusion, part of animals were used to measure the cerebral infarction volume by TTC staining; ischemic cortex of another part of animals were used to measure the content of intracellular free calcium by flow cytometry, the tNOS, iNOS activity and the content of NO by spectrophotometric method, the content of cGMP by radioimmunoassay. The neurological function score and infarction volume rate in Isc/R group rats increased significantly than that in sham group; The content of intracellular calcium ([Ca2+]) of cortex neuron and cGMP, the activities of tNOS and iNOS, and the content of NO in Isc/R group were higher than that in sham group obviously (P < 0.01); These consequence we mentioned of N1, N2, N3 and Nim group were lower than that of Isc/R. NCS-382 + N3 group could significantly antagonize the above effect of N3. Thus, NCS-356 has protective effects against ischemia-reperfusion brain injury by activating GHBR. The neuroprotective effect of GHBR is related with decreasing the content of [Ca2+]i, NO, cGMP and tNOS, iNOS activity in MCAO rats.

  5. A mobile tomographic gamma camera system for acute studies

    SciTech Connect

    Dale, S.; Holmberg, M.; Larsson, H.

    1997-04-01

    A mobile tomographic gamma camera system, called Cardiotom Mark 1, has been developed for imaging the myocardium and other small organs. The Cardiotom system is based on a tomographic technique, ectomography, which is a limited view angle method using a rotating slant hole collimator (RSHC) and a stationary detector to produce projection images. This enables the ectomographic system to be implemented as a mobile system. With the system developed, almost 200 perfusion studies have been performed. The system is based on a second-hand detector and a 30{degree} RSHC. By segmenting the collimator, total system efficiency is increased and acquisition time can be reduced by a factor equal to the number of segments. The system developed is PC-based and totally self-contained with data acquisition, reconstruction, and image presentation. The mobility of the system and the fact that the examination requires no patient cooperation enable acute studies of myocardial perfusion in the critically ill patient, either in the intensive care unit or the emergency room. A mobile system with three-dimensional imaging can offer new possibilities in cardiological research and diagnosis.

  6. A Mobile Automated Tomographic Gamma Scanning System - 13231

    SciTech Connect

    Kirkpatrick, J.M.; LeBlanc, P.J.; Nakazawa, D.; Petroka, D.L.; Kane Smith, S.; Venkataraman, R.; Villani, M.

    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 transport 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 keV/channel resolution to

  7. Human CD4-8- -derived clones. Phenotypic and functional characteristics and variation between donors in patterns of T-cell receptor gamma gene rearrangements.

    PubMed

    Christmas, S E

    1989-06-01

    Clones were derived from highly purified human CD4-8- lymphocytes from three different donors and maintained in the presence of interleukin 2 and phytohaemagglutinin. Considerable variation was noted between donors in the phenotype and T-cell receptor (TCR) gamma gene rearrangements of CD4-8- -derived clones. In one donor, most clones remained CD4-8- and all were CD3+WT31- and therefore expressed gamma/delta heterodimers. TCR gamma gene rearrangements almost all involved C gamma 1. In contrast, most clones from a second donor were CD3+WT31+, and therefore expressed alpha/beta heterodimers, and many were positive for CD4 or CD8. Most clones from a third donor were CD3+WT31- with a high proportion of TCR gamma gene rearrangements involving C gamma 2. The V gamma 9JP rearrangement was exclusively confined to CD3+WT31- clones and was present in the majority of clones. Almost all CD3+WT31- clones showed TCR beta as well as gamma gene rearrangements. Most CD3+WT31- clones with at least one chromosome rearranged to C gamma 1 exhibited high non-major histocompatibility complex (MHC)-restricted cytotoxic activity, while most of those with two C gamma 2 rearrangements, and therefore expressing a non-disulphide-linked gamma/delta heterodimer, had low activity. Preincubation of effector cells with anti-CD3 strongly inhibited the cytotoxicity of CD3+WT31- clones while that of CD3+WT31+ clones was enhanced. This implicates the CD3-gamma/delta complex in target cell recognition by cytotoxic gamma/delta-bearing T-cell clones. The results show that there is heterogeneity between donors in the relative proportions of CD4-8- -derived clones expressing alpha/beta heterodimers and the different forms of the gamma/delta heterodimer.

  8. Cannabinoid receptor agonist WIN 55,212-2 inhibits rat cortical dialysate gamma-aminobutyric acid levels.

    PubMed

    Ferraro, L; Tomasini, M C; Cassano, T; Bebe, B W; Siniscalchi, A; O'Connor, W T; Magee, P; Tanganelli, S; Cuomo, V; Antonelli, T

    2001-10-15

    The effects of the cannabinoid receptor agonist WIN 55,212-2 (0.1-5 mg/kg i.p.) on endogenous extracellular gamma-aminobutyric acid (GABA) levels in the cerebral cortex of the awake rat was investigated by using microdialysis. WIN 55,212-2 (1 and 5 mg/kg i.p.) was associated with a concentration-dependent decrease in dialysate GABA levels (-16% +/- 4% and -26% +/- 4% of basal values, respectively). The WIN 55,212-2 (5 mg/kg i.p.) induced-inhibition was counteracted by a dose (0.1 mg/kg i.p.) of the CB(1) receptor antagonist SR141716A, which by itself was without effect on cortical GABA levels. These findings suggest that cannabinoids decrease cortical GABA levels in vivo, an action that might underlie some of the cognitive and behavioral effects of acute exposure to marijuana.

  9. A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding.

    PubMed

    Warmerdam, P A; van de Winkel, J G; Vlug, A; Westerdaal, N A; Capel, P J

    1991-08-15

    The low-affinity human Fc gamma RIIa is encoded by a single gene with allelic variation, defined by low-responder and high-responder alleles (LR and HR). The HR Fc gamma RIIa transcript interacts strongly with murine (m) IgG1 complexes, in contrast to the LR Fc gamma RIIa. Furthermore, the transcripts can be discriminated by mAb 41H16, which recognizes an epitope expressed on the HR Fc gamma RIIa molecule. We report that this receptor is also polymorphic in its reactivity with human (h) IgG2. Binding studies using well-defined hIgG dimers revealed that LR Fc gamma RIIa molecules can efficiently bind hIgG2, in contrast to HR Fc gamma RIIa. Previous work of others showed one amino acid difference between the allelic forms of Fc gamma RII. We, however, found a second amino acid difference between both allelic forms. In this study, hybrid Fc gamma RIIa molecules were constructed to determine the epitope for mAb 41H16 and the binding domain for mIgG1 and hIgG2 complexes. Our data point to the importance of the amino acid at position 131, located in the second Ig-like domain of Fc gamma RIIa. When an arginine residue is present at amino acid position 131, the receptor is recognized by mAb 41H16. Furthermore, the receptor can bind mIgG1-sensitized indicator E, but binds hIgG2 dimers only weakly. When a histidine residue is present at this amino acid position, hIgG2 dimers do bind efficiently to Fc gamma RII, whereas mIgG1-sensitized E and mAb 41H16 exhibit a strongly diminished binding.

  10. 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.

  11. Most human CD3+WT31- clones with T cell receptor C gamma 1 rearrangements show strong non-MHC-restricted cytotoxic activity in contrast to those with C gamma 2 rearrangements.

    PubMed

    Christmas, S E

    1989-04-01

    Clones expressing CD3 in the absence of WT31 expression were obtained by growing highly purified WT31- cells in the presence of interleukin 2 and phytohemagglutinin. Most clones showed rearrangements of T cell receptor (TcR) gamma genes on both chromosomes involving all five currently identified J gamma segments. About a third of these clones had a rearranged 12 kb Kpn I band with the J gamma probe, consistent with a V9JPC gamma 1 rearrangement. All clones with both chromosomes rearranged to C gamma 2 had low or intermediate cytotoxic activity while most of those with at least one chromosome rearranged to C gamma 1 had high cytotoxic activity against both natural killer-sensitive and natural killer-resistant targets. This applied both to clones with and without the V9JPC gamma 1 rearrangement. Of three clones with both C gamma 1 and C gamma 2 rearrangements two had high activity and the other was only weakly cytotoxic. In addition, most clones showed rearrangement of TcR beta genes. Some clones were capable of secreting levels of interferon-gamma and tumor necrosis factor-alpha which were as high as those produced by CD3+4+WT31+ T cell clones. The results suggest that most human CD3+WT31- clones expressing a disulfide-linked C gamma 1/delta heterodimer are capable of mediating strong non-major histocompatibility complex-restricted cytotoxicity whereas those expressing non-disulfide-linked C gamma 2/delta heterodimers are not.

  12. 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

    SciTech Connect

    Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro; Yasuda, Osamu; Fukuda, Masaya; Tokutomi, Yoshiko; Dong, Yi-Fei; Ogawa, Hisao; Kim-Mitsuyama, Shokei

    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, 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 of

  13. 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.

  14. The neuroactive steroid allopregnanolone suppresses hypothalamic gonadotropin-releasing hormone release through a mechanism mediated by the gamma-aminobutyric acidA receptor.

    PubMed

    Calogero, A E; Palumbo, M A; Bosboom, A M; Burrello, N; Ferrara, E; Palumbo, G; Petraglia, F; D'Agata, R

    1998-07-01

    The central nervous system (CNS) is able to synthesize and/or metabolize steroid hormones. These neuroactive steroids are capable of modulating several brain functions and, among these, they seem to regulate the hypothalamic-pituitary-gonadal (HPG) axis. Indeed, recent observations have shown that 5 alpha-pregnane-3 alpha-ol-20-one (allopregnanolone), one of the most abundant naturally occurring neuroactive steroids, suppresses ovulation and sexual behaviour when administered within the CNS. The present study was undertaken to evaluate the effects of allopregnanolone and its inactive stereoisomer, 5 alpha-pregnane-3 beta-ol-20-one, upon the release of gonadotropin-releasing hormone (GnRH) from individually-incubated hemihypothalami. Allopregnanolone suppressed GnRH release in a concentration-dependent manner with maximal activity in the nanomolar range, a range at which this neurosteroid is capable of playing a biological action. The specificity of allopregnanolone suppression of GnRH release was provided by the lack of effect of its known inactive stereoisomer. To evaluate the involvement of gamma-aminobutyric acidA (GABAA) receptor, we examined the effects of two neurosteroids with GABA-antagonistic properties, pregnanolone sulfate (PREG-S) and dehydroepiandrosterone sulfate (DHEAS), and of bicuculline, a selective antagonist of the GABA binding site on the GABAA receptor, on allopregnanolone (10 nM)-suppressed GnRH release. Both PREG-S and bicuculline overcame the inhibitory effects of allopregnanolone on GnRH release, whereas DHEAS did not. To substantiate the involvement of the GABAA receptor further, we tested the effects of muscimol, a selective agonist for this receptor, which suppressed GnRH release. In conclusion, allopregnanolone suppressed hypothalamic GnRH release in vitro and this effect appeared to be mediated by an interaction with the GABAA receptor. We speculate that the inhibitory effect of allopregnanolone on the HPG axis may also be caused by

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

    PubMed Central

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

    2014-01-01

    Gamma-aminobutyric acid type A receptors (GABAARs) 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 GABAARs determine their function and pharmacological profile. GABAARs are heteropentamers of subunits, and (α1)2(β3)2(γ2L)1 is a common subtype. Biochemical and biophysical studies of GABAARs require larger quantities of receptors of defined subunit composition than are currently available. We previously reported high-level production of active human α1β3 GABAAR 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)3GK–1D4 GABAAR. These cells achieved expression levels of 70–90 pmol [3H]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 [3H]flunitrazepam to [3H]muscimol binding sites and sensitivity of GABA-induced currents to benzodiazepines and zinc. The α1β3γ2L GABAARs 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 [3H]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 [3H]muscimol binding were maintained in the purified state. PMID:24288268

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

    SciTech Connect

    Gerdin, Anna Karin; Surve, Vikas V.; Joensson, Marie; Bjursell, Mikael; Edenro, Anne; Schuelke, Meint; Saad, Alaa; Bjurstroem, Sivert; Lundgren, Elisabeth Jensen; Snaith, Michael; Fransson-Steen, Ronny; Toernell, Jan; Bohlooly-Y, Mohammad . E-mail: mohammad.bohlooly@astrazeneca.com

    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, 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.

  17. 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.

  18. 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

    SciTech Connect

    Culia, C.T.; Stubbs, L.J.; Montgomery, C.S.; Russell, L.B.; Rinchik, E.M.

    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 not 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.

  19. 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

    SciTech Connect

    Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan; Bigge, Christopher F.; Chen, Jing; Davis, Jo Ann; Dudley, Danette A.; Edmunds, Jeremy J.; Esmaeil, Nadia; Geyer, Andrew; Heemstra, Ronald J.; Jalaie, Mehran; Ohren, Jeffrey F.; Ostroski, Robert; Ellis, Teresa; Schaum, Robert P.; Stoner, Chad

    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 partial 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.

  20. Automatic pneumatic source-control system for positioning gamma and neutron calibration sources

    SciTech Connect

    Hunt, G.F.

    1980-10-17

    A microcomputer-based source-control system was developed to move gamma and neutron calibration sources into position for sample irradiation. In addition to monitoring interlocks and system status, the computer calculates for gamma sources the time required for a requested exposure at a specified distance. All system use data is stored, and monthly reports are generated.

  1. Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta.

    PubMed

    Farcet, J P; Gaulard, P; Marolleau, J P; Le Couedic, J P; Henni, T; Gourdin, M F; Divine, M; Haioun, C; Zafrani, S; Goossens, M

    1990-06-01

    Peripheral T-cell lymphomas consist of a clinically heterogeneous group of malignant disorders whose immunophenotype usually corresponds to that of normal mature T cells. We describe and correlate the clinical, histopathologic, phenotypic, and genotypic findings in two patients with malignant lymphoma presenting with hepatosplenic disease. The morphologic pattern of lymphoma was that of a sinusal/sinusoidal infiltration in spleen, marrow, and liver. This morphologic characteristic was associated with the presence of a productive clonal rearrangement of the T-cell receptor (TCR) delta gene. Lymphoma cells expressed a CD3-TCR-gamma delta- phenotype. They were also double negative (ie, CD4-CD8-) and lacked the CD5 and CD7 antigens. In one patient, tumor progression was associated with phenotypic changes that resulted in a CD3-TCR-gamma delta- phenotype with the same delta-gene rearrangement as initially. These observations suggest the existence of a new type of peripheral T-cell lymphoma characterized by its hepatosplenic presentation, and by the sinusal/sinusoidal tropism and the TCR-gamma delta phenotype of the malignant cells. PMID:2140703

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

    NASA Technical Reports Server (NTRS)

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

  3. Homology modeling of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABA receptor channels and Surflex-docking of fipronil.

    PubMed

    Cheng, Jin; Ju, Xiu-Lian; Chen, Xiang-Yang; Liu, Gen-Yan

    2009-09-01

    To further explore the mechanism of selective binding of the representative gamma-aminobutyric acid receptors (GABARs) noncompetitive antagonist (NCA) fipronil to insect over mammalian GABARs, three-dimensional models of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABAR were generated by homology modeling, using the cryo-electron microscopy structure of the nicotinic acetylcholine receptor (nAChR) of Torpedo marmorata as a template. Fipronil was docked into the putative binding site of the human alpha 1 beta 2 gamma 2 and house fly beta 3 receptors by Surflex-docking, and the calculated docking energies are in agreement with experimental results. The GABA receptor antagonist fipronil exhibited higher potency with house fly beta 3 GABAR than with human alpha 1 beta 2 gamma 2 GABAR. Furthermore, analyses of Surflex-docking suggest that the H-bond interaction of fipronil with Ala2 and Thr6 in the second transmembrane segment (TM2) of these GABARs plays a relatively important role in ligand selective binding. The different subunit assemblies of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABARs may result in differential selectivity for fipronil.

  4. T cell receptor gamma gene status of human alpha/beta+ and gamma/delta+ T cell clones: absence of V9JP rearrangements in alpha/beta+ clones is not a result of a lack of rearrangements involving more 5' J gamma segments.

    PubMed

    Christmas, S E

    1989-11-01

    T cell receptor (TCR) gamma gene rearrangements were examined in panels of human T cell clones expressing TCR alpha/beta or gamma/delta heterodimers. Over half of the alpha/beta+ clones had both chromosomes rearranged to C gamma 2 but this was the case for only 20% of the gamma/delta+ clones. While more than half of the gamma/delta+ clones showed a V9JP rearrangement, this configuration was absent from all 49 alpha/beta+ clones analysed. However, this was not a result of all rearrangements being to the more 3' J gamma genes as 11 alpha/beta+ clones had rearrangement(s) to JP1, the most 5' J gamma gene segment. Both alpha/beta+ and gamma/delta+ clones showed a similar pattern of V gamma gene usage in rearrangements to J gamma 1 or J gamma 2 with a lower proportion of the more 3' genes being rearranged to J gamma 2 than for the more 5' genes. Several alpha/beta+ and several gamma/delta+ clones had noncoordinate patterns of rearrangement involving both C gamma 1 and C gamma 2. Eleven out of fourteen CD8+ clones tested had both chromosomes rearranged to C gamma 2 whereas all clones derived from CD4-8- cells and having unconventional phenotypes (CD4-8- or CD4+8+) had at least one C gamma 1 rearrangement. Twelve out of twenty-seven CD4+ clones also had this pattern, suggesting that CD4-8+ clones had a tendency to utilize more 3' J gamma gene segments than CD4+ clones. There was some evidence for interdonor variation in the proportions of TCR gamma rearrangements to C gamma 1 or C gamma 2 in alpha/beta+ clones as well as gamma/delta+ clones. The results illustrate the unique nature of the V9JP rearrangement in gamma/delta+ clones and the possible use of a sequential mechanism of TCR gamma gene rearrangements during T cell differentiation is discussed.

  5. Cloning, purification, crystallization and preliminary X-ray analysis of the catalytic domain of human receptor-like protein tyrosine phosphatase [gamma] in three different crystal forms

    SciTech Connect

    Kish, Kevin; McDonnell, Patricia A.; Goldfarb, Valentina; Gao, Mian; Metzler, William J.; Langley, David R.; Bryson, James W.; Kiefer, Susan E.; Carpenter, Brian; Kostich, Walter A.; Westphal, Ryan S.; Sheriff, Steven

    2013-03-07

    Protein tyrosine phosphatase {gamma} is a membrane-bound receptor and is designated RPTP{gamma}. RPTP{gamma} and two mutants, RPTP{gamma}(V948I, S970T) and RPTP{gamma}(C858S, S970T), were recombinantly expressed and purified for X-ray crystallographic studies. The purified enzymes were crystallized using the hanging-drop vapor-diffusion method. Crystallographic data were obtained from several different crystal forms in the absence and the presence of inhibitor. In this paper, a description is given of how three different crystal forms were obtained that were used with various ligands. An orthorhombic crystal form and a trigonal crystal form were obtained both with and without ligand, and a monoclinic crystal form was only obtained in the presence of a particularly elaborated inhibitor.

  6. The agile alert system for gamma-ray transients

    SciTech Connect

    Bulgarelli, A.; Trifoglio, M.; Gianotti, F.; Fioretti, V.; Chen, A. W.; Pittori, C.; Verrecchia, F.; Lucarelli, F.; Santolamazza, P.; Fanari, G.; Giommi, P.; Pellizzoni, A.; and others

    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 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.

  7. 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.

  8. IFN-gamma-receptor signaling ameliorates transplant vasculopathy through attenuation of CD8+ T-cell-mediated injury of vascular endothelial cells.

    PubMed

    Bolinger, Beatrice; Engeler, Daniel; Krebs, Philippe; Miller, Simone; Firner, Sonja; Hoffmann, Matthias; Palmer, Douglas C; Restifo, Nicholas P; Tian, Yinghua; Clavien, Pierre-Alain; Ludewig, Burkhard

    2010-03-01

    Occlusive transplant vasculopathy (TV) is the major cause for chronic graft rejection. Since endothelial cells (EC) are the first graft cells encountered by activated host lymphocytes, it is important to delineate the molecular mechanisms that coordinate the interaction of EC with activated T cells. Here, the interaction of CD8(+) T cells with Ag-presenting EC in vivo was examined using a transgenic heart transplantation model with beta-galactosidase (beta-gal) expression exclusively in EC (Tie2-LacZ hearts). We found that priming with beta-gal peptide-loaded DC failed to generate a strong systemic IFN-gamma response, but elicited pronounced TV in both IFN-gamma receptor (IFNGR)-competent, and ifngr(-/-) Tie2-LacZ hearts. In contrast, stimulation of EC-specific CD8(+) T cells with beta-gal-recombinant mouse cytomegalovirus (MCMV-LacZ) in recipients of ifngr(+/+) Tie2-LacZ hearts did not precipitate significant TV. However, MCMV-LacZ infection of recipients of ifngr(-/-) Tie2-LacZ hearts led to massive activation of beta-gal-specific CD8 T cells, and led to development of fulminant TV. Further analyses revealed that the strong systemic IFN-gamma "storm" associated with MCMV infection induced upregulation of programmed death-1 ligand 1 (PD-L1) on EC, and subsequent attenuation of programmed death-1 (PD-1)-expressing EC-specific CD8(+) T cells. Thus, IFNGR signaling in ECs activates a potent peripheral negative feedback circuit that protects vascularized grafts from occlusive TV. PMID:20049875

  9. Instructions for calibrating gamma detectors using the Canberra-Nuclear Data Genie Gamma Spectroscopy System

    SciTech Connect

    Brunk, J.L.

    1995-09-01

    A straight forward protocol provides a way to guide the calibration of a gamma detector for a particular geometry and material. Several programs have used the Low Level Gamma Counting Facility of the Health and Ecological Assessment Division of the Lawrence Livermore National Laboratory to count a variety of large environmental samples contained in several unique geometries. The equipment and calibration requirements needed to analyze these types of samples are explained. This document describes the calibration protocol that has been developed and describes how it is used to calibrate the detectors.

  10. The Advanced Gamma-Ray Imaging System (AGIS): Science Highlights

    SciTech Connect

    Buckley, J.; Coppi, P.; Digel, S.; Funk, S.; Krawczynski, H.; Krennrich, F.; Pohl, M.; Romani, R.; Vassiliev, V.; /UCLA

    2011-11-21

    The Advanced Gamma-ray Imaging System (AGIS), a future gamma-ray telescope consisting of an array of {approx}50 atmospheric Cherenkov telescopes distributed over an area of {approx}1 km{sup 2}, will provide a powerful new tool for exploring the high-energy universe. The order-of-magnitude increase in sensitivity and improved angular resolution could provide the first detailed images of {gamma}-ray emission from other nearby galaxies or galaxy clusters. The large effective area will provide unprecedented sensitivity to short transients (such as flares from AGNs and GRBs) probing both intrinsic spectral variability (revealing the details of the acceleration mechanism and geometry) as well as constraining the high-energy dispersion in the velocity of light (probing the structure of spacetime and Lorentz invariance). A wide field of view ({approx}4 times that of current instruments) and excellent angular resolution (several times better than current instruments) will allow for an unprecedented survey of the Galactic plane, providing a deep unobscured survey of SNRs, X-ray binaries, pulsar-wind nebulae, molecular cloud complexes and other sources. The differential flux sensitivity of {approx}10{sup -13} erg cm{sup -2} sec{sup -1} will rival the most sensitive X-ray instruments for these extended Galactic sources. The excellent capabilities of AGIS at energies below 100 GeV will provide sensitivity to AGN and GRBs out to cosmological redshifts, increasing the number of AGNs detected at high energies from about 20 to more than 100, permitting population studies that will provide valuable insights into both a unified model for AGN and a detailed measurement of the effects of intergalactic absorption from the diffuse extragalactic background light. A new instrument with fast-slewing wide-field telescopes could provide detections of a number of long-duration GRBs providing important physical constraints from this new spectral component. The new array will also have excellent

  11. Expression of the alpha/beta and gamma/delta T-cell receptors in 57 cases of peripheral T-cell lymphomas. Identification of a subset of gamma/delta T-cell lymphomas.

    PubMed Central

    Gaulard, P.; Bourquelot, P.; Kanavaros, P.; Haioun, C.; Le Couedic, J. P.; Divine, M.; Goossens, M.; Zafrani, E. S.; Farcet, J. P.; Reyes, F.

    1990-01-01

    Fifty-seven cases of peripheral T-cell lymphoma were studied for cell expression of the T-cell receptor (TCR) chains, using monoclonal antibodies specific for the beta chain (beta F1) of the alpha/beta TCR, and for the delta chain (anti-TCR delta-1) of the gamma/delta TCR. Three different patterns were demonstrated: in 39 cases (69%), the phenotype (CD3+beta F1+TCR delta-1-) was that of most normal T cells. A second pattern was found on six cases (10%), which were of CD3+beta F1-TCR delta-1+ phenotype, and in which DNA analysis showed a clonal rearrangement of the delta locus in the five cases studied. It is suggested that these cases are the neoplastic counterpart of the small subpopulation of normal T cells that express gamma delta receptor. It is of considerable interest that these gamma delta lymphomas had unusual clinicopathologic presentations, as one case corresponded to a lethal midline granuloma and the five others to hepatosplenic lymphomas with a sinusal/sinusoidal infiltration in spleen, marrow, and liver. The fact that the distribution of the neoplastic gamma delta cells in the splenic red pulp resembles that of normal gamma delta cells reinforces the concept of a preferential homing of gamma delta T cells to this tissue. A third pattern (CD3 +/- beta F1-TCR delta-1-) was seen in 12 cases (21%), in which, by contrast to normal post-thymic T cells, no evidence of either alpha beta or gamma delta T cell receptor was found. Images Figure 1 Figure 2 Figure 2 Figure 3 PMID:1698028

  12. Functional RNAi screen targeting cytokine and growth factor receptors reveals oncorequisite role for interleukin-2 gamma receptor in JAK3 mutation-positive leukemia

    PubMed Central

    Agarwal, Anupriya; MacKenzie, Ryan J.; Eide, Christopher A.; Davare, Monika A.; Watanabe-Smith, Kevin; Tognon, Cristina E.; Mongoue-Tchokote, Solange; Park, Byung; Braziel, Rita M.; Tyner, Jeffrey W.; Druker, Brian J.

    2014-01-01

    To understand the role for cytokine and growth factor receptor-mediated signaling in leukemia pathogenesis we designed a functional RNAi screen targeting 188 cytokine and growth factor receptors that we found highly expressed in primary leukemia specimens. Using this screen we identified interleukin-2 gamma receptor (IL2Rγ) as a critical growth determinant for the JAK3A572V mutation-positive AML cell line. We observed that knockdown of IL2Rγ abrogates phosphorylation of JAK3 and downstream signaling molecules, JAK1, STAT5, MAPK and pS6 ribosomal protein. Overexpression of IL2Rγ in murine cells increased the transforming potential of activating JAK3 mutations, whereas absence of IL2Rγ completely abrogated the clonogenic potential of JAK3A572V as well as the transforming potential of additional JAK3 activating mutations such as JAK3M511I. In addition, mutation at the IL2Rγ interaction site in the FERM domain of JAK3 (Y100C) completely abrogated JAK3-mediated leukemic transformation. Mechanistically, we found IL2Rγ contributes to constitutive JAK3 mutant signaling by increasing JAK3 expression and phosphorylation. Conversely, we found that mutant but not wild type JAK3 increased the expression of IL2Rγ, indicating IL2Rγ and JAK3 contribute to constitutive JAK/STAT signaling through their reciprocal regulation. Overall we demonstrate a novel role for IL2Rγ in potentiating oncogenesis in the setting of JAK3-mutation positive leukemia. Additionally, our study highlights an RNAi-based functional assay that can be used to facilitate the identification of non-kinase cytokine and growth factor receptor targets for inhibiting leukemic cell growth. PMID:25109334

  13. Peroxisome proliferator-activated receptor gamma regulates expression of the anti-lipolytic G-protein-coupled receptor 81 (GPR81/Gpr81).

    PubMed

    Jeninga, Ellen H; Bugge, Anne; Nielsen, Ronni; Kersten, Sander; Hamers, Nicole; Dani, Christian; Wabitsch, Martin; Berger, Ruud; Stunnenberg, Hendrik G; Mandrup, Susanne; Kalkhoven, Eric

    2009-09-25

    The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPARgamma target genes that may contribute to the reduction of circulating free fatty acids after TZD treatment have been identified, the relevant PPARgamma target genes that may exert the anti-lipolytic effect of TZDs are unknown. Here we identified the anti-lipolytic human G-protein-coupled receptor 81 (GPR81), GPR109A, and the (human-specific) GPR109B genes as well as the mouse Gpr81 and Gpr109A genes as novel TZD-induced genes in mature adipocytes. GPR81/Gpr81 is a direct PPARgamma target gene, because mRNA expression of GPR81/Gpr81 (and GPR109A/Gpr109A) increased in mature human and murine adipocytes as well as in vivo in epididymal fat pads of mice upon rosiglitazone stimulation, whereas small interfering RNA-mediated knockdown of PPARgamma in differentiated 3T3-L1 adipocytes showed a significant decrease in Gpr81 protein expression. In addition, chromatin immunoprecipitation sequencing analysis in differentiated 3T3-L1 cells revealed a conserved PPAR:retinoid X receptor-binding site in the proximal promoter of the Gpr81 gene, which was proven to be functional by electromobility shift assay and reporter assays. Importantly, small interfering RNA-mediated knockdown of Gpr81 partly reversed the inhibitory effect of TZDs on lipolysis in 3T3-L1 adipocytes. The coordinated PPARgamma-mediated regulation of the GPR81/Gpr81 and GPR109A/Gpr109A genes (and GPR109B in humans) presents a novel mechanism by which TZDs may reduce circulating free fatty acid levels and perhaps ameliorate insulin resistance in obese patients.

  14. How efficacious are 5-HT1B/D receptor ligands: an answer from GTP gamma S binding studies with stably transfected C6-glial cell lines.

    PubMed

    Pauwels, P J; Tardif, S; Palmier, C; Wurch, T; Colpaert, F C

    1997-01-01

    The intrinsic activity of a series of 5-hydroxytryptamine (serotonin, 5-HT) receptor ligands was analysed at recombinant h5-HT1B and h5-HT1D receptor sites using a [35S]GTP gamma S binding assay and membrane preparations of stably transfected C6-glial cell lines. Compounds either stimulated or inhibited [35S]GTP gamma S binding to a membrane preparation containing either h5-HT1B or h5-HT1D receptors. The potencies observed for most of the compounds at the h5-HT1B receptor subtype correlated with their potencies measured by inhibition of stimulated cAMP formation on intact cells. Apparent agonist potencies in the [35S]GTP gamma S binding assay to C6-glial/h5-HT1D membranes were, with the exception of 2-[5-[3-(4-methylsulphonylamino)benzyl-1 2,4-oxadiazol-5-yl]-1H-indol-3-yl] ethanamine (L694247), 5- to 13-times lower than in the cAMP assay on intact cells. This suggests that receptor coupling in the h5-HT1D membrane preparation is less efficient than that in the intact cell. It further appeared that 6-times more h5-HT1D than h5-HT1B binding sites were required to attain a similar, maximal (73%), 5-HT-stimulated [35S]GTP gamma S binding response: Hence, the h5-HT1B receptor in C6-glial cell membranes could be more efficiently coupled, even though some compounds more readily displayed intrinsic activity at h5-HT1D receptor sites [e.g. dihydroergotamine and (2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR127935)]. Efficacy differences were apparent for most of the compounds (sumatriptan, zolmitriptan, rizatriptan, N-methyl-3-[pyrrolidin-2(R)-ylmethyl]-1H-indol-5-ylmethyl sulfonamide (CP122638), dihydroergotamine, naratriptan and GR127935) that stimulated [35S]GTP gamma S binding compared to the native agonist 5-HT. The observed maximal responses were different for the h5-HT1B and h5-HT1D receptor subtypes. Few compounds behaved as full agonists: L694247, zolmitriptan and sumatriptan did so at

  15. Gamma-butyrolactone (GBL) disruption of passive avoidance learning in the day-old chick appears to be due to its effect on GABAB not gamma-hydroxybutyric [corrected] acid (GHB) receptors.

    PubMed

    Sherry, Joanne M; Hazi, Agnes; Hale, Mathew W; Milsome, Sarah L; Crowe, Simon F

    2009-02-11

    Gamma-butyrolactone (GBL) is a prodrug to gamma-hydroxybutyric acid (GHB) and metabolises to GHB when ingested. Discrimination stimulus studies report generalisation of effects of GHB to GBL. While amnesia is one of the most commonly reported symptoms of GHB's ingestion in human users, as yet few studies have examined this effect. Although an endogenous GHB specific receptor is present in the brain, several studies have indicated that the clinical effects of exogenous doses of GBL/GHB are due to its action on GABA(B) receptors rather than on the GHB receptor. In this series of studies, New Hampshire x White leghorn cockerels were trained using a modified version of the passive avoidance learning task. Subcutaneous injections of GBL induced a memory deficit by 10 min post-training, which persisted for at least 24 h. No effect on memory was seen with administration of the specific GHB agonist NCS-356 (gamma-p-chlorophenyl-trans-4-hydroxycrotonate). The GBL-induced memory deficit appeared similar to the deficit produced by baclofen, where the antagonist facilitated learning. Additionally, GBL-induced memory deficit was ameliorated by application of a GABA(B) antagonist. The results support the hypothesis that GBL exerts its influence on memory via the GABA(B) receptor rather than by the specific GHB receptor.

  16. Two mutational hotspots in the interleukin-2 receptor {gamma} chain gene causing human X-linked severe combined immunodeficiency

    SciTech Connect

    Pepper, A.E.; Puck, J.M.; Buckley, R.H.

    1995-09-01

    Human severe combined immunodeficiency (SCID), a syndrome of profoundly impaired cellular and humoral immunity, is most commonly caused by mutations in the X-linked gene for interleukin-2 (IL-2) receptor {gamma} chain (IL2RG). For mutational analysis of IL2RG in males with SCID, SSCP screening was followed by DNA sequencing. Of 40 IL2RG mutations found in unrelated SCID patients, 6 were point mutations at the CpG dinucleotide at cDNA 690-691, encoding amino acid R226. This residue lies in the extracellular domain of the protein in a region not previously recognized to be significantly conserved in the cytokine receptor gene family, 11 amino acids upstream from the highly conserved WSXWS motif. Three additional instances of mutation at another CpG dinucleotide at cDNA 879 produced a premature termination signal in the intracellular domain of IL2RG, resulting in loss of the SH2-homologous intracellular domain known to be essential for signaling from the IL-2 receptor complex. Mutations at these two hotspots constitute >20% of the X-linked SCID mutations found by our group and a similar proportion of all reported IL2RG mutations. 41 refs., 5 figs., 1 tab.

  17. A Case Study Correlating Innovative Gamma Ray Scanning Detection Systems Data to Surface Soil Gamma Spectrometry Results - 13580

    SciTech Connect

    Thompson, Shannon; Rodriguez, Rene; Billock, Paul; Lit, Peter

    2013-07-01

    HydroGeoLogic (HGL), Inc. completed a United States Environmental Protection Agency (USEPA) study to characterize radiological contamination at a site near Canoga Park, California. The characterized area contained 470 acres including the site of a prototype commercial nuclear reactor and other nuclear design, testing, and support operations from the 1950's until 1988 [1]. The site history included radiological releases during operation followed by D and D activities. The characterization was conducted under an accelerated schedule and the results will support the project remediation. The project has a rigorous cleanup to background agenda and does not allow for comparison to risk-based guidelines. To target soil sample locations, multiple lines of evidence were evaluated including a gamma radiation survey, geophysical surveys, historical site assessment, aerial photographs, and former worker interviews. Due to the time since production and decay, the primary gamma emitting radionuclide remaining is cesium-137 (Cs-137). The gamma ray survey covered diverse, rugged terrain using custom designed sodium iodide thallium-activated (NaI(Tl)) scintillation detection systems. The survey goals included attaining 100% ground surface coverage and detecting gamma radiation as sensitively as possible. The effectiveness of innovative gamma ray detection systems was tested by correlating field Cs-137 static count ratios to Cs-137 laboratory gamma spectrometry results. As a case study, the area encompassing the former location of the first nuclear power station in the U. S. was scanned, and second by second global positioning system (GPS)-linked gamma spectral data were evaluated by examining total count rate and nuclide-specific regions of interest. To compensate for Compton scattering from higher energy naturally occurring radionuclides (U-238, Th-232 and their progeny, and K-40), count rate ratios of anthropogenic nuclide-specific regions of interest to the total count rate were

  18. T lymphocytes bearing the gamma delta T cell receptor are susceptible to steroid-induced programmed cell death.

    PubMed

    Spinozzi, F; Agea, E; Bistoni, O; Travetti, A; Migliorati, G; Moraca, R; Nicoletti, I; Riccardi, C; Paoletti, F P; Vaccaro, R

    1995-05-01

    The mechanisms by which glucocorticoids suppress immune responses have not yet been clearly defined. In steroid-sensitive pathological conditions, an increase in gamma delta T cells can occur in certain untreated systemic autoimmune disorders and seems to be a peristent feature in most cases of systemic lupus erythematosus (SLE). Our previously published data demonstrated that immunosuppressive therapy normalized this expanded SLE T cell subset in parallel with clinical remission of the symptoms. To establish how corticosteroid treatment determines the disappearance of peripheral blood gamma delta T lymphocytes, circulating alpha beta and gamma delta T lymphocytes from seven SLE subjects with active disease and seven healthy individuals were cultured in the presence or absence of 10(-7) M Dexamethasone (DEX). Cell suspensions were then analysed for DNA fragmentation, characteristic of apoptotic cell death, by a new cytofluorimetric method. Conventional agarose-gel electrophoresis on the same T cell populations was carried out for comparison. Regular follow-ups for 6 months revealed in vivo steroid treatment determined a dramatic fall in SLE blood gamma delta T cells, and in vitro experiments seem to indicate that DEX-triggered apoptotic signals are confined to the double negative (CD4-CD8-) gamma delta T cell subpopulation which disappears after in vivo immunosuppressive therapy. Clinical and pathological remission of some autoimmune diseases is often obtained by corticosteroids. Our results offer new insights on the mechanisms through these hormones exert their potent inhibitory activities on immune system cells postulated to play a role in the generation of autoimmune responses. PMID:7725070

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

    SciTech Connect

    Du, Jing; Sun, Bing; Chen, Kui; Fan, Li; Wang, Zhao

    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 cerebellar 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.

  20. Interferon-Gamma Receptor Signaling Plays an Important Role in Restraining Murine Ovarian Tumor Progression

    PubMed Central

    Bian, Guanglin; Leigh, Nicholas D.; Du, Wei; Zhang, Lei; Li, Li; Cao, Xuefang

    2016-01-01

    Immune cell-derived cytotoxic pathways have been implicated in antitumor immune responses. The goal of this study is to characterize how these cytotoxic pathways influence ovarian cancer development. We have utilized the TgMISIIR-TAg transgenic mouse model which expresses the transforming SV40 TAg in the ovary, leading to spontaneous development of ovarian tumors that closely mimic human epithelial ovarian cancer. To test how perforin (Prf1), granzyme B (GzmB) and interferon-gamma (IFNg) impact tumor occurrence and progression, we bred the TgMISIIR-TAg transgene into Prf1−/−, GzmB−/−, and IFNgR1−/− mice. The transgenic females developed peritoneal tumors at 9–15 weeks and succumbed at 184 ± 37 days of age with 100% penetrance (n=41). Knockout of these cytotoxic genes does not affect tumor occurrence. However, loss of function in the IFNg signaling pathway significantly expedited tumor progression with all of the IFNg R1−/− TgMISIIR-TAg females succumbing to tumor outgrowth at 167 ± 27 days of age (p=0.0074, n=24). In contrast, loss of function of Prf1 or GzmB did not significantly impact tumor progression and host survival. Since tumor cells in the IFNg R1−/− TgMISIIR-TAg mice are IFNg R1 deficient, we used the implantable MOSEC (mouse ovarian surface epithelial cell) tumor line to validate that IFNg R signaling in host immune cells but not in tumor cells impacts tumor progression. Indeed, when the IFNg -responsive MOSEC cells were inoculated, IFNg R1−/− mice exhibited significantly higher tumor burden compared to WT mice. Furthermore, a MOSEC-splenocyte co-culture system confirmed that IFNg R1−/− immune cells were less effective than WT immune cells in controlling MOSEC tumor growth in vitro. Together, these results indicate that the IFNg R signaling pathway plays an important role in restraining murine ovarian tumor progression.

  1. Exposure to receptor-activator of NFkappaB ligand renders pre-osteoclasts resistant to IFN-gamma by inducing terminal differentiation.

    PubMed

    Huang, Willis; O'Keefe, Regis J; Schwarz, Edward M

    2003-01-01

    While it has been established that IFN-gamma is a strong activator of macrophages and a potent inhibitor of osteoclastogenesis in vitro, it is also known that this cytokine is produced in particular settings of inflammatory bone loss, such as infection and psoriatic arthritis. Because of the different kinetics between rapid IFN-gamma macrophage activation (<24 hours) and the slower receptor-activator of NFkappaB ligand (RANKL) osteoclast differentiation (7 days), we postulated that IFN-gamma would have different effects on early-stage and late-stage osteoclast precursors. In RAW264.7 cells and primary splenocyte cultures, pretreatment with RANKL rendered these cells resistant to maximally anti-osteoclastogenic doses of IFN-gamma. These cells were also resistant to IFN-gamma-induced nitric oxide production, morphological change, and surface upregulation of CD11b and receptor-activator of NFkappaB, suggesting that early exposure of osteoclast precursors to RANKL induces a broad resistance to the cellular effects of IFN-gamma. Changes in STAT1 activation did not correlate with this resistance, as IFN-gamma activated STAT1 equally in both early-stage and late-stage pre-osteoclasts. Furthermore, we failed to observe changes in TRAF6 expression following IFN-gamma treatment in pre-osteoclasts. Together these data support a model of inflammatory bone loss in which early exposure to RANKL can prime osteoclast precursors to form in the presence of high levels of IFN-gamma using mechanisms independent of the signal molecules STAT1 and TRAF6.

  2. Identification of artificial gamma-emitting nuclides using a scintillator-based gamma-ray spectral logging system

    SciTech Connect

    Conaway, J.G.

    1991-01-01

    The standard spectral gamma ray logging system used at the Nevada Test Site (NTS) contains a large sodium iodide detector which provides high efficiency but low energy resolution. To enhance the capabilities of this system for identifying artificial gamma-emitting nuclides, I developed and implemented a simple procedure for extracting artificial components from low-resolution gamma-ray spectra. This procedures uses three bias spectra, developed by a consultant using numerical modeling, representing the spectral response of the downhole instrument to naturally occurring potassium, uranium and thorium family gamma rays in a large-diameter air-filled borehole. To extract the artificial spectral components, the three basis spectra are first scaled to the recorded field spectrum using the usual spectral windows for K, U and Th; these windows bracket the photopeaks at 1.46, 1.76 and 2.61 MeV. Since most of the contribution from artificial nuclides will fall below 1.26 MeV (the lower limit of the potassium window) this scaling process should be insensitive to the presence of artificial nuclides. The scaled basis spectra are then subtracted from the field data, leaving a residual spectrum consisting of noise plus the contribution of any artificial gamma-emitting nuclides. This process is repeated for each spectrum in the log, or the spectra can be accumulated over any desired depth range for better statistics. Rather than inspect each spectrum visually, a parameter can be computed which indicates the presence of artificial nuclides; this parameter can be plotted along with the usual K, U and Th concentration estimates as a function of depth. These techniques have been used successfully on field data and provide us with an inexpensive screening tool to detect artificial nuclides along boreholes. 11 refs., 6 figs.

  3. EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer

    PubMed Central

    Brand, Lucas J.; Olson, Margaret E.; Ravindranathan, Preethi; Guo, Hong; Kempema, Aaron M.; Andrews, Timothy E.; Chen, Xiaoli; Raj, Ganesh V.; Harki, Daniel A.; Dehm, Scott M.

    2015-01-01

    The androgen receptor (AR) is a driver of prostate cancer (PCa) cell growth and disease progression. Therapies for advanced PCa exploit AR dependence by blocking the production or action of androgens, but these interventions inevitably fail via multiple mechanisms including mutation or deletion of the AR ligand binding domain (LBD). Thus, the development of new inhibitors which act through non-LBD interfaces is an unmet clinical need. EPI-001 is a bisphenol A-derived compound shown to bind covalently and inhibit the AR NH2-terminal domain (NTD). Here, we demonstrate that EPI-001 has general thiol alkylating activity, resulting in multilevel inhibitory effects on AR in PCa cell lines and tissues. At least one secondary mechanism of action associated with AR inhibition was found to be selective modulation of peroxisome proliferator activated receptor-gamma (PPARγ). These multi-level effects of EPI-001 resulted in inhibition of transcriptional activation units (TAUs) 1 and 5 of the AR NTD, and reduced AR expression. EPI-001 inhibited growth of AR-positive and AR-negative PCa cell lines, with the highest sensitivity observed in LNCaP cells. Overall, this study provides new mechanistic insights to the chemical biology of EPI-001, and raises key issues regarding the use of covalent inhibitors of the intrinsically unstructured AR NTD. PMID:25669987

  4. Peroxisome proliferator-activated receptor gamma and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles.

    PubMed

    Ray, Denise M; Spinelli, Sherry L; Pollock, Stephen J; Murant, Thomas I; O'Brien, Jamie J; Blumberg, Neil; Francis, Charles W; Taubman, Mark B; Phipps, Richard P

    2008-01-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands are important regulators of lipid metabolism, inflammation, and diabetes. We previously demonstrated that anucleate human platelets express the transcription factor PPARgamma and that PPARgamma ligands blunt platelet activation. To further understand the nature of PPARgamma in platelets, we determined the platelet PPARgamma isoform(s) and investigated the fate of PPARgamma following platelet activation. Our studies demonstrated that human platelets contain only the PPARgamma1 isoform and after activation with thrombin, TRAP, ADP or collagen PPARgamma is released from internal stores. PPARgamma release was blocked by a cytoskeleton inhibitor, Latrunculin A. Platelet-released PPARgamma was complexed with the retinoid X receptor (RXR) and retained its ability to bind DNA. Interestingly, the released PPARgamma and RXR were microparticle associated and the released PPARgamma/RXR complex retained DNA-binding ability. Additionally, a monocytic cell line, THP-1, is capable of internalizing PMPs. Further investigation following treatment of these cells with the PPARgamma agonist, rosiglitazone and PMPs revealed a possible transcellular mechanism to attenuate THP-1 activation. These new findings are the first to demonstrate transcription factor release from platelets, revealing the complex spectrum of proteins expressed and expelled from platelets, and suggests that platelet PPARgamma has an undiscovered role in human biology. PMID:18217139

  5. Susceptibility to dengue hemorrhagic fever in vietnam: evidence of an association with variation in the vitamin d receptor and Fc gamma receptor IIa genes.

    PubMed

    Loke, Hsin; Bethell, Delia; Phuong, Cao Xuan Thanh; Day, Nick; White, Nicholas; Farrar, Jeremy; Hill, Adrian

    2002-07-01

    Dengue is an increasingly important cause of morbidity and mortality in the tropics, with more than a billion people at risk each year. Immunologic enhancement is thought to contribute to disease pathogenesis. Only a very small proportion of infected individuals develop life-threatening dengue hemorrhagic fever (DHF). In a large case-control study with 400 DHF patients and 300 matched controls, we have assessed five polymorphic non-HLA host genetic factors that might influence susceptibility to DHF. The less frequent t allele of a variant at position 352 of the vitamin D receptor (VDR) gene was associated with resistance to severe dengue (P = 0.03). Homozygotes for the arginine variant at position 131 of the Fc gammaRIIA gene, who have less capacity to opsonize IgG2 antibodies, may also be protected from DHF (one-tailed P = 0.03). No associations were found with polymorphisms in the mannose binding lectin, interleukin-1 (IL-4), and IL-1 receptor antagonist genes. Further studies to confirm these associations are warranted.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  7. Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L GABA A receptors accounts for both direct activation and agonist modulation.

    PubMed

    Rüsch, Dirk; Zhong, Huijun; Forman, Stuart A

    2004-05-14

    At clinical concentrations, the potent intravenous general anesthetic etomidate enhances gamma-aminobutyric acid, type A (GABA(A)) receptor activity elicited with low gamma-aminobutyric acid (GABA) concentrations, whereas much higher etomidate concentrations activate receptors in the absence of GABA. Therefore, GABA(A) receptors may possess two types of etomidate sites: high affinity GABA-modulating sites and low affinity channel-activating sites. However, GABA modulation and direct activation share stereoselectivity for the (R)(+)-etomidate isomer and display parallel dependence on GABA(A) beta subunit isoforms, suggesting that these two actions may be mediated by a single class of etomidate site(s) that exert one or more molecular effects. In this study, we assessed GABA modulation by etomidate using leftward shifts of electrophysiological GABA concentration responses in cells expressing human alpha1beta2gamma2L receptors. Etomidate at up to 100 microm reduced GABA EC(50) values by over 100-fold but without apparent saturation, indicating the absence of high affinity etomidate sites. In experiments using a partial agonist, P4S, etomidate both reduced EC(50) and increased maximal efficacy, demonstrating that etomidate shifts the GABA(A) receptor gating equilibrium toward open states. Results were quantitatively analyzed using equilibrium receptor gating models, wherein a postulated class of equivalent etomidate sites both directly activates receptors and enhances agonist gating. A Monod-Wyman-Changeux co-agonist mechanism with two equivalent etomidate sites that allosterically enhance GABA(A) receptor gating independently of agonist binding most simply accounts for direct activation and agonist modulation. This model also correctly predicts the actions of etomidate on GABA(A) receptors containing a point mutation that increases constitutive gating activity.

  8. Measurements of alpha-gamma coincidences with an optimized dual-parameter multichannel system.

    PubMed

    Jurado Vargas, M; Caro Marroyo, B; Martín Sánchez, A

    2013-12-01

    Measurements of alpha-gamma coincidences have usually been carried out using a single channel to detect alpha-particles of a given energy, and a multichannel analyser for the detection of the corresponding coincident gamma-rays. An alpha-gamma coincidence chamber coupled to the electronic chain ending with a dual-parameter multichannel analyser has been developed and optimized. This system simultaneously stores alpha-particle, gamma-ray, and alpha-gamma coincidence spectra, which allows a general analysis to be made of the degree of coincidence between each alpha-particle and each gamma-ray emission. With this technique, a two-dimensional spectrum was obtained and analysed using "contour graphics". An application to the study of the decay scheme of (241)Am is described. PMID:24140879

  9. Short communication: Fc gamma receptors IIa and IIIa genetic polymorphisms do not predict HIV-1 disease progression in Kenyan women.

    PubMed

    Weis, Julie F; McClelland, R Scott; Jaoko, Walter; Mandaliya, Kishor N; Overbaugh, Julie; Graham, Susan M

    2015-03-01

    Genetic polymorphisms of the Fc gamma receptors (FcγR) IIa and IIIa have been implicated in the rate of HIV-1 disease progression, but results are inconsistent. We aimed to determine the association between these polymorphisms and disease progression in a cohort of HIV-1 seroconverters from Mombasa, Kenya. Neither FcγRIIa nor FcγRIIIa genotypes were predictive of set point viral load, viral load increase, CD4 decline, or HIV-1 disease progression (time to CD4 count <200 cells/mm(3), death, or treatment initiation). Our results suggest that FcγR polymorphisms might not be an important indicator of viral control and disease progression in this population.

  10. Enhancement of macrophage candidacidal activity by interferon-gamma. Increased phagocytosis, killing, and calcium signal mediated by a decreased number of mannose receptors.

    PubMed Central

    Maródi, L; Schreiber, S; Anderson, D C; MacDermott, R P; Korchak, H M; Johnston, R B

    1993-01-01

    In contrast to its macrophage-activating capacity, IFN-gamma downregulates expression of the macrophage mannose receptor (MMR), which mediates uptake of Candida and other microorganisms. We found that IFN-gamma induced a concentration-dependent increase in the capacity of human monocyte-derived macrophages to ingest and kill both opsonized and unopsonized Candida albicans and to release superoxide anion upon stimulation with Candida. Mannan or mannosylated albumin inhibited this activated uptake of unopsonized Candida, but glucan did not. Addition of mAb to complement receptor (CR) 3 did not inhibit ingestion; macrophages that lacked CR3 (leukocyte adhesion defect) showed normal upregulation of ingestion by IFN-gamma. The increased candidacidal activity of IFN-gamma-activated macrophages was associated with reduced expression of MMR by a mean of 79% and decreased pinocytic uptake of 125I-mannosylated BSA by 73%; K(uptake) of pinocytosis was not changed. Exposure of resident macrophages to unopsonized Candida did not elicit a transient increase in intracellular free Ca2+ ([Ca2+]i); macrophages activated by IFN-gamma expressed a brisk increase in [Ca2+]i on exposure to Candida. These data suggest that macrophage activation by IFN-gamma can enhance resistance to C. albicans infection in spite of downregulation of the MMR, perhaps through enhanced coupling of the MMR to microbicidal functions. PMID:8390485

  11. Fc Gamma Receptor Signaling in Mast Cells Links Microbial Stimulation to Mucosal Immune Inflammation in the Intestine

    PubMed Central

    Chen, Xiao; Feng, Bai-Sui; Zheng, Peng-Yuan; Liao, Xue-Qing; Chong, Jasmine; Tang, Shang-Guo; Yang, Ping-Chang

    2008-01-01

    Microbes and microbial products are closely associated with the pathogenesis of inflammatory bowel disease (IBD); however, the mechanisms behind this connection remain unclear. It has been previously reported that flagellin-specific antibodies are increased in IBD patient sera. As mastocytosis is one of the pathological features of IBD, we hypothesized that flagellin-specific immune responses might activate mast cells that then contribute to the initiation and maintenance of intestinal inflammation. Thirty-two colonic biopsy samples were collected from IBD patients. A flagellin/flagellin-specific IgG/Fc gamma receptor I complex was identified on biopsied mast cells using both immunohistochemistry and co-immunoprecipitation experiments; this complex was shown to co-localize on the surfaces of mast cells in the colonic mucosa of patients with IBD. In addition, an ex vivo study showed flagellin-IgG was able to bind to human mast cells. These cells were found to be sensitized to flagellin-specific IgG; re-exposure to flagellin induced the mast cells to release inflammatory mediators. An animal model of IBD was then used to examine flagellin-specific immune responses in the intestine. Mice could be sensitized to flagellin, and repeated challenges with flagellin induced an IBD-like T helper 1 pattern of intestinal inflammation that could be inhibited by pretreatment with anti-Fc gamma receptor I antibodies. Therefore, flagellin-specific immune responses activate mast cells in the intestine and play important roles in the pathogenesis of intestinal immune inflammation. PMID:18974296

  12. Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-{gamma} ligand, rosiglitazone

    SciTech Connect

    Wakui, Yuta; Inoue, Jun; Ueno, Yoshiyuki; Fukushima, Koji; Kondo, Yasuteru; Kakazu, Eiji; Obara, Noriyuki; Kimura, Osamu; Shimosegawa, Tooru

    2010-05-28

    Although chronic infection of hepatitis B virus (HBV) is currently managed with nucleot(s)ide analogues or interferon-{alpha}, the control of HBV infection still remains a clinical challenge. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor, that plays a role in glucose and lipid metabolism, immune reactions, and inflammation. In this study, the suppressive effect of PPAR ligands on HBV replication was examined in vitro using a PPAR{alpha} ligand, bezafibrate, and a PPAR{gamma} ligand, rosiglitazone. The effects were examined in HepG2 cells transfected with a plasmid containing 1.3-fold HBV genome. Whereas bezafibrate showed no effect against HBV replication, rosiglitazone reduced the amount of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen in the culture supernatant. Southern blot analysis showed that the replicative intermediates of HBV in the cells were also inhibited. It was confirmed that GW9662, an antagonist of PPAR{gamma}, reduced the suppressive effect of rosiglitazone on HBV. Moreover, rosiglitazone showed a synergistic effect on HBV replication with lamivudine or interferon-{alpha}-2b. In conclusion, this study showed that rosiglitazone inhibited the replication of HBV in vitro, and suggested that the combination therapy of rosiglitazone and nucleot(s)ide analogues or interferon could be a therapeutic option for chronic HBV infection.

  13. 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

  14. 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.

  15. Distinction between the effects of barbiturates, benzodiazepines and phenytoin on responses to gamma-aminobutyric acid receptor activation and antagonism by bicuculline and picrotoxin.

    PubMed Central

    Simmonds, M. A.

    1981-01-01

    1 Interactions of depressant and anticonvulsant drugs with the neuronal gamma-aminobutyric acid (GABA) receptor + effector system have been examined on afferent fibres to the rat cuneate nucleus in vitro. Three types of interaction have been measured: (a) potentiation of depolarizing responses to the GABA analogue, muscimol: (b) reduction in the potency of bicuculline as an antagonist of muscimol at the GABA receptor: (c) reduction in the potency of picrotoxin as an antagonist of muscimol acting on the effector mechanism. 2 Phenobarbitone reduced the potency of picrotoxin in doses which did not affect the potency of bicuculline and which caused only a small potentiation of muscimol. Pentobarbitone did not show such selectivity, a reduction in potency of picrotoxin always being accompanied by a reduction in potency of bicuculline and a substantial potentiation of muscimol. 3 Flurazepam and lorazepam both reduced the potency of picrotoxin without affecting that of bicuculline and with very little potentiation of muscimol. Phenytoin had no effect on the potency of picrotoxin whilst potentiating muscimol to the same extent as phenobarbitone. 4 The spectrum of drug activity in reducing the potency of picrotoxin correlates well with the reported anticonvulsant effects of these drugs against kindled amygdaloid seizures. Potentiation of muscimol and reduction of bicuculline potency appear more closely related to hypnotic properties. PMID:6265019

  16. Innovative Gamma Ray Spectrometer Detection Systems for Conducting Scanning Surveys on Challenging Terrain - 13583

    SciTech Connect

    Palladino, Carl; Mason, Bryan; Engle, Matt; LeVangie, James; Dempsey, Gregg; Klemovich, Ron

    2013-07-01

    The Santa Susana Field Laboratory located near Simi Valley, California was investigated to determine the nature and extent of gamma radiation anomalies. The primary objective was to conduct gamma scanning surveys over 100 percent of the approximately 1,906,000 square meters (471 acre) project site with the most sensitive detection system possible. The site had challenging topography that was not conducive to traditional gamma scanning detection systems. Terrain slope varied from horizontal to 48 degrees and the ground surface ranged from flat, grassy meadows to steep, rocky hillsides. In addition, the site was home to many protected endangered plant and animal species, and archaeologically significant sites that required minimal to no disturbance of the ground surface. Therefore, four innovative and unique gamma ray spectrometer detection systems were designed and constructed to successfully conduct gamma scanning surveys of approximately 1,076,000 square meters (266 acres) of the site. (authors)

  17. (Development of gamma emitting, receptor-binding, radiotracers for imaging the brain and pancreas)

    SciTech Connect

    Not Available

    1989-01-01

    This progress report covers the period from March 1, 1987 to Feb. 28, 1988. In studies to better understand the nature of the m-AChR receptor subtypes, we have generated a manuscript which has been submitted for publication in Life sciences entitled: The effect of chronic atropine and diisopropylfluorophosphate on rat brain muscarinic acetylcholine receptor subtype concentrations. We have also developed a more direct synthesis of 3-quinuclidinyl 4-iodobenzilate and its analogues. During this contract period, we have been involved with the synthesis of analogues 3-quinuclidinyl benzilate (QNB). We have determined the affinity constants of various compounds synthesized this year for the muscarinic receptor from rat corpus striatum. We have continued our investigation of the m-AChR in pancreas. 25 refs., 3 figs., 5 tabs.

  18. Ligands and Regulatory Modes of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Avians.

    PubMed

    Navidshad, Bahman; Royan, M

    2015-01-01

    Nutrient and gene interaction is an important aspect of poultry metabolism that determines performance capacity. New technological tools in biochemistry and biotechnology make it possible to explore the molecular base of phenotypic characteristics of poultry production. Fats act as energy deposits in the poultry body and are an essential constituent of animal cell membranes. From a functional standpoint, it has been suggested that ingested lipids change liver fatty acid synthesis and other lipogenic enzymes by regulating mRNA synthesis. Nuclear hormone receptors are ligand-activated transcription factors that control several genes involved in lipid metabolism. The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors. Three separate PPAR genes have been identified; they are known as α, δ, and γ. The most important metabolic effect of PPARγ in chicken is its task in adipogenesis. Reviewing the ligands of chicken PPARγ gene can be useful to a better understanding of PPARγ regulatory functions.

  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. 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.

  1. Networked gamma radiation detection system for tactical deployment

    NASA Astrophysics Data System (ADS)

    Mukhopadhyay, Sanjoy; Maurer, Richard; Wolff, Ronald; Smith, Ethan; Guss, Paul; Mitchell, Stephen

    2015-08-01

    A networked gamma radiation detection system with directional sensitivity and energy spectral data acquisition capability is being developed by the National Security Technologies, LLC, Remote Sensing Laboratory to support the close and intense tactical engagement of law enforcement who carry out counterterrorism missions. In the proposed design, three clusters of 2″ × 4″ × 16″ sodium iodide crystals (4 each) with digiBASE-E (for list mode data collection) would be placed on the passenger side of a minivan. To enhance localization and facilitate rapid identification of isotopes, advanced smart real-time localization and radioisotope identification algorithms like WAVRAD (wavelet-assisted variance reduction for anomaly detection) and NSCRAD (nuisance-rejection spectral comparison ratio anomaly detection) will be incorporated. We will test a collection of algorithms and analysis that centers on the problem of radiation detection with a distributed sensor network. We will study the basic characteristics of a radiation sensor network and focus on the trade-offs between false positive alarm rates, true positive alarm rates, and time to detect multiple radiation sources in a large area. Empirical and simulation analyses of critical system parameters, such as number of sensors, sensor placement, and sensor response functions, will be examined. This networked system will provide an integrated radiation detection architecture and framework with (i) a large nationally recognized search database equivalent that would help generate a common operational picture in a major radiological crisis; (ii) a robust reach back connectivity for search data to be evaluated by home teams; and, finally, (iii) a possibility of integrating search data from multi-agency responders.

  2. Regulation of retinoid X receptor gamma expression by fed state in mouse liver

    SciTech Connect

    Park, Sangkyu; Lee, Yoo Jeong; Ko, Eun Hee; Kim, Jae-woo

    2015-02-27

    Glucose metabolism is balanced by glycolysis and gluconeogenesis with precise control in the liver. The expression of genes related to glucose metabolism is regulated primarily by glucose and insulin at transcriptional level. Nuclear receptors play important roles in regulating the gene expression of glucose metabolism at transcriptional level. Some of these nuclear receptors form heterodimers with RXRs to bind to their specific regulatory elements on the target promoters. To date, three isotypes of RXRs have been identified; RXRα, RXRβ and RXRγ. However, their involvement in the interactions with other nuclear receptors in the liver remains unclear. In this study, we found RXRγ is rapidly induced after feeding in the mouse liver, indicating a potential role of RXRγ in controlling glucose or lipid metabolism in the fasting–feeding cycle. In addition, RXRγ expression was upregulated by glucose in primary hepatocytes. This implies that glucose metabolism governed by RXRγ in conjunction with other nuclear receptors. The luciferase reporter assay showed that RXRγ as well as RXRα increased SREBP-1c promoter activity in hepatocytes. These results suggest that RXRγ may play an important role in tight control of glucose metabolism in the fasting–feeding cycle. - Highlights: • Refeeding increases the RXRγ expression level in mouse liver. • RXRγ expression is induced by high glucose condition in primary hepatocytes. • RXRγ and LXRα have synergistic effect on SREBP-1c promoter activity. • RXRγ binds to LXRE(-299/-280) located within SREBP-1c promoter region and interacts with LXRα.

  3. Working Memory Deficits in Retinoid X receptor [gamma]-Deficient Mice

    ERIC Educational Resources Information Center

    Wietrzych, Marta; Meziane, Hamid; Sutter, Anne; Ghyselinck, Norbert; Chapman, Paul F.; Chambon, Pierre; Krezel, Wojciech

    2005-01-01

    Retinoid signaling has been recently shown to be required for mnemonic functions in rodents. To dissect the behavioral and molecular mechanisms involved in this requirement, we have analyzed the spatial and recognition working memory in mice carrying null mutations of retinoid receptors RAR[subscript [beta

  4. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation.

    PubMed Central

    Adams, M; Montague, C T; Prins, J B; Holder, J C; Smith, S A; Sanders, L; Digby, J E; Sewter, C P; Lazar, M A; Chatterjee, V K; O'Rahilly, S

    1997-01-01

    Activation of peroxisome proliferator-activated receptor (PPAR) gamma, a nuclear receptor highly expressed in adipocytes, induces the differentiation of murine preadipocyte cell lines. Recently, thiazolidinediones (TZDs), a novel class of insulin-sensitizing compounds effective in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) have been shown to bind to PPARgamma with high affinity. We have examined the effects of these compounds on the differentiation of human preadipocytes derived from subcutaneous (SC) and omental (Om) fat. Assessed by lipid accumulation, glycerol 3-phosphate dehydrogenase activity, and mRNA levels, subcultured preadipocytes isolated from either SC or Om depots did not differentiate in defined serum-free medium. Addition of TZDs (BRL49653 or troglitazone) or 15-deoxyDelta12,14prostaglandin J2 (a natural PPARgamma ligand) enhanced markedly the differentiation of preadipocytes from SC sites, assessed by all three criteria. The rank order of potency of these agents in inducing differentiation matched their ability to activate transcription via human PPARgamma. In contrast, preadipocytes from Om sites in the same individuals were refractory to TZDs, although PPARgamma was expressed at similar levels in both depots. The mechanism of this depot-specific TZD response is unknown. However, given the association between Om adiposity and NIDDM, the site-specific responsiveness of human preadipocytes to TZDs may be involved in the beneficial effects of these compounds on in vivo insulin sensitivity. PMID:9399962

  5. Peroxisome proliferator-activated receptor-gamma calls for activation in moderation: lessons from genetics and pharmacology.

    PubMed

    Knouff, Chris; Auwerx, Johan

    2004-12-01

    The peroxisome proliferator-activated receptor gamma (PPARgamma) is a prototypical member of the nuclear receptor superfamily and integrates the control of energy, lipid, and glucose homeostasis. PPARgamma can bind a variety of small lipophilic compounds derived from metabolism and nutrition. These ligands, in turn, determine cofactor recruitment to PPARgamma, regulating the transcription of genes in a variety of metabolic pathways. PPARgamma is the main target of the thiazolidinedione class of insulin-sensitizing drugs, which are currently a mainstay of therapy for type 2 diabetes. However, this therapy has a number of side effects. Here, we review the clinical consequences of PPARgamma polymorphisms in humans, as well as several studies in mice using general or tissue-specific knockout techniques. We also discuss the recent pharmacological literature describing a variety of new PPARgamma partial agonists and antagonists, as well as pan-PPAR agonists. The results of these studies have added to the understanding of PPARgamma function, allowing us to hypothesize a general mechanism of PPARgamma action and speculate on future trends in the use of PPARgamma as a target in the treatment of type II diabetes. PMID:15583022

  6. 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

  7. Protein kinase activity associated with Fc. gamma. /sub 2a/ receptor of a murine macrophage like cell line, P388D/sub 1/

    SciTech Connect

    Hirata, Y.; Suzuki, T.

    1987-12-15

    The properties of protein kinase activity associated with Fc receptor specific for IgG/sub 2a/(Fc..gamma../sub 2a/R) of a murine macrophage like cell line, P388D/sub 1/, were investigated. IgG/sub 2a/-binding protein isolated from the detergent lysate of P388D/sub 1/ cells by affinity chromatography of IgG-Sepharose was found to contain four distinct proteins of M/sub r/ 50,000, 43,000, 37,000, and 17,000, which could be autophosphorylated upon incubation with (..gamma..-/sup 32/P)ATP. The autophosphorylation of Fc..gamma../sub 2a/ receptor complex ceased when exogenous phosphate acceptors (casein or histone) were added in the reaction mixture. Phosphorylation of casein catalyzed by Fc..gamma../sub 2a/ receptor complex was dependent on casein concentration, increased with time or temperature, was dependent on the concentration of ATP and Mg/sup 2 +/, and was maximum at pH near 8. Casein phosphorylation was significantly inhibited by a high concentration of Mn/sup 2 +/ or KCl or by a small amount of heparin and was enhanced about 2-fold by protamine. Casein kinase activity associated with Fc..gamma../sub 2a/ receptor used ATP as substrate with an apparent K/sub m/ of 2 ..mu..M as well as GTP with an apparent K/sub m/ of 10 ..mu..M. Prior heating (60/sup 0/C for 15 min) or treatment with protease (trypsin or Pronase) of Fc..gamma../sub 2a/ receptor complex almost totally abolished casein kinase activity. Thin-layer chromatography of a partial acid hydrolysate of the phosphorylated casein showed that the site of phosphorylation is at a seryl residue. These results suggest that Fc..gamma../sub 2//sub a/ receptor forms a molecule complex with protein kinase, whose characteristics resemble those of type II casein kinase but are different from those of cyclic nucleotide dependent protein kinase or from those of C protein kinase.

  8. 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.; Kelly, D. G.

    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.

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

    SciTech Connect

    Andrews, M. T.; Corcoran, E. C.; Goorley, J. T.; Kelly, D. G.

    2015-03-01

    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.

  10. Structural analysis of the human interferon gamma receptor: a small segment of the intracellular domain is specifically required for class I major histocompatibility complex antigen induction and antiviral activity.

    PubMed Central

    Cook, J R; Jung, V; Schwartz, B; Wang, P; Pestka, S

    1992-01-01

    Mutations of the human interferon gamma (IFN-gamma) receptor intracellular domain have permitted us to define a restricted region of that domain as necessary for both induction of class I major histocompatibility complex antigen by IFN-gamma and protection against encephalomyocarditis virus. This region consists of five amino acids (YDKPH), all of which are conserved in the human and murine receptors. Tyr-457 and His-461 are essential for activity. Approximately 80% of the amino acids of the intracellular domain of the receptor is not required for major histocompatibility complex class I antigen induction or for antiviral protection against encephalomyocarditis virus. The observation that there was no protection by IFN-gamma against vesiculostomatitis virus indicates that other factors, in addition to chromosome 21 accessory factor(s), are required to generate the full complement of transduction signals from the human IFN-gamma receptor. Images PMID:1454813

  11. 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

  12. Importance of the gamma-aminobutyric acid(B) receptor C-termini for G-protein coupling.

    PubMed

    Grünewald, Sylvia; Schupp, Bettina J; Ikeda, Stephen R; Kuner, Rohini; Steigerwald, Frank; Kornau, Hans-Christian; Köhr, Georg

    2002-05-01

    Functional gamma-aminobutyric acid(B) (GABA(B)) receptors assemble from two subunits, GABA(B(1)) and GABA(B(2).) This heteromerization, which involves a C-terminal coiled-coil interaction, ensures efficient surface trafficking and agonist-dependent G-protein activation. In the present study, we took a closer look at the implications of the intracellular C termini of GABA(B(1)) and GABA(B(2)) for G-protein coupling. We generated a series of C-terminal mutants of GABA(B(1)) and GABA(B(2)) and tested them for physical interaction, surface trafficking, coupling to adenylyl cyclase, and G-protein-gated inwardly rectifying potassium channels in human embryonic kidney (HEK) 293 cells as well as on endogenous calcium channels in sympathetic neurons of the superior cervical ganglion (SCG). We found that the C-terminal interaction contributes only partly to the heterodimeric assembly of the subunits, indicating the presence of an additional interaction site. The described endoplasmic reticulum retention signal within the C terminus of GABA(B(1)) functioned only in the context of specific amino acids, which constitute part of the GABA(B(1)) coiled-coil sequence. This finding may provide a link between the retention signal and its shielding by the coiled coil of GABA(B(2).) In HEK293 cells, we observed that the two well-known GABA(B) receptor antagonists [S-(R*,R*)]-[3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl) phosphinic acid (CGP54626) and (+)-(2S)-5,5-dimethyl-2-morpholineacetic acid (SCH50911) CGP54626 and SCH50911 function as inverse agonists. The C termini of GABA(B(1)) and GABA(B(2)) strongly influenced agonist-independent G-protein coupling, although they were not necessary for agonist-dependent G-protein coupling. The C-terminal GABA(B) receptor mutants described here demonstrate that the active receptor conformation is stabilized by the coiled-coil interaction. Thus, the C-terminal conformation of the GABA(B) receptor may determine its

  13. 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%.

  14. Protons inhibit Cl- conductance by direct or allosteric interaction with the GABA-binding site in the rat recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptor.

    PubMed

    Wang, Ming-De; Rahman, Mozibur; Zhu, Di

    2005-12-28

    Functional roles of external pH on the Cl- conductance were examined on Xenopus oocytes expressing rat recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptors. Acidic pH inhibited GABA-response in a reversible and concentration-dependent manner, significantly increasing the EC50 without appreciably changing the slope or maximal currents induced by GABA in the alpha1beta2gamma2L and alpha1beta2 receptors. In contrast, protonation did not influence the pentobarbital-gated currents in the alpha1beta2gamma2L receptors, suggesting that protons do not modulate channel activity by directly affecting the channel gating process. Protons competitively inhibited the bicuculline-induced antagonism on GABA in the alpha1beta2gamma2L receptors. The data support the hypothesis that protons inhibit GABAA receptor function by direct or allosteric interaction with the GABA-binding site.

  15. Systemic cancer immunotherapy with Toll-like receptor 7 agonists

    PubMed Central

    Hotz, Christian; Bourquin, Carole

    2012-01-01

    Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. PMID:22720251

  16. Use of chemical modifications and site-directed mutagenesis to probe the functional role of thiol groups on the. gamma. subunit of Torpedo californica acetylcholine receptor

    SciTech Connect

    Pradier, L.; Yee, A.S.; McNamee, M.G. )

    1989-08-08

    Alkylation of Torpedo californica purified nicotinic acetylcholine receptor (AChR) with N-phenylmaleimide (NPM) under nonreducing conditions led to ion flux inhibition without affecting ligand binding properties. The {gamma} subunit was shown to be preferentially labeled by ({sup 3}H)NPM with partial labeling of the {alpha} subunit at higher NPM concentrations. Alkylation occurs at cysteine residues as confirmed by amino acid analysis. Cyanogen bromide peptide mapping of the {gamma} subunit indicates that at least two residues corresponding to Cys-416, -420, or -451 are labeled. Residues 416 and 420 are part of the proposed amphipathic helix, and the functional role of these two cysteines is further investigated by site-directed mutagenesis of T. californica AChR cDNAs and expression of the mutants in Xenopus laevis oocytes following injection of SP6 transcripts. Several features of SP6 transcripts are shown to be important for efficient translation in vivo. Mutations Cys {yields} Ser{gamma}416,420 and Cys {yields} Phe{gamma}416 did not perturb either the receptor functional properties or its expression levels. The double mutant Cys {yields} Phe{gamma}416,420 displayed a 30% decrease of normalized AChR activity. The relatively small effect of large steric mutations in the amphipathic helix argues against its presence in the tightly packed transmembrane domain of the protein.

  17. Multi-gamma-source CT imaging system: a feasibility study with the Poisson noise

    NASA Astrophysics Data System (ADS)

    Wi, Sunhee; Cho, Seungryong

    2016-03-01

    This study was performed to test the feasibility of multi-gamma-source CT imaging system. Gamma-source CT employs radioisotopes that emit monochromatic energy gamma-rays. The advantages of gamma-source CT include its immunity to beam hardening artifacts, its capacity of quantitative CT imaging, and its higher performance in low contrast imaging compared to the conventional x-ray CT. Radioisotope should be shielded by use of a pin-hole collimator so as to make a fine focal spot. Due to its low gamma-ray flux in general, the reconstructed image from a single gamma-source CT would suffer from high noise in data. To address this problem, we proposed a multi-gamma source CT imaging system and developed an iterative image reconstruction algorithm accordingly in this work. Conventional imaging model assumes a single linear imaging system typically represented by Mf = g. In a multi-gamma-source CT system however, the inversion problem is not any more based on a single linear system since one cannot separate a detector pixel value into multiple ones that are corresponding to each rays from the sources. Instead, the imaging model can be constructed by a set of linear system models each of which assumes an estimated measurement g. Based on this model, the proposed algorithm has a weighting step which distributes each projection data into multiple estimated measurements. We used two gamma sources at various positions and with varying intensities in this numerical study to demonstrate its feasibility. Therefore, the measured projection data(g) is separated into each estimated projection data(g1, g2) in this study. The proposed imaging protocol is believed to contribute to both medical and industrial applications.

  18. Determination of the optimal positions for installing gamma ray detection systems at Tehran Research Reactor

    NASA Astrophysics Data System (ADS)

    Sayyah, A.; Rahmani, F.; Khalafi, H.

    2015-09-01

    Dosimetric instruments must constantly monitor radiation dose levels in different areas of nuclear reactor. Tehran Research Reactor (TRR) has seven beam tubes for different research purposes. All the beam tubes extend from the reactor core to Beam Port Floor (BPF) of the reactor facility. During the reactor operation, the gamma rays exiting from each beam tube outlet produce a specific gamma dose rate field in the space of the BPF. To effectively monitor the gamma dose rates on the BPF, gamma ray detection systems must be installed in optimal positions. The selection of optimal positions is a compromise between two requirements. First, the installation positions must possess largest gamma dose rates and second, gamma ray detectors must not be saturated in these positions. In this study, calculations and experimental measurements have been carried out to identify the optimal positions of the gamma ray detection systems. Eight three dimensional models of the reactor core and related facilities corresponding to eight scenarios have been simulated using MCNPX Monte Carlo code to calculate the gamma dose equivalent rate field in the space of the BPF. These facilities are beam tubes, thermal column, pool, BPF space filled with air, facilities such as neutron radiography facility, neutron powder diffraction facility embedded in the beam tubes as well as biological shields inserted into the unused beam tubes. According to the analysis results of the combined gamma dose rate field, three positions on the north side and two positions on the south side of the BPF have been recognized as optimal positions for installing the gamma ray detection systems. To ensure the consistency of the simulation data, experimental measurements were conducted using TLDs (600 and 700) pairs during the reactor operation at 4.5 MW.

  19. Enhancement by GABA of the association rate of picrotoxin and tert-butylbicyclophosphorothionate to the rat cloned alpha 1 beta 2 gamma 2 GABAA receptor subtype.

    PubMed Central

    Dillon, G. H.; Im, W. B.; Carter, D. B.; McKinley, D. D.

    1995-01-01

    1. We examined how gamma-aminobutyric acid (GABA) influences interaction of picrotoxin and tert-butylbicyclophosphorothionate (TBPS) with recombinant rat alpha 1 beta 2 gamma 2 GABAA receptors stably expressed in human embryonic kidney cells (HEK293), as monitored with changes in Cl- currents measured by the whole-cell patch clamp technique. 2. During application of GABA (5 microM) for 15 s, picrotoxin and TBPS dose-dependently accelerated the decay of inward GABA-induced currents (a holding potential of -60 mV under a symmetrical Cl- gradient). The drugs, upon preincubation with the receptors, also reduced the initial current amplitude in a preincubation time and concentration-dependent manner. This indicates their interaction with both GABA-bound and resting receptors. 3. The half maximal inhibitory concentration for picrotoxin and TBPS at the beginning of a 15 s GABA (5 microM) pulse was several times greater than that obtained at the end of the pulse. GABA thus appears to enhance picrotoxin and TBPS potency, but only at concentrations leading to occupancy of both high and low affinity GABA sites, i.e., 5 microM. Preincubation of the receptors with the drugs in the presence of GABA at 200 nM, which leads to occupancy of only high affinity GABA sites in the alpha 1 beta 2 gamma 2 subtype, produced no appreciable change in potency of picrotoxin or TBPS. This indicates that they preferentially interact with multiliganded, but not monoliganded receptors, unlike U-93631, a novel ligand to the picrotoxin site, which has higher affinity to both mono- and multiliganded receptors than resting receptors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582470

  20. 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.

  1. Measurements of gamma-ray production cross sections for shielding materials of space nuclear systems

    NASA Technical Reports Server (NTRS)

    Orphan, V. J.; John, J.; Hoot, C. G.

    1972-01-01

    Measurements of secondary gamma ray production from neutron interactions have been made over the entire energy range of interest in shielding applications. The epithermal capture gamma ray yields for both resolved gamma ray lines and continuum have been measured from thermal energies to 100 KeV for natural tungsten and U-238, two important candidate shield materials in SNAP reactor systems. Data are presented to illustrate the variation of epithermal capture gamma ray yields with neutron energy. The gamma ray production cross sections from (n,xy) reactions have been measured for Fe and Al from the threshold energies for inelastic scattering to approximately 16 MeV. Typical Fe and Al cross sections obtained with high-neutron energy resolution and averaged over broad neutron-energy groups are presented.

  2. Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats.

    PubMed

    Buckingham, R E; Al-Barazanji, K A; Toseland, C D; Slaughter, M; Connor, S C; West, A; Bond, B; Turner, N C; Clapham, J C

    1998-08-01

    Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia. PMID:9703335

  3. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review.

    PubMed

    Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M; Heiss, Elke H; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M; Atanasov, Atanas G

    2014-11-01

    Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements.

  4. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review

    PubMed Central

    Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M.; Heiss, Elke H.; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M.; Atanasov, Atanas G.

    2014-01-01

    Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements. PMID:25083916

  5. Interferon-gamma potentiates NMDA receptor signaling in spinal dorsal horn neurons via microglia–neuron interaction

    PubMed Central

    Sonekatsu, Mayumi; Yamanaka, Manabu; Nishio, Naoko; Tsutsui, Shunji; Yamada, Hiroshi; Yoshida, Munehito; Nakatsuka, Terumasa

    2016-01-01

    Background Glia–neuron interactions play an important role in the development of neuropathic pain. Expression of the pro-inflammatory cytokne →cytokine Interferon-gamma (IFNγ) is upregulated in the dorsal horn after peripheral nerve injury, and intrathecal IFNγ administration induces mechanical allodynia in rats. A growing body of evidence suggests that IFNγ might be involved in the mechanisms of neuropathic pain, but its effects on the spinal dorsal horn are unclear. We performed blind whole-cell patch-clamp recording to investigate the effect of IFNγ on postsynaptic glutamate-induced currents in the substantia gelatinosa neurons of spinal cord slices from adult male rats. Results IFNγ perfusion significantly enhanced the amplitude of NMDA-induced inward currents in substantia gelatinosa neurons, but did not affect AMPA-induced currents. The facilitation of NMDA-induced current by IFNγ was inhibited by bath application of an IFNγ receptor-selective antagonist. Adding the Janus activated kinase inhibitor tofacitinib to the pipette solution did not affect the IFNγ-induced facilitation of NMDA-induced currents. However, the facilitatory effect of IFNγ on NMDA-induced currents was inhibited by perfusion of the microglial inhibitor minocycline. These results suggest that IFNγ binds the microglial IFNγ receptor and enhances NMDA receptor activity in substantia gelatinosa neurons. Next, to identify the effector of signal transmission from microglia to dorsal horn neurons, we added an inhibitor of G proteins, GDP-β-S, to the pipette solution. In a GDP-β-S–containing pipette solution, IFNγ-induced potentiation of the NMDA current was significantly suppressed after 30 min. In addition, IFNγ-induced potentiation of NMDA currents was blocked by application of a selective antagonist of CCR2, and its ligand CCL2 increased NMDA-induced currents. Conclusion Our findings suggest that IFNγ enhance the amplitude of NMDA-induced inward currents in substantia

  6. Telmisartan, an AT1 receptor blocker and a PPAR gamma activator, alleviates liver fibrosis induced experimentally by Schistosoma mansoni infection

    PubMed Central

    2013-01-01

    Background 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. Methods 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. Results 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

  7. Solar System Gamma Ray observations using Fermi-LAT detector

    SciTech Connect

    Giglietto, N.

    2009-04-08

    The Fermi Gamma-ray Space Telescope, launched in June 2008, is an international space mission dedicated to the study of the high-energy gamma rays from the Universe. The main instrument aboard Fermi is the Large Area Telescope (LAT), a pair conversion telescope equipped with the state-of-the art in gamma-ray detectors technology, and operating at energies >30 MeV. During first two months of data taking, Fermi has detected high-energy gamma rays from the quiet Sun and the Moon. This emission is produced by interactions of cosmic rays; by nucleons with the solar and lunar surface, and electrons with solar photons in the heliosphere. While the Moon was detected by EGRET on CGRO with low statistics, Fermi provides high-sensitivity measurements on a daily basis allowing both short- and long-term variability to be studied. Since Galactic cosmic rays are at their maximum flux at solar minimum we expect that the quiescent solar and lunar emission to be a maximum during the period covered by this report. Fermi is the only mission capable of monitoring the Sun at energies above several hundred MeV over the full 24th solar cycle. We present first analysis showing images of Moon and the quiet emission of the solar disk, giving a description of the analysis tools used.

  8. Agonists of proteinase-activated receptor-2 enhance IFN-gamma-inducible effects on human monocytes: role in influenza A infection.

    PubMed

    Feld, Micha; Shpacovitch, Victoria M; Ehrhardt, Christina; Kerkhoff, Claus; Hollenberg, Morley D; Vergnolle, Nathalie; Ludwig, Stephan; Steinhoff, Martin

    2008-05-15

    Proteinase-activated receptor-2 (PAR(2)) is expressed by different types of human leukocytes and involved in the development of inflammatory and infectious diseases. However, its precise role in the regulation of human monocyte and macrophage function during viral infection remains unclear. Also, the ability of PAR(2) agonists to enhance the effects induced by immune mediators during infection or inflammation is still poorly investigated. Therefore, we investigated the ability of a PAR(2) agonist to enhance IFN-gamma-induced suppression of influenza A virus replication in human monocytes. We found that this effect correlates with an increased abundance of IkappaBalpha after costimulation of cells with PAR(2) agonist and IFN-gamma. Remarkably, coapplication of PAR(2) agonist and IFN-gamma also enhances the effects of IFN-gamma on IFN-gamma-inducible protein 10 kDa release, and CD64 and alphaVbeta3 surface expression by human monocytes. Together, these findings indicate a potentially protective role of PAR(2) activation during the progression of influenza A virus infection. This effect could be associated with the ability of PAR(2) agonists to enhance IFN-gamma-induced protective effects on human monocytes.

  9. 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

    SciTech Connect

    Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

    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) production 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.

  10. Genomic organization and recombinational unit duplication-driven evolution of ovine and bovine T cell receptor gamma loci

    PubMed Central

    Vaccarelli, Giovanna; Miccoli, Maria C; Antonacci, Rachele; Pesole, Graziano; Ciccarese, Salvatrice

    2008-01-01

    Background In humans and mice ("γδ low species") less than 5% of the peripheral blood T lymphocytes are gamma/delta T cells, whereas in chicken and artiodactyls ("γδ high species") gamma/delta T cells represent about half of the T cells in peripheral blood. In cattle and sheep (Bovidae) two paralogous T cell receptor gamma loci (TRG1 and TRG2) have been found. TRG1 is located on 4q3.1, within a region of homology with the human TRG locus on chromosome 7, while TRG2 localizes on 4q2.2 and appears to be unique to ruminants. The purpose of this study was the sequencing of the genomic regions encompassing both loci in a "γδ high" organism and the analysis of their evolutionary history. Results We obtained the contiguous genomic sequences of the complete sheep TRG1 and TRG2 loci gene repertoire and we performed cattle/sheep sequence analysis comparison using data available through public databases. Dot plot similarity matrix comparing the two sheep loci with each other has shown that variable (V), joining (J) and constant (C) genes have evolved through a series of duplication events involving either entire cassettes, each containing the basic V-J-J-C recombinational unit, or single V genes. The phylogenetic behaviour of the eight enhancer-like elements found in the sheep, compared with the single copy present in the human TRG locus, and evidence from concordant insertions of repetitive elements in all analyzed TRGJ blocks allowed us to infer an evolutionary scenario which highlights the genetic "flexibility" of this region and the duplication-driven evolution of gene cassettes. The strong similarity of the human and Bovidae intergenic J-J-C regions, which display an enhancer-like element at their 3' ends, further supports their key role in duplications. Conclusion We propose that only duplications of entire J-J-C regions that possessed an enhancer-like element at their 3' end, and acquired at least one V segment at their 5' end, were selected and fixed as

  11. Emerging role of the peroxisome proliferator-activated receptor-gamma in hepatocellular carcinoma

    PubMed Central

    Hsu, Hui-Tzu; Chi, Chin-Wen

    2014-01-01

    Hepatocellular carcinoma (HCC) is the major leading cause of cancer death worldwide. Hepatitis B virus, hepatitis C virus, alcohol consumption, non-alcoholic fatty liver disease, and diabetes are the major risks for developing HCC. Until now, recurrence and metastasis are the major cause of death in HCC patients. Therefore, identification of new effective molecular targets is an urgent need for treatment of HCC. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor which could be activated by PPARγ agonists such as thiazolidinediones, and natural PPARγ ligand (such as 15-deoxy-Δ12,14-prostaglandin J2, 15d-PGJ2). Increasing in vitro and in vivo evidence has demonstrated that PPARγ agonists exhibit an inhibitory role on tumor cell growth, migration, and invasion, suggesting that PPARγ activation may play an important role in the regulation of growth of HCC. It has been reported that PPARγ activation by thiazolidinediones or overexpression of PPARγ by virus-mediated gene transfer has shown growth inhibitory effects in hepatoma cells, but the expression level of PPARγ in HCC tissues still remains conflicting. Notably, a novel PPARγ agonist, honokiol, has recently been found to activate the PPARγ/RXR heterodimer, and has also exhibited significant anti-cancer effects in hepatoma cells. In the present review, we summarized studies on the role and the molecular regulation of PPARγ in HCC development in vitro and in vivo. PPARγ has the potential to be a therapeutic target for future treatment of HCC. PMID:27508182

  12. Ligand-independent activation of the glucocorticoid receptor by ursodeoxycholic acid: Repression of IFN-{gamma}-induced MHC class II gene expression via a glucocorticoid receptor-dependent pathway

    SciTech Connect

    Tanaka, Hirotoshi; Makino, Yuichi; Miura, Takanori

    1996-02-15

    The therapeutic effectiveness of ursodeoxycholic acid (UDCA) for various autoimmune liver diseases strongly indicates that UDCA possesses immunomodulatory activities. Experimental evidence also supports this notion, since, for example, UDCA has been shown to suppress secretion of IL-2, IL-4, and IFN-{gamma} from activated T lymphocytes, and Ig production from B lymphocytes. To investigate the mechanical background of UDCA-mediated immunomodulation, we asked whether UDCA interacts with the intracellular signal transduction pathway, especially whether it is involved in immunosuppressive glucocorticoid hormone action. For this purpose, we used a cloned Chinese hamster ovary cell line, CHOpMTGR, in which glucocorticoid receptor cDNA was stably integrated. In immunocytochemical analysis, we found that treatment with UDCA promoted the nuclear translocation of the glucocorticoid receptor in a ligand-independent fashion, which was further confirmed by immunoprecipitation assays. Moreover, the translocated glucocorticoid receptor demonstrated sequence-specific DNA binding activity. Transient transfection experiments revealed that treatment of the cells with UDCA marginally enhanced glucocorticoid-responsive gene expression. We also showed that UDCA suppressed IFN-{gamma}-mediated induction of MHC class II gene expression via the glucocorticoid receptor-mediated pathway. Together, UDCA-dependent promotion of translocation of the glucocorticoid receptor may be associated with, at least in part, its immunomodulatory action through glucocorticoid receptor-mediated gene regulation. 68 refs., 8 figs.

  13. Effects of hippocampal injections of a novel ligand selective for the alpha 5 beta 2 gamma 2 subunits of the GABA/benzodiazepine receptor on Pavlovian conditioning.

    PubMed

    Bailey, David J; Tetzlaff, Julie E; Cook, James M; He, Xiaohui; Helmstetter, Fred J

    2002-07-01

    Benzodiazepine pharmacology has led to greater insight into the neural mechanisms underlying learning and anxiety. The synthesis of new compounds capable of modulating responses produced by these receptors has been made possible by the development of an isoform model of the GABA(A)/benzodiazepine receptor complex. In the current experiment, rats were pretreated with several concentrations of the novel ligand RY024 (an alpha 5 beta 2 gamma 2 -selective benzodiazepine receptor inverse agonist) in the hippocampus and were trained in a Pavlovian fear conditioning paradigm. RY024 independently produced fear-related behavior prior to training and, at the highest concentration, decreased the strength of conditioning observed 24 h after training. These data provide further evidence for the involvement of hippocampal GABA(A)/benzodiazepine receptors in learning and anxiety.

  14. 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.

  15. Development of a high resolution gamma camera system using finely grooved GAGG scintillator

    NASA Astrophysics Data System (ADS)

    Yamamoto, Seiichi; Kataoka, Jun; Oshima, Tsubasa; Ogata, Yoshimune; Watabe, Tadashi; Ikeda, Hayato; Kanai, Yasukazu; Hatazawa, Jun

    2016-06-01

    High resolution gamma cameras require small pixel scintillator blocks with high light output. However, manufacturing a small pixel scintillator block is difficult when the pixel size becomes small. To solve this limitation, we developed a high resolution gamma camera system using a finely grooved Ce-doped Gd3Al2Ga3O12 (GAGG) plate. Our gamma camera's detector consists of a 1-mm-thick finely grooved GAGG plate that is optically coupled to a 1-in. position sensitive photomultiplier tube (PSPMT). The grooved GAGG plate has 0.2×0.2 mm pixels with 0.05-mm wide slits (between the pixels) that were manufactured using a dicing saw. We used a Hamamatsu PSPMT with a 1-in. square high quantum efficiency (HQE) PSPMT (R8900-100-C12). The energy resolution for the Co-57 gamma photons (122 keV) was 18.5% FWHM. The intrinsic spatial resolution was estimated to be 0.7-mm FWHM. With a 0.5-mm diameter pinhole collimator mounted to its front, we achieved a high resolution, small field-of-view gamma camera. The system spatial resolution for the Co-57 gamma photons was 1.0-mm FWHM, and the sensitivity was 0.0025%, 10 mm from the collimator surface. The Tc-99m HMDP administered mouse images showed the fine structures of the mouse body's parts. Our developed high resolution small pixel GAGG gamma camera is promising for such small animal imaging.

  16. Polyacetylenes from Notopterygium incisum–New Selective Partial Agonists of Peroxisome Proliferator-Activated Receptor-Gamma

    PubMed Central

    Liu, Xin; Noha, Stefan M.; Malainer, Clemens; Kramer, Matthias P.; Cocic, Amina; Kunert, Olaf; Schinkovitz, Andreas; Heiss, Elke H.; Schuster, Daniela

    2013-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPARγ agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPARγ activation using a PPARγ-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPARγ agonists in the luciferase reporter model. Since PPARγ activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 µM) in the luciferase reporter model was blocked upon co-treatment with the PPARγ antagonist T0070907 (1 µM). Falcarindiol bound to the purified human PPARγ receptor with a Ki of 3.07 µM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPARγ expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPARγ agonists, having potential to be further explored as pharmaceutical leads or dietary supplements. PMID:23630612

  17. Peroxisome proliferator-activated receptor gamma in the human pituitary gland: expression and splicing pattern in adenomas versus normal pituitary.

    PubMed

    Occhi, G; Albiger, N; Berlucchi, S; Gardiman, M; Scanarini, M; Scienza, R; Fassina, A; Mantero, F; Scaroni, C

    2007-07-01

    Pituitary adenomas are slow-growing tumours arising within the pituitary gland. If secreting, they give rise to well-known syndromes such as Cushing's disease or acromegaly; when hormonally inactive, they come to clinical attention often with local mass effects or pituitary deficiency. Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor with a key role in fat and glucose metabolism, but also involved in several neoplasia, has recently been detected in pituitary adenomas. In the present study, we evaluated the occurrence and splicing profile of PPARgamma in 43 cases of pituitary adenoma of different subtypes and compared it to 12 normal pituitary glands. By real-time polymerase chain reaction, PPARgamma was expressed as much in adrenocorticotrophic hormone (ACTH)-secreting and ACTH-silent adenomas as in controls, with a moderate underexpression in somatotrophinomas and prolactinomas and overexpression in 54% of nonfunctioning pituitary adenomas (NFPA). There was no apparent qualitative change in the splicing profile of pathological pituitary glands, nor was the presence of specific isoforms with dominant negative effects against PPARgamma detected. Western blotting revealed similar expression levels in the different subgroups of pituitary adenomas and normal glands. Immunohistochemistry confirmed PPARgamma expression in approximately one-half of analysed samples. The intra- and intergroup differences observed in pituitary adenomas may represent new elements in the process of understanding the different clinical responses of Cushing's and Nelson patients to PPARgamma-ligand treatment. Moreover, the higher level of PPARgamma expression detected in the NFPA subgroup may suggest its possible role as a molecular target in these pituitary adenomas, paving the way for investigations on the effectiveness of treatment with thiazolidinediones in such patients. PMID:17561883

  18. The mouse CCR2 gene is regulated by two promoters that are responsive to plasma cholesterol and peroxisome proliferator-activated receptor {gamma} ligands

    SciTech Connect

    Chen Yiming; Green, Simone R.; Ho, Jessica; Li, Andrew; Almazan, Felizidad; Quehenberger, Oswald . E-mail: oquehenberger@ucsd.edu

    2005-06-24

    We have previously shown that the expression of monocyte CCR2, the receptor for monocyte chemoattractant protein-1, is induced by plasma cholesterol. The present study examines the mechanisms that regulate monocyte CCR2 expression in hypercholesterolemia using a mouse model. Our data demonstrate that in the mouse, CCR2 expression in circulating monocytes is controlled by two promoters P1 and P2. The two distinct transcripts, which encode the same protein, are produced by alternative splicing in the 5'-untranslated region. Both promoters are constitutively active, but only P2 is stimulated by cholesterol. However, both promoters are repressed by peroxisome proliferator-activated receptor {gamma}.

  19. Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with asprin hypersensitivity in asthmatics

    PubMed Central

    Oh, Sun-Hee; Park, Se-Min; Park, Jong-Sook; Jang, An-Soo; Lee, Yong-Mok; Uh, Soo-Taek; Kim, Young Hoon; Choi, In-Seon; Kim, Mi-Kyeong; Park, Byeong Lae

    2009-01-01

    Purpose Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors activated by ligands of the nuclear hormone receptor superfamily. The activation of PPARγ regulates inflammation by downregulating the production of Th2 type cytokines and eosinophil function. In addition, a range of natural substances, including arachidonate pathway metabolites such as 15-hydroxyeicosatetranoic acid (15-HETE), strongly promote PPARG expression. Therefore, genetic variants of the PPARG gene may be associated with the development of aspirin-intolerant asthma (AIA). We investigated the relationship between single nucleotide polymorphism (SNP) of the PPARG gene and AIA. Methods Based on the results of an oral aspirin challenge, asthmatics (n=403) were categorized into two groups: those with a decrease in FEV1 of 15% or greater (AIA) or less than 15% (aspirin-tolerant asthma, ATA). We genotyped two single nucleotide polymorphisms in the PPARG gene from Korean asthmatics and normal controls (n=449): +34C>G (Pro12Ala) and +82466C>T (His449His). Results Logistic regression analysis showed that +82466C>T and haplotype 1 (CC) were associated with the development of aspirin hypersensitivity in asthmatics (P=0.04). The frequency of the rare allele of +82466C>T was significantly higher in AIA patients than in ATA patients in the recessive model [P=0.04, OR=3.97 (1.08-14.53)]. In addition, the frequency of PPARG haplotype 1 was significantly lower in AIA patients than in ATA patients in the dominant model (OR=0.25, P=0.04). Conclusions The +82466C>T polymorphism and haplotype 1 of the PPARG gene may be linked to increased risk for aspirin hypersensitivity in asthma. PMID:20224667

  20. Altered promoter recycling rates contribute to dominant-negative activity of human peroxisome proliferator-activated receptor-gamma mutations associated with diabetes.

    PubMed

    Li, Gang; Leff, Todd

    2007-04-01

    The transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) plays an important role in regulating lipid and glucose metabolism and improves insulin sensitivity in diabetic patients when activated by thiazolidinedione drugs. Several loss-of-function mutations in PPARgamma have been identified that cause lipodystrophy and diabetes in humans. Because affected individuals are heterozygotes and have one normal PPARgamma allele, it is of interest to know whether these mutations act in a dominant-negative fashion to inhibit the activity of the wild-type (WT) receptor. Here we compare the molecular phenotypes of two previously identified PPARgamma mutations: P467L, reported to be dominant negative; and F388L, reported to be devoid of dominant-negative activity. We developed a competitive chromatin immunoprecipitation assay to measure the relative ability of mutant PPARgamma to compete with WT receptor for binding to a PPAR regulatory element (PPRE)-containing promoter. By determining the ratio of mutant and WT receptors bound to a PPRE over time, we estimated the relative promoter turnover rate of each receptor. This assay demonstrated that PPARgamma bearing the P467L had a reduced promoter turnover rate compared with the F388L receptor, and over time out-competed the WT receptor for promoter binding sites. We propose that the P467L receptor is dominant negative because in a cell containing both WT and mutant receptors, the majority of the PPAR-regulated promoters will be occupied by the transcriptionally defective mutant receptor. In contrast, the F388L mutation lacks dominant-negative activity because its more rapid promoter turnover rate prevented it from out-competing the WT receptor for promoter binding sites.

  1. Radiation detection system for portable gamma-ray spectroscopy

    DOEpatents

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

    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.

  2. 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.

  3. Experimental approaches for the development of gamma spectroscopy well logging system

    SciTech Connect

    Shin, Jehyun; Hwang, Seho; Kim, Jongman; Won, Byeongho

    2015-03-10

    This article discusses experimental approaches for the development of gamma spectroscopy well logging system. Considering the size of borehole sonde, we customize 2 x 2 inches inorganic scintillators and the system including high voltage, preamplifier, amplifier and multichannel analyzer (MCA). The calibration chart is made by test using standard radioactive sources so that the measured count rates are expressed by energy spectrum. Optimum high-voltage supplies and the measurement parameters of each detector are set up by experimental investigation. Also, the responses of scintillation detectors have been examined by analysis according to the distance between source and detector. Because gamma spectroscopy well logging needs broad spectrum, high sensitivity and resolution, the energy resolution and sensitivity as a function of gamma ray energy are investigated by analyzing the gamma ray activities of the radioactive sources.

  4. Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors functional regulation during enhanced liver cell proliferation by GABA and 5-HT chitosan nanoparticles treatment.

    PubMed

    Shilpa, Joy; Pretty, Mary Abraham; Anitha, Malat; Paulose, Cheramadathikudyil Skaria

    2013-09-01

    Liver is one of the major organs in vertebrates and hepatocytes are damaged by many factors. The liver cell maintenance and multiplication after injury and treatment gained immense interest. The present study investigated the role of Gamma aminobutyric acid (GABA) and serotonin or 5-hydroxytryptamine (5-HT) coupled with chitosan nanoparticles in the functional regulation of Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors mediated cell signaling mechanisms, extend of DNA methylation and superoxide dismutase activity during enhanced liver cell proliferation. Liver injury was achieved by partial hepatectomy of male Wistar rats and the GABA and 5-HT chitosan nanoparticles treatments were given intraperitoneally. The experimental groups were sham operated control (C), partially hepatectomised rats with no treatment (PHNT), partially hepatectomised rats with GABA chitosan nanoparticle (GCNP), 5-HT chitosan nanoparticle (SCNP) and a combination of GABA and 5-HT chitosan nanoparticle (GSCNP) treatments. In GABA and 5-HT chitosan nanoparticle treated group there was a significant decrease (P<0.001) in the receptor expression of Gamma aminobutyric acid B and a significant increase (P<0.001) in the receptor expression of 5-hydroxy tryptamine 2A when compared to PHNT. The cyclic adenosine monophosphate content and its regulatory protein, presence of methylated DNA and superoxide dismutase activity were decreased in GCNP, SCNP and GSCNP when compared to PHNT. The Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors coupled signaling elements played an important role in GABA and 5-HT chitosan nanoparticles induced liver cell proliferation which has therapeutic significance in liver disease management.

  5. Association of a coding polymorphism in Fc gamma receptor 2A and graft survival in re-transplant candidates.

    PubMed

    Arnold, Marie-Luise; Fuernrohr, Barbara G; Weiß, Katrin M; Harre, Ulrike; Wiesener, Michael S; Spriewald, Bernd M

    2015-10-01

    The family of Fc gamma receptors (FcγRs) is involved in mediating immunological effector functions. FcγRs are differentially expressed on immune cells and can act either activating or inhibitory, with FcγR2A belonging to the first group. The polymorphism H131R (rs1801274) in FCGR2A has been associated with acute rejection and can shift the overall balance between activating and inhibitory FcγRs. Anti-HLA allo-antibodies in transplant recipients have been identified as risk factor for organ survival after transplantation. In this study we genotyped FCGR2A H131R in 200 patients who had undergone kidney transplantation and experienced loss of graft function. FCGR2A polymorphism was related to graft survival and anti-HLA antibodies. Graft survival was calculated as the time interval between transplantation and return to chronic dialysis after transplantation. The gene frequency of FCGR2A R/R131 was found significantly more often in patients with earlier (⩽60months) compared to patients with later (>60months) graft failure. Overall patients homozygous for R/R131 had a significantly shorter graft survival, compared to H/H131 or H/R131 which is even more pronounced, when anti-HLA antibodies were present. These data suggest, that FCGR2A polymorphisms constitute a risk factor for graft loss following kidney transplantation and that this effect is related to anti-HLA antibodies. PMID:26429312

  6. Rosiglitazone stimulates peroxisome proliferator-activated receptor gamma expression and directly affects in vitro steroidogenesis in porcine ovarian follicles.

    PubMed

    Rak-Mardyła, Agnieszka; Karpeta, Anna

    2014-07-01

    Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) synthetic activator from the group of thiazolidinediones often used in the treatment of chronic diseases such as type 2 diabetes and other forms of insulin resistance. The present in vitro study assessed the direct effects of rosiglitazone at 25 and 50 μM doses on PPARγ gene expression, steroid secretion (progesterone [P4], androstenedione [A4], testosterone [T], and estradiol), and protein expression of PPARγ, 3βHSD, CYP17, 17βHSD, CYP19 by porcine ovarian follicles from prepubertal and cycling animals. We analyzed also steroid enzymatic activity by conversion of pregnen-3β-ol-20-one to P4, P4 to A4, and A4 to T. Our results indicated that rosiglitazone increased significantly PPARγ expression, P4 secretion, 3βHSD activity, and protein expression. Rosiglitazone decreased A4 and T secretion by reducing the expression and activity of CYP17 and 17βHSD and did not change estradiol secretion and CYP19. Similarly results was observed both in prepubertal and cycling pigs. Our results indicate that these direct effects of rosiglitazone on ovarian steroidogenesis provide a framework for testing several potential new mechanisms of PPAR-γ actions on porcine ovarian function. PMID:24681211

  7. Ligands for peroxisome proliferator-activated receptor gamma inhibit growth of pancreatic cancers both in vitro and in vivo.

    PubMed

    Itami, A; Watanabe, G; Shimada, Y; Hashimoto, Y; Kawamura, J; Kato, M; Hosotani, R; Imamura, M

    2001-11-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed largely in adipose tissues and plays an important role in adipocyte differentiation. Several studies have recently shown that ligands of PPARgamma could lead to growth inhibition in some malignancies. In our study, we focused on pancreatic cancers, because the prognosis of advanced pancreatic cancer has not significantly improved due to its resistance to various chemotherapeutic regimens, so that a novel strategy should be required. We show here that PPARgamma is expressed in 5 pancreatic cancer cell lines detected in both mRNA and protein level as well as in human primary and metastatic pancreatic carcinomas examined by immunohistochemical studies. A specific ligand of PPARgamma, troglitazone, led to G1 accumulation with the increase in p27(Kip1), but not p21(Waf1/Cip1) and inhibited cellular proliferation in a pancreatic cancer cell line, Panc-1. The overexpression of PPARgamma in a pancreatic cancer cell line, KMP-3, caused lipid accumulation, which suggested cell growth in some cancers might be inhibited, at least in part, through terminal differentiation in the adipogenic lineage. In addition, implanted Panc-1 tumors in nude mice showed significant inhibition of tumor growth, when treated with pioglitazone, another specific ligand of PPARgamma. Our results suggest that ligands of PPARgamma may be a novel therapeutic agent for the treatment of pancreatic carcinomas.

  8. Rosehip Extract Inhibits Lipid Accumulation in White Adipose Tissue by Suppressing the Expression of Peroxisome Proliferator-activated Receptor Gamma.

    PubMed

    Nagatomo, Akifumi; Nishida, Norihisa; Matsuura, Yoichi; Shibata, Nobuhito

    2013-06-01

    Recent studies have shown that Rosa canina L. and tiliroside, the principal constituent of its seeds, exhibit anti-obesity and anti-diabetic activities via enhancement of fatty acid oxidation in the liver and skeletal muscle. However, the effects of rosehip, the fruit of this plant, extract (RHE), or tiliroside on lipid accumulation in adipocytes have not been analyzed. We investigated the effects of RHE and tiliroside on lipid accumulation and protein expression of key transcription factors in both in vitro and in vivo models. RHE and tiliroside inhibited lipid accumulation in a dose-dependent manner in 3T3-L1 cells. We also analyzed the inhibitory effect of RHE on white adipose tissue (WAT) in high-fat diet (HFD)-induced obesity mice model. Male C57BL/6J mice were fed HFD or HFD supplemented with 1% RHE (HFDRH) for 8 weeks. The HFDRH-fed group gained less body weight and had less visceral fat than the HFD-fed group. Liver weight was significantly lower in the HFDRH-fed group and total hepatic lipid and triglyceride (TG) content was also reduced. A significant reduction in the expression of peroxisome proliferator-activated receptor gamma (PPARγ) was observed in epididymal fat in the HFDRH-fed group, in comparison with controls, through Western blotting. These results suggest that downregulation of PPARγ expression is involved, at least in part, in the suppressive effect of RHE on lipid accumulation in WAT.

  9. Rosehip Extract Inhibits Lipid Accumulation in White Adipose Tissue by Suppressing the Expression of Peroxisome Proliferator-activated Receptor Gamma

    PubMed Central

    Nagatomo, Akifumi; Nishida, Norihisa; Matsuura, Yoichi; Shibata, Nobuhito

    2013-01-01

    Recent studies have shown that Rosa canina L. and tiliroside, the principal constituent of its seeds, exhibit anti-obesity and anti-diabetic activities via enhancement of fatty acid oxidation in the liver and skeletal muscle. However, the effects of rosehip, the fruit of this plant, extract (RHE), or tiliroside on lipid accumulation in adipocytes have not been analyzed. We investigated the effects of RHE and tiliroside on lipid accumulation and protein expression of key transcription factors in both in vitro and in vivo models. RHE and tiliroside inhibited lipid accumulation in a dose-dependent manner in 3T3-L1 cells. We also analyzed the inhibitory effect of RHE on white adipose tissue (WAT) in high-fat diet (HFD)-induced obesity mice model. Male C57BL/6J mice were fed HFD or HFD supplemented with 1% RHE (HFDRH) for 8 weeks. The HFDRH-fed group gained less body weight and had less visceral fat than the HFD-fed group. Liver weight was significantly lower in the HFDRH-fed group and total hepatic lipid and triglyceride (TG) content was also reduced. A significant reduction in the expression of peroxisome proliferator-activated receptor gamma (PPARγ) was observed in epididymal fat in the HFDRH-fed group, in comparison with controls, through Western blotting. These results suggest that downregulation of PPARγ expression is involved, at least in part, in the suppressive effect of RHE on lipid accumulation in WAT. PMID:24471115

  10. 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.

  11. Imaging and measuring the biophysical properties of Fc gamma receptors on single macrophages using atomic force microscopy

    SciTech Connect

    Li, Mi; Liu, Lianqing; Xi, Ning; Wang, Yuechao; Xiao, Xiubin; Zhang, Weijing

    2013-09-06

    Highlights: •Nanoscale cellular ultra-structures of macrophages were observed. •The binding affinities of FcγRs were measured directly on macrophages. •The nanoscale distributions of FcγRs were mapped on macrophages. -- Abstract: Fc gamma receptors (FcγR), widely expressed on effector cells (e.g., NK cells, macrophages), play an important role in clinical cancer immunotherapy. The binding of FcγRs to the Fc portions of antibodies that are attached to the target cells can activate the antibody-dependent cell-mediated cytotoxicity (ADCC) killing mechanism which leads to the lysis of target cells. In this work, we used atomic force microscopy (AFM) to observe the cellular ultra-structures and measure the biophysical properties (affinity and distribution) of FcγRs on single macrophages in aqueous environments. AFM imaging was used to obtain the topographies of macrophages, revealing the nanoscale cellular fine structures. For molecular interaction recognition, antibody molecules were attached onto AFM tips via a heterobifunctional polyethylene glycol (PEG) crosslinker. With AFM single-molecule force spectroscopy, the binding affinities of FcγRs were quantitatively measured on single macrophages. Adhesion force mapping method was used to localize the FcγRs, revealing the nanoscale distribution of FcγRs on local areas of macrophages. The experimental results can improve our understanding of FcγRs on macrophages; the established approach will facilitate further research on physiological activities involved in antibody-based immunotherapy.

  12. 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. PMID:27541269

  13. Peroxisome proliferator-activated receptor gamma ligands induce growth inhibition and apoptosis of human B lymphocytic leukemia.

    PubMed

    Zang, Chuanbing; Liu, Hongyu; Posch, Maximilian G; Waechter, Maries; Facklam, Margit; Fenner, Martin H; Ruthardt, Martin; Possinger, Kurt; Phillip Koeffler, H; Elstner, Elena

    2004-04-01

    This study examined the expression and structural intactness of peroxisome proliferator-activated receptor gamma (PPARgamma) in human acute lymphocytic leukemia (ALL) cells and determined the effect of PPARgamma ligands on growth and apoptosis of these cells. We noted that all lymphocytic leukemia cell lines expressed PPARgamma and no PPARgamma mutations were found in these cell lines as indicated by SSCP analysis. Effect of the PPARgamma ligands on the proliferation, differentiation and apoptosis of B type ALL cells was further examined. Treatment of these cells with the PPARgamma ligands Pioglitazone (PGZ) and 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) resulted in growth inhibition in a dose-dependent manner which was associated with a G1 to S cell cycle arrest. However, this effect appeared to be PPARgamma-independent since several PPARgamma antagonists could not reverse this effect. No differentiation was induced by this treatment. Four out of five cell lines underwent apoptosis after culture with the PPARgamma ligands. This effect was partially caspase-dependent because a pan-caspase inhibitor partially reversed this effect. In conclusion, our results suggest that PPARgamma ligands may offer a new therapeutic approach to aid in the treatment of ALL. PMID:15109539

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

    SciTech Connect

    Wang Xueqing; Huang Guangcun; Mei Shuang; Qian Jin; Ji Juling; Zhang Jinsheng

    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}) and 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.

  15. Quantitative determination of MK-0767, a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist, in human plasma by liquid chromatography-tandem mass spectrometry.

    PubMed

    Song, Hengchang; Yan, Kerri; Xu, Xiaohui; Lo, Man-Wai

    2004-10-15

    5-[2,4-Dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)-phenyl]methyl]benzamide (I, MK-0767 or KRP-297, Fig. 1), is a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist. A LC-MS/MS method for the determination of I in human plasma has been successfully developed, validated and applied to clinical programs. The analyte and internal standard (II) are extracted from 0.05 mL plasma via solid phase extraction (SPE). HPLC is used for the separation of I and II from possible co-extracted endogenous and other compounds. Detection is by MS/MS in multiple reaction monitoring (MRM) mode using a TurboIonSpray probe. The whole sample preparation is automated by using a Packard Multiprobe liquid handling system. The linear range is 4-2000 ng/mL in plasma. Recoveries were 71.1% and 69.4% for I and II, respectively. The method exhibited good linearity, reproducibility and sensitivity, selectivity and robustness when used for the analysis of clinical samples.

  16. Generation of Interleukin-2 Receptor Gamma Gene Knockout Pigs from Somatic Cells Genetically Modified by Zinc Finger Nuclease-Encoding mRNA

    PubMed Central

    Watanabe, Masahito; Nakano, Kazuaki; Matsunari, Hitomi; Matsuda, Taisuke; Maehara, Miki; Kanai, Takahiro; Kobayashi, Mirina; Matsumura, Yukina; Sakai, Rieko; Kuramoto, Momoko; Hayashida, Gota; Asano, Yoshinori; Takayanagi, Shuko; Arai, Yoshikazu; Umeyama, Kazuhiro; Nagaya, Masaki; Hanazono, Yutaka; Nagashima, Hiroshi

    2013-01-01

    Zinc finger nuclease (ZFN) is a powerful tool for genome editing. ZFN-encoding plasmid DNA expression systems have been recently employed for the generation of gene knockout (KO) pigs, although one major limitation of this technology is the use of potentially harmful genome-integrating plasmid DNAs. Here we describe a simple, non-integrating strategy for generating KO pigs using ZFN-encoding mRNA. The interleukin-2 receptor gamma (IL2RG) gene was knocked out in porcine fetal fibroblasts using ZFN-encoding mRNAs, and IL2RG KO pigs were subsequently generated using these KO cells through somatic cell nuclear transfer (SCNT). The resulting IL2RG KO pigs completely lacked a thymus and were deficient in T and NK cells, similar to human X-linked SCID patients. Our findings demonstrate that the combination of ZFN-encoding mRNAs and SCNT provides a simple robust method for producing KO pigs without genomic integration. PMID:24130776

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

    SciTech Connect

    Arnold, Ralf . E-mail: ralf.arnold@medizin.uni-magdeburg.de; 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 of 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.

  18. The time-of-flight system on the Goddard medium energy gamma-ray telescope

    NASA Technical Reports Server (NTRS)

    Ross, R. W.; Chesney, J. R.

    1979-01-01

    A scintillation counter time of flight system, incorporated into the Goddard 50 cm by 50 cm spark chamber gamma ray telescope is described. The system, which utilizes constant fractions timing and particle position compensation and digitizes up to 10 ns time differences to six bit accuracy in less than 500 ns is analyzed. The performance of this system during balloon flight is discussed.

  19. Interaction between peroxisome proliferator-activated receptor gamma and smoking on cardiovascular disease.

    PubMed

    Ding, Xiang; Wang, Rong; Liu, Li; Yu, Qiushi; Wang, Zhiquan; Ma, Zhiqiang; Zhu, Qiming

    2016-01-01

    The aim of this study was to investigate the association between peroxisome proliferator-activator receptor-γ (PPAR-γ) genotype and additional gene-smoking interaction on cardiovascular disease (CVD) based on a Chinese population. A total of 1248 subjects (613 men, 635 women), with a mean age of 55.5±11.8 years old, were selected, including 620 CVD patients and 628 normal controls. Logistic regression was performed to investigate association between single nucleotide polymorphism (SNP) and CVD. Generalized MDR (GMDR) was used to analysis the gene-environment interaction, cross-validation consistency, the testing balanced accuracy, and the sign test, to assess each selected interaction were calculated. The carriers of homozygous mutant of two SNP revealed increased CVD risk than those with wild-type homozygotes, OR (95% CI) were 1.31 (1.16-1.95) and 1.68 (1.29-2.06), respectively. GMDR analysis for one- to three-locus models indicated that there was a significant two-locus model (p=0.0107) involving rs1805192 and smoking, indicating a potential gene-gene interaction between rs1805192 and smoking. Overall, the two- locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 62.17%. We found that smokers with Pro/Ala or Ala/Ala genotype have highest CVD risk, compared to non-smokers with Pro/Pro genotype, OR (95% CI) was 3.46 (1.31-3.42), after covariates adjustment. We found a significant association between genotypes of variants in rs10865710 and rs1805192 with increased CVD risk and a potential gene-gene interaction between rs1805192 and smoking.

  20. 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.

  1. 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.

  2. 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.

  3. Implementation of gamma-ray instrumentation for solid solar system bodies using neutron activation method

    NASA Astrophysics Data System (ADS)

    Litvak, M. L.; Golovin, D. V.; Jun, I.; Kozyrev, A. S.; Mitrofanov, I. G.; Sanin, A. B.; Shvetsov, V. N.; Timoshenko, G. N.; Zontikov, A.

    2016-06-01

    In this paper we present the results of ground tests performed with a flight model and with industry prototypes of passive and active gamma ray spectrometers with the objective of understanding their capability to distinguish the elemental composition of planetary bodies in the solar system. The gamma instrumentation, which was developed for future space missions was used in the measurements at a special ground test facility where a simulant of planetary material was fabricated with a martian-like composition. In this study, a special attention was paid to the gamma lines from activation reaction products generated by a pulsed neutron generator. The instrumentation was able to detect and identify gamma lines attributed to O, Na, Mg, Al, Si, K, Ca and Fe.

  4. Chemokines, chemokine receptors and the gastrointestinal system

    PubMed Central

    Miyazaki, Hiroshi; Takabe, Kazuaki; Yeudall, W Andrew

    2013-01-01

    The biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors, which include epidermal growth factor receptor agonists and members of the transforming growth factor β family. Furthermore, the recent explosion of research in the field of chemokine function as mediators of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches. In this review, we will summarize recently reported findings in chemokine biology with a focus on the gastrointestinal tract. PMID:23704819

  5. Improved readout system for multi-crystal gamma cameras

    DOEpatents

    Derenzo, S.E.

    1985-08-21

    A radioisotope camera having an array of scintillation crystals arranged in N rows and M columns and adapted to be struck by gamma-rays from a subject, a separate solid state photodetector optically coupled to each crystal, and N + M amplifiers connected to the photodetectors to distinguish the particular row and column of an activated photodetector. One of the anode or cathode leads of each photodetector is coupled to the row amplifier associated with the row containing that photodetector while the other of the two leads is coupled to the column amplifier associated with the column containing that photodetector.

  6. EBT-P gamma-ray shielding system

    SciTech Connect

    Gohar, Y.

    1981-12-01

    An elaborate study was carried out for the coil and biological shield of the ELMO Bumpy Torus proof-of-principle (EBT-P) device. A three-dimensional scoping study for the coil shield was performed for four different shielding options to define the heat load for each component and check the compliance with the design criterion of 10 watts maximum heat per coil from the gamma ray sources. Also, a detailed biological dose survey was performed which included: (a) the dose equivalent inside and outside the building, (b) the dose equivalent from the two mazes of the machine room, and (c) the skyshine contribution to the dose equivalent.

  7. Mapping the functional topography of Fc gamma with monoclonal antibodies: localization of epitopes interacting with the binding sites of Fc receptor on human K cells.

    PubMed

    Sármay, G; Jefferis, R; Klein, E; Benczur, M; Gergely, J

    1985-10-01

    A panel of monoclonal antibodies (mAb) specific for the C gamma 2, C gamma 3 or inter C gamma 2/C gamma 3 domain epitopes was tested for inhibition of antibody-dependent cellular cytotoxicity (ADCC) specific for anti-D IgG-coated erythrocytes. Significant inhibition of ADCC was demonstrable for some antibodies having specificity for C gamma 2 or C gamma 3 domain epitopes, while others gave no inhibition. Fab fragments of a representative C gamma 2-specific antibody (A55) and C gamma 3-specific antibody (x3a8) retained their inhibitory capacity in lymphocyte-mediated ADCC, but only A55 Fab inhibited monocyte-mediated lysis. Furthermore, the Fab portion of A55 completely abolished the complement-dependent enhancement of ADCC mediated by concanavalin A-stimulated cells, while x3a8 Fab had no effect in this system. On the other hand, x3a8 Fab inhibited the binding of anti-D IgG-sensitized erythrocytes to lymphocytes while A55 Fab did not influence this latter interaction. The results suggest that C gamma 2 domain-FcR interaction is essential for the triggering of lytic process both in lymphocyte and in monocyte-mediated ADCC, while C gamma 3 domain has no role in the latter but is responsible for the appropriate contact between effector lymphocytes and target cells. A site in the region of Lys274 appears to be critical for triggering of both lymphocyte and monocyte-mediated ADCC.

  8. Efficient silkworm expression of human GPCR (nociceptin receptor) by a Bombyx mori bacmid DNA system

    SciTech Connect

    Kajikawa, Mizuho; Sasaki, Kaori; Wakimoto, Yoshitaro; Toyooka, Masaru; Motohashi, Tomoko; Shimojima, Tsukasa; Takeda, Shigeki; Park, Enoch Y.; Maenaka, Katsumi

    2009-07-31

    Guanine nucleotide-binding protein (G protein) coupled receptors (GPCRs) are frequently expressed by a baculovirus expression vector system (BEVS). We recently established a novel BEVS using the bacmid system of Bombyx mori nucleopolyhedrovirus (BmNPV), which is directly applicable for protein expression in silkworms. Here, we report the first example of GPCR expression in silkworms by the simple injection of BmNPV bacmid DNA. Human nociceptin receptor, an inhibitory GPCR, and its fusion protein with inhibitory G protein alpha subunit (G{sub i}{alpha}) were both successfully expressed in the fat bodies of silkworm larvae as well as in the BmNPV viral fraction. Its yield was much higher than that from Sf9 cells. The microsomal fractions including the nociceptin receptor fusion, which are easily prepared by only centrifugation steps, exhibited [{sup 35}S]GTP{gamma}S-binding activity upon specific stimulation by nociceptin. Therefore, this rapid method is easy-to-use and has a high expression level, and thus will be an important tool for human GPCR production.

  9. 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

  10. 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

    2016-05-01

    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

  11. 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

  12. Performance degradation of QAM based inter-satellite optical communication system under gamma irradiation

    NASA Astrophysics Data System (ADS)

    Liu, Yun; Zhao, Shanghong; Gong, Zizheng; Zhao, Jing; Li, Xuan

    2016-01-01

    Main devices in quadrature amplitude modulation (QAM) based inter-satellite optical communication system were irradiated to a total dose of 20 krad with the dose rate of 5 rad/s using a Co60 radiation source. Gamma irradiation impacts on devices were analyzed and on the basis, system performance degradation was simulated. Variety of system BER along with onboard working time for different inter-satellite links was presented. In addition, some adaption methods were proposed to reduce gamma irradiation induced degradation.

  13. Effects of negative allosteric modulators of gamma-aminobutyric acidA receptors on complex behavioral processes in monkeys.

    PubMed

    Auta, J; Winsauer, P J; Faust, W B; Lambert, P; Moerschbaecher, J M

    1997-01-01

    A multiple schedule of repeated acquisition and performance of conditional discriminations was used to characterize the effects of two negative allosteric modulators of the gamma-aminobutyric acid (GABAA) receptor (ethyl beta-carboline-3-carboxylate [beta-CCE] and N-methyl-beta-carboline-3-carboxamide [FG-7142]), a hallucinogenic beta-carboline derivative (harmine), a benzodiazepine receptor antagonist (flumazenil) and a positive allosteric modulator (alprazolam). In the acquisition component, subjects acquired a different discrimination each session. Acquisition of a discrimination was defined by a decrease in errors as the session progressed. In the performance component, the discrimination was the same each session. Responding in both components was maintained by food presentation under a variable-ratio schedule. Incorrect responses in both components produced a 5-sec timeout. Alprazolam (0.1-18 mg/kg), beta-CCE (0.01-0.32 mg/kg), FG-7142 (0.1-18 mg/kg) and harmine (0.1-1.8 mg/kg) all dose-dependently decreased response rate in both components. However, accuracy of responding-was differentially affected by the drugs. Alprazolam selectively and dose-dependently increased percent errors in acquisition, whereas beta-CCE increased acquisition errors only at the highest doses tested in each subject. In contrast, FG-7142 and harmine had no effects on percent errors at doses that virtually eliminated responding. In all cases, performance accuracy was generally not affected. Flumazenil, at doses that had little or no effect (0.1 and 0.32 mg/kg) or occasionally decreased response rates (1 mg/kg) when administered alone, dose-dependently antagonized the rate-decreasing and error-increasing effects of beta-CCE, FG-7142 and alprazolam. In contrast, flumazenil failed to antagonize the effects of harmine. Thus, the negative allosteric modulators only moderately disrupted acquisition in comparison with the positive allosteric modulator, but the effects of both types of

  14. The role of GABAB receptors in the vestibular oculomotor system in mice.

    PubMed

    Shimizu, Naoki; Wood, Scott; Kushiro, Keisuke; Perachio, Adrian; Makishima, Tomoko

    2016-04-01

    Systemic administration of a gamma-amino butyric acid type B (GABAB) receptor agonist, baclofen, affects various physiological and psychological processes. To date, the effects on oculomotor system have been well characterized in primates, however those in mice have not been explored. In this study, we investigated the effects of baclofen focusing on vestibular-related eye movements. Two rotational paradigms, i.e. sinusoidal rotation and counter rotation were employed to stimulate semicircular canals and otolith organs in the inner ear. Experimental conditions (dosage, routes and onset of recording) were determined based on the prior studies exploring the behavioral effects of baclofen in mice. With an increase in dosage, both canal and otolith induced ocular responses were gradually affected. There was a clear distinction in the drug sensitivity showing that eye movements derived from direct vestibulo-ocular reflex pathways were relatively unaltered, while the responses through higher-order neural networks in the vestibular system were substantially decreased. These findings were consistent with those observed in primates suggesting a well-conserved role of GABAB receptors in the oculomotor system across frontal-eyed and lateral-eyed animals. We showed here a previously unrecognized effect of baclofen on the vestibular oculomotor function in mice. When interpreting general animal performance under the drug, the potential contribution of altered balance system should be taken into consideration. PMID:26778789

  15. Differentiation between actinic reticuloid and cutaneous T cell lymphoma by T cell receptor gamma gene rearrangement analysis and immunophenotyping.

    PubMed Central

    Bakels, V; van Oostveen, J W; Preesman, A H; Meijer, C J; Willemze, R

    1998-01-01

    AIMS: Differentiation between actinic reticuloid and cutaneous T cell lymphoma can be extremely difficult. Demonstration of clonal T cell receptor (TCR) gene rearrangements has been suggested as a potential diagnostic criterion, but the results obtained thus far have been conflicting. This study investigated whether TCR gamma gene rearrangement analysis, using polymerase chain reaction (PCR) in combination with denaturing gradient gel electrophoresis (DGGE) and immunohistochemistry, can serve as a diagnostic criterion. METHODS: PCR/DGGE was performed on skin, peripheral blood mononuclear cells, and/or lymph nodes of seven patients with actinic reticuloid, 11 patients with Sézary syndrome, and 15 patients with a benign form of erythroderma. The results of PCR/DGGE and Southern blot analysis of TCR beta gene rearrangements were compared. In addition, CD4:CD8 ratios in skin and peripheral blood samples were investigated. RESULTS: Clonal T cell populations were detected in 19 of 21 samples obtained from patients with Sézary syndrome but were not detected in any of the 12 samples from patients with actinic reticuloid. Clonal T cells were detected in the peripheral blood of only one of 15 patients with a benign form of erythroderma. PCR/DGGE and Southern blot analysis gave concordant results in 28 of 29 samples. Immunophenotypic analysis demonstrated increased proportions of CD8+ T cells in skin (seven of seven cases) and peripheral blood (four of seven cases) of patients with actinic reticuloid. CONCLUSION: The results of this study demonstrate that gene rearrangement analysis, in combination with immunohistochemistry, may be an important adjunct in differentiating between actinic reticuloid and cutaneous T cell lymphoma. In patients suspected of having actinic reticuloid, application of both techniques is recommended. Images PMID:9602691

  16. A compact neutron beam generator system designed for prompt gamma nuclear activation analysis.

    PubMed

    Ghassoun, J; Mostacci, D

    2011-08-01

    In this work a compact system was designed for bulk sample analysis using the technique of PGNAA. The system consists of (252)Cf fission neutron source, a moderator/reflector/filter assembly, and a suitable enclosure to delimit the resulting neutron beam. The moderator/reflector/filter arrangement has been optimised to maximise the thermal neutron component useful for samples analysis with a suitably low level of beam contamination. The neutron beam delivered by this compact system is used to irradiate the sample and the prompt gamma rays produced by neutron reactions within the sample elements are detected by appropriate gamma rays detector. Neutron and gamma rays transport calculations have been performed using the Monte Carlo N-Particle transport code (MCNP5).

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

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 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...

  18. A coded aperture imaging system optimized for hard X-ray and gamma ray astronomy

    NASA Technical Reports Server (NTRS)

    Gehrels, N.; Cline, T. L.; Huters, A. F.; Leventhal, M.; Maccallum, C. J.; Reber, J. D.; Stang, P. D.; Teegarden, B. J.; Tueller, J.

    1985-01-01

    A coded aperture imaging system was designed for the Gamma-Ray imaging spectrometer (GRIS). The system is optimized for imaging 511 keV positron-annihilation photons. For a galactic center 511-keV source strength of 0.001 sq/s, the source location accuracy is expected to be + or - 0.2 deg.

  19. Readout system for multi-crystal gamma cameras

    DOEpatents

    Derenzo, Stephen E.

    1987-01-01

    A radioisotope camera (10) having an array (12) of scintillation crystals (13) arranged in N rows and M columns and adapted to be struck by gamma-rays from a subject, a separate solid state photodetector (15 ) optically coupled to each crystal (13), and N+M amplifiers (24) connected to the photodetectors (15) to distinguish the particular row and column of an activated photodetector. One of the anode or cathode leads (33 or 34) of each photodetector (15) is coupled to the row amplifier (24) associated with the row containing that photodetector while the other of the two leads (34 or 33) is coupled to the column amplifier (24) associated with the column containing that photodetector.

  20. 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.

  1. SWEPP gamma-ray spectrometer system software user`s guide

    SciTech Connect

    Femec, D.A.

    1994-08-01

    The SWEPP Gamma-Ray Spectrometer (SGRS) System has been developed by the Radiation Measurement and Development Unit of the Idaho National Engineering Laboratory to assist in the characterization of the radiological contents of contact-handled waste containers at the Stored Waste Examination Pilot Plant (SWEPP). In addition to determining the concentrations of gamma-ray-emitting radionuclides, the software also calculates attenuation-corrected isotopic mass ratios of specific interest, and provides controls for SGRS hardware as required. This document serves as a user`s guide for the data acquisition and analysis software associated with the SGRS system.

  2. Increased frequency of {gamma}{delta} T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis: Reactivity, cytotoxicity, and T cell receptor V gene rearrangements

    SciTech Connect

    Stinissen, P.; Vandevyver, C.; Medaer, R.

    1995-05-01

    Infiltrating {gamma}{delta} T cells are potentially involved in the central nervous system demyelination in multiple sclerosis (MS). To further study this hypothesis, we analyzed the frequency and functional properties of {gamma}{delta} T cells in peripheral blood (PB) and paired cerebrospinal fluid (CSF) of patients with MS and control subjects, including patients with other neurologic diseases (OND) and healthy individuals. The frequency analysis was performed under limiting dilution condition using rIL-2 and PHA. After PHA stimulation, a significantly increased frequency of {gamma}{delta} T cells was observed in PB and in CSF of MS patients as compared with PB and CSF of patients with OND. The frequency was represented equally in OND patients and normal individuals. Similarly, the IL-2-responsive {gamma}{delta} T cells occurred at a higher frequency in PB of MS than of control subjects. Forty-three percent of the {gamma}{delta} T cell clones isolates from PB and CSF of MS patients responded to heat shock protein (HSP70) but not HSP65, whereas only 2 of 30 control {gamma}{delta} T cell clones reacted to the HSP. The majority of the {gamma}{delta} T cell clones were able to induce non-MHC-restricted cytolysis of Daudi cells. All clones displayed a substantial reactivity to bacterial superantigens staphylococcal enterotoxin B and toxic shock syndrome toxin-1, irrespective of their {gamma}{delta} V gene usage. Furthermore, the {gamma}{delta} T cell clones expressed predominantly TCRDV2 and GV2 genes, whereas the clones derived from CSF of MS patients expressed either DV1 or DV2 genes. The obtained {gamma}{delta} clones, in general, represented rather heterogeneous clonal origins, even though a predominant clonal origin was found in a set of 10 {gamma}{delta} clones derived from one patient with MS. The present study provides new evidence supporting a possible role of {gamma}{delta} T cells in the secondary inflammatory processes in MS. 39 refs., 5 figs., 4 tabs.

  3. Characterization of the promoter of the human gene encoding the high-affinity IgG receptor: Transcriptional induction by. gamma. -interferon is mediated through common DNA response elements

    SciTech Connect

    Pearse, R.N.; Feinman, R.; Ravetch, J.V. )

    1991-12-15

    Expression of the high-affinity receptor for IgG (Fc{sub {gamma}}RI) is restricted to cells of myeloid lineage and is induced by {gamma}-interferon (IFN-{gamma}) but not by IFN-{alpha}/{beta}. The organization of the human Fc{sub {gamma}}RI gene has been determined and the DNA elements governing its cell type-restricted transcription and IFN-{gamma} induction are reported here. A 39-nucleotide sequence (IFN-{gamma} response region, or GRR) is defined that is both necessary and sufficient for IFN-{gamma} inducibility. Sequence analysis of the GRR reveals the presence of promoter elements initially defined for the major histocompatibility complex class 2 genes: i.e., X, H, and {gamma}-IRE sequences. Comparison of a number of genes whose expression is induced selectively by IFN-{gamma} indicated that the presence of these elements is a general feature of IFN-{gamma}-responsive genes. The studies suggest that the combination of X, H, and {gamma}-IRE elements is a common motif in the pathway of transcriptional induction by this lymphokine.

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

    SciTech Connect

    Yoshikawa, M.; Morimoto, M.; Shima, Y.; Kohagura, J.; Sakamoto, M.; Nakashima, Y.; Imai, T.; Yasuhara, R.; Yamada, I.; Kawahata, K.; Funaba, H.; Minami, T.

    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-TS 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.

  5. Cognitive performance and peripheral endocannabinoid system receptor expression in schizophrenia.

    PubMed

    Ferretjans, Rodrigo; de Campos, Salvina Maria; Ribeiro-Santos, Rafael; Guimarães, Fernanda Carneiro; de Oliveira, Keliane; Cardoso, Ana Cecília Alves; Araújo, Marcio Sobreira; Teixeira-Carvalho, Andrea; Martins-Filho, Olindo Assis; Teixeira, Antonio L; Salgado, João V

    2014-07-01

    Schizophrenia is a chronic psychiatric syndrome characterized by generalized cognitive deficits that are associated with functional impairment. The endocannabinoid system (ECS) modulates neurotransmission and neuronal plasticity and is important for cognitive functioning. Evidence points to the involvement of this neuromodulatory system in the pathophysiology of schizophrenia and that alteration of the ECS on peripheral lymphocytes could reflect central changes. The objective of this study was to compare levels of peripheral endocannabinoid receptor expression in patients with schizophrenia and healthy subjects and find evidence of association between peripheral expression of those receptors and cognitive performance. Patients with stabilized schizophrenia (N=53) and controls (N=22) underwent clinical and cognitive evaluation, and assessment of cannabinoid receptor expression on the surface of peripheral immune cells (lymphocytes, natural killer cells and monocytes) by flow cytometry. Patients with schizophrenia had lower levels of cannabinoid receptor expression on total T lymphocytes, but after controlling for possible confounders this difference did not remain significant. In patients, increased cannabinoid receptor expression on lymphocytes and monocytes was significantly correlated with worst cognitive performance. These data provide additional evidence of the involvement of the ECS in the pathophysiology of cognitive deficits in schizophrenia.

  6. Imaging of opioid receptors in the central nervous system

    PubMed Central

    Henriksen, Gjermund

    2008-01-01

    In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of μ-, κ and δ-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation—mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs—have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging. PMID:18048446

  7. Total Measurement Uncertainty for the Plutonium Finishing Plant (PFP) Segmented Gamma Scan Assay System

    SciTech Connect

    WESTSIK, G.A.

    2001-06-06

    This report presents the results of an evaluation of the Total Measurement Uncertainty (TMU) for the Canberra manufactured Segmented Gamma Scanner Assay System (SGSAS) as employed at the Hanford Plutonium Finishing Plant (PFP). In this document, TMU embodies the combined uncertainties due to all of the individual random and systematic sources of measurement uncertainty. It includes uncertainties arising from corrections and factors applied to the analysis of transuranic waste to compensate for inhomogeneities and interferences from the waste matrix and radioactive components. These include uncertainty components for any assumptions contained in the calibration of the system or computation of the data. Uncertainties are propagated at 1 sigma. The final total measurement uncertainty value is reported at the 95% confidence level. The SGSAS is a gamma assay system that is used to assay plutonium and uranium waste. The SGSAS system can be used in a stand-alone mode to perform the NDA characterization of a container, particularly for low to medium density (0-2.5 g/cc) container matrices. The SGSAS system provides a full gamma characterization of the container content. This document is an edited version of the Rocky Flats TMU Report for the Can Scan Segment Gamma Scanners, which are in use for the plutonium residues projects at the Rocky Flats plant. The can scan segmented gamma scanners at Rocky Flats are the same design as the PFP SGSAS system and use the same software (with the exception of the plutonium isotopics software). Therefore, all performance characteristics are expected to be similar. Modifications in this document reflect minor differences in the system configuration, container packaging, calibration technique, etc. These results are supported by the Quality Assurance Objective (QAO) counts, safeguards test data, calibration data, etc. for the PFP SGSAS system. Other parts of the TMU analysis utilize various modeling techniques such as Monte Carlo N

  8. Kernel Integration Code System--Multigroup Gamma-Ray Scattering.

    1988-02-15

    GGG (G3) is the generic designation for a series of computer programs that enable the user to estimate gamma-ray scattering from a point source to a series of point detectors. Program output includes detector response due to each source energy, as well as a grouping by scattered energy in addition to a simple, unscattered beam result. Although G3 is basically a single-scatter program, it also includes a correction for multiple scattering by applying a buildupmore » factor for the path segment between the point of scatter and the detector point. Results are recorded with and without the buildup factor. Surfaces, defined by quadratic equations, are used to provide for a full three-dimensional description of the physical geometry. G3 evaluates scattering effects in those situations where more exact techniques are not economical. G3 was revised by Bettis and the name was changed to indicate that it was no longer identical to the G3 program. The name S3 was chosen since the scattering calculation has three steps: calculation of the flux arriving at the scatterer from the point source, calculation of the differential scattering cross section, and calculation of the scattered flux arriving at the detector.« less

  9. 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.

  10. Provocative pattern of rearrangements of the genes for the gamma and beta chains of the T-cell receptor in human leukemias.

    PubMed Central

    Goorha, R; Bunin, N; Mirro, J; Murphy, S B; Cross, A H; Behm, F G; Quertermous, T; Seidman, J; Kitchingman, G R

    1987-01-01

    To examine the distribution of rearrangements of the gamma- and beta-chain T-cell receptor (TCR) genes in T- and non-T acute lymphoblastic leukemias (ALLs), and potentially to determine which genes rearrange first in ontogeny, we analyzed high molecular weight DNA from 102 patients with acute leukemia. Rearranged gamma- and beta-chain genes were found in all T-cell ALLs (22/22) examined. Overall, 27% (18/66) of B-lineage ALLs had beta-chain gene rearrangements, and 41% (24/58) had gamma-chain gene rearrangements, but the distribution of rearranged genes varied according to the stage of B-cell differentiation. The gamma-chain genes were rearranged in 11% (1/9) of the B-lineage patients negative for the common acute lymphoblastic leukemia antigen (cALLA) and 50% (23/46) of cALLA+ ALL patients, while the beta-chain genes were not rearranged in any of the 7 cALLA- ALL patients examined but were rearranged in 32% (18/56) of the cALLA+ patients. Neither TCR gene was found to be rearranged in acute nonlymphoid leukemia patients (0/12) or in patients with B-cell (surface immunoglobulin-positive) leukemia (0/3). Of the 44 cALLA+ patients in which a direct comparison of gamma- and beta-chain gene rearrangements could be made, 34% had both genes rearranged, 16% had only gamma-chain gene rearrangements, and the remaining 50% had both genes in the germ-line configuration. beta-Chain rearrangements have not been found in the absence of gamma-chain rearrangements, thus supporting a proposed hierarchy of TCR gene rearrangements. A provocative finding was that only a small percentage (11%) of the patients with cALLA- B precursor cell ALLs had rearranged TCR genes, while 50% of the cALLA+ leukemia patients had at least gamma-chain rearrangement, raising a question as to whether indeed cALLA- cells are precursors to cALLA+ cells. Interestingly, 18% (2/11) of the cytoplasmic immunoglobulin (cIg)-positive cALLA+ (pre-B) ALLs involved TCR gene rearrangements, compared to 60% (21/35) of

  11. Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA

    PubMed Central

    Wang, Ping; Eshaq, Randa S.; Meshul, Charles K.; Moore, Cynthia; Hood, Rebecca L.; Leidenheimer, Nancy J.

    2015-01-01

    GABAA receptors mediate fast inhibitory neurotransmission in the brain. Dysfunction of these receptors is associated with various psychiatric/neurological disorders and drugs targeting this receptor are widely used therapeutic agents. Both the efficacy and plasticity of GABAA receptor-mediated neurotransmission depends on the number of surface GABAA receptors. An understudied aspect of receptor cell surface expression is the post-translational regulation of receptor biogenesis within the endoplasmic reticulum (ER). We have previously shown that exogenous GABA can act as a ligand chaperone of recombinant GABAA receptors in the early secretory pathway leading us to now investigate whether endogenous GABA facilitates the biogenesis of GABAA receptors in primary cerebral cortical cultures. In immunofluorescence labeling experiments, we have determined that neurons expressing surface GABAA receptors contain both GABA and its degradative enzyme GABA transaminase (GABA-T). Treatment of neurons with GABA-T inhibitors, a treatment known to increase intracellular GABA levels, decreases the interaction of the receptor with the ER quality control protein calnexin, concomittantly increasing receptor forward-trafficking and plasma membrane insertion. The effect of GABA-T inhibition on the receptor/calnexin interaction is not due to the activation of surface GABAA or GABAB receptors. Consistent with our hypothesis that GABA acts as a cognate ligand chaperone in the ER, immunogold-labeling of rodent brain slices reveals the presence of GABA within the rough ER. The density of this labeling is similar to that present in mitochondria, the organelle in which GABA is degraded. Lastly, the effect of GABA-T inhibition on the receptor/calnexin interaction was prevented by pretreatment with a GABA transporter inhibitor. Together, these data indicate that endogenous GABA acts in the rough ER as a cognate ligand chaperone to facilitate the biogenesis of neuronal GABAA receptors. PMID

  12. Operability test report for the TK-900 beta/gamma liquid effluent monitoring system

    SciTech Connect

    Weissenfels, R.D.

    1995-04-10

    This operability test report will verify that the 221-B beta/gamma liquid effluent monitoring system installed near the east end of the six inch chemical sewer header, functions as intended by design. An off-line, skid mounted, beta/gamma radiation monitor and pH monitor was installed near stairwell three in the 221-B electrical gallery by Project W-007H. The skid mounted monitoring system includes two radiation detectors and a pH meter, both with local digital displays. Output signals from each monitor are also received and displayed by the Facility Process Monitor and Control System (FPMCS). Pumps, motors, gauges, valves and transport lines complement the skid monitoring system. The system is part of BAT/AKART for the BCE liquid effluent system.

  13. Operability test procedure for the TK-900 beta/gamma liquid effluent monitoring system

    SciTech Connect

    Weissenfels, R.D.

    1995-02-24

    This operability test procedure will verify that the 221-B beta/gamma liquid effluent monitoring system, installed near the east end of the six inch chemical sewer header, functions as intended by design. An off-line, skid mounted, beta/gamma radiation monitor and pH monitor was installed near stairwell three in the 221-B electrical gallery by Project W-007H. The skid mounted monitoring system includes two radiation detectors and a pH meter, both with local digital displays. Output signals from each monitor are also received and displayed by the Facility Process Monitor and Control System (FPMCS). Pumps, motors, gauges, valves and transport lines complement the skid monitoring system. The system is part of BAT/AKART for the BCE liquid effluent system.

  14. T-cell receptor gene expression by human gamma delta T-cell clones from peripheral blood and reproductive tissues in relation to non-MHC-restricted cytotoxic function.

    PubMed

    Christmas, S E

    1991-06-01

    T-cell receptor gamma and delta gene expression was determined using V-region-specific monoclonal antibodies in conjunction with Southern blot analysis in panels of gamma delta T-cell clones from human peripheral blood (n = 77) and reproductive tissue (n = 9). Whereas 53 out of 77 (69%) clones from peripheral blood expressed V gamma 9 and V delta 2J1, only 2 out of 9 (22%) from reproductive tissues expressed V delta 2J1. Two out of eight decidual clones expressed both V gamma 9 and V delta 1J1, while this configuration was rare in clones from peripheral blood. The majority of clones from the peripheral blood of one donor expressed V gamma 8 and V delta 3J1. Clones were identified which expressed V delta 1J1 in the disulphide-linked C gamma 1 form of the receptor and which expressed a gene other than V delta 1 in the non-disulphide-linked C gamma 2 form, indicating incomplete concordance between expression of V delta 1 and C gamma 2. V delta 3 could be expressed in the disulphide-linked or non-disulphide-linked form of the receptor. At least 5 out of 77 peripheral clones were expressing V delta genes other than V delta 1, V delta 2, or V delta 3 in conjunction with C gamma 1 or C gamma 2. There was a strong but incomplete correlation between high non-NHC-restricted cytotoxic function and C gamma 1 expression. Clones from the same donor expressing both V gamma 9JPC gamma 1 and V delta 2J1 showed either high or negligible cytotoxicity, and cytotoxic clones expressing C gamma 2 were found. Thus no complete correlation between cytotoxic function and expression of a particular form of the gamma delta heterodimer was identified. The results also suggest that gamma delta T cells from reproductive tissues are less likely to express V delta 2J1 than those from peripheral blood.

  15. Functions of gamma-band synchronization in cognition: from single circuits to functional diversity across cortical and subcortical systems.

    PubMed

    Bosman, Conrado A; Lansink, Carien S; Pennartz, Cyriel M A

    2014-06-01

    Gamma-band activity (30-90 Hz) and the synchronization of neural activity in the gamma-frequency range have been observed in different cortical and subcortical structures and have been associated with different cognitive functions. However, it is still unknown whether gamma-band synchronization subserves a single universal function or a diversity of functions across the full spectrum of cognitive processes. Here, we address this question reviewing the mechanisms of gamma-band oscillation generation and the functions associated with gamma-band activity across several cortical and subcortical structures. Additionally, we raise a plausible explanation of why gamma rhythms are found so ubiquitously across brain structures. Gamma band activity originates from the interplay between inhibition and excitation. We stress that gamma oscillations, associated with this interplay, originate from basic functional motifs that conferred advantages for low-level system processing and multiple cognitive functions throughout evolution. We illustrate the multifunctionality of gamma-band activity by considering its role in neural systems for perception, selective attention, memory, motivation and behavioral control. We conclude that gamma-band oscillations support multiple cognitive processes, rather than a single one, which, however, can be traced back to a limited set of circuit motifs which are found universally across species and brain structures.

  16. System gamma as a function of image- and monitor-dynamic range.

    PubMed

    Kane, David; Bertalmío, Marcelo

    2016-01-01

    System gamma is the end-to-end exponent that describes the relationship between the relative luminance values at capture and the reproduced image. The system gamma preferred by subjects is known to vary with the background luminance condition and the image in question. We confirm the previous two findings using an image database with both high and low dynamic range images (from 102 to 107), but also find that the preferred system gamma varies with the dynamic range of the monitor (CRT, LCD, or OLED). We find that the preferred system gamma can be predicted in all conditions and for all images by a simple model that searches for the value that best flattens the lightness distribution, where lightness is modeled as a power law of onscreen luminance. To account for the data, the exponent must vary with the viewing conditions. The method presented allows the inference of lightness perception in natural scenes without direct measurement and makes testable predictions for how lightness perception varies with the viewing condition and the distribution of luminance values in a scene. The data from this paper has been made available online. PMID:27271806

  17. 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.

  18. 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.

  19. 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.

  20. Association between peroxisome proliferator-activated receptor-alpha, delta, and gamma polymorphisms and risk of coronary heart disease

    PubMed Central

    Qian, Yufeng; Li, Peiwei; Zhang, Jinjie; Shi, Yu; Chen, Kun; Yang, Jun; Wu, Yihua; Ye, Xianhua

    2016-01-01

    Abstract Objectives: Risk of coronary heart disease (CHD) has been suggested to be associated with polymorphisms of peroxisome proliferator-activated receptors (PPARs), while the results were controversial. We aimed to systematically assess the association between PPAR polymorphisms and CHD risk. Methods: A case–control study with 446 subjects was conducted to evaluate the association between CHD risk and C161T polymorphism, which was of our special interest as this polymorphism showed different effects on risks of CHD and acute coronary syndrome (ACS). Meta-analyses were conducted to assess all PPAR polymorphisms. Either a fixed- or a random-effects model was adopted to estimate overall odds ratios (ORs). Results: In the case–control study, T allele carriers of C161T polymorphism were not significantly associated with CHD risk (Odds ratio (OR) = 0.74, 95% confidence interval (CI) 0.47–1.15, P = 0.19), while T allele carriers showed higher risk of ACS (OR = 1.63, 95% CI 1.00–2.65, P = 0.048). The meta-analysis indicated that compared with CC homozygous, T allele carriers had lower CHD risk (OR = 0.69, 95% CI 0.59–0.82, P < 0.001) but higher ACS risk (OR = 1.43, 95% CI 1.09–1.87, P = 0.010). Three other polymorphisms were also found to be significantly associated with CHD risk under dominant model: PPAR-alpha intron 7G/C polymorphism (CC+GC vs GG, OR 1.42, 95% CI 1.13–1.78, P = 0.003), L162V polymorphism (VV+LV vs LL, OR 0.74, 95% CI 0.56–0.97, P = 0.031), and PPAR-delta +294T/C polymorphism (CC+TC vs TT, OR 1.51, 95% CI 1.12–2.05, P = 0.007). Conclusions: The results suggested that PPAR-alpha intron 7G/C and L162V, PPAR-delta +294T/C and PPAR-gamma C161T polymorphisms could affect CHD susceptibility, and C161T polymorphism might have different effects on CHD and ACS. PMID:27512842

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

    SciTech Connect

    Bugaev, V.; Buckley, J.; Krawczynski, H.; Diegel, S.; Romani, R.; Falcone, A.; Fegan, S.; Vassiliev, V.; Finley, J.; Guarino, V.; Hanna, D.; Kaaret, P.; Konopelko, A.; Ramsey, B.; Weekes, T.

    2008-12-24

    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 {approx}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.

  2. 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.

  3. 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.

  4. A novel mutation in IFN-gamma receptor 2 with dominant negative activity: biological consequences of homozygous and heterozygous states.

    PubMed

    Rosenzweig, Sergio D; Dorman, Susan E; Uzel, Gulbu; Shaw, Stephen; Scurlock, Amy; Brown, Margaret R; Buckley, Rebecca H; Holland, Steven M

    2004-09-15

    We identified two siblings homozygous for a single base pair deletion in the IFN-gammaR2 transmembrane domain (791delG) who presented with multifocal Mycobacterium abscessus osteomyelitis (patient 1) and disseminated CMV and Mycobacterium avium complex infection (patient 2), respectively. Although the patients showed no IFN-gammaR activity, their healthy heterozygous parents showed only partial IFN-gammaR activity. An HLA-identical bone marrow transplant from the mother led patient 1 to complete hemopoietic reconstitution, but only partial IFN-gammaR function. We cloned and expressed fluorescent fusion proteins of the wild-type IFN-gammaR2, an IFN-gammaR2 mutant previously described to produce a complete autosomal recessive deficiency (278del2), and of 791delG to determine whether the intermediate phenotype in the 791delG heterozygous state was caused by haploinsufficiency or a dominant negative effect. When cotransfected together with the wild-type vector into IFN-gammaR2-deficient fibroblasts, the fusion protein with 791delG inhibited IFN-gammaR function by 48.7 +/- 5%, whereas fusion proteins with 278del2 had no inhibitory effect. Confocal microscopy of 791delG fusion proteins showed aberrant diffuse intracellular accumulation without plasma membrane localization. The fusion protein created by 791delG did not complete Golgi processing, and was neither expressed on the plasma membrane, nor shed extracellularly. The mutant construct 791delG exerts dominant negative effects on IFN-gamma signaling without cell surface display, suggesting that it is acting on pathways other than those involved in cell surface recognition of ligand.

  5. The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells

    PubMed Central

    Ching, Jared; Amiridis, Stephanie; Stylli, Stanley S.; Bjorksten, Andrew R.; Kountouri, Nicole; Zheng, Thomas; Paradiso, Lucy; Luwor, Rodney B.; Morokoff, Andrew P.; O'Brien, Terence J.; Kaye, Andrew H.

    2015-01-01

    Glioma cells release glutamate through expression of system xc−, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARγ) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of ≥ 30 μM pioglitazone (p < 0.05). The PPARγ antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARγ dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at ≥ 30 μM and 100 μM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 μM and 30 μM (p < 0.05) respectively. The effect on viability was partially dependent on PPARγ activation in U87MG cells but not U251MG cells, whereby PPARγ blockade with GW9662 had a synergistic effect. We conclude that PPARγ agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate. PMID:26046374

  6. Peroxisome proliferator-activated receptors in the cardiovascular system

    PubMed Central

    Bishop-Bailey, David

    2000-01-01

    Peroxisome proliferator-activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARα, -δ, and -γ, which are members of the steriod receptor superfamily. The first member of the family (PPARα) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. Defined functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARα being involved in β-oxidation pathways, and PPARγ in the differentiation of adipocytes. Little is known about the functions of PPARδ, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clofibrate, and anti-diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the field of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands. PMID:10696077

  7. Interferon-gamma is a strong modulator of NK susceptibility and expression of beta 2-microglobulin but not of transferrin receptors of K562 cells.

    PubMed

    Grönberg, A; Kiessling, R; Fiers, W

    1985-10-01

    The human cell line K562 was treated with human natural leukocyte interferon (IFN-alpha) and recombinant immune interferon (IFN-gamma). Cell cultures exposed to both types of IFNs displayed a reduced susceptibility to the cytotoxic activity of human PBL (NK activity). While this effect occurred preferentially at high doses of IFN-alpha, as little as 10 U/ml of IFN-gamma caused a marked decrease in susceptibility to NK-cell-mediated lysis. Using a monoclonal antibody against human beta2-microglobulin (beta2M) a low level of specific binding to K562 cells was detected. The binding increased after treatment with IFN-alpha (1.4-fold) and IFN-gamma (1.7-fold). The expression of transferrin receptors (TR) was not changed significantly. A hybrid cell line between K562 and a Burkitt's lymphoma-derived cell line displayed a similar pattern of response to IFN-alpha and IFN-gamma as did K562, when effects on NK susceptibility, beta2M expression, and TR expression were studied. The Burkitt's lymphoma line PUT showed no consistent changes in expression of beta2M and TR. These results demonstrate that IFN-gamma is highly efficient in modulating the NK susceptibility, and the expression of beta2M on K562. The presented data do not support a role for expression of TR as the only property that determines the degree of NK susceptibility, since there was no correlation between NK susceptibility and TR expression among the cell lines tested or when IFN-treated and untreated cells were compared.

  8. gamma-Aminobutyric acidA (GABAA) receptors modulate [3H]GABA release from isolated neuronal growth cones in the rat.

    PubMed

    Lockerbie, R O; Gordon-Weeks, P R

    1985-04-19

    Potassium-induced release of gamma-[3H]aminobutyric acid [( 3H]GABA) from a growth cone-enriched fraction isolated from neonatal rat forebrain was inhibited by the GABA mimetic muscimol in a dose-dependent manner (IC50 15 nM). The GABA antagonist bicuculline completely reversed the effect of muscimol. Bicuculline alone slightly potentiated the K+-induced release of [3H]GABA. Baclofen, a proposed selective agonist for a bicuculline-insensitive GABAB receptor, was found to cause only a slight reduction in the K+-induced release of [3H]GABA. These results are compatible with the presence of a negative feedback mechanism mediated by GABAA receptors for controlling [3H]GABA release from growth cones of the developing rat forebrain.

  9. Performance analysis of relay-aided free-space optical communication system over gamma-gamma fading channels with pointing errors

    NASA Astrophysics Data System (ADS)

    Fu, Hui-hua; Wang, Ping; Wang, Ran-ran; Liu, Xiao-xia; Guo, Li-xin; Yang, Yin-tang

    2016-07-01

    The average bit error rate ( ABER) performance of a decode-and-forward (DF) based relay-assisted free-space optical (FSO) communication system over gamma-gamma distribution channels considering the pointing errors is studied. With the help of Meijer's G-function, the probability density function (PDF) and cumulative distribution function (CDF) of the aggregated channel model are derived on the basis of the best path selection scheme. The analytical ABER expression is achieved and the system performance is then investigated with the influence of pointing errors, turbulence strengths and structure parameters. Monte Carlo (MC) simulation is also provided to confirm the analytical ABER expression.

  10. Systems for increasing the sensitivity of gamma-ray imagers

    DOEpatents

    Mihailescu, Lucian; Vetter, Kai M.; Chivers, Daniel H.

    2012-12-11

    Systems that increase the position resolution and granularity of double sided segmented semiconductor detectors are provided. These systems increase the imaging resolution capability of such detectors, either used as Compton cameras, or as position sensitive radiation detectors in imagers such as SPECT, PET, coded apertures, multi-pinhole imagers, or other spatial or temporal modulated imagers.

  11. 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

    2016-05-01

    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

  12. Bile acid nuclear receptor FXR and digestive system diseases

    PubMed Central

    Ding, Lili; Yang, Li; Wang, Zhengtao; Huang, Wendong

    2015-01-01

    Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases. PMID:26579439

  13. Bile acid nuclear receptor FXR and digestive system diseases.

    PubMed

    Ding, Lili; Yang, Li; Wang, Zhengtao; Huang, Wendong

    2015-03-01

    Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases. PMID:26579439

  14. Functional modulation of cerebral gamma-aminobutyric acidA receptor/benzodiazepine receptor/chloride ion channel complex with ethyl beta-carboline-3-carboxylate: Presence of independent binding site for ethyl beta-carboline-3-carboxylate

    SciTech Connect

    Taguchi, J.; Kuriyama, K. )

    1990-05-01

    Effect of ethyl beta-carboline-3-carboxylate (beta-CCE) on the function of gamma-aminobutyric acid (GABA)A receptor/benzodiazepine receptor/chloride ion channel complex was studied. Beta-CCE noncompetitively and competitively inhibited (3H)flunitrazepam binding to benzodiazepine receptor, but not (3H)muscimol binding to GABAA receptor as well as t-(3H)butylbicycloorthobenzoate (( 3H) TBOB) binding to chloride ion channel, in particulate fraction of the mouse brain. Ro15-1788 also inhibited competitively (3H) flunitrazepam binding. On the other hand, the binding of beta-(3H)CCE was inhibited noncompetitively and competitively by clonazepam and competitively by Ro15-1788. In agreement with these results, benzodiazepines-stimulated (3H)muscimol binding was antagonized by beta-CCE and Ro15-1788. Gel column chromatography for the solubilized fraction from cerebral particulate fraction by 0.2% sodium deoxycholate (DOC-Na) in the presence of 1 M KCl indicated that beta-(3H)CCE binding site was eluted in the same fraction (molecular weight, 250,000) as the binding sites for (3H)flunitrazepam, (3H)muscimol and (3H)TBOB. GABA-stimulated 36Cl- influx into membrane vesicles prepared from the bovine cerebral cortex was stimulated and attenuated by flunitrazepam and beta-CCE, respectively. These effects of flunitrazepam and beta-CCE on the GABA-stimulated 36Cl- influx were antagonized by Ro15-1788. The present results suggest that the binding site for beta-CCE, which resides on GABAA receptor/benzodiazepine receptor/chloride ion channel complex, may be different from that for benzodiazepine. Possible roles of beta-CCE binding site in the allosteric inhibitions on benzodiazepine binding site as well as on the functional coupling between chloride ion channel and GABAA receptor are also suggested.

  15. Organization of the human T cell receptor [zeta]/[eta] gene and its genetic linkage to the Fc[gamma]RII-Fc[gamma]RIII gene cluster

    SciTech Connect

    Jensen, J.P.; Hou, D.; Taylor, A. ); Dean, M. ); Ramsburg, M. ); Weissman, A.W. DCBDC/National Cancer Institute National Institute of Health, Bethesda, MD )

    1992-04-15

    The [zeta]-subunit is the most recently characterized stoichiometric human TCR component. In this study the authors describe the molecular organization of the human [zeta]-gene. The [zeta] transcript is generated as the spliced product of eight exons that are separated by distances of 0.7 kb to more than 8 kb. Ribonuclease protection studies revealed multiple transcription initiation sites distributed over a range of approximately 115 bases. A variable number tandem repeat restriction fragment polymorphism contained within the structural gene has allowed for the localization of [zeta] within the human genome. Additionally, a restriction fragment polymorphism within the Fc[gamma]RII-Fc[gamma]RIII gene cluster has allowed for its localization on the map of human chromosome 1q and for the establishment of its linkage to the [zeta]-gene locus. A region that is highly homologous on a nucleotide level with the [eta]-exon of the murine [zeta]-gene is localized to the 3[prime] region of the human [zeta]-gene. Surprisingly, translation of this region into protein results in a structure that is markedly divergent from its murine counterpart. This finding has important implications regarding the potential role of [eta] in T cell function. 60 refs., 7 figs., 1 tab.

  16. Radial Electron Temperature and Density Measurements Using Thomson Scattering System in GAMMA 10/PDX

    NASA Astrophysics Data System (ADS)

    Yoshikawa, M.; Ohta, K.; Wang, X.; Chikatsu, M.; Kohagura, J.; Shima, Y.; Sakamoto, M.; Imai, T.; Nakashima, Y.; Yasuhara, R.; Yamada, I.; Funaba, H.; Minami, T.

    2015-11-01

    A Thomson scattering (TS) system in GAMMA 10/PDX has been developed for the measurement of radial profiles of electron temperature and density in a single plasma and laser shot. The TS system has a large solid angle optical collection system and high-sensitivity signal detection system. The TS signals are obtained using four-channel high-speed digital oscilloscopes controlled by a Windows PC. We designed the acquisition program for six oscilloscopes to obtain 10-Hz TS signals in a single plasma shot, following which the time-dependent electron temperatures and densities can be determined. Moreover, in order to obtain larger TS signal intensity in the edge region, we added a second collection mirror. The radial electron temperatures and densities at six radial positions in GAMMA 10/PDX were successfully obtained.

  17. 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.

  18. Molecular and Physiological Mechanisms of Membrane Receptor Systems Functioning

    PubMed Central

    Severin, E.S.; Savvateeva, M.V.

    2011-01-01

    Molecular physiology is a new interdisciplinary field of knowledge that looks into how complicated biological systems function. The living cell is a relatively simple, but at the same time very sophisticated biological system. After the sequencing of the human genome, molecular physiology has endeavored to investigate the systems of cellular interactions at a completely new level based on knowledge of the spatial organization and functions of receptors, their ligands, and protein-protein interactions. In recent years, the achievements in molecular physiology have centered on the study of sensor reception mechanisms and intercellular data transfer, as well as the immune system physiology, amongst other processes. PMID:22649671

  19. Does the kappa opioid receptor system contribute to pain aversion?

    PubMed Central

    Cahill, Catherine M.; Taylor, Anna M. W.; Cook, Christopher; Ong, Edmund; Morón, Jose A.; Evans, Christopher J.

    2014-01-01

    The kappa opioid receptor (KOR) and the endogenous peptide-ligand dynorphin have received significant attention due the involvement in mediating a variety of behavioral and neurophysiological responses, including opposing the rewarding properties of drugs of abuse including opioids. Accumulating evidence indicates this system is involved in regulating states of motivation and emotion. Acute activation of the KOR produces an increase in motivational behavior to escape a threat, however, KOR activation associated with chronic stress leads to the expression of symptoms indicative of mood disorders. It is well accepted that KOR can produce analgesia and is engaged in chronic pain states including neuropathic pain. Spinal studies have revealed KOR-induced analgesia in reversing pain hypersensitivities associated with peripheral nerve injury. While systemic administration of KOR agonists attenuates nociceptive sensory transmission, this effect appears to be a stress-induced effect as anxiolytic agents, including delta opioid receptor agonists, mitigate KOR agonist-induced analgesia. Additionally, while the role of KOR and dynorphin in driving the dysphoric and aversive components of stress and drug withdrawal has been well characterized, how this system mediates the negative emotional states associated with chronic pain is relatively unexplored. This review provides evidence that dynorphin and the KOR system contribute to the negative affective component of pain and that this receptor system likely contributes to the high comorbidity of mood disorders associated with chronic neuropathic pain. PMID:25452729

  20. 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

    2003-03-01

    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.

  1. A General-Purpose Monte Carlo Gamma-Ray Transport Code System for Minicomputers.

    1981-08-27

    Version 00 The OGRE code system was designed to calculate, by Monte Carlo methods, any quantity related to gamma-ray transport. The system is represented by two codes which treat slab geometry. OGRE-P1 computes the dose on one side of a slab for a source on the other side, and HOTONE computes energy deposition in addition. The source may be monodirectional, isotropic, or cosine distributed.

  2. Feasibility tests of a dual modality system for imaging using gamma rays and NIR light

    NASA Astrophysics Data System (ADS)

    Uzunov, Nikolay; Atroshchenko, Kostiantyn; Baneva, Yanka; Bello, Michele; De Rosa, Matteo; Fontana, Cristiano Lino; Moschini, Giuliano; Rossi, Paolo

    2013-04-01

    We are developing a dual system for small-animal imaging in multimodality studies, which consists of a highspatial resolution gamma-camera and a scanner for Near-Infra-Red (NIR) light. The gamma-camera is assembled from a position-sensitive photomultiplier and a scintillation-crystal with parallel-hole collimator. On the other hand, the NIR imaging is designed for near-object scanning, and features two operational modes: Transmission and Fluorescence. In the Transmission mode, the NIR light, coming from five different wavelength LEDs, crosses the sample and is subsequently measured by an array sensor. In the Fluorescence mode, the emission from nanoparticles, such as singlewalled carbon nanotubes (SWCNTs) administered in the imaged object, is excited using the laser. The gamma-camera energy and spatial resolutions have been measured. This latter has been assessed by using specially-designed phantoms like capillary tubes or volumes with cavities filled with a radioactive solution. The NIR-scanner spatial resolution has been determined along two perpendicular directions using standards, placed at different distances from the sensor. The results show that both the NIR scanning-system and the gamma-camera feature good imaging-parameters and can be applied to multimodality studies.

  3. Study of Comet Nucleus Gamma-Ray Spectrometer Penetration System

    NASA Technical Reports Server (NTRS)

    Adams, G. L.; Amundsen, R. J.; Beardsley, R. W.; Cash, R. H.; Clark, B. C.; Knight, T. C. D.; Martin, J. P.; Monti, P.; Outteridge, D. A.; Plaster, W. D.

    1986-01-01

    A penetrator system has been suggested as an approach for making in situ measurements of the composition and physical properties of the nucleus of a comet. This study has examined in detail the feasibility of implementing the penetrator concept. The penetrator system and mission designs have been developed and iterated in sufficient detail to provide a high level of confidence that the concept can be implemented within the constraints of the Mariner Mark 2 spacecraft.

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

    SciTech Connect

    Zhao Weiling; Payne, Valerie; Tommasi, Ellen; Diz, Debra I.; Hsu, F.-C.; Robbins, Mike E. . E-mail: mrobbins@wfubmc.edu

    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 of 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.

  5. A novel peroxisome proliferator-activated receptor alpha/gamma agonist, BPR1H0101, inhibits topoisomerase II catalytic activity in human cancer cells.

    PubMed

    Kao, Yu-Hsun; Hsieh, Hsing-Pang; Chitlimalla, Santhosh Kumar; Pan, Wen-Yu; Kuo, Ching-Chuan; Tsai, Yuan-Chin; Lin, Wen-Hsing; Chuang, Shuang-En; Chang, Jang-Yang

    2008-02-01

    Peroxisome proliferator-activated receptor (PPAR) gamma agonists are used clinically for treating diabetes mellitus and cancer. 2-Methyl-2[(1-{3-phenyl-7-propylbenzol[d]isoxazol-6-yl}oxy)propyl]-1H-4-indolyl) oxy]propanoic acid (BPR1H0101) is a novel synthetic indole-based compound, discovered through research to identify new PPARgamma agonists, and it acts as a dual agonist for PPARgamma and PPARalpha. Isobologram analysis demonstrated that BPR1H0101 is capable of antagonistic interaction with the topoisomerase (topo) II poison, VP16. A study of its mechanism showed that BPR1H0101 could inhibit the catalytic activity of topo II in vitro, but did not produce detectable topo II-mediated DNA strand breaks in human oral cancer KB cells. Furthermore, BPR1H0101 could inhibit VP16-induced topo II-mediated DNA cleavage and ataxia-telangiectasia-mutated phosphorylation in KB cells. The results suggest that BPR1H0101 can interfere with the topo II reaction by inhibiting catalytic activity before the formation of the intermediate cleavable complex; consequently, it can impede VP16-induced topo II-mediated DNA cleavage and cell death. This is the first identified PPARalpha/gamma agonist that can serve as a topo II catalytic inhibitor, to interfere with VP16-induced cell death. The result might have relevance to the clinical use of the PPARalpha/gamma agonist in combination chemotherapy. PMID:18176111

  6. Detection of T-cell receptor gamma chain V gene rearrangements using the polymerase chain reaction: application to the study of clonal disease cells in acute lymphoblastic leukemia.

    PubMed

    Taylor, J J; Rowe, D; Williamson, I K; Christmas, S E; Proctor, S J; Middleton, P G

    1991-05-01

    This report describes the development and characterization of a method for the amplification of rearranged V-J segments of the human T-cell receptor gamma chain (TCRG) locus using an adaptation of the polymerase chain reaction (PCR) technique. The technique uses a single pair of 'consensus' primers to amplify rearrangements involving the V gamma I subgroup genes, which are common in malignant cells from acute lymphoblastic leukemia (ALL) patients. Using this method we were able to detect rearrangements in the TCRG locus in disease cells from patients with T-cell ALL (12 of 12), common ALL (10 of 14), and Null cell ALL (2 of 2) at presentation. Monoallelic and biallelic rearrangements involving V gamma I subgroup genes were identified by restriction analysis of PCR products from DNA samples from a T-cell leukemic cell line, T-cell clones, and disease cells from patients with ALL of T-and B-cell lineage at presentation. These results confirmed the presence of cell clones within the presentation samples and, in one case, confirmed the persistence of the original malignant cell clone at relapse. This is a rapid and specific method for the detection and characterization of rearrangements of the TCRG locus without recourse to Southern blotting. Therefore, the PCR technique described herein can provide the basis for the study of clonal evolution and minimal residual disease on a high proportion of patients with ALL.

  7. PPAR{gamma} regulates the expression of cholesterol metabolism genes in alveolar macrophages

    SciTech Connect

    Baker, Anna D.; Malur, Anagha; Barna, Barbara P.; Kavuru, Mani S.; Malur, Achut G.; Thomassen, Mary Jane

    2010-03-19

    Peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPAR{gamma} has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPAR{gamma} regulates cholesterol influx, efflux, and metabolism. PPAR{gamma} promotes cholesterol efflux through the liver X receptor-alpha (LXR{alpha}) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPAR{gamma} knockout (PPAR{gamma} KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXR{alpha} and ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPAR{gamma} would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPAR{gamma}) to restore PPAR{gamma} expression in the alveolar macrophages of PPAR{gamma} KO mice. Our results show that the alveolar macrophages of PPAR{gamma} KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPAR{gamma} (1) induced transcription of LXR{alpha} and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPAR{gamma} regulates cholesterol metabolism in alveolar macrophages.

  8. System and method for resolving gamma-ray spectra

    DOEpatents

    Gentile, Charles A.; Perry, Jason; Langish, Stephen W.; Silber, Kenneth; Davis, William M.; Mastrovito, Dana

    2010-05-04

    A system for identifying radionuclide emissions is described. The system includes at least one processor for processing output signals from a radionuclide detecting device, at least one training algorithm run by the at least one processor for analyzing data derived from at least one set of known sample data from the output signals, at least one classification algorithm derived from the training algorithm for classifying unknown sample data, wherein the at least one training algorithm analyzes the at least one sample data set to derive at least one rule used by said classification algorithm for identifying at least one radionuclide emission detected by the detecting device.

  9. A delta T-cell receptor deleting element transgenic reporter construct is rearranged in alpha beta but not gamma delta T-cell lineages.

    PubMed Central

    Shutter, J; Cain, J A; Ledbetter, S; Rogers, M D; Hockett, R D

    1995-01-01

    T cells can be divided into two groups on the basis of the expression of either alpha beta or gamma delta T-cell receptors (TCRs). Because the TCR delta chain locus lies within the larger TCR alpha chain locus, control of the utilization of these two receptors is important in T-cell development, specifically for determination of T-cell type: rearrangement of the alpha locus results in deletion of the delta coding segments and commitment to the alpha beta lineage. In the developing thymus, a relative site-specific recombination occurs by which the TCR delta chain gene segments are deleted. This deletion removes all D delta, J delta, and C delta genes and occurs on both alleles. This delta deletional mechanism is evolutionarily conserved between mice and humans. Transgenic mice which contain the human delta deleting elements and as much internal TCR delta chain coding sequence as possible without allowing the formation of a complete delta chain gene were developed. Several transgenic lines showing recombinations between deleting elements within the transgene were developed. These lines demonstrate that utilization of the delta deleting elements occurs in alpha beta T cells of the spleen and thymus. These recombinations are rare in the gamma delta population, indicating that the machinery for utilization of delta deleting elements is functional in alpha beta T cells but absent in gamma delta T cells. Furthermore, a discrete population of early thymocytes containing delta deleting element recombinations but not V alpha-to-J alpha rearrangements has been identified. These data are consistent with a model in which delta deletion contributes to the implementation of a signal by which the TCR alpha chain locus is rearranged and expressed and thus becomes an alpha beta T cell. PMID:8524269

  10. Cholinergic receptor activation induces a relative facilitation of synaptic responses in the entorhinal cortex during theta- and gamma-frequency stimulation of parasubicular inputs.

    PubMed

    Sparks, D W; Chapman, C A

    2013-01-29

    The parasubiculum sends its single major output to layer II of the entorhinal cortex, and it may therefore interact with inputs to the entorhinal cortex from other cortical areas, and help to shape the activity of layer II entorhinal cells that project to the hippocampal formation. Cholinergic inputs are thought to contribute to the generation of theta- and gamma-frequency activities in the parasubiculum and entorhinal cortex, and the present study assessed how cholinergic receptor activation affects synaptic responses of the entorhinal cortex to theta- and gamma-frequency stimulation. Depth profiles of field excitatory postsynaptic potentials (fEPSPs) in acute brain slices showed a short-latency negative fEPSP in layer II, consistent with the activation of excitatory synaptic inputs to layer II. Application of the cholinergic agonist carbachol (CCh) suppressed synaptic responses and enhanced paired-pulse facilitation. CCh also resulted in a marked relative facilitation of synaptic responses evoked during short 5-pulse trains of stimulation at both theta- and gamma-frequencies. Application of the M(1) antagonist pirenzepine, but not the M(2) antagonist methoctramine, blocked the facilitation of responses. Inhibition of the M-current or block of GABA(B) receptors had no effect, but the facilitation effect was partially blocked by the N-methyl-d-aspartate (NMDA) antagonist APV, indicating that NMDA receptors play a role. Application of ZD7288, a selective inhibitor of the hyperpolarization-activated cationic current I(h), almost completely blocked the relative facilitation of responses, and the less potent I(h)-blocker Cs(+) also resulted in a partial block. The relative facilitation of synaptic responses induced by CCh is therefore likely mediated by multiple mechanisms including the cholinergic suppression of transmitter release that enhances transmitter availability during repetitive stimulation, NMDA receptor-mediated effects on pre- or postsynaptic function, and

  11. Agonist-dependent single channel current and gating in alpha4beta2delta and alpha1beta2gamma2S GABAA receptors.

    PubMed

    Keramidas, Angelo; Harrison, Neil L

    2008-02-01

    The family of gamma-aminobutyric acid type A receptors (GABA(A)Rs) mediates two types of inhibition in the mammalian brain. Phasic inhibition is mediated by synaptic GABA(A)Rs that are mainly comprised of alpha(1), beta(2), and gamma(2) subunits, whereas tonic inhibition is mediated by extrasynaptic GABA(A)Rs comprised of alpha(4/6), beta(2), and delta subunits. We investigated the activation properties of recombinant alpha(4)beta(2)delta and alpha(1)beta(2)gamma(2S) GABA(A)Rs in response to GABA and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one (THIP) using electrophysiological recordings from outside-out membrane patches. Rapid agonist application experiments indicated that THIP produced faster opening rates at alpha(4)beta(2)delta GABA(A)Rs (beta approximately 1600 s(-1)) than at alpha(1)beta(2)gamma(2S) GABA(A)Rs (beta approximately 460 s(-1)), whereas GABA activated alpha(1)beta(2)gamma(2S) GABA(A)Rs more rapidly (beta approximately 1800 s(-1)) than alpha(4)beta(2)delta GABA(A)Rs (beta < 440 s(-1)). Single channel recordings of alpha(1)beta(2)gamma(2S) and alpha(4)beta(2)delta GABA(A)Rs showed that both channels open to a main conductance state of approximately 25 pS at -70 mV when activated by GABA and low concentrations of THIP, whereas saturating concentrations of THIP elicited approximately 36 pS openings at both channels. Saturating concentrations of GABA elicited brief (<10 ms) openings with low intraburst open probability (P(O) approximately 0.3) at alpha(4)beta(2)delta GABA(A)Rs and at least two "modes" of single channel bursting activity, lasting approximately 100 ms at alpha(1)beta(2)gamma(2S) GABA(A)Rs. The most prevalent bursting mode had a P(O) of approximately 0.7 and was described by a reaction scheme with three open and three shut states, whereas the "high" P(O) mode ( approximately 0.9) was characterized by two shut and three open states. Single channel activity elicited by THIP in alpha(4)beta(2)delta and alpha(1)beta(2)gamma(2S) GABA

  12. 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.

  13. The Role of PPAR Gamma in Systemic Sclerosis.

    PubMed

    Dantas, Andréa Tavares; Pereira, Michelly Cristiny; de Melo Rego, Moacyr Jesus Barreto; da Rocha, Laurindo Ferreira; Pitta, Ivan da Rocha; Marques, Cláudia Diniz Lopes; Duarte, Angela Luzia Branco Pinto; Pitta, Maira Galdino da Rocha

    2015-01-01

    Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPARγ ligands have been studied in vitro and in vivo and some theories have emerged leading to new insights. Aberrant PPARγ function seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-β/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPARγ as an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis. PMID:26064084

  14. An automated system for gamma radiation field mapping

    NASA Astrophysics Data System (ADS)

    Gould, Robert; Tarpinian, James E.; Kenney, Edward S.

    1990-12-01

    Remote radiation survey equipment was sorely needed at Chernobyl but adequate systems did not exist. The current state of the art still consists of a survey meter mounted on a robotic carriage, which scans an area at many points on a grid. This process is both time consuming and somewhat inaccurate. The system we have developed will overcome these limitations, and would provide significant savings in man-hours and man-rem over manual survey techniques. The system we have developed consists of a collimated ionization chamber mounted in a scanning head. The measurement process is similar to that used in medical computed tomography (CT) imaging and consists of a series of collimator rotations and translations. The key to this work is the use of a collimator to provide position information with a position insensitive detector. In addition, an inverse filter image reconstruction technique has been used to reduce the distortion effects due to the scanner and scanning process in the resulting maps. This technique models the distortion as a linear, space invariant degrading function which is removed in a deconvolution process. We have constructed first- and second-generation prototype scanners, and developed software to produce three-dimensional radiation field "iso-dose" maps. The iso-dose maps will be superimposed on three-dimensional computer-aided design and drafting (CADD) drawings of the radiation area, aiding in the characterization of the source of radiation.

  15. gamma-Hydroxybutyrate (GHB) induces GABA(B) receptor independent intracellular Ca2+ transients in astrocytes, but has no effect on GHB or GABA(B) receptors of medium spiny neurons in the nucleus accumbens.

    PubMed

    Molnár, T; Antal, K; Nyitrai, G; Emri, Z

    2009-08-18

    We report on cellular actions of the illicit recreational drug gamma-hydroxybutyrate (GHB) in the brain reward area nucleus accumbens. First, we compared the effects of GHB and the GABA(B) receptor agonist baclofen. Neither of them affected the membrane currents of medium spiny neurons in rat nucleus accumbens slices. GABAergic and glutamatergic synaptic potentials of medium spiny neurons, however, were reduced by baclofen but not GHB. These results indicate the lack of GHB as well as postsynaptic GABA(B) receptors, and the presence of GHB insensitive presynaptic GABA(B) receptors in medium spiny neurons. In astrocytes GHB induced intracellular Ca(2+) transients, preserved in slices from GABA(B) receptor type 1 subunit knockout mice. The effects of tetrodotoxin, zero added Ca(2+) with/without intracellular Ca(2+) store depletor cyclopiazonic acid or vacuolar H-ATPase inhibitor bafilomycin A1 indicate that GHB-evoked Ca(2+) transients depend on external Ca(2+) and intracellular Ca(2+) stores, but not on vesicular transmitter release. GHB-induced astrocytic Ca(2+) transients were not affected by the GHB receptor-specific antagonist NCS-382, suggesting the presence of a novel NCS-382-insensitive target for GHB in astrocytes. The activation of astrocytes by GHB implies their involvement in physiological actions of GHB. Our findings disclose a novel profile of GHB action in the nucleus accumbens. Here, unlike in other brain areas, GHB does not act on GABA(B) receptors, but activates an NCS-382 insensitive GHB-specific target in a subpopulation of astrocytes. The lack of either post- or presynaptic effects on medium spiny neurons in the nucleus accumbens distinguishes GHB from many drugs and natural rewards with addictive properties and might explain why GHB has only a weak reinforcing capacity.

  16. Sequential appearance of T-cell receptor gamma delta- and alpha beta-bearing intestinal intra-epithelial lymphocytes in mice after irradiation.

    PubMed

    Yoshikai, Y; Ishida, A; Murosaki, S; Ando, T; Nomoto, K

    1991-12-01

    We have previously reported that T-cell receptor (TcR) gamma delta-bearing T cells precede TcR alpha beta-bearing T cells in appearance in the thymus after whole-body irradiation. In the present study, the kinetics of appearance of intestinal intra-epithelial lymphocytes (IEL) was examined in mice after whole-body irradiation with a lethal dose of 9.5 Gy or with a sublethal dose of 6 Gy. The number of CD3+ IEL decreased to the lowest value 4 days after irradiation with 9.5 Gy, and thereafter increased to half as many as the normal level by day 7. Thy-1+TcR alpha beta- IEL and Thy-TcR alpha beta- IEL recovered considerably by day 7 after the irradiation, whereas Thy-1+TcR alpha beta+ IEL and Thy-1+TcR alpha beta+ IEL hardly recovered at this stage. All mice died within 12 days after irradiation with a lethal dose of 9.5 Gy. On the other hand, when irradiation dose was decreased to 6 Gy, all mice survived beyond 40 days after irradiation. The number of CD3+ IEL recovered to the normal level by 10 days after irradiation with 6 Gy. Consistently with the results in mice irradiated with a lethal dose, the first cells to increase in IEL of mice irradiated with a sublethal dose were TcR gamma delta+ IEL expressing Thy-1 antigen. The number of Thy-1+TcR gamma delta+ IEL increased to approximately two-fold as many as that in normal mice by day 10, while TcR alpha beta+ IEL began to increase in number from day 20 after irradiation and recovered to the normal level by day 40 after irradiation. Thus, sequential appearance of TcR gamma delta+ and TcR alpha beta+ IEL was evident after irradiation, similar to that seen in the thymus after irradiation. The IEL on day 10 after a sublethal irradiation, which is composed mainly of Thy-1+TcR gamma delta+ IEL, exhibited a strong cytolytic activity against P815 in the presence of anti-CD3 mAb, suggesting that the early appearing Thy-1+TcR gamma delta+ IEL may play important roles in epithelial immunity at an early stage after irradiation.

  17. Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron.

    PubMed Central

    Byrd, T F; Horwitz, M A

    1989-01-01

    We have investigated the role of iron in the intracellular biology of Legionella pneumophila in human monocytes and in the effector arm of cell-mediated immune defense against this intracellular bacterial pathogen. To determine if L. pneumophila intracellular multiplication is iron dependent, we studied the effect of the iron chelator deferoxamine on L. pneumophila infection of monocytes. Deferoxamine at 15 microM completely inhibited L. pneumophila intracellular multiplication. The inhibitory effect of deferoxamine was reversed with equimolar iron-saturated transferrin but not apotransferrin. To examine the potential role of iron in monocyte activation, we investigated the influence of iron-saturated transferrin on L. pneumophila multiplication in IFN gamma-activated monocytes. Iron transferrin, but not apotransferrin, neutralized the capacity of activated monocytes to inhibit L. pneumophila multiplication. To explore a potential mechanism by which activated monocytes might limit the availability of intracellular iron, we examined transferrin receptor expression on nonactivated and activated monocytes cultured in vitro for 5 d. By fluorescence-activated flow cytometry, activated monocytes exhibited markedly fewer transferrin receptors than nonactivated monocytes. By Scatchard analysis of 125I-transferrin binding to monocytes, nonactivated monocytes had 38,300 +/- 12,700 (mean +/- SE) transferrin binding sites, whereas activated monocytes had 10,300 +/- 1,600, a reduction of 73%. Activated and nonactivated monocytes had a similar mean Kd (1.8 +/- 0.2 nM). This study demonstrates that (a) L. pneumophila intracellular multiplication is iron dependent; (b) activated monocytes inhibit L. pneumophila multiplication by limiting the availability of intracellular iron; and (c) transferrin receptors are downregulated on IFN gamma-activated monocytes. Images PMID:2496141

  18. Gamma-gamma colliders

    SciTech Connect

    Kim, K.J.; Sessler, A.

    1996-06-01

    Gamma-gamma colliders make intense beams of gamma rays and have them collide so as to make elementary particles. The authors show, in this article, that constructing a gamma-gamma collider as an add-on to an electron-positron linear collider is possible with present technology and that it does not require much additional cost. Furthermore, they show that the resulting capability is very interesting from a particle physics point of view. An overview of a linear collider, with a second interaction region devoted to {gamma}{gamma} collisions is shown.

  19. Networked alpha and gamma spectral acquisition and analysis system

    SciTech Connect

    Wilcox, C.M.; Gross, J.M.

    1993-10-01

    This manual assumes a knowledge of (terminology used and a working familiarity with) the windowing system and mouse of the Sun computer workstation. See the appropriate Sun manuals for additional information. ALDO, the alpha detector control program, is used to control, monitor, and edit log information associated with the collection of alpha spectra. Actual data collection and control functions are performed by Mizar Real-Time computers for which ALDO acts as a friendly user command interface and status display. It is normally started as part of your login procedure, but may also be started from the ``NETSPEC Utilities`` submenu of the root menu. The root menu is obtained by pushing the right mouse button when the cursor is over the root window (background picture). To become a user of ALDO and the other programs in the NETSPEC system, contact the person who performs systems administration tasks for the Sun computers. Most user interaction with ALDO is by means of mouse manipulation of screen items such as buttons, checkboxes, and sliders. The action of pushing the left mouse button when the cursor is over an item is called selecting that item. The left mouse button is therefore called the select button. The right mouse button is the menu button because a limited number of options may be displayed when that button is pressed when the cursor is over an item with a triangle (inverted delta). In this document, names of selectable items are printed in bold when they are first mentioned or when emphasis is helpful. In general, items which do not apply to the current context are either disabled or made invisible in order to prevent selection.

  20. 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.

  1. Stoichiometry of expressed alpha(4)beta(2)delta gamma-aminobutyric acid type A receptors depends on the ratio of subunit cDNA transfected.

    PubMed

    Wagoner, Kelly R; Czajkowski, Cynthia

    2010-05-01

    The gamma-aminobutyric acid type A receptor (GABA(A)R) is the target of many depressants, including benzodiazepines, anesthetics, and alcohol. Although the highly prevalent alphabetagamma GABA(A)R subtype mediates the majority of fast synaptic inhibition in the brain, receptors containing delta subunits also play a key role, mediating tonic inhibition and the actions of endogenous neurosteroids and alcohol. However, the fundamental properties of delta-containing GABA(A)Rs, such as subunit stoichiometry, are not well established. To determine subunit stoichiometry of expressed delta-containing GABA(A)Rs, we inserted the alpha-bungarotoxin binding site tag in the alpha(4), beta(2), and delta subunit N termini. An enhanced green fluorescent protein tag was also inserted into the beta(2) subunit to shift its molecular weight, allowing us to separate subunits using SDS-PAGE. Tagged alpha(4)beta(2)delta GABA(A)Rs were expressed in HEK293T cells using various ratios of subunit cDNA, and receptor subunit stoichiometry was determined by quantitating fluorescent alpha-bungarotoxin bound to each subunit on Western blots of surface immunopurified tagged GABA(A)Rs. The results demonstrate that the subunit stoichiometry of alpha(4)beta(2)delta GABA(A)Rs is regulated by the ratio of subunit cDNAs transfected. Increasing the ratio of delta subunit cDNA transfected increased delta subunit incorporation into surface receptors with a concomitant decrease in beta(2) subunit incorporation. Because receptor subunit stoichiometry can directly influence GABA(A)R pharmacological and functional properties, considering how the transfection protocols used affect subunit stoichiometry is essential when studying heterologously expressed alpha(4)beta(2)delta GABA(A)Rs. Successful bungarotoxin binding site tagging of GABA(A)R subunits is a novel tool with which to accurately quantitate subunit stoichiometry and will be useful for monitoring GABA(A)R trafficking in live cells.

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

    SciTech Connect

    Odell, D. Mackenzie Odell; Harpring, Larry J.; Moore, Frank S. Jr.; French, Phillip J.; Gordon, John R.

    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 and 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.

  3. Measurements with Pinhole and Coded Aperture Gamma-Ray Imaging Systems

    SciTech Connect

    Raffo-Caiado, Ana Claudia; Solodov, Alexander A; Abdul-Jabbar, Najeb M; Hayward, Jason P; Ziock, Klaus-Peter

    2010-01-01

    From a safeguards perspective, gamma-ray imaging has the potential to reduce manpower and cost for effectively locating and monitoring special nuclear material. The purpose of this project was to investigate the performance of pinhole and coded aperture gamma-ray imaging systems at Oak Ridge National Laboratory (ORNL). With the aid of the European Commission Joint Research Centre (JRC), radiometric data will be combined with scans from a three-dimensional design information verification (3D-DIV) system. Measurements were performed at the ORNL Safeguards Laboratory using sources that model holdup in radiological facilities. They showed that for situations with moderate amounts of solid or dense U sources, the coded aperture was able to predict source location and geometry within ~7% of actual values while the pinhole gave a broad representation of source distributions

  4. Investigation of Toll-Like Receptor-2 (2258G/A) and Interferon Gamma (+874T/A) Gene Polymorphisms among Infertile Women with Female Genital Tuberculosis

    PubMed Central

    Bhanothu, Venkanna; Lakshmi, Vemu; Theophilus, Jane P.; Rozati, Roya; Badhini, Prabhakar; Vijayalaxmi, Boda

    2015-01-01

    Background Toll-like receptor 2 (TLR2) and interferon-gamma (IFN-γ) coordinate with a diverse array of cellular programs through the transcriptional regulation of immunologically relevant genes and play an important role in immune system, reproductive physiology and basic pathology. Alterations in the functions of TLR2 2258G (guanine)/ A, IFN-γ (+874T/A) and signalling molecules that result from polymorphisms are often associated with susceptibility or resistance, which may, in turn, establish the innate host response to various infectious diseases. Presently, we proposed to investigate the risk of common single nucleotide polymorphism (SNP) of TLR2 and IFN-γ genes, for their effect on infertility in women with female genital tuberculosis (FGTB) and healthy women as controls. Methodology/Principal Findings Genotyping of TLR2 and IFN-γ gene polymorphisms was performed by amplification refractory mutation system multi-gene/multi-primer polymerase chain reaction followed by restriction fragment length polymorphism in 175 FGTB patients and 100 healthy control women (HCW). The TLR2 polymorphism [adenine (A) allele] was observed in 57.7 and 58.0% of FGTB patients and HCW, respectively. The IFN-γ (+874T/A) polymorphism (A allele) was significant in 74.3 and 71.0% of FGTB patients and HCW, respectively, while the odds ratios for the AA and TA genotypes for predisposition of FGTB were found to be 0.304 and 1.650 in HCW, respectively. The SNP of TLR2 was not associated with FGTB but the SNP of IFN-γ was found to be associated with mycobacteria infections and to induce infertility. Conclusions/Significance At present, we hypothesize that infertile women with FGTB and HCW without tuberculosis (TB) have identical frequency of TLR variants, which may be adequate in the production of IFN-γ in response to Mycobacterium tuberculosis infections. Thus, the study appears to be the first of its kind reporting a mutation in the IFN-γ gene [+874 T (thymine) to A] responsible for

  5. X-ray and gamma ray detector readout system

    DOEpatents

    Tumer, Tumay O; Clajus, Martin; Visser, Gerard

    2010-10-19

    A readout electronics scheme is under development for high resolution, compact PET (positron emission tomography) imagers based on LSO (lutetium ortho-oxysilicate, Lu.sub.2SiO.sub.5) scintillator and avalanche photodiode (APD) arrays. The key is to obtain sufficient timing and energy resolution at a low power level, less than about 30 mW per channel, including all required functions. To this end, a simple leading edge level crossing discriminator is used, in combination with a transimpedance preamplifier. The APD used has a gain of order 1,000, and an output noise current of several pA/ Hz, allowing bipolar technology to be used instead of CMOS, for increased speed and power efficiency. A prototype of the preamplifier and discriminator has been constructed, achieving timing resolution of 1.5 ns FWHM, 2.7 ns full width at one tenth maximum, relative to an LSO/PMT detector, and an energy resolution of 13.6% FWHM at 511 keV, while operating at a power level of 22 mW per channel. Work is in progress towards integration of this preamplifier and discriminator with appropriate coincidence logic and amplitude measurement circuits in an ASIC suitable for a high resolution compact PET instrument. The detector system and/or ASIC can also be used for many other applications for medical to industrial imaging.

  6. 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.

  7. Mice from a genetically resistant background lacking the interferon gamma receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell 1-type CD4+ T cell response

    PubMed Central

    1995-01-01

    Mice with homologous disruption of the gene coding for the ligand- binding chain of the interferon (IFN) gamma receptor and derived from a strain genetically resistant to infection with Leishmania major have been used to study further the role of this cytokine in the differentiation of functional CD4+ T cell subsets in vivo and resistance to infection. Wild-type 129/Sv/Ev mice are resistant to infection with this parasite, developing only small lesions, which resolve spontaneously within 6 wk. In contrast, mice lacking the IFN- gamma receptor develop large, progressing lesions. After infection, lymph nodes (LN) and spleens from both wild-type and knockout mice showed an expansion of CD4+ cells producing IFN-gamma as revealed by measuring IFN-gamma in supernatants of specifically stimulated CD4+ T cells, by enumerating IFN-gamma-producing T cells, and by Northern blot analysis of IFN-gamma transcripts. No biologically active interleukin (IL) 4 was detected in supernatants of in vitro-stimulated LN or spleen cells from infected wild-type or deficient mice. Reverse transcription polymerase chain reaction analysis with primers specific for IL-4 showed similar IL-4 message levels in LN from both types of mice. The IL-4 message levels observed were comparable to those found in similarly infected C57BL/6 mice and significantly lower than the levels found in BALB/c mice. Anti-IFN-gamma treatment of both types of mice failed to alter the pattern of cytokines produced after infection. These data show that even in the absence of IFN-gamma receptors, T helper cell (Th) 1-type responses still develop in genetically resistant mice with no evidence for the expansion of Th2 cells. PMID:7869054

  8. TRAIL/TRAIL Receptor System and Susceptibility to Multiple Sclerosis

    PubMed Central

    García-León, Juan Antonio; Pinto-Medel, María Jesús; Oliver-Martos, Begoña; Ortega-Pinazo, Jesús; Suardíaz, Margarita; García-Trujillo, Lucía; Guijarro-Castro, Cristina; Benito-León, Julián; Prat, Isidro; Varadé, Jezabel; Álvarez-Lafuente, Roberto; Urcelay, Elena

    2011-01-01

    The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values<0.05 were successfully replicated: rs4894559 in TRAIL gene, p = 9.8×10−4, OR = 1.34; rs4872077, in TRAILR-1 gene, p = 0.005, OR = 1.72; and rs1001793 in TRAILR-2 gene, p = 0.012, OR = 0.84. The combination of the alleles G/T/A in these SNPs appears to be associated with a reduced risk of developing MS (p = 2.12×10−5, OR = 0.59). These results suggest that genes of the TRAIL/TRAIL receptor system exerts a genetic influence on MS. PMID:21814551

  9. Production of gamma-ray bursts in massive binary systems

    NASA Astrophysics Data System (ADS)

    Joss, Paul C.

    Long γ-ray bursts may be produced by hypernova events in the rapidly rotating cores of massive stars. A serious problem that must be confronted in this scenario is how the core of the hypernova progenitor retains or acquires sufficient angular momentum to produce the requisite axisymmetric collapse. Physical processes during the evolution of an isolated massive star will tend to extract any initial angular momentum from the stellar core, rendering it difficult for such a star to become a hypernova. However, a substantial fraction of massive stars are members of binary systems. Tidal locking, mass transfer, and/or stellar merger in an evolved massive binary may transfer orbital angular momentum to the core of one of the stars (or the merged star), sufficient to produce the progenitor of a hypernova. To investigate this issue, we have substantially refined a binary stellar evolution code that we had previously developed. The code includes the effects of mass and angular momentum transfer between the component stars and the subsequent transport of angular momentum through one of the stars. This transport is effected by dynamical and secular shear instabilities, convective motions, the critical layer instability, and gravity waves. Our code treats in a self-consistent way the dynamical distortion of the star resulting from the induced rapid differential rotation. The results of numerical computations with our refined code indicate that late main-sequence or early post-main-sequence accretion from a binary companion onto a star with an initial mass greater than ˜ 20 solar masses produces a rapidly rotating core within the accretor. The rotation will often be sufficiently rapid to provide the initial conditions necessary for a hypernova event, and the concomitant emission of a γ-ray burst, when the core collapses. We also find that the merger of a late post-main-sequence star with its binary companion may lead to a hypernova event in the stellar core, but is unlikely

  10. Verification of Gamma Knife extend system based fractionated treatment planning using EBT2 film

    SciTech Connect

    Natanasabapathi, Gopishankar; Bisht, Raj Kishor

    2013-12-15

    Purpose: This paper presents EBT2 film verification of fractionated treatment planning with the Gamma Knife (GK) extend system, a relocatable frame system for multiple-fraction or serial multiple-session radiosurgery.Methods: A human head shaped phantom simulated the verification process for fractionated Gamma Knife treatment. Phantom preparation for Extend Frame based treatment planning involved creating a dental impression, fitting the phantom to the frame system, and acquiring a stereotactic computed tomography (CT) scan. A CT scan (Siemens, Emotion 6) of the phantom was obtained with following parameters: Tube voltage—110 kV, tube current—280 mA, pixel size—0.5 × 0.5 and 1 mm slice thickness. A treatment plan with two 8 mm collimator shots and three sectors blocking in each shot was made. Dose prescription of 4 Gy at 100% was delivered for the first fraction out of the two fractions planned. Gafchromic EBT2 film (ISP Wayne, NJ) was used as 2D verification dosimeter in this process. Films were cut and placed inside the film insert of the phantom for treatment dose delivery. Meanwhile a set of films from the same batch were exposed from 0 to 12 Gy doses for calibration purposes. An EPSON (Expression 10000 XL) scanner was used for scanning the exposed films in transparency mode. Scanned films were analyzed with inhouse written MATLAB codes.Results: Gamma index analysis of film measurement in comparison with TPS calculated dose resulted in high pass rates >90% for tolerance criteria of 1%/1 mm. The isodose overlay and linear dose profiles of film measured and computed dose distribution on sagittal and coronal plane were in close agreement.Conclusions: Through this study, the authors propose treatment verification QA method for Extend frame based fractionated Gamma Knife radiosurgery using EBT2 film.

  11. 1990 yearly calibration of Pacific Northwest Laboratory's gross-gamma borehole geophysical logging system

    SciTech Connect

    Arthur, R.J.

    1990-08-01

    This report describes the 1990 yearly calibration of a gross-gamma geophysical pulse logging system owned by the US Department of Energy (DOE) and operated by Pacific Northwest Laboratory (PNL). The calibration was conducted to permit the continued use of this system for geological and hydrologic studies associated with remedial investigation at the Hanford Site. Primary calibrations to equivalent uranium units were conducted in borehole model standards that were recently moved to the Hanford Site from the DOE field calibration facility in Spokane, Washington. The calibrations were performed in borehole models SBL/SBH and SBA/SBB, which contain low equivalent-uranium concentrations. The integrity of the system throughout the previous year from gamma-ray monitoring was demonstrated using the before- and after-logging field calibration readings with the field source in calibration Positions 1 and 2. Most of the Position 1 readings are within an 8% limit that is set by the governing PNL technical reference procedure as a critical value above which the instrument is considered suspect. Many of the Position 2 readings exceed the 8% limit; however, the fluctuation was traced to field-source geometry variability that affected Position 1 count rates by up to 6% and Position 2 count rates by as much as 16%. Correlations were established based on two similar approaches for relating observed count rate in before- and after-logging field calibrations to equivalent uranium concentrations. The temperature drift of the gamma-ray probe was documented and amounts to less than 0.1%/{degree}C within the temperature range 0{degree}C to 42{degree}C. The low-energy cutoff for the gross gamma-ray probe was determined to be between 46.5 and 59.5 keV. 10 refs., 4 figs., 13 tabs.

  12. Peroxisome Proliferator-Activated Receptor Alpha (PPARa), Beta (PPARI3), and Gamma (PPARy) Expression in Human Fetal Tissues.

    EPA Science Inventory

    Peroxisome proliferator-activated receptors (PPARs) regulate lipid and glucose homeostasis, are targets of pharmaceuticals, and are also activated by environmental contaminants. Almost nothing is known about expression of PPARs during human fetal development. This study uses qPCR...

  13. Peroxisome Proliferator Activated Receptors Alpha, Beta, and Gamma mRNA and protein expression in human fetal tissues

    EPA Science Inventory

    Peroxisome proliferator-activated receptors (PPARs) regulate lipid and glucose homeostasis, are targets of pharmaceuticals, and are also activated by environmental contaminants. Almost nothing is known about expression of PPARs during human fetal development. This study examine...

  14. Analogues of gamma-aminobutyric acid (GABA) and trans-4-aminocrotonic acid (TACA) substituted in the 2 position as GABAC receptor antagonists.

    PubMed

    Chebib, M; Vandenberg, R J; Johnston, G A

    1997-12-01

    1. gamma-Aminobutyric acid (GABA) and trans-4-aminocrotonic acid (TACA) have been shown to activate GABAC receptors. In this study, a range of C2, C3, C4 and N-substituted GABA and TACA analogues were examined for activity at GABAC receptors. 2. The effects of these compounds were examined by use of electrophysiological recording from Xenopus oocytes expressing the human rho 1 subunit of GABAC receptors with the two-electrode voltage-clamp method. 3. trans-4-Amino-2-fluorobut-2-enoic acid was found to be a potent agonist (KD = 2.43 microM). In contrast, trans-4-amino-2-methylbut-2-enoic acid was found to be a moderately potent antagonist (IC50 = 31.0 microM and KB = 45.5 microM). These observations highlight the possibility that subtle structural substitutions may change an agonist into an antagonist. 4. 4-Amino-2-methylbutanoic acid (KD = 189 microM), 4-amino-2-methylenebutanoic acid (KD = 182 microM) and 4-amino-2-chlorobutanoic acid (KD = 285 microM) were weak partial agonists. The intrinsic activities of these compounds were 12.1%, 4.4% and 5.2% of the maximal response of GABA, respectively. These compounds more effectively blocked the effects of the agonist, GABA, giving rise to KB values of 53 microM and 101 microM, respectively. 5. The sulphinic acid analogue of GABA, homohypotaurine, was found to be a potent partial agonist (KD = 4.59 microM, intrinsic activity 69%). 6. It was concluded that substitution of a methyl or a halo group in the C2 position of GABA or TACA is tolerated at GABAC receptors. However, there was dramatic loss of activity when these groups were substituted at the C3, C4 and nitrogen positions of GABA and TACA. 7. Molecular modelling studies on a range of active and inactive compounds indicated that the agonist/competitive antagonist binding site of the GABAC receptor may be smaller than that of the GABAA and GABAB receptors. It is suggested that only compounds that can attain relatively flat conformations may bind to the GABAC receptor

  15. Early stimulation and late inhibition of peroxisome proliferator-activated receptor gamma (PPAR gamma) gene expression by transforming growth factor beta in human aortic smooth muscle cells: role of early growth-response factor-1 (Egr-1), activator protein 1 (AP1) and Smads.

    PubMed Central

    Fu, Mingui; Zhang, Jifeng; Lin, Yimin; Zhu, Xiaojun; Zhao, Luning; Ahmad, Mushtaq; Ehrengruber, Markus U; Chen, Yuqing E

    2003-01-01

    Transforming growth factor beta (TGF beta) and peroxisome proliferator-activated receptor gamma (PPAR gamma) play major roles in the development of vascular diseases. It has been documented that PPAR gamma activation inhibits the TGF beta signal pathway in vascular smooth muscle cells (VSMC). Here we examined whether TGF beta can regulate PPAR gamma expression. Northern blot analyses revealed that both TGF beta 1 and 2 exert a biphasic effect (early stimulation and late repression) on PPAR gamma gene expression in VSMC. TGF beta rapidly and transiently induced early growth-response factor-1 (Egr-1) expression through the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 (MEK1)/ERK-mediated pathway. Inhibition of MEK1/ERK by PD98059 not only abrogated the induction of Egr-1 but also abolished the rapid and transient induction of PPAR gamma by TGF beta. Furthermore, overexpression of NAB2, a repressor of Egr-1 activation, also blocked the induction of PPAR gamma by TGF beta in VSMC, suggesting that Egr-1 mediates the rapid and transient induction of PPAR gamma by TGF beta. With regard to the TGF beta repression of PPAR gamma expression, activator protein 1 (AP1) and Smad3/4 dramatically inhibited the PPAR gamma promoter activity in transient-transfection studies. In contrast, adenovirus-mediated overexpression of a dominant-negative form of c-Jun partially rescued the TGF beta-induced PPAR gamma repression in VSMC. Taken together, our data demonstrate that Egr-1, AP1 and Smad are part components of the TGF beta signal transduction pathway that regulates PPAR gamma expression. PMID:12457461

  16. Development of a membrane-anchored ligand and receptor yeast two-hybrid system for ligand-receptor interaction identification

    PubMed Central

    Li, Jingjing; Gao, Jin; Han, Lei; Zhang, Yinjie; Guan, Wen; Zhou, Liang; Yu, Yan; Han, Wei

    2016-01-01

    Identifying interactions between ligands and transmembrane receptors is crucial for understanding the endocrine system. However, the present approaches for this purpose are still not capable of high-throughput screening. In this report, a membrane-anchored ligand and receptor yeast two-hybrid (MALAR-Y2H) system was established. In the method, an extracellular ligand is linked with an intracellular split-ubiquitin reporter system via a chimeric transmembrane structure. Meanwhile, the prey proteins of transmembrane receptors are fused to the other half of the split-ubiquitin reporter system. The extracellular interaction of ligands and receptors can lead to the functional recovery of the ubiquitin reporter system in yeast, and eventually lead to the expression of report genes. Consequently, the system can be used to detect the interactions between extracellular ligands and their transmembrane receptors. To test the efficiency and universality of the method, interactions between several pairs of ligands and receptors of mouse were analyzed. The detecting results were shown to be thoroughly consistent with the present knowledge, indicating MALAR-Y2H can be utilized for such purpose with high precision, high efficiency and strong universality. The characteristics of the simple procedure and high-throughput potential make MALAR-Y2H a powerful platform to study protein-protein interaction networks between secreted proteins and transmembrane proteins. PMID:27762338

  17. Imaging system for cardiac planar imaging using a dedicated dual-head gamma camera

    SciTech Connect

    Majewski, Stanislaw; Umeno, Marc M.

    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.

  18. 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.

  19. Receptor-mediated mitophagy in yeast and mammalian systems

    PubMed Central

    Liu, Lei; Sakakibara, Kaori; Chen, Quan; Okamoto, Koji

    2014-01-01

    Mitophagy, or mitochondria autophagy, plays a critical role in selective removal of damaged or unwanted mitochondria. Several protein receptors, including Atg32 in yeast, NIX/BNIP3L, BNIP3 and FUNDC1 in mammalian systems, directly act in mitophagy. Atg32 interacts with Atg8 and Atg11 on the surface of mitochondria, promoting core Atg protein assembly for mitophagy. NIX/BNIP3L, BNIP3 and FUNDC1 also have a classic motif to directly bind LC3 (Atg8 homolog in mammals) for activation of mitophagy. Recent studies have shown that receptor-mediated mitophagy is regulated by reversible protein phosphorylation. Casein kinase 2 (CK2) phosphorylates Atg32 and activates mitophagy in yeast. In contrast, in mammalian cells Src kinase and CK2 phosphorylate FUNDC1 to prevent mitophagy. Notably, in response to hypoxia and FCCP treatment, the mitochondrial phosphatase PGAM5 dephosphorylates FUNDC1 to activate mitophagy. Here, we mainly focus on recent advances in our understanding of the molecular mechanisms underlying the activation of receptor-mediated mitophagy and the implications of this catabolic process in health and disease. PMID:24903109

  20. Altered B cell receptor signaling in human systemic lupus erythematosus

    PubMed Central

    Jenks, Scott A.; Sanz, Iñaki

    2009-01-01

    Regulation of B cell receptor signaling is essential for the development of specific immunity while retaining tolerance to self. Systemic lupus erythematosus (SLE) is characterized by a loss of B cell tolerance and the production of anti-self antibodies. Accompanying this break down in tolerance are alterations in B cell receptor signal transduction including elevated induced calcium responses and increased protein phosphorylation. Specific pathways that negatively regulate B cell signaling have been shown to be impaired in some SLE patients. These patients have reduced levels of the kinase Lyn in lipid raft microdomains and this reduction is inversely correlated with increased CD45 in lipid rafts. Function and expression of the inhibitory immunoglobulin receptor FcγRIIB is also reduced in Lupus IgM- CD27+ memory cells. Because the relative contribution of different memory and transitional B cell subsets can be abnormal in SLE patients, we believe studies targeted to well defined B cell subsets will be necessary to further our understanding of signaling abnormalities in SLE. Intracellular flow cytometric analysis of signaling is a useful approach to accomplish this goal. PMID:18723129

  1. Functional characterization of T cells bearing the gamma/delta T-cell receptor in patients with primary Sjögren's syndrome.

    PubMed

    Gerli, R; Agea, E; Muscat, C; Bertotto, A; Ercolani, R; Bistoni, O; Bini, P; Spinozzi, F; Venanzi, F

    1993-01-01

    High percentages of gamma/delta+ T cells in the peripheral blood of a subgroup of patients with primary Sjögren's syndrome (SS) were found. This allowed us to purify and analyze them without their being previously expanded in vitro, and to investigate, therefore, the role of these cells in the pathological immune response which characterizes such systemic autoimmune disorders. The results showed poor proliferation of patient gamma/delta+ T cells in response to anti-CD3, due not to macrophage-dependent suppression but to defective interleukin 2 (IL-2) synthesis. Despite the defective proliferation patient gamma/delta+ cells, unlike those of the normal controls, provided a helper effect in inducing B cells to secrete immunoglobulins (Ig), particularly when they were preincubated with IL-2. The relative increase in a gamma/delta+ T cell subset which, although it secretes low levels of IL-2, is able to provide help for B-cell Ig synthesis, suggests that this T-cell subpopulation may be functional in vivo and may be involved in the pathological immune response encountered in pSS. PMID:8353984

  2. First results of electron temperature measurements by the use of multi-pass Thomson scattering system in GAMMA 10

    SciTech Connect

    Yoshikawa, M. Nagasu, K.; Shimamura, Y.; Shima, Y.; Kohagura, J.; Sakamoto, M.; Nakashima, Y.; Imai, T.; Ichimura, M.; Yasuhara, R.; Yamada, I.; Funaba, H.; Kawahata, K.; Minami, T.

    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.

  3. Measured Activities of Al and Ni in gamma-(Ni) and gamma'-(Ni)3Al in the Ni-Al-Pt System

    NASA Technical Reports Server (NTRS)

    Copland, Evan

    2007-01-01

    Adding Pt to Ni-Al coatings is critical to achieving the required oxidation protection of Ni-based superalloys, but the nature of the Pt effect remains unresolved. This research provides a fundamental part of the answer by measuring the influence of Pt on the activities of Al and Ni in gamma-(Ni), gamma prime-(Ni)3Al and liquid in the Ni-Al-Pt system. Measurements have been made at 25 compositions in the Ni-rich corner over the temperature range, T = 1400-1750 K, by the vapor pressure technique with a multiple effusion-cell mass spectrometer (multi-cell KEMS). These measurements clearly show adding Pt (for X(sub Pt) less than 0.25) decreases a(Al) while increasing a(Ni). This solution behavior supports the idea that Pt increases Al transport to an alloy / Al2O3 interface and also limits the interaction between the coating and substrate alloys in the gamma-(Ni) + gamma prime-(Ni)3Al region. This presentation will review the progress of this study.

  4. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha activation of CYP7A1 during food restriction and diabetes is still inhibited by small heterodimer partner.

    PubMed

    Shin, Dong-Ju; Osborne, Timothy F

    2008-05-30

    Cholesterol 7alpha-hydroxylase (CYP7A1) catalyzes the rate-limiting step in the classic pathway of hepatic bile acid biosynthesis from cholesterol. During fasting and in type I diabetes, elevated levels of peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1alpha) induce expression of the Cyp7A1 gene and overexpression of PGC-1alpha in hepatoma cells stimulates bile acid synthesis. Using Ad-PGC-1alpha-RNA interference to induce acute disruption of PGC-1alpha in mice, here we show that PGC-1alpha is necessary for fasting-mediated induction of CYP7A1. Co-immunoprecipitation and promoter activation studies reveal that the induction of CYP7A1 is mediated by direct interaction between PGC-1alpha and the AF2 domain of liver receptor homolog-1 (LRH-1). In contrast, the very similar PGC-1beta could not substitute for PGC-1alpha. We also show that transactivation of PGC-1alpha and LRH-1 is repressed by the small heterodimer partner (SHP). Treatment of mice with GW4064, a synthetic agonist for farnesoid X receptor, induced SHP expression and decreased both the recruitment of PGC-1alpha to the Cyp7A1 promoter and the fasting-induced expression of CYP7A1 mRNA. These data suggest that PGC-1alpha is an important co-activator for LRH-1 and that SHP targets the interaction between LRH-1 and PGC-1alpha to inhibit CYP7A1 expression. Overall, these studies provide further evidence for the important role of PGC-1alpha in bile acid homeostasis and suggest that pharmacological targeting of farnesoid X receptor in vivo can be used to reverse the increase in CYP7A1 associated with adverse metabolic conditions.

  5. Physiological and receptor-selective retinoids modulate interferon gamma signaling by increasing the expression, nuclear localization, and functional activity of interferon regulatory factor-1.

    PubMed

    Luo, Xin M; Ross, A Catharine

    2005-10-28

    Synergistic actions between all-trans-retinoic acid (atRA) and interferon gamma (IFNgamma) on modulation of cellular functions have been reported both in vitro and in vivo. However, the mechanism of atRA-mediated regulation of IFNgamma signaling is poorly understood. In this study, we have used the human lung epithelial cell line A549 to examine the effect of atRA on IFNgamma-induced expression of IFN regulatory factor-1 (IRF-1), an important transcription factor involved in cell growth and apoptosis, differentiation, and antiviral and antibacterial immune responses. At least 4 h of pretreatment with atRA followed by suboptimal concentrations of IFNgamma induced a faster, higher, and more stable expression of IRF-1 than IFNgamma alone. Actinomycin D completely blocked the induction of IRF-1 by the combination, suggesting regulation at the transcriptional level. Further, we found that activation of signal transducer and activator of transcription-1 was induced more dramatically by atRA and IFNgamma than by IFNgamma alone. Expression of IFNgamma receptor-1 on the cell surface was also increased upon atRA pretreatment. Experiments using receptor-selective retinoids revealed that ligands for retinoic acid receptor-alpha (RARalpha), including atRA, 9-cis-retinoic acid, and Am580, sequentially increased the levels of IFNgamma receptor-1, activated signal transducer and activator of transcription-1, and IRF-1 and that an RARalpha antagonist was able to inhibit the effects of atRA and Am580. In addition, atRA pretreatment affected the transcriptional functions of IFNgamma-induced IRF-1, increasing its nuclear localization and DNA binding activity as well as the transcript levels of IRF-1 target genes. These results suggest that atRA, an RARalpha ligand, regulates IFNgamma-induced IRF-1 by affecting multiple components of the IFNgamma signaling pathway, from the plasma membrane to the nuclear transcription factors.

  6. MODULAR CAUSTIC SIDE SOLVENT EXTRACTION UNIT (MCU) GAMMA MONITORS SYSTEM FINAL REPORT

    SciTech Connect

    Casella, V

    2005-12-15

    The Department of Energy (DOE) selected Caustic-Side Solvent Extraction (CSSX) as the preferred technology for the removal of radioactive cesium from High-Level Waste (HLW) at the Savannah River Site (SRS). Before the full-scale Salt Waste Processing Facility (SWPF) becomes operational, the Closure Business Unit (CBU) plans to process a portion of dissolved saltcake waste through a Modular CSSX Unit (MCU). This work was derived from Technical Task Request SP-TTR-2004-00013, ''Gamma Monitor for MCU''. The deliverables for this task are the hardware and software for the gamma monitors and a report summarizing the testing and acceptance of this equipment for use in the MCU. Gamma-ray monitors are required to: (1) Measure the Cs-137 concentration in the decontaminated salt solution before entering the DSS (Decontaminated Salt Solution) Hold Tank, (2) Measure the Cs-137 concentration in the strip effluent before entering the Strip Effluent Hold Tank, (3) Verify proper operation of the solvent extraction system by verifying material balance within the process (The DSS Hold Tank Cs-137 concentration will be very low and the Cs-137 concentration in the Strip Effluent Hold Tank will be fifteen times higher than the Cs-137 concentration in the Feed Tank.) Sodium iodide monitors are used to measure the Cs-137 concentration in the piping before the DSS Hold tank, while GM monitors are used for Cs-137 measurements before the Strip Effluent Hold Tank. Tungsten shields were designed using Monte Carlo calculations and fabricated to reduce the process background radiation at the detector positions. These monitors were calibrated with NIST traceable standards that were specially made to be the same as the piping being monitored. Since this gamma ray monitoring system is unique, specially designed software was written and acceptance tested by Savannah River National Laboratory personnel. The software is a LabView-based application that serves as a unified interface for controlling

  7. 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

  8. A Single Tower Configuration of the Modular Gamma Box Counter System - 13392

    SciTech Connect

    Morris, K.; Nakazawa, D.; Francalangia, J.; Gonzalez, H.

    2013-07-01

    Canberra's Standard Gamma Box Counter System is designed to perform accurate quantitative assays of gamma emitting nuclides for a wide range of large containers including B-25 crates and ISO shipping containers. Using a modular building-block approach, the system offers tremendous flexibility for a variety of measurement situations with wide ranges of sample activities and throughput requirements, as well as the opportunity to modify the configuration for other applications at a later date. The typical configuration consists of two opposing towers each equipped with two high purity germanium detectors, and an automated container trolley. This paper presents a modified configuration, consisting of a single tower placed inside a measurement trailer with three detector assemblies, allowing for additional vertical segmentation as well as a viewing a container outside the trailer through the trailer wall. An automatic liquid nitrogen fill system is supplied for each of the detectors. The use of a forklift to move the container for horizontal segmentation is accommodated by creating an additional operational and calibration set-up in the NDA 2000 software to allow for the operator to rotate the container and assay the opposite side, achieving the same sensitivity as a comparable two-tower system. This Segmented Gamma Box Counter System retains the core technologies and design features of the standard configuration. The detector assemblies are shielded to minimize interference from environmental and plant background, and are collimated to provide segmentation of the container. The assembly positions can also be modified in height and distance from the container. The ISOCS calibration software provides for a flexible approach to providing the calibrations for a variety of measurement geometries. The NDA 2000 software provides seamless operation with the current configuration, handling the data acquisition and analysis. In this paper, an overview of this system is discussed

  9. A simple way of obtaining a composite video output signal from the GAMMA-11 computing system.

    PubMed

    Richardson, R L

    1978-08-01

    Many departments of nuclear medicine are currently using the GAMMA-11 computer to process clinical images. Often practitioners would like to display the output pictures on conventional cathode-ray monitors that they already have. Some may want to record the images on a video tape recorder. Both of these devices require a composite video signal, which the computer does not provide. Such a signal can be obtained, however, by combining two signals that the system does produce. A number of relatively complicated systems for doing this have been suggested. The desired result can be obtained, however, by using two ten-cent resistors in the simple circuit described in this paper.

  10. Computer Assisted Gamma and X-Ray Tomography: Applications to Multiphase Flow Systems.

    SciTech Connect

    Kumar, Sailesh B.; Dudukovic, Milorad P.; Toseland, Bernard A.

    1997-03-01

    The application of X-ray and gamma ray transmission tomography to the study of process engineering systems is reviewed. The fundamental principles of tomography, the algorithms for image reconstruction, the measurement method and the possible sources of error are discussed in detail. A case study highlights the methodology involved in designing a scanning system for the study of a given process unit, e.g., reactor, separations column etc. Results obtained in the authors` laboratory for the gas holdup distribution in bubble columns are also presented. Recommendations are made for the Advanced Fuels Development Unit (AFDU) in LaPorte, TX.

  11. High and low energy gamma beam dump designs for the gamma beam delivery system at ELI-NP

    NASA Astrophysics Data System (ADS)

    Yasin, Zafar; Matei, Catalin; Ur, Calin A.; Mitu, Iani-Octavian; Udup, Emil; Petcu, Cristian

    2016-03-01

    The Extreme Light Infrastructure - Nuclear Physics (ELI-NP) is under construction in Magurele, Bucharest, Romania. The facility will use two 10 PW lasers and a high intensity, narrow bandwidth gamma beam for stand-alone and combined laser-gamma experiments. The accurate estimation of particle doses and their restriction within the limits for both personel and general public is very important in the design phase of any nuclear facility. In the present work, Monte Carlo simulations are performed using FLUKA and MCNPX to design 19.4 and 4 MeV gamma beam dumps along with shielding of experimental areas. Dose rate contour plots from both FLUKA and MCNPX along with numerical values of doses in experimental area E8 of the facility are performed. The calculated doses are within the permissible limits. Furthermore, a reasonable agreement between both codes enhances our confidence in using one or both of them for future calculations in beam dump designs, radiation shielding, radioactive inventory, and other calculations releated to radiation protection. Residual dose rates and residual activity calculations are also performed for high-energy beam dump and their effect is negligible in comparison to contributions from prompt radiation.

  12. Monte Carlo modeling of neutron and gamma-ray imaging systems

    SciTech Connect

    Hall, J.

    1996-04-01

    Detailed numerical prototypes are essential to design of efficient and cost-effective neutron and gamma-ray imaging systems. We have exploited the unique capabilities of an LLNL-developed radiation transport code (COG) to develop code modules capable of simulating the performance of neutron and gamma-ray imaging systems over a wide range of source energies. COG allows us to simulate complex, energy-, angle-, and time-dependent radiation sources, model 3-dimensional system geometries with ``real world`` complexity, specify detailed elemental and isotopic distributions and predict the responses of various types of imaging detectors with full Monte Carlo accuray. COG references detailed, evaluated nuclear interaction databases allowingusers to account for multiple scattering, energy straggling, and secondary particle production phenomena which may significantly effect the performance of an imaging system by may be difficult or even impossible to estimate using simple analytical models. This work presents examples illustrating the use of these routines in the analysis of industrial radiographic systems for thick target inspection, nonintrusive luggage and cargoscanning systems, and international treaty verification.

  13. Histamine H(3) receptor-mediated inhibition of depolarization-induced, dopamine D(1) receptor-dependent release of [(3)H]-gamma-aminobutryic acid from rat striatal slices.

    PubMed

    Arias-Montaño, J A; Floran, B; Garcia, M; Aceves, J; Young, J M

    2001-05-01

    1. A study was made of the regulation of [(3)H]-gamma-aminobutyric acid ([(3)H]-GABA) release from slices of rat striatum by endogenous dopamine and exogenous histamine and a histamine H(3)-agonist. Depolarization-induced release of [(3)H]-GABA was Ca(2+)-dependent and was increased in the presence of the dopamine D(2) receptor family antagonist, sulpiride (10 microM). The sulpiride-potentiated release of [(3)H]-GABA was strongly inhibited by the dopamine D(1) receptor family antagonist, SCH 23390 (1 microM). Neither antagonist altered basal release. 2. The 15 mM K(+)-induced release of [(3)H]-GABA in the presence of sulpiride was inhibited by 100 microM histamine (mean inhibition 78+/-3%) and by the histamine H(3) receptor-selective agonist, immepip, 1 microM (mean inhibition 81+/-5%). The IC(50) values for histamine and immepip were 1.3+/-0.2 microM and 16+/-2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H(3) receptor antagonist, thioperamide, 1 microM. 3. The inhibition of 15 mM K(+)-induced [(3)H]-GABA release by immepip was reversed by the H(3) receptor antagonist, clobenpropit, K(d) 0.11+/-0.04 nM. Clobenpropit alone had no effect on basal or stimulated release of [(3)H]-GABA. 4. Elevated K(+) caused little release of [(3)H]-GABA from striatal slices from reserpinized rats, unless the D(1) partial agonist, R(+)-SKF 38393, 1 microM, was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 microM immepip to the level obtained in the absence of SKF 38393. 5. These observations demonstrate that histamine H(3) receptor activation strongly inhibits the dopamine D(1) receptor-dependent release of [(3)H]-GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones.

  14. The MEGA (Muon decays into an Electron and a GAmma ray) hardware trigger system

    SciTech Connect

    Szymanski, J.J.; Amann, J.F.; Black, J.K.; Cooper, M.D.; Wright, S.C.; Crocker, J.; Sanders, H.

    1988-01-01

    The MEGA experiment is designed to search for the rare decay ..mu.. ..-->.. e ..gamma.. with a branching ratio sensitivity of /approximately/10/sup -13/. As is typical of rare-decay experiments, extensive, online filtering of the data is required for MEGA. The MEGA experiment uses a hardware pattern-recognition system based on Programmable Array Logic (PAL) devices. Additional events are eliminated in an online ACP system before data are written to tape. The MEGA trigger system is generally applicable where high-rate, short-propagation-delay trigger systems are required. This report contains an introduction to the MEGA experiment, a discussion of the MEGA hardware trigger system and a discussion of the system's measured performance. 4 refs., 3 figs.

  15. Identification of Receptor Ligands and Receptor Subtypes Using Antagonists in a Capillary Electrophoresis Single-Cell Biosensor Separation System

    NASA Astrophysics Data System (ADS)

    Fishman, Harvey A.; Orwar, Owe; Scheller, Richard H.; Zare, Richard N.

    1995-08-01

    A capillary electrophoresis system with single-cell biosensors as a detector has been used to separate and identify ligands in complex biological samples. The power of this procedure was significantly increased by introducing antagonists that inhibited the cellular response from selected ligand-receptor interactions. The single-cell biosensor was based on the ligand-receptor binding and G-protein-mediated signal transduction pathways in PC12 and NG108-15 cell lines. Receptor activation was measured as increases in cytosolic free calcium ion concentration by using fluorescence microscopy with the intracellular calcium ion indicator fluo-3 acetoxymethyl ester. Specifically, a mixture of bradykinin (BK) and acetylcholine (ACh) was fractionated and the components were identified by inhibiting the cellular response with icatibant (HOE 140), a selective antagonist to the BK B_2 receptor subtype (B_2BK), and atropine, an antagonist to muscarinic ACh receptor subtypes. Structurally related forms of BK were also identified based on inhibiting B_2BK receptors. Applications of this technique include identification of endogenous BK in a lysate of human hepatocellular carcinoma cells (Hep G2) and screening for bioactivity of BK degradation products in human blood plasma. The data demonstrate that the use of antagonists with a single-cell biosensor separation system aids identification of separated components and receptor subtypes.

  16. Electron temperature measurements by the use of multi-pass Thomson scattering system in GAMMA 10/PDX

    NASA Astrophysics Data System (ADS)

    Yoshikawa, M.; Ohta, K.; Wang, X.; Morishita, M.; Chikatsu, M.; Shima, Y.; Kohagura, J.; Yasuhara, R.; Sakamoto, M.; Nakashima, Y.; Imai, T.; Ichimura, M.; Yamada, I.; Funaba, H.; Kawataha, K.; Minami, T.

    2015-08-01

    A multi-pass (MP) Thomson scattering (TS) system modeled on the GAMMA 10/PDX TS system was constructed for enhancing the Thomson scattered signals. The MPTS system has a polarization-based configuration with an image relaying system. The former MPTS system in GAMMA 10/PDX can measure only four passing signals. We changed the larger aperture polarization control device for improving the MP laser confinement and obtaining the over four passing MPTS signals. The integrated MPTS signals increased about 1.2 times larger than that in the former system.

  17. MODULAR CAUSTIC SIDE SOLVENT EXTRACTION UNIT GAMMA MONITORS SYSTEM FINAL REPORT

    SciTech Connect

    Casella, V

    2007-06-25

    The Department of Energy (DOE) selected Caustic-Side Solvent Extraction (CSSX) as the preferred technology for the removal of radioactive cesium from High-Level Waste (HLW) at the Savannah River Site (SRS). Before the full-scale Salt Waste Processing Facility (SWPF) becomes operational, the liquid Waste Organization (LWO) plans to process a portion of dissolved saltcake waste through a Modular CSSX Unit (MCU). This work was derived from Technical Task Request SP-TTR-2004-00013, ''Gamma Monitor for MCU.'' The deliverables for this task are the hardware and software for the gamma monitors and a report summarizing the testing and acceptance of this equipment for use in the MCU. Revision of this report is a deliverable in Technical Task Report SP-TTR-2006-00010, ''NaI Shield Box Testing.'' Gamma-ray monitors were developed to: {lg_bullet} Measure the Cs-137 concentration in the decontaminated salt solution before entering the DSS (Decontaminated Salt Solution) Hold Tank, {lg_bullet} Measure the Cs-137 concentration in the strip effluent before entering the Strip Effluent Hold Tank, {lg_bullet} Verify proper operation of the solvent extraction system by verifying material balance within the process (The DSS Hold Tank Cs-137 concentration will be very low and the Cs-137 concentration in the Strip Effluent Hold Tank will be approximately fifteen times higher than the Cs-137 concentration in the Feed Tank.)

  18. Distribution of gamma exposure rates in a reactor effluent stream flood plain system.

    PubMed

    Gladden, J B; Brown, K L; Smith, M H; Towns, A

    1985-01-01

    Ground-level gamma dosimetry surveys were conducted along the length of a radiocesium-contaminated reactor effluent stream flood plain system to determine the extent and patterns of isotope distribution over a decade after reactor releases were stopped. The maximum mean exposure rates were found at upstream locations near the source of the contamination and in a downstream sedimentary delta. Gamma exposure rates were not uniformly distributed and high exposure rates were generally restricted to small areas of the flood plain. There was little similarity in either the spatial distribution or magnitudes of maximum gamma exposure rates across flood plains along the stream. Frequency the measured exposure rates tended to be highly skewed and most closely approximated the log-normal distribution in most areas along the stream. However, the complex and changing patterns of dose distributions strongly affected the ability to predict the probability of encountering unusually high exposure rates. Complex statistical and distributional models are required to provide precise descriptions of the dosimetry environment in such complex ecosystems and different models could be required on a site-by-site basis.

  19. Microprogrammed coupling system for photovoltaic generators with multiple receptors

    NASA Astrophysics Data System (ADS)

    Chaumain, G.; Barlaud, M.; Rouan, P.; Requier, Jp.

    The organization, operational guidelines, and storage recommendations for an impedance adaptor-equipped photovoltaic array power system are outlined. The possibility of power losses through defective cells by maintaining the electrical independence of each module and installing automatic power-tracking device controls for each module. The overall distribution is handled by a microprocessor. A chopper is added for dc generator systems, together with a programmable receptor with a static performance adapted to the generator. Impedance adaptation is achieved by a governing algorithm in the microprocessor which adjusts the output in reference to ideal IV curves stored in memory. Storage is used in both a buffer mode, to take care of power transients, and to compensate for the changing nature of renewable energy sources. The system presented is also recommended for use with wind turbines and other electricity generation equipment.

  20. RSV neutralization by palivizumab, but not by monoclonal antibodies targeting other epitopes, is augmented by Fc gamma receptors.

    PubMed

    van Mechelen, Lenny; Luytjes, Willem; de Haan, Cornelis A M; Wicht, Oliver

    2016-08-01

    Palivizumab efficiently blocks respiratory syncytial virus (RSV) infection in vitro. However, virus neutralization assays generally omit Fc region-mediated effects. We investigated the neutralization activity of RSV-specific monoclonal antibodies on cells with Fc receptors. Subneutralizing concentrations of antibodies resulted in antibody-dependent enhancement of RSV infection in monocytic cells. Contrary to antibodies targeting other epitopes, the neutralization by palivizumab was augmented in cells with Fc receptors. This unrecognized characteristic of palivizumab may be relevant for its performance in vivo.

  1. RSV neutralization by palivizumab, but not by monoclonal antibodies targeting other epitopes, is augmented by Fc gamma receptors.

    PubMed

    van Mechelen, Lenny; Luytjes, Willem; de Haan, Cornelis A M; Wicht, Oliver

    2016-08-01

    Palivizumab efficiently blocks respiratory syncytial virus (RSV) infection in vitro. However, virus neutralization assays generally omit Fc region-mediated effects. We investigated the neutralization activity of RSV-specific monoclonal antibodies on cells with Fc receptors. Subneutralizing concentrations of antibodies resulted in antibody-dependent enhancement of RSV infection in monocytic cells. Contrary to antibodies targeting other epitopes, the neutralization by palivizumab was augmented in cells with Fc receptors. This unrecognized characteristic of palivizumab may be relevant for its performance in vivo. PMID:27185625

  2. Identification of a second T-cell antigen receptor in human and mouse by an anti-peptide gamma-chain-specific monoclonal antibody.

    PubMed Central

    Ioannides, C G; Itoh, K; Fox, F E; Pahwa, R; Good, R A; Platsoucas, C D

    1987-01-01

    We developed a monoclonal antibody (mAb) (9D7) against a synthetic peptide (P13K) selected from the deduced amino acid sequence of the constant region of the gamma chain of the murine T-cell antigen receptor (TCR) (amino acids 118-130). Using this mAb, we identified a putative second TCR expressed on peripheral blood lymphocytes from a patient with severe combined immunodeficiency (SCID) that were propagated in culture with recombinant interleukin 2 (rIL-2) and Con A. This mAb immunoprecipitated two polypeptide chains of 40 and 58 kDa under nonreducing conditions and of 40 and 56 kDa under reducing conditions from 125I-labeled denatured lysates of T3+ WT31- lymphocytes expanded in culture from a SCID patient. These polypeptide chains were not disulfide linked and were not present on human peripheral blood lymphocytes from normal donors cultured for 5 days with phytohemagglutinin or for 2 weeks with rIL-2 and polyclonal activators or on cells of the Jurkat lymphoblastoid human T-cell line. Chemical crosslinking of 125I-labeled cells followed by immunoprecipitation with anti-Leu-4 mAb under nonreducing or reducing conditions revealed that the 40- and 56-kDa polypeptide chains were associated with the T3 differentiation antigen. These results were confirmed by sequential immunoprecipitation with anti-Leu-4 mAb followed by 9D7 anti-P13K mAb. The 9D7 anti-P13K mAb immunoprecipitated two polypeptide chains of 43 and 64 kDa from denatured lysates of lymphocytes from a patient with severe common variable immunodeficiency (CVI) that were expanded in culture with rIL-2 and Con A. Thus, this second TCR may be composed of two polypeptide chains (gamma gamma'), both of which appear to be the product of the gamma-chain gene. These experiments were done with polyclonal cell populations. Cloned T3+ WT31- cell populations are required to determine whether this TCR contains two gamma polypeptide chains. In contrast, only one polypeptide chain of 56 kDa was immunoprecipitated by the

  3. Interaction between Calpain 5, Peroxisome proliferator-activated receptor-gamma and Peroxisome proliferator-activated receptor-delta genes: a polygenic approach to obesity

    PubMed Central

    Sáez, María E; Grilo, Antonio; Morón, Francisco J; Manzano, Luis; Martínez-Larrad, María T; González-Pérez, Antonio; Serrano-Hernando, Javier; Ruiz, Agustín; Ramírez-Lorca, Reposo; Serrano-Ríos, Manuel

    2008-01-01

    Context Obesity is a multifactorial disorder, that is, a disease determined by the combined effect of genes and environment. In this context, polygenic approaches are needed. Objective To investigate the possibility of the existence of a crosstalk between the CALPAIN 10 homologue CALPAIN 5 and nuclear receptors of the peroxisome proliferator-activated receptors family. Design Cross-sectional, genetic association study and gene-gene interaction analysis. Subjects The study sample comprise 1953 individuals, 725 obese (defined as body mass index ≥ 30) and 1228 non obese subjects. Results In the monogenic analysis, only the peroxisome proliferator-activated receptor delta (PPARD) gene was associated with obesity (OR = 1.43 [1.04–1.97], p = 0.027). In addition, we have found a significant interaction between CAPN5 and PPARD genes (p = 0.038) that reduces the risk for obesity in a 55%. Conclusion Our results suggest that CAPN5 and PPARD gene products may also interact in vivo. PMID:18657264

  4. 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.

  5. A clinical gamma camera-based pinhole collimated system for high resolution small animal SPECT imaging.

    PubMed

    Mejia, J; Galvis-Alonso, O Y; Castro, A A de; Braga, J; Leite, J P; Simões, M V

    2010-12-01

    The main objective of the present study was to upgrade a clinical gamma camera to obtain high resolution tomographic images of small animal organs. The system is based on a clinical gamma camera to which we have adapted a special-purpose pinhole collimator and a device for positioning and rotating the target based on a computer-controlled step motor. We developed a software tool to reconstruct the target's three-dimensional distribution of emission from a set of planar projections, based on the maximum likelihood algorithm. We present details on the hardware and software implementation. We imaged phantoms and heart and kidneys of rats. When using pinhole collimators, the spatial resolution and sensitivity of the imaging system depend on parameters such as the detector-to-collimator and detector-to-target distances and pinhole diameter. In this study, we reached an object voxel size of 0.6 mm and spatial resolution better than 2.4 and 1.7 mm full width at half maximum when 1.5- and 1.0-mm diameter pinholes were used, respectively. Appropriate sensitivity to study the target of interest was attained in both cases. Additionally, we show that as few as 12 projections are sufficient to attain good quality reconstructions, a result that implies a significant reduction of acquisition time and opens the possibility for radiotracer dynamic studies. In conclusion, a high resolution single photon emission computed tomography (SPECT) system was developed using a commercial clinical gamma camera, allowing the acquisition of detailed volumetric images of small animal organs. This type of system has important implications for research areas such as Cardiology, Neurology or Oncology.

  6. A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression.

    PubMed

    Laganière, Josée; Tremblay, Gilles B; Dufour, Catherine R; Giroux, Sylvie; Rousseau, François; Giguère, Vincent

    2004-04-30

    The orphan nuclear estrogen-related receptor alpha (ERRalpha) and transcriptional cofactor peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) are involved in the regulation of energy metabolism. Recently, extensive cross-talk between PGC-1alpha and ERRalpha has been demonstrated. The presence of PGC-1alpha is associated with an elevated expression of ERRalpha, and the two proteins can influence the transcriptional activities of one another. Using a candidate gene approach to detect regulatory variants within genes encoding nuclear receptors, we have identified a 23-bp sequence (ESRRA23) containing two nuclear receptor recognition half-site motifs that is present in 1-4 copies within the promoter of the human ESRRA gene encoding ERRalpha. The ESRRA23 sequence contains a functional ERR response element that is specifically bound by ERRalpha, and chromatin immunoprecipitation shows that endogenous ERRalpha occupies its own promoter in vivo. Strikingly, introduction of PGC-1alpha in HeLa cells by transient transfection induces the activity of the ESRRA promoter in a manner that is dependent on the presence of the ESRRA23 element and on its dosage. Coexpression of ERRalpha and PGC-1alpha results in a synergistic activation of the ESRRA promoter. In experiments using ERRalpha null fibroblasts, the ability of PGC-1alpha to stimulate the ESRRA promoter is considerably reduced but can be restored by addition of ERRalpha. Taken together, these results demonstrate that an interdependent ERRalpha/PGC-1alpha-based transcriptional pathway targets the ESRRA23 element to dictate the level of ERRalpha expression. This study further suggests that this regulatory polymorphism may provide differential responses to ERRalpha/PGC-1alpha-mediated metabolic cues in the human population.

  7. Differential transcriptional activation of peroxisome proliferator-activated receptor gamma by omega-3 and omega-6 fatty acids in MCF-7 cells.

    PubMed

    Thoennes, S R; Tate, P L; Price, T M; Kilgore, M W

    2000-02-25

    While the role of dietary fats in breast cancer remains controversial, the recent cloning of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor, from human breast cancer cells lines provides a potential molecular link. Several fatty acids from four classes of dietary fats were tested for their ability to mediate the transcriptional activity of PPARgamma in MCF-7 and MDA-MB-231 cells using growth media with minimal serum. Whereas omega-3 fatty acids inhibit transactivation of PPARgamma to levels below control, omega-6, monounsaturated and saturated fatty acids stimulate the activity of the transcriptional reporter. These studies indicate that individual fatty acids differentially regulate the transcriptional activity of PPARgamma by selectively acting as agonists or antagonists. Furthermore, the transcriptional activation of PPARgamma correlates with cell proliferation in MCF-7 cells. Understanding the effects of individual fats on breast cancer cells and PPARgamma transactivation could provide important new insights into the epidemiology of breast cancer and the role of dietary fat.

  8. Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by alpha5 subunit-containing gamma-aminobutyric acid type A receptors.

    PubMed

    Caraiscos, Valerie B; Elliott, Erin M; You-Ten, Kong E; Cheng, Victor Y; Belelli, Delia; Newell, J Glen; Jackson, Michael F; Lambert, Jeremy J; Rosahl, Thomas W; Wafford, Keith A; MacDonald, John F; Orser, Beverley A

    2004-03-01

    The principal inhibitory neurotransmitter in the mammalian brain, gamma-aminobutyric acid (GABA), is thought to regulate memory processes by activating transient inhibitory postsynaptic currents. Here we describe a nonsynaptic, tonic form of inhibition in mouse CA1 pyramidal neurons that is generated by a distinct subpopulation of GABA type A receptors (GABA(A)Rs). This tonic inhibitory conductance is predominantly mediated by alpha5 subunit-containing GABA(A)Rs (alpha5GABA(A)Rs) that have different pharmacological and kinetic properties compared to postsynaptic receptors. GABA(A)Rs that mediate the tonic conductance are well suited to detect low, persistent, ambient concentrations of GABA in the extracellular space because they are highly sensitive to GABA and desensitize slowly. Moreover, the tonic current is highly sensitive to enhancement by amnestic drugs. Given the restricted expression of alpha5GABA(A)Rs to the hippocampus and the association between reduced alpha5GABA(A)R function and improved memory performance in behavioral studies, our results suggest that tonic inhibition mediated by alpha5GABA(A)Rs in hippocampal pyramidal neurons plays a key role in cognitive processes.

  9. In Silico Prediction of Gamma-Aminobutyric Acid Type-A Receptors Using Novel Machine-Learning-Based SVM and GBDT Approaches

    PubMed Central

    Huang, Yong; Ju, Ying

    2016-01-01

    Gamma-aminobutyric acid type-A receptors (GABAARs) belong to multisubunit membrane spanning ligand-gated ion channels (LGICs) which act as the principal mediators of rapid inhibitory synaptic transmission in the human brain. Therefore, the category prediction of GABAARs just from the protein amino acid sequence would be very helpful for the recognition and research of novel receptors. Based on the proteins' physicochemical properties, amino acids composition and position, a GABAAR classifier was first constructed using a 188-dimensional (188D) algorithm at 90% cd-hit identity and compared with pseudo-amino acid composition (PseAAC) and ProtrWeb web-based algorithms for human GABAAR proteins. Then, four classifiers including gradient boosting decision tree (GBDT), random forest (RF), a library for support vector machine (libSVM), and k-nearest neighbor (k-NN) were compared on the dataset at cd-hit 40% low identity. This work obtained the highest correctly classified rate at 96.8% and the highest specificity at 99.29%. But the values of sensitivity, accuracy, and Matthew's correlation coefficient were a little lower than those of PseAAC and ProtrWeb; GBDT and libSVM can make a little better performance than RF and k-NN at the second dataset. In conclusion, a GABAAR classifier was successfully constructed using only the protein sequence information. PMID:27579307

  10. Catalase potentiates retinoic acid-induced THP-1 monocyte differentiation into macrophage through inhibition of peroxisome proliferator-activated receptor gamma.

    PubMed

    Ding, Qiurong; Jin, Ting; Wang, Zhenzhen; Chen, Yan

    2007-06-01

    Macrophage differentiation plays a pivotal role in cardiovascular diseases and many other physiological processes. However, the role of reaction oxygen species in macrophage differentiation has not been elucidated. Here, we report functional characterization of catalase, an enzyme that degrades hydrogen peroxide (H(2)O(2)), in THP-1 monocyte differentiation. Treatment of THP-1 cells with catalase was able to synergize with all-trans retinoic acid (ATRA) to enhance macrophage differentiation, demonstrated by changes of cell adherence, cell cycle arrest, nitroblue tetrazolium reduction, and expression of differentiation markers including CD68, CD11b, and matrix metalloproteinase 9 (MMP9). ATRA could stimulate retinoic acid (RA) receptor-mediated transcription, but this was not affected by catalase. However, ATRA and catalase were capable of reducing transcriptional activity mediated by peroxisome proliferator-activated receptor gamma (PPARgamma). Consistently, PPARgamma antagonists enhanced, and PPARgamma agonists inhibited MMP9 expression stimulated by ATRA and catalase in THP-1 cells. Therefore, these data indicate that catalase is able to potentiate ATRA-induced macrophage differentiation by inhibition of PPARgamma activity, underscoring an important interplay between H(2)O(2), RA, and PPARgamma in macrophages.

  11. Lnk is an important modulator of insulin-like growth factor-1/Akt/peroxisome proliferator-activated receptor-gamma axis during adipogenesis of mesenchymal stem cells

    PubMed Central

    Lee, Jun Hee; Lee, Sang Hun; Lee, Hyang Seon; Ji, Seung Taek; Jung, Seok Yun; Kim, Jae Ho; Bae, Sun Sik

    2016-01-01

    Adipogenic differentiation of mesenchymal stem cells (MSCs) is critical for metabolic homeostasis and nutrient signaling during development. However, limited information is available on the pivotal modulators of adipogenic differentiation of MSCs. Adaptor protein Lnk (Src homology 2B3 [SH2B3]), which belongs to a family of SH2-containing proteins, modulates the bioactivities of different stem cells, including hematopoietic stem cells and endothelial progenitor cells. In this study, we investigated whether an interaction between insulin-like growth factor-1 receptor (IGF-1R) and Lnk regulated IGF-1-induced adipogenic differentiation of MSCs. We found that wild-type MSCs showed greater adipogenic differentiation potential than Lnk–/– MSCs. An ex vivo adipogenic differentiation assay showed that Lnk–/– MSCs had decreased adipogenic differentiation potential compared with wild-type MSCs. Interestingly, we found that Lnk formed a complex with IGF-1R and that IGF-1 induced the dissociation of this complex. In addition, we observed that IGF-1-induced increase in the phosphorylation of Akt and mammalian target of rapamycin was triggered by the dissociation of the IGF-1R–Lnk complex. Expression levels of a pivotal transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) and its adipogenic target genes (LPL and FABP4) significantly decreased in Lnk–/– MSCs. These results suggested that Lnk adaptor protein regulated the adipogenesis of MSCs through the IGF-1/Akt/PPAR-γ pathway. PMID:27610032

  12. In Silico Prediction of Gamma-Aminobutyric Acid Type-A Receptors Using Novel Machine-Learning-Based SVM and GBDT Approaches.

    PubMed

    Liao, Zhijun; Huang, Yong; Yue, Xiaodong; Lu, Huijuan; Xuan, Ping; Ju, Ying

    2016-01-01

    Gamma-aminobutyric acid type-A receptors (GABAARs) belong to multisubunit membrane spanning ligand-gated ion channels (LGICs) which act as the principal mediators of rapid inhibitory synaptic transmission in the human brain. Therefore, the category prediction of GABAARs just from the protein amino acid sequence would be very helpful for the recognition and research of novel receptors. Based on the proteins' physicochemical properties, amino acids composition and position, a GABAAR classifier was first constructed using a 188-dimensional (188D) algorithm at 90% cd-hit identity and compared with pseudo-amino acid composition (PseAAC) and ProtrWeb web-based algorithms for human GABAAR proteins. Then, four classifiers including gradient boosting decision tree (GBDT), random forest (RF), a library for support vector machine (libSVM), and k-nearest neighbor (k-NN) were compared on the dataset at cd-hit 40% low identity. This work obtained the highest correctly classified rate at 96.8% and the highest specificity at 99.29%. But the values of sensitivity, accuracy, and Matthew's correlation coefficient were a little lower than those of PseAAC and ProtrWeb; GBDT and libSVM can make a little better performance than RF and k-NN at the second dataset. In conclusion, a GABAAR classifier was successfully constructed using only the protein sequence information. PMID:27579307

  13. Aqueous Extract of Paris polyphylla (AEPP) Inhibits Ovarian Cancer via Suppression of Peroxisome Proliferator-Activated Receptor-Gamma Coactivator (PGC)-1alpha.

    PubMed

    Wang, Chia-Woei; Tai, Cheng-Jeng; Choong, Chen-Yen; Lin, Yu-Chun; Lee, Bao-Hong; Shi, Yeu-Ching; Tai, Chen-Jei

    2016-06-03

    Chemotherapy, a major approach was used in carcinoma treatment, always involves the development of drug resistance as well as side-effects that affect the quality of patients' lives. An association between epithelial-mesenchymal transition (EMT) and chemotherapy resistance was established recently. We demonstrate in this paper that the aqueous extract of Paris polyphylla (AEPP)-a traditional Chinese medicine-can be used in various cancer types for suppression of carcinogenesis. We evaluated the suppressions of EMT and mitochondrial activity by AEPP treatment in a high-glucose (HG) induced-human ovarian carcinoma cell line (OVCAR-3 cells). The mitochondrial morphology was investigated using MitoTracker Deep Red FM staining. Our results indicated that AEPP reduced the viability of OVCAR-3 cells considerably through induction of apoptosis. However, this inhibitory potential of AEPP was attenuated by HG induction in OVCAR-3 cells. The levels of estrogen-related receptor (ERR)-alpha activator and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha were elevated by HG induction, but were suppressed by AEPP treatment. Down-regulations of cell survival and EMT were oberved in OVCAR-3 cells through suppression of PGC-1alpha by AEPP treatment. These results were confirmed through PGC-1alpha knockdown and overexpression in OVCAR-3 cells. Thus, AEPP can be beneficial for treating ovarian cancer and has potential for development of an integrative cancer therapy against ovarian cancer proliferation, metastasis, and migration.

  14. Lnk is an important modulator of insulin-like growth factor-1/Akt/peroxisome proliferator-activated receptor-gamma axis during adipogenesis of mesenchymal stem cells.

    PubMed

    Lee, Jun Hee; Lee, Sang Hun; Lee, Hyang Seon; Ji, Seung Taek; Jung, Seok Yun; Kim, Jae Ho; Bae, Sun Sik; Kwon, Sang-Mo

    2016-09-01

    Adipogenic differentiation of mesenchymal stem cells (MSCs) is critical for metabolic homeostasis and nutrient signaling during development. However, limited information is available on the pivotal modulators of adipogenic differentiation of MSCs. Adaptor protein Lnk (Src homology 2B3 [SH2B3]), which belongs to a family of SH2-containing proteins, modulates the bioactivities of different stem cells, including hematopoietic stem cells and endothelial progenitor cells. In this study, we investigated whether an interaction between insulin-like growth factor-1 receptor (IGF-1R) and Lnk regulated IGF-1-induced adipogenic differentiation of MSCs. We found that wild-type MSCs showed greater adipogenic differentiation potential than Lnk (-/-) MSCs. An ex vivo adipogenic differentiation assay showed that Lnk (-/-) MSCs had decreased adipogenic differentiation potential compared with wild-type MSCs. Interestingly, we found that Lnk formed a complex with IGF-1R and that IGF-1 induced the dissociation of this complex. In addition, we observed that IGF-1-induced increase in the phosphorylation of Akt and mammalian target of rapamycin was triggered by the dissociation of the IGF-1R-Lnk complex. Expression levels of a pivotal transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) and its adipogenic target genes (LPL and FABP4) significantly decreased in Lnk (-/-) MSCs. These results suggested that Lnk adaptor protein regulated the adipogenesis of MSCs through the IGF-1/Akt/PPAR-γ pathway. PMID:27610032

  15. Aqueous Extract of Paris polyphylla (AEPP) Inhibits Ovarian Cancer via Suppression of Peroxisome Proliferator-Activated Receptor-Gamma Coactivator (PGC)-1alpha.

    PubMed

    Wang, Chia-Woei; Tai, Cheng-Jeng; Choong, Chen-Yen; Lin, Yu-Chun; Lee, Bao-Hong; Shi, Yeu-Ching; Tai, Chen-Jei

    2016-01-01

    Chemotherapy, a major approach was used in carcinoma treatment, always involves the development of drug resistance as well as side-effects that affect the quality of patients' lives. An association between epithelial-mesenchymal transition (EMT) and chemotherapy resistance was established recently. We demonstrate in this paper that the aqueous extract of Paris polyphylla (AEPP)-a traditional Chinese medicine-can be used in various cancer types for suppression of carcinogenesis. We evaluated the suppressions of EMT and mitochondrial activity by AEPP treatment in a high-glucose (HG) induced-human ovarian carcinoma cell line (OVCAR-3 cells). The mitochondrial morphology was investigated using MitoTracker Deep Red FM staining. Our results indicated that AEPP reduced the viability of OVCAR-3 cells considerably through induction of apoptosis. However, this inhibitory potential of AEPP was attenuated by HG induction in OVCAR-3 cells. The levels of estrogen-related receptor (ERR)-alpha activator and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha were elevated by HG induction, but were suppressed by AEPP treatment. Down-regulations of cell survival and EMT were oberved in OVCAR-3 cells through suppression of PGC-1alpha by AEPP treatment. These results were confirmed through PGC-1alpha knockdown and overexpression in OVCAR-3 cells. Thus, AEPP can be beneficial for treating ovarian cancer and has potential for development of an integrative cancer therapy against ovarian cancer proliferation, metastasis, and migration. PMID:27271583

  16. Lnk is an important modulator of insulin-like growth factor-1/Akt/peroxisome proliferator-activated receptor-gamma axis during adipogenesis of mesenchymal stem cells

    PubMed Central

    Lee, Jun Hee; Lee, Sang Hun; Lee, Hyang Seon; Ji, Seung Taek; Jung, Seok Yun; Kim, Jae Ho; Bae, Sun Sik

    2016-01-01

    Adipogenic differentiation of mesenchymal stem cells (MSCs) is critical for metabolic homeostasis and nutrient signaling during development. However, limited information is available on the pivotal modulators of adipogenic differentiation of MSCs. Adaptor protein Lnk (Src homology 2B3 [SH2B3]), which belongs to a family of SH2-containing proteins, modulates the bioactivities of different stem cells, including hematopoietic stem cells and endothelial progenitor cells. In this study, we investigated whether an interaction between insulin-like growth factor-1 receptor (IGF-1R) and Lnk regulated IGF-1-induced adipogenic differentiation of MSCs. We found that wild-type MSCs showed greater adipogenic differentiation potential than Lnk–/– MSCs. An ex vivo adipogenic differentiation assay showed that Lnk–/– MSCs had decreased adipogenic differentiation potential compared with wild-type MSCs. Interestingly, we found that Lnk formed a complex with IGF-1R and that IGF-1 induced the dissociation of this complex. In addition, we observed that IGF-1-induced increase in the phosphorylation of Akt and mammalian target of rapamycin was triggered by the dissociation of the IGF-1R–Lnk complex. Expression levels of a pivotal transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) and its adipogenic target genes (LPL and FABP4) significantly decreased in Lnk–/– MSCs. These results suggested that Lnk adaptor protein regulated the adipogenesis of MSCs through the IGF-1/Akt/PPAR-γ pathway.

  17. Estrogen receptor alpha activation enhances mitochondrial function and systemic metabolism in high-fat-fed ovariectomized mice.

    PubMed

    Hamilton, Dale J; Minze, Laurie J; Kumar, Tanvi; Cao, Tram N; Lyon, Christopher J; Geiger, Paige C; Hsueh, Willa A; Gupte, Anisha A

    2016-09-01

    Estrogen impacts insulin action and cardiac metabolism, and menopause dramatically increases cardiometabolic risk in women. However, the mechanism(s) of cardiometabolic protection by estrogen remain incompletely understood. Here, we tested the effects of selective activation of E2 receptor alpha (ERα) on systemic metabolism, insulin action, and cardiac mitochondrial function in a mouse model of metabolic dysfunction (ovariectomy [OVX], insulin resistance, hyperlipidemia, and advanced age). Middle-aged (12-month-old) female low-density lipoprotein receptor (Ldlr)(-/-) mice were subjected to OVX or sham surgery and fed "western" high-fat diet (WHFD) for 3 months. Selective ERα activation with 4,4',4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) (PPT), prevented weight gain, improved insulin action, and reduced visceral fat accumulation in WHFD-fed OVX mice. PPT treatment also elevated systemic metabolism, increasing oxygen consumption and core body temperature, induced expression of several metabolic genes such as peroxisome proliferator-activated receptor gamma, coactivator 1 alpha, and nuclear respiratory factor 1 in heart, liver, skeletal muscle, and adipose tissue, and increased cardiac mitochondrial function. Taken together, selective activation of ERα with PPT enhances metabolic effects including insulin resistance, whole body energy metabolism, and mitochondrial function in OVX mice with metabolic syndrome. PMID:27582063

  18. A performance study of an electron-tracking Compton camera with a compact system for environmental gamma-ray observation

    NASA Astrophysics Data System (ADS)

    Mizumoto, T.; Tomono, D.; Takada, A.; Tanimori, T.; Komura, S.; Kubo, H.; Matsuoka, Y.; Mizumura, Y.; Nakamura, K.; Nakamura, S.; Oda, M.; Parker, J. D.; Sawano, T.; Bando, N.; Nabetani, A.

    2015-06-01

    An electron-tracking Compton camera (ETCC) is a detector that can determine the arrival direction and energy of incident sub-MeV/MeV gamma-ray events on an event-by-event basis. It is a hybrid detector consisting of a gaseous time projection chamber (TPC), that is the Compton-scattering target and the tracker of recoil electrons, and a position-sensitive scintillation camera that absorbs of the scattered gamma rays, to measure gamma rays in the environment from contaminated soil. To measure of environmental gamma rays from soil contaminated with radioactive cesium (Cs), we developed a portable battery-powered ETCC system with a compact readout circuit and data-acquisition system for the SMILE-II experiment [1,2]. We checked the gamma-ray imaging ability and ETCC performance in the laboratory by using several gamma-ray point sources. The performance test indicates that the field of view (FoV) of the detector is about 1 sr and that the detection efficiency and angular resolution for 662 keV gamma rays from the center of the FoV is (9.31 ± 0.95) × 10-5 and 5.9° ± 0.6°, respectively. Furthermore, the ETCC can detect 0.15 μSv/h from a 137Cs gamma-ray source with a significance of 5σ in 13 min in the laboratory. In this paper, we report the specifications of the ETCC and the results of the performance tests. Furthermore, we discuss its potential use for environmental gamma-ray measurements.

  19. Signal transduction by the CD2 antigen in T cells and natural killer cells: requirement for expression of a functional T cell receptor or binding of antibody Fc to the Fc receptor, Fc gamma RIIIA (CD16).

    PubMed

    Spruyt, L L; Glennie, M J; Beyers, A D; Williams, A F

    1991-12-01

    Crosslinking of CD2 antigen on T lymphocytes and natural killer (NK) cells leads to a rise in cytoplasmic-free Ca2+ concentration ([Ca2+]i). However, CD2 seems unlikely to interact directly with the second messenger pathways since signaling via CD2 is poor in T cells that lack the T cell receptor (TCR) and is absent in L cells or insect cells that express CD2. In contrast, NK cells that are also TCR- can be triggered via CD2, but it is unclear as to whether the CD16 Fc receptor (FcR) may facilitate this effect. The CD16 transmembrane molecule is expressed in a complex with the zeta homodimer or the zeta/gamma heterodimer and these dimers are also associated with the TCR complex. Thus, it seemed that zeta chains may provide the link between signaling on NK cells and T cells. This could be tested on TCR- cells since when CD16 is transfected into T cells it is expressed in a complex with TCR zeta homodimer or the zeta/gamma heterodimer. At first, potentiation of CD2 signaling was seen on TCR- Jurkat cells expressing CD16, but this was found to be dependent on trace levels (1%) of IgG in F(ab')2 antibody preparations. With pure F(ab')2, the effect was lost. Signaling on a rat NK cell line was also re-examined with F(ab')2 antibodies that had no IgG contamination, and again no signal transduction via CD2 was seen. We thus conclude that there is no clear evidence for potent signaling via CD2 on cells that lack a TCR complex and that TCR zeta chain expressed at the cell surface is not sufficient to potentiate signaling via CD2 as measured by an increase in [Ca2+]i.

  20. Signal transduction by the CD2 antigen in T cells and natural killer cells: requirement for expression of a functional T cell receptor or binding of antibody Fc to the Fc receptor, Fc gamma RIIIA (CD16)

    PubMed Central

    1991-01-01

    Crosslinking of CD2 antigen on T lymphocytes and natural killer (NK) cells leads to a rise in cytoplasmic-free Ca2+ concentration ([Ca2+]i). However, CD2 seems unlikely to interact directly with the second messenger pathways since signaling via CD2 is poor in T cells that lack the T cell receptor (TCR) and is absent in L cells or insect cells that express CD2. In contrast, NK cells that are also TCR- can be triggered via CD2, but it is unclear as to whether the CD16 Fc receptor (FcR) may facilitate this effect. The CD16 transmembrane molecule is expressed in a complex with the zeta homodimer or the zeta/gamma heterodimer and these dimers are also associated with the TCR complex. Thus, it seemed that zeta chains may provide the link between signaling on NK cells and T cells. This could be tested on TCR- cells since when CD16 is transfected into T cells it is expressed in a complex with TCR zeta homodimer or the zeta/gamma heterodimer. At first, potentiation of CD2 signaling was seen on TCR- Jurkat cells expressing CD16, but this was found to be dependent on trace levels (1%) of IgG in F(ab')2 antibody preparations. With pure F(ab')2, the effect was lost. Signaling on a rat NK cell line was also re-examined with F(ab')2 antibodies that had no IgG contamination, and again no signal transduction via CD2 was seen. We thus conclude that there is no clear evidence for potent signaling via CD2 on cells that lack a TCR complex and that TCR zeta chain expressed at the cell surface is not sufficient to potentiate signaling via CD2 as measured by an increase in [Ca2+]i. PMID:1683892

  1. Construction and testing of a neutron and gamma spectrometry system using pulse shape discrimination with an organic scintillator

    NASA Astrophysics Data System (ADS)

    Pope, Robert S.

    1993-03-01

    The goal of this thesis was to construct and test a neutron detector to measure the energy spectrum of 1 to 14-MeV neutrons in the presence of gammas. A spectrometer based on the process of pulse shape discrimination (PSD) was constructed, in which the scintillator NE-213 was used. The primary neutron/gamma sources used were 78-mCi and 4.7-Ci Pu-239Be sources, while 4.7-micro-Ci and 97.6-micro-Ci Na-22 gamma sources were used for energy calibration and additional testing of the detector. Proton recoil spectra and Compton electron spectra were unfolded with the neutron and gamma unfolding code FORIST to generate the incident neutron and gamma spectra, respectively. FORIST, which was written for a CDC computer, was modified to run on a VAX 6420. The experimental spectra were compared to those in the literature. The locations of the peaks in the Pu-239Be spectrum agreed with the literature to within 8.3%, the Pu-239Be gamma spectrum agreed to within 0.7%, while the Na-22 gamma spectrum agreed exactly. Uncertainties in the detection system and unfolding procedure are on the order of 5-10%. This thesis is intended to be a summary of the relevant literature and a user's guide to the PSD spectrometer.

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

    SciTech Connect

    Tsukahara, Tamotsu; Haniu, Hisao; Matsuda, Yoshikazu

    2013-04-12

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

  3. Biodistribution of an anti-interleukin 2 receptor monoclonal antibody in rat recipients of a heart allograft, and its use as a rejection marker in gamma scintigraphy

    SciTech Connect

    Thedrez, P.; Paineau, J.; Jacques, Y.; Chatal, J.F.; Pelegrin, A.; Bouchaud, C.; Soulillou, J.P. )

    1989-09-01

    Anti-interleukin-2 receptor monoclonal antibodies have been shown to prevent allograft rejection. This paper reports on the biodistribution of a mouse MoAb directed at the 55 Kd alpha chain of rat interleukin-2 receptor (IL2-R) during allograft rejection. Only a low percentage (approximately 1%) of intact 125I-labeled MoAb was detected in the rejected graft, and irrelevant control IgG1 was found at a similar level. This suggests that most of the injected intact MoAb bound to graft tissue via its monomorphic Fc segment. In contrast, OX39 F(ab')2 fragments showed a preferential localization in the rejected allograft and did not bind to the LEW-to-LEW syngeneic heart graft. Irrelevant F(ab')2 did not concentrate in the allogeneic graft. Accordingly, F(ab')2 fragments from OX39 or irrelevant MoAb were used for gamma-scintigraphy on allograft recipients together with biodistribution studies. Results show that scintigraphy was able to detect allograft accumulation of 131I OX39 F(ab')2, whereas no imaging was obtained when OX39 F(ab')2 was used in the syngeneic combination or when irrelevant 131-IgG1 F(ab')2 was given to allograft recipients. This method, applied to the clinical situation, could be of interest for detection of early graft rejection episodes by immunoscintigraphy using reagents specific for activation determinants on lymphocyte membranes, such as anti-interleukin-2 receptor MoAb.

  4. Propofol induces apoptosis and inhibits the proliferation of rat embryonic neural stem cells via gamma-aminobutyric acid type A receptor.

    PubMed

    Wang, J W; Cheng, W W; Xu, T; Yang, Z Y

    2015-11-23

    We investigated the effect of propofol on the proliferation and viability of rat embryonic neural stem cells (rENSCs) and the potential mechanisms involved. rENSCs were isolated and cultured in vitro and treated with 1, 10, or 50 μM propofol, while the control group was treated with 0.1 μM dimethyl sulfoxide. The effect of propofol on the proliferation and viability of rENSCs was examined by proliferation and apoptosis assays. Real-time polymerase chain reaction was employed to analyze the mRNA expression of checkpoint kinase 1 (Chk1) and p53 in rENSCs exposed to propofol. Immunoprecipitation assay and western blotting analysis were performed to analyze the effect of propofol on Chk1 and p53 activity. The gamma-aminobutyric acid type A (GABAA) receptor antagonist securinine was added to the rENSCs before being treated with propofol to investigate the role of the GABAA receptor in propofol-triggered effects on rENSCs. rENSCs specifically expressing nestin protein were successfully isolated and cultured for experiments. The inhibitory effect of propofol on rENSCs increased dose-dependently. The percentage of apoptotic cells increased to 11.7% and the activity of Chk1 and p53 enhanced after treatment with 50 μM propofol. However, addition of securinine abrogated propofol-induced apoptosis and activation of Chk1. The GABAA receptor mediates propofol-induced apoptosis and proliferation inhibition of rENSCs, possibly by modulating the Chk1/p53 signaling pathway.

  5. Target and peripheral dose during patient repositioning with the Gamma Knife automatic positioning system (APS) device.

    PubMed

    Tran, Tuan-Anh; Stanley, Thomas R; Malhotra, Harish K; De Boer, Steven F; Prasad, Dheerendra; Podgorsak, Matthew B

    2010-01-28

    The GammaPlan treatment planning system does not account for the leakage and scatter dose during APS repositioning. In this study, the dose delivered to the target site and its periphery from the defocus stage and intershot couch transit (couch motion from the focus to defocus position and back) associated with APS repositioning are measured for the Gamma Knife model 4C. A stereotactic head-frame was attached to a Leksell 16 cm diameter spherical phantom with a calibrated ion chamber at its center. Using a fiducial box, CT images of the phantom were acquired and registered in the GammaPlan treatment planning system to determine the coordinates of the target (center of the phantom). An absorbed dose of 10 Gy to the 50% isodose line was prescribed to the target site for all measurements. Plans were generated for the 8, 14 and 18 mm collimator helmets to determine the relationship of measured dose to the number of repositions of the APS system and to the helmet size. The target coordinate was identical throughout entire study and there was no movement of the APS between various shots. This allowed for measurement of intershot transit dose at the target site and its periphery. The couch was paused in the defocus position, allowing defocus dose measurements at the intracranial target and periphery. Measured dose increases with frequency of repositioning and with helmet collimator size. During couch transit, the target receives more dose than peripheral regions; however, in the defocus position, the greatest dose is superior to the target site. The automatic positioning system for the Leksell Gamma Knife model 4C results in an additional dose of up to 3.87 +/- 0.07%, 4.97 +/- 0.04%, and 5.71 +/- 0.07% to the target site; its periphery receives additional dose that varies depending on its position relative to the target. There is also dose contribution to the patient in the defocus position, where the APS repositions the patient from one treatment coordinate to another

  6. 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.

  7. [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.

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

    SciTech Connect

    LaPorte, S.L.; Juo, Z.S.; Vaclavikova, J.; Colf, L.A.; Qi, X.; Heller, N.M.; Keegan, A.D.; Garcia, K.C.

    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 in 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.

  9. Structural model for gamma-aminobutyric acid receptor noncompetitive antagonist binding: widely diverse structures fit the same site.

    PubMed

    Chen, Ligong; Durkin, Kathleen A; Casida, John E

    2006-03-28

    Several major insecticides, including alpha-endosulfan, lindane, and fipronil, and the botanical picrotoxinin are noncompetitive antagonists (NCAs) for the GABA receptor. We showed earlier that human beta(3) homopentameric GABA(A) receptor recognizes all of the important GABAergic insecticides and reproduces the high insecticide sensitivity and structure-activity relationships of the native insect receptor. Despite large structural diversity, the NCAs are proposed to fit a single binding site in the chloride channel lumen lined by five transmembrane 2 segments. This hypothesis is examined with the beta(3) homopentamer by mutagenesis, pore structure studies, NCA binding, and molecular modeling. The 15 amino acids in the cytoplasmic half of the pore were mutated to cysteine, serine, or other residue for 22 mutants overall. Localization of A-1'C, A2'C, T6'C, and L9'C (index numbers for the transmembrane 2 region) in the channel lumen was established by disulfide cross-linking. Binding of two NCA radioligands [(3)H]1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane and [(3)H] 3,3-bis-trifluoromethyl-bicyclo[2,2,1]heptane-2,2-dicarbonitrile was dramatically reduced with 8 of the 15 mutated positions, focusing attention on A2', T6', and L9' as proposed binding sites, consistent with earlier mutagenesis studies. The cytoplasmic half of the beta3 homopentamer pore was modeled as an alpha-helix. The six NCAs listed above plus t-butylbicyclophosphorothionate fit the 2' to 9' pore region forming hydrogen bonds with the T6' hydroxyl and hydrophobic interactions with A2', T6', and L9' alkyl substituents, thereby blocking the channel. Thus, widely diverse NCA structures fit the same GABA receptor beta subunit site with important implications for insecticide cross-resistance and selective toxicity between insects and mammals.

  10. Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1

    PubMed Central

    Wang, Wei; Yang, Jian; Liu, Hui; Lu, Dong; Chen, Xiongfeng; Zenonos, Zenon; Campos, Lia S.; Rad, Roland; Guo, Ge; Zhang, Shujun; Bradley, Allan; Liu, Pentao

    2011-01-01

    Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by expressing four transcription factors: Oct4, Sox2, Klf4, and c-Myc. Here we report that enhancing RA signaling by expressing RA receptors (RARs) or by RA agonists profoundly promoted reprogramming, but inhibiting it using a RAR-α dominant-negative form completely blocked it. Coexpressing Rarg (RAR-γ) and Lrh-1 (liver receptor homologue 1; Nr5a2) with the four factors greatly accelerated reprogramming so that reprogramming of mouse embryonic fibroblast cells to ground-state iPSCs requires only 4 d induction of these six factors. The six-factor combination readily reprogrammed primary human neonatal and adult fibroblast cells to exogenous factor-independent iPSCs, which resembled ground-state mouse ES cells in growth properties, gene expression, and signaling dependency. Our findings demonstrate that signaling through RARs has critical roles in molecular reprogramming and that the synergistic interaction between Rarg and Lrh1 directs reprogramming toward ground-state pluripotency. The human iPSCs described here should facilitate functional analysis of the human genome. PMID:21990348

  11. Gamma radiation impact on performance of OOK, DPSK and homodyne BPSK based optical inter-satellite communication system

    NASA Astrophysics Data System (ADS)

    Liu, Yun; Zhao, Shanghong; Gong, Zizheng; Hou, Rui; Qiang, Ruoxin

    2015-09-01

    Performance of optical inter-satellite communication system is influenced by the harsh space radiation environment. Gamma radiation effects on main devices of communication system are analyzed and on the basis of existing experimental data, performance degradation of on off keying (OOK), differential phase shift keying (DPSK) and homodyne binary phase shift keying (BPSK) based system under 1 kGy gamma irradiation is simulated. Variation of Q factors and bit error ratio of these systems with different radiation position are achieved and discussed. The result shows that it is more urgent to improve the radiation hardness of transmitter, and the introduction of local laser is a considerable method to reduce gamma radiation impact on system performance.

  12. Modulated gamma-ray emission from compact millisecond pulsar binary systems

    NASA Astrophysics Data System (ADS)

    Bednarek, W.

    2014-01-01

    Context. A significant number of the millisecond pulsars (MSPs) have been discovered within binary systems. Tens of these MSPs emit γ-rays that are modulated with the pulsar period since this emission is produced in the inner pulsar magnetosphere. In several such binary systems, the masses of the companion stars have been derived allowing two classes of objects to be distinguished, which are called the black widow and the redback binaries. Pulsars in these binary systems are expected to produce winds that create conditions for acceleration of electrons, when colliding with stellar winds. These electrons should interact with the anisotropic radiation from the companion stars producing γ-ray emission modulated with the orbital period of the binary system, similar to what is observed in the massive TeV γ-ray binary systems. Aims: We consider the interaction of a MSP wind with a very inhomogeneous stellar wind from the companion star within binary systems of the black widow and redback types. Our aim is to determine the features of γ-ray emission produced in the collision region of the winds from a few typical MSP binary systems. Methods: It is expected that the pulsar wind should mix efficiently with the inhomogeneous stellar wind. The mixed winds move outside the binary with relatively low velocity. Electrons accelerated in such mixed, turbulent winds can interact with the magnetic field and strong radiation from the companion star, producing not only synchrotron radiation but also γ-rays in the inverse Compton process, fluxes of which are expected to be modulated on the periods of the binary systems. Applying numerical methods, we calculated the GeV-TeV gamma-ray spectra and the light curves expected from some MSP binary systems. Results: Gamma-ray emission, produced within the binary systems, is compared with the sensitivities of the present and future gamma-ray telescopes. It is concluded that energetic MSP binary systems create a new class of TeV

  13. Optimization of measure parameters for an X- and gamma-ray spectrometry portable system

    NASA Astrophysics Data System (ADS)

    Fernandes, Jaquiel S.; Appoloni, Carlos R.

    2008-01-01

    In order to optimize the use of a system for in situ gamma ( γ)- and X-ray spectrometry composed of a 3×3×1 mm 3 Cadmium Telluride (CdTe) detector with respect to the detection of low-activity radioactive sources, a two level factorial planning was accomplished, involving three factors that could modify the system response. This planning was made with a 137Cs punctual source, analyzing the X-ray energy line of 32 keV from 137mBa. It was concluded that, for the system optimization, the best configuration for the involved parameters was to work with the detector at temperature of -22 °C, shaping time of 3 μs and rise time discrimination (RTD) with value 3.

  14. A Topological Array Trigger for AGIS, the Advanced Gamma ray Imaging System

    SciTech Connect

    Krennrich, F.; Anderson, J.; Byrum, K.; Dawson, J.; Drake, G.; Haberichter, W.; Kreps, A.; Smith, A.; Buckley, J.; Krawczynski, H.; Imran, A.; Schroedter, M.

    2008-12-24

    Next generation ground based {gamma}-ray observatories such as AGIS{sup 1} and CTA{sup 2} are expected to cover a 1 km{sup 2} area with 50-100 imaging atmospheric Cherenkov telescopes. The stereoscopic view ol air showers using multiple view points raises the possibility to use a topological array trigger that adds substantial flexibility, new background suppression capabilities and a reduced energy threshold. In this paper we report on the concept and technical implementation of a fast topological trigger system, that makes use of real time image processing of individual camera patterns and their combination in a stereoscopic array analysis. A prototype system is currently under construction and we discuss the design and hardware of this topological array trigger system.

  15. 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

  16. Characterization of thymus-derived lymphocytes expressing Ti alpha-beta CD3 gamma delta epsilon zeta-zeta, Ti alpha-beta CD3 gamma delta epsilon eta-eta or Ti alpha-beta CD3 gamma delta epsilon zeta-zeta/zeta- eta antigen receptor isoforms: analysis by gene transfection

    PubMed Central

    1990-01-01

    To characterize the function of the CD3 eta subunit of the T cell receptor (TCR), we have used cDNAs encoding CD3 zeta, CD3 eta, or both to reconstitute a variant of a cytochrome c-specific, I-Ek-restricted murine T cell hybridoma, termed MA5.8, which lacks CD3 zeta and CD3 eta proteins. We provide direct evidence that assembly and surface expression of TCRs can be mediated by either of these subunits separately or together. However, the level of TCR expression on zeta transfectants is up to one order of magnitude greater than that on eta transfectants, implying that CD3 eta is weakly associated with the pentameric Ti alpha-beta CD3 gamma delta epsilon complex and/or inefficient at salvaging the incomplete TCR from lysosomal degradation. As a component of the TCR, the CD3 eta subunit preferentially forms a heterodimer with CD3 zeta, but is also able to form a CD3 eta-eta homodimer. Crosslinking of Ti alpha-beta CD3 gamma delta epsilon zeta- zeta, Ti alpha-beta CD3 gamma delta epsilon eta-eta, or Ti alpha-beta CD3 gamma delta epsilon zeta-zeta/zeta-eta TCR isotypes with anti-CD3 epsilon monoclonal antibody or a cytochrome c peptide epitope on I-Ek antigen-presenting cells mediates signal transduction resulting in reversible cell-cycle arrest of transfected clones. Given the potential for diversity of signals generated by these functional TCR isotypes and the expression of the CD3 eta gene product in the thymus, CD3 eta is likely to play a role in selection and/or activation of thymocytes during development. PMID:2145389

  17. A Visualization Code System for Gamma and Neutron Shielding Calculations, Version 2.0

    2008-08-01

    EASYQAD, Version 2.0, is a standalone Windows XP or Windows 7 code system which facilitates gamma and neutron shielding calculations with user friendly graphical interfaces. It is used to analyze radiation shielding problems and includes: - 8 kinds of geometry types - Various flexible source options - Common material library - Various detector types The update contents of EASYQAD Version 2.0 are below: - Addition of starting option with ‘P-code’ files - Addition of multi-sourcemore » calculation function - Expansion of source geometries - Addition of warning message - Modifications of EASYQAD program errors a. Coordination application problem in source division b. Source position error c. Rotation problem of source geometry d. Program running error in using more than six gamma energy distribution e. EASYQAD display problem of the right elliptic cylinder, ellipsoid and truncated right cone geometries Through intuitive windows and their interactions inside EASYQAD, the user can specify the dimensions of 3D-shapes, their material compositions, their densities, the type of radioactive sources, the locations of the sources, the type and positions of detectors. With the ease of using these sequences, shielding problems will become simpler and more clearly understandable to the analyzer. Furthermore, the error checking system can prevent users from making mistakes by automatically debugging the user inputs and giving modal dialog windows. The included AECL implementation of QAD-CGGP-A, Version 95.2 (C00645MNYCP00), is run from the user interface.« less

  18. Effect of gamma radiation on chlorobutyl rubber vulcanized by three different crosslinking systems

    NASA Astrophysics Data System (ADS)

    Scagliusi, Sandra R.; Cardoso, Elisabeth L. C.; Lugao, Ademar B.

    2012-09-01

    The development of halogenated butyl rubber (chlorobutyl) in the 1950s and 1960s greatly extended the usefulness of butyl. Their properties allowed the development of more durable tubeless tires with the air retaining innerliner, chemically bonded to the body of the tire. Tire innerliners are by far the largest application for halobutyl. When polymers are subjected to high energy radiation, a number of chemical reactions may occur following the initial ionization and excitation events. These reactions lead to changes in the molecular weight of the polymer through scission (S) and crosslinking (X) of the molecules and affect the physical and mechanical properties. In the halobutyl rubbers the chain scission may predominate. This work aims to show effects of gamma radiation in properties of chlorobutyl rubbers vulcanized with sulfur, sulfur donor and phenolic resin. The butyl rubber has been already studied by us previously. The samples were characterized before and after irradiation. Gamma radiation doses used were: 25 kGy, 50 kGy, 100 kGy, 150 kGy and 200 kGy, in order to identify which cure system is the most stable under irradiation. In this study we observed that the properties of all samples were affected irrespective of the vulcanization system.

  19. Remote Gamma Scanning System for Characterization of BWR and PWR Fuel Rod Sections

    SciTech Connect

    Crowell, Shannon L.; Alzheimer, James M.

    2011-08-08

    Sometimes challenges with the design and deployment of automated equipment in remote environments deals more with the constraints imposed by the remote environment than it does with the details of the automation. This paper discusses the development of a scanning system used to provide gamma radiation profiles of irradiated fuel rod segments. The system needed the capability to provide axial scans of cut segments of BWR and PWR fuel rods. The scanning location is A-Cell at the Radiochemical Processing Laboratory (RPL) at the Hanford site in Washington State. The criteria for the scanning equipment included axial scanning increments of a tenth of an inch or less, ability to scan fuel rods with diameters ranging from 3/8 inch to 5/8 inch in diameter, and fuel rod segments up to seven feet in length. Constraints imposed by the environment included having the gamma detector and operator controls on the outside of the hot cell and the scanning hardware on the inside of the hot cell. This entailed getting a narrow, collimated beam of radiation from the fuel rod to the detector on the outside of the hot cell while minimizing the radiation exposure caused by openings for the wires and cables traversing the hot cell walls. Setup and operation of all of the in-cell hardware needed to accommodate limited access ports and use of hot cell manipulators. The radiation levels inside the cell also imposed constraints on the materials used.

  20. Rehabilitation of gamma

    NASA Astrophysics Data System (ADS)

    Poynton, Charles A.

    1998-07-01

    Gamma characterizes the reproduction of tone scale in an imaging system. Gamma summarizes, in a single numerical parameter, the nonlinear relationship between code value--in an 8-bit system, from 0 through 255--and physical intensity. Nearly all image coding systems are nonlinear, and so involve values of gamma different from unity. Owing to poor understanding of tone scale reproduction, and to misconceptions about nonlinear coding, gamma has acquired a terrible reputation in computer graphics and image processing. In addition, the world-wide web suffers from poor reproduction of grayscale and color images, due to poor handling of nonlinear image coding. This paper aims to make gamma respectable again.

  1. Chemosensory signals and their receptors in the olfactory neural system.

    PubMed

    Ihara, S; Yoshikawa, K; Touhara, K

    2013-12-19

    Chemical communication is widely used among various organisms to obtain essential information from their environment required for life. Although a large variety of molecules have been shown to act as chemical cues, the molecular and neural basis underlying the behaviors elicited by these molecules has been revealed for only a limited number of molecules. Here, we review the current knowledge regarding the signaling molecules whose flow from receptor to specific behavior has been characterized. Discussing the molecules utilized by mice, insects, and the worm, we focus on how each organism has optimized its reception system to suit its living style. We also highlight how the production of these signaling molecules is regulated, an area in which considerable progress has been recently made.

  2. Gamma Knife

    MedlinePlus

    ... results are sent to the Gamma Knife®'s planning computer system. Together, physicians ( radiation oncologists and neurosurgeons) and medical physicists delineate targets and normal anatomical structures. They use a planning computer program to determine the exact spatial relationship between ...

  3. Identification of a second T-cell antigen receptor in human and mouse by an anti-peptide. gamma. -chain-specific monoclonal antibody

    SciTech Connect

    Ioannides, C.G.; Itoh, K.; Fox, F.E.; Pahwa, R.; Good, R.A.; Platsoucas, C.D.

    1987-06-01

    The authors developed a monoclonal antibody (mAb) (9D7) against a synthetic peptide (P13K) selected from the deduced amino acid sequence of the constant region of the lambda chain of the murine T-cell antigen receptor (TCR) (amino acids 118-130). Using this mAb, they identified a putative second TCR expressed on peripheral blood lymphocytes from a patient with severe combined immunodeficiency (SCID) that were propagated in culture with recombinant interleukin 2 (rIL-2) and Con A. This mAb immunoprecipitated two polypeptide chains of 40 and 58 kDa under nonreducing conditions and of 40 and 56 kDa under reducing conditions from /sup 125/I-labeled denatured lysates of T3/sup +/ WT31/sup -/ lymphocytes expanded in culture from a SCID patient. Chemical crosslinking of /sup 125/I-labeled cells followed by immunoprecipitation with anti-Leu-4 mAb under nonreducing or reducing conditions revealed that the 40- and 56-kDa polypeptide chains were associated with the T3 differentiation antigen. These experiments were done with polyclonal cell populations. Cloned T3/sup +/ WT31/sup -/ cell populations are required to determine whether the TCR contains two lambda polypeptide chains. Using the same 9D7 anti-P18K mAb and immunoblotting analysis, they identified a 35 kDa ..gamma..-chain polypeptide under reducing conditions expressed on purified L3T4/sup -/ Lyt2/sup -/ BALB/c mouse thymocytes. This ..gamma..-chain TCR is disulfide linked and has a molecular mass of 80 kDa under nonreducing conditions.

  4. Peroxisome-proliferator activator receptor-gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion.

    PubMed

    Kavoussi, S K; Witz, C A; Binkley, P A; Nair, A S; Lebovic, D I

    2009-10-01

    The aim of this study was to investigate whether peroxisome proliferator-activated receptor (PPAR)-gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well-established in vitro model of the early endometriotic lesion. The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study. EM42 cells, LP9 cells or both were treated with the PPAR-gamma agonist ciglitazone (CTZ) at varying concentrations (10, 20 and 40 microM) x 48 h with subsequent co-culture of EM42 and LP9 cells. The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control (EM42 and LP9 cells co-cultured without prior treatment with CTZ). Next, attachment of CTZ-treated and untreated EM42 cells to hyaluronic acid (HA), a cell adhesion molecule (CAM) on peritoneal mesothelial cells, were assessed. Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ, treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27% (P < 0.01). Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37% (P < 0.01). Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66% (P = 0.056). CTZ did not decrease invasion of EM42 cells through the LP9 monolayer. CTZ may inhibit EM42 cell proliferation. In conclusion, CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion. PMID:19643817

  5. Cloning, Expression Analysis, and Molecular Modeling of the Gamma-Aminobutyric Acid Receptor Alpha2 Subunit Gene from the Common Cutworm, Spodoptera litura

    PubMed Central

    Zuo, Hongliang; Gao, Lu; Hu, Zhen; Liu, Haiyuan; Zhong, Guohua

    2013-01-01

    Intensive research on the molecule structures of the gamma-nminobutyric acid (GABA) receptor in agricultural pests has great significance to the mechanism investigation, resistance prevention, and molecular design of novel pesticides. The GABA receptor a2 (SlGABARα2) subunit gene in Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae) was cloned using the technologies of reverse transcription PCR and rapid amplification of cDNA ends. The gemonic DNA sequence of SlGABARα2 has 5164 bp with 8 exons and 7 introns that were in accordance with the GT-AG splicing formula. The complete mRNA sequence of SlGABARα2 was 1965 bp, with an open reading frame of 1500 bp encoding a protein of 499 amino acids. The GABA receptor is highly conserved among insects. The conserved regions include several N-glycosylation, Oglycosylation, and phosphorylation sites, as well as 4 transmembrane domains. The identities that SlGABARα2 shared with the GABA receptor a2 subunit of Spodoptera exigua, Heliothis virescens, Chilo suppressalis, Plutella xylostella, Bombyx mori ranged from 99.2% to 87.2% at the amino acid level. The comparative 3-dimensional model of SlGABARα2 showed that its tertiary structure was composed of 4 major α-helixes located at the 4 putative transmembrane domains on one side, with some β-sheets and 1 small α-helix on the other side. SlGABARα2 may be attached to the membrane by 4 α-helixes that bind ions in other conserved domains to transport them through the membrane. The results of quantitative real time PCR demonstrated that SlGABARα2 was expressed in all developmental stages of S. litura. The relative expression level of SlGABARα2 was the lowest in eggs and increased with larval growth, while it declined slightly in pupae and reached the peak in adults. The expressions of SlGABARα2 in larvae varied among different tissues; it was extremely high in the brain but was low in the midgut, epicuticle, Malpighian tube, and fat body. PMID:23909412